Clinical trial NCT01273064: Standard of Care (SOC) With or Without CTS-1027 in Hepatitis C (HCV) Null-Responders
Official title: A Placebo-Controlled, Multicenter, Double-Blind, Randomized Trial of Pegylated Interferon Plus Ribavirin With or Without CTS-1027 in HCV Null-Responders
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hepatitis C
Keywords: HCV
Null Responders
Lead sponsor: Conatus Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2011-01-10
Enrollment: 114
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Sustained Virologic Response
timeFrame: Baseline and 24 weeks after the end of treatment (Week 72)
Secondary outcomes:
measure: Greater Than 2 Log Decline in HCV-RNA at Study Weeks 12, 24 and 48
timeFrame: Baseline, and Study Weeks 12, 24, and 48
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Coronado
country: United States
facility: Southern California Liver Centers
state: California
city: La Jolla
country: United States
facility: Scripps Clinic
state: California
city: Loma Linda
country: United States
facility: Loma Linda University MC
state: California
city: Pasadena
country: United States
facility: Huntington Medical Research Institute
state: California
city: San Diego
country: United States
facility: Medical Associates Research Group
state: California
city: San Diego
country: United States
facility: UCSD
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Atlanta
country: United States
facility: Atlanta Medical Center, Inc.
state: Georgia
city: Atlanta
country: United States
facility: Liver Center of Atlanta
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Maywood
country: United States
facility: Loyola University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: St. Louis
country: United States
facility: St. Louis University
state: Missouri
city: Bronx
country: United States
facility: Einstein College of Medicine (Jacobi Medical Center)
state: New York
city: New York
country: United States
facility: Concorde Medical Group
state: New York
city: New York
country: United States
facility: New York University
state: New York
city: New York
country: United States
facility: Weill Medical College of Cornell
state: New York
city: New York
country: United States
facility: Columbia Presbyterian Medical Center
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Consultants for Clinical Research
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: Albert Einstein Medical Center
state: Pennsylvania
city: Fort Worth
country: United States
facility: Baylor All Saints Medical Center
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch at Galveston
state: Texas
city: Houston
country: United States
facility: Research Specialists of Texas
state: Texas
city: Houston
country: United States
facility: St. Luke's Episcopal Hospital
state: Texas
city: Houston
country: United States
facility: University of Texas HSC at Houston
state: Texas
city: Houston
country: United States
facility: VAMC Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Fairfax
country: United States
facility: Metropolitan Research Group Washington DC
state: Virginia
city: Newport News
country: United States
facility: Liver Institute of Virginia
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University (VCU)
state: Virginia
city: Seattle
country: United States
facility: Benaroya Research Institute at Virginia Mason
state: Washington
Study officials:
affiliation: Conatus Pharmaceuticals Inc.
name: Erin Castelloe, MD
role: STUDY_CHAIR
References: