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

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00515827
• Other study ID #: A5244
• Secondary ID: 10440ACTG A5244
• Status: Completed
• Phase: Phase 2
• Start date: November 2007
• Est. completion date: November 2008

Study information

• Verified date: January 2019
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 53
• Est. completion date: November 2008
• Est. primary completion date: September 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Raltegravir (MK-0518)
400 mg tablet taken orally twice daily
• Placebo
400 mg placebo tablet taken orally twice daily

Locations

Country	Name	City	State
United States	University of Colorado Hospital CRS	Aurora	Colorado
United States	Alabama Therapeutics CRS	Birmingham	Alabama
United States	Beth Israel Deaconess Med. Ctr., ACTG CRS	Boston	Massachusetts
United States	Massachusetts General Hospital ACTG CRS	Boston	Massachusetts
United States	Unc Aids Crs	Chapel Hill	North Carolina
United States	Northwestern University CRS	Chicago	Illinois
United States	MetroHealth CRS	Cleveland	Ohio
United States	Duke Univ. Med. Ctr. Adult CRS	Durham	North Carolina
United States	Columbia P&S CRS	New York	New York
United States	Cornell CRS	New York	New York
United States	Harlem ACTG CRS	New York	New York
United States	NY Univ. HIV/AIDS CRS	New York	New York
United States	Stanford CRS	Palo Alto	California
United States	Hosp. of the Univ. of Pennsylvania CRS	Philadelphia	Pennsylvania
United States	Pitt CRS	Pittsburgh	Pennsylvania
United States	Univ. of Rochester ACTG CRS	Rochester	New York
United States	Washington U CRS	Saint Louis	Missouri
United States	Ucsf Aids Crs	San Francisco	California
United States	University of Washington AIDS CRS	Seattle	Washington
United States	Harbor-UCLA Med. Ctr. CRS	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

References & Publications (4)

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 int — View 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. — View 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. Epub 2007 Jun 25. — View 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. Erratum in: J Acquir Immune Defic Syndr. 2007 Apr 1;44(4):492. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	At Weeks 10 and 12
Secondary	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.	At pre-entry, entry, weeks 10 and 12
Secondary	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	At pre-entry, entry, and week 12
Secondary	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	At pre-entry, entry, and week 12
Secondary	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.	At pre-entry, entry, and week 12
Secondary	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.	At pre-entry, entry, and week 12
Secondary	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.	From first day of treatment to week 12
Secondary	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.	From week 12 to week 24
Secondary	Number of Participants Who Discontinued Study Drug	Participants who discontinued randomized study treatment for any reason	From first day of treatment to week 12

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