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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: CTS-1027
* Drug: Pegylated interferon
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CTS-1027, Peg IFN, Ribavirin<br>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<br>* CTS-1027 supplied in 5 and 10 mg tablets, 15 mg taken twice daily, for up to 48 weeks<br>Drug: Pegylated interferon<br>* 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.<br>* Other names: Pegasys;Drug: Ribavirin<br>* 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.<br>* Other names: Copegus;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCV, Null Responder