ReSURFACE‐2 2017.

Study characteristics
Methods	RCT, active/placebo‐controlled, double‐blind trial Date of study: 12 February 2013 ‐ 28 September 2015 Location: 132 sites in Austria, Belgium, Canada, Czech Republic, Denmark, France, Germany, Hungary, Italy, Israel, Netherlands, Poland, and the USA Phase 3
Participants	Randomised: 1090 participants Inclusion criteria Clinical diagnosis of moderate‐severe plaque psoriasis for ≥ 6 months prior to enrolment Candidate for phototherapy or systemic therapy Premenopausal female participants must agree to abstain from heterosexual activity or use a medically approved method of contraception or use appropriate effective contraception as per local regulations or guidelines For the extension study: must have completed Part 3 of the base study For the extension study: must have achieved ≥ PASI 50 response by the end of Part 3 of the base study Exclusion criteria Non‐plaque forms of psoriasis Presence or history of severe psoriatic arthritis and is well‐controlled on current treatment regimen Women of childbearing potential who are pregnant, intend to become pregnant, or are lactating Participant is expected to require topical therapy, phototherapy, or systemic therapy during the trial Presence of any infection or history of recurrent infection requiring treatment with systemic antibiotics Previous use of etanercept, tildrakizumab (MK‐3222), or other interleukin‐23 (IL‐23)/T‐ helper cell 17 (Th‐17) pathway inhibitors including p40, p19, and IL‐17 antagonists Latex allergy or sensitivity Active or untreated latent TB Dropouts and withdrawals 64/1090 (5.9%): Tildra 200 (14), Tildra 100 (12), ETA (24), PBO (14) Lost to follow‐up: Tildra 200 (1), Tildra 100 (2), ETA (3), PBO (3) AEs: Tildra 200 (2), Tildra 100 (1), ETA (5), PBO (2) Lack of efficacy: Tildra 200 (1), Tildra 100 (0), ETA (0), PBO (2) Drug non‐compliance: Tildra 200 (1), Tildra 100 (0), ETA (0), PBO (0) Participant: Tildra 200 (5), Tildra 100 (7), ETA (6), PBO (5) Protocol deviation: Tildra 200 (2), Tildra 100 (1), ETA (0), PBO (1) Physician decision: Tildra 200 (0), Tildra 100 (0), ETA (4), PBO (0) Pregnancy: Tildra 200 (0), Tildra 100 (1), ETA (1), PBO (0) Disease progression: Tildra 200 (0), Tildra 100 (0), ETA (1), PBO (0) Others: Tildra 200 (2), Tildra 100 (0), ETA (4), PBO (1)
Interventions	Intervention Tildrakizumab 200 mg (SC on weeks 0, 4, 16, 28, 40 and 52), n = 314 Control interventions Tildrakizumab 100 mg (SC on weeks 0, 4, 16, 28, 40 and 52), n = 307 Etanercept 50 mg (twice weekly until week 12 and once weekly from week 12 to week 28), n = 313 Placebo, n = 156
Outcomes	At week 12 Primary outcome (composite outcome) PASI 75 PGA 0/1 Secondary outcomes PASI 75 and PGA 0/1 (at weeks 28, 40, and 52) PASI 90 (at weeks 12, 28, 40, and 52) PASI 100 (at weeks 12, 28, 40, and 52) DLQI (at weeks 12, 28, 40, and 52) AEs
Notes	Funding Quote (p 276): "Funding Merck & Co" Conflicts of interest Quote (p 287): "Declaration of interests: KR has served as a consultant or paid speaker for, or participated in clinical trials sponsored by, Abbvie, Amgen, Biogen‐Idec, Celgene, Centocor, Covagen, Forward Pharma, GlaxoSmithKline, Janssen‐Cilag, Leo, Lilly, Medac, Merck & Co, Novartis, Pfizer, Vertex, and Takeda. KAP has served as a consultant or paid speaker for, or participated in clinical trials sponsored by, Amgen, Anacor, AbbVie, Active Biotech, Allergan, Astellas, AstraZeneca, Basilea, Bayer, Biogen‐Idec, BMS, Boehringer‐Ingelheim, CanFite, Celgene, Dermira, Eli‐Lilly, Forward Pharma, Genentech, GlaxoSmithKline, Janssen, Kyowa Hako Kirin, Kythera, Leo Pharma, Merck & Co, Merck‐Serono, Novartis, Pfizer, Regeneron, Rigel, Roche, Sanofi‐Genzyme, Takeda, UCB, Valeant, Xenon, and Xoma. AB has served as a scientific adviser and clinical study investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Dermira, Genentech, GSK, Janssen, Lilly, Merck & Co, Novartis, Pfizer, Regeneron, Sandoz, Sanofi Genzyme, Sun, UCB, and Valeant, and as a paid speaker for Lilly. SKT has participated in trials supported by grants from Merck & Co. RS has served as a consultant or paid speaker for, or participated in clinical trials sponsored by, Leo Pharma, Amgen, Novartix, Merck & Co, Celgene, Coherus Biosciences, Janssen, Regeneron, MedImmune, GlaxoSmithKline, Cutanea, Samson Clinical, Boehringer Ingelheim, Pfiizer, MSD, Oncobiologics, Roche, Eli Lilly, and Bayer. DT has served as a consultant, advisory board member, or an investigator for Abbott (AbbVie), Almiral, Amgen, Astellas, Biogen‐Idec, Boehringer Ingelheim, Celgene, Dignity, Forward‐Pharma, Galderma, GlaxoSmithKline, Isotechnika, Janssen‐Cilag, Leo Pharma, Lilly, Maruho, Medac, Medimmune, Merck & Co, Merck‐Serono, Novartis, Pfizer, Regeneron, Sandoz, Sanofi‐Aventis, and Takeda. KN is a former employee of Merck & Co; AM, NC, QL, KL, CLR, and SG are current Merck & Coemployees. ABK is a consultant and investigator for Merck & Co, Amgen, AbbVie, Janssen, Novartis, Dermira, and Pfizer, a consultant for Sun Pharmaceuticals, Bristol‐Myers Squibb, Lilly, and VBL, and has received fellowship funding from Janssen."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote (p 278): "In reSURFACE 1, participants were randomly assigned (2:2:1) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo...In reSURFACE 2, participants were randomly assigned (2:2:1:2) to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg...Parexel International, the contract research organisation, generated computergenerated randomisation sequences, and an interactive voice‐response system and interactive web‐response system was used by Parexel to allocate participants to groups. Randomised treatment assignments on day 1 were done by region" Comment: Probably done
Allocation concealment (selection bias)	Low risk	Quote (p 278): "In reSURFACE 1, participants were randomly assigned (2:2:1) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo...In reSURFACE 2, participants were randomly assigned (2:2:1:2) to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg...Parexel International, the contract research organisation, generated computergenerated randomisation sequences, and an interactive voice‐response system and interactive web‐response system was used by Parexel to allocate participants to groups. Randomised treatment assignments on day 1 were done by region" Comment: Probably done
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote (p 279): "Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. A double‐masking technique was used, in which tildrakizumab and its matching placebo or etanercept and its matching placebo were identical in appearance and packaging. Additional placebo doses were administered to maintain masking. The team doing the analysis was blinded until the database was locked." Comment: probably done
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote (p279): "Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. A double‐masking technique was used, in which tildrakizumab and its matching placebo or etanercept and its matching placebo were identical in appearance and packaging. Additional placebo doses were administered to maintain masking. The team doing the analysis was blinded until the database was locked." Comment: probably done
Incomplete outcome data (attrition bias) All outcomes	Low risk	Dealing with missing data Quote (pp 280‐1): "We specified full‐analysis‐set, intention‐to‐treat, and per protocol patient populations in the study protocols...Patients with missing data were treated as non‐responders (non‐responder imputation [NRI])." Randomised 1090, Analysed 1090
Selective reporting (reporting bias)	Low risk	Comment: the protocol for the study was available on ClinicalTrials.gov (NCT01729754) The prespecified outcomes and those mentioned in the Methods section appeared to have been reported Results are posted on ClinicalTrials.gov