IXORA‐S 2017.

Study characteristics
Methods	RCT, active‐controlled, double‐blind study Date of study: September 2015 ‐ October 2017 Location: USA (multicentric) Phase 3
Participants	Randomised: 302 participants (median age 43.5, males 202) Inclusion criteria: Chronic plaque psoriasis for ≥ 6 months before baseline Failure, contraindication, or intolerability to ≥ 1 systemic therapy (including ciclosporin, methotrexate, or phototherapy) PASI score ≥ 10 at screening and at baseline Participant must agree to use reliable method of birth control during the study; women must continue using birth control for ≥ 15 weeks after stopping treatment Exclusion criteria Predominant pattern of pustular, erythrodermic, and/or guttate forms of psoriasis History of drug‐induced psoriasis Cannot avoid excessive sun exposure or use of tanning booths for ≥ 4 weeks before baseline and during the study Have received systemic nonbiologic psoriasis therapy or phototherapy within 4 weeks of baseline, or have had topical psoriasis treatment within 2 weeks of baseline Concurrent or recent use of any biologic agent within the following washout periods: etanercept < 28 days; infliximab, adalimumab, or alefacept < 60 days; golimumab < 90 days; rituximab < 12 months; or any other biologic agent < 5 half‐lives prior to baseline Have prior use of ustekinumab, or have any condition or contraindication to ustekinumab that would preclude the participant from participating in this protocol Have previously completed or withdrawn from this study, participated in any other study with ixekizumab, have participated in any study investigating other interleukin (IL)‐17 or IL‐12/23 antagonists, or have received treatment with other IL‐17 or IL‐12/23 antagonists Have had a live vaccination within 12 weeks of baseline, or intend to have a live vaccination during the course of the study or within 15 weeks of completing treatment in this study Have had a vaccination with Bacillus Calmette‐Guérin (BCG) within 12 months of baseline or intend to have vaccination with BCG during the course of the study or within 12 months of completing treatment in this study Have a known allergy or hypersensitivity to latex Have had any major surgery within 8 weeks of baseline or will require such during the study Have active or history of malignant disease within 5 years prior to baseline Significant uncontrolled disorder Ongoing infection or serious infection within 12 weeks of baseline; serious bone or joint infection within 24 weeks of baseline Are women who are lactating or breastfeeding Dropouts and withdrawals 6/302 (2%): Ixe group (4), USK group (2) Discontinued before receiving 1 dose: Ixe group (1), USK group (0) AEs: Ixe group (2), USK group (0) Lack of efficacy: Ixe group (0), USK group (1) Patient: Ixe group (1), USK group (0) Other: Ixe group (0), USK group (1)
Interventions	Intervention Ixekizumab (160 mg ixekizumab given as 2 SC injections at baseline followed by 80 mg ixekizumab given as a single SC injection once every 2 weeks from week 2 through week 12. After week 12 participants will receive 80 mg ixekizumab every 4 weeks through week 52), n = 136 Control intervention Ustekinumab (45 mg ustekinumab given as SC injection for participants ≤ 100 kg and 90 mg SC injection for participants > 100 kg at weeks 0, 4, 16, 28, and 40), n = 166
Outcomes	At week 12, Primary outcome PASI 90 Secondary outcomes PASI 75 PGA DLQI
Notes	Funding Quote (p 1014): "This study was funded in full by Eli Lilly and Company, Indianapolis, IN, U.S.A" Conflicts of interest Quote (Appendix 1): "K.R. has served as advisor and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Amgen, Biogen, Boehringer Ingelheim, Celgene, Covagen, Forward Pharma, GlaxoSmithKline, Janssen‐Cilag, LEO Pharma, Lilly, Medac, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Takeda, UCB Pharma and Xenoport. A.P. has served as an advisor and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Amgen, Biogen, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Janssen‐Cilag, LEO Pharma, Lilly, Medac, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron and UCB. J.P.L. has served as an advisor and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Amgen, Boehringer Ingelheim, Celgene, Galderma, Janssen, LEO Pharma, Lilly, Merck‐Serono, Novartis, Pfizer, Regeneron, Roche and UCB Pharma. C.F. has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Centocor, Janssen‐Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis and Pfizer. G.M. has served as an investigator for Lilly. L.E.F. has served as an advisor for and/or participated in clinical trials sponsored by AbbVie, Amgen, Celgene, Eli Lily and Company, Galderma, Janssen‐Cilag and Novartis. M.L. has worked as a consultant and/or clinical trial investigator for AbbVie, Allergan Amgen, Anacor, Boehringer Ingelheim, Celgene, Dr Reddy’s, Janssen, LEO Pharma, Lilly, Merck‐Serono, Novartis, Oncobio‐ logics, Pfizer, Regeneron, Roche, Xenon Pharma, Valeant, Bayer, L’Oreal and Galderma. Y.D, C.H., S.W. and S.H. are employees of Eli Lilly and Company, and receive salary from and own stock in the company. C.P. has served as a consultant and/or investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis and Pfizer."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote (p 1015): "This 52‐week, phase IIIb, multicentre, controlled, double‐blind, parallel‐group trial (IXORA‐S, NCT02561806) was conducted at 51 sites across 13 countries. Patients were randomized (1: 1) via an interactive web‐response system to receive either ixekizumab or ustekinumab. Randomization was stratified by study centre and patient weight (≤ 1000 kg vs. > 1000 kg)." Comment: probably done
Allocation concealment (selection bias)	Low risk	Quote (p 1015): "This 52‐week, phase IIIb, multicentre, controlled, double‐blind, parallel‐group trial (IXORA‐S, NCT02561806) was conducted at 51 sites across 13 countries. Patients were randomized (1: 1) via an interactive web‐response system to receive either ixekizumab or ustekinumab. Randomization was stratified by study centre and patient weight (≤ 1000 kg vs. > 1000 kg)." Comment: probably done
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote (p 1015): "To maintain the blinding, patients randomized to ixekizumab received placebo injections matching the ustekinumab dose regimen, and patients in the ustekinumab group received dummy injections of ixekizumab. Unblinded site personnel responsible for ustekinumab and ustekinumab placebo injections were involved in neither the clinical assessments nor the treatment decisions, and kept the patients and investigators blinded from treatment allocation" Comment: probably done
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote (p 1015): "To maintain the blinding, patients randomized to ixekizumab received placebo injections matching the ustekinumab dose regimen, and patients in the ustekinumab group received dummy injections of ixekizumab. Unblinded site personnel responsible for ustekinumab and ustekinumab placebo injections were involved in neither the clinical assessments nor the treatment decisions, and kept the patients and investigators blinded from treatment allocation" Comment: probably done
Incomplete outcome data (attrition bias) All outcomes	Low risk	Dealing with missing data Qjuote (p 1016): "Patients were analysed according to the treatment they were assigned at randomization (intention‐to‐treat population). The primary‐analysis model was a logistic regression for the PASI 90 response end point after 12 weeks of treatment, with terms for treatment group, weight and geographical region. Missing data were imputed via nonresponder imputation (NRI), assuming that patients without data had no response" Patients randomized, patients analyzed Comment: Done
Selective reporting (reporting bias)	Low risk	Comment: the protocol for the study was available on ClinicalTrials.gov (NCT02561806) The prespecified outcomes and those mentioned in the Methods section appeared to have been reported Results are posted on ClinicalTrials.gov