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    EudraCT Number:2019-000599-40
    Sponsor's Protocol Code Number:KH176-202
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-09-05
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2019-000599-40
    A.3Full title of the trial
    A Phase IIb double-blind, randomised, placebo-controlled, multi-centre, confirmative three-way cross-over study on cognitive function with two doses of KH176 in subjects with a genetically confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the efficacy of KH176 in patients with a genetically confirmed mitochondrial DNA mutation. Patients to be allocated randomly to placebo or investigational drug in different periods; meaning each patient will receive both placebo as well as the investigational drug. Assignment of actual treatment order will be unknown to patient and doctor.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberKH176-202
    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.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.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 pointBas Nieuwenhuis
    B.5.3 Address:
    B.5.3.1Street AddressBroederplein 41-43
    B.5.3.2Town/ cityZeist
    B.5.3.3Post code3703 CD
    B.5.4Telephone number0031 30 6569129
    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 nameKH176
    D.3.2Product code KH176
    D.3.4Pharmaceutical form Powder for 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 INNKH176
    D.3.9.3Other descriptive nameKH176
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit Bq/mg becquerel(s)/milligram
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    A genetically confirmed mitochondrial desoxyribonucleic acid (DNA) transfer ribonucleic acid (tRNA)Leu(UUR) m.3243A>G mutation (including but not limited to MELAS, MIDD and mixed compositions).
    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 KH176 during a 4 week treatment period on the attention domain score of cognitive functioning, as assessed by the visual identification test of the Cogstate computerised cognitive testing battery.
    E.2.2Secondary objectives of the trial
    To evaluate the effect of KH176 during a 4-week treatment period on the cognitive domains:
    1. executive functioning
    2. working memory
    3. psychomotor function
    4. visual learning
    5. verbal learning
    To evaluate the effect of KH176 during a 4-week treatment period on:
    1. TAP
    2. BDI
    3. HADS
    4. NMDAS
    5. number of headache days, intensity and duration, and use of medication to relieve headache
    6. hearing
    7. smell identification
    8. Cognitive Failure Questionnaire (CFQ)
    9. Neuro-QoL Fatigue Short Form
    To evaluate the effect of KH176 during a 4-week treatment period on:
    1. the tolerability and safety of two doses of KH176 following 28 days of oral administration
    2. Electrocardiogram (ECG) intervals, rhythm and morphology
    Other objectives:
    1. To investigate the multiple dose pharmacokinetics of KH176 following 28 days of oral administration
    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. Confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation (heteroplasmy ≥ 20%, urinary epithelial cells).
    4. Positive NMDAS score >10 at Screening.
    5. Three or more clinical features, with no other causative unifying diagnosis, found to commonly occur in subjects with a m.3243A>G mutation:
    - Deafness
    - Developmental delay
    - Diabetes Mellitus
    - Epilepsy
    - Gastrointestinal complaints
    - Progressive External Ophtalmoplegia (PEO) and retinopathy
    - Ataxia
    - Exercise intolerance
    - Fatigue
    - Migraine (with or without aura), specified by at least five attacks fulfilling diagnostic criteria B-D:
    B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)
    C. Headache has at least two of the following four characteristics:
    1. unilateral location
    2. pulsating quality
    3. moderate or severe pain intensity
    4. aggravation or causing avoidance of routine physical activity (e.g. walking or climbing stairs)
    D. During headache at least one of the following:
    1. nausea and/or vomiting
    2. photophobia and phonophobia
    6. Attentional dysfunction score (Cogstate Identification test) ≥ 0.2 standard deviations poorer than healthy controls at Screening.
    7. 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.
    8. Objectified Left Ventricular Ejection Fraction (LVEF) ≥45% (echocardiography, or otherwise).
    9. Left Ventricular (LV) wall thickness ≤15 mm.
    10. Left atrium dilatation ≤ 40 mL/m2.
    Note: No need to test LV parameters (criteria #7, #8, #9) if favorable echocardiography (or otherwise) results dated less than 6 months prior to Screening are available.
    11. Women of childbearing potential 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. Sexual abstinence is an acceptable contraceptive method only as true abstinence: when this is in line with the preferred and usual lifestyle of the patient. [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, male subjects with female partners of childbearing potential must be willing to use condoms during the entire study.
    12. 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. Participation in a study of an investigational product in the preceding 3 months prior to the first dose or during this study.
    3. Documented history of ventricular tachycardia (HR>110 beats/min).
    4. (Family) history of acute heart failure, unexplained syncope of congenital long QT syndrome.
    5. Clinically relevant abnormal laboratory, vital signs or physical or mental health 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; QTc > 450 ms (local, machine read), T-top inversion in >1 consecutive lead.
    7. Serum Hyper-potassium (> 5.0 mEq/L).
    8. Serum Hypo-potassium (< 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. Poor nutritional state as judged by the investigator.
    14. History of hypersensitivity or idiosyncrasy to any of the components of the investigational drug.
    15. Within 4 weeks prior to dosing, the use of:
    a. (multi)vitamins, co-enzyme Q10, Vitamine 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 Johns wort, pioglitazone, troglitazone).
    e. any medication known to affect cardiac repolarisation (all anti-psychotics, several anti-depressants: nor/amytriptilline, fluoxetine, anti-emetics: domperidone (motilium) granisetron, ondansetron).
    f. any medication metabolised by CYP with a narrow therapeutical width.
    E.5 End points
    E.5.1Primary end point(s)
    Changes from baseline (measured at pre-dose Day 1) to end of treatment (Day 28 of each treatment period) in:
    • the attention domain score of cognitive functioning, as assessed by the visual identification test of the Cogstate computerised cognitive testing battery.
    E.5.1.1Timepoint(s) of evaluation of this end point
    For each treatment period: pre-dose day 1 (baseline) and day 28
    Follow up (28 days after day 28 of last treatment period)
    E.5.2Secondary end point(s)
    Changes from baseline (measured at pre-dose Day 1) to end of treatment (Day 28 of each treatment period) in the following domains of cognitive functioning:
    • executive functioning
    • working memory
    • psychomotor function
    • visual learning
    • verbal learning
    Changes from baseline (measured at pre-dose Day 1) to end of treatment (Day 28 of each treatment period) in:
    • Test of Attentional Performance (TAP): Alertness and Mental Flexibility
    • Hospital Anxiety and Depression Scale (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 (PTA)
    • smell identification test (UPSIT)
    • CFQ (overall score and 4 subscores)
    • Neuro-QoL Fatigue Short Form
    E.5.2.1Timepoint(s) of evaluation of this end point
    For each treatment period: pre-dose day 1 (baseline) and day 28
    Follow up (28 days after day 28 of last 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 No
    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. 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 No
    E.8.1.6Cross over Yes
    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 Yes
    E. description
    Other dosage of the same IMP
    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.8.5.1Number 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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F. of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F. of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F. of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F. of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F. of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F. of subjects for this age range: 0
    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 27
    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)
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-12-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-22
    P. End of Trial
    P.End of Trial StatusOngoing
    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
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