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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

Primary Purpose

HIV Infections

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Raltegravir (MK-0518)
Placebo
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring Treatment Experienced

Eligibility Criteria

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

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

Sites / Locations

  • Alabama Therapeutics CRS
  • Stanford CRS
  • Ucsf Aids Crs
  • Harbor-UCLA Med. Ctr. CRS
  • University of Colorado Hospital CRS
  • Northwestern University CRS
  • Massachusetts General Hospital ACTG CRS
  • Beth Israel Deaconess Med. Ctr., ACTG CRS
  • Washington U CRS
  • Cornell CRS
  • NY Univ. HIV/AIDS CRS
  • Columbia P&S CRS
  • Harlem ACTG CRS
  • Univ. of Rochester ACTG CRS
  • Unc Aids Crs
  • Duke Univ. Med. Ctr. Adult CRS
  • MetroHealth CRS
  • Hosp. of the Univ. of Pennsylvania CRS
  • Pitt CRS
  • University of Washington AIDS CRS

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Raltegravir then Placebo (Arm A)

Placebo then Raltegravir (Arm B)

Arm Description

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

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

Outcomes

Primary Outcome Measures

HIV-1 RNA Level
HIV-1 RNA level, as measured by single copy assay (units are copies/ml), 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
Change in HIV-1 RNA level, as measured by single copy assay (units are copies/ml), 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
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
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
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
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
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
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
Participants who discontinued randomized study treatment for any reason

Full Information

First Posted
August 10, 2007
Last Updated
November 2, 2021
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00515827
Brief Title
Effect of Addition of Raltegravir (MK-0518) to PI- or NNRTI-Based ART Regimens in HIV Infected Subjects With Undetectable Viral Load
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
November 2007 (undefined)
Primary Completion Date
September 2008 (Actual)
Study Completion Date
November 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

Brief Summary
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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections
Keywords
Treatment Experienced

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare Provider
Allocation
Randomized
Enrollment
53 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Raltegravir then Placebo (Arm A)
Arm Type
Experimental
Arm Description
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
Arm Title
Placebo then Raltegravir (Arm B)
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Raltegravir (MK-0518)
Intervention Description
400 mg tablet taken orally twice daily
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
400 mg placebo tablet taken orally twice daily
Primary Outcome Measure Information:
Title
HIV-1 RNA Level
Description
HIV-1 RNA level, as measured by single copy assay (units are copies/ml), 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.
Time Frame
At Weeks 10 and 12
Secondary Outcome Measure Information:
Title
Change in HIV-1 RNA Level
Description
Change in HIV-1 RNA level, as measured by single copy assay (units are copies/ml), 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.
Time Frame
At pre-entry, entry, weeks 10 and 12
Title
Change in Total CD4 Cell Count
Description
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
Time Frame
At pre-entry, entry, and week 12
Title
Change in Total CD8 Cell Count
Description
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
Time Frame
At pre-entry, entry, and week 12
Title
Change in CD4+/CD38+/HLA-DR+ Percent
Description
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.
Time Frame
At pre-entry, entry, and week 12
Title
Change in CD8+/CD38+/HLA-DR+ Percent
Description
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.
Time Frame
At pre-entry, entry, and week 12
Title
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
Description
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.
Time Frame
From first day of treatment to week 12
Title
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
Description
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.
Time Frame
From week 12 to week 24
Title
Number of Participants Who Discontinued Study Drug
Description
Participants who discontinued randomized study treatment for any reason
Time Frame
From first day of treatment to week 12

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rajesh T Gandhi, MD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Joseph J Eron Jr., MD
Organizational Affiliation
University of North Carolina, Chapel Hill
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
John W Mellors, MD
Organizational Affiliation
University of Pittsburgh Medical Center
Official's Role
Study Chair
Facility Information:
Facility Name
Alabama Therapeutics CRS
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294-2050
Country
United States
Facility Name
Stanford CRS
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304-5350
Country
United States
Facility Name
Ucsf Aids Crs
City
San Francisco
State/Province
California
ZIP/Postal Code
94110
Country
United States
Facility Name
Harbor-UCLA Med. Ctr. CRS
City
Torrance
State/Province
California
ZIP/Postal Code
90502
Country
United States
Facility Name
University of Colorado Hospital CRS
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Northwestern University CRS
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Massachusetts General Hospital ACTG CRS
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Beth Israel Deaconess Med. Ctr., ACTG CRS
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Washington U CRS
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Cornell CRS
City
New York
State/Province
New York
ZIP/Postal Code
10011
Country
United States
Facility Name
NY Univ. HIV/AIDS CRS
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Columbia P&S CRS
City
New York
State/Province
New York
ZIP/Postal Code
10032-3732
Country
United States
Facility Name
Harlem ACTG CRS
City
New York
State/Province
New York
ZIP/Postal Code
10037
Country
United States
Facility Name
Univ. of Rochester ACTG CRS
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Unc Aids Crs
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27514
Country
United States
Facility Name
Duke Univ. Med. Ctr. Adult CRS
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
MetroHealth CRS
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44109
Country
United States
Facility Name
Hosp. of the Univ. of Pennsylvania CRS
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Pitt CRS
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213-2582
Country
United States
Facility Name
University of Washington AIDS CRS
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
17434401
Citation
Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, Gonzalez CJ, Chen J, Harvey CM, Isaacs RD; Protocol 005 Team. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007 Apr 14;369(9569):1261-1269. doi: 10.1016/S0140-6736(07)60597-2.
Results Reference
background
PubMed Identifier
17591678
Citation
Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, Azrolan N, Iwamoto M, Wagner JA, Wenning LA. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos. 2007 Sep;35(9):1657-63. doi: 10.1124/dmd.107.016196. Epub 2007 Jun 25.
Results Reference
background
PubMed Identifier
17133211
Citation
Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT, Cooper DA, Liporace R, Schwartz R, Isaacs R, Gilde LR, Wenning L, Zhao J, Teppler H. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006 Dec 15;43(5):509-15. doi: 10.1097/QAI.0b013e31802b4956. Erratum In: J Acquir Immune Defic Syndr. 2007 Apr 1;44(4):492.
Results Reference
background
PubMed Identifier
20711481
Citation
Gandhi RT, Zheng L, Bosch RJ, Chan ES, Margolis DM, Read S, Kallungal B, Palmer S, Medvik K, Lederman MM, Alatrakchi N, Jacobson JM, Wiegand A, Kearney M, Coffin JM, Mellors JW, Eron JJ; AIDS Clinical Trials Group A5244 team. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med. 2010 Aug 10;7(8):e1000321. doi: 10.1371/journal.pmed.1000321.
Results Reference
result
PubMed Identifier
22083073
Citation
Gandhi RT, Coombs RW, Chan ES, Bosch RJ, Zheng L, Margolis DM, Read S, Kallungal B, Chang M, Goecker EA, Wiegand A, Kearney M, Jacobson JM, D'Aquila R, Lederman MM, Mellors JW, Eron JJ; AIDS Clinical Trials Group (ACTG) A5244 Team. No effect of raltegravir intensification on viral replication markers in the blood of HIV-1-infected patients receiving antiretroviral therapy. J Acquir Immune Defic Syndr. 2012 Mar 1;59(3):229-35. doi: 10.1097/QAI.0b013e31823fd1f2.
Results Reference
derived

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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

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