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

Hepatitis C Clinical Trial

Official title:

A Placebo-Controlled, Multicenter, Double-Blind, Randomized Trial of Pegylated Interferon Plus Ribavirin With or Without CTS-1027 in HCV Null-Responders

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01273064
• Other study ID #: CTS-1027-05
• Status: Terminated
• Phase: Phase 2
• First received: December 21, 2010
• Last updated: June 4, 2012
• Start date: January 2011
• Est. completion date: October 2011

Study information

• Verified date: June 2012
• Source: Conatus Pharmaceuticals Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 114
• Est. completion date: October 2011
• Est. primary completion date: September 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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

2. 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

3. Screening HCV-RNA viral load of > 5.0 log (i.e., >100,000 IU/mL)

4. alpha-fetoprotein (AFP) less than or equal to 100 ng/mL

5. 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

6. Thyroid Stimulating Hormone (TSH) within normal limits

7. 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)

8. 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:

1. < 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)

2. 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

3. Hepatic encephalopathy

4. Hepatocellular carcinoma (HCC) or suspicion of HCC clinically or on ultrasound (or other imaging techniques)

5. Clinically significant ocular findings such as retinopathy, cotton wool spots, optic nerve disorder, retinal hemorrhage, or other abnormality

6. Known history or presence of human immunodeficiency virus (HIV) infection

7. Co-infection with hepatitis B virus (HBV)

8. If female: pregnant, lactating, or positive serum or urine pregnancy test

9. Male partners of women who are currently pregnant

10. Renal impairment (creatinine > 1.2 x ULN), serum creatinine clearance < 50 mL/min, or hepatorenal syndrome with ascites

11. Hospitalization for liver disease within 60 days of screening

12. History of alcohol abuse (> 50 g per day) within the past year

13. History of severe psychiatric disease, especially depression, characterized by:

• Suicide attempt

• Hospitalization for psychiatric disease

• Period of disability as a result of psychiatric disease

14. Prior exposure to CTS-1027

15. Patients who qualify as a null-responder based on treatment(s) other than pegylated interferon and ribavirin

16. History or presence of clinically concerning cardiac arrhythmias or prolongation of pre-dose corrected Q-T interval (QTc) of > 450 milliseconds

17. History of or current autoimmune disease

18. Diagnosis of or symptoms suggestive of fibromyalgia

19. Currently on liver transplantation waiting list or recipient of any organ transplant

20. 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

21. Exposure to any other investigational treatment for any aspect of disease associated with HCV during the past 6 months

22. 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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis C

Intervention

Drug:
• CTS-1027
Supplied in 30mg, 10mg, or 5mg tablets (depending on dose arm) taken twice daily for up to 48 weeks.
• pegylated interferon
180 micrograms in 0.5 ml of solution subcutaneously (SQ), delivered in single use syringes administered once per week, for up to 48 weeks.
• Ribavirin
200 mg capsules of ribavirn 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
• Placebo
Tablets identical in appearance to CTS-1027 containing inactive ingredients. Placebo arm patients: Two tablets taken twice daily, for a total daily dose of four tablets. 30 mg CTS-1027 patients: One tablet taken twice daily, for a total daily dose of two tablets. One bottle of placebo is added to the 30mg kits in order to maintain the study blind (all patients recieve two-bottle kits of CTS-1027 and/or placebo).

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Conatus Pharmaceuticals Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Sustained Virologic Response	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.	Baseline and 24 weeks after the end of treatment (Week 72)	No
Secondary	Greater Than 2 Log Decline in HCV-RNA at 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.	Baseline, and Study Weeks 12, 24, and 48	No