NK‐104.203 2013.

Study characteristics
Methods	Study design: Randomised controlled trial Study grouping: Parallel group Methods: 4‐week placebo washout run‐in period; 12‐week randomised double‐blind placebo‐controlled study with evening dosing
Participants	Baseline Characteristics 1 mg n: 49 Total cholesterol: 281.85 mg/dL (7.29 mmol/L) LDL cholesterol: 177.6 mg/dL (4.59 mmol/L) HDL cholesterol: 50.2 mg/dL (1.30 mmol/L) Triglycerides: 274.3 mg/dL (3.10 mmol/L) 2 mg n: 50 Total cholesterol: 281.85 mg/dL (7.29 mmol/L) LDL cholesterol: 177.6 mg/dL (4.59 mmol/L) HDL cholesterol: 50.2 mg/dL (1.30 mmol/L) Triglycerides: 274.3 mg/dL (3.10 mmol/L) 4 mg n: 48 Total cholesterol: 289.58 mg/dL (7.49 mmol/L) LDL cholesterol: 181.5 mg/dL (4.69 mmol/L) HDL cholesterol: 54.1 mg/dL (1.40 mmol/L) Triglycerides: 274.3 mg/dL (3.10 mmol/L) Placebo n: 50 Total cholesterol: 281.85 mg/dL (7.29 mmol/L) LDL cholesterol: 181.5 mg/dL (4.69 mmol/L) HDL cholesterol: 46.3 mg/dL (1.20 mmol/L) Triglycerides: 265.5 mg/dL (3.00 mmol./L) Overall n: 197 Included criteria: 18‐75 years; females of childbearing potential to be on oral contraception of at least 3 months; and willingness to adhere to the National Cholesterol Education Program (NCEP) Step‐1 or equivalent diet. Subjects had primary mixed or combined hyperlipidaemia with LDL‐C level ≥ 135 and ≤ 300 mg/dL (≥ 3.5 and ≤ 7.8 mmol/L) and TG ≥ 175 and ≤ 500 mg/dL (≥ 2.0 and ≤ 5.7 mmol/L). Excluded criteria: pregnancy, or not taking oral contraception; • BMI > 33 kg/m2; • alcohol abuse; • hypersensitivity to HMG‐CoA reductase inhibitors; • use of prohibited concomitant medications; • compliance 80% during run in period; • diabetes or fasting serum glucose ≥ 7 mmol/L at Visit 2; • renal impairment or serum creatinine > 1.8 mg/dL or nephrotic syndrome; • uncontrolled hypertension or diastolic blood pressure (DBP) ≥110 mmHg or systolic blood pressure (SBP) ≥ 180 mmHg; • history of myocardial infarction, unstable angina, stroke, transient ischaemic attack (TIA), percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG); • NYHA class 3 or 4 congestive cardiac failure; • active liver disease or AST or alanine aminotransferase (ALT) > 2 times ULN; • muscular or neuromuscular disease or creatinine kinase (CK) > 3 times ULN without explanation; • malignancy within past 10 years; • known cataracts; • human immunodeficiency virus (HIV) infection; • severe depression or suicidal tendencies; • Type I, IIb, III, IV or V hyperlipidaemia; • familial hypercholesterolaemia or LDL‐C > 250 mg/dL at Visit 3; and • hypercholesterolaemia secondary to hypothyroidism Baseline Group Characteristics:NR
Interventions	Intervention Characteristics 1 mg 2 mg 4 mg Placebo
Outcomes	LDL cholesterol Outcome type: Continuous Unit of measure: Percentage change from baseline Direction: Lower is better Total cholesterol Outcome type: Continuous Unit of measure: Percentage change from baseline Direction: Lower is better HDL cholesterol Outcome type: Continuous Unit of measure: Percentage change from baseline Direction: Higher is better Triglycerides Outcome type: Continuous Unit of measure: Percentage change from baseline Direction: Lower is better WDAE Outcome type: Dichotomous
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Judgement Comment: Method of sequence generation was not reported.
Allocation concealment (selection bias)	Low risk	Judgement Comment: A centralised randomising system was used.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Judgement Comment: double‐blind. Study medication was blinded and investigators did not receive lipid values during treatment period until after study completion.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Judgement Comment: Lipid parameters were measured in a remote laboratory.
Selective reporting (reporting bias)	Low risk	Judgement Comment: LDL cholesterol outcome was reported.
Other bias	High risk	Judgement Comment: The study was sponsored by Laboratories Negma, a pharmaceutical company in France.
Incomplete outcome data (attrition bias) Total cholesterol	Low risk	[(261 ‐ 251)/261)]*100 = 3.8% participants were not included in the efficacy analysis.
Incomplete outcome data (attrition bias) LDL cholesterol)	Low risk	[(261 ‐ 251)/261)]*100 = 3.8% participants were not included in the efficacy analysis.
Incomplete outcome data (attrition bias) HDL cholesterol	Low risk	[(261 ‐ 251)/261)]*100 = 3.8% participants were not included in the efficacy analysis.
Incomplete outcome data (attrition bias) Triglycerides	Low risk	[(261 ‐ 251)/261)]*100 = 3.8% participants were not included in the efficacy analysis.
Blinding of outcome assessment (detection bias)WDAEs	Unclear risk	Blinding method was not described.
Selective reporting (reporting bias) for WDAEs	Low risk	WDAE outcome reported