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HIV-1 InfectionPhase 2NCT02605304

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

A Phase 2 study testing Ledipasvir/sofosbuvir and Ribavirin in people with HIV-1 Infection and Hepatitis C, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 2 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
HIV-1 Infection, Hepatitis C
What is being tested?
Ledipasvir/sofosbuvir and Ribavirin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
7 participants
Where
2 sitesUnited States
Study dates
17 Feb 2016to 20 Mar 2017
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • 7804 Weill Cornell Chelsea CRS

    New York, New York, 10010

  • Ucsf Aids Crs (801)

    San Francisco, California, 94110

Other trials in United States

About this study

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

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.

Read the 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.

Being tested
Ledipasvir/sofosbuvir, Ribavirin
Medical subject headings
Hepatitis C

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ledipasvir/sofosbuvirDrug

    Also called LDV/SOF, Harvoni

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

  • RibavirinDrug

    Also called RBV

    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.

Study groups in NCT02605304
Study groupRoleWhat they receive
Arm A: LDV/SOF + RBVExperimentalLedipasvir/sofosbuvir + ribavirin for 12 weeks, followed by 24 weeks of post-treatment follow-up.
Receives: Drug: Ledipasvir/sofosbuvir; Drug: Ribavirin
Arm B: LDV/SOFExperimentalLedipasvir/sofosbuvir for 24 weeks, followed by 24 weeks of post-treatment follow-up.
Receives: Drug: Ledipasvir/sofosbuvir

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 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).

  2. 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.

    Measured: 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 outcomes (6)

  1. 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.

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

  2. 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.

    Measured: 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).

  3. 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.

    Measured: 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).

  4. 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).

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

  5. 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).

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

  6. 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.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Nov 2015 (estimated)
  2. Study start17 Feb 2016
  3. Primary completion20 Jan 2017
  4. Study completion20 Mar 2017

Why it stopped: The study experienced enrollment difficulties.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
7 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02605304
Sponsor's protocol ID
ACTG A5348
Other IDs
UM1AI068636
Status last verified
Apr 2018
First submitted
12 Nov 2015
Last updated
2 May 2018
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 29091342

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ledipasvir/sofosbuvir and Ribavirin in people with HIV-1 Infection and Hepatitis C, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 2 May 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 15 Feb 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With Sustained Virologic Response at 12 Weeks After Treatment Discontinuation (SVR12) (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).). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02605304, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 May 2018.

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