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    Summary
    EudraCT Number:2015-000511-40
    Sponsor's Protocol Code Number:ANRS_VRI04_(DALIA_2)
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-10-30
    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 ConcernedFrance - ANSM
    A.2EudraCT number2015-000511-40
    A.3Full title of the trial
    Phase II, randomized, multicentric, clinical trial of a therapeutic vaccination, with ex vivo generated autologous Dentritic Cells pulsed with HIV lipopetides, combined or not with a TLR-3 agonist (poly-ICLC, Hiltonol), in the control of viral replication following antiretroviral treatment interruption in HIV-1 infected patients
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Not Applicable
    A.4.1Sponsor's protocol code numberANRS_VRI04_(DALIA_2)
    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 supportInserm-ANRS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHenri Mondor Hospital
    B.5.2Functional name of contact pointJean-Daniel Lelièvre
    B.5.3 Address:
    B.5.3.1Street Address51 avenue de Lattre de Tassigny
    B.5.3.2Town/ cityCréteil
    B.5.3.3Post code94010
    B.5.3.4CountryFrance
    B.5.4Telephone number+33(0)149 81 24 09
    B.5.5Fax number+33(0)149 81 24 69
    B.5.6E-mailjean-daniel.lelievre@aphp.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP Role
    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 No
    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 nameInserm-ANRS/HIVAX-DC
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPCutaneous use
    Subcutaneous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Yes
    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 Yes
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    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 No
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 namePoly-ICLC (Hiltonol®)
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular 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) Yes
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntramuscular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Human Immunodeficiency Virus (HIV) Infection
    E.1.1.1Medical condition in easily understood language
    Not applicable
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10020161
    E.1.2Term HIV infection
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    E.2.2Secondary objectives of the trial
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Transcriptomic prick test; qVOA
    E.3Principal inclusion criteria
    1.Documented HIV-1 infection (Elisa and Western Blot)
    2.Age ≥ 18 years and ≤ 68 years on the day of screening
    3.Weight ≥50kg
    4.Nadir CD4 count > 300 cells/mm3 (Nadir refers to the lowest ever measured CD4 count)
    5.CD4 ≥ 500 cells/mm3 on at least two consecutive measurements* (including the screening value) within the previous 6 months prior to enrollment (one CD4 value between 350 and 500 cells/mm3 is permitted)
    6.Plasma HIV-1 RNA < 50 copies/mL on at least two consecutive measurements* (including the screening value) within the previous 6 months prior to enrollment (occasional so called ‘blip’ up to 200 copies/mL is permitted)
    * If no measurement available in the last 6 months, a measurement performed in the last 12 months is accepted.
    7.On stable c-ART without interruption for at least 18 months prior to screening
    8.Willing to interrupt c-ART for up to 24 weeks and to change c-ART regimen if required
    9.If sexually active, willing to use a reliable method of reducing the risk of transmission to their sexual partners during treatment interruption (which could include PrEP for their sexual partners)
    10.If heterosexually active and able to have children, willing to use a highly effective method† of contraception with partner from 2 weeks before enrollment until 18 weeks after the last injection and until the end of the trial)
    †combined oral contraceptive pill; injectable or implanted contraceptive; IUD/IUS; physiological or anatomical sterility (inself or partner)
    11.If women of childbearing potential‡, willing to undergo blood beta-HCG at screening and urine pregnancy tests prior to each injection
    ‡A woman will be considered of childbearing potential following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
    12.Laboratory parameters at screening:
    - polynuclear neutrophils ≥ 1 000/mm3
    - haemoglobin ≥ 10 g/dL
    - platelets ≥ 100 000/mm3
    - calculated creatinine clearance ≥ 60 mL/min
    - lipase ≤ 1.5 x N
    - AST, ALT, total bilirubin§ ≤ 2.5 x N
    - proteinuria ≤ 1 g/L (++)
    - anti-nuclear antibodies (ANA) titer ≤ 1/320
    - anticardiolipin antibodies (ACA) ≤ 30 U
    - no lupus anticoagulant
    - except patients under atazanavir
    13.Willing and able to comply with visit schedule and to provide blood samples according to the protocol
    14.Written informed consent (at the latest the day of screening visit and before all exams to be done in the context of the trial) (article L1122-1-1 of French Code de la Santé Publique)
    15.Participant covered by Health Insurance (article L1121-11 of French Code de la Santé Publique)
    E.4Principal exclusion criteria
    1.Pregnant or breast-feeding woman
    2.Woman expecting to conceive during the trial period
    3.HIV-2 infection or co-infection
    4.History of CDC category C clinical events (1993)
    5.Previous known virological failures defined by loss of virological suppression with the presence of resistant mutations for at least 3 classes of antiretroviral drugs
    6.Concomitant or previous conditions that preclude injection of vaccines
    7.History of experimental vaccinations against HIV
    8.Documented history of a serious ARs (SARs) to any vaccine
    9.Previous treatment with chemotherapy (except for chemotherapy injected into skin lesions for Kaposi’s sarcoma)
    10.Treatment with systemic corticoids or immuno-suppressive agents ongoing or in the previous 12 weeks before randomisation in the trial
    11.Administration of an inactivated vaccine within 30 days or a live vaccine within 60 days prior to randomisation
    12.Planned administration during the follow-up of participants of a vaccine other than those recommended in France as part of the usual care of patients
    13.Presence of a skin condition or marking that precludes inspection of the injection site
    14.History of psychiatric disorders
    15.History of cancer (except basal cellular skin carcinoma or Kaposi’s sarcoma)
    16.History of significant neurological disease, cardiovascular disease (angina, myocardial infarction, transient ischemic attack, stroke); participants with controlled blood pressure are eligible
    17.Personal history of clinical autoimmune disease or reactive arthritis or family history of rheumatoid arthritis (parents or siblings)
    18.Ongoing diseases including uncontrolled active severe infection, cardiac, pulmonary (excluding mild asthma), thyroid, renal or neurological (peripheral or central) diseases
    19.Progressive infection (not controlled at the time of inclusion), including syphilis
    20.STI in the last year
    21.Active or latent tuberculosis (unless prophylaxis in past as per local practice)
    22.Liver disease including hepatitis B (positive HBs antigen and/or positive DNA) or hepatitis C (positive anti-HCV Ab or positive PCR)
    23.Positive serology for HTLV1
    24.A clinically significant abnormality on ECG according to the judgement of the investigator
    25.History of severe local or general reaction to vaccination defined as
    a.local: extensive, indurated redness and swelling involving most of the antero-lateral thigh or the major circumference of the arm, not resolving within 72 hours
    b.general: fever  39.5oC within 48 hours; anaphylaxis; bronchospasm; laryngeal oedema; collapse; convulsions or encephalopathy within 72 hours
    26.Grade 2 or worse routine laboratory parameters. Hyperbilirubinaemia to be considered an exclusion criterion only when confirmed to be conjugated bilirubinaemia
    27.Difficult venous access for apheresis
    28.History of anaphylaxis or proven allergy to an allergen that can be used during apheresis
    29.History of documented bleeding diathesis, or any condition that may be associated with a prolonged bleeding time
    30.Subject placed under judicial protection (article L1122-2 of French Code de la Santé Publique)
    31.Subject participating in another research involving human subjects with an exclusion period still ongoing at the screening visit
    E.5 End points
    E.5.1Primary end point(s)
    Virological efficacy endpoint (control of viral replication)
    •Dynamics of plasma HIV-1 RNA rebound during ATI: Area under the curve of plasma HIV-1 RNA during the ATI period from week 24 to 48 (or to the time of ART resumption) for participants eligible to interrupt ART at week 24 normalized for duration of ATI

    Safety endpoint
    •Number and proportion of participants with a discontinuation of the randomized intervention strategy (i.e. discontinuation of injections) due to an adverse event that is considered related or possibly related to product(s) (arms 1 or 2)
    E.5.2Secondary end point(s)
    Secondary safety endpoints:
    -changes in T CD4 lymphocytes in periods with and without c-ART
    -proportion of participants having T CD4 lymphocytes <350/mm3 after ART interruption (up to 6 months of ART interruption)

    Number and proportions of participants with:
    -grade 3 and worse solicited clinical and laboratory adverse events
    -any event that results in resuming c-ART during the ATI
    -Serious Adverse Events
    -other clinical and laboratory adverse events

    Secondary immunogenicity endpoints:
    -magnitude and polyfunctionality of vaccine induced CD4 and CD8 T-cell responses, determined by intracellular flow cytometry (ICS) at different time points during the vaccination period

    Secondary virological endpoints:
    Until W48, i.e. after up to 6 months of antiretroviral treatment interruption:
    -slope of viral rebound during ATI
    -time from c-ART interruption to the earliest time of reaching detectable HIV-1 RNA ≥ 200 copies/mL on a separate sample
    -magnitude of viral load peak during ATI
    -magnitude of viral load setpoint during ATI
    -level of HIV-1 RNA copies/mL of plasma over time
    -time from start of ATI to reintroduction of c-ART
    -time to viral load suppression after restarting c-ART
    E.5.2.1Timepoint(s) of evaluation of this end point
    - week 0 to week 52 (secondary safety endpoint)
    - week 0 to week 24 (secondary immunogenicity)
    - week 24 to week 48 (secondary virological endpoint)
    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 No
    E.6.7Pharmacodynamic No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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) Yes
    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 concerned10
    E.8.5The trial involves multiple Member States No
    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
    The trial will be closed when the data entered into the database is checked and the safety database locked
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    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: 47
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 Yes
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 50
    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)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-02-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-13
    P. End of Trial
    P.End of Trial StatusOngoing
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