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

NCT ID: NCT00988780

Last Updated: 2012-11-27

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

NA

Total Enrollment

276 participants

Study Classification

INTERVENTIONAL

Study Start Date

2009-12-31

Study Completion Date

2013-04-30

Brief Summary

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

Detailed Description

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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.

Conditions

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Immune Reconstitution Inflammatory Syndrome HIV HIV Infections

Keywords

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Immune reconstitution inflammatory syndrome CCR5 antagonist Maraviroc HIV treatment naive

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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Maraviroc

Maraviroc 600mg po BID

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

Group Type EXPERIMENTAL

maraviroc

Intervention Type DRUG

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.

Placebo

Placebo po BID

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

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

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.

Interventions

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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.

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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Selzentry Stocrin Truvada Stocrin Truvada

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Witwatersrand, South Africa

OTHER

Sponsor Role collaborator

Case Western Reserve University

OTHER

Sponsor Role collaborator

The Wistar Institute

OTHER

Sponsor Role collaborator

University of Pennsylvania

OTHER

Sponsor Role collaborator

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

OTHER

Sponsor Role lead

Responsible Party

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Juan G. Sierra Madero

Infectious Diseases Specialist

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Ian Sanne, MBBCH, FCP

Role: PRINCIPAL_INVESTIGATOR

University of the Witwatersrand. Themba Lethu Clinic.

Michael M. Lederman, MD

Role: PRINCIPAL_INVESTIGATOR

Center for AIDS Research. Case Western Reserve University

Luis J Montaner, M.Sc.

Role: PRINCIPAL_INVESTIGATOR

HIV-1 Immunopathogenesis Laboratory. The Wistar Institute

Livio Azzoni, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

HIV-1 Immunopathogenesis Laboratory. The Wistar Institute

Juan G Sierra Madero, MD

Role: PRINCIPAL_INVESTIGATOR

Insituto Nacional de Nutricion de Ciencias Medicas y Nutricion Salvador Zubiran

Susan Ellenberg, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine

Irini Sereti, M.D., MHS

Role: PRINCIPAL_INVESTIGATOR

National Institute of Allergy and Infectious Diseases (NIAID)

Locations

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NIH/NIAD

Bethesda, Maryland, United States

Site Status

Center for AIDS Research. Case Western Reserve University

Cleveland, Ohio, United States

Site Status

Center for Clinical Epidemiology and Biostatistics. University of Pennsylvania School of Medicine

Philadelphia, Pennsylvania, United States

Site Status

HIV-1 Immunopathogenesis Laboratory. The Wistar Institute

Philadelphia, Pennsylvania, United States

Site Status

Hospital General de León

León, Guanajuato, Mexico

Site Status

Hospital Civil de Guadalajara

Guadalajara, Jalisco, Mexico

Site Status

Hospital General de México

Mexico City, Mexico City, Mexico

Site Status

Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

Mexico City, Mexico City, Mexico

Site Status

Hospital Central Dr. Ignacio Morones Prieto

San Luis Potosí City, San Luis Potosí, Mexico

Site Status

Clinical HIV Research Unit. Themba Lethu Clinic. Helen Joseph Hospital

Johannesburg, Gauteng, South Africa

Site Status

Countries

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United States Mexico South Africa

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Sierra-Madero JG, Ellenberg SS, Rassool MS, Tierney A, Belaunzaran-Zamudio PF, Lopez-Martinez A, Pineirua-Menendez A, Montaner LJ, Azzoni L, Benitez CR, Sereti I, Andrade-Villanueva J, Mosqueda-Gomez JL, Rodriguez B, Sanne I, Lederman MM; CADIRIS study team. Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution inflammatory syndrome in HIV (CADIRIS): a double-blind, randomised, placebo-controlled trial. Lancet HIV. 2014 Nov;1(2):e60-7. doi: 10.1016/S2352-3018(14)70027-X. Epub 2014 Oct 21.

Reference Type DERIVED
PMID: 26423989 (View on PubMed)

Sierra-Madero JG, Ellenberg S, Rassool MS, Tierney A, Belaunzaran-Zamudio PF, Lopez-Martinez A, Pineirua-Menendez A, Montaner LJ, Azzoni L, Benitez CR, Sereti I, Andrade-Villanueva J, Mosqueda-Gomez JL, Rodriguez B, Sanne I, Lederman MM; CADIRIS study team. A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of a Chemokine Receptor 5 (CCR5) Antagonist to Decrease the Occurrence of Immune Reconstitution Inflammatory Syndrome in HIV-Infection: The CADIRIS Study. Lancet HIV. 2014 Nov 1;1(2):e60-e67. doi: 10.1016/S2352-3018(14)70027-X.

Reference Type DERIVED
PMID: 26366430 (View on PubMed)

Other Identifiers

Review additional registry numbers or institutional identifiers associated with this trial.

The CADIRIS Study

Identifier Type: -

Identifier Source: org_study_id