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Effect of Addition of Raltegravir (MK-0518) to PI- or NNRTI-Based ART Regimens in HIV Infected Subjects With Undetectable Viral Load

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00515827
First received: August 10, 2007
Last updated: November 25, 2013
Last verified: November 2013
  Purpose

Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in vitro activity against HIV-1 strains including those resistant to currently available antiretroviral drugs. The purpose of this study is to assess the effectiveness of raltegravir in further reducing viral load in HIV infected patients that have already achieved viral suppression below the level of detection of standard viral load assays when added to antiretroviral therapy (ART).


Condition Intervention Phase
HIV Infections
Drug: Raltegravir (MK-0518)
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
Official Title: A Double-Blind, Randomized, Pilot Study to Measure the Effect of Treatment Intensification With a Potent Integrase Inhibitor, Raltegravir (MK-0518), on the Level of Persistent Plasma Viremia Below 50 Copies/ml in Subjects on Protease Inhibitor- or Non-Nucleoside Reverse Transcriptase Inhibitor-Containing Regimens

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • HIV-1 RNA Level [ Time Frame: At Weeks 10 and 12 ] [ Designated as safety issue: No ]
    HIV-1 RNA level, as measured by single copy assay, averaged at weeks 10 and 12. The quantification limit of single copy assay was determined by the volume of plasma tested. When averaging the week 10 and 12 measurements, if one of both measurements were below the single copy assay lower limits, the lower limit of quantification was used to compute the average and the result was treated as below the averaged value.


Secondary Outcome Measures:
  • Change in HIV-1 RNA Level [ Time Frame: At pre-entry, entry, weeks 10 and 12 ] [ Designated as safety issue: No ]
    Change in HIV-1 RNA level, as measured by single copy assay, from baseline to weeks 10/12 . When averaging the measurements at pre-entry and entry, and at weeks 10 and 12, measurements below the lower limit of quantification (LLQ) were imputed a value of the LLQ divided by 2.

  • Change in Total CD4 Cell Count [ Time Frame: At pre-entry, entry, and week 12 ] [ Designated as safety issue: No ]
    CD4 cell counts were assessed by flow cytometry at pre-entry and entry (the baseline value was the average of the two measurements) and at week 12

  • Change in Total CD8 Cell Count [ Time Frame: At pre-entry, entry, and week 12 ] [ Designated as safety issue: No ]
    CD8 cell counts were assessed by flow cytometry at pre-entry and entry (the baseline value was the average of the two measurements) and at week 12

  • Change in CD4+/CD38+/HLA-DR+ Percent [ Time Frame: At pre-entry, entry, and week 12 ] [ Designated as safety issue: No ]
    Level of CD4+ T-cell activation was determined by measuring the percentage of cells that expressed both the activation marker CD38 and Human leukocyte antigen (HLA)-DR. Levels measured at pre-entry and entry were averaged. Change from baseline to week 12 was defined as CD4+/CD38+/HLA-DR+% at week 12 minus CD4+/CD38+/HLA-DR+% at baseline.

  • Change in CD8+/CD38+/HLA-DR+ Percent [ Time Frame: At pre-entry, entry, and week 12 ] [ Designated as safety issue: No ]
    Level of CD8+ T-cell activation was determined by measuring the percentage of cells that expressed both the activation marker CD38 and Human leukocyte antigen (HLA)-DR. Levels measured at pre-entry and entry were averaged. Change from baseline to week 12 was defined as CD8+/CD38+/HLA-DR+% at week 12 minus CD8+/CD38+/HLA-DR+% at baseline.

  • Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From First Day of Treatment to Week 12 [ Time Frame: From first day of treatment to week 12 ] [ Designated as safety issue: Yes ]
    Participant who experienced at least one study related grade 2 or higher signs/symptoms, grade 3 or higher laboratory abnormalities and clinical events that are "possibly", "probably" or "definitely" related to study treatment. DAIDS Toxicity Grading Table (2004) was used for grading.

  • Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From Week 12 to Week 24 [ Time Frame: From week 12 to week 24 ] [ Designated as safety issue: Yes ]
    Participant who experienced at least one study related grade 2 or higher signs/symptoms, grade 3 or higher laboratory abnormalities and clinical events that are 'possibly', probably', or definitely' related to study treatment. DAIDS Toxicity Grading Table (2004) was used for grading.

  • Number of Participants Who Discontinued Study Drug [ Time Frame: From first day of treatment to week 12 ] [ Designated as safety issue: No ]
    Participants who discontinued randomized study treatment for any reason


Enrollment: 53
Study Start Date: November 2007
Study Completion Date: November 2008
Primary Completion Date: September 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Raltegravir then Placebo (Arm A)
400 mg raltegravir (MK-0518) administered twice daily in addition to optimized background regimen (OBR) from entry to Week 12; halt raltegravir at Week 12 and add placebo twice daily for 12 weeks
Drug: Raltegravir (MK-0518)
400 mg tablet taken orally twice daily
Drug: Placebo
400 mg placebo tablet taken orally twice daily
Experimental: Placebo then Raltegravir (Arm B)
Placebo administered twice daily in addition to OBR from entry until Week 12; halt placebo at Week 12 and add 400 mg raltegravir tablet twice daily for 12 weeks
Drug: Raltegravir (MK-0518)
400 mg tablet taken orally twice daily
Drug: Placebo
400 mg placebo tablet taken orally twice daily

Detailed Description:

Although ART has reduced the morbidity and mortality from HIV-1 infection, most individuals who stop ART experience rapid viral rebound. Effective ART can suppress viral load to less than 50 copies/ml; however, current treatment regimens cannot completely eliminate the infection. The primary purpose of this study was to assess the ability of the HIV-1 integrase inhibitor, raltegravir, to reduce viral load when added to ART regimens of HIV-1 infected patients who have achieved viral suppression to less than 50 copies/ml.

The study lasted 24 weeks. Participants were randomly assigned to one of two arms. Participants in Arm A were administered raltegravir in addition to their usual ART regimen from study entry until Week 12. At Week 12, subjects halted raltegravir use and received a placebo until Week 24. Participants in Arm B were administered the placebo in addition to their usual ART regimen from study entry until Week 12. At Week 12, subjects halted the placebo and received raltegravir until Week 24. A real-time polymerase chain reaction (PCR) single copy assay (SCA) capable of detecting 1 copy of HIV RNA was used to assay viral load. The cross-over design allowed assessment of the effect of intensification with raltegravir between the two arms at Weeks 10/12 and every participant enrolled in the study receiving raltegravir for 12 weeks. Primary analysis focused on weeks 10/12 measurement and with no washout period, typical analysis of cross-over design was not intended.

All participants had scheduled visits at Weeks 0, 2, 4, 10, 12, 14, 16, 22, and 24. A targeted physical exam occurred at all visits. Blood and urine collection occurred at selected visits. A medical/medication assessment occurred at trial entry. Drug dispensing and an adherence questionnaire occurred at some visits. A pregnancy test occurred at select visits. Participants' background ART medications were not provided by the study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV-1 Infection
  • ART for at least 12 months prior to study entry that includes at least two NRTIs and either an NNRTI or a ritonavir-boosted PI
  • No change in ART regimen for at least 3 months prior to study entry
  • CD4 count of 200 or more at screening
  • Viral load below the limit of quantification of an ultrasensitive assay for at least 6 months prior to study entry
  • Viral load less than 50 copies/ml using Roche Amplicor HIV-1 RNA Ultrasensitive assay within 60 days of study entry
  • All viral load assays obtained within 6 months prior to study entry lower than limits of quantification on all tests
  • Pre-ART viral load level greater than 100,000 copies/ml
  • Detectable viral load of 1 copy or more on the screening SCA
  • Available pre-study entry plasma sample for SCA viral load determination
  • Absolute neutrophil count of 750/mm3 or more
  • Hemoglobin of 9 g/dL or more for female subjects and 10 g/dL or more for male subjects
  • Platelet count of 50,000/mm3 or more
  • Calculated creatinine clearance of 30 ml/min or more
  • AST, ALT, and alkaline phosphate less than or equal to 5 x ULN
  • Total bilirubin less than or equal to 2.5 x ULN. If subject is taking indinavir or atazanavir at screening, total bilirubin must be less than or equal to 5 x ULN.
  • Negative serum or urine pregnancy test within 48 hours prior to study entry for females with reproductive potential
  • Willing to use acceptable means of contraception

Exclusion Criteria:

  • Previous documented virologic failure on an antiretroviral regimen
  • Unstable clinical condition that would preclude the subject from undergoing study procedures
  • Use of immunosuppressive medications within 60 days prior to study entry. Participants using inhaled or nasal steroids are not excluded.
  • Opportunistic infection within 60 days prior to study entry
  • Allergy or sensitivity to components of study drug
  • Active drug or alcohol abuse
  • Serious illness requiring systemic treatment within 60 days prior to study entry
  • Receipt of non-HIV vaccination within 30 days prior to study entry
  • Receipt of any HIV vaccines
  • Plan to change background ART within 24 weeks after study entry
  • Pregnant or breastfeeding
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00515827

Locations
United States, Alabama
Alabama Therapeutics CRS
Birmingham, Alabama, United States, 35294-2050
United States, California
Stanford CRS
Palo Alto, California, United States, 94304-5350
Ucsf Aids Crs
San Francisco, California, United States, 94110
Harbor-UCLA Med. Ctr. CRS
Torrance, California, United States, 90502
United States, Colorado
University of Colorado Hospital CRS
Aurora, Colorado, United States, 80045
United States, Illinois
Northwestern University CRS
Chicago, Illinois, United States, 60611
United States, Massachusetts
Beth Israel Deaconess Med. Ctr., ACTG CRS
Boston, Massachusetts, United States, 02215
Massachusetts General Hospital ACTG CRS
Boston, Massachusetts, United States, 02114
United States, Missouri
Washington U CRS
St. Louis, Missouri, United States, 63110
United States, New York
Cornell CRS
New York, New York, United States, 10011
Harlem ACTG CRS
New York, New York, United States, 10037
HIV Prevention & Treatment CRS
New York, New York, United States, 10032
NY Univ. HIV/AIDS CRS
New York, New York, United States, 10016
Univ. of Rochester ACTG CRS
Rochester, New York, United States, 14642
United States, North Carolina
Unc Aids Crs
Chapel Hill, North Carolina, United States, 27514
Duke Univ. Med. Ctr. Adult CRS
Durham, North Carolina, United States, 27710
United States, Ohio
MetroHealth CRS
Cleveland, Ohio, United States, 44109
United States, Pennsylvania
Hosp. of the Univ. of Pennsylvania CRS
Philadelphia, Pennsylvania, United States, 19104
Pitt CRS
Pittsburgh, Pennsylvania, United States, 15213-2582
United States, Washington
University of Washington AIDS CRS
Seattle, Washington, United States, 98104
Sponsors and Collaborators
Investigators
Study Chair: Rajesh T Gandhi, MD Massachusetts General Hospital
Study Chair: Joseph J Eron Jr., MD University of North Carolina, Chapel Hill
Study Chair: John W Mellors, MD University of Pittsburgh
  More Information

Additional Information:
Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00515827     History of Changes
Other Study ID Numbers: A5244, 10440, ACTG A5244
Study First Received: August 10, 2007
Results First Received: January 25, 2011
Last Updated: November 25, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Treatment Experienced

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
RNA Virus Infections
Retroviridae Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Reverse Transcriptase Inhibitors
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 19, 2014