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    Summary
    EudraCT Number:2016-003248-34
    Sponsor's Protocol Code Number:IMPAACTP1110
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2016-11-02
    Trial results View 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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2016-003248-34
    A.3Full title of the trial
    A PHASE I TRIAL TO EVALUATE THE SAFETY AND PHARMACOKINETICS OF RALTEGRAVIR IN HIV-1-EXPOSED NEONATES AT HIGH RISK OF ACQUIRING HIV-1 INFECTION
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A PHASE I TRIAL TO EVALUATE THE SAFETY AND PHARMACOKINETICS OF RALTEGRAVIR
    A.3.2Name or abbreviated title of the trial where available
    A PHASE I TRIAL TO EVALUATE THE SAFETY AND PHARMACOKINETICS OF RALTEGRAVIR IN HIV-1-EXPOSED NEONATES
    A.4.1Sponsor's protocol code numberIMPAACTP1110
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01780831
    A.5.4Other Identifiers
    Name:Merck & Co., Inc. protocol code numberNumber:MK-0518-080
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/155/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNIAID and NICHD
    B.1.3.4CountryUnited States
    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 supportMerck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNational Institute of Allergy and Infectious Diseases, NIH
    B.5.2Functional name of contact pointRegulatory Affairs Branch
    B.5.3 Address:
    B.5.3.1Street Address5601 Fishers Lane, Room 9B30
    B.5.3.2Town/ cityRockville, Maryland
    B.5.3.3Post code20852
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1301 435 3737
    B.5.5Fax number+1240-627-3111
    B.5.6E-mailocpostoffice@niaid.nih.gov
    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 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 nameIsentress
    D.3.2Product code MK-0518
    D.3.4Pharmaceutical form Granules for oral suspension
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRaltegravir
    D.3.9.2Current sponsor codeMK-0518
    D.3.9.3Other descriptive nameRALTEGRAVIR POTASSIUM
    D.3.9.4EV Substance CodeSUB25668
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    New born babies at risk of acquiring HIV from their infected mothers.
    E.1.1.1Medical condition in easily understood language
    Babies at risk of acquiring HIV from their mothers.
    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 10053529
    E.1.2Term Vertical human immunodeficiency virus transmission
    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 safety and tolerability through 6 weeks of life of raltegravir oral granules for suspension when administered during the first 6 weeks of life with standard PMTCT ARV prophylaxis to infants exposed to HIV-1 assessed at risk of infection.
    - To evaluate the pharmacokinetics of raltegravir oral granules for suspension during the first 6 weeks of life along with standard PMTCT ARV prophylaxis.
    - To determine an appropriate dose of raltegravir oral granules for suspension for use in neonates and infants during the first 6 weeks of life.
    E.2.2Secondary objectives of the trial
    - To assess safety and tolerability of raltegravir oral granules for suspension through 24 weeks of life when administered during the first 6 weeks of life with standard PMTCT ARV prophylaxis to infants exposed to HIV-1 assessed at risk of infection.
    - To investigate the relationship between neonatal raltegravir elimination and UGT1A1 genotype and whether there is an association of UGT1A1 (*28/*28) and SLCO1B3 (rs2117032-C/T) with hyperbilirubinemia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Maternal Inclusion Criteria:
    • Mother is living with HIV and either i) known to have HIV diagnosis prior to labor (testing obtained and designated per local SOC in the medical record and either on or recently started CART prior to delivery) or ii) identified as having HIV diagnosis at the time of labor or in the immediate postpartum period. More information on this criterion can be found in the protocol.
    • Risk of mothers transmitting HIV to their infants:
    - Cohort 1 and Cohort 2 (RAL-naive): Mother living with HIV is at "high risk" of transmitting HIV to infant as evidenced by any of the following: Mother has not received any ARV therapy during the current pregnancy prior to the onset of labor and delivery; HIV RNA level greater than 1000 copies/mL within 4 weeks (28 days) prior to delivery; receipt of ARV for less than 4 weeks (28 days) before delivery; on ARVs for 4 weeks or longer but has not taken any ARV for more than 7 days prior to delivery; or mother has documented drug resistant virus to at least one class of ARV drugs.
    - Cohort 2 RAL-exposed: there was no requirement that the mother living with HIV is at "high-risk" of transmitting HIV to her infant.
    • Maternal written informed consent for study participation

    Infant Inclusion Criteria:
    • Age at enrollment (Note: The full-term infants were HIV-exposed and may have received standard of care ARV prophylaxis/treatment before enrollment):
    - Cohort 1 and Cohort 2 RAL-naive: Aged 48 hours or less.
    - Cohort 2 RAL-exposed: Aged 60 hours or less.
    • Infant gestational age at birth at least 37 weeks
    • No known severe congenital malformation or other medical condition not compatible with life or that would interfere with study participation or interpretation, as judged by the examining clinician
    • Birth weight at least 2 kg
    • Able to take oral medications
    • Parent or legal guardian able and willing to provide signed informed consent
    • For Cohort 1 and Cohort 2 RAL-exposed groups:
    - Cohort 1 RAL-exposed: Infants born to mothers who received RAL during pregnancy with last dose taken within 7 days before delivery.
    - Cohort 2 RAL-exposed: Infants born to a mother who received at least one dose of RAL within 2 to 24 hours prior to delivery.
    E.4Principal exclusion criteria
    Maternal Exclusion Criteria:
    • Known maternal-fetal blood group incompatibility as evidenced by the presence of an unexpected clinically significant maternal red cell antibody that is known to be capable of causing hemolytic disease of the fetus/newborn
    • Mother will be receiving RAL as part of her combination antiretroviral (cART) regimen after delivery and intending to breastfeed her infant
    • For Cohort 1 and Cohort 2 RAL-naive groups:
    - Cohort 1 RAL-naive: Mother who received RAL prior to and through delivery unless last RAL dosing during prenatal period was >7 days prior to delivery
    - Cohort 2 RAL-naive: Mother who received RAL prior to and through delivery

    Infant Exclusion Criteria:
    • Infant with bilirubin exceeding the American Academy of Pediatrics guidelines for phototherapy, using the infant's gestational age and risk factors as described in the protocol.
    • Clinical evidence of renal disease such as edema, ascites, or encephalopathy.
    • Receipt of disallowed medications (phenytoin, phenobarbital, or rifampin).
    E.5 End points
    E.5.1Primary end point(s)
    1. Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 6 Weeks of Life
    2. AUC24 for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth)
    3. Cmax for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth)
    4. AUC24 for Cohort 2 Initial RAL Dose (Within 48 and 12-60 Hours of Birth for RAL-naive and RAL-exposed Groups, Respectively)
    5. Clast for Cohort 2 Initial RAL Dose (Within 48 and Between 12-60 Hours of Birth for RAL-naïve and RAL-exposed Groups, Respectively)
    6. RAL AUC12 for Cohort 2 at 15-18 Days of Life
    7. RAL C12 for Cohort 2 at 15-18 Days of Life
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. From first dosing of RAL through 6 weeks of life
    2. and 3. Cohort 1 RAL dose #1 (within 48 hours of birth) intensive PK sampling: within 30 min pre-dose; and 1-2, 4-8, 12 (±1), 24 (±1) hours post-dose.
    4. and 5. Cohort 2 initial dose (within 48 and between 12-60 hours of birth for RAL-naive and RAL-exposed, respectively) intensive PK sampling: within 1 hour pre-dose; and 1-2, 6-10, 20-24 hours post-dose.
    6. and 7. Intensive PK sampling for Cohort 2 at 15-18 days of life: within 1 hour pre-dose; and 1-2, 4-6, 8-12 hours post-dose.

    E.5.2Secondary end point(s)
    1. Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 24 Weeks of Life
    2. Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 6 Weeks of Life
    3. Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 24 Weeks of Life
    4. Cohort 1 Dose #1 Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group
    5. Cohort 2 Initial Dose Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group
    6. Cohort 2 Neonatal RAL Elimination (CL/F) at 15-18 Days of Life by UGT1A1 Genotype Group
    7. Number of Cohort 1 Infants With Hyperbilirubinemia by UGT1A1 Genotype
    8. Number of Cohort 2 Infants With Hyperbilirubinemia by UGT1A1 Genotype
    9. Number of Cohort 1 Infants With Hyperbilirubinemia by SLCO1B3 Genotype
    10. Number of Cohort 2 Infants With Hyperbilirubinemia by SLCO1B3 Genotype
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. and 3. From first RAL dose through 24 weeks of life
    2. From first RAL dose through 6 weeks of life
    4. Cohort 1 Dose #1 Intensive PK sampling: within 30 min pre-dose; and 1-2, 4-8, 12, 24 h post-dose
    5. Intensive PK sampling - Cohort 2 initial dose: within 1 h pre-dose; and 1-2, 6-10, 20-24 h post-dose
    6. Intensive PK sampling - Cohort 2 at 15-18 days of life: within 1 h pre-dose; and 1-2 h post-dose, 4-6, 8-12 h post-dose
    7. and 9. Specimens for bilirubin testing collected at study entry; Days 3-4, 7-10 of life; and Weeks 2, 6, 24 of life for Cohort 1
    8. and 10. Specimens for bilirubin testing collected at study entry; after 2nd dose; Days 6-9, 15-18, 28-32 of life; and Weeks 5-6, 8-10, 24 of life for Cohort 2
    4. to 10. Specimen for genotype testing collected at study entry
    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 Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study Yes
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    safety and pharmacokinetic
    E.7.2Therapeutic exploratory (Phase II) No
    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 No
    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 trial1
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    Brazil
    South Africa
    Thailand
    United States
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 52
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 52
    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) No
    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 No
    F.3.3Specific vulnerable populations Yes
    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 Yes
    F.3.3.4Nursing women Yes
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Neonates
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 52
    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)
    No need for care after subjects completed study participation.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation IMPAACT
    G.4.3.4Network Country United States
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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