Paul ESTEEM‐2, 2015

Methods	RCT, active/placebo‐controlled, double blind Date of study: 29 October 2012–25 March 2016 Location: 40 centres in Europe & USA
Participants	Randomised: 413 participants (mean age 45 years, 276 male) Inclusion criteria Participants with moderate‐severe psoriasis (PASI ≥ 12 or BSA ≥ 10), age ≥ 18 years Exclusion criteria Pregnancy, immunosuppression, kidney insufficiency, liver insufficiency, past history of malignant tumours, active infection, uncontrolled cardiovascular disorder, uncontrolled diabetes, uncontrolled hypertension Dropouts and withdrawals 62/413 (15%); apremilast group (36), placebo group (26) Error of randomization, did not receive study medication; apremilast group (1), placebo group (1) AEs: apremilast group (12), placebo group (8) Lack of efficacy: apremilast group (3), placebo group (2) Withdrawal consent: apremilast group (9), placebo group (7) Lost to follow‐up: apremilast group (6), placebo group (6) Protocol violation: apremilast group (2), placebo group (1) Non compliance: apremilast group (1), placebo group (0) Other reason:apremilast group (2), placebo group (1)
Interventions	Intervention A. Apremilast (n = 275), orally, 30 mg twice a day until week 32 Control intervention B. Placebo (n = 138), orally (same drug administration)
Outcomes	Assessments at 16 weeks Primary outcomes of the trial PASI 75 Secondary outcomes of the trial PASI 50 PASI 90 PASI 100 PGA 0/1 DLQI Pruritus VAS AEs
Notes	Funding source: Quote (p 1387): "This study was sponsored by Celgene Corporation" Declarations of interest (Appendix): C.P. has served as an investigator and consultant for AbbVie, Amgen, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis and Pfizer. J. Cather has been an investigator for Amgen, Celgene, Galderma, Merck, Novartis and Pfizer, and has served on advisory boards for AbbVie, Janssen, OrthoBiotech and Medac. M.G. has been an investigator for AbbVie, Allergan, Celgene, Dermira, Dr. Reddy’s Laboratories, Eli Lilly, Galderma, Janssen Pharmaceutical, Kythera, Kyowa Hakko Kirin Pharma, LEO Pharma, Merck, Novartis, Pfizer, Regeneron and Takeda, and has served as a speaker for AbbVie, Actelion, Amgen, Astellas, Galderma, Janssen Pharmaceutical, LEO Pharma, Novartis and Pfizer. Y.P. has been an investigator for AbbVie, Amgen, Astellas, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Centocor/Janssen, Eli Lilly, Galderma, Isotechnika, LEO Pharma, Merck, Novartis, Pfizer, Pharmascience, Regeneron, Schering and Stiefel/GSK, and has served as a speaker for AbbVie, Amgen, Galderma, Janssen, LEO Pharma and Novartis. U.M. has been an advisor for and/or received speaker honoraria from and/or received grants from and/or participated in clinical trials for Abbott/AbbVie, Almirall‐Hermal, Amgen, BASF, Biogen Idec, Celgene, Centocor, Eli Lilly, Forward Pharma, Galderma, Janssen, LEO Pharma, Medac, MSD, Miltenyi Biotech, Novartis, Pfizer, Teva, VBL and XenoPort. C.F. has served on the advisory board for and/or received speaker honoraria from Celgene, Novartis, Janssen and AbbVie. J. Crowley has been an investigator for AbbVie, Amgen, AstraZeneca, Celgene, Janssen, Maruho, Merck, Pfizer and Regeneron; has served on the advisory board for AbbVie, Amgen, Celgene and Lilly; and has been a speaker for AbbVie and Amgen."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote (p 1388): "Patient were randomised (2:1) via an interactive voice response system..." Comment: no description of the method used to guarantee the random sequence generation
Allocation concealment (selection bias)	Low risk	Quote (p 1388): "Patient were randomised (2:1) via an interactive voice response system..." Comment: probably done
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote (p 1388) "identically matching placebo tablets twice daily during the placebo controlled phase" Comment: Probably done
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote (p 1388): "double‐blind" Comment: probably done
Incomplete outcome data (attrition bias) All outcomes	Low risk	Randomly assigned 413, analysed 411 Management of missing data: Quote (p 1389‐90): "Efficacy assessments were conducted for the modified intention‐to‐treat population... The last‐observation‐carried‐forward methodology was used...." Comment: we judged this as a low risk of bias
Selective reporting (reporting bias)	Low risk	Comment: the protocol for the study was available on ClinicalTrials.gov (NCT00235820). The pre‐specified outcomes and those mentioned in the methods section appeared to have been reported.