Coronary Artery Disease, Hypertriglyceridemia
Conditions
Keywords
coronary artery disease,, LCQ908,, hyperlipidemia,, hypertriglyceridemia,, pradigastat
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.
Interventions
DRUGpradigastat (LCQ908)
pradigastat tablets were supplied to the investigators at dose strengths of 10 mg and 20 mg as individual patient packs.
DRUGPlacebo
matching placebo tablets
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 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. |
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Other Related Lipid Parameters (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 | — |
| Number of Participants With Adverse Events (Part A, Cohort 1) | approximately 40 days | — |
| C-reactive Protein (CRP) Level (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 | — |
| Number of Participants With Adverse Events (Part A, Cohort 2) | approximately 40 days | — |
| 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. |
| 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. |
| Pharmacokinetics of Pradigastat (LCQ908): Plasma Concentration (Part A) | Part A: Day 4 and day 5 of each treatment period | — |
Countries
United States
Participant flow
Recruitment details
Study was terminated upon Part A interim analysis. Total 41 patients randomized to Part A i.e.17 patients in cohort 1 and 24 patients in Cohort 2.
Participants by arm
| Arm | Count |
|---|---|
| Part A, Cohort 1: Pradigastat (LCQ908) Followed by Placebo Cohort 1 consisted of patients with evidence of stable symptomatic or obstructive coronary artery disease and mild to moderate hypertriglyceridemia. All patients who randomized to this sequence received 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 | 8 |
| Part A, Cohort 1: Placebo Followed by Pradigastat (LCQ908) Cohort 1 consisted of patients with evidence of stable symptomatic or obstructive coronary artery disease and mild to moderate hypertriglyceridemia. All patients who randomized to this sequence received 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 20 mg (2 x 10-mg tablets) daily for two days | 9 |
| Part A, Cohort 2: Pradigastat (LCQ908) Followed by Placebo Cohort 2 consisted of patients with stable asymptomatic non-obstructive coronary artery disease or coronary heart disease risk equivalents and mild to moderate hypertriglyceridemia.. All patients who randomized to this sequence received 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 | 11 |
| Part A, Cohort 2: Placebo Followed by Pradigastat (LCQ908) Cohort 2 consisted of patients with stable asymptomatic non-obstructive coronary artery disease or coronary heart disease risk equivalents and mild to moderate hypertriglyceridemia. All patients who randomized to this sequence received 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 20 mg (2 x 10-mg tablets) daily for two days | 13 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Treatment Period 1 (5 Days [Day 1 - 5]) | Adverse Event | 0 | 0 | 1 | 1 |
| Treatment Period 1 (5 Days [Day 1 - 5]) | Protocol deviation | 1 | 0 | 0 | 0 |
| Treatment Period 1 (5 Days [Day 1 - 5]) | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Part A, Cohort 1: Pradigastat (LCQ908) Followed by Placebo | Part A, Cohort 1: Placebo Followed by Pradigastat (LCQ908) | Part A, Cohort 2: Pradigastat (LCQ908) Followed by Placebo | Part A, Cohort 2: Placebo Followed by Pradigastat (LCQ908) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 59.6 years STANDARD_DEVIATION 6.67 | 58.4 years STANDARD_DEVIATION 8.79 | 56.7 years STANDARD_DEVIATION 9.79 | 56.1 years STANDARD_DEVIATION 8.85 | 57.5 years STANDARD_DEVIATION 8.5 |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 4 Participants | 6 Participants | 16 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 7 Participants | 7 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 17 | 6 / 17 | 22 / 24 | 13 / 24 |
| serious Total, serious adverse events | 0 / 17 | 0 / 17 | 0 / 24 | 1 / 24 |
Outcome results
Primary
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.
Time frame: Baseline and on treatment day 85 +/- 3 days
Population: The study was terminated based on the interim analysis after patients completed Part A. Part B of the study was never started.
Primary
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.
Time frame: Baseline, and on day 5 of each of the two treatment periods
Population: Efficacy analysis set - Patients who took \> 80% of study drug as assessed by drug accountability, had no major protocol deviations, and had a valid assessment of MPRi at both baseline and post-treatment visits. Patients who had no baseline or post-treatment MPRi data in 1 of 2 periods were excluded from the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A, Cohort 1: Pradigastat (LCQ908) | Change From Baseline in Myocardial Perfusion Reserve Index (MPRi) Overall Mean (Part A, Cohort 1) | -0.22 myocardial perfusion reserve index | Standard Error 0.24 |
| Part A, Cohort 1: Placebo | Change From Baseline in Myocardial Perfusion Reserve Index (MPRi) Overall Mean (Part A, Cohort 1) | 0.32 myocardial perfusion reserve index | Standard Error 0.24 |
Primary
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.
Time frame: Baseline and on day 5 of each of the two treatment periods
Population: Efficacy analysis set- Patients who took \> 80% of study drug as assessed by drug accountability, had no major protocol deviations, and had a valid assessment of total exercise duration at both baseline and post-treatment visits. Patients who had no baseline or post-treatment exercise duration data in 1 of 2 periods were excluded from the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A, Cohort 1: Pradigastat (LCQ908) | Change From Baseline in Total Exercise Duration (Part A, Cohort 1) | -1.52 minute | Standard Error 0.46 |
| Part A, Cohort 1: Placebo | Change From Baseline in Total Exercise Duration (Part A, Cohort 1) | -1.00 minute | Standard Error 0.4 |
Primary
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.
Time frame: Baseline and on day 5 of each of the two treatment periods
Population: The study was terminated based on the interim analysis after patients completed Part A. This outcome measure was not part of interim analysis; hence it is not done. .
Primary
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.
Time frame: Baseline and on day 5 of each of the two treatment periods
Population: The study was terminated based on the interim analysis after patients completed Part A. This outcome measure was not part of interim analysis; hence it is not done. .
Secondary
Adiponectin Level ( Part B)
Time frame: Part B; Baseline, day 15, day 43 and day 85
Population: The study was terminated based on the interim analysis on Part A, cohort 1 after patients completed Part A. Part B of the study was not commenced.
Secondary
C-reactive Protein (CRP) Level (Part A)
Time frame: Baseline, day 4 and day 5, of each treatment period
Population: The study was terminated based on the interim analysis on Part A, Cohort 1 after patients completed Part A. The analysis of this assessment was not part of interim analysis; hence it is not done.
Secondary
Interleukin-6 (IL-6) Level (Part A)
Time frame: Baseline, day 4 and day 5, of each treatment period
Population: The study was terminated based on the interim analysis on Part A, Cohort 1 after patients completed Part A. The analysis of this assessment was not part of interim analysis; hence it is not done.
Secondary
Number of Participants With Adverse Events (Part A, Cohort 1)
Time frame: approximately 40 days
Population: The safety analysis set included all patients who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A, Cohort 1: Pradigastat (LCQ908) | Number of Participants With Adverse Events (Part A, Cohort 1) | Any Adverse Events | 16 Participants |
| Part A, Cohort 1: Pradigastat (LCQ908) | Number of Participants With Adverse Events (Part A, Cohort 1) | Serious Adverse Events | 0 Participants |
| Part A, Cohort 1: Pradigastat (LCQ908) | Number of Participants With Adverse Events (Part A, Cohort 1) | Death | 0 Participants |
| Part A, Cohort 1: Placebo | Number of Participants With Adverse Events (Part A, Cohort 1) | Any Adverse Events | 6 Participants |
| Part A, Cohort 1: Placebo | Number of Participants With Adverse Events (Part A, Cohort 1) | Serious Adverse Events | 0 Participants |
| Part A, Cohort 1: Placebo | Number of Participants With Adverse Events (Part A, Cohort 1) | Death | 0 Participants |
Secondary
Number of Participants With Adverse Events (Part A, Cohort 2)
Time frame: approximately 40 days
Population: The safety analysis set included all patients who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A, Cohort 1: Pradigastat (LCQ908) | Number of Participants With Adverse Events (Part A, Cohort 2) | Any Adverse Events | 22 Participants |
| Part A, Cohort 1: Pradigastat (LCQ908) | Number of Participants With Adverse Events (Part A, Cohort 2) | Serious Adverse Events | 0 Participants |
| Part A, Cohort 1: Pradigastat (LCQ908) | Number of Participants With Adverse Events (Part A, Cohort 2) | Death | 0 Participants |
| Part A, Cohort 1: Placebo | Number of Participants With Adverse Events (Part A, Cohort 2) | Any Adverse Events | 15 Participants |
| Part A, Cohort 1: Placebo | Number of Participants With Adverse Events (Part A, Cohort 2) | Serious Adverse Events | 1 Participants |
| Part A, Cohort 1: Placebo | Number of Participants With Adverse Events (Part A, Cohort 2) | Death | 0 Participants |
Secondary
Other Related Lipid Parameters (Part A)
Time frame: Baseline, day 4 and day 5 of each treatment period
Population: The study was terminated based on the interim analysis on Part A, Cohort 1 after patients completed Part A. The analysis of this assessment was not part of interim analysis; hence it is not done.
Secondary
Pharmacokinetics of Pradigastat (LCQ908): Plasma Concentration (Part A)
Time frame: Part A: Day 4 and day 5 of each treatment period
Population: The study was terminated based on the interim analysis on Part A, Cohort 1 after patients completed Part A. The analysis of this assessment was not part of interim analysis; hence it is not done.
Secondary
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.
Time frame: 0 hour (before breakfast), 2 and 4 hours post high-fat breakfast on day 5
Population: The efficacy analysis set included all patients who took more than 80% of study medication as assessed by drug accountability, had no major protocol deviations, and had a valid assessment of the primary efficacy variables at both baseline and post treatment visits.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A, Cohort 1: Pradigastat (LCQ908) | Postprandial Triglycerides (Part A, Cohort 1) | Day 5 Hr 4 | 1.29 ratio | Standard Error 1.09 |
| Part A, Cohort 1: Pradigastat (LCQ908) | Postprandial Triglycerides (Part A, Cohort 1) | Day 5 Hr 0 | 1.15 ratio | Standard Error 1.08 |
| Part A, Cohort 1: Pradigastat (LCQ908) | Postprandial Triglycerides (Part A, Cohort 1) | Day 5 Hr 2 | 1.21 ratio | Standard Error 1.08 |
| Part A, Cohort 1: Placebo | Postprandial Triglycerides (Part A, Cohort 1) | Day 5 Hr 2 | 1.40 ratio | Standard Error 1.07 |
| Part A, Cohort 1: Placebo | Postprandial Triglycerides (Part A, Cohort 1) | Day 5 Hr 0 | 0.97 ratio | Standard Error 1.08 |
| Part A, Cohort 1: Placebo | Postprandial Triglycerides (Part A, Cohort 1) | Day 5 Hr 4 | 1.71 ratio | Standard Error 1.08 |
Secondary
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.
Time frame: 0 hour (before breakfast), 2 and 4 hours post high-fat breakfast on day 5
Population: The efficacy analysis set included all patients who took more than 80% of study medication as assessed by drug accountability, had no major protocol deviations, and had a valid assessment of the primary efficacy variables at both baseline and post treatment visits.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A, Cohort 1: Pradigastat (LCQ908) | Postprandial Triglycerides (Part A, Cohort 2) | Day 5 Hr 0 | 1.16 ratio | Standard Error 1.08 |
| Part A, Cohort 1: Pradigastat (LCQ908) | Postprandial Triglycerides (Part A, Cohort 2) | Day 5 Hr 2 | 1.15 ratio | Standard Error 1.07 |
| Part A, Cohort 1: Pradigastat (LCQ908) | Postprandial Triglycerides (Part A, Cohort 2) | Day 5 Hr 4 | 1.14 ratio | Standard Error 1.08 |
| Part A, Cohort 1: Placebo | Postprandial Triglycerides (Part A, Cohort 2) | Day 5 Hr 0 | 1.09 ratio | Standard Error 1.08 |
| Part A, Cohort 1: Placebo | Postprandial Triglycerides (Part A, Cohort 2) | Day 5 Hr 2 | 1.38 ratio | Standard Error 1.07 |
| Part A, Cohort 1: Placebo | Postprandial Triglycerides (Part A, Cohort 2) | Day 5 Hr 4 | 1.56 ratio | Standard Error 1.08 |