Efficacy of LCQ908 on Cardiovascular Risk

Phase 2

Terminated

Conditions: Hypertriglyceridemia
Coronary Artery Disease

Interventions: Drug: pradigastat (LCQ908)
Drug: Placebo

Registration Number: NCT01474434

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This is a study designed to evaluate the potential for the pradigastat (LCQ908) to impact cardiovascular risk.

Detailed Description: This study had 2 parts. Part A was a multicenter, double-blind, randomized, placebo-controlled, non-confirmatory crossover study assessing response to a high-fat meal challenge in the setting of pradigastat versus placebo. Part A had 2 cohorts i.e. Cohort 1 patients with stable coronary artery disease and hypertriglyceridemia and Cohort 2 patients with asymptomatic non-obstructive coronary artery disease or elevated coronary heart disease risk and hypertriglyceridemia.

Part B was a double blinded phase designed to assess response to three months of chronic treatment with pradigastat versus placebo on a normal diet.

The trial was terminated after the interim analysis of Part A, Cohort 1. The interim analysis results indicated that the high-fat meal challenge did not induce any impairment on either myocardial perfusion reserve index (MPRi) or exercise treadmill performance. Part B was never started.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 41

Inclusion Criteria

History of coronary artery disease
Elevated triglycerides
On medication to help lower cholesterol

Exclusion Criteria

Poorly controlled diabetic patients and/or change in diabetic medication within 12 weeks of screening
History of myocardial infarction (heart attack) within 6 months of screening
History of a procedure to open a blocked coronary artery within 12 months of enrollment
History of Coronary Artery Bypass Graft (CABG) surgery
History of congestive heart failure
History of significant heart valve disease

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo followed by pradigastat (LCQ908)	pradigastat (LCQ908)	Placebo (5-day treatment period) followed by a 30-day washout period followed by pradigastat 80 mg (4 x 20-mg tablets) loading dose daily for three days followed by p20 mg (2 x 10-mg tablets) daily for two days
Pradigastat (LCQ908) followed by placebo	pradigastat (LCQ908)	Pradigastat 80 mg (4 x 20-mg tablets) loading dose daily for three days followed by pradigastat 20 mg (2 x 10-mg tablets) daily for two days followed by a 30-day washout period in between followed by 5-day placebo treatment
Placebo followed by pradigastat (LCQ908)	Placebo	Placebo (5-day treatment period) followed by a 30-day washout period followed by pradigastat 80 mg (4 x 20-mg tablets) loading dose daily for three days followed by p20 mg (2 x 10-mg tablets) daily for two days
Pradigastat (LCQ908) followed by placebo	Placebo	Pradigastat 80 mg (4 x 20-mg tablets) loading dose daily for three days followed by pradigastat 20 mg (2 x 10-mg tablets) daily for two days followed by a 30-day washout period in between followed by 5-day placebo treatment

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Myocardial Perfusion Reserve Index (MPRi) Overall Mean (Part A, Cohort 1)	Baseline, and on day 5 of each of the two treatment periods	MPRi (myocardial perfusion reserve index) is a measure of coronary microvascular function. Myocardial perfusion scans using 0.05 mmol/kg of gadolinium contrast were acquired at rest and under stress (pharmacological stress induced with adenosine 140 μg/kg/min for three minutes). An independent central reader performed the cardiac image analysis of all time points including the calculation of the myocardial perfusion reserve index from the ratio of the global stress myocardial blood flow divided by the resting blood flow values. Higher/increased index indicates improved flow/better outcome. This primary endpoint was only for Part A, Cohort 1 patients.
Aortic Plaque Inflammation (Part B)	Baseline and on treatment day 85 +/- 3 days	This endpoint was palnned for analysis on Part B patients which was never started becasue study got terminated on Part A interim analysis.
Time to Onset of Angina (Part A, Cohort 1)	Baseline and on day 5 of each of the two treatment periods	Time to onset of angina was defined as the elapsed time between the start of exercise and the onset of anginal chest pain as reported by the patient and recorded by the performing investigator.
Change From Baseline in Total Exercise Duration (Part A, Cohort 1)	Baseline and on day 5 of each of the two treatment periods	Total exercise duration was the elapsed time between the start of exercise and termination of exercise for severe angina, dyspnea or extreme fatigue. This primary endpoint was only for Part A, Cohort 1 patients.
Time to Onset of Exercise-induced Ischemia(Part A, Cohort 1)	Baseline and on day 5 of each of the two treatment periods	Exercise-induced ischemia was defined as the new development of horizontal or down-sloping ST-segment depression (≥ 1mm at 60 milliseconds after the J point) versus baseline tracings.

Secondary Outcome Measures

Name	Time	Method
Postprandial Triglycerides (Part A, Cohort 2)	0 hour (before breakfast), 2 and 4 hours post high-fat breakfast on day 5	For both each treatment period, postprandial triglycerides were measured on Day 5 i.e. on 0 hour (before breakfast), two hours and four hours post high-fat breakfast. Results are from an ANCOVA model on change from baseline in the log domain with log(baseline), treatment, sequence and period as fixed effects. Baseline is the Day -1 value within period. The data reported is ratio of geometric mean between post-treatment and baseline data.
Number of Participants With Adverse Events (Part A, Cohort 2)	approximately 40 days
Other Related Lipid Parameters (Part A)	Baseline, day 4 and day 5 of each treatment period
Interleukin-6 (IL-6) Level (Part A)	Baseline, day 4 and day 5, of each treatment period
C-reactive Protein (CRP) Level (Part A)	Baseline, day 4 and day 5, of each treatment period
Adiponectin Level ( Part B)	Part B; Baseline, day 15, day 43 and day 85
Postprandial Triglycerides (Part A, Cohort 1)	0 hour (before breakfast), 2 and 4 hours post high-fat breakfast on day 5	For both each treatment period, postprandial triglycerides were measured on Day 5 i.e. on 0 hour(before breakfast), two hours and four hours post high-fat breakfast. Results are from an ANCOVA model on change from baseline in the log domain with log(baseline), treatment, sequence and period as fixed effects. Baseline is the Day -1 value within period. The data reported is ratio of geometric mean between post-treatment and baseline data.
Number of Participants With Adverse Events (Part A, Cohort 1)	approximately 40 days
Pharmacokinetics of Pradigastat (LCQ908): Plasma Concentration (Part A)	Part A: Day 4 and day 5 of each treatment period