ECM compared with NECT plus cimetidine for cystic fibrosis

Patient or population: adults with cystic fibrosis

Settings: outpatients

Intervention: ECM (Creon®) with food

Comparison: NECT (Pancrex V) with food and adjuvant cimetidine 40 minutes before meals

Change in weight (kg)

Follow‐up: 1 month

MD 0.40 (‐0.10 to 0.90)

12
(1)

⊕⊝⊝⊝
very low^a,b

The overall difference was not significant (P = 0.12), although the results favour ECM.

This is a cross‐over trial but the results have been analysed as a parallel trial (Stead 1987).

Change in height

Change in BMI

Frequency in bowel symptoms: abdominal pain (% of days affected)

Follow‐up: 1 month

MD ‐10.50 (‐21.40 to 0.40)

12
(1)

⊕⊝⊝⊝
very low^b,c

P = 0.06

The trial also reported on stool frequency and the analysis showed that stool frequency was less in the ECM group (MD ‐0.70 (95% CI 0.90 to ‐0.50) P = 0.00001), but caution should be taken due to the risk of bias within the trial (particularly from blinding) and very small sample size.

CFA: change in FFE (g/day)

Follow‐up: 1 month

MD ‐6.70 (‐14.70 to 1.30)

12
(1)

⊕⊕⊝⊝
low^b,d

Adverse events

Pulmonary exacerbations

*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).
BMI: body mass index; CFA: co‐efficient of fat absorption; CI: confidence interval; ECM: enteric‐coated microspheres; FFE: fecal fat excretion; MD: mean difference; NECT: non‐enteric‐coated tablets.

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.

ECM compared with ECT for cystic fibrosis

Patient or population: children and adults with cystic fibrosis

Settings: outpatients

Intervention: ECM (Creon®) with food

Comparison: ECT with food (Pancrex V Forte (Stead 1986); not stated (Vyas 1990))

Change in weight (kg)

Follow‐up: 1 month

MD 0.32 (‐0.03 to 0.67)

41
(2)

⊕⊝⊝⊝
very low^a,b

The results favour ECM but this was not statistically significant (P = 0.07). Both trials included in this outcome were cross‐over trials that were analysed as parallel trials.

Change in height

Change in BMI

Frequency of bowel symptoms:

abdominal pain (% of days affected)

Follow‐up: 1 month

MD ‐7.96 (‐12.97 to ‐2.94)

41
(2)

⊕⊝⊝⊝
very low^a,b

P = 0.002

Stool frequency (number/day) was also reported by the same two trials and was found to be significantly lower for the ECM group than the ECT group, MD ‐0.58 (95% CI ‐0.85 to ‐0.30), P = 0.0001 (Stead 1986; Vyas 1990).

CFA: change in FFE (g/day)

Follow‐up: 1 month

MD ‐11.79 (‐17.42 to ‐6.15)

41
(2)

⊕⊕⊝⊝
low^b,c

The results should be viewed with caution as both trials were cross‐over trials which were analysed as parallel trials.

Adverse events

Pulmonary exacerbations

*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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
BMI: body mass index; CFA: co‐efficient of fat absorption; CI: confidence interval; ECM: enteric‐coated microspheres; ECT: enteric‐coated tablets; FFE: fecal fat excretion; MD: mean difference.

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.

ECM compared with ECMM for cystic fibrosis

Patient or population: children with cystic fibrosis and proven pancreatic insufficiency

Settings: hospital patients in 3 centres

Intervention: ECM (Creon 8000 MS®)

Comparison: ECMM (Creon 10000 MMS®)

Change in weight

Change in height

Change in BMI

Frequency of bowel symptoms

Follow‐up: 1 month

N/A

54
(1)

⊕⊝⊝⊝
very low^a,b,c

No data were provided and results were reported narratively in the paper.

CFA: change in FFE (g/day)

Follow‐up: 1 month

MD ‐1.70 (‐6.57 to 3.17)

22
(1)

⊕⊝⊝⊝
very low^b,c,d

P = 0.49

Adverse events

Pulmonary exacerbations

*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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
BMI: body mass index; CFA: co‐efficient of fat absorption; CI: confidence interval; ECM: enteric‐coated microspheres; ECMM: enteric‐coated mini‐microspheres; FFE: fecal fat excretion; MD: mean difference.

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.

ECM (Creon®) compared with another ECM for cystic fibrosis

Patient or population: children and adults with cystic fibrosis

Settings: outpatients

Intervention: ECM (Creon®)

Comparison: a different ECM (Pancrease® (Elliott 1992; Williams 1990), Nutrizyme® (Lacy 1992), Zenpep® (Taylor 2015)

Change in weight (kg)

Follow‐up: 1 month

MD 0 (‐0.28 to 0.28)

83
(1)

⊕⊕⊕⊝
moderate^a

P = 1.0

The control preparation in this trial was Zenpep® (Taylor 2015).

3 further trials measured this outcome, but did not provide data for analysis.The 3 trials all reported no statistically significant change in weight (Elliott 1992; Lacy 1992; Williams 1990).

Change in height

Change in BMI

Frequency of bowel symptoms: proportion of days with abdominal pain

Follow‐up: 1 month

MD 0 (‐0.06 to 0.06)

83
(1)

⊕⊕⊝⊝
low^a,b

P = 1.0

Only 1 trial provided data for analysis (Taylor 2015). A further 2 trials reported no significant difference in the proportion of days with abdominal pain although didn't provide data for analysis (Elliott 1992; Williams 1990)

The same 3 trials reported on stool frequency, but showed no statistically significant difference between groups. Only 1 trial provided data for analysis, MD 0 (95% CI ‐0.28 to 0.28) P = 1.0 (Taylor 2015).

Flatulence was measured in one trial (Taylor 2015) but no significant difference was found between groups MD 0 (‐0.12 to 0.12) P = 1.0

CFA: CFA (%)

Follow‐up: 1 month

MD 1.35 (‐1.43 to 4.13)

110
(2)

⊕⊕⊕⊝
moderate^a

A further trial comparing 2 preparations of ECM (Elliott 1992) and another comparing 3 preparations of ECM (Lacy 1992) found no significant difference for this outcome (no data available for analysis).

Adverse events

Follow‐up: 1 month

NA

1
(83)

⊕⊕⊝⊝
low^a,b

Pulmonary exacerbations

*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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
BMI: body mass index; CFA: co‐efficient of fat absorption; CI: confidence interval; ECM: enteric‐coated microspheres; MD: mean difference.

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.

ECM compared with TPE for cystic fibrosis

Patient or population: children with cystic fibrosis

Settings: home setting

Intervention: ECM (Creon®) (1.2 ‐ 2.4 g/day)

Comparison: lyophilized TPE (4 ‐ 8 g/day)

Change in weight (kg)

Follow‐up: 1 month

N/A

17
(1)

⊕⊝⊝⊝
very low^a,b,c

No data available for analysis (Vidailhet 1987).

Change in height

Change in BMI

Frequency of bowel symptoms

CFA: change in FFE (g/day)

Follow‐up: 1 month

MD ‐1.60 (‐3.31 to 0.11)

17
(1)

⊕⊝⊝⊝
very low^a,b,c

P = 0.07 (Vidailhet 1987)

Adverse events

Pulmonary exacerbations

*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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
BMI: body mass index; CFA: co‐efficient of fat absorption; CI: confidence interval; ECM: enteric‐coated microspheres; FFE: fecal fat excretion; MD: mean difference; TPE: total pancreatic extracts.

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.

ECM compared with other enteric‐coated preparations for cystic fibrosis

Patient or population: children with cystic fibrosis

Settings: outpatients

Intervention: ECM Creon®

Comparison: another enteric‐coated preparation (Pancreon forte (conventional) (Henker 1987); Pancrex V® (Petersen 1984))

Change in weight (kg)

Follow‐up: 1 month

N/A

56
(2)

⊕⊝⊝⊝
very low^a,b,c

No data were available for analysis and so results have been reported narratively from the 2 papers (Henker 1987); Petersen 1984).

Change in height

Follow‐up: 1 month

.N/A

45
(1)

⊕⊝⊝⊝
very low^a,b,c

No data were available for analysis and so results have been reported narratively from the paper (Henker 1987).

Change in BMI

Follow‐up: 1 month

1 trial measured the height and weight of participants, but did not report BMI and we were unable to calculate BMI ourselves since investigators did not report the actual data (Henker 1987).

Frequency of bowel symptoms: stool frequency

Follow‐up: 1 month

N / A

56
(2)

⊕⊝⊝⊝
very low^a,b,c

No data were available for analysis and so results have been reported narratively from the papers (Henker 1987; Petersen 1984).

CFA: fat absorption

Follow‐up: 1 month

N / A

56
(2)

⊕⊝⊝⊝
very low^a,b,c

No data were available for analysis and so results have been reported narratively from the papers (Henker 1987; Petersen 1984).

Adverse events

Pulmonary exacerbations

*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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
BMI: body mass index; CFA: co‐efficient of fat absorption; CI: confidence interval; ECM: enteric‐coated microspheres; FFE: fecal fat excretion.

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.

Low‐dose compared with high‐dose PERT for cystic fibrosis

Patient or population: children and adults with cystic fibrosis

Settings: home setting

Intervention: high‐dose PERT (Nutrizyme 22 (22,000 BP units of lipase) (Assoufi 1994); Altu‐135 25,000 units of lipase; Altu‐135 100,000 units of lipase Borowitz 2005))

Comparison: low‐dose PERT (Nutrizyme GR (10,000 BP units of lipase) (Assoufi 1994); Altu‐135 5000 units of lipase (Borowitz 2005))

Change in weight (kg)

N/A

17
(1)

⊕⊝⊝⊝
very low^a,b,c

No data available for analysis so results have been presented narratively (Assoufi 1994).

Change in height

Change in BMI

Frequency of bowel symptoms: stool frequency

Follow‐up: 1 month

N/A

17
(1)

⊕⊝⊝⊝
very low^a,b,c

No data available for analysis so results have been presented narratively (Assoufi 1994).

A further trial looking at ALTU‐135 reported there was a single episode of DIOS requiring hospitalisation in 1 participant in the low‐dose group (Borowitz 2005).

CFA: FFE (g/day)

Follow‐up: 1 month

N/A

17
(1)

⊕⊝⊝⊝
very low^a,b,c

No data available for analysis so results have been presented narratively (Assoufi 1994).

A further trial reported this outcome but only at 14 days which does not fit our inclusion criteria (Borowitz 2005).

Adverse events

N/A

146
(2)

⊕⊝⊝⊝
very low^a,c,d

Pulmonary exacerbations

1 trial reported pulmonary exacerbations, but the distribution of events across the groups was not reported (Borowitz 2005).

*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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
BMI: body mass index; CFA: co‐efficient of fat absorption; CI: confidence interval; FFE: fecal fat excretion; PERT: pancreatic enzyme therapy.

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.

Liprotamase compared with porcine PERT for cystic fibrosis

Patient or population: children aged 7 years or over and adults with cystic fibrosis

Settings: outpatients

Intervention: liprotamase (oral, soluble, non‐enterically‐coated, non‐porcine PERT)

Comparison: porcine PERT (oral, enterically‐coated PERT prepared from a porcine source)

Change in weight (kg)

Follow‐up: 7 weeks

N/A

128
(1)

⊕⊕⊝⊝
low^a

Mean body weight was reported at baseline and after 7 weeks in both groups, but no SDs were given (Konstan 2018a).

Change in height

Follow‐up: 7 weeks

Although height was measured at 7 weeks, no results were reported only the statement that height was stable through the trial period for both treatment arms.

Change in BMI

Follow‐up: 7 weeks

Although BMI was measured at 7 weeks, no results were reported only the statement that BMI was stable through the extension period for both treatment arms..

Frequency of bowel symptoms: abdominal pain

Follow‐up: 7 weeks

128
(1)

⊕⊕⊝⊝
low^a

No data were provided for inclusion in the analysis (Konstan 2018a).

CFA: change from baseline (%)

Follow‐up: 7 weeks

128
(1)

⊕⊕⊝⊝
low^a

The Konstan trial reported a significant decrease in CFA from baseline at seven weeks in the lipromatase group compared to the pancrelipase group, MD (SE) ‐11.85 (2.12). This trial was a non‐inferiority trial and the investigators stated that lipromatase missed the non‐inferiority criterion.

Adverse events

Follow‐up: 7 weeks

128
(1)

⊕⊕⊝⊝
low^a

No data were provided and so results are reported narratively.

Pulmonary exacerbations: number of exacerbations

Follow‐up: 7 weeks

OR 0.56 (0.13 to 2.45)

128
(1)

⊕⊕⊝⊝
low^a

No significant difference was observed between groups, P = 0.44

.*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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
BMI: body mass index; CFA: co‐efficient of fat absorption; CI: confidence interval; FFE: fecal fat excretion; MD: mean difference; OR: odds ratio; PERT: pancreatic enzyme therapy; SD: standard deviation.

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.