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RecruitingPhase 1ACTRN12612000176864

A Randomized, Double-blind, Placebo-controlled, First-in-human, 3-Part Study of Orally Administered ALS-002158 to Evaluate the Safety, Tolerability and Pharmacokinetics of Single Ascending Dosing and Food-effect in Healthy Volunteers, and Multiple Ascending Dosing in Subjects with Chronic Hepatitis C Genotype 1 Infection.

Sponsor

CPR Pharma Services

Enrollment

78 participants

Start Date

Dec 15, 2011

Study Type

Interventional

Conditions

Chronic Hepatitis C infection

Summary

This study is to assess the safety and tolerability and how the investigational drug acts in the body. Healthy volunteers are being used for this trial and patients who suffer from Chronic Hepatitis C infection. There will be one dose given to the healthy volunteers first and then the results from that will determine the dose levels of the Investigational product to be given in the second part of the study to healthy volunteers. They will also test a dose given before eating and after eating a meal. In the third part of the study, the results from these two parts will determine dosing for patients who suffer from CHC.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 65 Yearss

Inclusion Criteria28

  • Subjects must meet all of the following criteria to be included in the study:
  • Subject has provided written consent.
  • In the investigator’s opinion, the subject is able to understand and comply with protocol requirements, instructions, and protocol.
  • Subject is in good health as deemed by the investigator, based on the findings of a medical evaluation including medical history, physical examination, laboratory tests,
  • and ECG.
  • Creatinine Clearance of greater than 50 mL/min (Cockroft-Gault)
  • Male or female, 18–55 years of age for Healthy Volunteers and 18-65 for subjects with CHC.
  • Body mass index (BMI) 18–32 kg/m2 inclusive, minimum weight 50 kg for Healthy Volunteers and 18-36 kg/m2 for subjects with CHC, minimum weight of 50 kg in both populations.
  • No more than 25% of patients in any cohort may be enrolled with Body mass Index of equal or greater than 30 kg/m2.
  • A female is eligible to participate in this study if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, bilateral
  • oophorectomy or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea and follicle stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females
  • If male, subject is surgically sterile or practicing specific forms of birth control) until 30 days after the end of the study.
  • In addition, CHC subjects enrolled into the MAD Part (Cohort 1,2 and 3) must also meet the following:
  • criteria:
  • Positive HCV antibody and a positive HCV RNA at screening.
  • Documentation of CHC infection of greater than 6 months duration at screening.
  • CHC genotype 1 infection at screening.
  • HCV RNA viral load greater than 10to the power of 5 and less than or equal to 10 to the power of 8 IU/mL using a sensitive quantitative assay, e.g., COBAS Taqman- 'Registered Trademark"- HCV Test (version 2.0, Roche).
  • Liver biopsy within two years or Fibroscan evaluation within 6 months prior to screening that clearly excludes cirrhosis (Knodell score <3, Metavir score <3, Ishak score <4). Fibroscan liver stiffness score must be <12 kPa.
  • Absence of hepatocellular carcinoma as indicated by an ultrasound scan conducted during screening.
  • No prior treatment for CHC.
  • Absence of history of clinical hepatic decompensation, e.g., variceal bleeding, ascites, hepatic encephalopathy, or active jaundice.
  • Laboratory values including:
  • prothombin time <1.5 × ULN
  • platelets >120,000/mm3
  • albumin >3.5 g/dL, bilirubin <1.5 mg/dL at screening (subjects with documented Gilbert’s disease allowed)
  • Serum ALT concentration <5 x Upper Limit of Normal
  • Alpha Fetoprotein concentration = ULN. If AFP is = ULN, absence of a hepatic mass must be demonstrated by ultrasound within the screening period.

Exclusion Criteria27

  • Subjects will be ineligible for this study if they meet any one of the following criteria:
  • Clinically significant cardiovascular, respiratory, renal, gastrointestinal, hematologic, neurologic, thyroid, or any uncontrolled medical illness or psychiatric disorder.
  • Positive test for HAV IgM, HBsAg, HCV Ab (HV only), or HIV Ab.
  • Abnormal screening laboratory results that are considered clinically significant by the investigator.
  • Liver function tests must all be within normal ranges for healthy volunteers (subjects with documented Gilbert’s disease allowed).
  • Drug allergy such as, but not limited to, sulfonamides and penicillins, including those experienced in previous trials with experimental drugs.
  • Any condition that, in the opinion of the investigator, would compromise the study or the well-being of the subject or prevent the subject from meeting the study
  • requirements.
  • Participation in an investigational drug trial or having received an investigational vaccine within 30 days or 5 half-lives (whichever is longer) prior receiving to study medication.
  • Clinically significant blood loss or elective blood donation of significant volume (i.e. >500 mL) within 60 days of first dose of study drug; >1 unit of plasma within 7 days of
  • first dose of study drug.
  • Clinically significant abnormal electrocardiogram (ECG) findings.
  • Pregnant or breast feeding females.
  • Unwilling to abstain from alcohol for 48 hours prior to the start of dosing until collection of the final PK sample during each dosing period.
  • For healthy volunteers, history regular consumption of >7 units of alcohol for females and >14 units per week for males (one unit is defined as 10 g alcohol) within 6 months
  • of first dose.
  • For healthy volunteers, history of regular use of tobacco-(i.e. greater than or equal to 20 cigarettes per day) or nicotine-containing products within 3 months of the screening visit. For subjects with CHC genotype 1 infection, history of regular use of tobacco- or nicotine-containing products is allowed.
  • The subject has a positive pre-study drug screen. A minimum list of drugs that will be screened for includes amphetamines, barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines.
  • Use of concomitant medications, including vitamins or herbal and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study
  • medication, unless in the opinion of the Investigator and Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • Subjects must not have received any medication known to be an inducer or inhibitor of CYP450 enzymes within 3 weeks prior to clinic check-in. Such medications will continue
  • to be prohibited until clinic discharge or commencement of CHC treatment.
  • Exposure to more than four new investigational entities within 12 months prior to the first dosing day.
  • Laboratory abnormalities including:
  • Thyroid Stimulating Hormone (TSH) >ULN
  • Hematocrit <34 %
  • White blood cell counts < 3,500/mm3
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Interventions

Part 1: Healthy Volunteers will receive one of 5 single ascending doses (SAD) of ALS-002158 ranging from 50 mg to 750 mg. ALS-002158 or placebo is administered orally via a syringe. Subjects in Part

Part 1: Healthy Volunteers will receive one of 5 single ascending doses (SAD) of ALS-002158 ranging from 50 mg to 750 mg. ALS-002158 or placebo is administered orally via a syringe. Subjects in Part 1 and subjects in Part 3 will receive standardized diets at scheduled times that do not conflict with study-related procedures. Prior to each dose of study medication, subjects will fast from food for at least 8 hours overnight until 4 hours post-dose. Except as part of dose administration, water may be consumed freely until 1 hour prior to dosing through 2 hours post-dosing. Cohort 1: 50mg Cohort 2: 100mg Cohort 3: 300mg Cohort 4: 500mg Cohort 5: 750mg Part 2: Eight Healthy Volunteers from Cohort 3 in Part 1 will receive a second single dose ALS-002158 or placebo (with a washout period of at least 7 days) to assess food effects on pharmacokinetics. Subjects in Part 2, the food effect study phase, will be given a standardized high-fat content meal within 30 minutes of their second dose; the meal will be completed 10 minutes prior to dosing. The meal will consist of the following: Two eggs fried in butter Two strips of bacon Two slices of toast with butter Four ounces of hash brown potatoes (fried with butter) Eight ounces (240 mL) of whole milk Part 3: Subjects with CHC genotype 1 infection will receive one of 3 doses of ALS-002158 (100 mg, 300 mg, or 500 mg) or placebo for 7 days. Prior to each dose of study medication subjects will fast from food for at least 8 hours overnight until 4 hours post dose. Except as part of dosing water may be consumed freely until 1 hour prior & 2 hours after dosing. Dosing may occur with food depending on the outcome of Part 2, the food effect study. Subjects may be dosed in a staggered fashion to accommodate post dosing assessments. Dosing should occur at the same time each day +/- 5 minutes (e.g., subject 1 is dosed at 7:00AM on MAD Days 1 through 7, subject 2 is dosed at 7:05AM on MAD Days 1-7, etc)

Locations(4)

New Zealand

Romania

France

Moldova, Republic Of

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ACTRN12612000176864