Clinical trial NCT00988780: Maraviroc (CCR5) Antagonism to Decrease the Incidence of the Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients
Official title: CCR5 Antagonism to Decrease the Incidence of the Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Immune Reconstitution Inflammatory Syndrome
HIV
HIV Infections
Keywords: Immune reconstitution inflammatory syndrome
CCR5 antagonist
Maraviroc
HIV
treatment naive
Lead sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Sponsor class: OTHER
Collaborators: name: University of Witwatersrand, South Africa
name: Case Western Reserve University
name: The Wistar Institute
name: University of Pennsylvania
First posted: 2009-10-02
Enrollment: 276
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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

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 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.

Primary outcomes:
measure: Time to occurrence of an IRIS event
timeFrame: The initial 24 week period of observation
Secondary outcomes:
measure: Time to occurrence of a severe IRIS event
timeFrame: The initial 24 week period of observation
measure: Occurrence of either an IRIS event or death
timeFrame: By 24 and 48 weeks
measure: Proportion of subjects who develops an IRIS case
timeFrame: By week 24
measure: Proportion of subjects who develop a severe IRIS case
timeFrame: Week 24
measure: Proportion of subjects who develop a confirmed, non dermatologic IRIS case
timeFrame: Week 24
measure: Proportion of subjects who develop an unmasking or paradoxical IRIS event
timeFrame: Week 24
measure: Frequency of cardiovascular, cerebrovascular, non AIDS related neoplasia, cirrhosis, renal failure and death in both treatment arms
timeFrame: During the study (from entry to week 60)
measure: Frequency of AIDS defining events and AIDS related events in both arms of treatment
timeFrame: From basline to study end
measure: General survival
timeFrame: At week 24 and 48
measure: Survival without IRIS
timeFrame: At weeks 24 and 48
measure: Proportion of patients with VL<50 copies/mL
timeFrame: At weeks 8, 24 and 48
measure: Changes form baseline in CD4+ cells count
timeFrame: From baseline to weeks 12, 24 and 48
measure: Safety and tolerability of the treatment regimens
timeFrame: Along the study
measure: Incidence of HIV drug resistance
timeFrame: Baseline to week 60
measure: Prevalence of CCR5 tropism
timeFrame: Baseline
measure: Prevalence of CCR5 HIV tropism
timeFrame: At virological failure occurrence
measure: Baseline predictors of IRIS
timeFrame: Baseline
measure: Genetic polymorphisms associated with the occurrence of IRIS
timeFrame: Baseline
measure: To evaluate the rol of biomarkers (CRP) in predicting or identifying IRIS and the effect of Maraviroc on this marker
timeFrame: Baseline to IRIS event
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: NIH/NIAD
state: Maryland
city: Cleveland
country: United States
facility: Center for AIDS Research. Case Western Reserve University
state: Ohio
city: Philadelphia
country: United States
facility: Center for Clinical Epidemiology and Biostatistics. University of Pennsylvania School of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: HIV-1 Immunopathogenesis Laboratory. The Wistar Institute
state: Pennsylvania
city: Leon
country: Mexico
facility: Hospital General de León
state: Guanajuato
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara
state: Jalisco
city: Mexico City
country: Mexico
facility: Hospital General de México
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
city: San Luis Potosí
country: Mexico
facility: Hospital Central Dr. Ignacio Morones Prieto
city: Johannesburg
country: South Africa
facility: Clinical HIV Research Unit. Themba Lethu Clinic. Helen Joseph Hospital
state: Gauteng
Study officials:
affiliation: University of the Witwatersrand. Themba Lethu Clinic.
name: Ian Sanne, MBBCH, FCP
role: PRINCIPAL_INVESTIGATOR
affiliation: Center for AIDS Research. Case Western Reserve University
name: Michael M. Lederman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: HIV-1 Immunopathogenesis Laboratory. The Wistar Institute
name: Luis J Montaner, M.Sc.
role: PRINCIPAL_INVESTIGATOR
affiliation: HIV-1 Immunopathogenesis Laboratory. The Wistar Institute
name: Livio Azzoni, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Insituto Nacional de Nutricion de Ciencias Medicas y Nutricion Salvador Zubiran
name: Juan G Sierra Madero, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine
name: Susan Ellenberg, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Irini Sereti, M.D., MHS
role: PRINCIPAL_INVESTIGATOR
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