Maraviroc (CCR5) Antagonism to Decrease the Incidence of the Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients (CADIRIS)

November 22, 2012 updated by: Juan G. Sierra Madero, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

CCR5 Antagonism to Decrease the Incidence of the Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients

The purpose of this study is to determine if Maraviroc administration can decrease IRIS incidence in HIV infected patients initiating ARV therapy.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

This is a randomized, double blind, placebo-controlled, multicenter study testing the utility of a CCR5 antagonist (Maraviroc) as an adjuvant to a standard HAART regimen to decrease the incidence of Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV-infected patients naïve to antiretroviral treatment. The study duration will be 60 weeks, 276 subjects (138 per arm) will be recruited. The population included will be HIV-infected patients starting antiretroviral (ARV) therapy at the participating centers in Mexico and South Africa with a CD4 T cell count <100 cells/ul. Subjects will be randomized to receive either Maraviroc (study drug) or placebo in addition to background ARV therapy. The background antiretroviral regimen for all subjects will be: Efavirenz 600mg QD + Tenofovir 300 mg / Emtricitabine 200 mg QD; subjects will be randomized to one of the following arms: Arm A: background ARV + maraviroc 600mg po BID; Arm B: background ARV + placebo po BID. Patients will be followed for 48 weeks. The primary endpoint will be the occurrence of a defined IRIS event by week 24 of follow up. The success of the ARV therapy will also be evaluated by virologic and immunologic response at 24 and 48 weeks. Three immunology sub-studies are planned: 1) Sub-study A will be conformed by a subgroup of 40 subjects (20 from Mexico and 20 from South Africa), additional blood sampling will be performed to evaluate expression of immune activation markers; movement of central memory T cells into cell cycle and frequencies of expandable pathogen-reactive CD4+ and CD8+ T cells in circulation; 2) Sub-study B will be conformed by another subgroup of 60 subjects (all from South Africa), additional blood sampling will be performed to evaluate monocyte and CD4 T cell gene expression as related to activation-induced apoptosis and cytokine secretion.; 3) Sub-study C will evaluate the incidence of thromboembolic disease in the study patients along with baseline evaluation of possible bio-markers of pro-coagulant state.

Study Type

Interventional

Enrollment (Anticipated)

276

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Mexico
      • Mexico City, Mexico, 06726
        • Hospital General de Mexico
      • Mexico City, Mexico, 14000
        • Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
      • San Luis Potosí, Mexico, 78240
        • Hospital Central Dr. Ignacio Morones Prieto
    • Guanajuato
      • Leon, Guanajuato, Mexico, 37230
        • Hospital General de Leon
    • Jalisco
      • Guadalajara, Jalisco, Mexico, 44280
        • Hospital Civil de Guadalajara
  • South Africa
    • Gauteng
      • Johannesburg, Gauteng, South Africa, 2092
        • Clinical HIV Research Unit. Themba Lethu Clinic. Helen Joseph Hospital
  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • NIH/NIAD
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • Center for AIDS Research. Case Western Reserve University
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Center for Clinical Epidemiology and Biostatistics. University of Pennsylvania School of Medicine
      • Philadelphia, Pennsylvania, United States, 19104
        • HIV-1 Immunopathogenesis Laboratory. The Wistar Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • HIV-1 infection, as documented by any licensed rapid test kit and confirmed by Western blot or ELISA test kit at any time prior to study enrollment.

Plasma HIV-1 RNA is acceptable as an alternative confirmatory test.

  • Men and women age > 18 years.
  • Have not received any antiretroviral treatment before entering the study.
  • Patients who received Single dose nevirapine or any duration of AZT for PMTC will not be considered ARV naïve.
  • CD4+ cell count of </=100 cells/mm3 obtained within 90 days prior to study entry.
  • HIV RNA level > 1,000 copies/mL obtained within 90 days prior to study entry.
  • Patients with an opportunistic or HIV-related infection may be included according to the clinical judgment of the main investigator in each center when the patient is ready and able to start ARV therapy.

  • Laboratory values obtained within 30 days prior to study entry:

    • Absolute neutrophil count (ANC) > 500/mm3.
    • Hemoglobin > 8.0 g/dL.
    • Platelet count > 50,000/mm3.
    • AST (SGOT), ALT (SGPT), and alkaline phosphatase minor of 5 times ULN.
    • Total bilirubin minor of 2.5 times ULN.
    • Creatinine clearance minor of 50* mL/min as estimated by the Cockcroft-Gault equation or Creatinine Clearance > 50ml/min as calculated by a formal creatinine clearance measurement
  • All women of reproductive potential (have not reached menopause or undergone hysterectomy, oophorectomy, or tubal ligation) must have a negative serum or urine b-HCG pregnancy test performed within 7 days before study entry.
  • Female subjects who are not of reproductive potential (have reached menopause or undergone hysterectomy, oophorectomy, or tubal ligation) or whose male partner has undergone successful vasectomy with resultant azoospermia or has azoospermia for any other reason, are eligible without requiring the use of contraception. Documentation of menopause, sterilization (hysterectomy, oophorectomy, tubal ligation, or vasectomy) and azoospermia by patient-reported history is acceptable.
  • All subjects must agree not to participate in a conception process (i.e., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the female study volunteer/male partner must agree to use a form of contraception as specified in the note below while receiving protocol-specified medication(s) and for one month after stopping the medication(s).
  • Ability and willingness of subject or legal guardian/representative to give written informed consent.

Exclusion Criteria:

  • Pregnancy and breast-feeding.
  • Active neoplasia or previous history of neoplasia. (Except localized non visceral Kaposi´s Sarcoma; localized squamous or basal cell carcinoma of the skin, or intraepithelial cervical neoplasia grade III or less).
  • Use of the following drugs within 180 days prior to study entry: systemic cancer chemotherapy, systemic investigational agents, and immunomodulators (growth factors, immune globulin, interleukins, interferons).
  • Use of systemic corticosteroids in the last 2 weeks prior to randomization.
  • Decompensated liver disease (defined as stage C of Child-Pugh classification) at the beginning of the study.
  • An altered mental status that in the opinion of the investigator, will compromise the adherence to the protocol.
  • Allergy/sensitivity to study drug(s) or their formulations that cannot be substituted by another agent as described in section 5.1
  • Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
  • Serious illness that renders a subject unable to take the antiretroviral study regimen.
  • Serious medical illness that in the opinion of the investigator compromises the adherence and/or follow up of the protocol.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Maraviroc

Maraviroc 600mg po BID

Background antiretroviral regimen (Efavirenz 600mg QD + Tenofovir 300 mg /Emtricitabine 200 mg QD) plus Maraviroc 600 mg BID
Drug: maraviroc

Maraviroc 600mg po BID every day from the entry visit until week 48 or until IRIS event or unacceptable toxicity develops.

Efavirenz 600 mg qd every day from the entry visit until week 48 or until IRIS event or unacceptable toxicity develops.

Tenofovir/Emtricitabine 300/200 mg qd from the entry visit until week 48 or until IRIS event or unacceptable toxicity develops.

Other Names:
  • Truvada
  • Stocrin
  • Selzentry
Placebo Comparator: Placebo

Placebo po BID

Background antiretroviral regimen (Efavirenz 600mg QD + Tenofovir 300 mg /Emtricitabine 200 mg QD plus Placebo po BID
Drug: Placebo

Placebo tablets po BID every day from the entry visit until week 48 or until IRIS event or unacceptable toxicity develops.

Efavirenz 600 mg qd every day from the entry visit until week 48 or until IRIS event or unacceptable toxicity develops.

Tenofovir/Emtricitabine 300/200 mg qd from the entry visit until week 48 or until IRIS event or unacceptable toxicity develops.

Other Names:
  • Truvada
  • Stocrin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Time to occurrence of an IRIS event
Time Frame: The initial 24 week period of observation
The initial 24 week period of observation

Secondary Outcome Measures

Outcome Measure
Time Frame
Time to occurrence of a severe IRIS event
Time Frame: The initial 24 week period of observation
The initial 24 week period of observation
Occurrence of either an IRIS event or death
Time Frame: By 24 and 48 weeks
By 24 and 48 weeks
Proportion of subjects who develops an IRIS case
Time Frame: By week 24
By week 24
Proportion of subjects who develop a severe IRIS case
Time Frame: Week 24
Week 24
Proportion of subjects who develop a confirmed, non dermatologic IRIS case
Time Frame: Week 24
Week 24
Proportion of subjects who develop an unmasking or paradoxical IRIS event
Time Frame: Week 24
Week 24
Frequency of cardiovascular, cerebrovascular, non AIDS related neoplasia, cirrhosis, renal failure and death in both treatment arms
Time Frame: During the study (from entry to week 60)
During the study (from entry to week 60)
Frequency of AIDS defining events and AIDS related events in both arms of treatment
Time Frame: From basline to study end
From basline to study end
General survival
Time Frame: At week 24 and 48
At week 24 and 48
Survival without IRIS
Time Frame: At weeks 24 and 48
At weeks 24 and 48
Proportion of patients with VL<50 copies/mL
Time Frame: At weeks 8, 24 and 48
At weeks 8, 24 and 48
Changes form baseline in CD4+ cells count
Time Frame: From baseline to weeks 12, 24 and 48
From baseline to weeks 12, 24 and 48
Safety and tolerability of the treatment regimens
Time Frame: Along the study
Along the study
Incidence of HIV drug resistance
Time Frame: Baseline to week 60
Baseline to week 60
Prevalence of CCR5 tropism
Time Frame: Baseline
Baseline
Prevalence of CCR5 HIV tropism
Time Frame: At virological failure occurrence
At virological failure occurrence
Baseline predictors of IRIS
Time Frame: Baseline
Baseline
Genetic polymorphisms associated with the occurrence of IRIS
Time Frame: Baseline
Baseline
To evaluate the rol of biomarkers (CRP) in predicting or identifying IRIS and the effect of Maraviroc on this marker
Time Frame: Baseline to IRIS event
Baseline to IRIS event

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Collaborators

University of Pennsylvania
University of Witwatersrand, South Africa
Case Western Reserve University
The Wistar Institute

Investigators

  • Principal Investigator: Ian Sanne, MBBCH, FCP, University of the Witwatersrand. Themba Lethu Clinic.
  • Principal Investigator: Michael M. Lederman, MD, Center for AIDS Research. Case Western Reserve University
  • Principal Investigator: Luis J Montaner, M.Sc., HIV-1 Immunopathogenesis Laboratory. The Wistar Institute
  • Principal Investigator: Livio Azzoni, MD, PhD, HIV-1 Immunopathogenesis Laboratory. The Wistar Institute
  • Principal Investigator: Juan G Sierra Madero, MD, Insituto Nacional de Nutricion de Ciencias Medicas y Nutricion Salvador Zubiran
  • Principal Investigator: Susan Ellenberg, Ph.D., Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine
  • Principal Investigator: Irini Sereti, M.D., MHS, National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2009

Primary Completion (Anticipated)

March 1, 2013

Study Completion (Anticipated)

April 1, 2013

Study Registration Dates

First Submitted

October 1, 2009

First Submitted That Met QC Criteria

October 1, 2009

First Posted (Estimate)

October 2, 2009

Study Record Updates

Last Update Posted (Estimate)

November 27, 2012

Last Update Submitted That Met QC Criteria

November 22, 2012

Last Verified

November 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • The CADIRIS Study

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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