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    Summary
    EudraCT Number:2015-000727-85
    Sponsor's Protocol Code Number:GS-US-104-0321
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2015-02-18
    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 number2015-000727-85
    A.3Full title of the trial
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Tenofovir DF as Part of an Optimized Antiretroviral Regimen in HIV-1-Infected Adolescents
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of Tenofovir DF as a part of treatment in HIV-1 Infected Adolescents
    A.4.1Sponsor's protocol code numberGS-US-104-0321
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00352053
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/018/2013
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGilead Sciences, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGilead Sciences, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGilead Sciences International Ltd.
    B.5.2Functional name of contact pointClinical Trials Mailbox
    B.5.3 Address:
    B.5.3.1Street AddressGranta Park
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeCB21 6GT
    B.5.3.4CountryUnited Kingdom
    B.5.5Fax number+441223897 284
    B.5.6E-mailclinicaltrials@gilead.com
    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 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 nameTenofovir disoproxil fumarate
    D.3.2Product code TDF
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    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 INNTENOFOVIR
    D.3.9.1CAS number 147127-20-6
    D.3.9.4EV Substance CodeSUB04721MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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 Yes
    D.3.11.13.1Other medicinal product typeAntiviral
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral 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-1 infection
    E.1.1.1Medical condition in easily understood language
    Human Immunodeficiency Virus infection
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10020192
    E.1.2Term HIV-1
    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
    The primary objective of this study was as follows:
    -To assess the efficacy of tenofovir DF plus a genotype-guided optimized background regimen (OBR) compared to placebo plus OBR in the treatment of HIV-1 infected antiretroviral treatment-experienced adolescents with plasma HIV-1 ribonucleic acid (RNA) levels ≥ 1000 copies/mL through 24 weeks of drug exposure.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are as follows:
    - To assess the efficacy of tenofovir DF plus a genotype-guided optimized background regimen (OBR) compared to placebo plus OBR in the treatment of HIV-1 infected antiretroviral treatment-experienced adolescents with plasma HIV-1 RNA levels ≥ 1000 copies/mL through 48 weeks of drug exposure.
    - To evaluate the safety and tolerability of tenofovir DF plus OBR compared to placebo plus OBR.
    - To measure changes in bone mineral density (BMD) in the two treatment arms.
    - To evaluate the long-term efficacy, safety, and tolerability of treatment with tenofovir DF through up to 336 weeks of drug exposure.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetic Substudy
    Patients receiving open-label tenofovir DF at selected sites will participate in a substudy to measure the steady state pharmacokinetics of tenofovir. Patients participating in the open-label extension may also be eligible for the substudy. The substudy will include an intensive PK profile, 4 weeks after starting open-label tenofovir DF. Specimens will be drawn over a period of 12 hours; 0, 1, 2, 4, 8, and 12 hours postdosing.
    E.3Principal inclusion criteria
    Chronic HIV-1 infected patients must meet all of the following inclusion criteria to be
    eligible for participation in this study;
    • Male or female
    • 12 years to < 18 years of age (consent of parent or guardian required)
    • Weight ≥ 35 kg
    • Able to swallow oral pills
    • Documented laboratory diagnosis of HIV infection (if no record exists, must be tested at
    screening visit)
    • Plasma HIV-1 RNA ≥ 1000 copies/mL
    • Prior antiretroviral treatment experience with at least 2 antiretroviral drug classes (Treatment with an agent is defined as > 8 weeks.)
    • Currently receiving combination antiretroviral therapy for at least 12 weeks
    • Naive to tenofovir DF
    • Absence of K65R mutation on genotypic testing
    • Ability to construct an optimized background regimen, not containing didanosine, based on resistance testing
    • Hepatic transaminases (AST and ALT) ≤ 3 × upper limit of normal (ULN)
    • Adequate hematologic function (absolute neutrophil count ≥ 750/mm3; platelets ≥ 75,000/mm3; hemoglobin ≥ 8.0 g/dL)
    • Serum amylase < 1.5 × ULN (patients with serum amylase ≥ 1.5 × ULN will remain eligible if serum lipase is ≤ 1.5 × ULN)
    • Adequate renal function
    • Estimated glomerular filtration rate ≥ 80 mL/min/1.73m2
    • Negative serum pregnancy test (females of child-bearing potential
    • Females of childbearing potential must agree to utilize highly effective contraception methods (two separate forms of contraception, one of which must be an effective barrier method, or be non-heterosexually active, practice sexual abstinence or have a vasectomized partner) from screening throughout the duration of study treatment and for 30 days following the last dose of study drug.
    • Male subjects must agree to utilize a highly effective method of contraception during heterosexual intercourse throughout the study period and for 30 days following discontinuation of investigational medicinal product. A highly effective method of contraception is defined as two separate forms of contraception, one of which must be an effective barrier method, or male subjects must be non-heterosexually active, practice sexual abstinence, or be vasectomized.
    • Parent or guardian able to give written informed consent prior to any screening evaluations and willing to comply with study requirements

    Inclusion Criteria for First 96-Week Open-Label Extension
    • Completed 48 weeks of treatment with study drug
    • Continues to be < 18 years of age (consent of parent or guardian required) at the start of participation in the extension

    Inclusion Criteria for Second 96-Week Open-Label Extension
    • Completed 144 weeks of treatment with study drug
    • Continues to be < 18 years of age (consent of parent or guardian required) at the start of participation in the extension

    Inclusion Criteria for Third 96-Week Open-Label Extension
    • Completed 240 weeks of treatment with study drug
    • Continues to be < 18 years of age (consent of parent or guardian required) at the start of participation in the extension
    E.4Principal exclusion criteria
    Patients who meet any of the following exclusion criteria are not to be enrolled in this study.
    • Patients requiring didanosine in background regimen
    • Patients needing ongoing therapy with any of the following:
    - Nephrotoxic agents
    • Aminoglycoside antibiotics
    • Cidofovir
    • Cisplatin
    • Foscarnet
    • IV amphotericin B
    • Voriconazole
    • IV pentamidine
    • IV vancomycin
    • Oral or IV ganciclovir
    • Probenecid
    -Systemic chemotherapeutic agents
    -Systemic corticosteroids
    -Interleukin-2 (IL-2) and other immunomodulating agents
    -Investigational agents (except with the expressed approval of the Sponsor) Administration of any of the above medications must be discontinued at least 30 days prior to the Baseline Visit and for the duration of the study period.
    • Any medication that is contraindicated with any antiretroviral within an OBR.
    • Pregnant or lactating patients
    • Evidence of a gastrointestinal malabsorption syndrome or chronic nausea or vomiting which may confer an inability to receive an orally administered medication
    • Current alcohol or substance abuse judged by the investigator to potentially interfere with patient compliance
    • Malignancy other than cutaneous Kaposi’s sarcoma (KS) or basal cell carcinoma. Patients with biopsy-confirmed cutaneous KS are eligible, but must not have received any systemic therapy for KS within 30 days of baseline and are not anticipated to require systemic therapy during the study
    • Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic therapy within 15 days prior to screening
    • Prior history of significant renal disease (i.e., nephrotic syndrome, renal dysgenesis, polycystic kidney disease, congenital nephrosis)
    • Prior history of significant bone disease (i.e., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, osteochondroses, multiple bone fractures)
    • Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for study or unable to comply with the dosing requirements
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is time-weighted average change from baseline through Week 24 (DAVG24) in plasma HIV-1 RNA.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline to 24 Weeks
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints in this study include:
    • The time-weighted average change from baseline through Week 48 (DAVG48) in plasma HIV-1 RNA
    • The proportion of patients achieving a HIV-1 RNA decrease of ≥ 1.0 log10 copies/mL
    • The proportion of patients with HIV-1 RNA < 400 copies/mL and < 50 copies/mL
    • Time to virologic failure up to the end of double-blind phase
    • Change from baseline in HIV-1 RNA
    • Change from baseline in CD4 cell count and CD4%
    E.5.2.1Timepoint(s) of evaluation of this end point
    At Week 24, Week 48, Week 96,Week 144, Week 192, Week 240, Week 288 and Week 336
    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 Yes
    E.6.6Pharmacokinetic Yes
    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) Yes
    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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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
    Panama
    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
    For those study patients who complete 336 weeks on study as outlined in the protocol, Gilead will provide tenofovir DF until a) the patient’s 18th birthday; or b) tenofovir DF receives marketing approval for pediatric patients in the country in which the patient is enrolled (Brazil, Panama, or the US); or c) Gilead is no longer the exclusive seller of tenofovir DF in the country in which the patient is enrolled (Brazil, Panama, or the US), whichever comes first.

    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days6
    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: 100
    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.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 81
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    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 Yes
    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.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 100
    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)
    For those study patients who complete 336 weeks on study as outlined in the protocol, Gilead will provide tenofovir DF until a) the patient’s 18th birthday; or b) tenofovir DF receives marketing approval for pediatric patients in the country in which the patient is enrolled (Brazil, Panama, or the US); or c) Gilead is no longer the exclusive seller of tenofovir DF in the country in which the patient is enrolled (Brazil, Panama, or the US), whichever comes first.
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
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