Type II Hyperlipidemia
Conditions
Keywords
Randomized, Double-Blind, Placebo Controlled, Parallel Arm, Type II Hyperlipidemia, Cholesteryl Ester Transferase Protein Inhibitor, CETP Inhibitor
Brief summary
The purpose of this study is to determine if a new drug, DRL-17822, is safe and effective in elevating high density lipoprotein cholesterol (HDL-C) and reducing low density lipoprotein cholesterol (LDL-C) in people with abnormal cholesterol levels that may put them at risk for heart disease.
Detailed description
Cardiovascular disease is a leading cause of death worldwide. Among cardiovascular disorders, coronary heart disease (CHD) caused by atherosclerosis is the most common cause of morbidity and mortality. Prevention, stabilization and regression of atherosclerotic plaques may have a major impact on reducing the risk of acute coronary events. LDL-C lowering agents, primarily the statins, are the current mainstay in the pharmacologic management of dyslipidemia. However even with stain use, residual CHD risk from dyslipidemia remains. Epidemiologic and observational studies have shown that HDL-C is also a strong independent predictor of CHD, suggesting that raising HDL-C levels might afford clinical benefit in the reduction of cardiovascular risk. Presently only niacin is approved by the FDA for HDL-C elevation and can raise HDL-C levels by 20-30%. However its use can be limited by a high incidence of flushing and, less commonly, by elevation of blood glucose and potential hepatic toxicity. Cholesteryl ester transfer protein (CETP) inhibitors are being explored for their ability to elevate HDL-C. A small molecule CETP inhibitor, torcetrapib, has been demonstrated to elevate HDL-C by 60-100%. However, a large clinical trial (ILLUMINATE) where it increased HDL-C by a mean of 72% compared to baseline was halted as it failed to show benefit. Post-hoc analysis of this study implicated an off-target increase in blood pressure as potentially counteracting any anti-atherosclerotic benefits. Post-hoc subgroup analysis showed that patients in the highest HDL-C quartile had a 57% reduction in the risk of cardiovascular events. Increased blood pressure appears to be specifically related to torcetrapib as two other small molecule CETP inhibitors, anacetrapib and dalcetrapib, have not shown this in clinical trials and have been well tolerated. DRL-17822 has also not shown elevation of blood pressure in either animals or in normal volunteers. This study will investigate the efficacy and tolerability of DRL-17822 as dyslipidemia monotherapy in patients with Type II hyperlipidemia.
Interventions
DRUGDRL-17822 or placebo
DRL-17822 50, 150 or 300 mg or matching placebo once daily after breakfast
Sponsors
PharmaNet
Dr. Reddy's Laboratories Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients with Type II hyperlipidemia having lipid values of HDL-C: males ≤ 44 mg/dL (≤1.13 mmol/L), females ≤ 54 mg/dL (≤1.39 mmol/L); LDL-C: ≥ 130 mg/dL (≥3.33 mmol/L); * Male or female, 18 to 70 years of age, inclusive. Female patients must be postmenopausal or surgically sterile. Men, unless surgically sterile must practice birth control from screening until the end of the study; * Ability and willingness to give written informed consent; * No clinically significant abnormal findings on medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory profiles of both blood and urine.
Exclusion criteria
* Patients with significant cardiac disease such as myocardial infarction, heart failure, coronary or peripheral artery angioplasty, bypass graft surgery, severe or unstable angina pectoris, cardiac arrhythmias, hypertension or any other disease which requires treatment; * Uncontrolled diabetes (HbA1c \> 8.0%); * History of symptomatic cerebrovascular disease such as symptomatic carotid artery disease, cerebrovascular hemorrhage, transient ischemic attack or carotid endarterectomy or any disease which requires treatment; * History of clinically significant hematologic, renal, hepatic, neurologic, endocrine, oncologic, pulmonary, immunologic or psychiatric disorders; * Any current or recent (within 4 weeks of run-in) concomitant therapy (apart from paracetamol/acetaminophen and non-steroidal anti-inflammatory drugs \[NSAIDs\]). Patients on previous concomitant treatment may enter the study if the treatment has been discontinued, when appropriate and if ethically justified, at least four weeks prior to run-in; * Body mass index (BMI)\> 35 kg/m(2); * Positive for hepatitis B, C or HIV or known history or concurrent tuberculosis; * Positive drug screen result (i.e., cocaine, opiates, amphetamine, cannabis, barbiturates, benzodiazepines and/or metadone); * Pregnant, breast feeding or women of child-bearing potential; * Regular use of non-drug therapies such as garlic supplements and St. John's Wort; * Presence or history of alcoholism or drug abuse; * Use of more than 21 units of alcohol per week for males or more than 14 units per week for females; * Smoking within 3 months prior to screening; * Relevant drug hypersensitivity or allergy or any serious adverse event reaction to lipid regulating agents; * Administration of study drug in another drug study within 90 days prior to enrollment or participation in another drug trial from screening to last follow-up of this study; Any surgical or medical condition which makes the patient unsuitable to participate in the opinion of the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in HDL-C From Baseline | 28 days | Percent change from baseline in HDL-C after 28 days of treatment in patients with Type II hyperlipidemia |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of DRL-17822 | 28 days | Incidence of treatment-related adverse events |
| Changes in Vital Signs Including Blood Pressure | 28 days | Vital sign abnormalities reported as treatment-emergent AEs |
| To Evaluate Trough Levels of DRL-17822 in Plasma | 28 days | Trough levels of DRL-17822 in plasma after 28 days of treatment |
| Changes in CETP Inhibition in Plasma | 28 days | Percent change from baseline in CETP Inhibition |
| Changes in Other Lipids and Apolipoproteins | 28 days | Change from baseline (LOCF, ITT population) |
Countries
Italy, Poland, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Capsule Once daily after breakfast | 45 |
| DRL-17822 50 mg Once daily after breakfast | 43 |
| DRL-17822 150 mg Once daily after breakfast | 44 |
| DRL-17822 300 mg Once daily after breakfast | 44 |
| Total | 176 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo Capsule | Total | DRL-17822 300 mg | DRL-17822 150 mg | DRL-17822 50 mg |
|---|---|---|---|---|---|
| Age, Continuous | 57.0 Years STANDARD_DEVIATION 8.49 | 55.8 Years STANDARD_DEVIATION 9.91 | 56.2 Years STANDARD_DEVIATION 10.74 | 54.2 Years STANDARD_DEVIATION 10.48 | 55.8 Years STANDARD_DEVIATION 9.93 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 45 Participants | 175 Participants | 44 Participants | 43 Participants | 43 Participants |
| Sex: Female, Male Female | 28 Participants | 99 Participants | 26 Participants | 19 Participants | 26 Participants |
| Sex: Female, Male Male | 17 Participants | 77 Participants | 18 Participants | 25 Participants | 17 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 | 8 / 45 | 4 / 43 | 6 / 43 | 2 / 44 |
| serious Total, serious adverse events | 1 / 45 | 1 / 43 | 0 / 43 | 0 / 44 |
Outcome results
Primary
Percent Change in HDL-C From Baseline
Percent change from baseline in HDL-C after 28 days of treatment in patients with Type II hyperlipidemia
Time frame: 28 days
Population: Intention to treat (ITT) analysis with last observation carried forward (LOCF) for missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Capsule | Percent Change in HDL-C From Baseline | 3.2 percent change from baseline | 95% Confidence Interval 16.723 |
| DRL-17822 50 mg | Percent Change in HDL-C From Baseline | 84.2 percent change from baseline | 95% Confidence Interval 42 |
| DRL-17822 150 mg | Percent Change in HDL-C From Baseline | 122.1 percent change from baseline | 95% Confidence Interval 60.035 |
| DRL-17822 300 mg | Percent Change in HDL-C From Baseline | 160.6 percent change from baseline | 95% Confidence Interval 57.325 |
Secondary
Changes in CETP Inhibition in Plasma
Percent change from baseline in CETP Inhibition
Time frame: 28 days
Population: ITT with LOCF
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Capsule | Changes in CETP Inhibition in Plasma | 7.2 percentage from baseline |
| DRL-17822 50 mg | Changes in CETP Inhibition in Plasma | 60.5 percentage from baseline |
| DRL-17822 150 mg | Changes in CETP Inhibition in Plasma | 79.7 percentage from baseline |
| DRL-17822 300 mg | Changes in CETP Inhibition in Plasma | 82.0 percentage from baseline |
Secondary
Changes in Other Lipids and Apolipoproteins
Change from baseline (LOCF, ITT population)
Time frame: 28 days
Population: ITT with LOCF
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo Capsule | Changes in Other Lipids and Apolipoproteins | LDL-C | 4.9 percentage change from baseline |
| Placebo Capsule | Changes in Other Lipids and Apolipoproteins | HDL-C/LDL-C Ratio | 0.6 percentage change from baseline |
| Placebo Capsule | Changes in Other Lipids and Apolipoproteins | Total Cholesterol | 1.5 percentage change from baseline |
| Placebo Capsule | Changes in Other Lipids and Apolipoproteins | Triglycerides | 4.5 percentage change from baseline |
| Placebo Capsule | Changes in Other Lipids and Apolipoproteins | Apo A1 | 1.8 percentage change from baseline |
| Placebo Capsule | Changes in Other Lipids and Apolipoproteins | Apo B | 2.9 percentage change from baseline |
| Placebo Capsule | Changes in Other Lipids and Apolipoproteins | Apo E | 3.9 percentage change from baseline |
| Placebo Capsule | Changes in Other Lipids and Apolipoproteins | Apo Lp(a) | 2.8 percentage change from baseline |
| DRL-17822 50 mg | Changes in Other Lipids and Apolipoproteins | Apo B | -15.1 percentage change from baseline |
| DRL-17822 50 mg | Changes in Other Lipids and Apolipoproteins | Apo A1 | 35.0 percentage change from baseline |
| DRL-17822 50 mg | Changes in Other Lipids and Apolipoproteins | HDL-C/LDL-C Ratio | 140.6 percentage change from baseline |
| DRL-17822 50 mg | Changes in Other Lipids and Apolipoproteins | Apo Lp(a) | -26.2 percentage change from baseline |
| DRL-17822 50 mg | Changes in Other Lipids and Apolipoproteins | Apo E | 2.6 percentage change from baseline |
| DRL-17822 50 mg | Changes in Other Lipids and Apolipoproteins | Triglycerides | -14.2 percentage change from baseline |
| DRL-17822 50 mg | Changes in Other Lipids and Apolipoproteins | Total Cholesterol | -0.9 percentage change from baseline |
| DRL-17822 50 mg | Changes in Other Lipids and Apolipoproteins | LDL-C | -15.4 percentage change from baseline |
| DRL-17822 150 mg | Changes in Other Lipids and Apolipoproteins | Apo E | 10.9 percentage change from baseline |
| DRL-17822 150 mg | Changes in Other Lipids and Apolipoproteins | Total Cholesterol | -0.8 percentage change from baseline |
| DRL-17822 150 mg | Changes in Other Lipids and Apolipoproteins | Triglycerides | 0.9 percentage change from baseline |
| DRL-17822 150 mg | Changes in Other Lipids and Apolipoproteins | Apo A1 | 44.8 percentage change from baseline |
| DRL-17822 150 mg | Changes in Other Lipids and Apolipoproteins | Apo B | -22.2 percentage change from baseline |
| DRL-17822 150 mg | Changes in Other Lipids and Apolipoproteins | Apo Lp(a) | 10.0 percentage change from baseline |
| DRL-17822 150 mg | Changes in Other Lipids and Apolipoproteins | LDL-C | -18.7 percentage change from baseline |
| DRL-17822 150 mg | Changes in Other Lipids and Apolipoproteins | HDL-C/LDL-C Ratio | 240.0 percentage change from baseline |
| DRL-17822 300 mg | Changes in Other Lipids and Apolipoproteins | Total Cholesterol | -0.8 percentage change from baseline |
| DRL-17822 300 mg | Changes in Other Lipids and Apolipoproteins | Triglycerides | -11.3 percentage change from baseline |
| DRL-17822 300 mg | Changes in Other Lipids and Apolipoproteins | HDL-C/LDL-C Ratio | 385.2 percentage change from baseline |
| DRL-17822 300 mg | Changes in Other Lipids and Apolipoproteins | LDL-C | -39.4 percentage change from baseline |
| DRL-17822 300 mg | Changes in Other Lipids and Apolipoproteins | Apo A1 | 59.1 percentage change from baseline |
| DRL-17822 300 mg | Changes in Other Lipids and Apolipoproteins | Apo Lp(a) | -37.7 percentage change from baseline |
| DRL-17822 300 mg | Changes in Other Lipids and Apolipoproteins | Apo E | 32.5 percentage change from baseline |
| DRL-17822 300 mg | Changes in Other Lipids and Apolipoproteins | Apo B | -28.9 percentage change from baseline |
Secondary
Changes in Vital Signs Including Blood Pressure
Vital sign abnormalities reported as treatment-emergent AEs
Time frame: 28 days
Population: ITT/Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Capsule | Changes in Vital Signs Including Blood Pressure | 2 participants |
| DRL-17822 50 mg | Changes in Vital Signs Including Blood Pressure | 1 participants |
| DRL-17822 150 mg | Changes in Vital Signs Including Blood Pressure | 1 participants |
| DRL-17822 300 mg | Changes in Vital Signs Including Blood Pressure | 2 participants |
Secondary
Safety and Tolerability of DRL-17822
Incidence of treatment-related adverse events
Time frame: 28 days
Population: Safety/ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Capsule | Safety and Tolerability of DRL-17822 | Severe AEs | 1 participants |
| Placebo Capsule | Safety and Tolerability of DRL-17822 | Treatment-related AEs | 4 participants |
| DRL-17822 50 mg | Safety and Tolerability of DRL-17822 | Severe AEs | 1 participants |
| DRL-17822 50 mg | Safety and Tolerability of DRL-17822 | Treatment-related AEs | 3 participants |
| DRL-17822 150 mg | Safety and Tolerability of DRL-17822 | Severe AEs | 0 participants |
| DRL-17822 150 mg | Safety and Tolerability of DRL-17822 | Treatment-related AEs | 3 participants |
| DRL-17822 300 mg | Safety and Tolerability of DRL-17822 | Treatment-related AEs | 4 participants |
| DRL-17822 300 mg | Safety and Tolerability of DRL-17822 | Severe AEs | 0 participants |
Secondary
To Evaluate Trough Levels of DRL-17822 in Plasma
Trough levels of DRL-17822 in plasma after 28 days of treatment
Time frame: 28 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Capsule | To Evaluate Trough Levels of DRL-17822 in Plasma | 315.6 ng/mL | Standard Deviation 227.2 |
| DRL-17822 50 mg | To Evaluate Trough Levels of DRL-17822 in Plasma | 826.2 ng/mL | Standard Deviation 1124.6 |
| DRL-17822 150 mg | To Evaluate Trough Levels of DRL-17822 in Plasma | 1341.3 ng/mL | Standard Deviation 1121.5 |