Immuno-stimulation With Maraviroc Combined to Antiretroviral Therapy in Advanced Late Diagnosed HIV-1 Infected Patients

Study Overview
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Brief Summary
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The objective of the OPTIMAL study is to demonstrate that the adjunction of Maraviroc to a combination of antiretroviral therapy in naive and late diagnosed HIV-1 infected patients counts may accelerate the kinetics of immune restoration and decrease the risk of disease progression and death. It is a randomized, versus placebo, double-blind trial, conducted in France, Spain and Italy.

Official Title
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Optimized Phase III Trial of Immuno-stimulation With Maraviroc, a CCR5 (Chemokine Receptor 5) Antagonist, Combined With Anti Retroviral Therapy in Advanced, Late Diagnosed HIV-1 Infected Patients With an AIDS-defining Event and/or CD4 (Cluster of Differentiation 4) Counts Below 200 Cells/mm³. ANRS 146 OPTIMAL

Conditions
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HIV-1 Infection, AIDS

Intervention / Treatment
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* Drug: Maraviroc (Celsentri)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed HIV-1 infection (ELISA and Western Blot tests positive) CD4+ T lymphocytes below or equal 200/mm³ or previous AIDS-defining-illness at diagnosis Patient naïve from any antiretroviral In women, use of a contraceptive method, and lack of actual pregnancy Patients with a coverage from social health After informed consent Exclusion Criteria: Current pregnancy, lack of contraceptive method, breast-feeding Current active tuberculosis (either suspected, diagnosed) Ongoing malignancies except cutaneous Kaposi's sarcoma. Patients with a previous cancer considered as cured for at least 6 months could be included in the study Current or previous severe cardiac failure, chronic respiratory disease, renal or liver insufficiency; any life-threatening organ failure Cognitive impairment, psychiatric disorders, severe depressive affects, unadapted behavior Use of cytostatic drugs, immunosuppressive agents, steroids PMN (polymorphonuclear neutrophil) below 750/mm³, platelets below 50,000/mm³, haemoglobin below 10 g/dL; ASAT (aspartate aminotransferase), ALAT (alanine aminotransferase) or bilirubin over 2.5 ULN; lipase over 2 ULN (Upper limit of normal), serum creatinine over 1.5 ULN; proteinuria over 1g/L; INR (International Normalized Ratio) abnormal Current or previous, during the 3 last months, use of immunomodulatory agents (G-CSF (granulocyte colony stimulating factor), IL-2 (Interleukin-2), GM-CSF (Granulocyte Macrophage colony stimulating factor), interferons, pentoxifylline) Hypersensitivity to peanut and /or soy products

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Maraviroc<br>Maraviroc 300, 600 or 1200mg per day | Drug: Maraviroc (Celsentri)<br>* Patients will take cART optimized regimen according to the recommended regimen as first line of treatment in most commonly used guidelines with Maraviroc at the following dose: 150 mg orally twice a day for patients receiving a Protease Inhibitor Ritonavir-boosted regimen (except Fosamprenavir), 300 mg orally twice a day for patients receiving a Fosamprenavir Ritonavir-boosted regimen or 600 mg orally twice a day for patients receiving Efavirenz-based regimen. Duration: 72 weeks.<br>|
| Placebo Comparator: Placebo<br>Placebo 300, 600 or 1200mg per day | Drug: Placebo<br>* Patients will take cART optimized regimen according to the recommended regimen as first line of treatment in most commonly used guidelines with Placebo at the following dose: 150 mg orally twice a day for patients receiving a Protease Inhibitor Ritonavir-boosted regimen (except Fosamprenavir), 300 mg orally twice a day for patients receiving a Fosamprenavir Ritonavir-boosted regimen or 600 mg orally twice a day for patients receiving Efavirenz-based regimen. Duration: 72 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To demonstrate the clinical benefit of the adjunction of Maraviroc to a combination of antiretroviral therapy defined as decrease of clinical events | The clinical benefit is the reduction of occurence of a composite outcome consisting of: New AID-defining event (1993 CDC(Centers for Disease Control) expanded surveillance definition) Non B or C events (Aspergillosis, Bartonellosis, Chagas disease, Leishmaniasis, Lymphoma, Microsporidiosis chronic intestinal, Nocardiosis, Penicillium marneffei extrapulmonary, Pneumocystis jiroveci extrapulmonary, Rhodococcus equi disease, Severe bacterial infections) Serious non-AIDS events (Cardiovascular disease, Chronic end stage renal disease, Liver failure, Non-AIDS defining cancers, IRIS) All cause of mortality | From Week 0 to Week 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety evaluation and Clinical, Immunological and pharmacological evaluation | The secondary end points: Clinical events (to compare Maraviroc and placebo arm for each component of the primary composite endpoint and other major outcomes) Immunological evaluation (T cells phenotypic analysis; seric markers of immune activation) Virological evaluation (plasma HIV viral load analysis; viral tropism testing,) Pharmacokinetic evaluation (plasma concentration of Maraviroc and relationship with virological response) Clinical and biological safety of the strategy (Adverse events >= grade 2 on ANRS scale of adverse event) Cost-effectiveness analysis | From Week 0 to Week 72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Late diagnosed HIV-1 infected patients, AIDS-defining events, Immune restoration