New Treatment Response in People With and Without Cirrhosis From Chronic Hepatitis C

NCT01888900 | Completed Phase 2 Results

• 2 other identifiers: 13015013-DK-0150
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

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.

Conditions

Cirrhosis; Chronic Hepatitis C; Hepatitis C; Hepatitis C, Chronic

Keywords

Hepatitis C; Non-Responders; Direct Acting Antivirals; Interferon Free; Cirrhosis

Outcome Measures

Primary Outcomes (1)

• Changes in Interferon Stimulated Genes in the Liver

  Change in raw expression in interferon stimulated genes at week 2 or 4 compared to baseline is obtained by subtracting either 2 or 4 week measurement from baseline measurement. Negative values reflect a decrease in expression and positive values reflect an increase in expression. The raw gene expression data was normalized using quantile normalization based on all the genes in the microarray.

  baseline and either 2 or 4 weeks

Secondary Outcomes (7)

• Rates of Rapid Virological Responder

  Week 4 post treatment

• Extended Rapid Virological Responder

  Both weeks 4 and 12 post treatment

• End of Treatment Responder

  Week 24 post treatment

• Sustained Virological Responder

  Week 12 post treatment

• Serum Aminotransferase Levels

  Week 12 post treatment

Study Arms (2)

Hepatitis C Virus Genotype 1A with QUAD

EXPERIMENTAL

Subjects will be started on combination therapy with asunaprevir, daclatasvir, peginterferon alfa-2a and ribavirin for 24 weeks.

Drug: QUAD

Hepatitis C Virus Genotype 1B with DUAL

EXPERIMENTAL

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.

Drug: DUAL

Interventions

DUAL DRUG

Asunaprevir and Daclatsvir

Hepatitis C Virus Genotype 1B with DUAL

QUAD DRUG

Asunaprevir, daclatsvir, peginterferon and ribavirin

Hepatitis C Virus Genotype 1A with QUAD

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults, ages 18 and above
• Chronic hepatitis C (HCV RNA in serum for more than 6 months)
• HCV Genotype 1
• HCV RNA in serum above 10,000 IU/mL
• Non-response to previous therapy with peginterferon and ribavirin categorized as null-response as defined by a less than 1 log IU/mL decline in HCV RNA at treatment week 4 or a less than 2 log IU/mL decline in HCV RNA at treatment week 12; and partial response as defined by a greater than or equal to 2 log decrease in HCV RNA at treatment week 12 but continued detection of HCV RNA at treatment week 24
• No contraindications to agents being used (asunaprevir, daclatasvir, peginterferon and ribavirin).
• No evidence or history of hepatic decompensation.
• Females of childbearing potential must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours before the first dose of study drug.
• Women of childbearing potential (WOCBP) and men must use highly effective methods of birth control to minimize the risk of pregnancy. WOCBP must follow instructions for birth control for the entire duration of the study including a minimum of 24 weeks after the last dose of P/R. Birth control requirements are or WOCBP and men who are sexually active with WOCBP
• Women must not be breastfeeding
• Fully informed, written consent to the study including repeat liver biopsy.
• \) Liver biopsy showing Ishak stages 0-2 or 5-6 within 12 weeks of initiating therapy OR a prior biopsy performed within 96 weeks of screening visit WITH saved tissue. Up to 10 subjects who do not fulfill the entry histologic criteria will be allowed to participate in the trial at the discretion of the investigator.
• Baseline sequence analysis of the NS5A region to exclude presence of mutations known to confer resistance to daclatasvir.
• a) Subject met a definition of virologic breakthrough or treatment futility, defined
• as:

You may not qualify if:

• Medical History and Concurrent Diseases
• Liver or any other organ transplant (including hematopoietic stem cell transplants) other than cornea and hair;
• Current or known history of cancer (except in situ carcinoma of the cervix or adequately treated basal or squamous cell carcinoma of the skin) within 5 years prior to enrollment
• Documented or suspected HCC, as evidenced by previously obtained imaging studies or liver biopsy (or on a screening imaging study/liver biopsy if this was performed)
• Evidence of decompensated liver disease including, but not limited to, radiologic criteria, a history or presence of ascites, bleeding varices, or hepatic encephalopathy
• Evidence of a medical condition contributing to chronic liver disease other than HCV (such as, but not limited to: hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposures)
• History of chronic hepatitis B virus (HBV) as documented by HBV serologies (eg, HBsAg-seropositive). Subjects with resolved HBV infection may participate (eg, HBsAb-seropositive with concurrent HBsAg-seronegative)
• Any gastrointestinal disease or surgical procedure that may impact the absorption of study drug. (Subjects who have had cholecystectomy are permitted to enter the study)
• History of HIV infection
• Hemophilia
• Uncontrolled diabetes (any subject with a confirmed screening HgA1c greater than or equal to 8.5 must be excluded)
• Confirmed, uncontrolled hypertension (any screening systolic blood pressure greater than or equal to 160 mmHg or diastolic blood pressure greater than or equal to 100 mmHg should be excluded unless discussed with the central medical monitor)
• Any other medical and/or social reason, including active substance abuse as defined by DSM-IV, Diagnostic Criteria for Drug and Alcohol Abuse, which in the opinion of the investigator would make the candidate inappropriate for participation in this study
• History of severe psychiatric disorders including but not limited to, schizophrenia, psychosis, bipolar disorder, post-traumatic stress disorder, mania, etc.
• Inability to tolerate oral medication;

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005 Sep;5(9):558-67. doi: 10.1016/S1473-3099(05)70216-4.

  PMID: 16122679 BACKGROUND

• Lavanchy D. The global burden of hepatitis C. Liver Int. 2009 Jan;29 Suppl 1:74-81. doi: 10.1111/j.1478-3231.2008.01934.x.

  PMID: 19207969 BACKGROUND

• Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus infection in Europe. J Hepatol. 2008 Jan;48(1):148-62. doi: 10.1016/j.jhep.2007.07.033. Epub 2007 Nov 5.

  PMID: 18022726 BACKGROUND

• Serti E, Park H, Keane M, O'Keefe AC, Rivera E, Liang TJ, Ghany M, Rehermann B. Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNalpha. Gut. 2017 Apr;66(4):724-735. doi: 10.1136/gutjnl-2015-310033. Epub 2016 Jan 4.

  PMID: 26733671 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Fibrosis; Hepatitis C, Chronic; Hepatitis C

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes

Results Point of Contact

• Title: Dr. Marc Ghany
• Organization: National Institute of Diabetes and Digestive and Kidney Diseases

marcg@mail.nih.gov

301-402-5515

Study Officials

• Marc G Ghany, M.D.

  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 26, 2013
• First Posted: June 28, 2013
• Study Start: May 1, 2013
• Primary Completion: November 1, 2015
• Study Completion: November 1, 2015
• Last Updated: February 7, 2017
• Results First Posted: December 12, 2016

Record last verified: 2016-12

Data Sharing

• IPD Sharing: Will share

Locations

US (1)