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    Summary
    EudraCT Number:2019-004195-19
    Sponsor's Protocol Code Number:DORAL
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-05-19
    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 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.
    Studio comparativo randomizzato di fase II che valuta la capacità della combinazione doravirina/raltegravir nel mantenere il successo virologico in pazienti infetti da virus HIV-1 con una viremia plasmatica HIV-RNA inferiore a 50 copie/mL in terapia antiretrovirale.
    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.
    Studio comparativo randomizzato di fase II che valuta la capacità della combinazione doravirina/raltegravir nel mantenere il successo virologico in pazienti infetti da virus HIV-1 con una viremia plasmatica HIV-RNA inferiore a 50 copie/mL in terapia antiretrovirale.
    A.3.2Name or abbreviated title of the trial where available
    DORAL
    DORAL
    A.4.1Sponsor's protocol code numberDORAL
    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 Tropical 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 supportCentre de Recherche et d’Etudes sur la Pathologie Tropical et le Sida (CREPATS)
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIRCCS SAN RAFFAELE HOSPITAL
    B.5.2Functional name of contact pointANTONELLA CASTAGNA
    B.5.3 Address:
    B.5.3.1Street AddressVIA STAMIRA D'ANCONA, 20
    B.5.3.2Town/ cityMILAN
    B.5.3.3Post code20127
    B.5.3.4CountryItaly
    B.5.4Telephone number+390226437934
    B.5.6E-mailcastagna.antonella1@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 PIFELTRO
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 (DORAVIRINA)
    D.3.2Product code MK-1439
    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.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 ISENTRESS
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme Limited
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 (RALTEGRAVIR)
    D.3.2Product code MK-0518
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    HIV-1 INFECTION
    INFEZIONE DA HIV-1
    E.1.1.1Medical condition in easily understood language
    HIV-1 VIRUS INFECTION
    INFEZIONE DA VIRUS HIV-1
    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 evaluate the virological efficacy at week 48 of once daily doravirine plus
    raltegravir dual therapy in HIV-1-infected patients suppressed on ART
    Valutare l'efficacia virologica alla settimana 48 di una dual therapy una volta al giorno con doravirina/raltegravir in pazienti affetti da HIV-1 soppressi e in ART
    E.2.2Secondary objectives of the trial
    To evaluate over 96 weeks:
    • 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)
    Valutare alla settimana 96:
    - L’Efficacia virologica della dual therapy con doravirina/raltegravir
    - La percentuale di pazienti con successo terapeutico alla settimana 48 e settimana 96
    - Il Profilo di resistenza in caso di fallimento virologico
    - l’Evoluzione delle cellule T CD4 e CD8 e il rapporto CD4/CD8
    - la Tollerabilità clinica e biologica della dual therapy doravirina/raltegravir
    - il Questionario sulla qualità della vita
    - il Questionario di osservazione
    - l’Evoluzione del serbatoio dell'HIV (il sangue intero sarà raccolto ai seguenti time-points D0, W48 e W96)
    E.2.3Trial contains a sub-study No
    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
    - Età ≥ 18 anni
    - Pazienti con infezione da HIV-1 documentata
    - CD4 ≥ 200/mm3
    - In regime stabile di ART combinata con almeno 2 farmaci per almeno 6 mesi
    - Plasma HIV-RNA VL ≤ 50 copie/mL negli ultimi 12 mesi prima di visita di screening (W-6/W-4), documentata da almeno 2 punti temporali con non più di un blip (definito come un plasma HIV-RNA VL tra 51 e 200 copie/ml seguite da un plasma HIV-RNA VL ≤ 50 copie/ml)
    - Naive a doravirina
    - Assenza di resistenza alla doravirina* e/o al raltegravir**(vedi elenco mutazioni sotto)
    - su tutti i genotipi di HIV con disponibilità di sequenze di geni RT e integrase
    - o sul genotipo eseguito al momento dello screening se il genotipo dell'HIV non è
    disponibile in caso di precedente insuccesso virologico.
    - modulo di consenso informato firmato

    **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 immunetherapy
    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
    - Assenza di una sequenza genotipica di RT e INI disponibile
    - Coinfezione HBV
    - Emoglobina <9 g/dL
    - Piastrine <80.000/mm3
    - Clearance della creatinina <60 mL/min (MDRD)
    - AST o ALT ≥5N
    - concomitante DAA per la terapia anti-HCV
    - Qualsiasi grave malattia concomitante
    - Qualsiasi farmaco con potenziale interazione con la doravirina
    - Trattamento concomitante con interferone, interleuchine o qualsiasi altra immunoterapia
    o chemioterapia
    - Trattamento profilattico o curativo concomitante per infezione opportunistica
    - Tutte le condizioni (uso di alcol, droghe, ecc.) giudicate dall'investigatore come interferenti con il trattamento del protocollo
    - Soggetti sotto tutela giudiziaria
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is 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
    Valutare la percentuale di pazienti con fallimento virologico prima o alla settimana 48.
    E.5.1.1Timepoint(s) of evaluation of this end point
    WEEK 48
    SETTIMANA 48
    E.5.2Secondary end point(s)
    To evaluate over 96 weeks:
    • 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
    -percentuale di pazienti che mantengono la soppressione virale (pVL<50 copie/mL, approccio istantaneo)
    -percentuale di pazienti con blip virologici
    -evoluzione delle cellule T CD4 e CD8 e rapporto CD4/CD8
    -profilo di resistenza in caso di fallimento virologico definito dal protocollo (PDVF)
    -percentuale di pazienti con mutazione di resistenza acquisita tra quelli con PDVF
    -frequenza degli avventi avversi di grado 3 e 4
    -qualità della vita valutata dall’auto-questionario
    -aderenza/osservanza valutata dall’auto-questionario
    E.5.2.1Timepoint(s) of evaluation of this end point
    WEEK 96
    SETTIMANA 96
    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 No
    E.6.4Safety No
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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 No
    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
    LVLP
    ULTIMA VISITA DELL'ULTIMO PAZIENTE
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 150
    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)
    NONE
    NESSUNO AL MOMENTO
    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 Decision2020-07-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-11-12
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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