Evaluating the Effectiveness of Boceprevir, Pegylated-Interferon Alfa 2b and Ribavirin in Treating Hepatitis C Virus (HCV) Infection in Adults With HIV and HCV Infection
NCT ID: NCT01482767
Last Updated: 2021-11-04
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
262 participants
INTERVENTIONAL
2012-04-30
2015-04-30
Brief Summary
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Detailed Description
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Participants were enrolled into one of two groups based on previous HCV treatment experience.
1. Group A: HCV treatment-naive participants who had never received treatment with PEG-IFN or experimental agents used to treat HCV, with or without RBV (N=170, refer to the note below).
2. Group B: HCV treatment-experienced participants who had received any treatment with standard interferon or with PEG-IFN with or without RBV, provided the last dose of treatment was 90 days or more before study entry (N=140, refer to the note below).
Note: The team correspondence with the FDA led to an amendment to close enrollment in December 2013, prior to the target sample sizes of 170 in Group A and 140 in Group B, as the study power could be lowered while still meeting the key study objectives.
All participants had to be on stable antiretroviral therapy (ART) for at least 8 weeks prior to study entry using a dual nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone plus one of the following: efavirenz (EFV), raltegravir (RAL), lopinavir (LPV)/ritonavir (RTV) 400/100 mg twice daily, atazanavir (ATV)/RTV, darunavir (DRV)/RTV 600/100 mg twice daily OR must not have received any ART for at least 4 weeks immediately prior to entry. Participation in this study lasted approximately 72 weeks.
HCV treatment-naive participants (Group A) were treated with PEG-IFN and RBV for 4 weeks (lead-in). Then BOC was added to the treatment regimen (triple therapy). Cirrhotic participants received 44 weeks of triple therapy. Among non-cirrhotics, the Week 8 HCV RNA was used to determine total duration of therapy. Those who had undetectable HCV RNA at Week 8 completed therapy at Week 28. Those with detectable HCV RNA at Week 8 received 32 weeks of triple therapy followed by 12 additional weeks of double-drug therapy with PEG-IFN/RBV. HCV treatment-experienced participants (Group B) also had a lead-in followed by 32 weeks of triple therapy and 12 weeks of PEG-IFN/RBV double therapy if non-cirrhotic, or by 44 weeks of triple therapy if cirrhotic.
Treatment was to be discontinued due to HCV virologic failure if:
1. HCV RNA ≥100 IU/mL at Week 12,
2. detectable HCV RNA at Week 24, or
3. confirmed HCV RNA \>1000 IU/mL any time after Week 12.
Undetectable HCV RNA was defined as below the lower limit of quantification (LLOQ) and target not detected (TND) by Roche COBAS® TaqMan® HCV Test v2.0.
Study visits were scheduled at screening and at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24 and 28 for both study groups. Group A participants who completed treatment at Week 28 had further study visits at Weeks 40, 52, 60, and 72. Participants who were prescribed 48-weeks of therapy (Group A and Group B) had further study visits at Weeks 32, 36, 40, 44, 48, 60, and 72. At each visit, a physical examination and blood collection were conducted. Participants also completed an HCV treatment adherence questionnaire. Select visits included urine collection and pregnancy testing (for women of reproductive potential). Plasma, serum, and peripheral blood mononuclear cells (PBMCs) were be stored for use in future studies. After experiencing HCV virologic failure as defined above or premature treatment discontinuation due to safety or other reasons, participants were followed on a separate schedule of events with visits every 12 weeks from Week 24 to 72. The evaluations at these follow-up visits were limited to safety evaluations and stored plasma/serum sample collection.
The A5294 study consisted of single-arm evaluations to assess the efficacy of BOC added to PEG-IFN/RBV in the two study populations:
1. HCV treatment-naive participants (Group A)
2. HCV treatment-experienced participants (Group B).
The two study populations were addressed together in this single trial - rather than in two separate trials - mainly for administrative efficiency. The analyses were conducted separately for each Study Group. The study was not designed for comparison. The pooled summaries for Baseline Characteristics provided in the Results Section in this record were prepared solely for the ClinicalTrials.gov results submission.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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HCV Treatment-Naive (Group A)
Participants were prescribed a lead-in with PEG-IFN and RBV for 4 weeks. After the lead-in, BOC was added. Cirrhotic participants received 44 weeks of triple therapy (BOC+PEG-IFN+RBV). Among non-cirrhotics, the Week 8 HCV RNA was used to determine total duration of therapy. Those who had undetectable HCV RNA at Week 8 completed therapy at Week 28. Those with detectable HCV RNA at Week 8 received 32 weeks of triple therapy followed by 12 additional weeks of PEG-IFN+RBV.
Pegylated-Interferon Alfa 2b (PEG-IFN)
1.5 mcg/kg subcutaneously (SC) once a week (based on participant's weight at entry) for up to 48 weeks depending on cirrhosis status and, in Group A, Week 8 HCV viral response.
Ribavirin (RBV)
800-1400 mg orally per day with food (based on participant's weight at entry) for up to 48 weeks depending on cirrhosis status and, in Group A, Week 8 HCV viral response.
Boceprevir (BOC)
800 mg orally every 8 hours with food from Week 5 to up to Week 48 depending on cirrhosis status and, in Group A, Week 8 HCV viral response
HCV Treatment-Experienced (Group B)
Participants were prescribed a lead-in with PEG-IFN and RBV for 4 weeks. After the lead-in, BOC was added. Cirrhotic participants received 44 weeks of triple therapy (BOC+PEG-IFN+RBV), and non-cirrhotics received 32 weeks of triple therapy followed by 12 additional weeks of PEG-IFN+RBV.
Pegylated-Interferon Alfa 2b (PEG-IFN)
1.5 mcg/kg subcutaneously (SC) once a week (based on participant's weight at entry) for up to 48 weeks depending on cirrhosis status and, in Group A, Week 8 HCV viral response.
Ribavirin (RBV)
800-1400 mg orally per day with food (based on participant's weight at entry) for up to 48 weeks depending on cirrhosis status and, in Group A, Week 8 HCV viral response.
Boceprevir (BOC)
800 mg orally every 8 hours with food from Week 5 to up to Week 48 depending on cirrhosis status and, in Group A, Week 8 HCV viral response
Interventions
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Pegylated-Interferon Alfa 2b (PEG-IFN)
1.5 mcg/kg subcutaneously (SC) once a week (based on participant's weight at entry) for up to 48 weeks depending on cirrhosis status and, in Group A, Week 8 HCV viral response.
Ribavirin (RBV)
800-1400 mg orally per day with food (based on participant's weight at entry) for up to 48 weeks depending on cirrhosis status and, in Group A, Week 8 HCV viral response.
Boceprevir (BOC)
800 mg orally every 8 hours with food from Week 5 to up to Week 48 depending on cirrhosis status and, in Group A, Week 8 HCV viral response
Eligibility Criteria
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Inclusion Criteria
* Presence of chronic HCV infection, defined by presence of plasma or serum HCV RNA in a participant with HCV antibody for at least 180 days, two documented HCV RNA positive results greater than 180 days apart, or positive HCV RNA with biopsy demonstrating chronic hepatitis. More information on this criterion can be found in the protocol.
* Serum or plasma HCV RNA level 10,000 IU/mL or greater obtained within 42 days prior to study entry.
* Screening HCV genotype 1 performed within 6 months prior to study entry.
* Liver biopsy or HCV FibroSURE™ test within 104 weeks prior to study entry with interpretation consistent with chronic HCV infection. If a liver biopsy HCV FibroSURE™ test had not been performed within 104 weeks prior to study entry, then either a biopsy or HCV FibroSURE™ test must have been obtained prior to enrollment. The cut-off value for the FibroSURE™ test was 0.74, where greater than 0.74 was interpreted as cirrhosis. More information on this criterion can be found in the protocol.
* Alpha feto protein (AFP) levels less than 50. If 50 or greater, they must have had a liver imaging study (e.g., ultrasound, computed tomography \[CT\] scan, magnetic resonance imaging \[MRI\] showing no evidence of hepatocellular carcinoma.
* HIV-1 infection. More information on this criterion can be found in the protocol.
* Currently not on any antiretroviral therapy (ART) for at least 4 weeks immediately prior to entry or on stable ART for at least 8 weeks prior to study entry using a dual NRTI backbone PLUS one of the following: EFV, RAL, LPV/RTV 400/100 mg twice daily, ATV/RTV, DRV/RTV 600/100 mg twice daily. Breaks in therapy for a maximum of 14 days were allowed. Dose modifications or changes in drugs during the 8 weeks prior to study entry were permitted unless the change in drug was due to treatment failure. More information on this criterion can be found in the protocol.
* CD4+ T-cell count greater than 200 cells/mm\^3 obtained within 42 days prior to study entry.
* For participants on ART, screening plasma HIV-1 RNA less than 50 copies/mL obtained within 42 days prior to study entry. For participants not on ART, plasma HIV-1 RNA less than 50,000 copies/mL obtained within 42 days prior to study entry.
* The following laboratory values within 42 days prior to entry:
* Absolute neutrophil count (ANC) 1000/mm\^3 or greater,
* Hemoglobin greater than 12 g/dL for men and greater than 11 g/dL for women,
* Platelet count greater than 80,000 per mm\^3,
* Creatinine less than 1.5 mg/dL,
* Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALT)/serum glutamic pyruvic transaminaseless (SGPT) less than or equal to 10 x the upper limit of normal (ULN),
* Direct bilirubin less than 1.5 mg/dL,
* International normalized ratio (INR) less than 1.5,
* Serum lipase less than or equal to 1.5 x ULN,
* Thyroid stimulating hormone (TSH) within normal range, unless accompanied by thyroid profile consistent with normal thyroid function.
* For female participants of reproductive potential, a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL performed within 42 days prior to study entry. More information on this criterion can be found in the protocol.
* All participants must have agreed not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization).
* When participating in sexual activity that could lead to pregnancy, participants must have agreed to use at least two reliable methods of contraception simultaneously while receiving protocol-specified medications, and for 6 months after stopping the medications. Such methods include:
* Condoms (male or female) with a spermicidal agent,
* Diaphragm or cervical cap with spermicide,
* Intrauterine device (IUD),
* Tubal ligation.
More information on this criterion can be found in the protocol.
* Participants not of reproductive potential were eligible without requiring the use of contraceptives. More information on this criterion can be found in the protocol.
* Ability and willingness of participant to provide written informed consent.
Exclusion Criteria
* Evidence of decompensated liver disease manifested by the presence of or history of ascites, variceal bleeding, or hepatic encephalopathy. If hepatic cirrhosis was determined by liver biopsy (Stage 4 Metavir or Stage 5, 6 Ishak) or by imaging, then participants had to be no more than Child-Pugh Class A and have a Child-Pugh-Turcotte (CPT) score of 6 or less. More information on this criterion can be found in the protocol.
* Other known causes of significant liver disease including chronic or acute hepatitis B, acute hepatitis A, hemochromatosis, or homozygote alpha-1 antitrypsin deficiency.
* Infection with any HCV genotype other than genotype 1, or mixed genotype infection.
* Uncontrolled or active depression or other psychiatric disorder such as untreated. Grade 3 psychiatric disorder or Grade 3 disorder not amenable to medical intervention that in the opinion of the site investigator might have precluded tolerability or safety of study requirements. Individuals with suicidal ideation or history of a suicidal attempt in the last 5 years prior to enrollment were excluded.
* History of uncontrolled seizure disorders.
* Serious illness including malignancy, active coronary artery disease within 24 weeks prior to study entry, or other chronic medical conditions that in the opinion of the site investigator may have precluded completion of the protocol.
* Presence of active or acute AIDS-defining opportunistic infections within 12 weeks prior to study entry. More information on this criterion can be found in the protocol.
* History of hemoglobinopathy (e.g., thalassemia) or any other cause of or tendency to hemolysis.
* History of major organ transplantation with an existing functional graft.
* History of autoimmune processes including Crohn's disease, ulcerative colitis, severe psoriasis, or rheumatoid arthritis that may be exacerbated by IFN use.
* Breastfeeding.
* Male participants with pregnant sexual partner.
* Use of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) within 14 days prior to study entry.
* Use of systemic corticosteroids, lovastatin, simvastatin, interferon gamma, tumor necrosis factor(TNF)-alpha inhibitors, rifampin, rifabutin, pyrazinamide, isoniazid, ganciclovir or hydroxyurea within 14 days prior to study entry.
* Previous use of any HCV protease or polymerase inhibitor.
* Active drug or alcohol use or dependence that, in the opinion of the site investigator, would have interfered with adherence to study requirements.
* Serious illness requiring systemic treatment and/or hospitalization within 42 days prior to entry.
18 Years
ALL
No
Sponsors
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National Institute of Allergy and Infectious Diseases (NIAID)
NIH
Responsible Party
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Principal Investigators
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Adeel A Butt, MD, MS
Role: STUDY_CHAIR
University of Pittsburgh
Kenneth E Sherman, MD, PhD
Role: STUDY_CHAIR
University of Cincinnati CRS
Locations
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Alabama CRS
Birmingham, Alabama, United States
University of Southern California CRS
Los Angeles, California, United States
UCLA CARE Center CRS
Los Angeles, California, United States
Stanford AIDS Clinical Trials Unit CRS
Palo Alto, California, United States
UCSD Antiviral Research Center CRS
San Diego, California, United States
Ucsf Hiv/Aids Crs
San Francisco, California, United States
Harbor-UCLA CRS
Torrance, California, United States
University of Colorado Hospital CRS
Aurora, Colorado, United States
Denver Public Health CRS
Denver, Colorado, United States
Georgetown University CRS (GU CRS)
Washington D.C., District of Columbia, United States
The Ponce de Leon Center CRS
Atlanta, Georgia, United States
Northwestern University CRS
Chicago, Illinois, United States
Rush University CRS
Chicago, Illinois, United States
IHV Baltimore Treatment CRS
Baltimore, Maryland, United States
Johns Hopkins University CRS
Baltimore, Maryland, United States
Massachusetts General Hospital CRS (MGH CRS)
Boston, Massachusetts, United States
Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS
Boston, Massachusetts, United States
Bmc Actg Crs
Boston, Massachusetts, United States
Wayne State Univ. CRS
Detroit, Michigan, United States
Henry Ford Hosp. CRS
Detroit, Michigan, United States
Washington University Therapeutics (WT) CRS
St Louis, Missouri, United States
Cooper Univ. Hosp. CRS
Camden, New Jersey, United States
New Jersey Medical School Clinical Research Center CRS
Newark, New Jersey, United States
Weill Cornell Chelsea CRS
New York, New York, United States
Columbia P&S CRS
New York, New York, United States
Weill Cornell Uptown CRS
New York, New York, United States
University of Rochester Adult HIV Therapeutic Strategies Network CRS
Rochester, New York, United States
Bronx-Lebanon Hosp. Ctr. CRS
The Bronx, New York, United States
Chapel Hill CRS
Chapel Hill, North Carolina, United States
Duke Univ. Med. Ctr. Adult CRS
Durham, North Carolina, United States
Cincinnati Clinical Research Site
Cincinnati, Ohio, United States
Case Clinical Research Site
Cleveland, Ohio, United States
MetroHealth CRS
Cleveland, Ohio, United States
Ohio State University CRS
Columbus, Ohio, United States
Penn Therapeutics, CRS
Philadelphia, Pennsylvania, United States
University of Pittsburgh CRS
Pittsburgh, Pennsylvania, United States
The Miriam Hospital Clinical Research Site (TMH CRS) CRS
Providence, Rhode Island, United States
Vanderbilt Therapeutics (VT) CRS
Nashville, Tennessee, United States
Trinity Health and Wellness Center CRS
Dallas, Texas, United States
Houston AIDS Research Team CRS
Houston, Texas, United States
Virginia Commonwealth University CRS
Richmond, Virginia, United States
University of Washington AIDS CRS
Seattle, Washington, United States
Puerto Rico AIDS Clinical Trials Unit CRS
San Juan, , Puerto Rico
Countries
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References
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Shire NJ, Welge JA, Sherman KE. Response rates to pegylated interferon and ribavirin in HCV/HIV coinfection: a research synthesis. J Viral Hepat. 2007 Apr;14(4):239-48. doi: 10.1111/j.1365-2893.2006.00824.x.
Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, Pound D, Davis MN, Galati JS, Gordon SC, Ravendhran N, Rossaro L, Anderson FH, Jacobson IM, Rubin R, Koury K, Pedicone LD, Brass CA, Chaudhri E, Albrecht JK; SPRINT-1 investigators. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010 Aug 28;376(9742):705-16. doi: 10.1016/S0140-6736(10)60934-8. Epub 2010 Aug 6.
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009).
Sherman KE, Kang M, Sterling R, Umbleja T, Marks K, Alston-Smith B, Greaves W, Butt A. BIRTH: A Phase 3 Trial of Boceprevir/Pegylated Interferon/Ribavirin in HCV/HIV. IDWeek. San Diego, CA. October, 2015. [Abstract 903]
Other Identifiers
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11774
Identifier Type: REGISTRY
Identifier Source: secondary_id
ACTG 5294
Identifier Type: -
Identifier Source: secondary_id
BIRTH
Identifier Type: -
Identifier Source: secondary_id
A5294 (BIRTH)
Identifier Type: -
Identifier Source: org_study_id