Efficacy of LCQ908 on Cardiovascular Risk

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

Detailed Description
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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.

Official Title
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A Randomized, Double-blind, Placebo Controlled Study to Assess the Efficacy of LCQ908 on Cardiovascular Risk

Conditions
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Coronary Artery Disease, Hypertriglyceridemia

Intervention / Treatment
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* Drug: pradigastat (LCQ908)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pradigastat (LCQ908) followed by placebo<br>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 | Drug: pradigastat (LCQ908)<br>* pradigastat tablets were supplied to the investigators at dose strengths of 10 mg and 20 mg as individual patient packs.<br>* Other names: Pradigastat;Drug: Placebo<br>* matching placebo tablets<br>|
| Experimental: Placebo followed by pradigastat (LCQ908)<br>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 | Drug: pradigastat (LCQ908)<br>* pradigastat tablets were supplied to the investigators at dose strengths of 10 mg and 20 mg as individual patient packs.<br>* Other names: Pradigastat;Drug: Placebo<br>* matching placebo tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Myocardial Perfusion Reserve Index (MPRi) Overall Mean (Part A, Cohort 1) | 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. | Baseline, and on day 5 of each of the two treatment periods | 
| Change From Baseline in Total Exercise Duration (Part A, Cohort 1) | 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. | Baseline and on day 5 of each of the two treatment periods | 
| Time to Onset of Angina (Part A, Cohort 1) | 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. | Baseline and on day 5 of each of the two treatment periods | 
| Time to Onset of Exercise-induced Ischemia(Part A, Cohort 1) | 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. | Baseline and on day 5 of each of the two treatment periods | 
| Aortic Plaque Inflammation (Part B) | This endpoint was palnned for analysis on Part B patients which was never started becasue study got terminated on Part A interim analysis. | Baseline and on treatment day 85 +/- 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (Part A, Cohort 1) |  | approximately 40 days | 
| Number of Participants With Adverse Events (Part A, Cohort 2) |  | approximately 40 days | 
| Postprandial Triglycerides (Part A, Cohort 1) | 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. | 0 hour (before breakfast), 2 and 4 hours post high-fat breakfast on day 5 | 
| Postprandial Triglycerides (Part A, Cohort 2) | 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. | 0 hour (before breakfast), 2 and 4 hours post high-fat breakfast on day 5 | 
| Pharmacokinetics of Pradigastat (LCQ908): Plasma Concentration (Part A) |  | Part A: Day 4 and day 5 of each treatment period | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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coronary artery disease,, LCQ908,, hyperlipidemia,, hypertriglyceridemia,, pradigastat