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    Summary
    EudraCT Number:2017-002837-48
    Sponsor's Protocol Code Number:HEAL-1-v1.5
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-07-24
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-002837-48
    A.3Full title of the trial
    HIV Eradication by combining Agents to reverse Latency in vivo (HEAL-1): a randomized controlled trial.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study on HIV eradication by using medicines together.
    A.3.2Name or abbreviated title of the trial where available
    HEAL-1
    A.4.1Sponsor's protocol code numberHEAL-1-v1.5
    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 SponsorErasmus MC
    B.1.3.4CountryNetherlands
    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 supportErasmus MC
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC
    B.5.2Functional name of contact pointCasper Rokx
    B.5.3 Address:
    B.5.3.1Street AddressWytemaweg 80
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015CN
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+310681336328
    B.5.6E-mailc.rokx@erasmusmc.nl
    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 Valproic acid
    D.2.1.1.2Name of the Marketing Authorisation holdersanofi-aventis
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameValproic acid
    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 Pyrimethamine
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 namepyrimethamine
    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
    Adults with human immunodeficiency virus type-1 infection on antiretroviral treatment with adequate viral suppression and good cellular immunity.
    E.1.1.1Medical condition in easily understood language
    HIV patients on treatment without signs of AIDS.
    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 longitudinally assess the effects by pyrimethamine and valproic acid on the HIV reservoir in HIV infected patients on antiretroviral therapy.
    E.2.2Secondary objectives of the trial
    1. The evaluation of the in vivo and ex vivo anti-HIV latency capacities of pyrimethamine and valproic acid.
    2. The evaluation of the in vivo effects pyrimethamine and valproic acid on the functionality and phenotype of the immune system.
    3. Explore biomarkers of, and correlations between, the reactivation capacities of pyrimethamine and valproic acid ex vivo and in vivo.
    4. The clinical safety and tolerability of administered compounds.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. HIV-1 infected patients ≥18 years.
    2. WHO performance status 0 or 1.
    3. Confirmed HIV-1 infection by 4th generation ELISA, Western Blot or PCR.
    4. Wild type HIV infection or polymorphisms associated with at highest low-level resistance to any class of ART according to Stanford HIV drug resistance database.
    5. On cART.
    6. Current plasma HIV-RNA <50 copies/mL for at least 365 days and measured on at least 2 occasions of which at least 1 must be obtained within 365 and 90 days prior to study entry.
    7. Current CD4 count at study entry of ≥200 cells/mm3.
    8. Pre-cART HIV-RNA ≥10.000 copies/mL.
    9. Pre-cART HIV-RNA ≥10.000 copies/mL.
    E.4Principal exclusion criteria
    1. Previous virological failure, defined as either acquired resistance mutations on cART or HIV-RNA >1000 copies/mL twice during cART.
    2. Uncontrolled hepatitis B or C co-infection.
    3. Prior exposure to any HDACi, BAFi or other known LRA.
    4. Prior exposure to cytotoxic chemotherapy during cART.
    5. Concurrent exposure to strong interacting medication on glucuronidation.
    6. Exposure within 90 days prior to study entry to immunomodulators, cytokines, systemic antifungals, dexamethasone, vitamin K antagonists, anti-epileptics, antipsychotica, carbapenems, mefloquine, colestyramine, Any documented opportunistic infection related to HIV in the last 90 days.
    7. Inadequate blood counts, renal and hepatic function tests
    a. Haemoglobin <6.5 mmol/L (males) or <6.0 mmol/L (females), leucocytes <2.5 x109/L, absolute neutrophil count <1000 cells/mm3, thrombocytes <100 x109/L, international standardized ratio >1.6, activated partial thromboplastin time >40 seconds.
    b. Estimated glomerular filtration rate <50 mL/min (CKD-EPI),
    c. ALAT or total bilirubin >2.5x upper limit of normal.
    d. All laboratory values must be obtained within 42 days prior to the baseline visit.
    8. Megaloblastic anemia due to folate deficiency.
    9. Pancreatitis in last 6 months, or chronic pancreatitis.
    10. Active malignancy during the past year with the exception of basal carcinoma of the skin, stage 0 cervical carcinoma, Kaposi Sarcoma treated with cART alone, or other indolent malignancies.
    11. Females in the reproductive age cannot participate. Males cannot participate if they refuse to abstain from sex or condom use in serodiscordant sexual contact during the study.
    12. Patients with active substance abuse or registered allergies to the investigational medical products.
    Last, any other condition (familial, psychological, sociological, geographical) which in the investigator’s opinion poses an unacceptable risk or would hamper compliance with the study protocol and follow up schedule, will prohibit participation.
    E.5 End points
    E.5.1Primary end point(s)
    The change in reservoir size in vivo at treatment initiation week 0 and at the end of treatment week 6 measured as the number of CD4 T-cells with multiply spliced HIV-RNA with nested PCR based tat/rev induced limiting dilution assay (TILDA, Procopio et al. EBiomedicine 2016). The change in reservoir size is compared between the treatment arms.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 0, week 2 and week 6.
    E.5.2Secondary end point(s)
    The secondary endpoints are exploratory.
    2.1 The change in reservoir size in vivo at treatment initiation week 0, at the end of treatment week 2, and at the end of the study week 6, measured with TILDA. The change in reservoir size is compared within and between the treatment arms.
    2.2 Potential synergism or additive effects of the administration of both drugs will be assessed.
    2.3 The change in cell-free HIV-RNA as measured by routine PCR and single copy assay, cell associated HIV-RNA, and cell-associated HIV-DNA at week 0, week 2 and week 6 within and between the treatment arms.
    2.4 The change in the level of histone acetylation and expression of BAF subunits at the RNA and at the protein level at week 0, week 2 and week 6 within and between the treatment arms.
    2.5 The change of the functionality and phenotype of innate immune cells, HIV specific CD4+ and CD8+ T cells and HIV specific B-cells using proliferation assays, flow cytometry, cytokine and cytotoxicity analysis at week 0, week 2 and week 6 within and between the treatment arms.
    2.6 Explore and correlate clinical and markers of the viral reservoir (HIV-DNA, HIV-RNA), immune function and phenotype, and the level of acetylation/BAF expression with the change in reservoir size (TILDA) within and between the treatment arms.
    2.7 Correlate the latency reversal activity with pyrimethamine and valproic acid in vitro in cell line based HIV latency models, in primary CD4 T cells ex vivo, and in vivo with TILDA, HIV-RNA, HIV-DNA and the level of acetylation/BAF expression.
    2.8 Number and percentage of clinical and biochemical AE according to the latest version of the Common Toxicity Criteria.
    2.9 Number and percentage of patients with HIV-1 RNA level greater than or equal to 20, 50 and 200 c/mL at week 0, week 2 and week 6 within and between the treatment arms.
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 0, week 2 and week 6.
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    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
    LVLS.
    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 months0
    E.8.9.1In the Member State concerned days0
    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: 28
    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 state28
    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)
    Patients wil return to their own HIV treating physician and resume their normal treatment.
    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 Decision2017-10-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-22
    P. End of Trial
    P.End of Trial StatusOngoing
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