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    Summary
    EudraCT Number:2007-004392-19
    Sponsor's Protocol Code Number:A5271022
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-03-19
    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
    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 number2007-004392-19
    A.3Full title of the trial
    A PHASE 2B MULTICENTER, RANDOMIZED, COMPARATIVE TRIAL OF UK-453,061 VERSUS ETRAVIRINE IN COMBINATION WITH DARUNAVIR/RITONAVIR AND A NUCLEOTIDE/NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR FOR THE TREATMENT OF ANTIRETROVIRAL EXPERIENCED HIV-1 INFECTED SUBJECTS WITH EVIDENCE OF NNRTI RESISTANT HIV-1
    A.4.1Sponsor's protocol code numberA5271022
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPfizer 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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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.3.2Product code UK-453,061
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 473921-12-9
    D.3.9.3Other descriptive name5-[[3,5-diethyl-1-(2-hydroxyethyl) -1H-pyrazol-4-yl]oxy]-1,3- benzenedicarbonitrile
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 RoleComparator
    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 Intelence
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International NV
    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 nameIntelence
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNetravirine
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    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
    HIV Infection
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10020161
    E.1.2Term HIV infection
    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 is to assess the efficacy of UK-453,061 when used in combination with darunavir/ritonavir and an optimized NRTI for the treatment of subjects with prior NNRTI use and documented evidence of NNRTI resistance associated mutations. Efficacy will be measured by the percentage of subjects with HIV-1 RNA <48 copies/mL at 24 weeks.
    E.2.2Secondary objectives of the trial
    • To assess efficacy as measured by percentage of subjects with HIV-1 RNA <48 copies/mL at 48 and 96 weeks.
    • To assess efficacy as measured by percentage of subjects with HIV-1 RNA <400 copies/mL.
    • To assess efficacy as measured by change from baseline in log10 transformed HIV 1 RNAlevels.
    • To assess the pharmacokinetics (PK) and pharmacokinetic/pharmacodynamic (PK/PD) relationship of UK-453,061.
    • To assess pharmacokinetic parameters of UK-453,061 AUC24, Cmax and C24h (PK sub-study).
    • To assess safety and tolerability of UK-453,061.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    There is a PK sub-study written within the same protocol (A5271022). To assess pharmacokinetic parameters of UK-453,061 AUC24, C max and C24h.
    E.3Principal inclusion criteria
    Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial:
    1. Evidence of a signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
    2. Male or female at least 18 years of age available for a follow-up period of at least 96 weeks.
    3. HIV-1 RNA viral load of ≥1,000 copies/mL measured by the Roche COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 test at the screening visit.
    4. Virologically failed a single NNRTI-based regimen with documented evidence of
    NNRTI resistance mutations at screening or on historical genotype. Subjects may have PI experience/resistance.
    5. Negative urine pregnancy test at the Day 1 visit, prior to receiving the first dose of study medication, for Women of Child Bearing Potential (WOCBP).
    NOTE: WOCBP includes any female who has experienced menarche and who has not
    undergone successful surgical sterilization or is not post-menopausal (ie, no menstrual periods for at least 2 years). Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products (intrauterine devices; barrier methods: eg, condom or diaphragm with spermicide) to prevent pregnancy, who are practicing abstinence, or who have a partner that is sterile (eg, vasectomy), should be considered to be of child bearing potential.
    6. Effective barrier contraception for WOCBP and males. In addition, WOCBP must use another acceptable method of contraception for the duration of the study and for 28 days after leaving the study. Acceptable contraception includes, but is not limited to oral, implanted or injectable hormone therapy and intrauterine devices.
    7. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
    E.4Principal exclusion criteria
    Subjects presenting with any of the following will not be included in the trial:
    1.Suspected or documented active,untreated HIV1 related opportunistic infection or other condition requiring acute therapy at the time of randomization.Subjects on a stable(>30days)secondaryOI prophylaxis regimen or chronic treatment are eligible for the study,as are subjects on a primary OI prophylaxis regimen of any duration,except Trimethoprim-sulfamethoxazole.Subjects on primar,secondary prophylaxis and therapy with Trimethoprim-sulfamethoxazole must be on therapy >60 days
    2.On therapy for Hepatitis B.
    3.Acute hepatitis B and/or C within 30 days of randomization.
    4.Hepatitis C, on therapy with interferon and/or ribavirin for <60 days.
    5.Absolute CD4+ cell count <200 cells/mm3.
    6.Lack of prior use of a NNRTI, even if the current or historical HIV-1 genotype exhibits resistance to NNRTIs.
    7.Previous use of darunavir or etravirine.
    8.Inability to use an active NRTI based on resistance testing and treatment history.
    9.Previous use of CCR5 antagonists, fusion inhibitors or integrase inhibitors for greater than 14 days cumulatively.
    10.Lactating (if female), or planned pregnancy during the trial period.
    11.Suspected acute HIV 1 infection.
    12.Initiation of therapy with a potentially myelosuppressive, neurotoxic, hepatotoxic and/or cytotoxic agent within 60 days prior to randomization or the expected need for such therapy during the study period.
    13.Malignancy requiring parenteral chemotherapy that must be continued for the duration of the trial.
    14.Documented or suspected pancreatitis within 30 days prior to randomization.
    15.Renal insufficiency defined as a serum creatinine greater than 3 times the upper limit of normal
    16.Total bilirubin ≥1.5 times the upper limit of normal.
    17.AST and/or ALT >3 times the upper limit of normal.
    18.Males with a baseline QT interval of 450 msec or female with a baseline QT of >470 msec.
    19.Presence of risk factors for prolongation of QT interval including heart failure, chronic hypokalemia, family history of long QT syndrome, concomitant use of medications that are known to prolong QT interval.
    20.Cardiac events(MI,bypass surgery, angioplasty) within 6 months of randomization.
    21.Cirrhosis of the liver.
    22.Absolute neutrophil count ≤750 cells/mm3.
    23.Platelet count ≤50,000 cells/mm3.
    24.Hemoglobin ≤7 g/dL.
    25.Presence of gross hematuria or grade 4 proteinuria at the time of screening.
    26.Inability to tolerate oral medication.
    27.Concomitant therapy with other investigational agents within 30 days prior to the enrollment into the study.
    28.Use of the following CYP3A4/UGT inhibitors/inducers/substrates are prohibited within 14 days of randomization:barbiturates(eg,phenobarbital),carbamazepine, oxycarbazepine,phenytoin,glucocorticoids(short-term[≤14 days]burst therapy will be allowed],rifampin/rifampicin,rifabutin,St.John’s Wort,voriconazole,ketoconazole, itraconazole, astemizole,terfanadine,sertindole,ergot derivatives,midazolam, triazolam,bepridil,cisapride, pimozide,clarithromycin,nefazadone,alfuzosin,amiodarone,flecainide,propafenone, quinidine,lovastatin,
    simvastatin and elithromycin. Prohibited medications must be discontinued at least 14 days prior to randomization.
    29.Contraindicated medications being taken at the time of randomization that must be continued during the study period, including immunomodulators for the treatment of HIV 1 infection (interferon for the ongoing treatment of hepatitis C infection is permitted, if the subject has been on it for >60 days see exclusion#4). Subjects diagnosed with hepatitis C may be treated for hepatitis C during the study if deemed necessary by the subject’s physician.
    30. Presence of resistance associated with etravirine, or UK-453,061 as listed below:
    •The presence of 3 or greater NNRTI-associated resistance mutations;
    •>5-fold change in the UK-453,061 IC50 compared to that of the reference virus on phenotypic testing;
    •Phenotypic resistance to etravirine, as defined by >2.9 fold change based on Monogram PhenoSense™ assay;
    •Potential UK-453,061 associated mutations: K101E, V108I, E138K, Y188L, G190E/Q, F227C/L, L234I, L100I+K103N;
    31.Presence of the following NRTI associated mutations:T69 insertion, Q151 complex.
    32.Evidence of either genotypic or phenotypic resistance to darunavir/ritonavir as determined by the Monogram Bioscience PhenoSense GTTM assay
    33.Any safety, behavioral, clinical, or administrative reasons that, in the Investigator’s judgment, would potentially compromise study compliance.
    34.Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective is to assess the efficacy of UK-453,061 when used in combination with darunavir/ritonavir and an optimized NRTI for the treatment of subjects with prior NNRTI use and documented evidence of NNRTI resistance associated mutations. Efficacy will be measured by the percentage of subjects with HIV-1 RNA <48 copies/mL at 24 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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Matched placebo for UK453061 dose. NRTI, darunavir/ritonavir, & etravirine will be open-label.
    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.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    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 EEA24
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months31
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months31
    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 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 75
    F.4.2.2In the whole clinical trial 189
    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)
    See Protocol section 5.7 Rescue Therapy.
    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 Decision2009-04-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-05-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-10-18
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