Scolaris Content Display Scolaris Content Display

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1 Topical metronidazole versus placebo, Outcome 1 Adverse events.
Figures and Tables -
Analysis 1.1

Comparison 1 Topical metronidazole versus placebo, Outcome 1 Adverse events.

Comparison 1 Topical metronidazole versus placebo, Outcome 2 Physician's global evaluation of improvement.
Figures and Tables -
Analysis 1.2

Comparison 1 Topical metronidazole versus placebo, Outcome 2 Physician's global evaluation of improvement.

Study

Interventions

Summary Outcomes

Comment

Notes

Barnhorst 1996

13 participants were treated with lid hygiene plus warm compresses plus metronidazole 0.75% gel in one eye BID, versus lid hygiene plus warm compresses in the other eye.

Within‐patient comparison.

No adverse events reported. Eye and eyelid grading pre‐post mean (SD) ‐1.5 (1.7) versus ‐1.0 (1.7).

Authors report significant improvement in treatment group but not in control group, P = 0.022 versus P = 0.10 [inappropriate analysis]. No direct comparison reported.

Eye pre‐post mean (SD) ‐0.4 (1.0) versus ‐0.3 (0.9). Eyelid pre‐post mean (SD) ‐1.1 (0.9) versus ‐0.7 (0.8)

Small group (13 participants),
within‐patient comparison.

Not much data. Participant not blinded.
Data skewed.

BID = twice a day

SD = standard deviation

Beutner 2005

557 were treated with metronidazole gel 1% QD versus 553 with metronidazole 1% cream QD versus 189 with metronidazole gel vehicle.

Adverse events 186/557 versus 176/553 versus 51/189.
Subjects rated as success according to physicians 38.4% versus 35.4% versus 27.5%.

Reduction in lesion count 66.7% versus 58.3% vs. 46.2%

Large vehicle effect.

QD = once daily

Bitar 1990

50 were treated with metronidazole cream 1% BID versus 50 with placebo cream BID.

Erythema and telangiectasia, no statistical difference.
Number of papules after a month 4.5 (4.24) versus 6.5 (4.96). Number of pustules 1.5 (1.41) versus 3.4 (4.94).

Data on papules and pustules are skewed.

BID = twice a day

Bjerke 1989

50 were treated with metronidazole cream 1% BID versus 47 with placebo cream BID.

Erythema: 3 score reduction 2% versus 5%, 2 score reduction 26% versus 5% and 1 score reduction 46% versus 45%, unchanged 26% versus 41%, worse 0% versus 5%.
Lesion count reduction 78% versus 48%, reduction of papules 75% versus 43%, reduction of pustules 100% versus 81%.

No SDs were reported.

BID = twice a day

N = number

SD = standard deviation

Bleicher 1987

40 were treated with metronidazole 0.75% BID versus 40 with placebo BID.

Adverse events, one complained of tearing when gel came to close to the eyes.
Reduction in erythema, 0.8 versus 0.3 (erythema rating 0 to 3, higher is worse).
Increase in telangiectasia of 0.3 at both sides (rating 0‐3)

Decrease in lesion counts, 65.1% versus 14.9%.

No SDs were reported. Within‐patient comparison.

BID = twice a day

SD = standard deviation

Breneman 1998

104 were treated with metronidazole 1% QD versus 52 with placebo QD.

Mean decrease in erythema score of 0.9 in metronidazole group versus 0.5 in placebo group.

Decrease in lesion count 8 versus 3.

No SDs were reported.

SD = standard deviation

QD = once daily

Dahl 1998

44 were treated with metronidazole 0.75% BID versus 44 with placebo BID.

At baseline 35/44 had no or mild erythema versus 32/44. At end of study this was 32/43 versus 24/44. Telangiectasia (no significant difference or effect)
Lesion count 3.3 versus 5.8, relapse rate 23% versus 42%, free of lesions 53% versus 32%.

No SDs reported.
N of adverse events unclear.

BID = twice a day

SD = standard deviation

Koçak 2002

20 patients were treated with metronidazole 0.75% gel BID versus 20 with placebo BID.

No local adverse events in any group

Mean change from baseline in papules ‐5.10 (23.36) versus 0.25 (11.25) with a MD of ‐5.35 (95% CI ‐16.71 to 6.01). Mean change from baseline in pustules ‐2.50 (13.65) versus ‐0.20 (9.20) with a MD of ‐2.30 (95% CI ‐9.51 to 4.91).

No effects on rhinophyma and telangiectasia.

Most data are skewed.

BID = twice a day

SD = standard deviation

Nielsen 1983a

41 were treated with metronidazole 1% QD versus 40 with placebo QD.

Reduction on erythema from 3.8 to 2.5 for metronidazole group and from 3.7 to 3.1 in placebo group. Authors state P < 0.05.

There were no effects on telangiectasia.

Papules count 8.6 versus 16.6, and pustules count 0.3 versus 0.8.

No SDs were reported.

SD = standard deviation

QD = once daily

Figures and Tables -
Analysis 1.3

Comparison 1 Topical metronidazole versus placebo, Outcome 3 Incomplete data on which further analysis is not possible.

Comparison 2 Topical azelaic acid versus placebo, Outcome 1 Participant‐assessed improvement of rosacea.
Figures and Tables -
Analysis 2.1

Comparison 2 Topical azelaic acid versus placebo, Outcome 1 Participant‐assessed improvement of rosacea.

Comparison 2 Topical azelaic acid versus placebo, Outcome 2 Physician's global evaluation of improvement.
Figures and Tables -
Analysis 2.2

Comparison 2 Topical azelaic acid versus placebo, Outcome 2 Physician's global evaluation of improvement.

Study

Intervention

Summary Outcomes

Comment

Notes

Bjerke 1999

76 were treated with azelaic cream 20% BID versus 38 with placebo BID.

Decrease in erythema 47.9% versus 37.9%, in telangiectasia 22.3% versus 23.5%.

Decrease in lesions 73.4% versus 50.6%.

No SDs were reported.

BID = twice a day

SD = standard deviation

Carmichael 1993

Azelaic cream 20% BID versus placebo BID.

Within‐patient comparison in 33 patients.

VAS scale of improvement 6.9 (1.15) to 2.6 (1.72) for azelaic acid treated side versus 7.0 (1.15) to 4.5 (2.30) for placebo treated side
Erythema index decreased from 539.6 (76.98) to 500.6 (84.45) at the azelaic acid treated side and from 533.5 (82.15) to 518.3 (95.36) at the placebo treated side
Telangiectasia (VAS scores) decreased from 4.3 (2.30) to 4.2 (1.71) at the azelaic acid treated side and from 4.4 (2.30) to 4.5 (2.30) at the placebo side

Papule count 2.5 (2.87) versus 6.3 (4.6), pustule count 0.0 (0.17) versus 0.4 (0.57).

Data are skewed.

BID = twice a day

Draelos 2013a

198 were treated with azelaic acid 15% foam BID versus 203 vehicle foam BID

There were no statistically significant differences between the 2 groups in end‐of‐treatment or end‐of‐study erythema and telangiectasia

BID = twice a day

Thiboutot 2003a

164 were treated with azelaic acid 15% BID versus 165 with vehicle BID.

Marked improvement or complete remission according to investigator: 51% versus 27% (investigators reported P < 0.001).
Overall improvement in erythema : 44% versus 29% (investigators reported P = 0.0017).
Overall improvement in telangiectasia: Unchanged in 77% versus 80% (investigators reported 'not statistically significant').
Change in number of inflammatory lesions from 17.5 to 6.8 versus 17.6 to 10.5.

No SDs were reported, can only be estimated from figures

BID = twice a day

SD = standard deviation

Thiboutot 2003b

169 were treated with azelaic acid 15% BID versus 166 with vehicle BID

Same reference describes 2 studies.

Marked improvement or complete remission according to investigator: 46% versus 31% (investigators reported P < 0.0048).

Overall improvement in erythema : 46% versus 28% (investigators reported P = 0.0005).
Overall improvement in telangiectasia: Unchanged in 73% versus 78% (investigators reported 'not statistically significant').

Change in number of inflammatory lesions from 17.8 to 8.9 versus 18.5 to 12.1.

No SDs were reported, can only be estimated from figures

BID = twice a day

SD = standard deviation

Figures and Tables -
Analysis 2.3

Comparison 2 Topical azelaic acid versus placebo, Outcome 3 Incomplete data on which further analysis is not possible.

Summary of findings for the main comparison. Metronidazole compared to placebo for rosacea

Metronidazole compared to placebo for rosacea

Patient or population: Participants with rosacea
Intervention: Metronidazole
Comparison: Placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Metronidazole

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity

See comment

See comment

Not estimable

252
(3 studies1)

⊕⊕⊕⊝
moderate2

Bjerke 1989 RR 1.68, 95% CI 1.25 to 2.28; P = 0.0007, Nielsen 1983a RR 3.05, 95% CI 1.57 to 5.94; P = 0.001, Bleicher 1987 (within‐participant study) RR 7. These are clinically important improvements

Proportion of participants with adverse event

161 per 1000

191 per 1000
(151 to 243)

RR 1.19
(0.94 to 1.51)

1773
(6 studies3)

⊕⊕⊕⊕
high

Most instances of these adverse events were mild and consisted of pruritus, skin irritation and dry skin

Physician‐assessed improvement in rosacea severity

288 per 1000

570 per 1000
(371 to 869)

RR 1.98
(1.29 to 3.02)

334
(3 studies4)

⊕⊕⊕⊝
moderate2,5

The results are both statistically significant and clinically important

Assessment of erythema or telangiectasia

See comment

See comment

Not estimable

602
(7 studies6)

⊕⊕⊕⊝
moderate5,7

In the separate studies (but not in Bitar 1990) there was a greater reduction of erythema in the groups treated with metronidazole, but data were inadequately reported. Except in Koçak 2002 data were adequately reported with a MD of ‐1.40 (95% CI ‐2.47 to ‐0.33; P = 0.01) in favour of metronidazole

Lesion count

See comment

See comment

Not estimable

1964
(8 studies8)

⊕⊕⊕⊝
moderate7

No SDs reported, data were skewed but appeared to support data of physician‐assessed improvement

Time needed until improvement of the skin lesions

See comment

See comment

Not estimable

514
(5 studies9)

⊕⊕⊕⊕
high

Based on interim data improvement started around four weeks

Duration of remission

409 per 1000

205 per 1000
(102 to 405)

RR 0.50
(0.25 to 0.99)

88
(1 study10)

⊕⊕⊕⊝
moderate11,12

9/44 in metronidazole group relapsed, versus 18/44 in vehicle group during six months follow‐up

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Bjerke 1989, Nielsen 1983a, Bleicher 1987
2 Downgraded one level due to serious imprecision (wide confidence intervals)
3Beutner 2005, Bitar 1990, Bjerke 1989, Breneman 1998, Koçak 2002, Nielsen 1983a
4Bjerke 1989, Breneman 1998, Nielsen 1983a
5 Although for two studies the sequence generation and allocation concealment was unclear (Bjerke 1989 and Nielsen 1983a), the blinding was ensured for both Bleicher 1987 and Nielsen 1983a, and stated as double‐blind for Bjerke 1989 and therefore we considered it unlikely that this would have an impact on this outcome assessment and decided only to downgrade for imprecision
6 Bitar 1990, Bjerke 1989, Bleicher 1987, Breneman 1998, Dahl 1998, Koçak 2002,Nielsen 1983a
7 Downgraded one level due to serious imprecision (small sample sizes in the individual studies, pooling not possible due to missing SDs)
8Beutner 2005, Bitar 1990, Bjerke 1989, Bleicher 1987, Breneman 1998, Dahl 1998, Koçak 2002, Nielsen 1983a
9Bitar 1990, Bjerke 1989, Bleicher 1987, Breneman 1998, Nielsen 1983a
10Dahl 1998

11 Although we judged the domains for sequence generation, allocation concealment as unclear and the method of blinding of participants and physicians was not reported, there was no attrition bias nor selective reporting and therefore we concluded there was no serious risk of bias for this outcome assessment

12 Downgraded one level due to serious imprecision (low sample size, optimal sample size is not met)

Figures and Tables -
Summary of findings for the main comparison. Metronidazole compared to placebo for rosacea
Summary of findings 2. Azelaic acid compared to placebo for rosacea

Azelaic acid compared to placebo for rosacea

Patient or population: Participants with rosacea
Intervention: Azelaic acid
Comparison: Placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Azelaic acid

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity
Marked improvement to complete remission on Likert scale

421 per 1000

636 per 1000
(552 to 733)

RR 1.46
(1.30 to 1.63)

1179
(4 studies1)

⊕⊕⊕⊕
high

This is a clinically important improvement in favour of azelaic acid

Proportion of participants with adverse event

See comment

See comment

Not estimable

1245
(5 studies2)

⊕⊕⊕⊕
high

Bjerke 1999 RR 1.00, 95% CI 0.62 to 1.62; P = 0.02, Carmichael 1993 (within‐participant) 24/33 on the azelaic acid side and 19/33 on placebo side, Draelos 2013a RR 2.39, 95% CI 1.12 to 5.09; P = 0.02, Thiboutot 2003a and Thiboutot 2003b 18% and 8% respectively for azelaic acid treated groups and limited to no data for the placebo groups

Physician‐assessed improvement in rosacea severity

497 per 1000

655 per 1000
(586 to 730)

RR 1.32
(1.18 to 1.47)

1179
(4 studies1)

⊕⊕⊕⊕
high

Data for these assessments from four studies illustrated that azelaic acid was more effective than placebo

Assessment of erythema or telangiectasia

See comment

See comment

Not estimable

1245
(5 studies2)

⊕⊕⊕⊕
high

Decrease in erythema in groups treated with azelaic acid ranged from 44% to 47.9% and for placebo from 28% to 37.9%, telangiectasia minimal changes. SDs missing

Lesion count

The mean lesion count in the control group was ‐9.5 inflammatory lesions

The mean lesion count in the control group was 3.90 lower (5.87 to 1.93 lower)

401
(1 study3)

⊕⊕⊕⊝
moderate4

No SDs were reported in (Bjerke 1999; Thiboutot 2003a; Thiboutot 2003b) and data were skewed in Carmichael 1993. All four studies showed a greater reduction in lesions in azelaic acid treated groups (see Analysis 2.3)

Time needed until improvement of the skin lesions

See comment

See comment

Not estimable

1245
(5 studies2)

⊕⊕⊕⊕
high

This was not a pre‐specified outcome, but all studies showed clear improvement after three to six weeks

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Bjerke 1999, Draelos 2013a, Thiboutot 2003a, Thiboutot 2003b
2Bjerke 1999, Carmichael 1993, Draelos 2013a, Thiboutot 2003a, Thiboutot 2003b
3Draelos 2013a
4 Downgraded one level due to serious imprecision (wide confidence interval)

Figures and Tables -
Summary of findings 2. Azelaic acid compared to placebo for rosacea
Summary of findings 3. Topical ivermectin compared to placebo for rosacea

Topical ivermectin compared to placebo for rosacea

Patient or population: Participants with rosacea
Intervention: Topical ivermectin
Comparison: Placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Topical ivermectin

HRQOL
DLQI and RosaQoL

See comment

See comment

Not estimable

1371
(2 studies1)

⊕⊕⊕⊕
high

Although data were statistically significant in favour of ivermectin, the clinical importance is unclear as MID in reduction of DLQI score was not reached and the MID is not yet established for RosaQoL2

Participant‐assessed improvement in rosacea severity
Likert scale, good to excellent improvement

See comment

See comment

Not estimable

1371
(2 studies1)

⊕⊕⊕⊕
high

RR 1.78, 95% CI 1.50 to 2.11 (Stein 2014a), RR 1.92, 95% CI 1.59 to 2.32 (Stein 2014b). Both studies showed a statistically significant and clinically important improvement in favour of topical ivermectin

Proportion of participants with adverse event

See comment

See comment

Not estimable

1371
(2 studies1)

⊕⊕⊕⊕
high

RR 0.54, 95% CI 0.29 to 1.01 (Stein 2014a), RR 1.00, 95% CI 0.55 to 1.82 (Stein 2014b)

Physician‐assessed improvement in rosacea severity
Investigator's Global Assessment of clear or almost clear

See comment

See comment

Not estimable

1371
(2 studies1)

⊕⊕⊕⊕
high

RR 3.30, 95% CI 2.27 to 4.79 (Stein 2014a), RR 2.10, 95% CI 1.57 to 2.81 (Stein 2014b). The results of both studies are in concordance with the assessments of the participants

Assessment of erythema or telangiectasia ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Lesion count

See comment

See comment

Not estimable

1371
(2 studies1)

⊕⊕⊕⊕
high

MD ‐8.40, 95% CI ‐9.93 to ‐6.87 (Stein 2014a), MD ‐8.90, 95% CI ‐10.45 to ‐7.35 (Stein 2014b). Both of these differences are statistically significant and clinically important

Time needed until improvement of the skin lesions

See comment

See comment

Not estimable

1371
(2 studies1)

⊕⊕⊕⊕
high

Improvement in both studies was seen after four weeks

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Stein 2014a, Stein 2014b
2 MID = minimal important difference

Figures and Tables -
Summary of findings 3. Topical ivermectin compared to placebo for rosacea
Summary of findings 4. Topical brimonidine compared to vehicle for rosacea

Topical brimonidine compared to vehicle for rosacea

Patient or population: Participants with rosacea
Intervention: Topical brimonidine
Comparison: Vehicle

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Topical brimonidine

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity
Patient Satisfaction Assessment ‐ grade 2 improvement

See comment

See comment

Not estimable

553
(2 studies1)

⊕⊕⊕⊕
high

At 3 hours RR 2.21, 95% CI 1.52 to 3.22 (Fowler 2013a) and RR 2.00, 95% CI 1.33 to 3.01 (Fowler 2013b). At each time point in both studies brimonidine was shown to be more effective than vehicle in an improvement which was statistically significant

Proportion of participants with adverse event

See comment

See comment

Not estimable

553
(2 studies1)

⊕⊕⊕⊕
high

RR 1.17, 95% CI 0.79 to 1.74 (Fowler 2013a), RR 1.40, 95% CI 0.97 to 2.02 (Fowler 2013b). Adverse events were mild and transient

Physician‐assessed improvement in rosacea severity ‐ not reported

See comment

See comment

Not estimable

See comment

No reporting of data other than "No aggravations in the severity of IGA were observed"

Assessment of erythema or telangiectasia
Clinician Erythema Assessment ‐ grade 2 improvement

See comment

See comment

Not estimable

553
(2 studies1)

⊕⊕⊕⊕
high

At 3 hours RR 2.82, 95% CI 1.85 to 4.30 (Fowler 2013a), RR 1.78, 95% CI 1.25 to 2.55 (Fowler 2013b)

Lesion count ‐ not reported

See comment

See comment

Not estimable

See comment

No reporting of data other than "No aggravations in the severity of lesion counts were observed"

Time needed until improvement of the skin lesions

See comment

See comment

Not estimable

553
(2 studies1)

⊕⊕⊕⊕
high

Improvement was seen within 30 min

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

There was no rebound or worsening of erythema after treatment cessation in comparison to baseline assessments

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Figures and Tables -
Summary of findings 4. Topical brimonidine compared to vehicle for rosacea
Summary of findings 5. Topical azelaic acid compared to topical metronidazole for rosacea

Topical azelaic acid compared to topical metronidazole for rosacea

Patient or population: Participants with rosacea
Intervention: Topical azelaic acid
Comparison: Topical metronidazole

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Topical metronidazole

Topical azelaic acid

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity

See comment

See comment

Not estimable

491
(3 studies1)

⊕⊕⊝⊝
low2,3

RR 1.23, CI 95% 1.04 to 1.44; P = 0.01 (Elewski 2003), RR 1.00, 95% CI 0.83 to 1.21 (Wolf 2006), Maddin 1999 (within‐participant) authors report P = 0.02 in favour of azelaic acid

Proportion of participants with adverse event

See comment

See comment

Not estimable

491
(3 studies1)

⊕⊕⊝⊝
low2,4

RR 3.64, 95% CI 1.81 to 7.31; P = 0.0003 (Elewski 2003), RR 0.74, 95% CI 0.52 to 1.07 (Wolf 2006). In Maddin 1999 1 participant reported stinging on azelaic acid treated site

Physician‐assessed improvement in rosacea severity

See comment

See comment

Not estimable

491
(3 studies1)

⊕⊕⊝⊝
low2,5

RR 1.26, 95% CI 1.03 to 1.53; P = 0.02 (Elewski 2003), RR 1.05, 95% CI 0.79 to 1.39 (Wolf 2006), Maddin 1999 score 2.7 (SD 1.0) versus 3.1 (SD 1.0) (higher is worse)

Assessment of erythema or telangiectasia

See comment

See comment

Not estimable

491
(3 studies)

⊕⊕⊝⊝
low2,6

RR 1.35, 95% CI 1.05 to 1.75; P = 0.02 (Elewski 2003), RR 0.99, 95% CI 0.69 to 1.42 (Wolf 2006), in Maddin 1999 the participants and physicians had contradictory judgements

Lesion counts

See comment

See comment

Not estimable

491
(3 studies1)

⊕⊕⊕⊝
moderate2

No SDs were reported, all three studies demonstrated a clinically important reduction in lesion count in both treatment arms

Time needed until improvement of the skin lesions

See comment

See comment

Not estimable

491
(3 studies1)

See comment

Improvement for both arms was seen after four to six weeks in all three studies

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Elewski 2003, Maddin 1999, Wolf 2006
2 Downgraded one level due to serious risk of bias (all three studies stated to be double‐blind, but method of blinding was not described)
3 Downgraded one level due to serious inconsistency (Elewski 2003 and Wolf 2006 no statistically significant difference (severe heterogeneity unexplained (I2 >60%), and the 95% CIs do overlap but lead to different interpretation of the effect estimate, but in Maddin 1999 azelaic was more effective)
4 Downgraded one level due to serious inconsistency (statistically significant difference in participants reporting adverse events in Elewski 2003 (in favour of metronidazole), not confirmed in Wolf 2006 (severe heterogeneity unexplained (I2>60% and the 95% CIs did not overlap))
5 Downgraded one level due to serious inconsistency (no statistically significant difference in Wolf 2006, but in Elewski 2003 and Maddin 1999 azelaic acid is more effective, severe heterogeneity unexplained and the 95% CI do overlap but lead to different interpretation of the effect estimate)
6 Downgraded one level due to inconsistency (no statistically significant difference in Wolf 2006, but in Elewski 2003 and Maddin 1999 azelaic acid is more effective according to physicians (but metronidazole is more effective according to participants in Maddin 1999)

Figures and Tables -
Summary of findings 5. Topical azelaic acid compared to topical metronidazole for rosacea
Summary of findings 6. Topical ivermectin compared to topical metronidazole for rosacea

Topical ivermectin compared to topical metronidazole for rosacea

Patient or population: Participants with rosacea
Intervention: Topical ivermectin
Comparison: Topical metronidazole

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Topical metronidazole

Topical ivermectin

HRQOL
DLQI, proportion of participants that reported at end of study that rosacea had no impact on QoL

640 per 1000

711 per 1000
(647 to 775)

RR 1.11
(1.01 to 1.21)

962
(1 study1)

⊕⊕⊕⊕
high

Reduction in DLQI was 5.18 in ivermectin group and 3.92 in metronidazole group (both meeting minimal important difference)

Participant‐assessed improvement in rosacea severity
Likert scale ‐ good to excellent improvement

748 per 1000

853 per 1000
(800 to 912)

RR 1.14
(1.07 to 1.22)

962
(1 study1)

⊕⊕⊕⊕
high

This is a statistically significant difference and in concordance with the results on number of participants that experienced no deleterious effect on their quality of life

Proportion of participants with adverse event

8 per 1000

19 per 1000
(6 to 61)

RR 2.28
(0.71 to 7.35)

962
(1 study1)

⊕⊕⊕⊝
moderate2

Physician‐assessed improvement in rosacea severity

754 per 1000

852 per 1000
(799 to 905)

RR 1.13
(1.06 to 1.20)

962
(1 study1)

⊕⊕⊕⊕
high

These assessments are consistent with the assessments of the participants

Assessment of erythema or telangiectasia ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Lesion count

The mean lesion count in the control groups was
‐23.60 inflammatory lesions

The mean lesion count in the intervention groups was
4.10 lower
(5.18 to 3.02 lower)

962
(1 study1)

⊕⊕⊕⊕
high

Both treatments showed clinically important reductions in lesion counts

Time needed until improvement of the skin lesions

See comment

See comment

Not estimable

962
(1 study1)

⊕⊕⊕⊕
high

This was not a predefined outcome, but clear improvement could be seen for both treatment arms around six weeks

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Taieb 2015
2 Downgraded one level due to serious imprecision (wide confidence interval due to low occurrence of events)

Figures and Tables -
Summary of findings 6. Topical ivermectin compared to topical metronidazole for rosacea
Summary of findings 7. Ciclosporin ophthalmic emulsion 0.05% compared to artificial tears for ocular rosacea

Ciclosporin ophthalmic emulsion 0.05% compared to artificial tears for ocular rosacea

Patient or population: Participants with ocular rosacea
Intervention: Ciclosporin ophthalmic emulsion 0.05%
Comparison: Artificial tears

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Artificial tears

Ciclosporinophthalmic emulsion 0.05%

HRQOL
Ocular Surface Disease Index (scale 0 to 100, 100 worst)

The mean OSDI in the control group was
16.9

The mean OSDI in the intervention group was
8.6 lower
(15.42 to 1.78 lower)

37
(1 study1)

⊕⊕⊝⊝
low2

The difference between change scores at end of study equates to a moderate improvement in quality of life in favour of ciclosporin ophthalmic emulsion

Participant‐assessed improvement in rosacea severity ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Proportion of participants with adverse event

RR 2.32
(0.10 to 53.42)

37
(1 study1)

⊕⊕⊝⊝
low2

Physician‐assessed improvement in rosacea severity
Schirmer score

The mean physician‐assessed improvement in rosacea severity in the control group was
‐1.4

The mean physician‐assessed improvement in rosacea severity in the intervention group was
4.1 higher
(1.66 to 6.54 higher)

37
(1 study1)

⊕⊕⊝⊝
low2

Assessment of erythema or telangiectasia ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Lesion count ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Time needed until improvement of the skin lesions ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Schechter 2009
2 Downgraded two levels due to very serious imprecision (very wide confidence interval due to low sample size, optimal information size is not met)

Figures and Tables -
Summary of findings 7. Ciclosporin ophthalmic emulsion 0.05% compared to artificial tears for ocular rosacea
Summary of findings 8. Clindamycin phosphate 1.2% + tretinoin 0.025% gel compared to placebo for rosacea

Clindamycin phosphate 1.2% + tretinoin 0.025% gel compared to placebo for rosacea

Patient or population: Participants with rosacea
Intervention: Clindamycin phosphate 1.2% + tretinoin 0.025% gel
Comparison: Placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Clindamycin phosphate 1.2% + tretinoin 0.025% gel

HRQOL
RosaQoL

See comment

See comment

Not estimable

83
(1 study1)

⊕⊕⊕⊝
moderate2

No mean scores were provided, only percentages of participants that had improved per item on the 21 survey items, no statistically significant difference for any item

Participant‐assessed improvement in rosacea severity ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Proportion of participants with adverse event

275 per 1000

674 per 1000
(390 to 1000)

RR 2.45
(1.42 to 4.23)

83
(1 study1)

⊕⊕⊕⊝
moderate3

Worsening of rosacea, facial scaling, as well as dry skin were reported most often in the active treatment group

Physician‐assessed improvement in rosacea severity
PGA as defined by Wilkin 2004

See comment

See comment

Not estimable

83
(1 study1)

⊕⊕⊕⊝
moderate2

None of the primary features of the PGA showed statistically significant differences between the treatment groups except for oedema in favour of placebo

Assessment of erythema or telangiectasia

150 per 1000

257 per 1000
(105 to 627)

RR 1.71
(0.70 to 4.18)

83
(1 study1)

⊕⊕⊕⊝
moderate3

RR 1.71 (95% CI 0.70 to 4.18) refers to erythema. Telangiectasia RR 2.42, 95% CI 0.95 to 6.17

Lesion count

The mean lesion count in the control group was
‐3.13 inflammatory lesions

The mean lesion count in the intervention group was
3.96 higher
(1.28 lower to 9.20 higher)

83
(1 study)

⊕⊕⊕⊝
moderate3

Time needed until improvement of the skin lesions ‐ not measured

See comment

See comment

Not estimable

See comment

There was no improvement

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Chang 2012
2 Downgraded one level due to serious imprecision (low sample size, optimal sample size is not met)
3 Downgraded one level due to serious imprecision (wide confidence interval due to low sample size, optimal sample size is not met)

Figures and Tables -
Summary of findings 8. Clindamycin phosphate 1.2% + tretinoin 0.025% gel compared to placebo for rosacea
Summary of findings 9. Tetracycline compared to placebo for rosacea

Tetracycline compared to placebo for rosacea

Patient or population: Participants with rosacea
Intervention: Tetracycline
Comparison: Placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Tetracycline

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity

474 per 1000

701 per 1000
(403 to 1000)

RR 1.48
(0.85 to 2.57)

39
(1 study1)

⊕⊕⊕⊝
moderate2

Proportion of participants with adverse event

53 per 1000

50 per 1000
(3 to 744)

RR 0.95
(0.06 to 14.13)

39
(1 study1)

⊕⊕⊕⊝
moderate2

Only one adverse event was reported in each group, diarrhoea in the tetracycline group, maculopapular rash in the placebo group

Physician‐assessed improvement in rosacea severity

See comment

See comment

Not estimable

107
(2 studies3)

⊕⊕⊕⊝
moderate2

RR 4.04, 95% CI 1.66 to 9.83; P = 0.002 (Marks 1971) and RR 1.72, 95% CI 1.18 to 2.50; P = 0.005 (Sneddon 1966)

Assessment of erythema or telangiectasia

See comment

See comment

Not estimable

39
(1 study1)

⊕⊕⊕⊝
moderate4

There were no significant changes in erythema (Marks 1971)

Lesion count

The mean lesion count in the control group was
1.41 inflammatory lesions

The mean lesion count in the intervention group was
14.64 lower

39
(1 study1)

⊕⊕⊕⊝
moderate5

Crude MD ‐14.64 but skewed data (Marks 1971)

Time needed until improvement of the skin lesions ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Marks 1971
2 Downgraded one level due to serious imprecision (wide confidence interval due to low sample size, optimal sample size is not met)
3Marks 1971 and Sneddon 1966
4 Downgraded one level due to serious imprecision (low sample size, optimal sample size is not met)
5 Downgraded one level due to serious imprecision (skewed data and low sample size, optimal sample size is not met)

Figures and Tables -
Summary of findings 9. Tetracycline compared to placebo for rosacea
Summary of findings 10. Doxycycline 40 mg compared to placebo for rosacea

Doxycycline 40 mg compared to placebo for rosacea

Patient or population: Participants with rosacea
Intervention: Doxycycline 40 mg
Comparison: Placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Doxycycline 40 mg

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Proportion of participants with adverse event

See comment

See comment

Not estimable

537
(2 studies1)

⊕⊕⊕⊕
high

RR 1.14, 95% CI 0.85 to 1.53 (Del Rosso 2007a) and RR 1.27, 95% CI 1.04 to 1.55 (Del Rosso 2007b)

Physician‐assessed improvement in rosacea severity
Investigator's Global Assessment, two point improvement

See comment

See comment

Not estimable

537
(2 studies1)

⊕⊕⊕⊕
high

RR 1.77, 95% CI 1.24 to 2.52; P = 0.002 (Del Rosso 2007a) and RR 1.41, 95% CI 0.87 to 2.29 (Del Rosso 2007b) and IGA score of 0 or 1 RR 1.59, 95% CI 1.02 to 2.47; P = 0.04 (Del Rosso 2007a) and RR 2.37, 95% CI 1.12 to 4.99; P = 0.02 (Del Rosso 2007b)

Assessment of erythema or telangiectasia
Clinician's Erythema Assessments scale 0 to 4

See comment

See comment

Not estimable

537
(2 studies1)

⊕⊕⊕⊕
high

Mean change in CEA ‐2.7 (doxycycline group) versus ‐1.8 (placebo group), investigators report P = 0.017 (Del Rosso 2007a); and ‐1.4 and ‐1.2 respectively (Del Rosso 2007b)

Lesion counts
Scale from: ‐4.3 to ‐11.8

See comment

See comment

Not estimable

537
(2 studies1)

⊕⊕⊕⊝
moderate2

MD ‐5.90, 95% CI ‐9.37 to ‐2.43; P = 0.0009 (Del Rosso 2007a) and MD ‐5.20, 95% CI ‐8.27 to ‐2.13; P = 0.0009 (Del Rosso 2007b)

Time needed until improvement of the skin lesions

See comment

See comment

Not estimable

537
(2 studies1)

⊕⊕⊕⊕
high

The steepest changes in graph plots occurred within three weeks in the doxycycline group

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Del Rosso 2007a and Del Rosso 2007b
2 Downgraded one level due to serious imprecision (wide confidence interval)

Figures and Tables -
Summary of findings 10. Doxycycline 40 mg compared to placebo for rosacea
Summary of findings 11. Azithromycin compared to doxycycline 100 mg for rosacea

Azithromycin compared to doxycycline 100 mg for rosacea

Patient or population: Participants with rosacea
Intervention: Azithromycin
Comparison: Doxycycline 100 mg

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Doxycycline 100 mg

Azithromycin

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity

800 per 1000

784 per 1000
(616 to 1000)

RR 0.98
(0.77 to 1.25)

67
(1 study1)

⊕⊝⊝⊝
very low2,3

There was no statistically significant difference between the groups, but in both treatment arms the majority of participants considered themselves improved

Proportion of participants with adverse event

67 per 1000

108 per 1000
(21 to 551)

RR 1.62
(0.32 to 8.26)

67
(1 study1)

⊕⊝⊝⊝
very low2,4

Physician‐assessed improvement in rosacea severity ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Assessment of erythema or telangiectasia ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Lesion counts

The mean lesions count in the control group was
2.34 inflammatory lesions

The mean lesions count in the intervention group was
0 higher

67
(1 study1)

⊕⊝⊝⊝
very low2,5

Lesion count decreased in azithromycin group from 19.24 (SD 9.67) to 1.90 (SD 3.28) at 3 months and for doxycycline from 18.86 (SD 8.95) to 2.34 (SD 3.47). Skewed data

Time needed until improvement of the skin lesions ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Duration of remission

See comment

See comment

Not estimable

67
(1 study1)

⊕⊝⊝⊝
very low2,3

No data on duration of remission, but both groups showed no statistically significant change between the third month of treatment and the second month post‐treatment in the mean inflammatory lesion counts

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Akhyani 2008
2 Downgraded two levels due to very serious risk of bias (allocation concealment was at high risk of bias, no blinding)
3 Downgraded one level due to serious imprecision (low sample size, optimal sample size is not met, optimal sample size is not met)
4 Downgraded one level due to serious imprecision (wide confidence interval due to low sample size, optimal sample size is not met)
5 Downgraded one level due to serious imprecision (large SDs and skewed data, low sample size, optimal sample size is not met)

Figures and Tables -
Summary of findings 11. Azithromycin compared to doxycycline 100 mg for rosacea
Summary of findings 12. Doxycycline 40 mg + metronidazole 1% gel compared to doxycycline 100 mg + metronidazole 1% gel for rosacea

Doxycycline 40 mg + metronidazole 1% gel compared to doxycycline 100 mg + metronidazole 1% gel for rosacea

Patient or population: Participants with rosacea
Intervention: Doxycycline 40 mg + metronidazole 1% gel
Comparison: Doxycycline 100 mg + metronidazole 1% gel

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Doxycycline 100 mg + metronidazole 1% gel

Doxycycline 40 mg + metronidazole 1% gel

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Proportion of participants with adverse event

553 per 1000

138 per 1000
(61 to 299)

RR 0.25
(0.11 to 0.54)

91
(1 study1)

⊕⊕⊝⊝
low2,3

The majority of these adverse events were gastrointestinal complaints

Physician‐assessed improvement in rosacea severity
Reduction in Investigator's Global Assessment

The mean physician‐assessed improvement in rosacea severity in the control group was
‐1.6

The mean physician‐assessed improvement in rosacea severity in the intervention group was
0.00 higher
(0.11 lower to 0.11 higher)

91
(1 study1)

⊕⊕⊝⊝
low2,4

Assessment of erythema or telangiectasia
Clinician's Erythema Assessment

The mean assessment of erythema or telangiectasia in the control group was
‐4.0

The mean assessment of erythema or telangiectasia in the intervention group was
0 higher

91
(1 study)

⊕⊕⊝⊝
low2,4

Reduction in CEA 4.2 in doxycycline 40 mg and 4.0 in doxycycline 100 mg group, investigator's state P = 0.50

Lesion count

The mean lesion count in the control group was
‐12.2 inflammatory lesions

The mean lesion count in the intervention group was
0.30 lower
(3.03 lower to 2.43 higher)

91
(1 study1)

⊕⊕⊝⊝
low2,3

Time needed until improvement of the skin lesions

See comment

See comment

Not estimable

91
(1 study1)

⊕⊕⊝⊝
low2,4

A clear improvement was seen from week four for both groups.

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Del Rosso 2008
2 Downgraded one level due to serious risk of selection bias and attrition bias (sequence generation and allocation concealment at unclear risk of bias, high drop‐out rate and although ITT analysis judged at unclear risk of bias)
3 Downgraded one level due to serious imprecision (wide confidence interval due to low sample size, optimal sample size is not met)
4 Downgraded one level due to serious imprecision (low sample size, optimal sample size is not met)

Figures and Tables -
Summary of findings 12. Doxycycline 40 mg + metronidazole 1% gel compared to doxycycline 100 mg + metronidazole 1% gel for rosacea
Summary of findings 13. Doxycycline 40 mg + azelaic acid gel compared to doxycycline 40 mg + metronidazole gel for rosacea

Doxycycline 40 mg + azelaic acid gel compared to doxycycline 40 mg + metronidazole gel for rosacea

Patient or population: Participants with rosacea
Intervention: Doxycycline 40 mg + azelaic acid gel
Comparison: Doxycycline 40 mg + metronidazole gel

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Doxycycline 40 mg + metronidazole gel

Doxycycline 40 mg + azelaic acid gel

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity
Excellent improvement on a 4‐point Likert scale

465 per 1000

489 per 1000
(368 to 651)

RR 1.05
(0.79 to 1.40)

207
(1 study1)

⊕⊕⊕⊕
high

Excellent improvement was reported in approximately half of each intervention group

Proportion of participants with adverse event

69 per 1000

19 per 1000
(4 to 89)

RR 0.27
(0.06 to 1.28)

207
(1 study1)

⊕⊕⊕⊕
high

Physician‐assessed improvement in rosacea severity
Investigator's Global Assessment of 0, 1 or 2 (clear to mild)

723 per 1000

781 per 1000
(672 to 918)

RR 1.08
(0.93 to 1.27)

207
(1 study1)

⊕⊕⊕⊕
high

Clinician's Erythema Assessment ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Lesion count

The mean lesion count in the control group was
‐9.4 inflammatory lesions

The mean lesion count in the intervention group was
1.10 lower
(4.91 lower to 2.71 higher)

207
(1 study1)

⊕⊕⊕⊝
moderate2

Time needed until improvement

See comment

See comment

207
(1 study1)

⊕⊕⊕⊕
high

From four weeks on improvement could be seen for both treatment arms

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Del Rosso 2010
2 Downgraded one level due to serious imprecision (wide confidence interval)

Figures and Tables -
Summary of findings 13. Doxycycline 40 mg + azelaic acid gel compared to doxycycline 40 mg + metronidazole gel for rosacea
Summary of findings 14. Minocycline 45 mg compared to minocycline 45 mg + azelaic acid gel for rosacea

Minocycline 45 mg compared to minocycline 45 mg + azelaic acid gel for rosacea

Patient or population: Participants with rosacea
Intervention: Minocycline 45 mg
Comparison: Minocycline 45 mg + azelaic acid gel

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Minocycline 45 mg + azelaic acid gel

Minocycline 45 mg

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Proportion of participants with adverse event

533 per 1000

368 per 1000
(208 to 651)

RR 0.69
(0.39 to 1.22)

60
(1 study1)

⊕⊕⊝⊝

low2,3

Physician‐assessed improvement in rosacea severity
Mean change in Investigator's Global Assessment (Likert scale 0 to 5). Scale from: 0 to 4.

The mean physician‐assessed improvement in rosacea severity in the control groups was
‐2.0 on IGA

The mean physician‐assessed improvement in rosacea severity in the intervention groups was
0.00 higher
(0.32 lower to 0.32 higher)

60
(1 study1)

⊕⊕⊝⊝

low2,3

Assessment of erythema or telangiectasia
Mean change in CEA scale (Likert scale 0 to 4). Scale from: 0 to 4.

The mean assessment of erythema or telangiectasia in the control group was
‐4 on CEA

The mean assessment of erythema or telangiectasia in the intervention group was
1.00 higher
(0.18 lower to 2.18 higher)

60
(1 study1)

⊕⊕⊝⊝

low2,3

Lesion count

The mean lesion count in the control group was
‐12 inflammatory lesions

The mean lesion count in the intervention group was
1.00 higher
(0.93 lower to 2.93 higher)

60
(1 study1)

⊕⊕⊝⊝

low2,3

In both groups there was a clinically important reduction in lesion counts of 11.00 (SD 4.49) in the minocycline group and 12.00 (SD 3.00) in the comparator group

Time needed until improvement

See comment

See comment

Not estimable

60
(1 study1)

⊕⊕⊝⊝

low2,3

Improvement was seen in both arms at four weeks

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Jackson 2013
2 Downgraded one level due to serious risk of performance and detection bias (blinding was assessed as at unclear risk of bias)
3 Downgraded one level due to serious imprecision (low sample size, optimal sample size is not met)

Figures and Tables -
Summary of findings 14. Minocycline 45 mg compared to minocycline 45 mg + azelaic acid gel for rosacea
Summary of findings 15. Topical metronidazole compared to oral (oxy)tetracycline for rosacea

Topical metronidazole compared to oral (oxy)tetracycline for rosacea

Patient or population: Participants with rosacea
Intervention: Topical metronidazole
Comparison: Oral (oxy)tetracycline

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Oral (oxy) tetracycline

Topical metronidazole

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity

See comment

See comment

Not estimable

182
(3 studies1)

⊕⊕⊕⊝
moderate2

RR 0.71, 95% CI 0.40 to 1.26 (Monk 1991), RR 0.96, 95% CI 0.80 to 1.17 (Nielsen 1983b) and in Schachter 1991 no exact data were provided other than that "both groups considered their condition much improved"

Proportion of participants with adverse event

See comment

See comment

Not estimable

258
(4 studies3)

⊕⊕⊕⊝
moderate4

No adverse event (Nielsen 1983b), RR 1.06, 95% CI 0.32 to 3.55 (Monk 1991), 12 adverse events reported in metronidazole group and 9 in tetracycline group (Schachter 1991), RR 0.70, 95% CI 0.30 to 1.65 (Veien 1986)

Physician‐assessed improvement in rosacea severity

See comment

See comment

Not estimable

81
(2 studies5)

⊕⊕⊕⊝
moderate2

RR 0.80, 95% CI 0.47 to 1.35 (Monk 1991), RR 1.00, 95% 0.89 to 1.13 (Nielsen 1983b)

Assessment of erythema or telangiectasia

See comment

See comment

Not estimable

258
(4 studies3)

⊕⊕⊝⊝
low2,6

Erythema score ‐1.4 versus ‐1.3 (Monk 1991), "the reduction of erythema was the same in both groups, and the number and extent of telangiectases were unchanged" (Nielsen 1983b), in Schachter 1991 no differences in erythema nor telangiectasia were seen in either group. In Veien 1986 the percentage of no improvement was 11.1 in the metronidazole group versus 12.5 in the tetracycline group

Lesion count

See comment

See comment

258
(4 studies3)

⊕⊕⊕⊝
moderate2

Complete clearance in 75% versus 66% of participants (Monk 1991), "the reduction of papules and pustules was the same in both groups" (Nielsen 1983b), decrease of 68% versus 77% in papule count and of 53% and 61% in pustule count (Schachter 1991). In Veien 1986 only medians were provided with 11.1 lesions in the metronidazole group and 0 in the tetracycline group

Time needed until improvement ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Monk 1991, Nielsen 1983b, Schachter 1991 (number of participants randomised in Schachter 1991 was unclear)
2 Downgraded one level due to serious imprecision (low sample sizes)
3Monk 1991, Nielsen 1983b, Schachter 1991, Veien 1986 (number of participants randomised in Schachter 1991 was unclear)
4 Downgraded one level due to serious imprecision (wide confidence intervals due to low sample sizes)
5Monk 1991, Nielsen 1983b
6 Downgraded one level due to serious heterogeneity (in contrast to the other three studies, Schachter 1991 did not show any improvement in erythema and telangiectasia

Figures and Tables -
Summary of findings 15. Topical metronidazole compared to oral (oxy)tetracycline for rosacea
Summary of findings 16. Low dose isotretinoin 0.3 mg/kg compared to doxycycline 50‐100 mg for rosacea

Low dose isotretinoin 0.3 mg/kg compared to doxycycline 100 mg for rosacea

Patient or population: Participants with rosacea
Intervention: Low dose isotretinoin 0.3 mg/kg
Comparison: Doxycycline 100 mg after 14 days tapered to 50 mg

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Doxycycline 100 mg

Low dose isotretinoin 0.3 mg/kg

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity1
Good to excellent improvement on 5‐point Likert scale

644 per 1000

792 per 1000
(676 to 921)

RR 1.23
(1.05 to 1.43)

261
(1 study2)

⊕⊕⊕⊕
high

Low dose isotretinoin is considered by the participants to be slightly more effective than doxycycline 100 mg

Proportion of participants with adverse event

171 per 1000

204 per 1000
(127 to 328)

RR 1.19
(0.74 to 1.92)

299
(1 study2)

⊕⊕⊕⊕
high

Physician‐assessed improvement in rosacea severity1
Complete remission or marked improvement on a 6‐point Likert scale)

689 per 1000

813 per 1000
(710 to 938)

RR 1.18
(1.03 to 1.36)

261
(1 study2)

⊕⊕⊕⊕
high

In agreement with the participant‐assessed changes

Assessment of erythema or telangiectasia
Improved or healed

783 per 1000

736 per 1000
(650 to 846)

RR 0.94
(0.83 to 1.08)

285
(1 study2)

⊕⊕⊕⊕
high

Telangiectasia were improved or "healed" RR 1.03, 95% CI 0.77 to 1.37

Lesion count1

The mean lesion count in the control group was
‐13 inflammatory lesions

The mean lesion count in the intervention group was
3 lower

261
(1 study2)

⊕⊕⊕⊕
high

Time needed until improvement ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Per‐protocol analysis
2Gollnick 2010

Figures and Tables -
Summary of findings 16. Low dose isotretinoin 0.3 mg/kg compared to doxycycline 50‐100 mg for rosacea
Summary of findings 17. Pulsed dye laser compared to Nd:YAG laser for rosacea

Pulsed dye laser compared to Nd:YAG laser for rosacea

Patient or population: Participants with rosacea
Intervention: Pulsed dye laser
Comparison: Nd:YAG laser

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Nd: YAG laser

Pulsed dye laser

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity1

The mean participant‐assessed improvement in rosacea severity in the control group was
34 percent

The mean participant‐assessed improvement in rosacea severity in the intervention group was
16.33 higher
(1.94 to 34.6 higher)

14
(1 study2)

⊕⊕⊝⊝

low3

Proportion of participants with adverse event1
Pain as assessed by VAS (0 to 10; higher score is worse)

See comment

See comment

Not estimable

14
(1 study2)

⊕⊕⊝⊝

low4

Pain was assessed on the PDL treated side 3.87 and 3.07 on the Nd:YAG side, the investigators state P = 0.0028

Physician‐assessed improvement in rosacea severity ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Assessment of erythema or telangiectasia1
Spectrophotometer to assess facial redness

The mean assessment of erythema or telangiectasia in the control group was
‐2.5 percent

The mean assessment of erythema or telangiectasia in the intervention group was
6.4 lower
(11.6 to 1.2 lower)

14
(1 study2)

⊕⊕⊝⊝

low3

Lesion count ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Time until improvement ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Within‐participant
2Alam 2013
3 Downgraded two levels due to very serious imprecision (very wide confidence interval due to low sample size, optimal sample size is not met)
4 Downgraded two levels due to very serious imprecision (very low sample size, optimal sample size is not met)

Figures and Tables -
Summary of findings 17. Pulsed dye laser compared to Nd:YAG laser for rosacea
Summary of findings 18. Pulsed dye laser compared to intense pulsed light therapy for rosacea

Pulsed dye laser compared to intense pulsed light therapy for rosacea

Patient or population: Participants with rosacea
Intervention: Pulsed dye laser (PDL)
Comparison: Intense pulsed light therapy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Intense Pulsed Light Therapy

Pulsed Dye Laser

HRQOL ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Participant‐assessed improvement in rosacea severity1
VAS. Scale from: 0 to 10 (0 being a poor and 10 an excellent result)

The mean participant‐assessed improvement in rosacea severity in the control group was
7

The mean participant‐assessed improvement in rosacea severity in the intervention group was
1 higher

40
(1 study2)

⊕⊕⊝⊝

low3,4

Median was 8 (range 2 to 10) for PDL group and 7 (range 2 to 10) for IPL group (10% and 90% percentiles)

Proportion of participants with adverse event
Pain as assessed with a VAS scale. Scale from: 0 to 10

Pain assessed on a VAS scale in the control group was
7

Pain assessed on a VAS scale in the intervention group was
3 lower

40
(1 study2)

⊕⊕⊝⊝

low3,4

Median was 4 (range 2 to 6) for PDL group and 7 (range 2 to 10) for IPL group (10% and 90% percentiles)

Physician‐assessed improvement in rosacea severity ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Assessment of erythema or telangiectasia
5‐point Likert scale

See comment

See comment

40
(1 study2)

⊕⊕⊕⊝

moderate4,5

On the PDL treated side 18 had an excellent (75% to 100% vessel clearance) response and 12 a good response (50% to 74% clearance) and on the IPL treated sides 11 had an excellent response and 19 a good response

Lesion count ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Time until improvement ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

Duration of remission ‐ not measured

See comment

See comment

Not estimable

See comment

No study addressed this outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Within‐participant design
2Nymann 2010
3 Downgraded one level due to serious performance and detection bias (investigators and participants were not blinded)
4 Downgraded one level due to serious imprecision (low sample size, optimal sample size is not met)
5 "Clinical efficacy was evaluated by one blinded trained physician"

Figures and Tables -
Summary of findings 18. Pulsed dye laser compared to intense pulsed light therapy for rosacea
Table 1. Glossary of unfamiliar terms

Term

Definition

Acne

A skin condition characterised by the inflammation or infection of sebaceous glands (usually attached to hair follicles) resulting in comedones (whiteheads and blackheads) and inflammatory lesions such as papules (pimples), pustules, and nodules)

Bacillus oleronius

A bacteria found in Demodex mites

Bacterial resistance

Resistance of a micro‐organism to an antimicrobial drug that was originally effective for treatment of infections caused by this micro‐organism

Body dysmorphic disorder

An anxiety disorder surrounding perceived flaws in one's own appearance

Cytokines

A small protein released by cells, and having a specific effect on the behavior of other cells, or on the interactions or communications between cells

Demodex folliculorum

A species of face mite found in human hair follicles

Down‐regulation

Process of reducing or suppressing a response to a stimulus

Epidermal barrier

The skin's front line of defence in the upper layer of the skin (the epidermis) against environmental factors such as UV light, chemicals, bacteria and other organisms and limits water loss from the body

Innate immune response

The first line generic defence of the immune system against infection and other organisms

Keratinocytes

A predominant cell type in the outermost layer of skin (epidermis), and when found in the basal layer, are referred to as 'basal cells' or 'basal keratinocytes'. Their main function is the formation of a barrier against environmental damage

Matrix‐Metalloproteinases

Zinc dependent enzymes that promote break down of proteins like collagen. They regulate various inflammatory and repair processes

Neurovascular dysregulation

A failure of the vascular response, vasodilation, and neurosensory symptoms to regulate properly

Dysfunction of both nerves and vascular elements, controlling the calibre of blood vessels

Nodule

Solid, raised area in or under the skin

Nodularities

An increased density of tissues

Pathophysiology

The functional changes that accompany a particular syndrome or disease (combined terms of ‘patho’ (path, related to disease) and ‘physiology’ (a branch of biology that specialises in the study of the functions of living organisms and their parts)

Phototype

A classification of skin type based on a person's sensitivity to sunlight

Pustule

A small bump on the skin containing purulent material (pus) in the top layer (epidermis) or beneath it (dermis)

Reactive oxygen species (ROS)

Chemically reactive molecules containing oxygen, or oxygen‐derived radicals, having important roles in cell signalling (communication and interaction) and homeostasis (the maintenance of a steady state)

Retinoids

Chemical compounds related chemically to Vitamin A

Stratum corneum

The outermost layer of the epidermis

Stye

A bacterial infection of a gland at the base of any eyelash, causing painful swelling on the inner or outer eyelid

Toll‐like receptors

A class of proteins that play a key role in the innate immune system, activating immune cell responses

Figures and Tables -
Table 1. Glossary of unfamiliar terms
Table 2. Pharmaceutical companies contacted

Name

Response

Additional

Comment

Bayer

Yes

Yes

Added information on Del Rosso 2010 Christopher Billis <[email protected]> and that ongoing studies were not yet published

Roche

Yes

No

ASTA Medica

Yes

No

Merck

Yes

No

Dumex‐Alpharma

Yes

No

Galderma

Yes

Yes

[email protected], [email protected]

August 2014 several times contact with Galderma NL, France and US, provided lots of extra information regarding brimonidine and ivermectin

AHP Pharma

No

No

Yamanouchi

No

No

Dermik Laboratories

No

No

CollaGenex

No

No

Taken over by Galderma

Figures and Tables -
Table 2. Pharmaceutical companies contacted
Table 3. Investigators contacted

Name

Response

Additional

Comment

Akhyani 2008

Yes

Yes

[email protected]. (sequence generation and allocation concealment) "In efficacy of azithromycin vs. doxycycline in the treatment of rosacea: a randomised open clinical trial" Patients were allocated to the trial using a randomised numbers table. Unfortunately this trial was not blinded" "The randomised number table generated by computer. The list was only in access of physician, and patients could not see that

Altinyazar 2005

Yes

Yes

After email contact with the primary investigator and following on from discussion between the review authors, this was judged to be quasi‐randomised, i.e. a CCT

Benkali 2014

Yes

Yes

[email protected], 1‐8‐2014 (sequence generation and allocation concealment)
1) Regarding the allocation sequence generated for the 4 subsequent groups consisting of different doses or regimen for topical applications, the randomisation list was created before the study started, with a 1:1:1:1 ratio and block size of 4. This randomisation list was generated by a designated biostatistician and was distributed to the clinical supply team in a sealed envelope (see the attached pdf file for the randomisation memo)

2) As explained above, only the 4 arms treated with topical products were to be randomised. The block size of 4 was not known by the sites, so foreseeing the next allocation was possible but unlikely. Since the study had 2 treatment groups for QD regimen and 2 treatment groups for BID regimen, subjects and the personnel who distributed the medication necessarily knew this information

Of note, the primary objective of this study was PK assessment (and not efficacy), an objective measure, and the primary comparison was topical versus eye drop which was in no way planned to be randomised or blinded

3) This study was not posted on CT.gov since it was classified as a phase 1 study

Berardesca 2008

Yes

Yes

[email protected]. After email communication with the investigators to clarify aspects of trial conduct, the criterion for sequence generation was changed from UNCLEAR to High risk, i.e. the study was not a RCT and participants appear to have been allocated to the intervention by alternation

Berardesca 2012

Yes

Yes

18‐8‐2014 [email protected] (sequence generation and allocation concealment and blinding)

29‐9‐2013 replies

1. This was a randomised, double‐blind, parallel‐group, placebo‐controlled study

Patients, having signed their informed consent and who satisfied all inclusion and exclusion criteria at inclusion visit were randomly assigned to one of two treatment groups (P‐3075 cream, placebo), according to a computer‐generated randomisation list

Patients were sequentially assigned to the next available randomisation number, starting from the lowest number provided to each investigational site

Furthermore, for ethical reason, in order to minimise the exposure to placebo, randomisation was unbalanced between the P‐3075 and placebo groups with a 2:1 ratio using blocks of 3 treatments

2/3. The double blind study design was guaranteed by the use of placebo cream units, which were identical to the active product in terms of size, shape, volume, colour. The tubes (P‐3075 and placebo) were identically labelled for clinical use as it is in a double‐blind procedure

4. Thank you for this observation (you are the first). We confirm that the correct value is ‐167.00 and not 167.00, as reported in our database. It was a typing error that was not detected when the manuscript was transformed in draft paper by the editor

5. As described in the paper, a 4‐point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe) was used by the investigators at each visit for the clinical evaluation of erythema

The results at Day 28 (end of treatment) showed that, in the P‐3075 group, erythema was absent in 27 patients (96.4%) and mild in 1 (3.6%), while in the placebo group, erythema was absent in 9 patients (64.3%) and mild in 5 (35.7%). There were no cases of moderate or severe intensity at Day 28 in both groups. The statistically significance values were reported in the paper as you underlined. For completeness the baseline clinical assessment for erythema was as follows: for P‐3075 absent in 7 patients, mild in 14, moderate in 6 and severe in 1 and for placebo absent in 3 patients, mild in 6 and moderate in 5

Beutner 2005

Yes

Yes

[email protected] and [email protected], [email protected]. Useful additional information provided by primary investigator, on randomisation, allocation concealment and characteristics of patients

Bribeche 2015

Yes

Yes

'[email protected]' 30‐8‐2014
Dear professor Bribeche (allocation concealment and blinding)
reply 7‐9‐2014: 1‐ During enrolment we used an allocation randomiser programme: http://www.randomizer.org/
2‐ Only the participants were blinded to treatment, praziquantel ointment and the placebo had the same colour (white), and ointment were given to participants in identical boxes for both groups (white box with a blue cover)
Next mail 7‐9‐2014: The reply to our first question is more on sequence generation, and not concealment of the allocation. Who was responsible for using that programme and who had access to the generated list?

Reply 10‐9‐2014: Me and professor Fedotov VP, were responsible for using this programme, both of us had access to the generated list and a doctor from our department (Dr Makurina); who was fully unaware of the aims of the study and overseen the enrolment

Buendia‐Bordera 2013

Can't find mail address, sent invite on LinkedIn

Chosidow 2014

NCT00882531

Yes

[email protected] and [email protected],18‐7‐2014
Is the NCT00882531 published and if so give us a pdf of the publication?

Reply 18‐7‐2014 "Hi Esther, we are still in processing the manuscript and hope submitting the paper before the end of 2014" and "We could send your our submitted manuscript?"

Cunliffe 1977

No

No

Dahl 2001

Yes

Yes

[email protected]."Subjects will be randomised to 1 of the 2 treatment groups at a ratio of 1:1. The randomisation process will be done in blocks of 4, stratified by investigators. The randomisation will be carried out using SAS PROC PLAN"

Del Rosso 2010

Yes

Yes

[email protected], 1‐8‐2014 ‎(sequence generation, allocation concealment)

Chris Billis ‎[[email protected]]‎‎; Keith Flanders ‎[[email protected]]‎
15‐8‐2014 Randomisation was done centrally by the generation of a randomisation list using the randomisation program RANCODE (version 3.6). Randomisation used blocks. Whole randomisation blocks were allocated to each site. In each study site, each newly enrolled patient was allocated to study medication with the lowest randomisation number available in that particular site at the subjects baseline visit. The patient randomisation number was entered into the CRF immediately after allocation. Each patient retained the randomisation number originally allocated at Baseline for the duration of the study

Six drug tubes (tubes with a blinded label to cover the trademarks) and 3 bottles were packaged by a CMO in individual numbered kit boxes. Each patient was issued an individual numbered kit box containing 6 tubes and 3 bottles of study materials. The study drug was not to be dispensed by the investigator, but was dispensed by and returned to qualified study personnel (e.g., practice or clinic nurses) not involved with the selection and the assessment of the patients. At the control visits after Weeks 4, 8 and 12, patients returned empty, partially used, and unused containers to qualified study personnel before being examined by the investigator. Study drug compliance was assessed by the qualified study personnel. The patient was advised not to discuss the treatment schedule with the investigator
19‐8‐2014 sent additional mail regarding SD of lesions
3‐9‐2014, resent, received 4‐9‐2014

Dreno 1998

Yes

No

Old study, no further data available

Draelos 2005b; Draelos 2006

Yes

Yes

[email protected]. On 2006. Sequence generation? "Subjects were randomised based on the order in which they presented to the office". Allocation concealment? "The research coordinator maintained the blind which was not shared with anyone, including the investigator."
5 dropouts but in which group? The dropouts were for personal reasons, not related to product. They were random between the groups
On 2005 Sequence generation? "Subjects were randomised based on severity of disease and the order in which they presented to the office". Allocation concealment? 'The research coordinator maintained the double blind." Dropouts? "The drop outs were one in each group."

Draelos 2009

No

No

[email protected], 2‐8‐2014 (sequence generation and allocation concealment and blinding, how many randomised to each group, separate data for participants with rosacea? losses to follow‐up?)

9‐8‐2014 sent again. No reaction

Draelos 2013a

Yes

Yes

[email protected], 2‐8‐2014 (blinding and details on RosaQoL data)

Reply 2‐8‐2014 This was the pivotal trial for FDA approval. The blind was maintained by dispensing the vehicle and the vehicle plus the active in identical containers. I do not have more detail on the QOL scores

Draelos 2013b

Yes

Yes

[email protected] (sequence generation, stratification and allocation concealment and blinding)

Reply 2‐8‐2014
I will answer your questions below:
1. the method used to generate the allocation sequence as “were divided equally into two groups” does not seem at random. Subjects were randomised in two balanced populations based on a computer generated randomisation sequence
2. How was stratification done during the sequence generation? That is, can you describe the method used to generate the allocation sequence in sufficient detail to allow us an assessment of whether it should produce comparable groups stratified for demographics and presence and severity of acne, eczema, rosacea and atopic dermatitis?
The data for each person was entered into a database and then the computer randomisation balanced the two groups for all of the characteristics you have mentioned
3. the method used to conceal the allocation sequence to ensure that intervention allocations could not have been foreseen in advance of, or during, enrolment i.e. participants and investigators enrolling participants could not foresee the upcoming assignment (this is not the same as blinding!!).
I realize that randomisation and blinding are not the same. The products were identically packaged
4. How were the investigators and participants blinded to the treatment the participants received?
Yes, both the investigator and the participant did not know the product identity which was concealed through identically appearing products packaged identically
5. Are there separate data for women on rosacea? No, the data was not analysed in this fashion.

follow‐up mail that allocation concealment is not yet satisfactorily answered
9‐8: sent again, no reply

Ertl 1994

Yes

No

Dr Levine, study 17 years old, no further data available

Fabi 2011

No

No

[email protected] 2‐8‐2014 (sequence generation and allocation concealment and dropouts?)

Follow‐up mail 11‐8‐2014 and 17‐8‐2014, no reply

Fowler 2007

Yes

Yes

[email protected] and [email protected]. "Randomisation was done by using a computer generated table provided by the sponsor. Neither subjects nor investigators and study staff had any control over this"

Fowler 2012a; Fowler 2012b; Fowler 2013a; Fowler 2013b

Yes

Yes

[email protected] and Jean Jacovella ([email protected]) 22‐8‐2014, 27‐8

Asked for separate exact data of PSA and CEA at different time points, wash‐out period and details on AE

Received replies 25‐9‐2014

Fowler 2013a

Yes

Yes

20‐7‐2014 asked Galderma if it is published (Patricia van Lith) is this Fowler 2013? 28‐7‐2014 confirmed (NCT01355471 and NCT01789775 are the same studies)

Received replies 25‐9‐2014

Freeman 2012

Yes

Yes

'[email protected]' 3‐8‐2014 (sequence generation and allocation concealment and blinding)
Follow‐up mail 11‐8‐2014
reply 12‐8‐2014 1) Random selection by study coordinator
2) Medication and placebo allocation was the responsibility of the study coordinator who randomly selected which product to provide each subject (2:1 ratio). The investigators were unaware of the selection process and the study coordinator was not privy, prior to selection of product, of the type or severity of disease of any subject

3) Investigators were not privy to the medication/placebo selection process. No medication tubes were shown to the investigators. No questions were asked about the topical product (i.e. Odor, color or feel). There was no communication between the study coordinator and the investigators regarding the medication/placebo selection

follow‐up mail 12‐8‐2014
Regarding 1) this answer still does not inform us the method, so what method did the study coordinator used?
Regarding 2) You describe that the investigators were unaware of selection process, but if the study coordinator was aware who received what, then the allocation was NOT concealed, even if he was not privy
Regarding 3) if the patients knew what they received they could tell the investigators, as slip of the tongue. So it might be that study coordinator did not say anything, the patients could say something to the investigator. So was there any possibility that patients knew what they received? And if not why not? Why did they not know what they received (as stated as double‐blinded)
Response: 12‐8‐2014: Randomisation: every third patient was given placebo to create a 2:1 ratio
Follow‐up mail: then it is not truly randomised but quasi‐randomised as you know every third patient gets placebo it is no longer at random and we have to exclude the study

Frucht‐Pery 1993

No

No

Gollnick 2010

Yes

Yes

3‐8‐2014 [email protected] [email protected] (sequence generation and allocation concealment clarification of N)
5‐9‐2014 follow‐up, and received replies with clear information

Huang 2012

No

No

18‐7‐2014 [email protected] (sequence generation and allocation concealment)

9‐8‐2014 follow‐up mail and 17‐8‐2014, no reply

Jackson 2007

No

No

Jackson 2013

Yes

Yes

[email protected] 9‐8‐2014
1. The dropouts are noted below: 5 total
Two adverse events were classified as possibly related to the study medication – an upset stomach and generalized urticaria in separate patients both receiving ER minocycline + azelaic acid 15%. Four adverse events in three patients (all receiving ER minocycline + azelaic acid 15%) were severe but not suspected to be related to the study medication (bilateral oophorectomy with dermoid cyst removal, gastric erosion after lap band surgery, a severe respiratory infection, and cholecystitis)

2. The CEA was a scale of 0 to 4 so there was a typo on 295. The IGA went from 0 to 5. As for the total CEA it was a combined number of the CEA for each location of the face as per the table below
APPENDIX B
Clinician’s Erythema Assessment Scale
ERYTHEMA Definition
0 None No redness present 1 Mild Slight pinkness 2 Moderate Definite redness 3 Significant Marked erythema 4 Severe Fiery redness
ERYTHEMA Score
• Check one box for each area of the face based upon the definitions given above • Enter the Erythema Score for each area of the face • Sum all of the individual Erythema Scores to obtain the Total Erythema Score
Erythema Score Forehead Chin Nose Right Cheek Left Cheek none (0) none (0) none (0) none (0) none (0) mild (1) mild (1) mild (1) mild (1) mild (1) moderate (2) moderate (2) moderate (2) moderate (2) moderate (2) significant (3) significant (3) significant (3) significant (3) significant (3) severe (4) severe (4) severe (4) severe (4) severe (4)

Jansen 1997

No

No

Jorizzo 1998

Yes

No

Karabulut 2008

Yes

Yes

[email protected]. After email contact with the primary investigator this study was excluded

Karsai 2008

No

No

Kendall 2014

Yes

Yes

[email protected] 6‐8‐2014 (sequence generation and allocation concealment and blinding and dropouts)

9‐9‐2014 reply:

I did not receive your previous e‐mails as my address is [email protected]

70 patients were enrolled in the study. Two subjects withdrew from the study and they were both in the brimonidine tartrate gel 0.5% treatment group in phase 1 and did not enter phase 2. One for an adverse event and one for a protocol deviation

Koch 1999

Yes

No

Appeared to be wrong R Koch

Koçak‐Altintas 2005

Yes

Yes

After extensive email contact, clarified as a CCT

Laquieze 2007

No

No

Lebwohl 1995

Yes

No

Old study, no further data available

Leyden 2011

Yes

No

[email protected] 7‐8‐2014 (sequence generation and allocation concealment)
Reply 12‐8‐2014: I am now Emeritus and mostly out of the loop and my clinical research nurse has retired. Nobody in the clinical trials unit was there when that study was done and I can't get the details you are asking for Sorry! Jim Leyden

Leyden 2014

Yes

Yes

19‐7‐2014, info@sol‐gel.com Ofer.Toledano@sol‐gel.com

My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already published?
NCT00940992 “A Study of DER 45‐EV Gel to Treat Rosacea (SGTDER45EV)”. Can you tell us if the NCT00940992 is published and if so give us a pdf of the publication?

Reply 19‐7‐2014 Ofer.Toledano@sol‐gel.com, Gaby.Peleg@sol‐gel.com . The study results were published by James Leyden in the JDD (journal of drugs in dermatology) in June 2014, volume 13, issue 6, p.685

Luger 2015

Yes

Yes

Mderma@uni‐muenster.de (allocation concealment and blinding)

Reply 18‐8‐2014
The generation of the random code list was performed in a validated environment by an independent CRO not involved in study conduct and monitoring using the software RANCODE Version 3.6. Central randomisation was performed by this CRO. For eligible subjects, investigators called the randomisation centre and provided the patient’s identification number and gender. Patients were subsequently randomised and the study centre was notified of the treatment number of the patient via telefax by the randomisation centre. Treatment allocation provided by the central randomisation service was documented in the CRF and monitored.
ad 2) The investigational product and its matching vehicle had a similar appearance and all subject kits were packaged in the same way. The randomisation list was kept strictly confidential. It was accessible only to authorized persons who were not involved in the conduct, monitoring and analysis of the study, until time of unblinding. Based on the randomisation list, sets of sealed individual code envelopes were prepared for emergency procedures. No emergency unblinding occurred during the study

Lupin 2014

No

No

Ulthera, Inc. Mark Lupin, M.D 23‐7‐2014 info @cosmedica.ca [email protected], sent several mails no reply (sequence generation and allocation concealment, dropouts)

Mostafa 2009

No

No

S Mokadem no response

National Rosacea Society

No

No

Neuhaus 2009

No

No

G Plewig

No

No

Powell 2005

Yes

No

A Rebora

No

No

Rigopoulos 2005

No

No

Sainthillier 2005

No

No

Salem 2013

No

No

[email protected] 10‐08‐2014 Resent 17‐8‐2014 and 3‐9‐2014 (sequence generation and allocation concealment and blinding), no replies

Seité 2013

Yes

Yes

[email protected] 16‐7‐2014 (sequence generation and allocation concealment and blinding, dropouts)
Reply 12‐8‐2014:

1. The allocation sequence was generated by a statistician using a specific software

2. As soon as they have been recruited (because they answered to the inclusion criteria) by the investigating dermatologist (only one = Dr Zelenkova) a number given chronologically, as indicated in the allocation sequence purchase to the investigator, was attributed to the patient (the first was the N°1, the 2nd the N° 2…)

3. After enrolment and at the end of the 1st visit, a nurse (in the absence of the investigating dermatologist) give the products allocated to the patient’s number. Both products was in the same packaging (blind white packaging) without any indication about formula reference (only reference of study and number of patient) and some information about use (topical use only…)

4. None dropped out between the stop of metronidazole treatment (Week 8) and the end of the study (week 16). 67 patients were included before metronidazole treatment, 1 dropped out due to irritative dermatitis at day 53 (before the end of the 8‐week Metronidazole treatment); So 66 patients remained after 8 weeks, 32 received the test formula and 34 the vehicle

5. More detail about the 66 patients included in this study are available (see below (printscreens))
25‐8‐2014, received additional info on Investigator's assessments

Sharquie 2006

No

No

Stein 2014b

Yes

Yes

19‐7‐2014 asked Galderma if NCT01493687 it is published and looks the same as NCT01494467 (Patricia van Lith), confirmed 28‐7 are the same and are Stein Gold
[email protected] and [email protected] on details DLQI and SDs

3‐9‐2014, received data

Taieb 2015

Yes

Yes

19‐7‐2014 asked Galderma if NCT01493947 is published (Patricia van Lith), confirmation 28‐7‐2014, EADV abstract 2014

alain.taieb@chu‐bordeaux.fr (sequence generation and allocation concealment and blinding, dropouts)
Response 19‐8‐2014

The study was a parallel group study of 960 subjects; however 1800 kit numbers are randomised in blocks of 6. The RANUNI routine of the SAS system was used to randomly assign, in balanced blocks, kit to a treatment (Ivermectin 1% cream, Metronidazole 0.75% cream). Prior to the start of the study, a randomisation list was generated by the statistician and was secured with restricted access. Treatment assignment was balanced into consecutive blocks in a 1:1 ratio and kit numbers were assigned sequentially in chronological order. The study design was investigator‐blinded. The integrity of the blinding was ensured by packaging the products in identical tubes, not allowing the investigator and subject to discuss study treatments, and requiring a third party other than the investigator to dispense the medication.

Study population and causes for withdrawal are summarised in the figure below

Thiboutot 2003a; Thiboutot 2003b; Thiboutot 2008; Thiboutot 2009

No

No

Tirnaksiz 2012

No

No

[email protected] 17‐8‐2014 ((sequence generation and allocation concealment)
resent 3‐9‐2014 no reply

Torok 2005

Yes

Yes

[email protected]. "The patients were not cognizant nor were they aware of the different formulations Nor their unique characteristics so they were easily utilized and dispensed in unmarked tubes". "Central randomisation that was computer generated"

Two 2014

Yes

Yes

[email protected] 17‐8‐2014 (sequence generation and allocation concealment and blinding)
resent 3‐9‐2014, received reply 4‐9‐2014

1. The allocation sequence was generated by an unblinded member of the study team who worked off‐site in a separate laboratory to group in a 2‐to‐1 fashion, so that 8 of those numbers were assigned to the treatment group, and 4 to the control group. As subjects were enrolled in the study, they were sequentially assigned a unique study identification number from 1‐12 by the blinded study coordinator, with the first subject to enrol in the study being assigned the study identification number of 1. The list matching study identification numbers to their corresponding treatment group was only accessible by this unblinded member of the study team

2. The allocation sequence was created prior to enrolling any subjects in the study, therefore ensuring that intervention allocations could not be foreseen in advance of, or during, enrolment

3. This study was conducted in a double‐blind fashion so that both participants and investigators were blinded as to which intervention group participants were assigned. As stated previously, randomisation was completed by an unblinded member of the study team who worked off‐site and had no contact with enrolled subjects. The list of treatment group assignments was stored on a password‐protected computer accessible only to this unblinded study team member. This same unblinded member of the study team was also responsible for preparing all study medication. Once prepared, the study medication was placed into a bottle labelled with the participant’s unique study identification number that was assigned to the participant at the time of enrolment in the trial. The unblinded study team member dispensed the bottles of prepared medication to the study’s clinical coordinator, who was also blinded, for distribution to subjects. Both the treatment and the control creams were identical in appearance and viscosity so that the two drugs could not be distinguished by look or feel
Resent regarding exact data IGE and CEA 12‐9‐2013
Received 12‐9‐2013 exact data + SD

Wilkin 1989; Wilkin 1993

No

No

Wittpenn 2005

Yes

Yes

Additional information could not be used

Wolf 2006

No

No

Yoo 2011

No

No

[email protected] 18‐8‐2014 (sequence generation and allocation concealment and blinding)

Resent 3‐9

ACTRN12614000004662

Yes

No

Medical Research Institute of New Zealand, Anna Hunt [email protected]. sent 23‐7‐2014

My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already published?
ACTRN12614000004662 “A single‐blind randomised controlled trial of topical Kanuka honey for the treatment of rosacea”. Can you tell us if ACTRN12614000004662 is published and if so give us a pdf of the publication?

email reply 29‐7‐2014

Dear Dr van Zuuren,

Thank you for your email and interest in our study. We are currently analysing this 138 participant Phase 3 study. It is not yet published, but we would be happy to send you the publication when that time comes

EUCTR2006‐001999‐20‐HU

Yes

No

23‐9‐2014, sent e‐mail to Galderma NL and several more to Galderma International, no reply

EUCTR2006‐003707‐40‐DE

Yes

No

23‐9‐2014, sent e‐mail to Galderma NL and several more to Galderma International, no reply

EUCTR2009‐013111‐35‐DE

Yes

No

23‐9‐2014, sent e‐mail to Galderma NL and several more to Galderma International, no reply

EUCTR2010‐018319‐13‐DE

Yes

No

23‐9‐2014, sent e‐mail to Galderma NL and several more to Galderma International, no reply

EUCTR2010‐021150‐19‐NL

Yes

No

Study of Mireille, is still ongoing

EUCTR2010‐023566‐43‐DE

Yes

No

23‐9‐2014 Dr. Bertil Wachall, [email protected]

2‐10‐2014 Thank you for your request concerning our permethrin rosacea trial (permethrin 5% and 2.5% vs metronidazole cream). Unfortunately, the data are not published or submitted up to now. We hope this will be done in the next months, but the principal investigator who is responsible for the publication seems to be very busy.

In addition, please be informed that we are currently conducting another permethrin trial (permethrin 5% vs placebo cream) in PPR‐patients. We expect the results of this trial in spring 2015 (we discussed with PI, study does NOT appear in EUCTR (EUDRACT‐Nr. 2013‐000979‐32)

EUCTR2011‐002057‐65‐DE

Yes

No

23‐9‐2014, sent e‐mail to Galderma NL and several more to Galderma International, no reply

EUCTR2011‐002058‐30‐DE

Yes

No

23‐9‐2014, sent e‐mail to Galderma NL and several more to Galderma International, no reply

EUCTR2011‐004791‐11‐CZ

Yes

No

23‐9‐2014, sent e‐mail to Galderma NL and several more to Galderma International, no reply

EUCTR2012‐001044‐22‐SE

Yes

No

23‐9‐2014, sent e‐mail to Galderma NL and several more to Galderma International, no reply

EUCTR2013‐005083‐26‐DE

Yes

No

23‐9‐2014, sent e‐mail to Galderma NL and several more to Galderma International, no reply

IRCT2014010516079N1

No

No

23‐9‐2014 [email protected], [email protected]

My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already completed or submitted for publication.
IRCT2014010516079N1 “Comparison of dapsone 5% Topical gel with metronidazole 0.75% efficacy in combination with oral doxycycline in papulopustular rosacea”. Can you tell us if IRCT2014010516079N1 is already completed? Or submitted for publication?

IRCT2014010516079N1

Yes

No

23‐9‐2014 [email protected]; [email protected]; [email protected]

My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already submitted for publication.
IRCT2014030416837N1 “Effects of permethrin 5% topical gel in comparison with placebo on Demodex density in rosacea patients: a double‐blind, randomised clinical trial”. Can you tell us if IRCT2014030416837N1 is already submitted for publication?

Reply: 23‐9‐2014

Dear Dr Zuuren

Many thanks for your query,

We are in the process of completing and submitting the article.

Regards,

Mehdi

JPRN‐UMIN000008315

Mari Wataya‐Kaneda [email protected]‐u.ac.jp not sent mail as they are still recruiting

NCT00041977

Yes

No

[email protected] 16‐7‐2014
My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion (NCT00041977 “A Multicentre, randomised, Double‐Blind, Placebo‐Controlled, Clinical Trial to Determine the Effects of Doxycycline Hyclate 20 Mg Tablets [Periostat(R)] Administered Twice Daily for the Treatment of Acne Rosacea”)

Has this study ever been published as I could not find it? If not, do you have a contact at CollaGenex Pharmaceuticals, as on the web site of clinicaltrials.gov this is not provided, but we found your name on it, also asked Galderma (Patricia van Lith)

Follow up mail to Dr Pariser 11‐8‐2014
Reply 13‐8: They sent me a study, but is not correct one, but on acne, so sent again request

NCT00249782

No

No

Allergan, results published on the Internet, as word doc and pdf we made several, but unsuccessful, attempts to contact Allergan

NCT00348335

Yes

No

[email protected], [email protected] 16‐7‐2014

My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion (NCT00348335 “Efficacy of topical cyclosporin 0.05% for the treatment of ocular rosacea”)
Has this study ever been published as I could not find it? (I do have the 2005 one)

Follow‐up mail 11‐8‐2014
Reply: 12‐8‐2014 The study was discontinued when early results showed that we did not have a reproducible method of quantifying injection. It was far too variable and did not appear to correspond at all to patients reporting symptomatic improvement.

John Wittpenn

NCT00417937

Yes

Yes

19‐7‐2014 Alan Fleischer <[email protected]>My colleagues and I are updating our Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already included in our review?
NCT00417937 “A Multicenter Trial of a Topical Medication for Papulopustular Rosacea Applied Twice Daily Versus Once Daily”. Is this the same study as published in Thiboutot DM, Fleisher AB, Del Rosso JQ, Graupe K. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. Journal of Drugs in Dermatology 2008;7(6):541‐6.? Or is it another one?

Reply 19‐7‐2014: I do believe that this is the exact same study. Sorry that my name appears in lots of clinical trials settings (Thiboutot 2008)

NCT00436527

Yes

No

19‐7‐2014, asked Galderma if it is published (Patricia van Lith), several follow‐up mails also to Maria‐Jose Rueda marie‐[email protected] last 11‐8‐2014
Follow‐up mails 14 august with several people of Galderma including Maria‐Jose Rueda and Jean Jacovella

NCT00483145

Yes

No

[email protected] 16‐7‐2014
My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion (NCT00483145 Laser‐mediated photodynamic therapy of acne vulgaris and rosacea). It has been completed in 2007.
Has this study ever been published as I could not find it?

Reply 16‐7‐2014: We were unsuccessful in recruiting rosacea patients and as thus, published a case report, which is attached. Results from treating acne patients were published as a RCT, we have removed this one from ongoing studies

NCT00495313

Yes

No

Sent 16‐7‐2014 message via LinkedIn, and Galderma (Patricia van Lith) several follow‐up mails also to Maria‐Jose Rueda marie‐[email protected] last 11‐8‐2014
Follow‐up mails 14 august with several people of Galderma including Maria‐Jose Rueda and Jean Jacovella

NCT00560703

Yes

No

16‐7‐2014, asked Galderma if it is published (Patricia van Lith) several follow‐up mails also to Maria‐Jose Rueda marie‐[email protected] last 11‐8‐2014
Follow‐up mails 14 august with several people of Galderma including Maria‐Jose Rueda and Jean Jacovella

NCT00617903

Yes

No

18‐7‐2014 clinical‐trials‐[email protected]
My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already published?
NCT00617903 “Exploration of Safety and Efficacy of AzA 15% Foam Twice a Day in Rosacea”. I found a study of Draelos published in 2013 in CUTIS, but that one included far more participants than the 84 mentioned in the NCT00617903 study.
Can you tell us if the NCT00617903 is published and if so give us a pdf of the publication?
11‐8‐2014 follow‐up mail
15‐8‐2014: Christopher Billis <[email protected]>, resent
15‐8‐2014, not published and no additional info

NCT00621218

No

No

18‐7‐2014 via website Valeant Pharmaceuticals who took over Coria Laboratories, asked if it is published

NCT00667173

No

No

18‐7‐2014 via website Valeant Pharmaceuticals who took over Dow Pharmaceutical Sciences, Inc, asked if it is published

NCT00697541

Yes

18‐7‐2014 asked Galderma if it is published (Patricia van Lith) several follow‐up mails also to Maria‐Jose Rueda marie‐[email protected] last 11‐8‐2014
Follow‐up mails 14 august with several people of Galderma including Maria‐Jose Rueda and Jean Jacovella

NCT01016782

No

No

19‐7‐2014, mail though website Sandoz. My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already published?
NCT01016782 “Study of 0444 Gel in the Treatment of Inflammatory Lesions of Rosacea)”. Can you tell us if the NCT01016782 is published and if so give us a pdf of the publication?

NCT01125930

Yes

No

19‐7‐2014, [email protected]. My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already published?
NCT01125930 “Atralin Gel for the Treatment of Rosacea”. Can you tell us if NCT01125930 is published and if so give us a pdf of the publication?
Reply 29‐7‐2014:

Dear Dr. van Zuuren, The study has not yet been published yet. When it has been accepted for publication, I can notify you. Thank you, Lisa Maier

NCT01134991

Yes

No

19‐7‐2014 [email protected]. My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already published? NCT01134991 “Study to Evaluate the Safety and Efficacy of Topical Minocycline FXFM244 in Rosacea Patients”. Can you tell us if NCT01134991 is published and if so give us a pdf of the publication?

Reply 21‐7 Dov Tamarkin, Ph.D. [email protected], study is still ongoing

NCT01186068

Yes

No

19‐7‐2014 [email protected] My colleagues and I are updating our Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already published?
NCT01186068 “A randomised, double‐blind, vehicle‐controlled, parallel‐group study of the dose‐response profile of V‐101 cream in subjects with erythematous rosacea”
Can you tell us if the NCT01186068 is published and if so give us a pdf of the publication? (By the way we will include your dose‐finding studies and phase III studies on brimonidine, and might need to contact you later about these.

Follow‐up 11‐8‐2014 [email protected]
Reply 12‐8‐2014 Dr Fowler: not published

NCT01257919

Yes

No

22‐7‐2014. Bayer sent though website, Novum, [email protected]

My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already published?

The study was supported by Bayer and Novum are listed as "locations" on clinicaltrials.gov

NCT01257919 “ Safety and Pharmacokinetics of Azelaic Acid Foam, 15% in Papulopustular Rosacea

Can you tell us if the study has been published if so could I request a pdf of the publication?

If not could we please access the data?
15‐8‐2014: Christopher Billis <[email protected]>, resent
15‐8‐2014, not published and no additional info

NCT01308619

Yes

20‐7‐2014 asked Galderma if it is published (Patricia van Lith) several follow‐up mails also to Maria‐Jose Rueda marie‐[email protected] last 11‐8‐2014
Follow‐up mails 14 august with several people of Galderma including Maria‐Jose Rueda and Jean Jacovella

NCT01398280

Yes

Yes

22‐7‐2014 Tissa Hata, MD, University of California, San Diego, [email protected]

My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already published?

NCT01398280 Effects of Aminocaproic Acid (ACA) on Rosacea‐specific Inflammation

If this has been published could I kindly ask for the citation and/or if you have a pdf available?

If it has not been published are the data available?
Follow‐up 11‐8‐2014 and 17‐8‐2014

17‐8‐2014: EvZ: This is Two 2014!!!

Reply: 18‐8‐2014: Thank you for your interest in our research. Attached is the paper which was published in the JID. Thanks! Tissa

NCT01426269

Yes

21‐7‐2014 asked Galderma if it is published (Patricia van Lith) several follow‐up mails also to Maria‐Jose Rueda marie‐[email protected] last 11‐8‐2014
Follow‐up mails 14 August with several people of Galderma including Maria‐Jose Rueda and Jean Jacovella

5‐9‐2014: [email protected]. ‎ 22‐9‐2014, received all we needed

NCT01449591

Yes

Yes

Novartis Pharmaceuticals, no contact details, sent mail through Dutch website
12‐8‐2014 reply [email protected]

U vraagt om informatie over de studie NCT01449591 (CBFH772A2203) met als compound BFH772.

De enige informatie die we nu kunnen delen over deze studie zijn gepubliceerd op ‘Novartis clinical trial database’, onder ‘Novartis Institute for Biomedical Research’, Dermatology/Skin, CBFH772 http://www.novctrd.com/ctrdWebApp/clinicaltrialrepository/public
22‐8‐2014: What was the rationale behind study, are they going to proceed with further studies? will it be published?

Reply 9‐9‐2014: BFH772 is currently under investigation and has not been approved for use other than for use as part of a clinical trial.
Therefore, at this present time, no further information can be provided other than what is publicly available at the previously indicated location (http://www.novctrd.com/ctrdWebApp/clinicaltrialrepository/public )
Whether or not results of trial NCT01449591 "Safety, Tolerability and Efficacy of BFH77s in Rosacea Patients" will be published in medical journals in the future cannot be anticipated at this stage.
Please do not hesitate to reach out to us again in six months' time to inquire about potential updates, if of interest.”

NCT01451619

Yes

No

22‐7‐2014. Merck Sharp & Dohme Corp, [email protected], [email protected], [email protected]
Reply 23‐7‐2014[email protected] I checked with our researchers and have been told that the study results have been submitted for publication and are currently under review for consideration by the Journal of Clinical Pharmacology. It is unclear at this point when the data may be available, as they are being considered by the publication

NCT01513863

Yes

No

19‐7‐2014 [email protected]. My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already published? NCT01513863 “A Therapeutic Equivalence Study of Two Metronidazole 1%Topical Gel Treatments for Patients With Rosacea (MTZG)”. Can you tell us if NCT01513863 is published and if so give us a pdf of the publication?

21‐7‐2014 reply Aimee Brown, [email protected]. "Thank you Dr. Zuuren for your inquiry, however this study has not yet been published."

NCT01555463

No

No

Bayer, mailed via website 22‐7‐2014
15‐8‐2014: Christopher Billis <[email protected]>, resent
15‐8‐2014, not published and no additional info

NCT01579084

No

No

Allergan, sent mail 22‐07‐2014 through website no response

NCT01614743

Yes

No

22‐7‐2014 Steven H. Dayan, Medical Director, DeNova Research, [email protected]

My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, could you kindly confirm the status?

It is reported on clinicaltrials.gov as This study is ongoing, but not recruiting participants

When do you expect to complete it or if it is completed ... publish the data?

Reply 22‐7‐2014. We appreciate your inquiry, and look forward to speaking with you. We are currently forwarding your message to Annie, our patient coordinator, and she will respond soon.

emailed again 29‐7 2014. reply 29‐7‐2014 of [email protected] I appreciate you reaching out to us. This study is in the process of being written up, unfortunately due to a signed confidentiality agreement, we cannot provide you with any of the data at this time

NCT01631656

Yes

Yes

Amy McMichael, Wake Forest School of Medicine

23‐7‐2014

[email protected], [email protected] (sequence generation, allocation concealment), several e‐mail exchanges, no replies to this

NCT01659853

Yes

No

20‐7‐2014 asked Galderma if it is published (Patricia van Lith), 28‐7‐2014, not yet published, but I thought already submitted so sent another mail. several follow‐up mails also to Maria‐Jose Rueda marie‐[email protected] last 11‐8‐2014
Follow‐up mails 14 August with several people of Galderma including Maria‐Jose Rueda and Jean Jacovella

NCT01735201

No

No

Allergan, results posted on clinicaltrials.gov [email protected], 23‐7‐2014

My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already published, we saw results published on clinicaltrials.gov? NCT01735201 “AGN‐199201 for the Treatment of Erythema With Rosacea”. Can you tell us if NCT01735201 is published and if so give us a pdf of the publication?

Follow‐up 11‐8‐2014 and 17‐8‐2014 no replies

NCT01740934

Yes

No

Rock Creek Pharmaceuticals, Inc. M Varga, 23‐7‐2014 [email protected]
response 1‐8‐2014: Thanks very much for your interest in our just concluded clinical trial, we are in the process of writing the clinical study report. We will make it available to you. If you have additional question, please do not hesitate to contact me.Dr Ernest Okorie,MD [email protected]

NCT01784133

No

No

Cutanea Life Sciences, Inc

23‐7‐2014, [email protected]

This study has been completed. My colleagues and I are conducting a Cochrane review (Interventions for rosacea) this study has been identified as potentially eligible for inclusion. Can you please indicate if the study has been published and if so could I request a pdf or the citation? If not are the data available?

10‐8‐2014 Resent e‐mail

NCT01828177

PreCision Dermatology, Inc.Syd Dromgoole, as study is still ongoing not sent mail

NCT01885000

Yes

Yes

21‐7‐2014 asked Galderma if it is published (Patricia van Lith) several follow‐up mails also to Maria‐Jose Rueda marie‐[email protected] last 11‐8‐2014
Follow‐up mails 14 august with several people of Galderma including Maria‐Jose Rueda and Jean Jacovella

19‐8‐2014 received poster abstracts Layton 2014

NCT01917539

Angela Chang, University of Miami [email protected] or Bradford Lee [email protected]

Still recruiting patients at the moment, not sent mail

NCT01933464

Anna Di Nardo, MD, PhD, University of California, San Diego. As study is still recruiting not sent mail

NCT01993446

No

No

Dermira, Inc. Beth Zib, [email protected] 23‐7‐2014

Follow‐up 11‐8‐2014 no replies

NCT02036229

Rina Segal, Rabin Medical Center, [email protected] not sent mail as not yet open to recruitment

NCT02052999

No

No

Amorepacific Corporation BeomJoon Kim, Professor Department of Dermatology, Chungang University Hospital, sent mail through website 23‐7‐2014

My colleagues and I are conducting a Cochrane review (Interventions for rosacea) and one of your studies have been identified as potentially eligible for inclusion, but not sure if it is already published?
NCT02052999 “Study to evaluate the efficacy and safety of PAC‐14028 cream in rosacea patients”. Can you tell us if NCT02052999 is published and if so give us a pdf of the publication? Study is performed by BeomJoon Kim

NCT02075671

George Washington University, Jack Short, [email protected] as they are still recruiting, not sent mail

NCT02120924

Actavis Inc. John Capicchioni Akesis, LLC As they are still recruiting, not sent mail

NCT02132117

No

No

Allergan [email protected] seems the same as NCT02131636 which I did NOT add?

NCT02131636 Efficacy and Safety of AGN‐199201 in Patients With Persistent Erythema Associated With Rosacea

NCT02132117 Safety and Efficacy of AGN‐199201 in Patients With Persistent Erythema Associated With Rosacea

Also NCT02095158 Longterm and efficacy and safety
[email protected] sent several mails, to ask if these are same studies, no replies

NCT02144181

Evaluation of the Safety and Efficacy of the Ulthera® System for the Treatment of Signs and Symptoms of Erythematotelangiectatic Rosacea

No

No

Ulthera, Inc. Mark Lupin, MD is LUPIN 2014 part of this? As they are still recruiting, not sent mail

e‐mail sent 29‐7‐2014 to confirm, [email protected]

Dear Colleagues

I have received no further response could you please confirm with Dr Lupin?There appears to be a poster in JAAD 2014 vol17 Iss 5 referring to this trial? NCT01756027

Evaluation of the safety and effectiveness of microfocused ultrasound with visualization (MFU‐V) for the treatment of erythematotelangiectatic rosacea Mark Lupin, MD, The Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada
I also have this trial NCT02144181 which appears to be still recruiting and the contact person is Dr Mark Lupin
Resent 22‐8‐2014 no replies

NCT02147691

Leon Kircik, M.D., Derm Research, PLLC [email protected] As they are still recruiting, not sent mail

NCT02204254

Florence Le Duff, leduff.f2@chu‐nice.fr, not sent e‐mail as they are still recruiting

RCT = randomised controlled trial
CCT = controlled clinical trial (quasi‐randomised)

Figures and Tables -
Table 3. Investigators contacted
Table 5. Checklist for describing and assessing patient‐reported outcomes (PROs) in clinical trials

1. What were PROs measuring?
a. What concepts were the PROs used in the study measuring?
b. What rationale (if any) for selection of concepts or constructs did the authors provide?
c. Were patients involved in the selection of outcomes measured by the PROs?

2. Omissions
a. Were there any important aspects of health (e.g. symptoms, function, perceptions) or quality of life (e.g. overall evaluation, satisfaction with life) that were omitted in this study from the perspectives of the patient, clinician, significant others, payers, or other administrators and decision‐makers?

3. If randomised trials and other studies measured PROs, what were the instruments' measurement strategies?
a. Did investigators use instruments that yield a single indicator or index number, a profile, or a battery of instruments?
b. If investigators measure PROs, did they use specific or generic measures, or both?

c. Who exactly completed the instruments?

4. Did the instruments work in the way they were supposed to work ‐ validity?
a. Had the instruments used been validated previously (provide reference)? Was evidence of prior validation for use in this population presented?
b. Were the instruments re‐validated in this study?

5. Did the instruments work in the way they were supposed to work ‐ ability to measure change?
a. Are the PROs able to detect change in patient status, even if those changes are small?

6. Can you make the magnitude of effect (if any) understandable to readers?
a. Can you provide an estimate of the difference in patients achieving a threshold of function or improvement, and the associated number needed to treat (NNT)?

Table 17.6.a

Patrick D, Guyatt GH, Acquadro C. Chapter 17: Patient‐reported outcomes. In: Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. The Cochrane Collaboration, 2009.

Figures and Tables -
Table 5. Checklist for describing and assessing patient‐reported outcomes (PROs) in clinical trials
Table 6. Included studies with no usable or irretrievable data

Study ID

Interventions and comparisons

N

Comments

Benkali 2014

Four different concentrations brimonidine tartrate gel

102

None of our outcomes were addressed

Blom 1984

Sulphur 10% cream versus lymecycline

40

Unclear how many were randomised to each group, minimal reporting of outcomes. Participants who failed to respond or got worse were switched to the alternative treatment, unclear who and how many

Buendia‐Bordera 2013

PDL + post‐laser serum versus PDL + placebo gel

31

Poster, very limited data reported, not able to contact PI

Draelos 2006

Azelaic acid 15% gel + habitual self‐selected skin cleanser and moisturizer versus

azelaic acid 15% gel + standardised PHA (polyhydroxy acid) containing cleanser, and anti‐aging moisturizer

67

None of our primary outcomes were addressed combined with that it was unclear how many participants were randomised to each intervention. Because very limited outcomes data were reported no reliable conclusions could be drawn

Draelos 2009

Facial foundation with niacinamide and N‐acetylglucosamine, cleanser and moisturizer versus marketed foundation + cleanser and moisturizer

146

Poster, lot of data missing, PI did not reply to e‐mail. Also included patients with sensitive skin, no separate data reported for participants with rosacea

Draelos 2013b

Gentle foaming cleanser containing hydrophobically modified polymers versus commercial gentle liquid non‐foaming facial cleanser

40

Participants with other skin diseases (atopic dermatitis, eczema, acne) were included and no separate data reported for participants with rosacea

Ertl 1994

Isotretinoin + topical tretinoin versus topical tretinoin versus isotretinoin

22

Data unreliable, its re‐analysis using the individual participant data confirmed its flawed analysis by the investigators

Espagne 1993

Metronidazole gel versus placebo gel

51

Allocation to intervention was based on up to four participants in each of 18 clinics but not all clinics enrolled four participants. The report did not provide any reassurance that the allocation sequence was adequately generated and no evidence that any form of central randomisation had been employed for the 18 clinics involved in this study

Fabi 2011

IPL + azelaic acid versus IPL

20

Poster, very limited data reported, PI failed to respond to several e‐mails

Guillet 1999

Metronidazole 75% gel versus metronidazole 0.75% lotion

114

Poster, very limited data reported, old study, not able to contact PI

Huang 2014

Doxycycline 40 mg versus placebo

170

Poster abstract, limited data, unclear how many were randomised to each group, PI failed to respond to several e‐mails

Jorizzo 1998

Metronidazole versus placebo

277

Unclear how many participants were initially recruited. Unclear how many participants started in each group, no SDs, dropout rate unclear. Data seem very skewed

Lupin 2014

MFU‐V one treatment versus MFU‐V two treatments

12

Poster abstract, limited data, unclear how many were randomised to each group, PI failed to respond to several e‐mails

NCT00249782

Dapsone 5% gel QD vs dapsone 5% BID, versus metronidazole gel versus dapsone + metronidazole gel versus vehicle

400

Unclear how many were randomised to each group, Allergan failed to respond to several e‐mails requesting further data

Rehmus 2006

Antiinflammatory cream versus placebo

40

Poster, no results provided, very limited data reported

Thiboutot 2005

Doxycycline versus placebo

134

Poster, lot of data are missing, PI did not reply to e‐mail

Utaş 1997

Ketoconazole oral versus ketoconazole cream versus ketoconazole oral + cream versus placebo cream versus placebo pills

53

Letter, limited and no exact data

Van Landuyt 1997

Clonidine versus placebo

60

Interim report only on first 30 participants, incomplete and very limited data

Wilkin 1989

Nadolol versus placebo, four arms, crossover, 3 periods

15

Small groups, unclear what dropout rate was. No separate data for period A

Wilkin 1993

Topical clindamycin versus tetracycline

43

Unclear how many participants were assigned to each group, dropouts not mentioned, no exact data provided

Wittpenn 2005

Topical ciclosporin A versus artificial tears

20

Unclear how many randomised to each group, poster with very limited data see also Table 3

Yoo 2011

PDL + calcium dobesilate versus PDL

6

Poster, with incomplete and missing data

Figures and Tables -
Table 6. Included studies with no usable or irretrievable data
Comparison 1. Topical metronidazole versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse events Show forest plot

6

1773

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.94, 1.51]

2 Physician's global evaluation of improvement Show forest plot

3

334

Risk Ratio (M‐H, Random, 95% CI)

1.98 [1.29, 3.02]

3 Incomplete data on which further analysis is not possible Show forest plot

Other data

No numeric data

Figures and Tables -
Comparison 1. Topical metronidazole versus placebo
Comparison 2. Topical azelaic acid versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Participant‐assessed improvement of rosacea Show forest plot

4

1179

Risk Ratio (M‐H, Random, 95% CI)

1.46 [1.30, 1.63]

2 Physician's global evaluation of improvement Show forest plot

4

1179

Risk Ratio (M‐H, Random, 95% CI)

1.32 [1.18, 1.47]

3 Incomplete data on which further analysis is not possible Show forest plot

Other data

No numeric data

Figures and Tables -
Comparison 2. Topical azelaic acid versus placebo