Combination Therapy for Chronic Hepatitis C Infection

NCT01805882 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 13006613-I-0066
• Study Type: interventional
• Target: 229
• Locations: 1 country
• Sites: 3

Brief Summary

Background: \- GS-7977, GS-5885, GS-9669, and GS-9451 are new drugs for treating hepatitis C virus (HCV) infection. GS-7977 may help treat the infection when used with other treatments like interferon therapy. GS-5885, and GS-9669, and GS-9451 also lower the amount of HCV in the body. Researchers want to see whether GS-7977 can be combined with any of the other three drugs to treat HCV infection. Some participants will take GS-7977 and GS-5885. Others will take GS-7977, GS-5885 and GS-9669 or GS-7977, GS-5885 and GS-9451. Objectives: \- To see whether GS-7977 with GS-5885 alone or in combination with either GS-9669 or 9451 can be used to treat HCV infection. Eligibility: Individuals at least 18 years of age who have chronic HCV infection and have never been treated for it. Individuals at least 18 years of age who have chronic HCV infection and have not responded to interferon therapy. Individuals at least 18 years of age who have chronic HCV infection with advanced liver disease and have never been treated for HCV Design: Participants will be screened with a physical exam and medical history. Blood samples will be collected. A liver biopsy may also be performed. Some participants will take the two study drugs and some will take three study drugs. Those who take GS-7977 and GS-5885 will have one daily tablet named fixed dose combination or FDC. Those who take GS-7977 and CS-9669 will have three daily tablets taken once daily. Those who take GS-7977 and GS-5885 and GS-9451 will take 2 pills once a day. GS-7977 and GS-5885 will be combined in one pill and GS-9451 will be in another pill. Treatment will be monitored with frequent blood tests. These tests will check liver function and the level of HCV infection. Participants may have other blood tests as needed for treatment. Participants will have 4, 6 or 12 weeks of treatment depending on which study drugs are scheduled to take. After they complete their schedule, they will stop treatment with the study drugs. They may also have another liver biopsy. Participants will have regular follow-up visits over the next 48 weeks. They will have physical exams and provide blood samples....

Conditions

Hepatitis C, Chronic

Keywords

Interferon Sparing; Directly Acting Antiviral; Ribavarin Sparing

Outcome Measures

Primary Outcomes (1)

• The Proportion of Subjects Who Achieve Sustained Viral Response (SVR12) 12 Weeks After the Stop of Treatment Drugs

  The primary outcome was the proportion of patients with sustained viral response measured 12 weeks after the stop of treatment. The viral response was assessed by serum HCV RNA concentrations lower than 43 IU/mL - the lower limit of quantification.

  12 weeks after stop of treatment

Study Arms (9)

A: HCV GT-1, tx naïve, 12 wks Sofosbuvir/Ledipasvir

EXPERIMENTAL

Oral treatment with Sofosbuvir 400mg (GS-7977) and Ledipasvir 90mg (GS-5885), once daily, for 12 weeks in HCV genotype 1, treatment naïve patients

Drug: Sofosbuvir; Drug: Ledipasvir

B: HCV GT-1, tx naïve, 6 wks Sofosbuvir/Ledipasvir/GS-9669

EXPERIMENTAL

Oral treatment with Sofosbuvir 400mg (GS-7977), Ledipasvir 90mg (GS-5885), GS-9669 500mg, once daily, for 6 weeks in HCV genotype 1, treatment naïve patients

Drug: Sofosbuvir; Drug: Ledipasvir; Drug: GS-9669

C: HCV GT-1, tx naïve, 6 wks Sofosbuvir/Ledipasvir/GS-9451

EXPERIMENTAL

Oral treatment with Sofosbuvir 400mg (GS-7977), Ledipasvir 90mg (GS-5885), GS-9451 80mg, once daily, for 6 weeks in HCV genotype 1, treatment naïve patients

Drug: Sofosbuvir; Drug: Ledipasvir; Drug: GS-9451

D: HCV GT-1, tx-relapsed, 12 wks Sofosbuvir/Ledipasvir

EXPERIMENTAL

Oral treatment with Sofosbuvir 400mg (GS-7977) and Ledipasvir 90mg (GS-5885), once daily, for 12 weeks in HCV genotype 1, treatment-relapsed patients who previously received Sofosbuvir plus Ribavirin

Drug: Sofosbuvir; Drug: Ledipasvir

E: HCV GT-4, tx naïve/expd, 12 wks Sofosbuvir/Ledipasvir

EXPERIMENTAL

Oral treatment with Sofosbuvir 400mg (GS-7977) and Ledipasvir 90mg (GS-5885), once daily, 12 weeks in HCV genotype 4 treatment naïve subjects and interferon treament experienced subjects

Drug: Sofosbuvir; Drug: Ledipasvir

F: HCV GT-1, tx naïve/expd 6 wks Sofosbuvir/Ledipasvir/GS-9451

EXPERIMENTAL

Oral treatment with Sofosbuvir 400mg (GS-7977) and Ledipasvir 90mg (GS-5885) and GS-9451 80mg, once daily, 6 weeks in HCV genotype 1 treatment naïve and treatment experienced subjects with advanced liver disease

Drug: Sofosbuvir; Drug: Ledipasvir; Drug: GS-9451

G: HCV GT-1, tx naïve, 4 wks Sofosbuvir, Ledipasvir, GS-9451

EXPERIMENTAL

Oral Treatment with Sofosbuvir 400mg (GS-7977) and Ledipasvir 90mg (GS-5885) with GS-9451 80mg, once daily, 4 weeks in HCV genotype 1 treatment naïve subjects with early stage liver disease

Drug: Sofosbuvir; Drug: Ledipasvir; Drug: GS-9451

H: HCV GT-1, tx naïve, 4 wks Sofos/Ledip/GS-9451/GS-9669

EXPERIMENTAL

Oral Treatment with Sofosbuvir 400mg (GS-7977) and Ledipasvir 90mg (GS-5885) with GS-9451 80mg, and GS-9669 250mg, once daily, 4 weeks in HCV genotype 1 treatment naïve subjects with early stage liver disease

Drug: Sofosbuvir; Drug: Ledipasvir; Drug: GS-9669; Drug: GS-9451

D Retx: HCV GT-1, Re-Treatment, 12 wks Sofosbuvir, Ledipasvir

EXPERIMENTAL

Oral treatment with Sofosbuvir 400mg (GS-7977) and Ledipasvir 90mg (GS-5885), once daily, 12 weeks in HCV genotype 1 subjects who failed HCV therapy in Arm B or Arm G or Arm H

Drug: Sofosbuvir; Drug: Ledipasvir

Interventions

Sofosbuvir DRUG

Also known as: Sofosbuvir (GS-7977)

A: HCV GT-1, tx naïve, 12 wks Sofosbuvir/Ledipasvir; B: HCV GT-1, tx naïve, 6 wks Sofosbuvir/Ledipasvir/GS-9669; C: HCV GT-1, tx naïve, 6 wks Sofosbuvir/Ledipasvir/GS-9451; D Retx: HCV GT-1, Re-Treatment, 12 wks Sofosbuvir, Ledipasvir; D: HCV GT-1, tx-relapsed, 12 wks Sofosbuvir/Ledipasvir; E: HCV GT-4, tx naïve/expd, 12 wks Sofosbuvir/Ledipasvir; F: HCV GT-1, tx naïve/expd 6 wks Sofosbuvir/Ledipasvir/GS-9451; G: HCV GT-1, tx naïve, 4 wks Sofosbuvir, Ledipasvir, GS-9451; H: HCV GT-1, tx naïve, 4 wks Sofos/Ledip/GS-9451/GS-9669

Ledipasvir DRUG

Also known as: Ledipasvir (GS-5885)

A: HCV GT-1, tx naïve, 12 wks Sofosbuvir/Ledipasvir; B: HCV GT-1, tx naïve, 6 wks Sofosbuvir/Ledipasvir/GS-9669; C: HCV GT-1, tx naïve, 6 wks Sofosbuvir/Ledipasvir/GS-9451; D Retx: HCV GT-1, Re-Treatment, 12 wks Sofosbuvir, Ledipasvir; D: HCV GT-1, tx-relapsed, 12 wks Sofosbuvir/Ledipasvir; E: HCV GT-4, tx naïve/expd, 12 wks Sofosbuvir/Ledipasvir; F: HCV GT-1, tx naïve/expd 6 wks Sofosbuvir/Ledipasvir/GS-9451; G: HCV GT-1, tx naïve, 4 wks Sofosbuvir, Ledipasvir, GS-9451; H: HCV GT-1, tx naïve, 4 wks Sofos/Ledip/GS-9451/GS-9669

GS-9669 DRUG

B: HCV GT-1, tx naïve, 6 wks Sofosbuvir/Ledipasvir/GS-9669; H: HCV GT-1, tx naïve, 4 wks Sofos/Ledip/GS-9451/GS-9669

GS-9451 DRUG

C: HCV GT-1, tx naïve, 6 wks Sofosbuvir/Ledipasvir/GS-9451; F: HCV GT-1, tx naïve/expd 6 wks Sofosbuvir/Ledipasvir/GS-9451; G: HCV GT-1, tx naïve, 4 wks Sofosbuvir, Ledipasvir, GS-9451; H: HCV GT-1, tx naïve, 4 wks Sofos/Ledip/GS-9451/GS-9669

Eligibility Criteria

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

You may qualify if:

• Eighteen years of age or older at screening.
• Female study participants with childbearing potential (as defined below) and all males must be willing to practice either:
• Abstinence from sexual intercourse or
• One or more forms of effective barrier contraception throughout dosing and for 30 days following the last dose. This cannot include hormonal contraception for female subjects.
• Effective forms of barrier contraception include:
• a male condom with spermicide
• use by female sexual partner of a female condom with spermicide
• Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) includes any female who:
• Has had a hysterectomy or
• Has had a bilateral oophorectomy (ovariectomy) or
• Is post-menopausal (a demonstration of a total cessation of menses for greater than or equal to1 year)
• Has had a bilateral tubal ligation or fallopian tube inserts
• Chronic HCV GT-1 or GT-4 infection as documented by greater than or equal to 1 measurement of serum HCV RNA greater than or equal to 2,000 international units per milliliter during screening and at least one of the following:
• A positive anti-HCV antibody, HCV RNA, or HCV genotype test result greater than or equal to 12 months prior to the baseline (day 0) visit together with current positive HCV RNA and anti-HCV antibody test results or
• Positive HCV RNA test and anti-HCV antibody test results together with a liver biopsy consistent with chronic HCV infection or a liver biopsy performed before enrollment with evidence of chronic hepatitis C infection disease, such as the presence of fibrosis.

You may not qualify if:

• Current or prior history of any of the following:
• Clinically-significant illness (other than HCV) or any other major medical disorder that may interfere with subject treatment, assessment or compliance with the protocol; subjects currently under evaluation for a potentially clinically-significant illness (other than HCV) are also excluded.
• Gastrointestinal disorder or post operative condition that could interfere with the absorption of the study drug.
• Poor venous access interfering with required study blood collection.
• Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).
• Solid organ transplantation.
• Significant pulmonary disease, significant cardiac disease or porphyria.
• Unstable psychiatric disease (Subjects with psychiatric illness that is well-controlled on a stable treatment regimen or currently not requiring medication may be included).
• Any malignancy or its treatment that in the opinion of the PI may cause ongoing interference with host immunity; subjects under evaluation for malignancy are not eligible.
• Significant drug allergy (such as anaphylaxis or hepatotoxicity).
• Substance abuse, which in the opinion of the investigator is likely to interfere with medication adherence or study compliance.
• Lactose allergy, patients with lactose intolerance will be evaluated on a case-by-case basis.
• Positive test results at screening for hepatitis B virus (HBV) surface antigen (HBsAg), HBV DNA (if medically indicated) or anti-HIV antibody (unless previously treated on 13-I-0159).
• Prior exposure to any direct-acting antivirals for HCV infection, except for patients who were previously treated studies 11-I-0258, 13-I-1059 or this study enrolling in Group D.
• History of clinically significant chronic liver disease due to other etiology (e.g., hemochromatosis, autoimmune hepatitis, Wilson s disease, alpha 1-antitrypsin deficiency, alcoholic liver disease, \> moderate non-alcoholic steatohepatitis and toxin exposures).

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (3)

Unity Health Care, Inc./DC General

Washington D.C., District of Columbia, 20002, United States

Location

Family Medical and Conseling Services

Washington D.C., District of Columbia, 20020, United States

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (10)

• Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006 May 16;144(10):705-14. doi: 10.7326/0003-4819-144-10-200605160-00004.

  PMID: 16702586 BACKGROUND

• Serfaty L, Aumaitre H, Chazouilleres O, Bonnand AM, Rosmorduc O, Poupon RE, Poupon R. Determinants of outcome of compensated hepatitis C virus-related cirrhosis. Hepatology. 1998 May;27(5):1435-40. doi: 10.1002/hep.510270535.

  PMID: 9581703 BACKGROUND

• Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003 Apr;9(4):331-8. doi: 10.1053/jlts.2003.50073.

  PMID: 12682882 BACKGROUND

• Townsend K, Petersen T, Gordon LA, Kohli A, Nelson A, Seamon C, Gross C, Tang L, Osinusi A, Polis MA, Masur H, Kottilil S. Effect of HIV co-infection on adherence to a 12-week regimen of hepatitis C virus therapy with ledipasvir and sofosbuvir. AIDS. 2016 Jan;30(2):261-6. doi: 10.1097/QAD.0000000000000903.

  PMID: 26691547 DERIVED

• Petersen T, Townsend K, Gordon LA, Sidharthan S, Silk R, Nelson A, Gross C, Calderon M, Proschan M, Osinusi A, Polis MA, Masur H, Kottilil S, Kohli A. High adherence to all-oral directly acting antiviral HCV therapy among an inner-city patient population in a phase 2a study. Hepatol Int. 2016 Mar;10(2):310-9. doi: 10.1007/s12072-015-9680-7. Epub 2015 Nov 26.

  PMID: 26612014 DERIVED

• Kohli A, Kattakuzhy S, Sidharthan S, Nelson A, McLaughlin M, Seamon C, Wilson E, Meissner EG, Sims Z, Silk R, Gross C, Akoth E, Tang L, Price A, Jolley TA, Emmanuel B, Proschan M, Teferi G, Chavez J, Abbott S, Osinusi A, Mo H, Polis MA, Masur H, Kottilil S. Four-Week Direct-Acting Antiviral Regimens in Noncirrhotic Patients With Hepatitis C Virus Genotype 1 Infection: An Open-Label, Nonrandomized Trial. Ann Intern Med. 2015 Dec 15;163(12):899-907. doi: 10.7326/M15-0642. Epub 2015 Nov 24.

  PMID: 26595450 DERIVED

• Wilson EM, Kattakuzhy S, Sidharthan S, Sims Z, Tang L, McLaughlin M, Price A, Nelson A, Silk R, Gross C, Akoth E, Mo H, Subramanian GM, Pang PS, McHutchison JG, Osinusi A, Masur H, Kohli A, Kottilil S. Successful Retreatment of Chronic HCV Genotype-1 Infection With Ledipasvir and Sofosbuvir After Initial Short Course Therapy With Direct-Acting Antiviral Regimens. Clin Infect Dis. 2016 Feb 1;62(3):280-288. doi: 10.1093/cid/civ874. Epub 2015 Oct 31.

  PMID: 26521268 DERIVED

• Kohli A, Kapoor R, Sims Z, Nelson A, Sidharthan S, Lam B, Silk R, Kotb C, Gross C, Teferi G, Sugarman K, Pang PS, Osinusi A, Polis MA, Rustgi V, Masur H, Kottilil S. Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study. Lancet Infect Dis. 2015 Sep;15(9):1049-1054. doi: 10.1016/S1473-3099(15)00157-7. Epub 2015 Jul 14.

  PMID: 26187031 DERIVED

• Kohli A, Osinusi A, Sims Z, Nelson A, Meissner EG, Barrett LL, Bon D, Marti MM, Silk R, Kotb C, Gross C, Jolley TA, Sidharthan S, Petersen T, Townsend K, Egerson D, Kapoor R, Spurlin E, Sneller M, Proschan M, Herrmann E, Kwan R, Teferi G, Talwani R, Diaz G, Kleiner DE, Wood BJ, Chavez J, Abbott S, Symonds WT, Subramanian GM, Pang PS, McHutchison J, Polis MA, Fauci AS, Masur H, Kottilil S. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet. 2015 Mar 21;385(9973):1107-13. doi: 10.1016/S0140-6736(14)61228-9. Epub 2015 Jan 13.

  PMID: 25591505 DERIVED

• Osinusi A, Kohli A, Marti MM, Nelson A, Zhang X, Meissner EG, Silk R, Townsend K, Pang PS, Subramanian GM, McHutchison JG, Fauci AS, Masur H, Kottilil S. Re-treatment of chronic hepatitis C virus genotype 1 infection after relapse: an open-label pilot study. Ann Intern Med. 2014 Nov 4;161(9):634-8. doi: 10.7326/M14-1211.

  PMID: 25364884 DERIVED

MeSH Terms

Conditions

Hepatitis C, Chronic

Interventions

Sofosbuvir; ledipasvir; GS-9669; GS-9451

Condition Hierarchy (Ancestors)

Hepatitis C; 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; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Uridine Monophosphate; Uracil Nucleotides; Pyrimidine Nucleotides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleotides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleotides

Results Point of Contact

• Title: Shyam Kottilil MD
• Organization: National Institute of Allergy and Infectious Diseases

Skottilil@ihv.umaryland.edu

+1 410 706 4872

Study Officials

• Henry Masur, M.D.

  National Institutes of Health Clinical Center (CC)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

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

Study Record Dates

• First Submitted: March 5, 2013
• First Posted: March 6, 2013
• Study Start: January 1, 2013
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: June 8, 2017
• Results First Posted: April 11, 2017

Record last verified: 2017-02

Data Sharing

• IPD Sharing: Will share

Locations

US (3)