Standard of Care (SOC) With or Without CTS-1027 in Hepatitis C (HCV) Null-Responders

Phase 2

Terminated

Conditions: Hepatitis C

Interventions: Drug: CTS-1027
Drug: pegylated interferon
Drug: Ribavirin
Drug: Placebo

Registration Number: NCT01273064

Lead Sponsor: Conatus Pharmaceuticals Inc.

Brief Summary: Placebo controlled, double-blind, multicenter study utilizing standard of care (SOC) treatment (ribavirin plus pegylated interferon) in combination with CTS-1027 in genotype 1 chronic Hepatitis C (HCV) patients who were null-responders to previous SOC therapy(ies).

Null-responders are defined as patients who failed to achieve a greater than 2 log drop in HCV-RNA (Hepatitis C Ribonucleic acid, also known as "viral load") levels after 12 weeks of treatment (know as an "early virologic response", or EVR) during previous SOC therapy.

If, during previous SOC treatment, a patient had a less than 2 log decline in HCV-RNA at Week 12 but greater than 2 log decline in HCV-RNA at any time from Week 12 to Week 24, that patient is not a null-responder, and is excluded from study participation. If, during previous SOC treatment, a Week 12 HCV-RNA was not obtained, the post Week 12 response must have been \< 2 log decline (and still HCV-RNA positive) in order for the patient to be defined as a null-responder.

Patients will be screened and have up to 4 weeks to qualify for study entry. During this screening period, clinical and laboratory tests will be performed. At Week 0/Day 1, patients will undergo centralized, stratified (based on ethnicity), randomization to one of four treatment arms: SOC + one of three doses of CTS-1027 or SOC + placebo. Study treatment will last 24, 48, or 60 weeks, based on each patient's response to study treatment. SOC + placebo patients who do not show a virologic response after 12 weeks of therapy will be rolled onto SOC + 15mg CTS-1027, while maintaining the study blind.

Detailed Description: Placebo controlled, double-blind, multicenter study utilizing Standard of Care (SOC) in combination with CTS-1027 in genotype 1 chronic hepatitis C (HCV) patients who were null-responders to previous SOC therapy(ies).

Null-responders are defined as patients who failed to achieve a greater than 2 log drop in HCV-RNA levels after 12 weeks of treatment (know as an early virologic response or EVR) during previous SOC therapy.

If, during previous SOC treatment, a patient had \< 2 log decline in HCV-RNA at Week 12 but \> 2 log decline in HCV-RNA at any time from Week 12 to Week 24, that patient is not a null-responder and is excluded from study participation. If, during previous SOC treatment, a Week 12 HCV-RNA was not obtained, the post Week 12 response must have been \< 2 log decline (and still HCV-RNA positive) in order for the patient to be defined as a null-responder.

Patients will be screened and have up to 4 weeks to qualify for study entry. During this screening period, clinical and laboratory tests will be performed. At Week 0/Day 1, patients will undergo centralized, stratified (based on ethnicity), randomization to one of four treatment arms: SOC + one of three doses of CTS-1027 or SOC + placebo. Study treatment will last 24, 48, or 60 weeks, based on each patient's response to study treatment.

The Principal Investigators, other site personnel, and patients will be blinded to the HCV-RNA results for the first 12 weeks of therapy.

At Week 12, the study treatment blind will be broken by the study's Interactive Web Randomization System (IWRS). However, the Principal Investigators, other investigative site personnel, patients, and Sponsor will remain blinded to treatment allocation until Week 24 (see below). The patients on the SOC + placebo arm will continue treatment as follows:

* Patients on SOC + placebo who do not achieve at least a 2 log decline in their HCV-RNA at Week 12 will be automatically rolled-over into the SOC + 15 mg CTS-1027 twice a day (BID) arm. The treatment duration for these patients will be 60 weeks (i.e., 12 weeks on SOC + placebo, followed by 48 weeks on SOC + 15 mg BID).

* Those patients on SOC + placebo who achieve ≥ 2 log decline at Week 12 will continue on SOC therapy until Week 48.

Patients in the SOC + CTS-1027 arms will continue with the same treatment regimen for the initial 24 weeks regardless of HCV-RNA changes.

At Week 24, the study blind will be formally broken. Patients will continue the study as follows:

* Patients in the SOC + CTS-1027 arms who achieve ≥ 2 log HCV-RNA decline by Week 24 will continue with the same treatment regimen they were assigned during the Double-Blind Phase for an additional 24 weeks.

* Patients in the SOC + CTS-1027 15 mg BID and the SOC + CTS-1027 30 mg BID arms who achieve a \<2 log HCV-RNA decline by Week 24 will escalate to the next higher dose of CTS-1027 for an additional 24 weeks.

* Patients in the SOC + CTS-1027 60 mg BID arm who do not achieve at least a 2 log HCV-RNA decline by Week 24 will be discontinued from the study.

All patients will be seen 4 and 12 weeks (Follow-Up Period) after the end of treatment. If a patient's HCV-RNA is undetectable at the end of treatment, he/she will be seen for an additional follow-up visit 24 weeks after the end of treatment.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 114

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 study
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, post Week 12 HCV-RNA response was < 2 log decline
Screening HCV-RNA viral load of > 5.0 log (i.e., >100,000 IU/mL)
alpha-fetoprotein (AFP) less than or equal to 100 ng/mL
Hemoglobin greater than or equal to 12 g/dL for women and greater than or equal to 13 g/dL for men, hemoglobin A1c less than or equal to 7.5 %, platelet count greater than or equal to 90 x 10^9/L, and white blood cell count greater than or equal to 1.5 x 10^9/L
Thyroid Stimulating Hormone (TSH) within normal limits
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 study.

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 4 seconds > control or INR (international normalized ratio) > 1.2
- Total bilirubin ≥ 1.5 mg/dL or direct bilirubin ≥ 1 mg/dL
- Serum albumin below normal limits
- aspartate aminotransferase (AST) or alanine aminotransferase (ALT)> 5 x upper limit of normal (ULN) at screening
- Presence of ascites
Hepatic encephalopathy
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 > 1.2 x ULN), serum 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
Patients who qualify as a null-responder based on treatment(s) other than pegylated interferon and ribavirin
History or presence of clinically concerning cardiac arrhythmias or prolongation of pre-dose corrected Q-T interval (QTc) of > 450 milliseconds
History of or current autoimmune disease
Diagnosis of or symptoms suggestive of fibromyalgia
Currently on liver transplantation waiting list or recipient of any organ transplant
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 five or more years
Exposure to any other investigational treatment for any aspect of disease associated with HCV during the past 6 months
Exposure to any investigational drug or device within 30 days of dosing, or scheduled receipt of another investigational drug or device during the course of this study.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CTS-1027 30 mg + ribavirin + pegylated interferon	Placebo	Standard of Care (ribavirin plus pegylated interferon) plus CTS-1027 30 mg, supplied in a blinded kit containing one bottle of 30 mg tablets, and one bottle of placebo tablets (in order to maintain blind). One tablet from each of the bottles is taken twice daily, for a total daily dose of 60 mg of CTS-1027.
CTS-1027 15 mg + ribavirin + pegylated interferon	pegylated interferon	Standard of Care (ribavirin plus pegylated interferon) plus CTS-1027 15 mg (supplied in a blinded kit containing one bottle each of of 5 mg and 10 mg tablets). One tablet from each of the CTS bottles is taken twice daily, for a total daily dose of 30 mg.
placebo + ribavirin + pegylated interferon	pegylated interferon	Standard of Care (ribavirin plus pegylated interferon) plus placebo (supplied in a blinded kit containing two bottles of placebo tablets). One tablet is taken from each of the placebo bottles twice daily, for a total daily dose of 4 tablets.
placebo + ribavirin + pegylated interferon	Placebo	Standard of Care (ribavirin plus pegylated interferon) plus placebo (supplied in a blinded kit containing two bottles of placebo tablets). One tablet is taken from each of the placebo bottles twice daily, for a total daily dose of 4 tablets.
CTS-1027 60 mg + ribavirin + peglyated interferon	pegylated interferon	Standard of Care (ribavirin plus pegylated interferon) plus CTS-1027, 60 mg (supplied in a blinded kit containing two bottles of 30 mg tablets). One tablet from each of the CTS bottles is taken twice daily, for a total daily dose of 120 mg.
CTS-1027 30 mg + ribavirin + pegylated interferon	CTS-1027	Standard of Care (ribavirin plus pegylated interferon) plus CTS-1027 30 mg, supplied in a blinded kit containing one bottle of 30 mg tablets, and one bottle of placebo tablets (in order to maintain blind). One tablet from each of the bottles is taken twice daily, for a total daily dose of 60 mg of CTS-1027.
CTS-1027 30 mg + ribavirin + pegylated interferon	pegylated interferon	Standard of Care (ribavirin plus pegylated interferon) plus CTS-1027 30 mg, supplied in a blinded kit containing one bottle of 30 mg tablets, and one bottle of placebo tablets (in order to maintain blind). One tablet from each of the bottles is taken twice daily, for a total daily dose of 60 mg of CTS-1027.
CTS-1027 60 mg + ribavirin + peglyated interferon	Ribavirin	Standard of Care (ribavirin plus pegylated interferon) plus CTS-1027, 60 mg (supplied in a blinded kit containing two bottles of 30 mg tablets). One tablet from each of the CTS bottles is taken twice daily, for a total daily dose of 120 mg.
CTS-1027 30 mg + ribavirin + pegylated interferon	Ribavirin	Standard of Care (ribavirin plus pegylated interferon) plus CTS-1027 30 mg, supplied in a blinded kit containing one bottle of 30 mg tablets, and one bottle of placebo tablets (in order to maintain blind). One tablet from each of the bottles is taken twice daily, for a total daily dose of 60 mg of CTS-1027.
CTS-1027 15 mg + ribavirin + pegylated interferon	Ribavirin	Standard of Care (ribavirin plus pegylated interferon) plus CTS-1027 15 mg (supplied in a blinded kit containing one bottle each of of 5 mg and 10 mg tablets). One tablet from each of the CTS bottles is taken twice daily, for a total daily dose of 30 mg.
placebo + ribavirin + pegylated interferon	Ribavirin	Standard of Care (ribavirin plus pegylated interferon) plus placebo (supplied in a blinded kit containing two bottles of placebo tablets). One tablet is taken from each of the placebo bottles twice daily, for a total daily dose of 4 tablets.
CTS-1027 60 mg + ribavirin + peglyated interferon	CTS-1027	Standard of Care (ribavirin plus pegylated interferon) plus CTS-1027, 60 mg (supplied in a blinded kit containing two bottles of 30 mg tablets). One tablet from each of the CTS bottles is taken twice daily, for a total daily dose of 120 mg.
CTS-1027 15 mg + ribavirin + pegylated interferon	CTS-1027	Standard of Care (ribavirin plus pegylated interferon) plus CTS-1027 15 mg (supplied in a blinded kit containing one bottle each of of 5 mg and 10 mg tablets). One tablet from each of the CTS bottles is taken twice daily, for a total daily dose of 30 mg.

Primary Outcome Measures

Name	Time	Method
Sustained Virologic Response	Baseline and 24 weeks after the end of treatment (Week 72)	Percent of patients that achieve a sustained virologic response (SVR) at Week 72 defined as HCV-RNA (Hepatitis C virus ribonucleic acid, also known as 'viral load') level below the quantification limit (BQL) at Week 72.

Secondary Outcome Measures

Name	Time	Method
Greater Than 2 Log Decline in HCV-RNA at Study Weeks 12, 24 and 48	Baseline, and Study Weeks 12, 24, and 48	Percent of patients experiencing a drop in Hepatitis C virus ribonucleic acid (HCV-RNA, also known as "viral load") levels in the blood equal to, or greater than, 2 log from before treatment (baseline) through 12, 24, and 48 weeks of treatment.

Trial Locations

Locations (45): Liver Center of Atlanta
🇺🇸
Atlanta, Georgia, United States
St. Louis University
🇺🇸
St. Louis, Missouri, United States
University of Massachusetts Memorial Medical Center
🇺🇸
Worcester, Massachusetts, United States
Metropolitan Research Group Washington DC
🇺🇸
Fairfax, Virginia, United States
Albert Einstein Medical Center
🇺🇸
Philadelphia, Pennsylvania, United States
Cleveland Clinic
🇺🇸
Cleveland, Ohio, United States
Rush University Medical Center
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Chicago, Illinois, United States
Huntington Medical Research Institute
🇺🇸
Pasadena, California, United States
Loma Linda University MC
🇺🇸
Loma Linda, California, United States
Southern California Liver Centers
🇺🇸
Coronado, California, United States
Weill Medical College of Cornell
🇺🇸
New York, New York, United States
New York Medical College
🇺🇸
Valhalla, New York, United States
Atlanta Medical Center, Inc.
🇺🇸
Atlanta, Georgia, United States
Loyola University
🇺🇸
Maywood, Illinois, United States
Tulane University Health Sciences Center
🇺🇸
New Orleans, Louisiana, United States
Ochsner Clinic Foundation
🇺🇸
New Orleans, Louisiana, United States
Einstein College of Medicine (Jacobi Medical Center)
🇺🇸
Bronx, New York, United States
Concorde Medical Group
🇺🇸
New York, New York, United States
New York University
🇺🇸
New York, New York, United States
Columbia Presbyterian Medical Center
🇺🇸
New York, New York, United States
Baylor All Saints Medical Center
🇺🇸
Fort Worth, Texas, United States
University of Texas Medical Branch at Galveston
🇺🇸
Galveston, Texas, United States
Virginia Commonwealth University (VCU)
🇺🇸
Richmond, Virginia, United States
Liver Institute of Virginia
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Newport News, Virginia, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Medical Associates Research Group
🇺🇸
San Diego, California, United States
Indiana University School of Medicine
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Indianapolis, Indiana, United States
Benaroya Research Institute at Virginia Mason
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Seattle, Washington, United States
UCSD
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San Diego, California, United States
University of Louisville
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Louisville, Kentucky, United States
Beth Israel Deaconess Medical Center
🇺🇸
Boston, Massachusetts, United States
Consultants for Clinical Research
🇺🇸
Cincinnati, Ohio, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Research Specialists of Texas
🇺🇸
Houston, Texas, United States
University of Utah
🇺🇸
Salt Lake City, Utah, United States
St. Luke's Episcopal Hospital
🇺🇸
Houston, Texas, United States
University of Texas HSC at Houston
🇺🇸
Houston, Texas, United States
University of Colorado Denver
🇺🇸
Aurora, Colorado, United States
Henry Ford Hospital
🇺🇸
Detroit, Michigan, United States
VAMC Houston
🇺🇸
Houston, Texas, United States
University of Miami
🇺🇸
Miami, Florida, United States
Yale University School of Medicine
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New Haven, Connecticut, United States
Scripps Clinic
🇺🇸
La Jolla, California, United States
University of Kansas Medical Center
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Kansas City, Kansas, United States