Clinical trial NCT01888900
Conditions: Cirrhosis Chronic Hepatitis C Hepatitis C Hepatitis C, Chronic
Keywords: Hepatitis C Non-Responders Direct Acting Antivirals Interferon Free Cirrhosis
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Start date: 2013-05-01; Completion date: 2015-11-01
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Some people who have chronic hepatitis C do not respond to the usual treatment with peginterferon and ribavirin. New chronic hepatitis treatments are being developed that may work better for different people. The treatments will look at how specific genes interact with the drugs. Researchers want to see how well these new drugs work in people whose chronic hepatitis C has not responded or only partly responded to the usual treatment drugs.

Objectives:

\- To compare new treatments for people with chronic hepatitis C.

Eligibility:

\- Individuals at least 18 years of age who have chronic hepatitis C that has not responded to standard treatments.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Liver scans and a biopsy will be taken before the start of treatment.
* Participants will be separated into two groups. One group will have the new treatment drugs (assunaprevir and daclatasvir). The second group will have these two drugs as well as peginterferon and ribavirin. All participants will have an initial 4-day hospital stay with regular blood tests to see how the start of the treatment works.
* The first group will take the new study drug tablets daily for 24 weeks. Those who do not respond to this treatment will also start to take peginterferon and ribavirin, and the treatment will continue for 24 weeks after starting the additional drugs.
* The second group will take all four drugs according to the standard dosing schedule for 24 weeks.
* Treatment will be monitored with frequent blood tests. Liver scans, biopsies, and other tests will be performed as directed by the study doctors.
* Participants will have 24 weeks of regular followup visits.

Detailed description:
Up to 70 patients with chronic hepatitis C, genotype 1, who were partial or null responders to optimal therapy with the combination of peginterferon and ribavirin will be enrolled into this pilot study on the use of asunaprevir and daclatasvir together or in combination with peginterferon alfa-2a and ribavirin to improve response to antiviral therapy. Two separate studies will be conducted based upon HCV genotype 1 subtype. For patients with HCV genotype 1b: Will undergo baseline testing for NS5A RAVs known to confer resistance to daclatasvir (L31/Y93). Subjects who harbor these NS5A resistance associated variants will be excluded from receiving dual therapy but would be offered quad therapy and managed as a HCV genotype 1a subject. After medical evaluation and liver biopsy, 30 HCV genotype 1b patients will receive combination therapy with asunaprevir and daclatasvir alone for 24 weeks and undergo paired liver biopsies, pre-treatment and either at 2 or 4 weeks after starting therapy. Patients in whom HCV RNA is greater than or equal to LLOQ at 8 weeks will either discontinue therapy at that point (early stopping rule for futility) or may have rescue therapy instituted at the discretion of the investigator with a QUAD regimen (asunaprevir and daclatasvir plus peginterferon and ribavirin) provided they meet pre-specified inclusion criteria. For patients with HCV genotype 1a: After medical evaluation and liver biopsy 40 (15 with cirrhosis and 15 with Ishak fibrosis 0-2; the remaining 10 slots will be allocated for individuals who do not meet the histological entry requirement i.e. Ishak 3-4) HCV genotype 1a patients will be started on combination therapy with asunaprevir, daclatasvir, peginterferon alfa-2a and ribavirin for 24 weeks. Patients will be randomized to undergo a second liver biopsy at study week 4 after starting therapy either before or 6 hours after the next scheduled peginterferon dose to assess intrahepatic interferon stimulated gene expression. Intrahepatic drug concentrations of asunaprevir and daclatasvir will be measured as part of an ancillary study. Patients in whom HCV RNA is greater than or euqal to LLOQ at 8 weeks will discontinue therapy (early stopping rule for futility). Routine serum chemistries, complete blood counts and HCV RNA levels will be monitored more frequently for the initial 4 days and then at standard intervals during the period of antiviral therapy. The major endpoints will be changes in interferon stimulated gene and protein expression in the liver and changes in HCV RNA levels in liver and serum between baseline and 4 weeks. Secondary endpoints will be rates of sustained virologic response 12 and 24 weeks off therapy.

Arms: arm 1: Subjects will be started on combination therapy with asunaprevir, daclatasvir, peginterferon alfa-2a and ribavirin for 24 weeks. arm 2: Subjects will receive combination therapy with asunaprevir and daclatasvir alone for 24 weeks and undergo paired liver biopsies, pre-treatment and either at 2 or 4 weeks after starting therapy.
Interventions: intervention 1: DUAL intervention 2: QUAD
Intervention descriptions: intervention 1: Asunaprevir and Daclatsvir intervention 2: Asunaprevir, daclatsvir, peginterferon and ribavirin

Protocol documents: