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    Summary
    EudraCT Number:2019-004195-19
    Sponsor's Protocol Code Number:CREPATS10
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-03-11
    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 number2019-004195-19
    A.3Full title of the trial
    A randomized comparative phase II trial evaluating the capacity of the dual combination doravirine/raltegravir to maintain virological success in HIV-1 infected patients with an HIV-RNA plasma viremia below 50 copies/mL under a current antiretroviral regimen
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized comparative phase II trial evaluating the capacity of the dual combination doravirine/raltegravir to maintain virological success in HIV-1 infected patients with an HIV-RNA plasma viremia below 50 copies/mL under a current antiretroviral regimen
    A.3.2Name or abbreviated title of the trial where available
    DORAL
    A.4.1Sponsor's protocol code numberCREPATS10
    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 SponsorCentre de Recherche et d’Etudes sur la Pathologie Tropicale et le Sida (CREPATS)
    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 supportCREPATS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationpitie salpetriere hospital
    B.5.2Functional name of contact pointPr Christine KATLAMA
    B.5.3 Address:
    B.5.3.1Street Address47-83 boulevard de l’Hôpital, Pavillon Laveran
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75013
    B.5.3.4CountryFrance
    B.5.4Telephone number33142160142
    B.5.5Fax number33142160126
    B.5.6E-mailchristine.katlama@aphp.fr
    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 ISENTRESS
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    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 nameIsentress
    D.3.2Product code J05AX08
    D.3.4Pharmaceutical form 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.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 Pifeltro
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    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 namePifeltro
    D.3.2Product code J05AR24
    D.3.4Pharmaceutical form 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    HIV disease
    E.1.1.1Medical condition in easily understood language
    HIV disease
    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 LLT
    E.1.2Classification code 10020160
    E.1.2Term HIV disease
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the virological efficacy at week 48 of once daily doravirine plus raltegravir dual therapy in HIV-1-infected patients suppressed on ART
    E.2.2Secondary objectives of the trial
    • Virological efficacy of the doravirine plus raltegravir dual therapy
    • To assess the proportion of patients in therapeutic success up to week 48 and week 96
    • Resistance profile in case of virological failure
    • Evolution of CD4 and CD8 T-cells, and CD4/CD8 ratio
    • Clinical and biological tolerability of the doravirine plus raltegravir dual therapy
    • Quality of life questionnaire
    • Observance questionnaire
    • Evolution of HIV-reservoir (Whole blood will be collected at D0, W48 and W96)
    • Evolution of the inflammation markers (on frozen plasma/serum samples at D0, W48 and W96 (analysis not yet funded)
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Seminal sub-study dated 16/01/2020 version 1.0
    This sub-study will be proposed to 30 patients in order to evaluate at D0 and W48 the potential suppressive effect of the dual DOR/RAL regimen on the HIV-RNA seminal viral load and the minimal free and total concentrations (Cmin) of RAL and DOR in seminal and blood plasma.
    It is known that semen-to-plasma ratio of raltegravir concentrations > 1 indicate a good penetration of raltegravir in the seminal compartment (ANRS-163 ETRAL, Lê MP, and co. Pharmacotherapy 2019).
    No data were available for doravirine but the modest protein binding (approximately 76 %) is in favour of the good penetration of doravirine in anatomical compartments.
    Total sperm samples will be collected at home the day of the patient visit using the dedicated container delivered by the investigator during the previous visit and then transferred to the participating site within the 6 hours following sample collection.

    Cerebrospinal fluid sub-study dated 16/01/2020 version 1.0
    The aim of this sub study is to evaluate the maintenance of HIV viral suppression as well as changes in neuronal injury and inflammatory markers in cerebrospinal fluid (CSF) in a group of patients receiving a 3 drug-regimen and after switching to a Doravirine+Raltegravir.
    CSF will be taken at D0 and week 48. HIV-1 RNA in plasma and CSF will be determined by real-time PCR (LOQ < 40 copies/mL).
    Neuronal damage marker Neurofilament light chain (NFL) as well as inflammatory markers (STREM2 and YKL40) will be measured in CSF at baseline and week 48.
    E.3Principal inclusion criteria
    • Age ≥ 18 years
    • Patients with HIV-1 documented infection
    • CD4 ≥ 200/mm3
    • On stable combined ART regimen with at least 2 drugs for at least 6 months
    • HIV-RNA plasma VL ≤ 50 copies/mL during the last 12 months prior to screening visit (W-6/W-4), documented by at least 2 time-points with no more than one blip (defined as one HIV-RNA plasma VL between 51 and 200 copies/mL followed by one HIV-RNA plasma VL ≤ 50 copies/mL)
    • Naive to doravirine
    • Absence of resistance to doravirine* and/or raltegravir**(see list mutations below)
    - on all HIV-genotypes with available RT and integrase gene sequences allowing resistance interpretation in case of previous virological failure
    - or on DNA genotype performed at screening if HIV genotype is not available in case of prior virological failure.
    • Signed informed consent form.
    • Patient affiliated to a social insurance regimen. For French patients only: subject enrolled in or a beneficiary of a Social Security programme (State Medical Aid or AME is not a Social Security programme).

    *Mutations associated to doravirine resistance are: V106A/M, Y188L, G190E/S, M230L, F227C, at least 2 among: A98G, L100I, K101E, V106I, E138K, Y181C/V, G190A or H221Y
    .
    **Mutations associated to raltegravir resistance are: T66A/K, E92Q, G118R, F121Y, G140A/S Y143A/C/G/H/R/S, Q148E/G/H/K/R, V151L, N155H/S/T, E157Q, S230R, R263K, L74 F/I + V75I.
    E.4Principal exclusion criteria
    • Absence of RT and INI HIV sequence available (past genotypes or failure of amplification of DNA at screening)
    • HBV co-infection
    • Hemoglobin <9 g/dL
    • Platelets <80,000/mm3
    • Creatinine clearance <60 mL/min (MDRD)
    • AST or ALT ≥5N
    • Concomitant DAA for anti-HCV therapy
    • Any severe concomitant illness
    • Any drug with potential drug-drug interaction with doravirine
    • Concomitant treatment using interferon, interleukins or any other immune-therapy or chemotherapy
    • Concomitant prophylactic or curative treatment for an opportunistic infection
    • All conditions (use of alcohol, drugs, etc.) judged by the investigator to possibly interfere with trial protocol compliance, adherence and/or trial treatment tolerance
    • Subjects under "sauvegarde de justice" (judicial protection due to temporarily and slightly diminished mental or physical faculties), or under legal guardianship
    • Subjects participating in another clinical trial evaluating different therapies and including an exclusion period that is still in force during the screening phase
    • Pregnant women or breastfeeding women
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of patients with virological failure before or at week 48. Protocol virological failure is defined as two pVL>50 copies/mL two weeks apart.
    E.5.1.1Timepoint(s) of evaluation of this end point
    at week 48
    E.5.2Secondary end point(s)
    • Proportion of patients maintaining viral suppression (pVL <50 copies/mL, Snapshot approach)
    • Evolution of CD4 and CD8 T-cells, and CD4/CD8 ratio
    • Proportion of patients with virological blips (HIV-RNA pVL>50 copies/mL followed by a second measurement <50 copies/mL)
    • Resistance profile in case of protocol defined virological failure (PDVF)
    • Proportion of patients with acquired resistance mutation among those with PDVF
    • Frequency of grade 3 and 4 events
    • Quality of life assessed by self-questionnaire at screening, D0, W24, W48, W72, W96
    • Observance assessed by self-questionnaire at D0, W24, W48, W96
    • Evolution of total cell HIV-DNA in PBMC from D0 to W48 and W96
    • Evolution of inflammation markers from D0 to W48 and W96 (not yet funded)
    • To assess HIV-RNA viral load and Cmin (Minimal Drug Concentration) of doravirine/raltegravir at D0 and W48 in human male genital compartment (Seminal sub-study, 30 patients)
    • Evaluate the maintenance of HIV viral suppression as well as changes in neuronal injury and inflammatory markers in cerebrospinal fluid (CSF) at D0 and W48 (CSF sub-study, 15 patients included in the Spanish centers) (sub-study not yet funded)
    E.5.2.1Timepoint(s) of evaluation of this end point
    96 weeks
    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 No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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
    All patients who discontinue trial medication will be followed up and requested to attend for trial visits up until week 96, even if they stop taking trial medication.
    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 months36
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months36
    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: 150
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 state150
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 150
    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 end of the trial occurs when the last patient still being followed realizes the week 96 visits, abandons or withdraws consent plus 6 months. At the end of the trial (six months after the last visit of the last patient), for each participant, according to the trial results, the investigator will decide to maintain or change the trial treatment. The patients will be followed with the best clinical practices.
    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 Decision2020-07-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-06
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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