12 Weeks of Ledipasvir (LDV)/Sofosbuvir (SOF) With Weight-based Ribavirin vs. 24 Weeks of LDV/SOF

Phase 2

Terminated

Conditions: HIV-1 Infection
Hepatitis C

Interventions: Drug: Ledipasvir/sofosbuvir
Drug: Ribavirin

Registration Number: NCT02605304

Lead Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

Brief Summary: People who are infected with Hepatitis C Virus (HCV) have a great chance of being cured of the infection when they are treated with sofosbuvir. However, in some instances, treatment with sofosbuvir-containing therapy does not work. It is not known if people respond to retreatment with sofosbuvir, after it did not work the first time. There is an important need to understand retreatment options in those instances. This clinical trial was done to study the response to two different regimens, ledipasvir/sofosbuvir and ledipasvir/sofosbuvir with ribavirin, and to see if they are safe and well-tolerated in HCV-infected persons whose previous treatment with sofosbuvir had failed.

Detailed Description: There is a pressing need to understand appropriate retreatment options for HCV-infected patients who fail direct acting antiviral (DAA)-based regimens. To date, over 100,000 prescriptions have been written for SOF. Recent data indicate that SOF-based treatment defined as SOF/RBV, SOF/pegylated-interferon (PEG-IFN)/RBV or SOF/simeprevir (SIM) +/- RBV have led to treatment response of 70-92% in HCV genotype (GT) 1 patients, depending on the regimen used and presence of liver cirrhosis. Thus, there is a growing number of individuals who have failed SOF-based regimens and are in need of a retreatment strategy, the majority of which are anticipated to be HCV GT1, given the US distribution of genotypes. There are no data to inform retreatment strategies for HIV-infected individuals with SOF failure, who have traditionally represented a harder to treat group and are impacted by DAA-antiretroviral (ARV) interactions.

This was a phase II retreatment study of HCV GT1 and HIV coinfected participants who had previous HCV virologic failure on a SOF-based regimen. Participants were randomized to one of two treatment arms: 12 weeks of LDV/SOF with weight-based RBV (Arm A) or 24 weeks of LDV/SOF alone (Arm B). The targeted sample size was 40, 20 participants in each arm.

Post-entry, the study visits were scheduled at weeks 1, 2, 4, 8, 12, 16, 20 and 24 after study entry (with week 16, 20, 24 visits limited to those on the 24-week regimen), and at 4, 12 and 24 weeks after treatment discontinuation. The total study duration was 36 weeks in Arm A and 48 weeks in Arm B. At each visit, a physical examination and blood collection were conducted. HCV RNA was tested at each visit. For female participants of reproductive potential, pregnancy tests were done. At on-treatment visits, participants also completed an HCV treatment adherence questionnaire. Urinalysis was conducted at all on-treatment visits and at 4 weeks post treatment. At select visits, plasma, whole blood, urine and dried blood spots were collected.

The study was randomized because there was clinical equipoise on the benefits and drawbacks in the two study arms. The study was not designed to be powered for comparisons between the randomized study arms, and no formal statistical comparisons were conducted. The primary analysis was conducted as a single-arm analysis for each regimen.

The study experienced enrollment difficulties due to the small number of HCV treatment failures from select SOF-based regimens who would be eligible for this study, and closed to accrual prematurely. The participants enrolled remained on study until completion of follow-up.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 7

Inclusion Criteria

Willing and able to provide written informed consent
Documentation of non-cirrhotic or cirrhotic status
HIV-1 infection
HIV antiretroviral treatment status (ART), CD4+ T-cell (CD4) count and HIV-1 RNA as follows: (1) not on ART with CD4 count >500 cells/mm^3 within 42 days of study entry, (2) elite controller not on ART with CD4 >200 cells/mm^3 within 42 days of study entry and HIV-1 RNA <500 copies/mL on all measurements within 48 weeks prior to study entry, (3) on a stable protocol-approved ART with CD4 count >200 cells/mm^3 and HIV-1 RNA <50 copies/mL within 42 days of study entry
HCV GT-1 within 12 months prior to study entry
Prior virologic treatment failure with SOF-containing regimen (SOF/RBV, SOF/PEG/RBV, and SOF/SIM)
Body mass index (BMI) ≥18 kg/m^2 within 42 days prior to study entry
Certain laboratory values obtained within 42 days prior to study entry
Hemoglobin ≥12.0 g/dL for male, ≥11.0 g/dL for female participants
Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase (ALT) (SGOT) <10 x ULN
For female participants of reproductive potential, a negative serum pregnancy test with a sensitivity of at least 25 mIU/mL performed at screening and within 48 hours prior to study entry
Agreement to use at least two reliable forms of contraceptive simultaneously while receiving study treatment and for 6 months afterward
Intention to comply with the dosing instructions and study schedule of assessments

Exclusion Criteria

Receipt of any investigational drug or device within 60 days prior to study entry
Prior exposure to a DAA other than SOF and SIM
Chronic liver disease of a non-HCV etiology
Presence of active or acute AIDS-defining opportunistic infections within 42 days prior to study entry
Active, serious infection (other than HIV-1 or HCV) requiring parenteral antibiotics, antivirals, or antifungals within 42 days prior to study entry
Hepatitis B virus (HBV) infection (defined as HBsAg positive) within 42 days prior to study entry
History of clinically significant hemoglobinopathy
Chronic current use of systemically administered immunosuppressive agents
History of solid organ transplantation
Current or prior history of clinical hepatic decompensation
History of a gastrointestinal disorder (or postoperative condition) that could interfere with the absorption of the study drug
History of significant or symptomatic pulmonary disease, cardiac disease, or porphyria that in the opinion of the investigator would interfere with the study
History of difficulty with blood collection and/or poor venous access for the purposes of phlebotomy
Active drug or alcohol use or dependence
Use of any prohibited concomitant medications per the LDV/SOF product labeling, within 42 days prior to study entry
Known hypersensitivity to RBV, SOF, LDV, their metabolites, or formulation excipients or any other contraindication to the use of RBV, SOF or LDV
Currently receiving zidovudine (ZDV), didanosine (ddI), stavudine (d4T) or tipranavir
Acute HIV infection defined as the phase immediately following infection during which anti-HIV antibodies are undetectable
Known hepatocellular carcinoma
Breastfeeding or pregnancy
A male participant with a pregnant female partner
Receipt of colony stimulating agents, including but not limited to erythropoietin, within 42 days prior to study entry

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B: LDV/SOF	Ledipasvir/sofosbuvir	Ledipasvir/sofosbuvir for 24 weeks, followed by 24 weeks of post-treatment follow-up.
Arm A: LDV/SOF + RBV	Ledipasvir/sofosbuvir	Ledipasvir/sofosbuvir + ribavirin for 12 weeks, followed by 24 weeks of post-treatment follow-up.
Arm A: LDV/SOF + RBV	Ribavirin	Ledipasvir/sofosbuvir + ribavirin for 12 weeks, followed by 24 weeks of post-treatment follow-up.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Sustained Virologic Response at 12 Weeks After Treatment Discontinuation (SVR12)	At 12 weeks after treatment discontinuation (i.e., at 24 weeks after study entry in Arm A and at 36 weeks after study entry in Arm B).	SVR12 was defined as HCV RNA below the LLOQ of the assay (either target detected \[TD\] or target not detected \[TND\]) at 12 weeks after treatment discontinuation. The sample within the visit window, closest to the targeted time was used. If there was no HCV RNA sample within visit window, then the participant was considered not to have achieved SVR12, unless there were preceding and subsequent HCV RNA measurements that were both \<LLOQ (either TD or TND). HCV RNA testing was conducted at a central laboratory using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, version 2.0 (Roche Diagnostics, Rotkreuz, Switzerland). Wilson (score) method was used for confidence intervals.
Percentage of Participants With Grade 3 or Higher Adverse Event (AE), Serious AE (SAE), or AE Reported as the Reason for Permanent Discontinuation of Study Treatment	From study treatment initiation to 30 days after study treatment discontinuation. Duration of treatment was 12 weeks in Arm A and 24 weeks in Arm B.	Percentage of participants who experienced an AE (diagnosis, sign/symptom or laboratory abnormality) of ≥Grade 3, SAE according to International Conference on Harmonisation (ICH) criteria, or AE reported as the reason for permanent study treatment discontinuation, during study treatment and up to 30 days after study treatment. Events that were ongoing at the same grade from prior to study treatment initiation were excluded. AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (V2.0) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening. The percentage of participants who experienced any event (overall), and the percentage of participants who experienced each component of the outcome are provided in the data table below. The categories are not mutually exclusive. A participant may have experienced multiple events. Each participant is counted at most once within category, and in the overall summary line.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Protocol-specified Renal Events	From study entry to study completion (Week 36 in Arm A, Week 48 in Arm B)	The study protocol defined renal events as (1) ≥Grade 2 creatinine clearance (CRCL) after study entry, or (2) new urinalysis proteinuria and/or glucosuria, defined as ≥1+ or an increase ≥1+ from baseline. The percentage of participants who experienced any renal event, and the percentages of participants who experienced each component of the outcome are provided in the data table below. The categories are not mutually exclusive. A participant may have experienced multiple events. Each participant is counted at most once within category, and in the overall summary line.
Percentage of Participants With Sustained Virologic Response at 4 Weeks After Treatment Discontinuation (SVR4)	At 4 weeks after treatment discontinuation (i.e., at 16 weeks after study entry in Arm A and at 28 weeks after study entry in Arm B).	SVR4 was defined as HCV RNA below the LLOQ of the assay (either TD or TND) at 4 weeks after treatment discontinuation. The sample within the visit window, closest to the targeted time was used. If there was no HCV RNA sample within visit window, then the participant was considered not to have achieved SVR4, unless there were preceding and subsequent HCV RNA measurements that were both \<LLOQ (either TD or TND). HCV RNA testing was conducted at a central laboratory using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, version 2.0 (Roche Diagnostics, Rotkreuz, Switzerland). Wilson (score) method was used for confidence intervals.
Number of Participants With HIV-1 RNA >50 Copies/mL	Entry (Week 0); at 4, 12 (and 24 in Arm B) weeks after study entry, and at 4 weeks after treatment discontinuation	HIV-1 RNA testing was performed at a central laboratory using Abbott RealTime HIV-1 assay (Abbott Laboratories, Lake Bluff, IL, USA).
Percentage of Participants With Sustained Virologic Response at 24 Weeks After Treatment Discontinuation (SVR24)	At 24 weeks after treatment discontinuation (i.e., at 36 weeks after study entry in Arm A and at 48 weeks after study entry in Arm B).	SVR24 was defined as HCV RNA below the LLOQ of the assay (either TD or TND) at 24 weeks after treatment discontinuation. The sample from a visit greater than 20 weeks after treatment discontinuation which was closest to the targeted week (24 weeks post treatment), not followed by any HCV RNA result ≥LLOQ, was used. If there was no HCV RNA sample within this window, then the participant was considered not to have achieved SVR24. HCV RNA testing was conducted at a central laboratory using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, version 2.0 (Roche Diagnostics, Rotkreuz, Switzerland). Wilson (score) method was used for confidence intervals.
Number of Participants With Unquantifiable HCV RNA	Entry (Week 0); at 1, 4, 8, 12 (and 16, 20, 24 in Arm B) weeks after study entry	Unquantifiable HCV was defined as HCV RNA below the LLOQ of the assay (15 IU/mL), either TD or TND. HCV RNA testing was conducted at a central laboratory using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, version 2.0 (Roche Diagnostics, Rotkreuz, Switzerland).
CD4+ T-cell (CD4) Count Change From Baseline	Entry and at 12 (and 24 in Arm B) weeks after study entry	Change in CD4 count was calculated as value at the post entry visit minus the value at study entry.

Trial Locations

Locations (2): Ucsf Aids Crs (801)
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San Francisco, California, United States
7804 Weill Cornell Chelsea CRS
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New York, New York, United States