Clinical trial NCT01051921: Study of CTS-1027 in Combination With Pegylated Interferon and Ribavirin in Hepatitis C Virus (HCV) Null-Responders
Official title: An Open-Label Trial of Pegylated Interferon Plus Ribavirin in Combination With CTS-1027 in HCV Null-Responders
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis C
Keywords: HCV
Null Responder
Lead sponsor: Conatus Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2010-01-20
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Early Virologic Response (EVR)
timeFrame: Baseline and Study week 12
Secondary outcomes:
measure: > 2 Log Decline in Hepatitis C Virus Ribonucleic Acid (HCV-RNA) at 24 Weeks
timeFrame: Baseline and Study week 24
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Scripps Clinic
state: California
city: San Diego
country: United States
facility: VA Medical Center, San Diego
state: California
city: Denver
country: United States
facility: University of Colorado Health Science Center
state: Colorado
city: Englewood
country: United States
facility: South Denver Gastroenterology
state: Colorado
city: Atlanta
country: United States
facility: Digestive Healthcare of Georgia
state: Georgia
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Novi
country: United States
facility: Henry Ford Medical Center-Columbus
state: Michigan
city: Plymouth
country: United States
facility: MN Clinical Research Center
state: Minnesota
city: St. Louis
country: United States
facility: St. Louis University
state: Missouri
city: Cincinnati
country: United States
facility: Consultants of Clinical Research, Ohio GI and Liver Institute
state: Ohio
city: Houston
country: United States
facility: Advanced Liver Therapies - Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: VA Medical Center, Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Science Center
state: Utah
city: Newport News
country: United States
facility: Liver Institute of Virginia
state: Virginia
city: Santurce
country: Puerto Rico
facility: Fundacion de Investigacion de Diego
Study officials:
affiliation: Conatus Pharmaceuticals Inc.
name: Erin Castelloe, MD
role: STUDY_CHAIR
References: