Study of A Combination Pill With GS-7977 and GS-5885 for Hepatitis C in People With HIV

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01878799
• Collaborator: (none)
• Enrollment: 50
• Location: 1
• Arm: 1
• Duration (Months): 15
• Patients Per Site Per Month: 3.3

Study Details

Study Description

Brief Summary

Background:

• Present treatment for hepatitis C includes the use of a weekly injection and two different pills. This treatment is associated with serious side effects. Drugs that can be taken by mouth and cure HCV infection without serious side effects would be a great help to the large number of people infected with HCV. GS-7977 and GS-5885 are new medications being developed to treat the hepatitis C virus (HCV) infection. They are still being researched and are not approved by the Food and Drug Administration. They are being developed as treatment for hepatitis C as a single pill taken once a day.

Objectives:

• To determine whether a combination of the two study drugs can safely and effectively treat HCV infection in people with HIV infection and who do not have cirrhosis of the liver.

Eligibility:

• Individuals who have HIV infection and have liver disease caused by infection with HCV.

Design:

• Participants will be screened with a physical exam and medical history. Blood samples will be collected. Urine samples will be collected from participants who might become pregnant. If a participant has not had a liver biopsy in the past 3 years, one will be required.

• Participants will take one pill daily for 12 weeks. This pill will be a combination of the two study drugs.

• Treatment will be monitored with frequent clinic visits and blood tests over a total of 60 weeks.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C; HIV	Drug: GS-7977/GS- 5885 FDC	Phase 2

Detailed Description

Chronic hepatitis C virus (HCV) infection is a major public health problem with an estimated 180 million people infected worldwide. In the US an estimated 4.1 million people are infected with HCV which is the principal cause of death from liver disease and leading indication for liver transplantation. Significant advances have been made with the approval of directly acting antivirals (DAA) namely the protease inhibitors, telaprevir (TVR) and boceprevir (BOC) which have been shown to significantly improve rates of sustained virologic response (SVR). Response rates to these new combinations in HIV/HCV are also very promising, however treatment has been characterized with high rates of toxicities.

Recently several trials have confirmed the efficacy of potent DAA therapy without concomitant IFN in the treatment of HCV monoinfected individuals. Given the improved response rates achieved with a combination of DAAs with fast HCV suppression and improved side-effect profiles; and the need for better therapy for HIV/HCV co-infected subjects, we propose a study to determine the safety, tolerability and efficacy of 12 weeks of treatment with a fixed dose combination of GS-7977 and GS-5885 in HIV/HCV Genotype 1 (GT-1) subjects. We hypothesize that anti-HCV therapy that does not rely on the host immune system will provide an enhanced rate of SVR among HIV/HCV GT-1 coinfected subjects. The findings from this study will aid in our understanding of determinants of response to an IFN-free regimen in HIV/HCV coinfected individuals.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Trial to Assess Safety, Tolerability, and Efficacy of the Fixed Dose Combination of GS-7977 and GS-5885 in HCV Genotype 1 Subjects Coinfected With HIV
• Study Start Date: Jun 1, 2013
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: HIV Subjects with HIV and HCV	Drug: GS-7977/GS- 5885 FDC; The GS-7977/GS-5885 FDC product combines a potent HCV nucleotide inhibitor and a potent HCV NS5A inhibitor and will be given for 12 weeks.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Achieved SVR12 (HCV RNA <LLOQ 12 Weeks After Completion of Treatment) [12 weeks after completion of treatment]

   The primary end point was sustained virologic response [plasma HCV RNA level <12 IU/mL by real-time HCV assay (Abbott)] at 12 weeks after treatment completion (SVR12) among all patients enrolled in the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

1. Eighteen years of age or older at screening.

2. HCV treatment-naive, as defined as no prior exposure to any IFN, RBV, or other approved or experimental HCV-specific direct-acting antiviral agent.

3. Participants must be willing to practice either:

4. Abstinence from sexual intercourse or

5. At least 2 forms of contraception including one barrier method from 2 weeks prior to Day 0 through 30 days after the last dose is received.

1. Female partners of male study subjects may rely upon hormonal contraception as one of the 2 methods; however female study subjects may not.

1. Chronic hepatitis C infection defined as one of the following:

2. Positive for anti-HCV antibody, HCV RNA, or an HCV genotype at least 6 months before screening, and positive for HCV RNA and anti-HCV antibody at the time of screening or

3. Positive for anti-HCV antibody and HCV RNA at the time of screening with a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed before enrollment with evidence of chronic hepatitis C disease, such as the presence of fibrosis).

4. HIV treatment status:

5. Documented HIV infection, ARV untreated for > 8 weeks preceding dosing and having either:

6. a CD4 T-cell count greater than or equal to 500 cells/mm3 within 8 weeks of Day 0 or

7. an HIV viral load less than 500 copies/mL with a stable CD4 count for at least 3 months.

8. Documented HIV infection on a stable, protocol-approved, ARV regimen for greater than or equal to 8 weeks prior to dosing and is expected to continue the current ARV regimen through the end of study with all of the following:

9. a CD4 T-cell count > 100 cells/mm3

10. a documented plasma HIV-1 RNA level less than the level of detection for at least 8 weeks preceding dosing.

If the lower limit of detection of the local HIV-1 RNA assay is < 50 copies/mL (e.g.,< 20 copies/mL), the Screening plasma HIV-1 RNA level cannot exceed 50 copies/mL.

1. HIV ARV agents including only combination regimens consisting of medications from the following list: tenofovir (TDF), emtricitabine (FTC), efavirenz, raltegravir, and rilpivirine administered according to their manufacturer s prescribing information. (reference Section 10.3 for additional information)

2. Documentation of hepatitis C genotype 1a, 1b or mixed 1a/1b

3. Absence of cirrhosis, defined as one of the following:

4. A liver biopsy performed within 36 calendar months of screening showing absence of cirrhosis.

5. FibroTest score of < 0.48 AND APRI of < 1 performed during the 8 weeks preceding dosing (In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, a liver biopsy is required).

6. Able to effectively communicate with the Investigator and other center personnel.

7. Willing to give written informed consent and comply with the study restrictions and requirements.

8. If opioid-dependent, subjects must be participating in a supervised treatment.

9. Participants must have a primary medical provider outside of OP8 and the NIH for medical management.

EXCLUSION CRITERIA:

Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:

1. Current or prior history of any of the following:

2. 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.

3. Gastrointestinal disorder or post-operative condition that could interfere with the absorption of the study drug.

4. Poor venous access interfering with required study blood collection.

5. Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).

6. Solid organ transplantation.

7. Significant pulmonary disease, significant cardiac disease or porphyria.

8. Unstable psychiatric disease (Subjects with psychiatric illness that is well-controlled on a stable treatment regimen or currently not requiring medication may be included).

9. 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.

10. Significant drug allergy (such as anaphylaxis or hepatotoxicity).

11. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson s disease, alfa-1 antitrypsin deficiency, cholangitis).

12. Patients with renal impairment or uncontrolled medical problems that could place them at high risk for developing renal impairment.

13. Positive test at screening for either HBsAg or quantifiable HBV DNA (completed only if necessary to rule out chronic HBV)

14. Current use of non-protocol approved ARVs.

15. A new AIDS-defining condition diagnosed within 30 days prior to screening or active, serious infection (other than HIV or HCV) requiring parenteral antibiotics, antivirals or antifungals within 30 days prior to Day 0.

16. Cirrhosis of the liver

17. Screening or baseline ECG with clinically significant ECG findings.

18. Abnormal hematological and biochemical parameters, including:

19. Neutrophil count < 750 cells/mm(3)

20. Hemoglobin < 9 g/dL. If Hgb is < 11g/dL in women or < 12 g/dL in men. Other causes of anemia should be excluded as medically indicated.

21. Platelet count less than or equal to 50,000 cells/mm(3)

22. Estimated GFR (calculated by the CKD-EP(I) equation) < 50 mL/min/per 1.73 m(2) if not on ARV or < 60 mL/min if on ARVs

23. ALT or AST greater than or equal to 10 times ULN

24. Serum lipase greater than or equal to 1.5 times ULN (at screening or during the screening period)

25. Direct bilirubin greater than or equal to 1.50 times ULN

26. Albumin less than or equal to 3.0 g/dL

27. INR greater than or equal to 1.5 times ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR.

28. Donation or loss of more than 400 mL blood within 8 weeks prior to first dose administration.

29. Poorly controlled diabetes mellitus indicated by hemoglobin A1C > 10% at screening for known diabetics.

30. Known hypersensitivity to, GS-5885, GS-7977, or formulation excipients.

31. Pregnant/Breastfeeding women.

32. Co-enrollment in other clinical trials is restricted, and requires approval of the Investigator.

Study staff should be notified of co-enrollment status.

1. Need for use of the following medications from 21 days prior to the start of study drugs through the end of treatment:

2. Hematologic stimulating agents (e.g. erythropoiesis-stimulating agents (ESAs); granulocyte colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

3. Chronic systemic immunosuppressants including, but not limited to, corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab)

4. Investigational agents or devices for any indication

5. Medications for disease conditions excluded from the protocol (e.g., active cancer, transplantation) are not listed under this Concomitant Medication section and are disallowed in the study.

6. Concomitant use of certain medications or herbal/natural supplements per PI discretion expected to result in pharmacokinetic interactions resulting in increases or decreases in exposure of study drug(s) as listed in Table of this protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Shyamasundaran Kottilil, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Study Documents (Full-Text)

None provided.

More Information

Publications

• Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, Kaslow RA, Margolis HS. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999 Aug 19;341(8):556-62.
• 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.
• Kim WR. The burden of hepatitis C in the United States. Hepatology. 2002 Nov;36(5 Suppl 1):S30-4. Review.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT01878799
• Other Study ID Numbers: 130159; 13-I-0159
• First Posted: Jun 17, 2013
• Last Update Posted: Sep 15, 2016
• Last Verified: Jul 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Direct Acting Antiviral; Treatment Naive; Interferon Sparing; Ribavirin Sparing
• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Hepatitis; Sofosbuvir; Ledipasvir

Study Results

Participant Flow

Arm/Group Title	Subjects With HIV and HCV on Antiretroviral Agents	Subjects With HIV and HCV Who Are Not on Antiretroviral Agents
Arm/Group Description	Subjects with HIV and HCV on antiretroviral agents given 'Drug: GS-7977 (sofosbuvir 400mg)/GS-5885 (ledipasvir 90mg) FDC' once daily by mouth for 12 weeks. The GS-7977/GS-5885 product combines a potent HCV nucleotide inhibitor and a potent HCV NS5A inhibitor.	Subjects with HIV and HCV not on antiretroviral agents given 'Drug: GS-7977 (sofosbuvir 400mg)/GS-5885 (ledipasvir 90mg) FDC' once daily by mouth for 12 weeks. The GS-7977/GS-5885 product combines a potent HCV nucleotide inhibitor and a potent HCV NS5A inhibitor.
Period Title: Overall Study
STARTED	37	13
COMPLETED	36	13
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Subjects With HIV and HCV on Antiretroviral Agents	Subjects With HIV and HCV Who Are Not on Antiretroviral Agents	Total
Arm/Group Description	Subjects with HIV and HCV on antiretroviral agents given 'Drug: GS-7977 (sofosbuvir 400mg)/GS-5885 (ledipasvir 90mg) FDC' once daily by mouth for 12 weeks. The GS-7977/GS-5885 product combines a potent HCV nucleotide inhibitor and a potent HCV NS5A inhibitor.	Subjects with HIV and HCV who are not on antiretroviral agents given 'Drug: GS-7977 (sofosbuvir 400mg)/GS-5885 (ledipasvir 90mg) FDC' once daily by mouth for 12 weeks. The GS-7977/GS-5885 product combines a potent HCV nucleotide inhibitor and a potent HCV NS5A inhibitor.	Total of all reporting groups
Overall Participants	37	13	50
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	32 86.5%	13 100%	45 90%
>=65 years	5 13.5%	0 0%	5 10%
Sex: Female, Male (Count of Participants)
Female	7 18.9%	6 46.2%	13 26%
Male	30 81.1%	7 53.8%	37 74%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 5.4%	0 0%	2 4%
Not Hispanic or Latino	35 94.6%	13 100%	48 96%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	31 83.8%	10 76.9%	41 82%
White	6 16.2%	3 23.1%	9 18%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Achieved SVR12 (HCV RNA <LLOQ 12 Weeks After Completion of Treatment)
Description	The primary end point was sustained virologic response [plasma HCV RNA level <12 IU/mL by real-time HCV assay (Abbott)] at 12 weeks after treatment completion (SVR12) among all patients enrolled in the study.
Time Frame	12 weeks after completion of treatment

Outcome Measure Data

Analysis Population Description

The analysis included all subjects who received at least one dose of study treatment.

Arm/Group Title	Subjects With HIV and HCV on Antiretroviral Agents	Subjects With HIV and HCV Who Are Not on Antiretroviral Agents
Arm/Group Description	Subjects with HIV and HCV on antiretroviral agents given 'Drug: GS-7977 (sofosbuvir 400mg)/GS-5885 (ledipasvir 90mg) FDC' once daily by mouth for 12 weeks. The GS-7977/GS-5885 product combines a potent HCV nucleotide inhibitor and a potent HCV NS5A inhibitor.	Subjects with HIV and HCV who are not on antiretroviral agents given 'Drug: GS-7977 (sofosbuvir 400mg)/GS-5885 (ledipasvir 90mg) FDC' once daily by mouth for 12 weeks. The GS-7977/GS-5885 product combines a potent HCV nucleotide inhibitor and a potent HCV NS5A inhibitor.
Measure Participants	37	13
Number (95% Confidence Interval) [percentage of participants]	97 262.2%	100 769.2%

Adverse Events

Time Frame	On or after the first dose of the study drug up to date of last dose of study drug (12 weeks) plus 30 days
Arm/Group Title	Subjects With HIV and HCV on Antiretroviral Agents		Subjects With HIV and HCV Who Are Not on Antiretroviral Agents
Arm/Group Description	Subjects with HIV and HCV on antiretroviral agents given 'Drug: GS-7977 (sofosbuvir 400mg)/GS-5885 (ledipasvir 90mg) FDC' once daily by mouth for 12 weeks. The GS-7977/GS-5885 product combines a potent HCV nucleotide inhibitor and a potent HCV NS5A inhibitor.		Subjects with HIV and HCV who are not on antiretroviral agents given 'Drug: GS-7977 (sofosbuvir 400mg)/GS-5885 (ledipasvir 90mg) FDC' once daily by mouth for 12 weeks. The GS-7977/GS-5885 product combines a potent HCV nucleotide inhibitor and a potent HCV NS5A inhibitor.
All Cause Mortality
	Subjects With HIV and HCV on Antiretroviral Agents		Subjects With HIV and HCV Who Are Not on Antiretroviral Agents
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Subjects With HIV and HCV on Antiretroviral Agents		Subjects With HIV and HCV Who Are Not on Antiretroviral Agents
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		1/13 (7.7%)
Infections and infestations
Pneumonia	0/37 (0%)		1/13 (7.7%)
Other (Not Including Serious) Adverse Events
	Subjects With HIV and HCV on Antiretroviral Agents		Subjects With HIV and HCV Who Are Not on Antiretroviral Agents
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/37 (97.3%)		13/13 (100%)
Gastrointestinal disorders
Abdominal pain upper	0/37 (0%)		1/13 (7.7%)
Constipation	0/37 (0%)		1/13 (7.7%)
Diarrhoea	2/37 (5.4%)		2/13 (15.4%)
Gastrooesophageal reflux disease	0/37 (0%)		1/13 (7.7%)
Nausea	2/37 (5.4%)		1/13 (7.7%)
General disorders
Fatigue	2/37 (5.4%)		3/13 (23.1%)
Pain	2/37 (5.4%)		3/13 (23.1%)
Immune system disorders
Seasonal allergy	0/37 (0%)		1/13 (7.7%)
Infections and infestations
Nasopharyngitis	4/37 (10.8%)		1/13 (7.7%)
Pneumonia	0/37 (0%)		1/13 (7.7%)
Tooth infection	0/37 (0%)		1/13 (7.7%)
Urinary tract infection	2/37 (5.4%)		0/13 (0%)
Injury, poisoning and procedural complications
Contusion	0/37 (0%)		1/13 (7.7%)
Investigations
Alanine aminotransferase increased	7/37 (18.9%)		2/13 (15.4%)
Amylase increased	13/37 (35.1%)		1/13 (7.7%)
Aspartate aminotransferase increased	9/37 (24.3%)		3/13 (23.1%)
Blood alkaline phosphatase increased	3/37 (8.1%)		0/13 (0%)
Blood bicarbonate abnormal	2/37 (5.4%)		1/13 (7.7%)
Blood bilirubin increased	0/37 (0%)		2/13 (15.4%)
Blood cholesterol increased	16/37 (43.2%)		5/13 (38.5%)
Blood creatinine increased	6/37 (16.2%)		0/13 (0%)
Hemoglobin decreased	4/37 (10.8%)		0/13 (0%)
Lipase increased	5/37 (13.5%)		0/13 (0%)
Low density lipoprotein increased	9/37 (24.3%)		3/13 (23.1%)
Neutrophil count decreased	8/37 (21.6%)		5/13 (38.5%)
Platelet count decreased	0/37 (0%)		1/13 (7.7%)
White blood cell count decreased	2/37 (5.4%)		1/13 (7.7%)
Metabolism and nutrition disorders
Decreased appetite	0/37 (0%)		1/13 (7.7%)
Hypercalcemia	2/37 (5.4%)		1/13 (7.7%)
Hyperglycemia	12/37 (32.4%)		9/13 (69.2%)
Hypernatremia	0/37 (0%)		2/13 (15.4%)
Hyperuricemia	2/37 (5.4%)		1/13 (7.7%)
Hypoalbuminemia	11/37 (29.7%)		8/13 (61.5%)
Hypocalcemia	0/37 (0%)		1/13 (7.7%)
Hypoglycemia	3/37 (8.1%)		1/13 (7.7%)
Hypokalemia	2/37 (5.4%)		1/13 (7.7%)
Hypomagnesemia	0/37 (0%)		2/13 (15.4%)
Hyponatremia	2/37 (5.4%)		0/13 (0%)
Hypophosphatemia	9/37 (24.3%)		1/13 (7.7%)
Musculoskeletal and connective tissue disorders
Flank pain	0/37 (0%)		1/13 (7.7%)
Myalgia	3/37 (8.1%)		1/13 (7.7%)
Pain in extremity	0/37 (0%)		1/13 (7.7%)
Nervous system disorders
Headache	4/37 (10.8%)		1/13 (7.7%)
Hypoesthesia	0/37 (0%)		1/13 (7.7%)
Somnolence	0/37 (0%)		1/13 (7.7%)
Psychiatric disorders
Anxiety	0/37 (0%)		1/13 (7.7%)
Confusional state	0/37 (0%)		1/13 (7.7%)
Renal and urinary disorders
Proteinuria	1/37 (2.7%)		1/13 (7.7%)
Renal disorder	0/37 (0%)		1/13 (7.7%)
Reproductive system and breast disorders
Erectile dysfunction	2/37 (5.4%)		0/13 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/37 (0%)		1/13 (7.7%)
Cough	0/37 (0%)		1/13 (7.7%)
Dyspnoea	0/37 (0%)		1/13 (7.7%)
Skin and subcutaneous tissue disorders
Dry skin	2/37 (5.4%)		0/13 (0%)
Social circumstances
Bereavement	0/37 (0%)		1/13 (7.7%)
Surgical and medical procedures
Tooth extraction	0/37 (0%)		1/13 (7.7%)
Vascular disorders
Hypertension	0/37 (0%)		1/13 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.