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Study flow diagram.
Figuras y tablas -
Figure 1

Study flow diagram.

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Risk of bias summary: reviewers' judgements about each risk of bias item for each included study.
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Figure 2

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

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Comparison 1 Briakinumab versus placebo, Outcome 1 Failure to induce clinical remission (7 & 9 weeks).
Figuras y tablas -
Analysis 1.1

Comparison 1 Briakinumab versus placebo, Outcome 1 Failure to induce clinical remission (7 & 9 weeks).

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Comparison 1 Briakinumab versus placebo, Outcome 2 Failure to Induce clinical remission (6 weeks).
Figuras y tablas -
Analysis 1.2

Comparison 1 Briakinumab versus placebo, Outcome 2 Failure to Induce clinical remission (6 weeks).

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Comparison 1 Briakinumab versus placebo, Outcome 3 Failure to induce clinical response (>= 100 points; 7 & 9 weeks).
Figuras y tablas -
Analysis 1.3

Comparison 1 Briakinumab versus placebo, Outcome 3 Failure to induce clinical response (>= 100 points; 7 & 9 weeks).

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Comparison 1 Briakinumab versus placebo, Outcome 4 Failure to induce clinical response (>= 100 points; 6 weeks).
Figuras y tablas -
Analysis 1.4

Comparison 1 Briakinumab versus placebo, Outcome 4 Failure to induce clinical response (>= 100 points; 6 weeks).

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Comparison 1 Briakinumab versus placebo, Outcome 5 Adverse events.
Figuras y tablas -
Analysis 1.5

Comparison 1 Briakinumab versus placebo, Outcome 5 Adverse events.

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Comparison 1 Briakinumab versus placebo, Outcome 6 Serious adverse events.
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Analysis 1.6

Comparison 1 Briakinumab versus placebo, Outcome 6 Serious adverse events.

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Comparison 1 Briakinumab versus placebo, Outcome 7 Withdrawals because of adverse events.
Figuras y tablas -
Analysis 1.7

Comparison 1 Briakinumab versus placebo, Outcome 7 Withdrawals because of adverse events.

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Comparison 2 Ustekinumab versus placebo, Outcome 1 Failure to induce clinical remission (6 weeks).
Figuras y tablas -
Analysis 2.1

Comparison 2 Ustekinumab versus placebo, Outcome 1 Failure to induce clinical remission (6 weeks).

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Comparison 2 Ustekinumab versus placebo, Outcome 2 Failure to induce clinical remission (6 weeks; sensitivity analysis).
Figuras y tablas -
Analysis 2.2

Comparison 2 Ustekinumab versus placebo, Outcome 2 Failure to induce clinical remission (6 weeks; sensitivity analysis).

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Comparison 2 Ustekinumab versus placebo, Outcome 3 Failure to induce clinical response (>= 70 points; 6 weeks).
Figuras y tablas -
Analysis 2.3

Comparison 2 Ustekinumab versus placebo, Outcome 3 Failure to induce clinical response (>= 70 points; 6 weeks).

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Comparison 2 Ustekinumab versus placebo, Outcome 4 Failure to induce clinical response (>= 70 points; 6 weeks; sensitivity analysis).
Figuras y tablas -
Analysis 2.4

Comparison 2 Ustekinumab versus placebo, Outcome 4 Failure to induce clinical response (>= 70 points; 6 weeks; sensitivity analysis).

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Comparison 2 Ustekinumab versus placebo, Outcome 5 Failure to Induce clinical response (>=100 points; 6 weeks).
Figuras y tablas -
Analysis 2.5

Comparison 2 Ustekinumab versus placebo, Outcome 5 Failure to Induce clinical response (>=100 points; 6 weeks).

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Comparison 2 Ustekinumab versus placebo, Outcome 6 Failure to Induce clinical response (>=100 points; 6 weeks; sensitivity analysis).
Figuras y tablas -
Analysis 2.6

Comparison 2 Ustekinumab versus placebo, Outcome 6 Failure to Induce clinical response (>=100 points; 6 weeks; sensitivity analysis).

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Comparison 2 Ustekinumab versus placebo, Outcome 7 Failure to induce clinical remission ‐ 90 mg, s.c. (6 weeks).
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Analysis 2.7

Comparison 2 Ustekinumab versus placebo, Outcome 7 Failure to induce clinical remission ‐ 90 mg, s.c. (6 weeks).

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Comparison 2 Ustekinumab versus placebo, Outcome 8 Failure to induce clinical response 90 mg s.c. (>= 70 points; 6 weeks).
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Analysis 2.8

Comparison 2 Ustekinumab versus placebo, Outcome 8 Failure to induce clinical response 90 mg s.c. (>= 70 points; 6 weeks).

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Comparison 2 Ustekinumab versus placebo, Outcome 9 Failure to induce clinical response 90 mg s.c. (>=100 points; 6 weeks).
Figuras y tablas -
Analysis 2.9

Comparison 2 Ustekinumab versus placebo, Outcome 9 Failure to induce clinical response 90 mg s.c. (>=100 points; 6 weeks).

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Comparison 2 Ustekinumab versus placebo, Outcome 10 Adverse events.
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Analysis 2.10

Comparison 2 Ustekinumab versus placebo, Outcome 10 Adverse events.

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Comparison 2 Ustekinumab versus placebo, Outcome 11 Serious adverse events.
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Analysis 2.11

Comparison 2 Ustekinumab versus placebo, Outcome 11 Serious adverse events.

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Comparison 2 Ustekinumab versus placebo, Outcome 12 Withdrawals because of adverse events.
Figuras y tablas -
Analysis 2.12

Comparison 2 Ustekinumab versus placebo, Outcome 12 Withdrawals because of adverse events.

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Summary of findings for the main comparison. Briakinumab compared to placebo for induction of remission in Crohn's disease

Briakinumab compared to placebo for induction of remission in Crohn's disease

Patient or population: induction of remission in Crohn's disease
Settings:
Intervention: Briakinumab
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

Briakinumab

Failure to induce clinical remission

(Mannon 2004)
CDAI (≤150 points)
Follow‐up: 9 weeks

812 per 10001

699 per 1000
(528 to 926)

RR 0.86
(0.65 to 1.14)

79
(1 study)

⊕⊕⊝⊝
low2,3

Failure to induce clinical remission

(Panaccione 2010)
CDAI (≤150 points)
Follow‐up: 6 weeks

913 per 10001

840 per 1000

(758 to 940)

RR 0.92

(0.83 to 1.03)

230

(1 study)

⊕⊕⊝⊝
low3,4

Failure to induce clinical response
(Mannon 2004)

CDAI ‐ (≥100 point reduction)
Follow‐up: 9 weeks

688 per 10001

447 per 1000
(289 to 681)

RR 0.65
(0.42 to 0.99)

79
(1 study)

⊕⊕⊝⊝
low5

Failure to induce clinical response
(Panaccione 2010)

CDAI ‐ (≥100 point reduction)
Follow‐up: 6 weeks

783 per 10001

642 per 1000

(525 to 775)

RR 0.82

(0.67 to 0.99)

230

(1 study)

⊕⊕⊕⊝
moderate6

Adverse events

(Panaccione 2010)

Follow‐up: 12 weeks

783 per 10001

705 per 1000

(587 to 838)

RR 0.90

(0.75 to 1.07)

230

(1 study)

⊕⊕⊕⊝
moderate7

Serious adverse events

(Panaccione 2010)
Follow‐up: 12 weeks

87 per 10001

45 per 1000
(15 to 140)

RR 0.52
(0.17 to 1.61)

246
(1 study)

⊕⊕⊝⊝
low8

Withdrawals due to adverse event**

(Pannaccione 2010)
Follow‐up: 12 weeks

44 per 10001

30 per 1000
(6 to 146)

RR 0.69
(0.14 to 3.31)

246
(1 study)

⊕⊕⊝⊝
low9

*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).

**Subject numbers are higher than those reported for the efficacy analyses of the individual studies due to the 200 mg, i.v. experimental group discontinuing enrolment during the induction phase due to poor patient enrolment (Panaccione, 2010). These patients were not included in the efficacy analyses, but were included in the safety analyses.
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 Control group risk estimates come from control arm of meta‐analysis, based on included trials
2 Downgraded one level due to sparse data (57 events)
3 Downgraded on level because the 95% CI around the effect estimate includes both benefit and no effect
4 Downgraded one level due to sparse data (196 events)
5 Downgraded two levels due to very sparse data (39 events)
6 Downgraded one level due to sparse data (153 events)
7 Downgraded one level due to sparse data (177 events)
8 Downgraded two levels due to very sparse data (13 events)
9 Downgraded two levels due to very sparse data (8 events)

Figuras y tablas -
Summary of findings for the main comparison. Briakinumab compared to placebo for induction of remission in Crohn's disease
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Summary of findings 2. Ustekinumab compared to placebo for induction of remission in Crohn's disease

Ustekinumab compared to placebo for induction of remission in Crohn's disease

Patient or population: patients with induction of remission in Crohn's disease
Settings:
Intervention: Ustekinumab
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

Ustekinumab

Failure to induce clinical remission
CDAI (≤ 150)
Follow‐up: 6 weeks

904 per 10001

832 per 1000
(795 to 868)

RR 0.92
(0.88 to 0.96)

1320
(3 studies)

⊕⊕⊕⊕
high

Sensitivity analysis excluding UNITI‐2 trial. These patients had more severe disease at study entry

Failure to induce clinical remission (6 mg/kg subgroup)
CDAI (≤ 150)
Follow‐up: 6 weeks

907 per 10001

835 per 1000
(789 to 880)

RR 0.92
(0.87 to 0.97)

916
(2 studies)

⊕⊕⊕⊝
moderate2

Failure to induce clinical response
CDAI (≥100 point reduction)
Follow‐up: 6 weeks

783 per 10001

642 per 1000
(603 to 689)

RR 0.82
(0.77 to 0.88)

1320
(3 studies)

⊕⊕⊕⊕
high

Sensitivity analysis excluding UNITI‐2 trial. These patients had more severe disease at study entry

Failure to induce clinical response (6 mg/kg subgroup)
CDAI (≥100 point reduction)
Follow‐up: 6 weeks

780 per 10001

647 per 1000
(601 to 710)

RR 0.83
(0.77 to 0.91)

916
(2 studies)

⊕⊕⊕⊕
high

Adverse events

Follow‐up: 8 weeks

639 per 10001

620 per 1000
(575 to 664)

RR 0.97
(0.9 to 1.04)

2023
(4 studies)

⊕⊕⊕⊕
high

Serious adverse events
Follow‐up: 8 weeks

64 per 10001

53 per 1000
(37 to 77)

RR 0.83
(0.58 to 1.2)

2023
(4 studies)

⊕⊕⊕⊝
moderate3

Withdrawals due to adverse event
Follow‐up: 8 weeks

54 per 10001

24 per 1000
(10 to 57)

RR 0.44
(0.18 to 1.05)

657
(2 studies)

⊕⊕⊝⊝
low4

*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).

**Subject numbers are higher than those reported for the efficacy analyses of the individual studies due to the omission of efficacy results for subjects receiving subcutaneous placebo and 90 mg ustekinumab, as well as subjects receiving 90mg s.c. and 4.5 mg/kg of ustekinumab in the open‐label arm of the study by Sandborn (2008). The results of these subjects were included in the safety analyses.
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 Control group risk estimates come from control arm of meta‐analysis, based on included trials
2 Downgraded one level due to heterogeneity detected for 6 mg/kg subgroup (I2 = 39%)
3 Downgraded one level due to sparse data (116 events)
4 Downgraded two levels due to very sparse data (20 events)

Figuras y tablas -
Summary of findings 2. Ustekinumab compared to placebo for induction of remission in Crohn's disease
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Table 1. Sensitivity Analysis: Fixed Effects vs. Random Effects Modelling

Outcome

Fixed Effects Modelling

Random Effects Modelling

Briakinumab /Remission (Mannon 2004)

RR 0.86 [0.65, 1.14]

RR 0.88 [0.68, 1.15]

Briakinumab /Remission (Panaccione 2015)

RR 1.05 [0.90, 1.22]

RR 0.92 [0.83, 1.03]

Ustekinumab /Remission

RR 0.94 [0.88, 1.01]

RR 0.95 [0.89, 1.02]

Briakinumab /Response (Mannon 2004)

RR 0.65 [0.42, 0.99]

RR 0.66 [0.44, 1.01]

Briakinumab /Response (Panaccione 2015)

RR 0.82 [0,67, 0.99]

RR 0.81 [0.67, 0.99]

Ustekinumab /Response

RR 0.79 [0.71, 0.89]

RR 0.80 [0.72, 0.90]
Figuras y tablas -
Table 1. Sensitivity Analysis: Fixed Effects vs. Random Effects Modelling
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Comparison 1. Briakinumab versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Failure to induce clinical remission (7 & 9 weeks) Show forest plot

1

79

Risk Ratio (M‐H, Fixed, 95% CI)

0.86 [0.65, 1.14]

1.1 1 mg/kg body weight each week

1

39

Risk Ratio (M‐H, Fixed, 95% CI)

0.92 [0.67, 1.26]

1.2 3 mg/kg body weight each week

1

40

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.48, 1.30]

2 Failure to Induce clinical remission (6 weeks) Show forest plot

1

230

Risk Ratio (M‐H, Fixed, 95% CI)

0.92 [0.83, 1.03]

2.1 IV Infusion of 400 mg

1

68

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.80, 1.13]

2.2 IV Infusion of 700 mg

1

162

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.78, 1.05]

3 Failure to induce clinical response (>= 100 points; 7 & 9 weeks) Show forest plot

1

79

Risk Ratio (M‐H, Fixed, 95% CI)

0.65 [0.42, 0.99]

3.1 1 mg/kg body weight each week

1

39

Risk Ratio (M‐H, Fixed, 95% CI)

0.73 [0.44, 1.22]

3.2 3 mg/kg body weight each week

1

40

Risk Ratio (M‐H, Fixed, 95% CI)

0.55 [0.27, 1.13]

4 Failure to induce clinical response (>= 100 points; 6 weeks) Show forest plot

1

230

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.67, 0.99]

4.1 400 mg iv of briakinumab

1

68

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.61, 1.12]

4.2 700 mg iv of briakinumab

1

162

Risk Ratio (M‐H, Fixed, 95% CI)

0.81 [0.63, 1.04]

5 Adverse events Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

6 Serious adverse events Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

7 Withdrawals because of adverse events Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected
Figuras y tablas -
Comparison 1. Briakinumab versus placebo
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Comparison 2. Ustekinumab versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Failure to induce clinical remission (6 weeks) Show forest plot

4

1947

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.86, 0.95]

1.1 1.0 mg/kg IV

1

175

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.82, 1.04]

1.2 3.0 mg/kg IV

1

176

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.83, 1.08]

1.3 4.5 mg/kg IV

1

53

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.67, 1.11]

1.4 6.0 mg/kg IV

3

1543

Risk Ratio (M‐H, Random, 95% CI)

0.90 [0.82, 0.98]

2 Failure to induce clinical remission (6 weeks; sensitivity analysis) Show forest plot

3

1320

Risk Ratio (M‐H, Fixed, 95% CI)

0.92 [0.88, 0.96]

2.1 1.0 mg/kg IV

1

175

Risk Ratio (M‐H, Fixed, 95% CI)

0.92 [0.82, 1.04]

2.2 3.0 mg/kg IV

1

176

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.83, 1.08]

2.3 4.5 mg/kg IV

1

53

Risk Ratio (M‐H, Fixed, 95% CI)

0.87 [0.67, 1.11]

2.4 6.0 mg/kg IV

2

916

Risk Ratio (M‐H, Fixed, 95% CI)

0.92 [0.87, 0.97]

3 Failure to induce clinical response (>= 70 points; 6 weeks) Show forest plot

4

1947

Risk Ratio (M‐H, Random, 95% CI)

0.73 [0.66, 0.81]

3.1 1 mg/kg IV

1

175

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.61, 0.98]

3.2 3 mg/kg IV

1

176

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.63, 1.03]

3.3 4.5 mg/kg IV

1

53

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.37, 0.94]

3.4 6 mg/kg IV

3

1543

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.61, 0.85]

4 Failure to induce clinical response (>= 70 points; 6 weeks; sensitivity analysis) Show forest plot

3

1320

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.71, 0.85]

4.1 1 mg/kg IV

1

175

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.61, 0.98]

4.2 3 mg/kg IV

1

176

Risk Ratio (M‐H, Fixed, 95% CI)

0.81 [0.63, 1.03]

4.3 4.5 mg/kg IV

1

53

Risk Ratio (M‐H, Fixed, 95% CI)

0.59 [0.37, 0.94]

4.4 6 mg/kg IV

2

916

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.71, 0.87]

5 Failure to Induce clinical response (>=100 points; 6 weeks) Show forest plot

4

1947

Risk Ratio (M‐H, Random, 95% CI)

0.77 [0.69, 0.87]

5.1 1.0 mg/kg IV

1

175

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.67, 1.01]

5.2 3.0 mg/kg IV

1

176

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.70, 1.04]

5.3 4.5 mg/kg IV

1

53

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.39, 0.89]

5.4 6.0 mg/kg IV

3

1543

Risk Ratio (M‐H, Random, 95% CI)

0.76 [0.63, 0.91]

6 Failure to Induce clinical response (>=100 points; 6 weeks; sensitivity analysis) Show forest plot

3

1320

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.77, 0.88]

6.1 1.0 mg/kg IV

1

175

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.67, 1.01]

6.2 3.0 mg/kg IV

1

176

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.70, 1.04]

6.3 4.5 mg/kg IV

1

53

Risk Ratio (M‐H, Fixed, 95% CI)

0.59 [0.39, 0.89]

6.4 6.0 mg/kg IV

2

916

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.77, 0.91]

7 Failure to induce clinical remission ‐ 90 mg, s.c. (6 weeks) Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

8 Failure to induce clinical response 90 mg s.c. (>= 70 points; 6 weeks) Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9 Failure to induce clinical response 90 mg s.c. (>=100 points; 6 weeks) Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

10 Adverse events Show forest plot

4

2023

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.90, 1.04]

11 Serious adverse events Show forest plot

4

2023

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.58, 1.20]

12 Withdrawals because of adverse events Show forest plot

2

657

Risk Ratio (M‐H, Fixed, 95% CI)

0.44 [0.18, 1.05]
Figuras y tablas -
Comparison 2. Ustekinumab versus placebo
Ir a la tabla de la revisión