Safety Study of Bile Acid to Treat Hypercholesteremia

Study Overview
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Brief Summary
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Preclinical data support the hypothesis that the administration of AHRO-001 reduces LDL cholesterol levels, improves HDL function, and finally, decreases atheromatous plaque burden.

Detailed Description
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4 sequential dosing cohorts, each cohort beginning with single dose (SDD), single day exposure, followed by one week of multiple daily dosing (MDD) with bid exposure, a 4 day drug honeymoon, then one week of MDD utilizing tid exposure. Each subsequent cohort utilizes the same SDD/MDD design, starting with SDD higher than prior SDD but a SDD significantly lower than prior tid MDD cohort just completed, the overall goal being to provide gradually increasing dose exposure contingent on satisfactory safety and tolerability of lower doses in the previous groups. Cohort 4 (MDD) utilizes best dose determined by Cohorts 1, 2 & 3 for 21 days. Estimated Duration of Subject Participation: 8-9 weeks Under Protocol Amendment Version 5.0, an additional cohort, Cohort 5, will concomitantly enroll 48 volunteers randomized to receive either AHRO-001 or placebo. Volunteers included in the study may be either currently receiving or not receiving a statin treatment. The 48 volunteers in Cohort 5 will thus be allocated to 3 treatment groups with 16 volunteers enrolled per group: Group A: AHRO-001 alone Group B: Statin + AHRO-001 Group C: Placebo SUBJECT POPULATION: Healthy volunteers, both males & infertile females, with asymptomatic mild to moderate hypercholesterolemia

Official Title
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Phase I Randomized Placebo Controlled Double Blind SAD and MAD Study of Oral AHRO-001 to Assess Safety, Tolerability &PK in Volunteers w/Mild/Moderate Hypercholesteremia

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: AHRO-001


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Males OR infertile Females 18-70 years of age, inclusive Asymptomatic mild to moderate hypercholesterolemia, (LDL =110-220 mg/dL) Cohort 5: on no statin or on a stable statin dose not meeting LDL >110 mg% Key Exclusion criteria Fasting triglycerides <90 or >250 mg/dl (<0.85 mmol/l or >2.8 mmol/l) Body Mass Index (BMI) <18 or >34 kg/m2 Diabetes mellitus (FBS > 125 mg% (>6.94 mmol/l) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >ULN Serum creatinine >ULN for gender Hemoglobin <11.5 g/dL Female volunteers of childbearing potential History of cancer in past 5 years Any disease requiring medication Use of investigational medication in past 3 months Positive results for illegal drugs, HBsAg, HBsAb, HCV or HIV Cohort 5:Prescription lipid lowering medications other than a statin in past 4 wks Cohort 5: History of gastrointestinal tract surgical resection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1, 500 mg<br>Cohort 1 receives SDD 500 mg AHRO-001; one week later receives MDD of 500 mg bid 7 days, then 500 mg tid 7 days | Drug: AHRO-001<br>* Cohort 1: 500 mg/dose, given as a single dose then as bid x7days and tid x 7days Cohort 2: 750 mg/dose, given as a single dose then as bid x7days and tid x 7days Cohort 3: 1000 mg/dose, given as a single dose then as bid x7days and tid x7days Cohort 4: 21 days dosing given at best tolerated dose determined by cohorts 1-3 Cohort 5: 12 wks dosing given at best tolerated dose determined by cohorts 1-4<br>* Other names: Hyodeoxycholic acid;|
| Experimental: Cohort 2, 750 mg<br>Cohort 2 receives SD of 750 AHRO-001, then 7 days of 750 mg BID AHRO-001, then 7 days of 750 mg TID AHRO-001. | Drug: AHRO-001<br>* Cohort 1: 500 mg/dose, given as a single dose then as bid x7days and tid x 7days Cohort 2: 750 mg/dose, given as a single dose then as bid x7days and tid x 7days Cohort 3: 1000 mg/dose, given as a single dose then as bid x7days and tid x7days Cohort 4: 21 days dosing given at best tolerated dose determined by cohorts 1-3 Cohort 5: 12 wks dosing given at best tolerated dose determined by cohorts 1-4<br>* Other names: Hyodeoxycholic acid;|
| Experimental: Cohort 3, 1000 mg<br>Cohort 3 identical design as Cohorts 1 and 2, but SD is 1000 mg AHRO-001. | Drug: AHRO-001<br>* Cohort 1: 500 mg/dose, given as a single dose then as bid x7days and tid x 7days Cohort 2: 750 mg/dose, given as a single dose then as bid x7days and tid x 7days Cohort 3: 1000 mg/dose, given as a single dose then as bid x7days and tid x7days Cohort 4: 21 days dosing given at best tolerated dose determined by cohorts 1-3 Cohort 5: 12 wks dosing given at best tolerated dose determined by cohorts 1-4<br>* Other names: Hyodeoxycholic acid;|
| Experimental: Cohort 4, 21 day dosing<br>Cohort 4 receives 21 days tid administration of AHRO-001 using the best tolerated dose as determined by cohorts 1, 2 & 3 | Drug: AHRO-001<br>* Cohort 1: 500 mg/dose, given as a single dose then as bid x7days and tid x 7days Cohort 2: 750 mg/dose, given as a single dose then as bid x7days and tid x 7days Cohort 3: 1000 mg/dose, given as a single dose then as bid x7days and tid x7days Cohort 4: 21 days dosing given at best tolerated dose determined by cohorts 1-3 Cohort 5: 12 wks dosing given at best tolerated dose determined by cohorts 1-4<br>* Other names: Hyodeoxycholic acid;|
| Experimental: Cohort 5, 12 weeks dosing<br>Cohort 5 receives 12 weeks tid administration of AHRO-001 using the best tolerated dose as determined by the first 4 cohorts. | Drug: AHRO-001<br>* Cohort 1: 500 mg/dose, given as a single dose then as bid x7days and tid x 7days Cohort 2: 750 mg/dose, given as a single dose then as bid x7days and tid x 7days Cohort 3: 1000 mg/dose, given as a single dose then as bid x7days and tid x7days Cohort 4: 21 days dosing given at best tolerated dose determined by cohorts 1-3 Cohort 5: 12 wks dosing given at best tolerated dose determined by cohorts 1-4<br>* Other names: Hyodeoxycholic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events | To assess the safety, tolerability and pharmacokinetics of AHRO-001 when administered first as a single daily dose x 1 day, then by a graduated increase from daily dosing x 1day to twice daily dosing x7 days, and ultimately to thrice daily dosing x7. Next dose can be started as soon as 6 volunteers will finish 2 weeks of administration of the previous dose. All dose increases occur only after drug washout and are only undertaken after medical review of the previous dose as determined by symptoms, vital signs, clinical examination, clinical laboratory results, urinalyses, electrocardiograms and adverse event reporting declares that progression of dosing is safe and appropriate | Participants will be followed through the course of their participation, approximately 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events | To assess the safety, tolerability and pharmacokinetics of AHRO-001 dosed tid for 21 days at best tolerated dose as determined in Cohorts 1-3. | Participants will be followed through the course of their participation, approximately 8 weeks | 
| Number of participants with adverse effects | To assess the safety, tolerability and pharmacokinetics of AHRO-001 administered orally as a tid regimen for 12 weeks in the presence or absence of a statin, at a dose determined by safety in the first 4 dose cohorts. | Participants will be followed through the course of their participation, approximately 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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atherosclerosis, atherosclerotic heart disease, hypercholesteremia, atherosclerotic plaque, hyperlipidemia