Anti‐IL‐12/23p40 antibodies for maintenance of remission in Crohn's disease

Sarah C Davies; Tran M Nguyen; Claire E Parker; John K MacDonald; Vipul Jairath; Reena Khanna

doi:10.1002/14651858.CD012804.pub2

Anticuerpos anti‐IL‐12/23p40 para el mantenimiento de la remisión en la enfermedad de Crohn

Appendices

Appendix 1. Appendix 1

Embase

1 random$.tw.

2 factorial$.tw.

3 (crossover$ or cross over$ or cross‐over$).tw.

4 placebo$.tw.

5 single blind.mp.

6 double blind.mp.

7 triple blind.mp.

8 (singl$ adj blind$).tw.

9 (double$ adj blind$).tw.

10 (tripl$ adj blind$).tw.

11 assign$.tw.

12 allocat$.tw.

13 crossover procedure/

14 double blind procedure/

15 single blind procedure/

16 triple blind procedure/

17 randomized controlled trial/

18 or/1‐17

19 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)

20 18 not 19

21 exp Crohn disease/ or crohn*.mp. or exp colon Crohn disease/

22 (inflammatory bowel disease* or IBD).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

23 21 or 22

24 ustekinumab.mp. or exp ustekinumab/

25 briakinumab.mp. or exp briakinumab/

26 (abt‐874 or "cnto 1275").mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

27 24 or 25 or 26

28 "interleukin 12".mp. or exp interleukin 12/

29 "interleukin 23".mp. or exp interleukin 23/

30 (IL‐12 or IL‐23 or p40).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

31 28 or 29 or 30

32 exp monoclonal antibody/ or exp antibody/ or antibod*.mp.

33 31 and 32

34 anti‐IL‐12 23p40.mp.

35 27 or 33 or 34

36 20 and 23 and 35

MEDLINE

1 random$.tw.

2 factorial$.tw.

3 (crossover$ or cross over$ or cross‐over$).tw.

4 placebo$.tw.

5 single blind.mp.

6 double blind.mp.

7 triple blind.mp.

8 (singl$ adj blind$).tw.

9 (double$ adj blind$).tw.

10 (tripl$ adj blind$).tw.

11 assign$.tw.

12 allocat$.tw.

13 randomized controlled trial/

14 or/1‐13

15 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)

16 14 not 15

17 exp Crohn disease/ or crohn*.mp.

18 ("inflammatory bowel disease*" or IBD).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

19 17 or 18

20 (ustekinumab or briakinumab or "CNTO 1275" or ABT‐874).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

21 interleukin 12.mp. or exp Interleukin‐12/

22 interleukin 23.mp. or exp Interleukin‐23/

23 (IL‐12 or IL‐23 or p40).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

24 21 or 22 or 23

25 antibod*.mp. or exp Antibodies/ or exp Antibodies, Monoclonal/

26 24 and 25

27 IL‐12 23p40.mp.

28 20 or 26 or 27

29 16 and 19 and 28

Cochrane Library (CENTRAL)

1 ustekinumab or briakinumab or ABT‐874 or CNTO 1275

2 interleukin 12 or interleukin 23 or IL‐12 or il‐23 or p40

3 antibod*

4 #2 and #3

5 anti‐il‐12/23p40

6 #1 or #4 or #5

7 #6 and (Crohn* or IBD or "inflammatory bowel disease*")

ClinicalTrials.gov, clinicaltrials.ifpma.org, and isrctn.com

(interleukin 12, interleukin‐12, IL‐12, interleukin 23, interleukin‐23, IL‐23, p40, ustekinumab, CNTO 1275, briakinumab and ABT‐874) were all searched with the search term: crohn*

Figure 1

Study flow diagram.

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Figure 2

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

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Analysis 1.1

Comparison 1 Ustekinumab versus placebo, Outcome 1 Failure to maintain clinical remission at 22 weeks.

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Analysis 1.2

Comparison 1 Ustekinumab versus placebo, Outcome 2 Failure to maintain clinical response at 22 weeks.

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Analysis 1.3

Comparison 1 Ustekinumab versus placebo, Outcome 3 Failure to maintain clinical remission at 44 weeks.

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Analysis 1.4

Comparison 1 Ustekinumab versus placebo, Outcome 4 Failure to maintain clinical response at 44 weeks.

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Analysis 1.5

Comparison 1 Ustekinumab versus placebo, Outcome 5 Adverse events.

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Analysis 1.6

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

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Analysis 1.7

Comparison 1 Ustekinumab versus placebo, Outcome 7 Withdrawal due to adverse events.

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Analysis 2.1

Comparison 2 Briakinumab versus placebo, Outcome 1 Failure to maintain clinical remission at 24 weeks.

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Analysis 2.2

Comparison 2 Briakinumab versus placebo, Outcome 2 Failure to maintain clinical response at 24 weeks.

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Analysis 2.3

Comparison 2 Briakinumab versus placebo, Outcome 3 Adverse events.

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Analysis 2.4

Comparison 2 Briakinumab versus placebo, Outcome 4 Serious adverse events.

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Analysis 2.5

Comparison 2 Briakinumab versus placebo, Outcome 5 Withdrawal due to adverse events.

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

Ustekinumab compared to placebo for maintenance of remission in Crohn's disease
Patient or population: people with moderate to severe Crohn's disease in remission Setting: outpatient Intervention: ustekinumab Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with ustekinumab	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Failure to maintain clinical remission Follow‐up: 22 weeks	726 per 1000	581 per 1000 (457 to 741)	RR 0.80 (0.63 to 1.02)	145 (1 RCT)	⊕⊕⊕⊝ moderate¹	Clinical remission was defined as a CDAI < 150 points.
Failure to maintain clinical response Follow‐up: 22 weeks	575 per 1000	305 per 1000 (207 to 455)	RR 0.53 (0.36 to 0.79)	145 (1 RCT)	⊕⊕⊕⊝ moderate²	Clinical response was defined as a ≥ 100‐point decrease from the baseline CDAI score.
Failure to maintain clinical remission Follow‐up: 44 weeks	641 per 1000	487 per 1000 (410 to 584)	RR 0.76 (0.64 to 0.91)	388 (1 RCT)	⊕⊕⊕⊝ moderate³	Clinical remission was defined as a CDAI < 150 points.
Failure to maintain clinical response Follow‐up: 44 weeks	557 per 1000	412 per 1000 (334 to 507)	RR 0.74 (0.60 to 0.91)	388 (1 RCT)	⊕⊕⊕⊝ moderate⁴	Clinical response was defined as a decrease from baseline in the CDAI score of ≥ 100 points or a CDAI score < 150.
Adverse events Follow‐up: 44 weeks	840 per 1000	789 per 1000 (731 to 865)	RR 0.94 (0.87 to 1.03)	541 (2 RCTs)	⊕⊕⊕⊕ high	Commonly reported adverse events included worsening Crohn's disease, abdominal pain, nausea, arthralgia, and headache.
Serious adverse events Follow‐up: 44 weeks	155 per 1000	115 per 1000 (75 to 179)	RR 0.74 (0.48 to 1.15)	541 (2 RCTs)	⊕⊕⊕⊝ moderate⁵	Commonly reported serious adverse events included malignant neoplasm, basal cell carcinoma, and injection site reactions.
Withdrawal due to adverse events Follow‐up: 44 weeks	14 per 1000	68 per 1000 (8 to 572)	RR 4.93 (0.59 to 41.18)	145 (1 RCT)	⊕⊕⊝⊝ low⁶	Adverse events leading to withdrawal included worsening Crohn's disease
*The risk in the intervention group (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). CDAI: Crohn's Disease Activity Index; CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level due to sparse data (95 events). ²Downgraded one level due to sparse data (64 events). ³Downgraded one level due to sparse data (210 events). ⁴Downgraded one level due to sparse data (179 events). ⁵Downgraded one level due to sparse data (70 events). ⁶Downgraded two levels due to very sparse data (6 events).

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

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Summary of findings 2. Briakinumab compared to placebo for maintenance of remission in Crohn's disease

Briakinumab compared to placebo for maintenance of remission in Crohn's disease
Patient or population: people with moderate to severe Crohn's disease in remission Setting: outpatient Intervention: briakinumab Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with briakinumab	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Failure to maintain clinical remission Follow‐up: 24 weeks	611 per 1000	513 per 1000 (354 to 733)	RR 0.84 (0.58 to 1.20)	99 (1 RCT)	⊕⊕⊝⊝ low¹	Clinical remission was defined as a CDAI score < 150 points.
Failure to maintain clinical response Follow‐up: 24 weeks	528 per 1000	338 per 1000 (211 to 538)	RR 0.64 (0.40 to 1.02)	99 (1 RCT)	⊕⊕⊝⊝ low²	Clinical response was defined as a decrease in CDAI score ≥ 100 points compared with week 0.
Adverse events Follow‐up: 24 weeks	643 per 1000	656 per 1000 (431 to 996)	RR 1.02 (0.67 to 1.55)	104 (1 RCT)	⊕⊕⊝⊝ low³	Common adverse events included upper respiratory tract infection, nausea, abdominal pain, and headache.
Serious adverse events Follow‐up: 24 weeks	71 per 1000	22 per 1000 (2 to 229)	RR 0.31 (0.03 to 3.21)	104 (1 RCT)	⊕⊕⊝⊝ low⁴	Serious adverse events included small bowel obstruction, deep vein thrombosis, and respiratory distress.
Withdrawals due to adverse events Follow‐up: 24 weeks	0 per 1000	0 per 1000 (0 to 0)	RR 0.82 (0.04 to 16.34)	104 (1 RCT)	⊕⊕⊝⊝ low⁵	We were unable to calculate absolute effects. 2% of briakinumab participants withdrew due to an adverse event compared to none of the placebo participants. Adverse events leading to withdrawal were not reported.
*The risk in the intervention group (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). CDAI: Crohn's Disease Activity Index; CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded two levels due to sparse data (54 events) and very wide confidence interval. ²Downgraded two levels due to very sparse data (40 events). ³Downgraded two levels due to sparse data (68 events) and very wide confidence interval. ⁴Downgraded two levels due to very sparse data (3 events). ⁵Downgraded two levels due to very sparse data (2 events).

Summary of findings 2. Briakinumab compared to placebo for maintenance of remission in Crohn's disease

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Comparison 1. Ustekinumab versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to maintain clinical remission at 22 weeks Show forest plot	1	145	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.63, 1.02]

2 Failure to maintain clinical response at 22 weeks Show forest plot	1	145	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.36, 0.79]

3 Failure to maintain clinical remission at 44 weeks Show forest plot	1	388	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.64, 0.91]

3.1 90 mg/8 weeks	1	193	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.56, 0.94]
3.2 90 mg/12 weeks	1	195	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.63, 1.03]
4 Failure to maintain clinical response at 44 weeks Show forest plot	1	388	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.60, 0.91]

4.1 90 mg/8 weeks	1	193	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.54, 0.99]
4.2 90 mg/12 weeks	1	195	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.56, 1.00]
5 Adverse events Show forest plot	2	541	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.87, 1.03]

6 Serious adverse events Show forest plot	2	541	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.48, 1.15]

7 Withdrawal due to adverse events Show forest plot	1	145	Risk Ratio (M‐H, Fixed, 95% CI)	4.93 [0.59, 41.18]

Comparison 1. Ustekinumab versus placebo

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Comparison 2. Briakinumab versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to maintain clinical remission at 24 weeks Show forest plot	1	99	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.58, 1.20]

1.1 200 mg	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.54, 2.02]
1.2 Continued 400 mg	1	35	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.43, 1.24]
1.3 700 mg	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.38, 1.63]
2 Failure to maintain clinical response at 24 weeks Show forest plot	1	99	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.40, 1.02]

2.1 200 mg	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.30, 1.78]
2.2 Continued 400 mg	1	35	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.30, 1.16]
2.3 700 mg	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.25, 1.60]
3 Adverse events Show forest plot	1	104	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.67, 1.55]

4 Serious adverse events Show forest plot	1	104	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.03, 3.21]

5 Withdrawal due to adverse events Show forest plot	1	104	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.04, 16.34]

Comparison 2. Briakinumab versus placebo

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Anticuerpos anti‐IL‐12/23p40 para el mantenimiento de la remisión en la enfermedad de Crohn

Appendices

Appendix 1. Appendix 1

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Appendices

Appendix 1. Appendix 1

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