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

Primary Purpose

HIV-1 Infection, Hepatitis C

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Ledipasvir/sofosbuvir

Ribavirin

About this trial

This is an interventional treatment trial for HIV-1 Infection

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Ucsf Aids Crs (801)
7804 Weill Cornell Chelsea CRS

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm A: LDV/SOF + RBV

Arm B: LDV/SOF

Arm Description

Ledipasvir/sofosbuvir + ribavirin for 12 weeks, followed by 24 weeks of post-treatment follow-up.

Ledipasvir/sofosbuvir for 24 weeks, followed by 24 weeks of post-treatment follow-up.

Outcomes

Primary Outcome Measures

Percentage of Participants With Sustained Virologic Response at 12 Weeks After Treatment Discontinuation (SVR12)

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

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

Percentage of Participants With Protocol-specified Renal Events

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)

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.

Percentage of Participants With Sustained Virologic Response at 24 Weeks After Treatment Discontinuation (SVR24)

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

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).

Number of Participants With HIV-1 RNA >50 Copies/mL

HIV-1 RNA testing was performed at a central laboratory using Abbott RealTime HIV-1 assay (Abbott Laboratories, Lake Bluff, IL, USA).

CD4+ T-cell (CD4) Count Change From Baseline

Change in CD4 count was calculated as value at the post entry visit minus the value at study entry.

Full Information

NCT ID

NCT02605304

First Posted

November 12, 2015

Last Updated

April 2, 2018

Sponsor

AIDS Clinical Trials Group

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

1. Study Identification

Unique Protocol Identification Number

NCT02605304

Brief Title

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

Official Title

Phase II Trial of Retreatment Strategies for Difficult-to-Treat Hepatitis C Virus (HCV)-Infected Individuals Who Have Failed Prior Direct Acting Antiviral (DAA)-Based Regimens

Study Type

Interventional

2. Study Status

Record Verification Date

April 2018

Overall Recruitment Status

Terminated

Why Stopped

The study experienced enrollment difficulties.

Study Start Date

February 17, 2016 (Actual)

Primary Completion Date

January 20, 2017 (Actual)

Study Completion Date

March 20, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AIDS Clinical Trials Group

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV-1 Infection, Hepatitis C

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

7 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A: LDV/SOF + RBV

Arm Type

Experimental

Arm Description

Ledipasvir/sofosbuvir + ribavirin for 12 weeks, followed by 24 weeks of post-treatment follow-up.

Arm Title

Arm B: LDV/SOF

Arm Type

Experimental

Arm Description

Ledipasvir/sofosbuvir for 24 weeks, followed by 24 weeks of post-treatment follow-up.

Intervention Type

Drug

Intervention Name(s)

Ledipasvir/sofosbuvir

Other Intervention Name(s)

LDV/SOF, Harvoni

Intervention Description

Participants were prescribed one fixed dose tablet of LDV 90 mg/SOF 400 mg orally per day.

Intervention Type

Drug

Intervention Name(s)

Ribavirin

Other Intervention Name(s)

RBV

Intervention Description

Based on weight at entry: For weight <75 kg, participants were prescribed 1000 mg of RBV per day, divided into two doses to be taken orally. For weight ≥75 kg: participants were prescribed 1200 mg of RBV per day, divided into two doses to be taken orally.

Primary Outcome Measure Information:

Title

Percentage of Participants With Sustained Virologic Response at 12 Weeks After Treatment Discontinuation (SVR12)

Description

Time Frame

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).

Title

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

Description

Time Frame

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.

Secondary Outcome Measure Information:

Title

Percentage of Participants With Protocol-specified Renal Events

Description

Time Frame

From study entry to study completion (Week 36 in Arm A, Week 48 in Arm B)

Title

Percentage of Participants With Sustained Virologic Response at 4 Weeks After Treatment Discontinuation (SVR4)

Description

Time Frame

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).

Title

Percentage of Participants With Sustained Virologic Response at 24 Weeks After Treatment Discontinuation (SVR24)

Description

Time Frame

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).

Title

Number of Participants With Unquantifiable HCV RNA

Description

Time Frame

Entry (Week 0); at 1, 4, 8, 12 (and 16, 20, 24 in Arm B) weeks after study entry

Title

Number of Participants With HIV-1 RNA >50 Copies/mL

Description

HIV-1 RNA testing was performed at a central laboratory using Abbott RealTime HIV-1 assay (Abbott Laboratories, Lake Bluff, IL, USA).

Time Frame

Entry (Week 0); at 4, 12 (and 24 in Arm B) weeks after study entry, and at 4 weeks after treatment discontinuation

Title

CD4+ T-cell (CD4) Count Change From Baseline

Description

Change in CD4 count was calculated as value at the post entry visit minus the value at study entry.

Time Frame

Entry and at 12 (and 24 in Arm B) weeks after study entry

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Annie Luetkemeyer, MD

Organizational Affiliation

University of California, San Francisco HIV/AIDS CRS

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Jennifer J. Kiser, PharmD

Organizational Affiliation

University of Colorado, Denver

Official's Role

Study Chair

Facility Information:

Facility Name

Ucsf Aids Crs (801)

City

San Francisco

State/Province

California

ZIP/Postal Code

94110

Country

United States

Facility Name

7804 Weill Cornell Chelsea CRS

City

New York

State/Province

New York

ZIP/Postal Code

10010

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

29091342

Citation

Tam E, Luetkemeyer AF, Mantry PS, Satapathy SK, Ghali P, Kang M, Haubrich R, Shen X, Ni L, Camus G, Copans A, Rossaro L, Guyer B, Brown RS Jr; RESCUE and ACTG A5348 study investigators. Ledipasvir/sofosbuvir for treatment of hepatitis C virus in sofosbuvir-experienced, NS5A treatment-naive patients: Findings from two randomized trials. Liver Int. 2018 Jun;38(6):1010-1021. doi: 10.1111/liv.13616. Epub 2017 Dec 5.

Results Reference

result

Links:

URL

http://rsc.tech-res.com/docs/default-source/safety/daids_ae_grading_table_v2_nov2014.pdf?sfvrsn=8

Description

DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014

URL

http://rsc.tech-res.com/docs/default-source/safety/manual_for_expedited_reporting_aes_to_daids_v2.pdf?sfvrsn=12

Description

Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

Learn more about this trial

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

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