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    Summary
    EudraCT Number:2014-003501-15
    Sponsor's Protocol Code Number:408-C-1403
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-12-18
    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
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2014-003501-15
    A.3Full title of the trial
    A PHASE 2 STUDY OF THE SAFETY, EFFICACY, AND PHARMACODYNAMICS OF RTA 408 IN THE TREATMENT OF MITOCHONDRIAL MYOPATHY
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A PHASE 2 STUDY OF THE SAFETY AND EFFICACY OF RTA 408 IN PATIENTS WITH MITOCHONDRIAL MYOPATHY
    A.4.1Sponsor's protocol code number408-C-1403
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02255422
    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 SponsorReata Pharmaceuticals, Inc.
    B.1.3.4Country
    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 supportREATA
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationReata Pharmaceuticals
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street Address2801 Gateway Drive, Suite 150
    B.5.3.2Town/ cityIrving, Texas
    B.5.3.3Post code75063
    B.5.4Telephone number19728652219
    B.5.6E-mail408C1403DNK@reatapharma.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 nameRTA 408
    D.3.2Product code RTA 408
    D.3.4Pharmaceutical form Capsule
    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 INNRTA 408
    D.3.9.1CAS number 1474034-05-3
    D.3.9.2Current sponsor codeRTA 408
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number10
    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 placeboCapsule
    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
    Mitochondrial myopathy as evidenced by the following 2 criteria (must meet both):
    a. Have a history of exercise intolerance with or without weakness and/or progressive exercise intolerance (in which modest exercise typically provokes heaviness, weakness, aching of active muscles, or tachycardia).
    b. Have a known primary mitochondrial DNA mutation of a nuclear DNA defect that is associated with reduced activity of at least 1 mitochondrially encoded respiratory chain complex
    E.1.1.1Medical condition in easily understood language
    Mitochondrial myopathy
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10027710
    E.1.2Term Mitochondrial myopathy
    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
    Primary:
    • To evaluate the change in peak work during maximal exercise testing
    • To evaluate the safety and tolerability of RTA 408
    E.2.2Secondary objectives of the trial
    Secondary:
    • To evaluate the change in 6-minute walk test (6MWT) distance
    Exploratory:
    • To evaluate the change in peak oxygen utilization during maximal exercise testing
    • To evaluate the change in peak serum lactate and pyruvate, peak heart rate, and rating of perceived exertion during submaximal exercise testing
    • To evaluate the change in Fatigue Severity Scale score
    • To evaluate the change in SF-36® Health Survey Update (SF-36) score
    • To evaluate the change in pharmacodynamic (PD) markers of activity in blood and muscle samples
    • To characterize the pharmacokinetics of RTA 408 and potential metabolites after oral administration of RTA 408 Capsules
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria:
    Patients must:
    1. Have mitochondrial myopathy as evidenced by the following 2 criteria (must meet both):
    a. Have a history of exercise intolerance with or without weakness and/or progressive exercise intolerance (in which modest exercise typically provokes heaviness, weakness, aching of active muscles, or tachycardia)
    b. Have a known primary mitochondrial DNA mutation or a nuclear DNA defect that is associated with reduced activity of at least 1 mitochondrially encoded respiratory chain complex
    2. Be male or female and ≥18 years of age and ≤75 years of age
    3. Have no changes to their exercise regimen within 30 days prior to Study Day 1 and be willing to remain on the same exercise regimen during the 16-week study period
    4. Have the ability to complete maximal exercise testing
    5. Have peak work during maximal exercise testing of ≤1.5 W/kg
    6. Have adequate kidney function defined as an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 4-variable formula
    7. Be able to swallow capsules
    8. Be willing and able to cooperate with all aspects of the protocol
    9. Be willing to practice the medically acceptable methods of birth control
    10. Provide written informed consent for study participation, approved by the appropriate Institutional Review Board
    E.4Principal exclusion criteria
    Exclusion criteria:
    Patients must not:
    1. Have uncontrolled diabetes (HbA1c >11.0%)
    2. Have B-type natriuretic peptide level >200 pg/mL
    3. Have a history of clinically significant left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:
    a. Clinically significant congenital or acquired valvular disease
    b. Pericardial constriction (based on echocardiogram performed at Screening Visit or within 30 days prior to Screening Visit)
    c. Restrictive or congestive cardiomyopathy (based on echocardiogram performed at Screening Visit or within 30 days prior to Screening Visit)
    d. Symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or angina)
    e. Evidence of left ventricular diastolic dysfunction
    f. History of atrial fibrillation
    g. History of unstable arrhythmias
    h. Cardiac insufficiency, defined as New York Heart Association Class >2
    4. Have known active fungal, bacterial, and/or viral infection, including human immunodeficiency virus or hepatitis virus (B or C)
    5. Have known or suspected active drug or alcohol abuse, as per investigator judgment
    6. Have clinically significant abnormalities of clinical hematology or biochemistry, including but not limited to elevations greater than 1.5 times the upper limit of normal of aspartate aminotransferase, alanine aminotransferase or creatinine. Levels above this threshold are allowable if attributable to muscle injury.
    7. Have any abnormal laboratory test value or clinically significant pre-existing medical condition that, in the opinion of the investigator, would put the patient at risk by study enrollment
    8. Have taken any of the following drugs within 7 days prior to Study Day 1 or plan to take any of these drugs during the time of study participation:
    a. Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, midazolam, sildenafil)
    b. Moderate or strong inhibitors or inducers of cytochrome P450 3A4 (e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice)
    c. Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin)
    9. Have a history of clinically significant liver disease (e.g., fibrosis, cirrhosis, hepatitis), or has, at screening, clinically relevant deviations in laboratory tests including any one of the following:
    a. alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 1.5-fold ULN,
    b. bilirubin > 1.2-fold ULN,
    c. alkaline phosphatase (ALP) > 2-fold ULN,
    d. kidney insufficiency as defined by creatinine level > 1.5 mg/dL,
    e. albumin < lower limit of normal (LLN)
    10. Have participated in any other interventional clinical study within 30 days prior to Study Day 1
    11. Have a cognitive impairment that may preclude ability to comply with study procedures
    12. Be unable to comply with the requirements of the study protocol or be unsuitable for the study for any reason, in the opinion of the investigator
    13. Have used antioxidant supplements, including but not limited to idebenone, coenzyme Q10, nicotinamide, and vitamin E above the recommended daily allowance, within 14 days prior to Study Day 1 or plan to take any of these supplements during the time of study participation
    14. Have taken chronic treatment with corticosteroids within 30 days prior to Study Day 1
    15. Have had significant suicidal ideation within 1 month prior to Screening Visit as per investigator judgment or any history of suicide attempts
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in peak work (W/kg) during maximal exercise testing using a bicycle ergometer.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Screening, week 4, week 12
    E.5.2Secondary end point(s)
    Efficacy: Parameters collected during maximal exercise testing (including peak work and peak oxygen utilization) and submaximal exercise testing; 6MWT distance; Fatigue Severity Scale results; and SF-36 test results
    Safety: Results of echocardiogram, electrocardiogram, vital sign measurements, weight, body mass index, physical examinations, adverse events, serious adverse events, concomitant medications, and laboratory test results (clinical chemistry, hematology, urinalysis, microscopy, and pregnancy tests [as indicated])
    Pharmacokinetic: RTA 408 plasma concentration data
    Pharmacodynamic: Parameters assessed from serum lactate and serum pyruvate during submaximal exercise testing, muscle needle biopsy biomarkers
    E.5.2.1Timepoint(s) of evaluation of this end point
    Screening, week 4, week 12 (some end points are also assessed at week 16 or at timepoints during the 12-week treatment period)
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) 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 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 trial3
    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 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
    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 years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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: 51
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    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)
    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 Decision2015-02-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-11-30
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