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    Summary
    EudraCT Number:2010-022293-14
    Sponsor's Protocol Code Number:OPTIMAL
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-03-08
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2010-022293-14
    A.3Full title of the trial
    Optimized Phase III Trial of Immuno-stimulation with Maraviroc, a CCR5 antagonist, combined with Anti Retroviral Therapy (cART) in advanced, Late diagnosed HIV-1 infected patients with an AIDS-defining event and/or CD4 counts below 200 cells/mm3.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    ANRS 146 OPTIMAL
    A.3.2Name or abbreviated title of the trial where available
    OPTIMAL 146 ANRS
    A.4.1Sponsor's protocol code numberOPTIMAL
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorInserm - ANRS
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfeizer/ViiV Healthcare France
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOspedale San Raffaele,Malattie Infettive
    B.5.2Functional name of contact pointStudy coordinator
    B.5.3 Address:
    B.5.3.1Street Addressvia stamira d'ancona,20
    B.5.3.2Town/ citymilano
    B.5.3.3Post code20127
    B.5.3.4CountryItaly
    B.5.4Telephone number+390226433646
    B.5.5Fax number+390226437903
    B.5.6E-mailparisi.mariarita@hsr.it
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name CELSENTRI 300
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCELSENTRI 300
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    Buccal use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name CELSENTRI 150
    D.2.1.1.2Name of the Marketing Authorisation holderPFIZER
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCELSENTRI 150
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCoated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCoated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Confirmed HIV-1 infection; Adult patients (age >18 years); CD4+ T lymphocytes < 200/mm3 and/or previous AIDS-defining-illness at W-2 or W-4; 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.
    E.1.1.1Medical condition in easily understood language
    Confirmed HIV-1 infection; Adult patients; CD4+ T lymphocytes <200/mm3 and/or previous AIDS-defining-illness at W2 or W4; Patient naïve from any antiretroviral; In women, use of a contraceptive method
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the clinical benefit of the adjunction of Maraviroc to a combination of antiretroviral therapy in naïve and late diagnosed HIV-1 infected patients.
    The clinical benefit is the reduction of the occurrence of a composite outcome consisting of new AIDS-defining event (ADE), Non B or C events, serious non-AIDS events, IRIS and death.
    E.2.2Secondary objectives of the trial
    - To compare Maraviroc to Placebo arm for each component of the primary composite end point and other major outcomes;
    - Impact of CCR5 tropism on primary and major secondary end points;
    - Immunologic evaluation;
    - Virological evaluation;
    - Pharmacology substudy;
    - Safety of the strategy;
    - Cost-effectiveness study.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Virological study (for all patients enrolled in France)
    Seminal compartment sub-study (for 20 patients in each group)
    E.3Principal inclusion criteria
    Confirmed HIV-1 infection; Adult patients (age > 18 years); CD4+ T lymphocytes < 200/mm3 and/or previous AIDS-defining-illness at W-2 or W-4; 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.
    E.4Principal 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 failurea, chronic respiratory diseaseb, renalc or liver insufficiency; any life-threatening organ failure; - Cognitive impairment, psychiatric disorders, severe depressive affects, inadapted behavior; - Use of cytostatic drugs, immunosuppressive agents, steroids. Treatment with steroids can be authorized if they are given for less than two months as adjuvant treatment for opportunistic infections; - PMN < 750/mm3, platelets < 50,000/mm3, haemoglobin < 10 g/dL; ASAT, ALAT or bilirubin > 2.5 ULN; lipase > 2 ULN, serum creatinine > 1.5 ULN; proteinuria > 1g/L; INR abnormal (Note: normal INR values are included between 0.8 and 1.3)d; - Current or previous, during the 3 last months, use of immunomodulatory agents (G-CSF, IL-2, GM-CSF, interferons, pentoxifylline);
    - Hypersensitivity to peanut and /or soy products.

    a: if a severe cardiac failure is suspected, an echocardiography should be performed (ejection fraction < 45% should not be included in the trial).
    b: Patients having a Chronic Obstructive Pulmonary Disease can not be included in the trial.
    c: Renal insufficiency defined by creatinine clearance < 60/mL.
    d: Patients taking anticoagulant can be included in the trial.
    E.5 End points
    E.5.1Primary end point(s)
    The primary composite end point is defined in the appendix XI and XII and includes the following events:
    o New ADE (opportunistic events consistent with the 1993 CDC expanded surveillance definition plus additional events associated with immunosuppression in the patient population targeted for enrolment) (APPENDIX XI).
    o Non B or C:
     Aspergillosis, invasive,
     Bartonellosis, includes bacillary angiomatosis and peliosis hepatis,
     Chagas disease (American trypanosomiasis) of the central nervous system (CNS),
     Leishmaniasis, visceral (kala-azar),
     Lymphoma, Hodgkin's,
     Lymphoma, non-Hodgkin's, other cell type,
     Microsporidiosis, chronic intestinal (> 1 month's duration),
     Nocardiosis,
     Penicillium marneffei, extrapulmonary,
     Pneumocystis jiroveci, extrapulmonary,
     Rhodococcus equi disease,
     Severe infections: defined by sepsis with bacteremia requiring overnight hospitalisation, or pneumonia requiring overnight hospitalisation.
    o Serious non-AIDS events (APPENDIX XII):
     Cardiovascular disease (CVD): myocardial infarction, stroke, coronary revascularization,
     Chronic end stage renal disease (ESRD),
     Liver failure,
     Non-AIDS-defining cancers except basal and squamous cell skin cancers,
     IRIS,
    o All causes of mortality (related or not to AIDS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    W4 and virological response at W24, W36, W48, W60 and W72
    E.5.2Secondary end point(s)
    Secondary end points are:
    o Clinical Events:
     New ADE (opportunistic events consistent with the 1993 CDC expanded surveillance definition plus additional events associated with immunosuppression in the patient population targeted for enrolment),
     Non B or C
     Serious non-AIDS events,
     Grade 4 events (APPENDIX XIII)
     All causes of mortality (related or not to AIDS).
    o Immunological end points (APPENDIX X):
     Absolute number of T CD4+ lymphocytes
     Percentage of patients with > 200 CD4+ T lymphocytes at W4, W8, W12, W24, W36, W48, W60, W72,
     Phenotypic analysis of CD4+ T lymphocytes, CD8+ T lymphocytes (naïve, central memory cells, and cytotoxic cells) and evolution of markers of immune activation (expression of HLA-DR and CD38 on CD4 and CD8 T cells) at W0, W8, W24, W60 (substudy),
     Seric markers of immune activation (inflammation): Hs-CRP, fibrinogen, IL-6, IL-1-beta, IFN-alpha, d-dimers, SAA and sCD14 at W0, W8, W24, W60 (substudy),
     Density of CCR5 and CXCR4 expression at W0, W8, W24 (substudy),
     Expression of homing receptors on CD4 T lymphocytes (% of cells CD4+a4b7+CCR9+) at W0, W8, W24 (substudy),
     Evaluation of HIV-1 and recall-antigen specific immune responses by Intra-Cellular Staining (ICS) at W0, W24 (substudy).
    o Virological end points (APPENDIX IX):
     Percentage of patients with a plasma HIV-1 RNA < 400 copies/mL and <50 copies/mL at W0, W4, W8, W12, W24, W36, W48, W60, W72,
     Plasma HIV-1 RNA at W-4, W0, W4, W8, W12, W24, W36, W48, W60, W72,
     Tropism testing performed by Tropisme Test Toulouse at baseline (W0) on plasma HIV-1 RNA and in patients with detectable plasma HIV-1 RNA during the study (on the first sample with HIV-1 RNA > 1000 copies/ml after week 24),
     Resistance testing performed in patients with detectable plasma HIV-1 RNA during the study (on the second sample with HIV-1 RNA > 400 copies/ml after week 24),
    Virological study (for all patients enrolled in France):
     HIV-1 DNA in PBMC (peripheral blood mononuclear cells) at W0, W24, W72 (whole blood samples),
     Tropism testing by genotypic analysis of the V3 loop to investigate (1) the correlation with virology response at W0 on plasma HIV RNA, and (2) the tropism evolution in patients with undetectable viral load at W0, W24, W72 on HIV-1 DNA.
    Seminal compartment sub-study (for 20 patients in each group):
     HIV viral load will be determined at W0, W24,
     HIV tropism will be determined at W0, W24.

    o Pharmacokinetic (PK) end points (APPENDIX VIII)
     PK analysis:
     Determinations of MVC trough plasma concentration of MVC (Cmin; 12  2 hours after the last drug intake) at W4 and W24 in all patients randomized in Group 2* using UPLC-MS/MS,
    • Distributions of MVC Cmin by dosing regimen and according to the associated PI Ritonavir-boosted or EFV,
    • Between and within patients variability of MVC Cmin,
     Substudy in 25 patients in each group to calculate the:
    • Steady-state plasma area under curve (AUC) of MVC at W4 based on the determination of 0h, 1h, 3h, 6h, 8h, 12h post dose concentrations of MVC,
    • Average of MVC concentration at W4 (Cave = AUC/12h),
    • Free fraction AUC (unbound to plasma protein) of MVC at W4,
     Determination of MVC Cmin for study discontinuations (before the end point) (adverse events, virological failure, etc.),
     Determination of MVC seminal at W24 in a subgroup of 20 patients from Group 2,
     Pharmacokinetic-Pharmacodynamic (PK-PD) relationship:
     Relationship between MVC Cmin at W4 and W24 and virological response at W8, W12, W36, W48, W60 and W72 in all patients randomized in Group 2*,
     Percentage of patients with a MVC Cmin ≥ 50 ng/mL by dosing group in all patients randomized in Group 2,
     Relationship between MVC Cave (free and total) at W4 and virological response at W24, W36, W48, W60 and W72 in a subgroup of 25 patients,
     Relationship between MVC Cmin (free and total) at W4 and virological response at W24, W36, W48, W60 and W72 in a subgroup of 25 patients,
     Analysis of MVC Cmin in patients demonstrating changes of their tropism results according to the genotype or/and the Tropisme Test Toulouse,
     Relationship between MVC Cmin at W24 in seminal plasma and virological response in seminal and blood plasma at W0 and W24 in a subgroup of patients.
     Drug-drug interactions by determination of associated PI Ritonavir-boosted or EFV plasma concentrations in all patients randomized in Group 2 using UPLC-MS/MS,
     Safety of the strategy,
     Cost-effectiveness study.
    E.5.2.1Timepoint(s) of evaluation of this end point
    W4 and virological response at W24, W36, W48, W60 and W72
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months18
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months18
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 408
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state408
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 408
    F.4.2.2In the whole clinical trial 408
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    the expected normal treatment of HIV infection
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-04-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-03-07
    P. End of Trial
    P.End of Trial StatusCompleted
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