UltIMMa‐2 2018.

Study characteristics
Methods	RCT, placebo/active‐controlled, double‐blind study Date of study: March 2016 to August 2016 Location: worldwide Phase 3
Participants	Randomised: 491 participants Inclusion criteria Men or women. Women of childbearing potential* must be ready and able to use highly effective methods of birth control per ICH M3(R2) that result in a low failure rate of < 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. *Women of childbearing potential are defined as: having experienced menarche and are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilised (e.g. tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy) Age ≥ 18 years at screening Diagnosis of chronic plaque psoriasis (with or without psoriatic arthritis) for ≥ 6 months before the first administration of study drug. Duration of diagnosis may be reported by the patient. Stable moderate‐severe chronic plaque psoriasis with or without psoriatic arthritis at both screening and baseline (randomisation) Have an involved BSA ≥ 10%, PASI score ≥ 12 and sPGA score of ≥ 3 Must be candidates for systemic therapy or phototherapy for psoriasis treatment, as assessed by the investigator Must be a candidate for treatment with Stelara (ustekinumab) according to local label Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation Exclusion criteria Non‐plaque forms of psoriasis (including guttate, erythrodermic, or pustular), current drug‐induced psoriasis (including an exacerbation of psoriasis from beta‐blockers, calcium channel blockers, or lithium), active ongoing inflammatory diseases other than psoriasis and psoriatic arthritis that might confound trial evaluations according to investigator's judgement Previous exposure to BI 655066 Currently enrolled in another investigational study or < 30 days (from screening) since completing another investigational study (participation in observational studies is permitted) Previous exposure to ustekinumab (Stelara) Use of any restricted medication, or any drug considered likely to interfere with the safe conduct of the study Major surgery performed within 12 weeks prior to randomisation or planned within 12 months after screening (e.g. hip replacement, aneurysm removal, stomach ligation) Known chronic or relevant acute infections including active TB, HIV or viral hepatitis; QuantiFERON TB test or PPD skin test will be performed according to local labelling for comparator products. If the result is positive, patients may participate in the study if further work‐up (according to local practice/guidelines) establishes conclusively that they have no evidence of active TB. If presence of latent TB is established, then treatment should have been initiated and maintained according to local country guidelines. Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal or squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix Evidence of a current or previous disease, medical condition (including chronic alcohol or drug abuse) other than psoriasis, surgical procedure (i.e. organ transplant), medical examination finding (including vital signs and ECG), or laboratory value at the screening visit outside the reference range that is in the opinion of the investigator, is clinically significant and would make the study participant unreliable to adhere to the protocol or to complete the trial, compromise the safety of the participant, or compromise the quality of the data History of allergy/hypersensitivity to a systemically administered biologic agent or its excipients Women who are pregnant, nursing, or who plan to become pregnant while in the trial Previous enrolment in this trial Dropouts and withdrawals 9/491 (1.8%); risankizumab group (2), ustekinumab group (3), placebo group (4) Withdrawal: risankizumab group (0), ustekinumab group (0), placebo group (3) Disease worsening: risankizumab group (0), ustekinumab group (0), placebo group (1) Lost to follow‐up: risankizumab group (2), ustekinumab group (2), placebo group (1) Other reason: risankizumab group (0), ustekinumab group (1), placebo group (0)
Interventions	Intervention A. Risankizumab, SC, 150 mg, n = 294 Control interventions B. Ustekinumab, SC, based on weight per label (45 mg for patients with body weight ≤ 100 kg or 90 mg for patients with body weight > 100 kg), n = 99 C. Placebo, n = 98
Outcomes	At week 16 Primary composite outcome PASI 90 PGA 0/1 Secondary outcomes PASI 75 at weeks 16 and 52 PASI 90 at week 52 PGA 0/1 at week 52
Notes	Funding source: Quote (p 650): "AbbVie and Boehringer Ingelheim" Declarations of interest: Quote (p 660): "KBG has received honoraria for serving as a consultant and/or grants as an investigator from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Dermira, Eli Lilly, GlaxoSmithKline, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, Sanofi‐Aventis, Sun, and UCB. BS has received honoraria as a consultant for AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Janssen, Leo Pharma, Medac, Meiji Seika Pharma, Menlo Therapeutics, Merck, Novartis, Ortho Dermatologics/Valeant, Pfizer, Regeneron, Sanofi Genzyme, Sebela, Sienna, Sirtris, Sun Pharma, and UCB pharma, and as scientific director for the CORRONA‐NPF Psoriasis Registry. He is an investigator for AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, GlaxoSmithKline, Janssen, Merck, Pfizer, and Sienna. ML has received grants as an investigator from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen Research & Development, Kadmon, Leo Pharma, Novartis, Pfizer, and ViDac and has received honoraria for serving as a consultant for Allergan, Aqua, Boehringer Ingelheim, Leo Pharma, Menlo, and Promius. MA has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant; and grants as an investigator from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Celgene, Centocor, Hexal, Janssen, Leo Pharma, Eli Lilly, Medac, Mundipharma, MSD, Novartis, Pfizer, Sandoz, UCB, and Xenoport. AB has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant; and grants as an investigator from AbbVie, Aclaris, Akros, Allergan, Almirall, Amgen, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Janssen, Leo Pharma, Meiji, Merck Sharp & Dohme, Novartis, Pfizer, Purdue Pharma, Regeneron, Sandoz, Sanofi Genzyme, Sienna pharmaceuticals, UCB, Valeant, and Vidac. YP has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, and grants as an investigator from AbbVie, Amgen, Baxalta, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Janssen/Centocor, Leo Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi‐Genzyme, Sun Pharma, Takeda, Valeant, and UCB. KAP has received honoraria or fees for serving on advisory boards, as a speaker, as a consultant, or as a steering committee member or grants as an investigator from AbbVie, Akros, Allergan, Amgen, Anacor, Arcutis, Astellas, AstraZeneca, Baxalta, Baxter, Boehringer Ingelheim, Bristol‐Myers Squibb, CanFite, Celgene, Coherus, Dermira, Eli Lilly, Forward Pharma, Galderma, Genentech, GlaxoSmithKline, Janssen, Kyowa‐Hakko Kirin, Leo Pharma, MedImmune, Meiji Seika Pharma, Merck (MSD), Merck‐Serono, Mitsubishi Pharma, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Takeda, UCB, and Valeant. HS has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, and grants as an investigator from AbbVie, Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, and Pfizer. LP has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, and grants as an investigator from AbbVie, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Eli Lilly, Janssen, Leo Pharma, Merck‐Serono, MSD, Novartis, Pfizer, Regeneron, Roche; Sandoz, and Sanofi Genzyme. PF has received honoraria and/or research grants from and/or served as an investigator and/or advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Celtaxsys, CSL, Cutanea, Dermira, Galderma, Genentech, GSK, iNova, Janssen, Leo Pharma, Lilly, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Roche, Sanofi, Sun Pharma, UCB Pharma, and Valeant. MO has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, and grants as an investigator from AbbVie, Actelion, Astellas, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Eisai, Eli Lilly, and Company, Galderma, Janssen, Kaken, Kyowa‐Kirin, Leo Pharma, Maruho, Mochida, Nichi‐Iko, Nippon Kayaku, Nippon Zoki, Novartis, Ono, Ohtsuka, Pola Pharma, Pfizer, Sanofi, Shionogi, Taiho, Tanabe‐Mitsubishi, Teijin, and Torii. MF is a full‐time employee of Boehringer Ingelheim. ZG, YG, and JMV are full‐time employees of AbbVie and own stock or options. EHZT, a former employee of AbbVie, currently owns stock. HB has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, and grants as an investigator from AbbVie, Almirall, Amgen, Bayer, Baxalta, Biocad, Boehringer Ingelheim, Celgene, Dermavant, Eli Lilly, Janssen, Leo Pharma, Menarini, MSD, Novartis, Pfizer, Pierre Fabre, Sandoz, Sun Pharmaceuticals, and UCB."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote (pp 651‐2): "UltIMMa‐1 and UltIMMa‐2 were replicate phase 3, randomised, double‐blind, placebo‐controlled and active comparator‐controlled...In each study, patients were randomly assigned (3:1:1) to receive risankizumab, ustekinumab, or matching placebo (appendix). Randomisation was stratified by weight (≤ 100 kg vs > 100 kg) and previous exposure to tumour necrosis factor (TNF) inhibitor (yes vs no); there was no restriction on the number of patients with prior TNF inhibitor exposure. Interactive response technology was used for randomisation and allocation of double‐blind treatment to each patient." Comment: probably done
Allocation concealment (selection bias)	Low risk	Quote (pp. 651‐2): "UltIMMa‐1 and UltIMMa‐2 were replicate phase 3, randomised, double‐blind, placebo‐controlled and active comparator‐controlled...In each study, patients were randomly assigned (3:1:1) to receive risankizumab, ustekinumab, or matching placebo (appendix). Randomisation was stratified by weight (≤ 100 kg vs > 100 kg) and previous exposure to tumour necrosis factor (TNF) inhibitor (yes vs no); there was no restriction on the number of patients with prior TNF inhibitor exposure. Interactive response technology was used for randomisation and allocation of double‐blind treatment to each patient." Comment: probably done
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote (pp. 651‐2): "UltIMMa‐1 and UltIMMa‐2 were replicate phase 3, randomised, double‐blind, placebo‐controlled and active comparator‐controlled...Patients, investigators, and study personnel involved in the trial conduct or analyses remained masked to treatment assignments until study completion. To maintain blinding, the studies utilised a double‐dummy strategy where in risankizumab and its matching placebo or ustekinumab and its matching placebo were identical in appearance." Comment: probably done
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote (pp. 651‐2): "UltIMMa‐1 and UltIMMa‐2 were replicate phase 3, randomised, double‐blind, placebo‐controlled and active comparator‐controlled...Patients, investigators, and study personnel involved in the trial conduct or analyses remained masked to treatment assignments until study completion. To maintain blinding, the studies utilised a double‐dummy strategy where in risankizumab and its matching placebo or ustekinumab and its matching placebo were identical in appearance." Comment: probably done
Incomplete outcome data (attrition bias) All outcomes	Low risk	Randomly assigned 491 Management of missing data: Quote (pp. 652‐3): "For both UltIMMa‐1 and UltIMMa‐2 studies, efficacy analyses were done in the intention‐to‐treat population (all randomised patients)... Missing efficacy data for categorical variables were handled with nonresponder imputation and for continuous variables with last observation carried forward". Table 2: 491 analysed participants Comment: done
Selective reporting (reporting bias)	Unclear risk	Comment: the protocol for the study was available on ClinicalTrials.gov (NCT0268435). The prespecified outcomes and those mentioned in the Methods section appeared to have been reported.