Title
Safety Study of Bile Acid to Treat Hypercholesteremia
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
Phase
Phase 1Lead Sponsor
AtheroNovaStudy Type
InterventionalStatus
Unknown statusIndication/Condition
HypercholesterolemiaIntervention/Treatment
hyodeoxycholic acid ...Study Participants
110Preclinical data support the hypothesis that the administration of AHRO-001 reduces LDL cholesterol levels, improves HDL function, and finally, decreases atheromatous plaque burden.
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
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
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
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.
Cohort 3 identical design as Cohorts 1 and 2, but SD is 1000 mg AHRO-001.
Cohort 4 receives 21 days tid administration of AHRO-001 using the best tolerated dose as determined by cohorts 1, 2 & 3
Cohort 5 receives 12 weeks tid administration of AHRO-001 using the best tolerated dose as determined by the first 4 cohorts.
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
