EFECTL 2017.

Methods	Design: three‐arm parallel‐group, open‐label randomised trial Number of study centres: 50 study centres in Japan Setting: outpatient clinics Patient recruitment: March 2009 to December 2012 Duration of study: 52 weeks Clinical setting: combined hyperlipidaemia
Participants	Enrolment (N): 236 in total, of interest are combination group with ezetimibe plus fenofibrate (N = 118) and fenofibrate group (N = 59) Randomised (N): combination group: 118; fenofibrate group 59; ezetimibe group: 59 Withdrawn (N): combination group: 30; fenofibrate group: 18; ezetimibe group: 15 Lost to follow‐up (N): combination group: ; fenofibrate group: Completed the study (N): combination group: 88; fenofibrate group: 41; ezetimibe group: 44 Analysed (N): combination group: 107; fenofibrate group: 51; ezetimibe group: 52 Age (years) (mean ± SD): combination group: 55.8 ± 12.6; fenofibrate group: 58.3 ± 10.4 Sex (male, N, %): combination group: 63 (58.9%); fenofibrate group: 31 (59.6%) Smoking history (N, %): not reported BMI (kg/m², mean ± SD):): combination group: 27.0 ± 4.4; fenofibrate group: 25.2 ± 2.9 Diabetes (N, %): combination group: 22 (20.6%); fenofibrate group: 10 (19.2%) Hypertension (N, %): combination group: 45 (42.1%); fenofibrate group: 24 (46.2%) Existing CHD: combination group:4 (%), fenofibrate group: 4 (%) History of MI (N, %): combination group: 1 (0.9 %); fenofibrate group: 1 (1.9 %) Statin pretreatment (N, %): not reported Inclusion criteria: Quote: "Eligible patients were men and women aged between 20 and 75 years at the time of obtaining informed consent. Patients were required to have a TG concentration of 200‐400 mg/dL and LDL‐C concentration of ≥140 mg/dL as calculated by the Friedewald formula at screening." Exclusion criteria: Quote: "1) use of probucol within the previous year; 2) familial hypercholesterolemia; 3) drug‐induced hyperlipidemia from steroids or other drugs; 4) history or complication of malignant tumor, pancreatitis, gallstones, gallbladder disease, drug abuse, alcoholism, recent MI or cerebrovascular disorder (within 3 months before the study), cardiac arrhythmia requiring drug treatment, uncontrolled diabetes mellitus, or serious liver or renal disorder; 5) drug hypersensitivity including history of hypersensitivity to fenofibrate or ezetimibe; 6) problems related to discontinuing prohibited drugs; 7) patients who were pregnant, lactating, possibly pregnant, or planning to become pregnant; 8) participation in other clinical research such as clinical trials; 9) condition successfully controlled by current anti‐hyperlipidemic drug; 10) participation otherwise judged inappropriate by the study physicians; 11) the screening tests resulted in a hemoglobin A1c (HbA1c) of ≥8%, aspartate amino‐transferase (AST) or alanine aminotransferase (ALT) concentrations twice the upper limits of the institutional reference range or ≥ 80 IU/L, or serum creatinine level of ≥ 1.5 mg/dL."
Interventions	Intervention: Arm 1 (combination group): fenofibrate (either 2 capsules of Lipidil 100 mg/capsule or 2 tablets of Lipidil 80 mg/tablet) plus ezetimibe (10 mg/day). Arm 2 (fenofibrate group): fenofibrate (either 2 capsules of Lipidil 100 mg/capsule or 2 tablets of Lipidil 80 mg/tablet). Arm 3 (ezetimibe group): ezetimibe (10 mg/day) We only included Arm 1 and Arm 2. Details of any 'run‐in' period: Quote: "If patients were under medication for dyslipidaemia, the study began with a 4‐week washout period, which was followed by a 4‐week observation period and 52‐week treatment period. Treatment‐naïve patients did not go through the washout period. During the observation period, patients who had been screened for eligibility were enrolled and randomly assigned." Concomitant medications: not reported Excluded medications: not reported
Outcomes	Primary: per cent changes in LDL‐C and TG concentrations. Secondary: the incidence of adverse events, including the incidence of gallstones detected by abdominal ultrasound; the incidence of abnormal findings for safety variables, including laboratory tests and physical examination; and the per cent change in HDL‐C. Others: per cent change in other lipid variables (high‐sensitivity assays for lipoprotein lipase (LPL), remnant lipoprotein cholesterol (RemL‐C), LDL particle size, HDL particle size, apolipoprotein (apo) A‐I, A‐II, B, B‐48, C‐II, C‐III, E, and phospholipid hydroperoxide); non‐lipid variables (high‐sensitivity assay for C‐reactive protein (hsCRP), adiponectin); per cent change in lipid variables in patients with familial combined hyperlipidaemia; trends in concentrations of serum lipid subclasses. In the results section of the article, the study reported one case of fatal arrhythmia occurred during the study. However, the investigator concluded that there was no causal relationship between arrhythmia and experimental drugs.
Notes	Funding: Quote: "the study were provided to the Comprehensive Support Project for Clinical Research of Lifestyle‐Related Disease of the Public Health Research Foundation, the Secretariat of the study, by Aska Pharmaceutical Co., Ltd., the manufacturer of fenofibrate.". "Neither the funder nor the sponsor had any role in study design, collection, analysis, or interpretation of data, writing the report, or the decision to submit the report for publication." UMIN000001224
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The allocation schedule was created by a data center. Random numbers were generated with the SAS for Windows release 9.1.3 statistical software program. "
Allocation concealment (selection bias)	Low risk	Quote: "The allocation schedule was created by a data center"; "A central registration system at the data center was used to ensure that allocation was concealed from other researchers".
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study, no blinding of participants and personnel.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Samples for the analysis of endpoints were tested at a central laboratory"; low risk of bias for mortality.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "9 patients in the combination group and 6 patients in the fenofibrate group were never treated with the study drug or drugs. Moreover, 2 patients in the combination group, 1 in the fenofibrate group were removed for protocol violations because of administration of the wrong study drug for their assigned group". Of the patients who completed the 52‐week treatments, 12 patients were found to have been ineligible (9 in the combination group, 1 in the fenofibrate group, and 2 in the ezetimibe group). These patients were included in the analysis."
Selective reporting (reporting bias)	Low risk	No protocol published, but a pre‐registration in a clinical trial registry was found (UMIN000001224). All prespecified outcomes were reported.
Other bias	Low risk	The study was industry funded, but neither the funder nor the sponsor had any role in study design, collection, analysis, or interpretation of data, writing the report, or the decision to submit the report for publication.