A 4-week, Randomized, Placebo-Controlled, Double-Blind, Efficacy and Safety Study of HS-25 in Adults With Primary Hypercholesterolemia

Study Overview
=================
Brief Summary
-----------------
To determine the efficacy of HS-25 (5, 10, 20 or 30 mg) in reducing low density lipoprotein-cholesterol (LDL-C) levels after a 4-week period of treatment in adults with primary hypercholesterolemia.

Detailed Description
-----------------
This is a 4-week, randomized, double-blind, placebo-controlled study designed to assess the effects of the cholesterol absorption inhibitor HS-25 on LDL-C levels in adults who have untreated LDL-C levels ranging from 130-189 mg/dL and fasting triglyceride levels < 350 mg/dL. Eligibility is restricted to 18-65 year old men or women who are using a highly effective birth control method or are not of childbearing potential. Patients with diabetes, a history of myocardial infarction or other clinical evidence of atherosclerotic vascular disease are not eligible for participation in the study.

Official Title
-----------------
A 4-week, Randomized, Placebo-Controlled, Double-Blind, Efficacy and Safety Study of HS-25 in Adults With Primary Hypercholesterolemia

Conditions
-----------------
Primary Hypercholesterolemia

Intervention / Treatment
-----------------
* Drug: HS-25
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men, or women using a highly effective birth control method or not of child-bearing potential, who are 18 to 65 years of age at Visit 1 (screening visit). LDL-C 130 to 189 mg/dL (inclusive) on a cholesterol lowering diet but no lipid modifying drug treatment for at least 6 weeks. A qualifying LDL-C value must be obtained at the beginning and end of the placebo run-in (Visit 2 and Visit 3) and the Visit 3 value must be within 15% of the value at Visit 2, higher or lower; the average of both qualifying values must be in the range of 130 to 189 mg/dL (inclusive) for inclusion in the study. TG ≤ 350 mg/dL on a cholesterol lowering diet but no lipid modifying drug treatment for at least 6 weeks and TG levels must be ≤ 350 mg/dL at both Visit 2 and Visit 3 Compliance of 80% to 120% with assigned study drug regimen during a 2 week placebo run-in phase. Exclusion Criteria: Women who are pregnant or breast feeding. History of stroke, myocardial infarction, unstable angina, heart failure or any arterial revascularization procedure (eg, carotid, coronary, aorta, peripheral arterial). History of diabetes or glycosylated hemoglobin (HbA1c) > 6.5. History of moderate to severe lactose intolerance (eg, unable to drink a glass of milk). History of hospitalization for treatment of a major psychiatric disorder. History of drug or alcohol abuse as defined by the Diagnostic and Statistical Manual (DSM-5) within the prior 12 months. History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for men (1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor) within 6 months prior to screening. Hospitalization for a duration > 24 hours for any reason within the prior 3 months that, in the opinion of the investigator, may affect adherence to study procedures. History of a positive test for human immunodeficiency virus, hepatitis B or hepatitis C. History of cancer with the exception of well-treated basal cell or squamous cell carcinoma of skin, or in-situ cervical carcinoma. Presence of any condition which, in the opinion of the investigator, is likely to compromise completion of this trial or not be in the best interest of the subject. History of intolerance to ezetimibe. Participation in a prior study of HS 25. Participation in a study of an investigational drug or device within the prior 3 months unless subject has documentation of placebo administration in a placebo-controlled drug treatment trial only. Treatment with a fibric acid derivative (eg, fenofibrate, gemfibrozil), probucol, warfarin, systemic corticosteroid, cyclosporine or other immunosuppressant agent within the prior 12 weeks. Anticipated need or frequent use of acetaminophen (> 2 gm/day, that is required > 4x/week). Vitamins, herbal and dietary supplements must be discontinued at screening unless subject has been on a long-term daily regimen and agrees to continue this regimen during the study. Alanine aminotransferase (ALT) > 1.0 × upper limit of normal (ULN) at Visit 1, Visit 2 or Visit 3. Aspartate aminotransferase (AST) > 1.0 × ULN at Visit 1, Visit 2 or Visit 3. Unexplained (not due to exercise or strenuous activity) creatinine kinase increase > 2 × ULN at Visit 1, Visit 2 or Visit 3. Estimated glomerular filtration rate (Modification of Diet in Renal Disease) < 60 mL/min/1.73m2 at Visit 1, Visit 2 or Visit 3. Thyroid stimulating hormone outside of the normal range. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical disease (eg, infectious disease) must not be enrolled. Any other laboratory abnormality considered by the investigator to be clinically significant. Any subject with an electrocardiogram (ECG) having a QTc interval ≥ 450 msec, or any other abnormality considered by the investigator to be clinically significant at the end of placebo run-in (Visit 3) should not be enrolled.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Assigned study drug (HS-25 or placebo) is to be administered orally once daily in the morning with or without food. Treatment duration 4 weeks.<br>|
| Active Comparator: HS-25 5 MG<br> | Drug: HS-25<br>* Assigned study drug (HS-25 or placebo) is to be administered orally once daily in the morning with or without food. Treatment duration 4 weeks.<br>|
| Active Comparator: HS-25 10 MG<br> | Drug: HS-25<br>* Assigned study drug (HS-25 or placebo) is to be administered orally once daily in the morning with or without food. Treatment duration 4 weeks.<br>|
| Active Comparator: HS-25 20 MG<br> | Drug: HS-25<br>* Assigned study drug (HS-25 or placebo) is to be administered orally once daily in the morning with or without food. Treatment duration 4 weeks.<br>|
| Active Comparator: HS-25 30 MG<br> | Drug: HS-25<br>* Assigned study drug (HS-25 or placebo) is to be administered orally once daily in the morning with or without food. Treatment duration 4 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline in LDL-C after 4 weeks of double-blind treatment |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with reported adverse events during a 4-week period of treatment as a measure of safety and tolerability of HS-25 |  | 4 weeks | 
| Percent change from baseline in LDL-C after a 1 and 2-week period of double-blind treatment |  | 1- and 2-weeks | 
| Percent change from baseline in apoprotein B, non-high density lipoprotein-cholesterol, total cholesterol, triglycerides, high density lipoprotein-cholesterol and apoprotein A1 levels after a 1, 2 and 4-week period of treatment |  | 1-, 2- and 4-week periods | 
| Mean concentration of HS-25 dose and its major metabolite (HS-25-M1) during treatment with HS-25 5, 10, 20 or 30 mg. |  | 1-, 2- and 4-week | 
| Correlation between trough HS-25 and HS-25-M1 levels and percent change in LDL-C, apoA1, apoB, non-HDL-C, TC, TG, and HDL-C during a 4-week period of HS-25 treatment. |  | 1-, 2- and 4-week | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hypercholesterolemia, cholesterol absorption inhibitor, placebo-controlled trial