Clinical trial NCT00401947: A Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of ACH-0137171 in Participants With Chronic Hepatitis C Infection
Official title: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study to Investigate the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of Multiple Doses of ACH-0137171 in Subjects With Chronic Hepatitis C Infection
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: HCV Infection
Keywords: HCV
Chronic
Hepatitis
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Achillion, a wholly owned subsidiary of Alexion
First posted: 2006-11-22
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to investigate the safety, tolerability, pharmacokinetics (PK), and antiviral activity of multiple doses of ACH-0137171 in participants with chronic hepatitis C virus (HCV) infection.

Detailed description: This was a randomized, double-blind, placebo-controlled, dose-escalation study of ACH-0137171 in participants with chronic HCV infection.

Sequential cohorts of 10 participants were randomized (8:2) to receive multiple doses of ACH-0137171 or placebo for 4 days (Days 1 through 4) with a single dose on Day 5 followed by a complete PK profile. Dosing was 300-600 milligrams (mg) administered either every 12 hours or every 6 hours (maximum daily dose of 2400 mg). All doses were administered with food.

The dose cohorts were as follows:

Study Schema:

Cohort 1: 300 mg ACH-0137171/placebo every 12 hours (600 mg/day) Cohort 2: 300 mg ACH-0137171/placebo every 6 hours (1200 mg/day) Cohort 3: 600 mg ACH-0137171/placebo every 6 hours (2400 mg/day)

A full review of all safety data will occur following each cohort. Depending on the data, the Sponsor, in consultation with the Principal Investigator(s), may consider modifying the planned dose escalation. The Sponsor may choose to interject an intermediate dose cohort between 2 planned dose escalations or repeat a given dose level, or extend the dosing period, or add an additional cohort. If a similar Grade 3 or 4 adverse event occurs in 3 or more participants and was considered to be at least possibly related to the study drug, escalation to a higher dose will not occur.

Serial HCV ribonucleic acid (RNA) measurements, PK measurements of plasma concentrations of ACH-0137171, and periodic safety monitoring occurred on Days 1 through 5. Additional HCV RNA and PK measurements were taken on Days 6 through 9. Follow-up safety evaluations will be completed 14 days after the last study drug administration (that is, on Days 12 and 19).

Eligibility criteria: Inclusion Criteria:

* Chronic HCV infection must be documented by positive anti-HCV antibody using a third-generation enzyme immunoassay and persistent detection of HCV RNA in the blood for at least 6 months.
* Participants must be infected with HCV genotype 1 (line probe assay; INNO-LiPA HCV II, Innogenetics) and maybe treatment-naïve or treatment-experienced (treatment experienced specifically means prior treatment with interferon, standard or pegylated, with or without ribavirin with therapy stopped \> 6 months prior to screening).
* Eligible participants must have had alanine aminotransferase and aspartate aminotransferase \< 5 x upper limit of normal (ULN), plasma HCV RNA \> 5 log10 international units (IU)/milliliter (mL), and have had no clinical or laboratory evidence of hepatic decompensation for inclusion (must have platelets \> 100,000/cubic millimeter \[mm\^3\], total bilirubin \< 1.5 x ULN, prothrombin time \< 1.5 x ULN, or albumin \> 3.0 grams/deciliter \[g/dL\] for inclusion).
* Women were eligible if not pregnant or breast-feeding.
* Women of childbearing potential (that is, not surgically sterile or confirmed post menopausal) must have had confirmed negative pregnancy tests. All participants must practice a medically acceptable form of contraception.

Exclusion Criteria:

* Human immunodeficiency virus or hepatitis B virus co-infection known cirrhosis.
* Prior history of clinical hepatic decompensation (ascites, jaundice, encephalopathy, or variceal hemorrhage), alcoholic or other forms of chronic liver disease, evidence of hepatocellular carcinoma (α-fetoprotein \> 50 nanograms/mL), creatinine clearance \< 80 mL/minute (using Cockcroft-Gault equation), hemoglobin \< 10 g/dL, neutrophils \< 1500/mm\^3, and abnormal thyroid function tests (thyroid stimulating hormone \> 2.5 microIU/mL, free T4 \> ULN), or, a positive test result for illicit drugs, alcohol, or drug abuse within the past 12 months.
* Participants who have had significant gastrointestinal, thyroid, renal, cardiovascular, pulmonary, oncologic, or neurological disease, or who are currently receiving immunomodulators (corticosteroids), investigational, nephrotoxic or hepatotoxic drugs (for example, phenytoin, carbamazepine, isonicotinic acid hydrazide, azole anti-fungal agents such as ketoconazole, and aminoglycoside antibiotics), non-steroidal anti-inflammatory agents, ibuprofen or acetaminophen (on a daily basis) will also be excluded.

Primary outcomes:
measure: To assess the short-term safety and tolerability of multiple, escalating, oral doses of ACH-0137171 in subjects with chronic hepatitis C infection.
measure: To characterize the plasma pharmacokinetics of ACH-0137171 following administration of multiple, escalating, oral doses in subjects with chronic hepatitis C infection.
measure: To assess the antiviral activity of ACH-0137171 as measured by plasma HCV RNA levels in subjects with chronic hepatitis C infection following administration of multiple, escalating, oral doses.
measure: To assess the correlation between antiviral activity and pharmacokinetic parameters.
Secondary outcomes:
measure: To perform viral dynamic and pharmacodynamic modeling of ACH 0137171 virologic response.
measure: To assess the biochemical response of ACH-0137171 as measured by the change from baseline of serum ALT and AST levels.
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Clinical Trial Site
state: Arizona
city: La Jolla
country: United States
facility: Clinical Trial Site
state: California
city: San Francisco
country: United States
facility: Clinical Trial Site
state: California
city: Boston
country: United States
facility: Clinical Trial Site
state: Massachusetts
city: New York
country: United States
facility: Clinical Trial Site
state: New York
city: Dallas
country: United States
facility: Clinical Trial Site
state: Texas
city: San Antonio
country: United States
facility: Clinical Trial Site
state: Texas
city: Berlin
country: Germany
facility: Clinical Trial Site
city: Utrecht
country: Netherlands
facility: Clinical Trial Site
Study officials:
References: