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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
University of Witwatersrand, South Africa
Case Western Reserve University
The Wistar Institute
University of Pennsylvania
Information provided by (Responsible Party):
Juan G. Sierra Madero, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
ClinicalTrials.gov Identifier:
NCT00988780
First received: October 1, 2009
Last updated: November 22, 2012
Last verified: November 2012
  Purpose

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


Condition Intervention
Immune Reconstitution Inflammatory Syndrome
HIV
HIV Infections
Drug: maraviroc
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: CCR5 Antagonism to Decrease the Incidence of the Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients

Resource links provided by NLM:


Further study details as provided by Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran:

Primary Outcome Measures:
  • Time to occurrence of an IRIS event [ Time Frame: The initial 24 week period of observation ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Time to occurrence of a severe IRIS event [ Time Frame: The initial 24 week period of observation ] [ Designated as safety issue: No ]
  • Occurrence of either an IRIS event or death [ Time Frame: By 24 and 48 weeks ] [ Designated as safety issue: Yes ]
  • Proportion of subjects who develops an IRIS case [ Time Frame: By week 24 ] [ Designated as safety issue: No ]
  • Proportion of subjects who develop a severe IRIS case [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  • Proportion of subjects who develop a confirmed, non dermatologic IRIS case [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  • Proportion of subjects who develop an unmasking or paradoxical IRIS event [ Time Frame: Week 24 ] [ Designated as safety issue: Yes ]
  • 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) ] [ Designated as safety issue: Yes ]
  • Frequency of AIDS defining events and AIDS related events in both arms of treatment [ Time Frame: From basline to study end ] [ Designated as safety issue: No ]
  • General survival [ Time Frame: At week 24 and 48 ] [ Designated as safety issue: No ]
  • Survival without IRIS [ Time Frame: At weeks 24 and 48 ] [ Designated as safety issue: No ]
  • Proportion of patients with VL<50 copies/mL [ Time Frame: At weeks 8, 24 and 48 ] [ Designated as safety issue: No ]
  • Changes form baseline in CD4+ cells count [ Time Frame: From baseline to weeks 12, 24 and 48 ] [ Designated as safety issue: No ]
  • Safety and tolerability of the treatment regimens [ Time Frame: Along the study ] [ Designated as safety issue: Yes ]
  • Incidence of HIV drug resistance [ Time Frame: Baseline to week 60 ] [ Designated as safety issue: No ]
  • Prevalence of CCR5 tropism [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • Prevalence of CCR5 HIV tropism [ Time Frame: At virological failure occurrence ] [ Designated as safety issue: No ]
  • Baseline predictors of IRIS [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • Genetic polymorphisms associated with the occurrence of IRIS [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Estimated Enrollment: 276
Study Start Date: December 2009
Estimated Study Completion Date: April 2013
Estimated Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:
  • Selzentry
  • Stocrin
  • Truvada
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:
  • Stocrin
  • Truvada

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.

  Eligibility

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

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.
  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: NCT00988780

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

Publications:

Responsible Party: Juan G. Sierra Madero, Infectious Diseases Specialist, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
ClinicalTrials.gov Identifier: NCT00988780     History of Changes
Other Study ID Numbers: The CADIRIS Study
Study First Received: October 1, 2009
Last Updated: November 22, 2012
Health Authority: Mexico: Ministry of Health
Mexico: Federal Commission for Sanitary Risks Protection
South Africa: Medicines Control Council
South Africa: Human Research Ethics Committee

Keywords provided by Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran:
Immune reconstitution inflammatory syndrome
CCR5 antagonist
Maraviroc
HIV
treatment naive

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immune Reconstitution Inflammatory Syndrome
Syndrome
Disease
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
Pathologic Processes
Retroviridae Infections
RNA Virus Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Emtricitabine
Anti-Infective Agents
Antiviral Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014