Weinstein 2016.

Study characteristics
Methods	Randomised, active‐comparator, parallel‐group, phase 3 superiority trial (PN031) with 2 arms comparison of fosaprepitant + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Enrolment period: 30 October 2012 to 03 November 2014 1150 patients screened 1015 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria aged ≥18 years with confirmed malignant disease scheduled to receive ≥ 1 i.v. dose of MEC on Day 1 (combinations of MEC ± low emetogenic chemotherapy (LEC) were permitted from Days 1 to 3 when part of an overall MEC regimen and were in accordance with current emetogenicity classification guidelines) Exclusion criteria vomiting in the 24‐h period before Day 1 antiemetic use within 48 h of Day 1 symptomatic primary or metastatic central nervous system malignancy causing nausea and/or vomiting use of any dose of cisplatin or other HEC Mean age ± SD, years: 60.0 ± 11.8 in fosaprepitant group, 59.1 ± 12.3 in control group Gender: male (409) + female (591) Tumour/cancer type: malignant disease (lung, breast, colorectal, gynaecological, gastrointestinal, head and neck, other) Chemotherapy regimen: MEC agents except for the combination of anthracycline and cyclophosphamide Country: 125 sites across 30 countries
Interventions	Experimental: arm A: fosaprepitant Day 1: fosaprepitant 150 mg intravenous (i.v.) infusion, ~ 30 minutes before chemotherapy + dexamethasone 12 mg orally (p.o.) ~ 30 minutes before chemotherapy + ondansetron 16 mg total dose: 8 mg p.o. ~ 30 to 60 minutes before chemotherapy, followed by 8 mg p.o. 8 hours after first dose + dexamethasone placebo, p.o. ~ 30 minutes before chemotherapy Days 2 to 3: ondansetron placebo, p.o. every 12 hours Control: arm B: fosaprepitant Day 1: fosaprepitant placebo, 150 mL i.v. infusion, ~ 30 minutes before chemotherapy + dexamethasone 20 mg, p.o. ~ 30 minutes before chemotherapy + ondansetron 16 mg total dose: 8 mg p.o. ~ 30 to 60 minutes before chemotherapy; followed by 8 mg p.o. 8 hours after first dose Days 2 to 3: ondansetron 8 mg p.o. every 12 hours
Outcomes	Primary endpoint(s) percentage of participants with complete response from 25 to 120 hours after initiation of moderately emetogenic chemotherapy [Time frame: 25 to 120 h after initiation of MEC] percentage of participants with infusion site thrombophlebitis [Time frame: Day 1 through Day 17, inclusive] percentage of participants with severe infusion site reaction [Time frame: Day 1 through Day 17, inclusive] Secondary endpoint(s) percentage of participants with complete response from 0 to 120 hours after initiation of MEC [Time frame: 0 to 120 h after initiation of MEC] percentage of participants with complete response from 0 to 24 hours after initiation of MEC [Time frame: 0 to 24 h after initiation of MEC] percentage of participants with no vomiting from 0 to 120 hours after initiation of MEC [Time frame: 0 to 120 h after initiation of MEC]
Notes	ClinicalTrials.gov identifier (NCT number): NCT01594749 this study was not supported by a grant; this work was supported by Merck & Co., Inc., Kenilworth, NJ, USA conflicts of interest: "CW is an employee and stockholder of Merck & Co., Inc. KJ has received honoraria for consultancy from Merck Sharp & Dohme (MSD), Merck & Co., Inc., Helsinn, and Pro‐Strakan. SG, EBB, and WV are employees and stockholders of Merck & Co., Inc., and LWL is an employee of Merck & Co., Inc. SN has received honoraria from Millenium and served as a consultant or in an advisory role for Amgen and Millenium (now Takeda Oncology). BLR has served as a consultant or in an advisory role for and has received payment for travel, accommodations, or expenses from MSD and Tesaro. BLR has also received payments for participation on speakers bureaus for MSD and Roche"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "subjects were randomized (1:1) to the single‐dose fosaprepitant or control regimen via an interactive voice response system/interactive web response system, and stratified based on sex"
Allocation concealment (selection bias)	Low risk	Quote: "study medications were supplied in a blinded manner as fosaprepitant/placebo i.v. bags, ..."
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the ITT and ASaT populations comprised 1000 and 1001 subjects, respectively (Figure 1)"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the ITT and ASaT populations comprised 1000 and 1001 subjects, respectively (Figure 1)"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias