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    Summary
    EudraCT Number:2017-000540-18
    Sponsor's Protocol Code Number:VX16-661-114
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-09-13
    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 ConcernedGermany - BfArM
    A.2EudraCT number2017-000540-18
    A.3Full title of the trial
    Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Safety, Efficacy, and Tolerability of Tezacaftor/Ivacaftor (TEZ/IVA) in an Orkambi-experienced Population Who Are Homozygous for the F508del-CFTR Mutation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Evaluate Safety, Efficacy, and Tolerability of TEZ/IVA in Subjects With Cystic Fibrosis (CF) Who Have Previously Discontinued Orkambi
    A.4.1Sponsor's protocol code numberVX16-661-114
    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 SponsorVertex Pharmaceuticals Incorporated
    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 supportVertex Pharmaceuticals Incorporated
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVertex Pharmaceuticals Incorporated
    B.5.2Functional name of contact pointClinical Trials and Medical Info
    B.5.3 Address:
    B.5.3.1Street Address50 Northern Avenue
    B.5.3.2Town/ cityBoston, MA
    B.5.3.3Post code02210
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018776348789
    B.5.5Fax number0015105958183
    B.5.6E-mailmedicalinfo@vrtx.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1281
    D.3 Description of the IMP
    D.3.1Product nametezacaftor/ivacaftor 100mg/150mg
    D.3.2Product code VX-661/VX-770
    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 INNtezacaftor
    D.3.9.1CAS number 1152311-62-0
    D.3.9.2Current sponsor codeVX-661
    D.3.9.3Other descriptive nameVX-661
    D.3.9.4EV Substance CodeSUB33135
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIVACAFTOR
    D.3.9.1CAS number 873054-44-5
    D.3.9.2Current sponsor codeVX-770
    D.3.9.3Other descriptive nameVX-770
    D.3.9.4EV Substance CodeSUB33103
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 Kalydeco 150 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderVertex Pharmaceuticals (Europe) Limited
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/008/556
    D.3 Description of the IMP
    D.3.1Product nameIvacaftor
    D.3.2Product code VX-770
    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 INNIVACAFTOR
    D.3.9.1CAS number 873054-44-5
    D.3.9.2Current sponsor codeVX-770
    D.3.9.3Other descriptive nameVX-770
    D.3.9.4EV Substance CodeSUB33103
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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
    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
    D.8 Placebo: 2
    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
    Cystic Fibrosis
    E.1.1.1Medical condition in easily understood language
    Cystic Fibrosis
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10011762
    E.1.2Term Cystic fibrosis
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the respiratory safety of TEZ/IVA in subjects with CF homozygous for F508del and who discontinued treatment with Orkambi due to respiratory symptoms considered related to treatment
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of tezacaftor in combination with ivacaftor (TEZ/IVA) in subjects with CF homozygous for F508del and who discontinued treatment with Orkambi due to respiratory symptoms considered related to treatment.
    • To evaluate patient-reported outcomes after treatment with TEZ/IVA in subjects with CF homozygous for F508del who discontinued with Orkambi due to respiratory symptoms considered related to treatment.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject (or subject’s legally appointed and authorized representative) will sign and date an informed consent form (ICF) and, where appropriate, an assent form.
    2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
    3. Males or females, aged 12 years or older on the date of informed consent or, where appropriate, date of assent.
    4. Prior discontinuation of Orkambi, with at least 1 respiratory sign or symptom considered related to therapy, including but not limited to the following:
    • Chest discomfort
    • Dyspnea (shortness of breath)
    • Respiration abnormal (chest tightness)
    • Asthma
    • Bronchial hyperreactivity
    • Bronchospasm
    • Wheezing
    • Asymptomatic reduction in relative change in ppFEV1 of >12% within 2 weeks after Orkambi initiation
    Discontinuation from Orkambi should primarily be due to a respiratory event. However, concomitant non-respiratory events will not exclude subjects from participation. Documentation of specific qualifying signs or symptoms is not required. Investigator attestation will be accepted if information is not present in source materials.
    5. Resolution or stabilization of qualifying event(s) >28 days prior to Screening.
    6. Discontinuation of Orkambi therapy must have occurred within approximately 12 weeks from the first dose of Orkambi. In the event that the subject reinitiated Orkambi, discontinuation of Orkambi therapy must have occurred within approximately 12 weeks from the time of the most recent initiation. Investigator attestation will be accepted if information is not present in source materials.
    7. Homozygous for F508del as documented in the subject’s medical record. If genotype documentation is not available in the medical record, genotyping will be performed during screening. If the screening genotype result is not received by the end of the Screening Period and all other eligibility criteria have been met, the subject may be randomized. Note: Subjects who have been randomized and whose screening genotype does not confirm study eligibility must be discontinued from the study as described in Section 9.9.
    8. FEV1 ≥25% and ≤90% of predicted normal for age, sex, and height (equations of Wang et al. or Hankinson et al. 12, 13) at Screening Visit (Section 11.3.1). Spirometry measurements must meet American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria for acceptability and repeatability (Section 11.3.1).
    9. Stable CF disease as judged by the investigator.
    10. Willing to remain on a stable CF medication regimen from screening through the Safety Follow-up Contact.

    E.4Principal exclusion criteria
    Subjects who meet any of the following exclusion criteria will not be eligible for this study:
    1. History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject
    Examples of such comorbidities may include, but are not limited to:
    • Respiratory:
    o Massive hemoptysis within the last 12 months
    o Any of the following within the past 12 months and not associated with an acute, resolved event:
    - Six-minute walk test distance <400 m
    - Resting arterial blood gas on room air showing PaCO2 >50 mm Hg or PaO2 <55 mm Hg
    - Systolic pulmonary arterial pressure (PAP) >35 mm Hg on echocardiography or a mean PAP >25 mm Hg measured by right heart catheterization, in the absence of a hypoxemic exacerbation or with an alternate etiology to explain the findings
    • Non-respiratory: history of cirrhosis with portal hypertension, history of and/or risk factors for ventricular arrhythmia (e.g., long QT syndrome, hypokalemia, heart failure, left ventricular hypertrophy, bradycardia, myocardial infarction, cardiomyopathy, morbid obesity, acute neurologic events [subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular accident, and intracranial trauma], autonomic neuropathy, and significant anemia)
    2. Recent rapid or progressive deterioration in respiratory status
    3. Receiving continuous oxygen at >2L/min or on face-mask ventilation
    4. Any of the following abnormal laboratory values at Screening:
    • Abnormal liver function defined as any 2 or more of the following: ≥3 × upper limit of normal (ULN) aspartate transferase (AST), ≥3 × ULN alanine transferase (ALT), ≥3 × ULN gamma-glutamyl transpeptidase, ≥3 × ULN alkaline phosphatase (ALP), or ≥2 × ULN total bilirubin.
    • Abnormal liver function defined as any increase of ≥5 × ULN AST or ALT.
    • Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease Study Equation) for subjects ≥18 years of age and ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt equation) for subjects aged 12 to 17 years (inclusive).
    5. Child-Pugh Class B or C hepatic impairment
    6. An acute upper or lower respiratory infection, pulmonary exacerbation, or change in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug)
    7. Documentation of colonization with organisms associated with a more rapid decline in pulmonary status (e.g. Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus)
    8. History of lung transplantation since most recent initiation of Orkambi
    9. History of alcohol or drug abuse in the past year as deemed by the investigator, including but not limited to cannabis, cocaine, and opiates
    10. Participation in an investigational drug study or use of a CFTR modulator (including Orkambi) within 28 days or 5 terminal half-lives before screening of the previous investigational study drug or CFTR modulator, whichever is longer
    • Ongoing participation in a noninterventional study (including observational studies and studies requiring assessments without administration of study drug) is permitted.
    11. Use of restricted medications or foods within the specified window before the first dose of study drug, or an anticipated need or use of restricted medication or foods after the first dose of study drug, as defined in Table 9-1
    12. Pregnant or nursing females: Females of child-bearing potential must have a negative pregnancy test at Screening and Day 1
    13. The subject or a close relative of the subject is the investigator or a sub-investigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study. An adult (aged 18 years or older) who is a relative of a study staff member may be randomized in the study provided that
    • the adult lives independently of and does not reside with the study staff member, or
    • the adult participates in the study at a site other than the site at which the family member is employed.
    E.5 End points
    E.5.1Primary end point(s)
    • Incidence of respiratory AEs
    E.5.1.1Timepoint(s) of evaluation of this end point
    Monitored throughout the study
    E.5.2Secondary end point(s)
    Key Secondary end point:
    1. Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline to the average of the Day 28 and Day 56 measurements.

    Secondary end points:
    2. Relative change in ppFEV1 from baseline to the average of the Day 28 and Day 56 measurements.
    3. Absolute change in Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain score from baseline to the average of the Day 28 and Day 56 measurements.
    4. Tolerability based on discontinuation of TEZ/IVA through Day 56
    5. Safety assessments based on AEs, clinical laboratory values (hematology, serum chemistry, coagulation studies, and urinalysis), vital signs, pulse oximetry, and postdose spirometry
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. from baseline to the average of the Day 28 and Day 56 measurements
    2. from baseline to the average of the Day 28 and Day 56 measurements
    3. from baseline to the average of the Day 28 and Day 56 measurements
    4. Monitored throughout the study
    5. Screening visit, Days 1, 15, 28, 56, ETT

    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 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 Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    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 Yes
    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 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Germany
    United States
    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
    LVLS
    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 months4
    E.8.9.1In the Member State concerned days16
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days8
    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: 18
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 18
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 72
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Minors are included in this study.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 22
    F.4.2.2In the whole clinical trial 90
    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
    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 Decision2017-11-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-08-09
    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
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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