IXORA‐R 2020.

Study characteristics
Methods	RCT, active/placebo‐controlled, double‐blind study Date of study: November 2018 to July 2019 Location: 124 sites, USA and Canada Phase 4
Participants	Randomised: 1027 participants Inclusion criteria Have chronic plaque psoriasis based on a diagnosis for at least 6 months before baseline as determined by the investigator Are a candidate for phototherapy and/or systemic therapy Have both an sPGA score of ≥ 3 and a PASI score ≥ 12 at screening and at baseline Have ≥ 10% BSA involvement at screening and baseline If male, agree to use a reliable method of birth control during the study If female, agree to use highly effective method of contraception Exclusion criteria Predominant pattern of pustular, erythrodermic, and/or guttate forms of psoriasis Have a history of drug‐induced psoriasis Had a clinically significant flare of psoriasis during the 12 weeks before baseline Use of tanning booths for at least 4 weeks before baseline Concurrent or recent use of any biologic agent within the following periods prior to baseline: etanercept < 28 days; infliximab, adalimumab, certolizumab pegol, or alefacept < 60 days; golimumab < 90 days; rituximab < 12 months; secukinumab < 5 months; or any other biologic agent (e.g. ustekinumab) < 5 half‐lives Have prior use of IL‐23p19 antagonists (e.g. guselkumab, tildrakizumab, risankizumab), or have any condition or contraindication as addressed in the local labelling for guselkumab that would preclude the person from participating in this protocol Have previously completed or withdrawn from this study, participated in any other study with ixekizumab or guselkumab, have participated in any study investigating other IL‐17 or IL‐23p19 antagonists, or have received treatment with ixekizumab Have previously failed to respond to an IL‐17 antagonist, per investigator assessment Have had a live vaccination within 12 weeks of baseline Have a known allergy or hypersensitivity to any biologic therapy Have had any major surgery within 8 weeks of baseline Have had a serious infection, have been hospitalised, or have received intravenous antibiotics for an infection within 12 weeks of baseline Are women who are pregnant, or who are lactating (breastfeeding) Baseline characteristics N = 1027, mean of age 49 years and 63.5% men Dropouts and withdrawals: Ixekizumab: 32/520, guselkumab 26/507 Withdrawal participants: ixekizumab 11, guselkumab 4 Adverse events: ixekizumab 6, guselkumab 7 Lost of follow‐up: ixekizumab 6, guselkumab 5 Protocol deviation: ixekizumab 3, guselkumab 0 Lack of efficacy: ixekizumab 2, guselkumab 1 Screen failure: ixekizumab 1, guselkumab 1 Other: ixekizumab 3, guselkumab 2
Interventions	Intervention A. Ixekizumab 160 mg at week 0 then 80 every 2 weeks from weeks 2 to 12, n = 520 Control interventions B. Guselkumab 100 mg at week 0, 4, and 12, n = 507 Participants on guselkumab received placebo injection at weeks 0, 2, 6, 8, and 10
Outcomes	At week 12 Primary outcome PASI 100 Secondary outcomes PASI 75 week 2 Proportion of participants achieving PASI 90 week 4 Proportion of participants achieving PASI 90 week 8 Proportion of participants achieving PASI 100 week 4 Proportion of participants achieving PASI 100 week 8 Proportion of participants achieving PASI 100 week 24 Proportion of participants achieving Static Physician Global Assessment week 12 Proportion of participants achieving PASI 50 week 1
Notes	Funding source (Quote p 1348): "Funding for this study was provided by Eli Lilly and Company, Indianapolis, IN, U.S.A. Eli Lilly and Company contributed to study design, data collection, data analysis, data interpretation, manuscript preparation and the decision to submit the paper for publication. An advisory committee was involved in the study design and data interpretation, together with authors from Eli Lilly and Company. Authors had full access to all group‐level data in the study, but not individual‐level data that would risk unblinding those authors who were also study investigators. Authors had final responsibility for the decision to submit for publication". Declarations of interest: Quote (Appendix 1): "A.B. has served as a scientific adviser and/or clinical study investigator for AbbVie, Aclaris, Almirall, Arena, Athenex, Boehringer Ingelheim, Bristol‐Myers Squibb, Dermavant, Dermira, Eli Lilly and Company, FLX Bio, Forte, Galderma, Janssen, LEO, Novartis, Ortho, Pfizer, Regeneron, Sandoz, Sanofi Genzyme, Sun Pharma and UCB Pharma, and as a paid speaker for AbbVie. K.P. has served as a scientific adviser and/or clinical study investigator for AbbVie, Akros, Allergan, Almirall, Amgen, Arcutis, Avillion, Bausch Health, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Dermavant, Dermira, Eli Lilly and Company, Galderma, Genentech/Roche, GlaxoSmithKline, Janssen, Kyowa Kirin, LEO, Meiji, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Sienna Pharmaceuticals, Sun Pharma, Takeda, UCB and Valeant; and as a paid speaker for AbbVie, Akros, Allergan, Almirall, Amgen, Bausch Health, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Dermavant, Dermira, Eli Lilly and Company, Galderma, Genentech/Roche, Janssen, Kyowa Kirin, LEO, Meiji, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Sienna Pharmaceuticals, Sun Pharma, Takeda, UCB and Valeant. A.G. has served as a consultant or speaker for Janssen, Celgene, Beiersdorf, Bristol‐Myers Squibb, AbbVie, UCB, Novartis, Incyte, Eli Lilly and Company, Allergan, Sun Pharmaceutical Industries, Xbiotech, LEO, Avotres Therapeutics and Boehringer Ingelheim; and received research/educational grants from Janssen, Incyte, Novartis, Xbiotech, UCB and Boehringer Ingelheim. A.J. has served as scientific advisor or clinical study investigator for AbbVie, Asana Biosciences, Castle Biosciences, Inc., Bristol‐Myers Squibb, Celgene, Dermira, Eli Lilly and Company, Galderma, Genentech/Roche, GlaxoSmithKline, LEO Pharma, Novartis, Pfizer, Purdue Pharma, Regeneron, Sanofi Genzyme, Sienna Pharmaceuticals, Sun Pharma and UCB Pharma, and as a paid speaker for Castle Biosciences, Inc., Eli Lilly and Company, Novartis, Regeneron and Sanofi Genzyme. K.R. has served as an advisor and paid speaker and has participated in clinical trials for AbbVie, Affibody, Almirall, Amgen, Avillion, Biogen, Boehringer Ingelheim, Celgene, Covagen, Forward Pharma, Fresenius Medical Care, GlaxoSmithKline, Janssen, Janssen‐Cilag, Kyowa Kirin, LEO Pharma, Eli Lilly and Company, Medac, Merck Sharp & Dohme, Novartis, Miltenyi Biotech, Ocean Pharma, Pfizer, Regeneron, Samsung Bioepis, Sanofi, Sun Pharma, Takeda, UCB, Valeant, XBiotech and Xenoport. C.M. has served as principal investigator, as a speaker or on a scientific advisory board for and received compensation in the form of honoraria from AbbVie, Amgen, Celgene, Janssen, LEO Pharma, GlaxoSmithKline, Bausch Health, Eli Lilly and Company, Novartis, Pfizer and UCB Pharma. K.B.G. has consulting relationships with AbbVie, Amgen, Celgene, Eli Lilly and Company, Janssen, Novartis, Pfizer, Dermira and Boehringer Ingelheim and has received grants from AbbVie, Amgen, Celgene and Janssen. L.K.F. has been an investigator and consultant for Eli Lilly and Company, Janssen and Pfizer; a consultant for UCB; and an investigator for AbbVie, Amgen, Galderma, LEO Pharma and Regeneron. R.G. Langley has served as principal investigator, as a speaker and on the scientific advisory board for and received compensation in the form of honoraria from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Janssen, LEO Pharma, Eli Lilly and Company, Merck, Novartis, Pfizer, Sun and UCB Pharma. Y.T. received grants for research from Maruho, LEO Pharma, Eisai, AbbVie, Kyowa Hakko Kirin, Taiho Pharmaceutical, Celgene, and Eli Lilly and Company, and honoraria for lectures from Torii Pharmaceutical, Maruho, LEO Pharma, Eisai, AbbVie, Kyowa Hakko Kirin, Eli Lilly and Company, Taiho Pharmaceutical, Mitsubishi Tanabe Pharma and Janssen. R.G. Lima, H.E., G.G., L.R., S.Y.P. and R.B. are employees and stockholders of Eli Lilly and Company. J.B. is a speaker and investigator for AbbVie, Celgene, Eli Lilly and Company, Janssen, Novartis and Ortho Dermatologics. He is an investigator for Amgen, Boehringer Ingelheim, Bristol‐Myers Squibb and LEO Pharma."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote (p 3): "Patients were allocated to treatment by a computer‐generated random sequence." Comment: adequate process
Allocation concealment (selection bias)	Low risk	Quote: "supplementary material S2 interactive web‐response system (IWRS). The IWRS was used to assign double‐blind investigational product to each patient. The Unblinded Site Personnel at the site confirmed that they located the correct assigned study drug package by entering a confirmation number found on the package into the IWRS. Designated Unblinded Site Personnel were responsible for receipt of study drug shipments, dispensing study drug, administering study drug (ixekizumab, guselkumab, and placebo), recording information in the Study Drug Administration Log, and confirming treatment assignments." Comment: interactive web‐response system guaranteed allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote (p 3): "Patients, investigators and all other personnel involved in the conduct of this ongoing study are to remain blinded to individual treatment assignments until all patients have completed the study." Comment: because the syringes looked different, participants were not allowed to see the syringe before, during, or after the drug administration Comment: not sure that the method was sufficiently efficient to guarantee blinding
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote (p 3): "Patients, investigators and all other personnel involved in the conduct of this ongoing study are to remain blinded to individual treatment assignments until all patients have completed the study. Because the syringes look different, patients were not allowed to see the syringe before, during, or after the drug administration. Unblinded Site Personnel were responsible for maintaining the blind of the patient (e.g. by means of a blindfold or other appropriate physical barrier means communicated to the sponsor for final approval). Designated Unblinded Site Personnel were not involved in any clinical aspects of the study, including clinical evaluations and adverse event assessments." Comment: no detailed description of means used to guarantee absence of communication between blinded and unblinded personnel
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: analysis for primary outcome and major secondary outcome was performed as ITT. Missing data were imputed using a nonresponder imputation method. The number of withdrawals was low and reasons comparable in each group.
Selective reporting (reporting bias)	Low risk	Comment: the protocol for the study was available on ClinicalTrials.gov (NCT03573323). The prespecified outcomes and those mentioned in the Methods section appeared to have been reported. Results are posted on ClinicalTrials.gov.