Study of CTS-1027 in Combination With Pegylated Interferon and Ribavirin in Hepatitis C Virus (HCV) Null-Responders (CTS-1027-04)

An Open-Label Trial of Pegylated Interferon Plus Ribavirin in Combination With CTS-1027 in HCV Null-Responders

The purpose of this study is to determine if the combination treatment of CTS-1027, pegylated interferon and ribavirin can improve the response rates in HCV patients who did not previously respond to pegylated interferon and ribavirin therapy.

Study Overview

• Status: Completed
• Conditions: Hepatitis C
• Intervention / Treatment: Drug: CTS-1027; Drug: Pegylated interferon; Drug: Ribavirin

Detailed Description

A subset of non-responders to standard of care treatments (pegylated interferon and ribavrin) is termed null responders. Null responders are the most treatment refractory population. Treatment for null responders is currently limited: retreatment with SOC results in approximately 5% sustained virologic response (SVR).

CTS-1027 may facilitate the activity of interferon by preventing MMP-induced cleavage and deactivation in both phases of clinical response to therapy. In addition, CTS-1027, like ribavirin, alone does not significantly affect viral replication, but both CTS-1027 and ribavirin are likely to impact response to therapy during the second and slower phase of the clinical response.

The potential of MMP inhibition to facilitate the action of interferon, together with ribavirin-driven up-regulation of interferon stimulated genes, has the potential to yield a potent host immune response in this highly resistant null-responder patient population. Again, since MMP inhibition is thought to target the second slower phase kinetics, the initial treatment duration in this trial will be 24 weeks.

This trial will evaluate the safety and efficacy of CTS-1027 combined with SOC in patients who did not previously respond to SOC therapy.

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • Santurce, Puerto Rico, 00909
    • Fundacion de Investigacion de Diego
• United States
  • California
    • La Jolla, California, United States, 92037
      • Scripps Clinic
    • San Diego, California, United States, 92161
      • VA Medical Center, San Diego
  • Colorado
    • Denver, Colorado, United States, 80262
      • University of Colorado Health Science Center
    • Englewood, Colorado, United States, 80113
      • South Denver Gastroenterology
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Digestive Healthcare of Georgia
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Health Sciences Center
  • Michigan
    • Novi, Michigan, United States, 48377
      • Henry Ford Medical Center-Columbus
  • Minnesota
    • Plymouth, Minnesota, United States, 55446
      • MN Clinical Research Center
  • Missouri
    • St. Louis, Missouri, United States, 63104
      • St. Louis University
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Consultants of Clinical Research, Ohio GI and Liver Institute
  • Texas
    • Houston, Texas, United States, 77030
      • Advanced Liver Therapies - Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • VA Medical Center, Houston
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Health Science Center
  • Virginia
    • Newport News, Virginia, United States, 23602
      • Liver Institute of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female patients of minimum adult legal age (according to local laws for signing the informed consent document), able to provide written informed consent, and understand and comply with the requirements of the trial

• HCV genotype 1 infected null responders to prior therapy comprised of pegylated interferon and ribavirin (standard of care, SOC) defined as:

  • Failure to achieve an early virologic response (< 2 log decline in HCV-RNA by Week 12), or
  • If Week 12 HCV-RNA was not obtained but Week 24 was obtained, Week 24 response was < 2 log decline
• Alpha-fetoprotein (AFP) <= 50 ng/mL
• Hemoglobin ≥ 12 g/dL, platelet count ≥ 125 x 10^9/L, and white blood cell count ≥ 1.5 x 10^9/L
• In the opinion of the Principal Investigator, the patient met the 80%/80%/80% rule during the previous pegylated interferon and ribavirin therapy (i.e., received at least 80% of the pegylated interferon and ribavirin doses, at least 80% of the dose size, for at least 80% of the treatment duration)
• Willingness to utilize two reliable forms of contraception (for both males and females of childbearing potential) from screening to at least six months after the completion of the trial.

Exclusion Criteria:

• < 2 log decline in HCV-RNA at Week 12 but > 2 log decline at any time from Week 12 to Week 24 during prior therapy with pegylated interferon and ribavirin (prior standard of care therapy)

• Decompensated or severe liver disease defined by one or more of the following criteria:

  • Prothrombin time 3 seconds > control
  • Direct bilirubin ≥ 1.5 x ULN
  • Serum albumin below normal limits
  • AST or ALT > 7 x ULN at screening

• Evidence of portal hypertension including:

  • Varices on esophagogastroduodenoscopy (EGD) with or without a history of gastrointestinal bleeding; or
  • Ascites

• Cirrhosis defined by one or both of the following criteria:

  • Liver biopsy showing cirrhosis
  • Other clinical signs and symptoms suggestive of cirrhosis
• Hepatocellular carcinoma (HCC) or suspicion of HCC clinically or on ultrasound (or other imaging techniques)
• Clinically significant ocular findings such as retinopathy, cotton wool spots, optic nerve disorder, retinal hemorrhage, or other abnormality
• Known history or presence of human immunodeficiency virus (HIV) infection
• Co-infection with hepatitis B virus (HBV)
• If female: pregnant, lactating, or positive serum or urine pregnancy test
• Male partners of women who are currently pregnant
• Renal impairment (creatinine > 1.5 x ULN), creatinine clearance < 50 mL/min, or hepatorenal syndrome with ascites
• Hospitalization for liver disease within 60 days of screening
• History of alcohol abuse (> 50 g per day) within the past year

• History of severe psychiatric disease, especially depression, characterized by:

  • Suicide attempt
  • Hospitalization for psychiatric disease
  • Period of disability as a result of psychiatric disease
• Prior exposure to CTS-1027
• Prior triple treatment comprised of pegylated interferon, ribavirin, and protease and/or polymerase inhibitors
• History or presence of clinically concerning cardiac arrhythmias or prolongation of pre-dose QTc interval of > 450 milliseconds
• Other concomitant disease or condition likely to significantly decrease life expectancy (e.g., moderate to severe congestive heart failure) or any malignancy other than curatively treated skin cancer (basal cell or squamous cell carcinomas), unless adequately treated or in complete remission for ten or more years
• Any patient who has received any investigational drug or device within 30 days of dosing, or who is scheduled to receive another investigational drug or device during the course of this trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CTS-1027, Peg IFN, Ribavirin; Study drug (CTS-1027) plus Standard of Care treatment (pegylated interferon and ribavirin). CTS-1027, 15 mg taken twice daily. Pegylated interferon, 180 μg injected once a week. Ribavirin, 1000 mg or 1200 mg daily (depending on patient weight), taken in two divided doses.

Drug: CTS-1027; CTS-1027 supplied in 5 and 10 mg tablets, 15 mg taken twice daily, for up to 48 weeks; Drug: Pegylated interferon; Pegylated interferon, 180 micrograms in 0.5 ml of solution injected subcutaneously (SQ) once per week, for up to 48 weeks. Packaged in single use syringes.; Other Names: Pegasys; Drug: Ribavirin; Ribavirin, 200 mg capsules taken in two divided daily doses totaling 1000 mg (5 capsules) for patients weighing 75 kg or less, or 1200 mg (6 capsules) for patients weighing more than 75 kg for up to 48 weeks.; Other Names: Copegus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early Virologic Response (EVR)	Early Virologic Response (EVR) is defined as the percent of patients who experienced a drop in HCV-RNA (Hepatitis C Ribonucleic acid, also known as "viral load") levels of more that 2 log from before treatment (baseline) through 12 Weeks of treatment.	Baseline and Study week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
> 2 Log Decline in Hepatitis C Virus Ribonucleic Acid (HCV-RNA) at 24 Weeks	Percent of patients experiencing a drop in HCV-RNA Hepatitis C virus ribonucleic acid, also known as "viral load") levels in the blood equal to, or greater than, 2 log from before treatment (baseline) through 24 weeks of treatment.	Baseline and Study week 24

Collaborators and Investigators

• Sponsor: Conatus Pharmaceuticals Inc.
• Investigators: Study Chair: Erin Castelloe, MD, Conatus Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): November 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: January 18, 2010
• First Submitted That Met QC Criteria: January 19, 2010
• First Posted (Estimate): January 20, 2010

Study Record Updates

• Last Update Posted (Estimate): April 16, 2012
• Last Update Submitted That Met QC Criteria: April 10, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: HCV; Null Responder
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis C; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Antineoplastic Agents; Interferons; Ribavirin
• Other Study ID Numbers: CTS-1027-04