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    Summary
    EudraCT Number:2020-000832-23
    Sponsor's Protocol Code Number:KH176-203
    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:2022-01-31
    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 number2020-000832-23
    A.3Full title of the trial
    A Phase IIb open-label, multi-centre, extension study to explore the long-term safety and efficacy of KH176 in subjects with a genetically confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation who have completed the Khenergyze study KH176-202.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The KHENEREXT study: An open-label long-term extension study to investigate the long-term safety and effectiveness of KH176 in subjects with a mitochondrial DNA mutation.
    A.3.2Name or abbreviated title of the trial where available
    KHENEREXT
    A.4.1Sponsor's protocol code numberKH176-203
    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 SponsorKhondrion B.V.
    B.1.3.4CountryNetherlands
    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 supportKhondrion B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJulius Clinical
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street AddressBroederplein 41-43
    B.5.3.2Town/ cityZeist
    B.5.3.3Post code3703 CD
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031306569900
    B.5.6E-mailregulatory@juliusclinical.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/3/14/1336
    D.3 Description of the IMP
    D.3.1Product nameSonlicromanol
    D.3.2Product code KH176
    D.3.4Pharmaceutical form Oral solution
    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 INNSonlicromanol
    D.3.9.2Current sponsor codeKH176
    D.3.9.3Other descriptive nameKH176
    D.3.9.4EV Substance CodeSUB198953
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number50 to 100
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    A genetically confirmed mitochondrial desoxyribonucleic acid (DNA) tRNALeu(UUR) m.3243A>G mutation (including but not limited to MELAS. MIDD and mixed phenotypes.
    E.1.1.1Medical condition in easily understood language
    Mitochondrial disease
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.0
    E.1.2Level PT
    E.1.2Classification code 10052641
    E.1.2Term Mitochondrial DNA mutation
    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 assess the long-term safety of KH176 during a 1-year treatment period, including:
    1. The tolerability and safety of KH176 100 mg bid (potentially reduced to 50 mg) following 1 year of oral administration
    2. Electrocardiogram (ECG) intervals, rhythm and morphology
    3. Thyroid sonography size and echo density
    E.2.2Secondary objectives of the trial
    To explore the effect of KH176 on the attention domain score of cognitive functioning, as assessed by the visual identification test of the Cogstate computerised cognitive testing battery.
    To explore the effect of KH176 during a one-year treatment period on the cognitive domains:
    1. executive functioning
    2. working memory
    3. psychomotor function
    4. visual learning
    5. verbal learning
    To explore the effect of KH176 during a one-year treatment period on:
    1. Test of Attentional Performance (TAP)
    2. Beck Depression Inventory (BDI)
    3. Hospital Anxiety and Depression Scale (HADS)
    4. Newcastle Mitochondrial Disease Scale for Adults (NMDAS)
    5. Number of headache days, intensity and duration, and use of medication to relieve headache
    6. Hearing (Pure Tone Audiometry (PTA) and speech recognition)
    7. Smell identification (UPSIT)
    8. Cognitive Failure Questionnaire (CFQ)
    9. Neuro-QoL Fatigue Short Form
    10. Five times Sit to Stand Test (5xSST)
    and other measures
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Males and females aged 18 years or older at screening.
    2. Ability and willingness to provide written Informed Consent prior to screening evaluations.
    3. Having fulfilled all inclusion and exclusion criteria and completed the full treatment period of study KH176-202 with evidence of potential benefit in at least one treatment period in the KH176-202 study.
    4. Disease appropriate physical and mental health as established at Screening by medical history, physical examination, ECG and vital signs recording, and results of clinical chemistry and haematology testing as judged by the investigator.
    5. Objectified Left Ventricular Ejection Fraction (LVEF) ≥45% (echocardiography, or otherwise).
    6. Left Ventricular (LV) wall thickness ≤15 mm.
    7. Left atrium dilatation ≤ 40 mL/m2.
    Note: No need to test LV parameters (criteria #5, #6, #7) if favourable echocardiography (or otherwise) results dated less than 13 months prior to Screening are available.
    8. Women of childbearing potential must be willing to use highly effective contraceptive methods during the entire study, i.e., combined (estrogen and progestogen containing) oral, intravaginal or transdermal hormonal contraception associated with inhibition of ovulation; oral, injectable or implantable progestogen-only hormonal contraception associated with inhibition of ovulation; use of an intrauterine device; an intrauterine hormone releasing
    system, bilateral tubal occlusion and vasectomy of the partner. Any hormonal contraception method must be supplemented with a barrier method (preferably male condom).
    Vasectomised partner is considered a highly effective birth control method provided that partner is the sole sexual partner of the subject and that the vasectomised partner has received medical assessment of the surgical success. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. Reliability of sexual abstinence
    needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    Note 1: Natural family planning methods, female condom, cervical cap or diaphragm are not considered adequate contraceptive methods in the context of this study.
    Note 2: To be considered not of childbearing potential, potential female subjects must be post-menopausal for at least two years, or have been surgically sterilised (bilateral tubal ligation, hysterectomy or bilateral oophorectomy) for at least 6 months prior to Screening.
    Note 3: KH176 has been shown non-genotoxic judged from the Ames test, Chromosomal Aberration test and in vivo Micronucleus test. Moreover, appreciable systemic exposure from the exposure to (~2.5 mL) semen is extremely unlikely. However, until reproductive toxicology studies have confirmed that KH176 does not adversely affect normal reproduction in adult males and females, as well as causing developmental toxicity in the offspring, the following
    contraceptive precautions must be adhered to:
    • male subjects with female partners of childbearing potential must be willing to use condoms during the entire study.
    • female partners of childbearing potential of male subjects must be willing to use adequate contraceptive methods during the entire study, i.e., a hormonal contraceptive method (pill, vaginal ring, patch, implant, injectable,
    hormonemedicated intrauterine device) or an intrauterine device.
    9. Able to comply with the study requirements, including swallowing study medication.
    E.4Principal exclusion criteria
    1. Surgery of gastro-intestinal tract that might interfere with absorption.
    2. Treatment with an investigational product (except KH176) within 3 months or 5 times the half-life of the investigational product (whichever is longer) prior to the first dose of the study medication.
    3. Documented history of ventricular tachycardia (HR>110 beats/min), PVC burden ≥5% or daytime Mobitz II AV block on any of the Holter assessments in the KH176-202 study or in the medical history.
    4. History of acute heart failure, (family) history of unexplained syncope or congenital long and short QT syndrome or sudden death.
    5. Clinically relevant abnormal laboratory, vital signs or physical or mental health;
    a) Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) > 3 x upper limit of normal (ULN), or bilirubin > 3 x ULN at screening. If a patient has ASAT or ALAT > 3 x ULN but < 3.5 x ULN, re-assessment is allowed at the investigator’s discretion.
    b) Estimated glomerular filtration rate ≤ 60 mL/min according to the CKD-EPI formula at screening.
    c) Systolic blood pressure > 150 mmHg at screening or baseline.
    d) All other clinically relevant parameters at screening or baseline as judged by the Investigator.
    6. Clinically relevant abnormal ECG or cardiac functioning, defined as ST-segment elevation > 1 mm in I, II, III, aVL, aVF, V3, V4, V5, V6; > 2 mm in V1, V2; Mean QTc of triplicate ECG recording > 450 ms for male subjects; mean QTc of triplicate ECG recording > 470ms for female subjects (Diagram-read), T-top inversion in >1 consecutive lead.
    7. Serum hyperkalemia (> 5.0 mEq/L).
    8. Serum hypokalemia (< 3.5 mEq/L).
    9. History of ischemic heart disease.
    10. Symptomatic heart failure.
    11. Clinically relevant aorta and/or mitralis valvular defect as judged by the investigator.
    12. Pregnancy or breast feeding (females).
    13. History of hypersensitivity or idiosyncrasy to any of the components of the investigational drug.
    14. Medical history of drug abuse (illegal drugs such as cannabinoids, amphetamines, cocaine, opiates or problematic use of prescription drugs such as benzodiazepines, opiates).
    15. The use of any of the following medication and/or supplements within 4 weeks or 5 times the half-life (whichever is longer) prior to the first dosing of the study medication:
    a. (multi)vitamins, co-enzyme Q10, Vitamin E, riboflavin, and antioxidant supplements (including, but not limited to idebenone/EPI-743, mitoQ or alternative names for similar products); unless stable for at least one month before first dosing and remaining stable throughout the study.
    b. any medication negatively influencing mitochondrial functioning (including but not limited to valproic acid, glitazones, statins, anti-virals, amiodarone, and non-steroidal anti-inflammatory drugs (NSAIDs)), unless stable for at least one month before first dosing and remaining stable throughout the study.
    Note: thus, mitoQ and any medication negatively influencing mitochondrial functioning are allowed as long as the dose has been stable for at least one month prior to first dosing and remains stable throughout the study.
    c. any strong Cytochrome P450 (CYP)3A4 inhibitors (all ‘conazoles-anti-fungals’, HIV antivirals, grapefruit).
    d. strong CYP3A4 inducers (including HIV antivirals, carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort, pioglitazone, troglitazone).
    e. any medication known to affect cardiac repolarisation unless QTc interval at screening is normal during stable treatment for a period of two weeks, or 5 half-lives of the medication and its major metabolite(s), whichever period is the shortest (all anti-psychotics, several anti-depressants, e.g. nor-/amitriptyline, fluoxetine, anti-emetics: domperidone, granisetron, ondansetron). For a complete list see https://crediblemeds.org.
    f. any medication metabolised by CYP3A4 with a narrow therapeutic width. For reference (Germany and United Kingdom): drug interaction table of Indiana University (http://medicine.iupui.edu/clinpharm/ddis/clinical-table/). For reference (The Netherlands): KNMP Kennisbank (https://www.knmp.nl/producten/knmp-kennisbank/inloggen-knmp-kennisbank).
    E.5 End points
    E.5.1Primary end point(s)
    Frequency of TEAEs throughout the treatment period.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From the signing of the ICF until the Follow-up Visit scheduled 28 days after the last intake of study medication.
    E.5.2Secondary end point(s)
    Changes from baseline to each assessment visit in the following domains of cognitive functioning:
    • the attention domain score of cognitive functioning, as assessed by the visual identification test of the Cogstate computerised cognitive testing battery
    • executive functioning
    • working memory
    • psychomotor function
    • visual learning
    • verbal learning
    Changes from baseline to each visit in:
    • TAP: Alertness
    • HADS, supplemented with a Beck Depression Index (BDI)
    • NMDAS Score
    • Number of headache days, intensity and duration and use of medication to relieve headache
    • Hearing (Pure Tone Audiometry (PTA) and speech audiometry)
    • Smell identification test (University of Pennsylvania Smell Identification Test (UPSIT))
    • CFQ (overall score and 4 sub scores)
    • Neuro-QoL Fatigue Short Form
    • Five Times Sit to Stand test (5XSST)
    • Mini-Balance Evaluation Systems Test (Mini-BESTest)
    • Handgrip strength (HS)
    • HbA1c
    • Mean daily insulin dose (weighted average daily dose over periods 0-3, 3-6, 6-9 and 9-12 months)
    • Mean daily oral antidiabetics dose (weighted average daily dose over periods 0-3, 3-6, 6-9 and 9-12 months)
    • Short Form McGill Pain Questionnaire (SF-MPQ)
    • RAND SF-36
    • Clinician-scored Global Impression of Change (CGIC)
    • Patient-scored Global Impression of Change (PGIC)
    • Patient-scored Impression of Change on patient-identified three most bothersome symptoms caused by mitochondrial disease (Most Bothersome Symptom Assessment (MBSA))
    E.5.2.1Timepoint(s) of evaluation of this end point
    Pre-dose day 1 (baseline, week 13, week 26, week 39, week 52, and Follow up (day 28 after last drug intake).
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Open label, long-term Follow-up
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA3
    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
    Denmark
    Germany
    United Kingdom
    Netherlands
    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
    End-of-Study is defined as the date the last patient performs the last visit in the trial, defined as Last Patient Last Visit, (LPLV). LPLV is the point of final data capture (the point at which all required data has been collected to answer the research question(s) in the protocol.
    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 months13
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months8
    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: 24
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 22
    F.4.2.2In the whole clinical trial 27
    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)
    After completion of this study, patients who elect to continue with KH176 treatment will be able to enter a compassionate use program
    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 Decision2022-04-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-08-08
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