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    Summary
    EudraCT Number:2021-002846-33
    Sponsor's Protocol Code Number:KL13332020-104A
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-08-18
    Trial 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 number2021-002846-33
    A.3Full title of the trial
    An interventional, randomised, double-blind, parallel-group, placebo-controlled, flexible-dose, adaptive study of the efficacy of KL1333 in adult patients with primary mitochondrial disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of KL1333 in adult patients with primary mitochondrial disease
    A.4.1Sponsor's protocol code numberKL13332020-104A
    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 SponsorAbliva AB
    B.1.3.4CountrySweden
    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 supportAbliva AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAbliva AB
    B.5.2Functional name of contact pointClinical Project Manager
    B.5.3 Address:
    B.5.3.1Street AddressMedicon Village
    B.5.3.2Town/ cityLund
    B.5.3.3Post code223 81
    B.5.3.4CountrySweden
    B.5.4Telephone number+46462756220
    B.5.6E-mailFia.Ence@abliva.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/3/17/1947
    D.3 Description of the IMP
    D.3.2Product code KL1333
    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 INNNot available
    D.3.9.1CAS number 1800405-30-4
    D.3.9.2Current sponsor codeKL1333
    D.3.9.3Other descriptive name2-isopropyl-3H-naphtho[2,1-d]imidazole-4,5-dione
    D.3.9.4EV Substance CodeSUB192761
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 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
    Adult patients with primary mitochondrial disease
    E.1.1.1Medical condition in easily understood language
    Primary mitochondrial diseases may be seen in any part of the body, characterized by fatigue, myopathy, exercise intolerance, and signs of metabolic dysfunction.
    E.1.1.2Therapeutic area Body processes [G] - Metabolic Phenomena [G03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10052637
    E.1.2Term Genetic mitochondrial abnormalities NEC
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objectives:
    Evaluate efficacy on selected disease expressions of primary mitochondrial disease (PMD) following 48 weeks of treatment with KL1333 by:
    − evaluating the efficacy of KL1333 versus placebo on fatigue symptoms and impacts on daily living
    − evaluating the efficacy of KL1333 versus placebo on functional lower extremity strength and endurance
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    • to evaluate the efficacy of KL1333 versus placebo on:
    − physical function and activities of daily living
    − patient and clinician global impression
    − assessment of mitochondrial disease progression
    − glycaemic control (glycated haemoglobin) – in patients with diabetes
    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 not a separate sub-study protocol. It is covered in the same protocol, but additional terminal PK parameters will be assessed in a sub-group of the patients.
    E.3Principal inclusion criteria
    Patients are eligible to be included in this study only if all of the following criteria apply:
    1. Age 18 years or older.
    2. A confirmed PMD diagnosis caused by a known pathogenic gene mutation or deletion of the mitochondrial genome (category 6 of the International Classification of Inborn Metabolic Disorders [ICIMD])12 according to American College of Medical Genetics (ACMG)/ Association of Molecular Pathology (AMP) criteria, with multisystemic disease expressions, including:
    a. m.3243A>G associated MELAS- MIDD spectrum disorders,
    b. single large scale mtDNA deletion associated KSS-CPEO spectrum disorders,
    c. other multisystemic mtDNA-related disease (including MERRF).
    3. Presence of chronic mitochondrial fatigue:
    • History of mitochondrial fatigue for at least 3 months prior to the Screening Visit
    AND
    • Presence of at least moderate level of fatigue, assessed by PROMIS® Fatigue PMD Short form raw score ≥ 27 at Screening and Baseline
    4. Presence of mitochondrial myopathy defined as:
    • Myopathy (proximal muscle weakness), NMDAS Section III Clinical Assessment, item 5 score ≥ 1, which reads: “mild but clear proximal weakness in hip flexion and shoulder abduction – MRC 4/5”. For the inclusion only hip flexion, but not shoulder abduction, should be taken into account.
    AND / OR
    • Exercise Tolerance: NMDAS Section I, item 9 score ≥ 1, which reads: “unlimited on flat – symptomatic on inclines or stairs”.
    5. Patients must be able to perform at least 2 repetitions and the maximal capacity must not exceed 17 repetitions in males or 16 repetitions in females in a 30s STS test at screening.
    6. Clinically stable, apart from symptoms associated with the diagnosis of mitochondrial disease, at Screening and Baseline, as determined by medical history, physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory evaluations at Screening, as assessed by the investigator.
    7. The patient is willing and able to attend study appointments within the specified time windows.
    8. Willingness and ability to complete electronic PROs.
    9. Willingness to maintain a stable diet during the Screening and study periods.
    10. Patients who take any mitochondrial disease-focused vitamins or supplemental therapies, including coenzyme Q10 (CoQ10), has been on a stable dose regimen of these for 3 months prior to randomisation and intends to stay on a stable dose for the duration of the study period.
    11. Willingness to suspend treatment with idebenone during the study.
    12. Female patient is not pregnant and at least one of the following conditions apply:
    a. Not a woman of childbearing potential (WOCBP)
    b. WOCBP must agree not to try and become pregnant and use a highly effective method of contraception from the time of informed consent through at least 36 days (~5 half-lives of KL1333 plus 30 days) after the last dose of investigational medicinal product (IMP) administration.
    13. Male patients with female partner(s) of childbearing potential must agree to use a male condom in addition to using highly effective contraception throughout the treatment period and for 96 days after the last dose of IMP administration. The requirement to use a male condom also applies to male patients with a pregnant or breastfeeding partner.
    14. Female patients must agree not to breastfeed starting at Screening and throughout the study period and for 36 days after the last dose of IMP administration.
    15. Female patients must agree to not donate ova throughout the study period and for 36 days after the last dose of IMP administration, and male patients must agree to not donate sperm throughout the study period and for 96 days after the last dose of IMP administration.
    E.4Principal exclusion criteria
    Patients are not eligible to be included in this study if any of the following criteria apply:
    1. Primary mitochondrial disease with predominant neurodegenerative phenotypes, such as, but not limited to, Leigh syndrome, Leber hereditary optic neuropathy (LHON) and Neuropathy-ataxia-retinitis pigmentosa syndrome (NARP).
    2. Primary mitochondrial disease nuclear DNA mutations or mutations causing mtDNA destabilisation. Genetic mtDNA variants of uncertain significance, likely pathogenic, or pathogenic mutations with degrees of heteroplasmy below what can be considered to definitely cause PMD.
    3. General fatigue or muscle weakness due to causes other than mitochondrial disease, in the opinion of the investigator.
    4. Significant cardiovascular disease (e.g., sustained or symptomatic arrhythmia; dilated heart chambers or reduced function; Mobitz II atrioventricular block or greater) OR abnormal ECG that is clinically significant, as determined by the investigator. Any QTcF > 450 msec for male patients and > 470 msec for female patients is exclusionary. In the case of an exclusionary QTcF, the ECG can be repeated twice and the average of 3 QTcF intervals should be used to determine the QTcF eligibility.
    5. Recent history of unstable disease, inadequately controlled neurological manifestations or not recovered from stroke-like episodes including but not limited to:
    a. stroke-like episodes within the last 6 months
    b. more than 1 seizure/month within the last 6 months
    c. hospitalised for Status Epilepticus within the last 6 months
    d. more than 4 days of migraine episodes/month within the last 6 months
    6. History of inflammatory bowel disease, gastric erosions, peptic ulcer disease, or gastrointestinal bleeding episodes. Gastroesophageal reflux disease diagnosed by objective endoscopic or radiographic means, and clinically symptomatic at any point over the last 6 months.
    7. The patient has one or more clinical laboratory test values outside the reference range, based on the blood and urine samples taken at the Screening Visit, that are of potential risk to the patient’s safety, or the patient has, at the Screening Visit:
    • estimated glomerular filtration rate (eGFR) calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation <60 mL/min/1.73 m2
    • a serum total bilirubin value > 1.5 times the upper limit of the reference range
    • a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value > 2 times the upper limit of the reference range
    8. The patient has, in the investigator’s opinion, severe ataxia, neuropathy, balance problems or other medical condition that would interfere with the evaluation of the 30s STS test.
    9. Untreated or undertreated sleep apnoea, in the opinion of the investigator.
    10. Use of idebenone within 14 days prior to the first dose.
    11. Patients with a history of unstable or severe pulmonary, immunological, oncological, hepatic disease, renal disease, or another medically significant illness other than PMD or takes medication that could, in the investigator’s opinion, interfere with the assessments of safety, tolerability, or efficacy, or interfere with the conduct or interpretation of the study.
    12. The patient is, in the investigator’s opinion, unlikely to comply with the protocol e.g. due to cognitive impairment or is unsuitable for any reason.
    13. The patient has an immediate family member (defined as family members residing at the same address) who participates in the study.
    14. Female patients with a positive pregnancy result at Screening or at Baseline.
    15. A patient cannot participate if they received an investigational drug 30 days or 5 half-lives prior to the Screening Visit (whichever is longer), or plans to use an investigational drug (other than the study intervention) during the study.
    16. Hypersensitivity to the active substance or to any of the excipients or placebo.
    E.5 End points
    E.5.1Primary end point(s)
    Patient-reported mitochondrial fatigue:
    • Patient-Reported Outcomes Measurement Information System(PROMIS®) Fatigue PMD short form
    Functional outcome:
    • 30 Second Sit-to-Stand Test (30s STS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 48
    E.5.2Secondary end point(s)
    Key secondary endpoints
    Patient-reported lower extremity function:
    • Neuro-QOL Lower Extremity Function (Mobility) - Short Form
    Secondary endpoints
    Patient-reported outcomes:
    • Individual Activity Assessments (IAA)
    • Patient Global Impression of PMD - Severity and change (PGIS, PGIC)
    Global impression of severity of PMD disease expression:
    • Clinician Global Impression of PMD - Severity and change (CGIS, CGIC)
    Assessments of mitochondrial disease progression:
    • Newcastle Mitochondrial Disease Adult Scale (NMDAS), Subscales I-III
    Mitochondrial diabetes, sub-group analysis
    • Glycated haemoglobin (HbA1c, in patients with diabetes)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 48
    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 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 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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Canada
    United States
    Turkey
    Belgium
    Denmark
    France
    Germany
    Italy
    Spain
    United Kingdom
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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 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: 162
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 18
    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 No
    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 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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 81
    F.4.2.2In the whole clinical trial 180
    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)
    Patients may be eligible to continue on study IMP (KL1333) dependent on their individual clinical assessment by study investigator and at the discretion of the sponsor.
    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 Decision2022-10-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-09-21
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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