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    Summary
    EudraCT Number:2020-003124-16
    Sponsor's Protocol Code Number:KH176-204
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-10-20
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2020-003124-16
    A.3Full title of the trial
    A randomized placebo controlled, double-blind phase II study to explore the safety, efficacy and pharmacokinetics of sonlicromanol in children with genetically confirmed mitochondrial disease.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The KHENERGYC study: a placebo controlled, double-blind study to explore the safety, efficacy and pharmacokinetics of sonlicromanol in children with a mitochondrial disease.
    A.4.1Sponsor's protocol code numberKH176-204
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/004/2021
    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 supportEuropees Fonds voor Regionale Ontwikkeling (EFRO)
    B.4.2CountryNetherlands
    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 organisationKhondrion B.V.
    B.5.2Functional name of contact pointGerrit Ruiterkamp
    B.5.3 Address:
    B.5.3.1Street AddressPhilips van Leydenlaan 15
    B.5.3.2Town/ cityNijmegen
    B.5.3.3Post code6525EX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031243617505
    B.5.6E-mailruiterkamp@khondrion.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/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 placeboOral solution
    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
    Genetically confirmed mitochondrial disease
    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.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of sonlicromanol on motor symptom severity (GMFM-88) in children with genetically confirmed mitochondrial defect known to affect oxidative phosphorylation during a 6 month treatment period.
    E.2.2Secondary objectives of the trial
    To evaluate the effect of Sonlicromanol on:
    • Fine manual motor skills
    • Physical performance
    • Spasticity
    • Dystonia
    • Ataxia
    • Disability
    • Mitochondrial disease signs and symptoms
    • Caregiver burden
    • Quality of Life
    • Clinician-scored global impression of change
    • Patient/Caregiver scored global impression of change
    • Patient/Caregiver scored impression of change on patient-identified 3 most bothersome
    symptoms caused by mitochondrial disease
    • Growth
    • Evaluation of safety and tolerability of sonlicromanol following 6 months of oral administration
    on TEAEs, vitals , ECG , Lab
    • Confirm the pediatric-equivalent dose (PED) of sonlicromanol and investigate the multiple dose pharmacokinetics of sonlicromanol and its active metabolite KH183
    • Biomarker/metabolomics analysis
    • Explore mortality
    • Health Economics and Outcomes Research information
    • Explore the acceptability and palatability of sonlicromanol
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age between 0 months and 17 years
    2. Genetically confirmed mitochondrial disease, of which the gene defect is known to decrease one or more oxidative phosphorylation system enzymes and who suffer from motor symptoms.
    3. Abnormal gross motor function and/or presence of at least one clinically significant motor symptom (ataxia, dystonia, chorea and/or spasticity) based on investigator judgement
    4. For randomization into the double blind placebo-controlled phase: GMFM Score ≤96
    5. For randomization into the double blind placebo-controlled phase: IMPDS Score ≥10
    6. Stable disease symptoms since the previous routine control visit (consistent with a score of “stable” on the item “disease course since previous IPMDS” of the IPMDS) in the opinion of the investigator
    7. Written informed (patient/parental/caregiver) consent, able and willing to comply with the study requirements of the study protocol.
    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 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 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 have been surgically sterilized (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, hormone-medicated intrauterine device) or an intrauterine device.
    E.4Principal exclusion criteria
    1. Surgery of gastro-intestinal tract with removal of piece(s) of stomach, duodenum or jejunum that might interfere with absorption. Feeding through gastrostomy tube is however allowed.
    2. Treatment with an investigational product 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. Clinically relevant cardiovascular disease or risk factors for arrythmia:
    a. Abnormal ECG (including QTcF exceeding the 95th percentile for the age- and sex-dependent QTc interval (https://www.qtcalculator.org) and/or abnormal structural of functional 2D ECHO
    b. Systolic Blood Pressure above the 95th percentile for the sex, age group and height percentile at screening or baseline on single measurement
    c. History of acute or chronic heart failure, (family) history of unexplained syncope or congenital long and short QT syndrome or sudden death
    d. Hyperkalemia or hypokalemia; hypomagnesiemia or hypermagnesieamia; hypocalcemia or hypercalcemia (local laboratory normal values)
    4. Clinically relevant abnormal laboratory results :
    a. Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) > 3 times upper limit of normal (ULN), or bilirubin > 3 x ULN. 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 below age-appropriate limits (according to the formula: 40.9*((1.8/Cystatine C)0.93):
    < 2 months: < 25 ml/min/1.73 m2
    2 months to 1 year: < 35 ml/min/1.73 m2
    > 1 year: < 60 ml/min/1.73 m2
    c. All other clinically relevant parameters at screening or baseline as judged by the investigator.
    5. History of hypersensitivity or idiosyncrasy to any of the components of the investigational product.
    6. Medical history of drug abuse (illegal drugs such as cannabinoids, amphetamines, cocaine, opiates or problematic use of prescription drugs such as benzodiazepines, opiates).
    7. 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 anti-oxidant supplements (including, but not limited to idebenone/EPI-743, mitoQ); 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, rifampicine, St. John’s wort, pioglitazone, troglitazone).
    e. any medication known to affect cardiac repolarisation, unless the 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: nor/amytriptilline, fluoxetine, anti-emetics: domperidone (Motilium®), granisetron, ondansetron).
    f. any medication metabolised by CYP3A4 with a narrow therapeutic width.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline (measured at pre-dose Day 1) to end of treatment in the Gross Motor Function Measure-88
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline (measured at pre-dose Day 1), week 5, week 13, week 27 (end of treatment), and week 29 (Follow-up)
    E.5.2Secondary end point(s)
    Changes from baseline (measured at pre-dose Day 1) to end of treatment of:
    1. 9 Hole Peg Test
    2. 10 meter walk test
    3. Modified Tardieu Scale for spasticity
    4. Barry-Albright Dystonia scale (BAD)
    5. Scale for the Assessment and Rating of Ataxia (SARA)
    6. Pediatric Evaluation of Disability Inventory (PEDI-CAT)
    7. International Paediatric Mitochondrial Disease Scale (IPMDS) (total and for each domain and individual item).
    8. Zarit-12 Burden scale
    9. NeuroQL-SF
    10. Clinician-scored global impression of change (7-point Likert scale)
    11. Patient/Caregiver scored global impression of change (7-point Likert scale)
    12. Patient/Caregiver scored impression of change on patient-identified 3 most bothersome symptoms caused by mitochondrial disease (7-point Likert scale)
    13. Growth and Weight

    Other endpoints:
    14. Proportion of responders on Clinician-scored and Patient/Caregiver scored global impression of change (defined as patients with any improvement from baseline)
    15. Pharmacokinetic endpoints (Tmax, Cmax, Ctrough, AUCinf, AUCtau, T1/2, and CL/F)
    16. Safety / tolerability endpoints (TEAEs, change from baseline in vital signs (SBP, DBP, PR), ECG and laboratory parameters)
    17. Overall survival
    18. Metabolomics and biomarkers in plasma and urine
    19. Palatability / acceptability endpoints: children self-report scales; parent report
    20. EQ-5D-Y (proxy version 1), Health Utilities Index (HUI)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline (measured at pre-dose Day 1), week 5, week 13, week 27 (end of treatment), and week 29 (Follow-up)
    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 Yes
    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 trial2
    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 EEA2
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years1
    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 years1
    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: 24
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 6
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 6
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    F.1.2Adults (18-64 years) No
    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
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 24
    F.4.2.2In the whole clinical trial 24
    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)
    At the end of the study all participants will be offered to continue treatment with sonlicromanol during an open label extension (OLE) trial for 12 months
    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 Decision2020-10-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-01-12
    P. End of Trial
    P.End of Trial StatusOngoing
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