| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical 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. |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess the long-term safety of sonlicromanol (KH176) during an 18-months treatment period, including:
1. The tolerability and safety of sonlicromanol 100 mg BID (potentially reduced to 50 mg BID) following 18 months of oral administration
2. Electrocardiogram (ECG) intervals, rhythm and morphology
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives
To explore the effect of sonlicromanol (KH176) on cognitive domains
To explore the effect of sonlicromanol during an 18 months treatment period on:
1. Test of Attentional Performance
2. Beck Depression Inventory
3. Hospital Anxiety and Depression Scale
4. Newcastle Mitochondrial Disease Scale for Adults
5. Number of headache days, intensity and duration, and use of medication
6. Hearing
7. Smell identification
8. Cognitive Failure Questionnaire
9. Neuro-QoL Fatigue
10. Five times Sit to Stand Test
11. Mini-Balance Evaluation Systems-Test
12. Handgrip Strength (
13. Glucose homeostasis / diabetes control
14. Short Form McGill Pain Questionnaire
15. RAND SF-36
16. Clinician-scored Global Impression of Change
17. Patient-scored Global Impression of Change
18. Patient-scored Impression of Change
Additional objectives
• Pharmacokinetic parameters of KH176/KH183
• Health Economics and Outcomes Research information
• Biomarker/metabolomics analysis
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
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: Sonlicromanol (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.
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| E.4 | Principal exclusion criteria |
1. Surgery of gastro-intestinal tract that might interfere with absorption.
2. Treatment with an investigational product (except sonlicromanol (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).
4. (Family) history of acute heart failure, unexplained syncope or congenital long QT syndrome.
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 Bloodpressure > 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; QTc > 450 ms (local, machine 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. 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); 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 (all anti-psychotics, several anti-depressants, e.g. anti-emetics: domperidone, granisetron, ondansetron).
f. any medication metabolised by CYP3A4 with a narrow therapeutic width. For reference (The Netherlands): KNMP Kennisbank (https://www.knmp.nl/producten/knmp-kennisbank/inloggen-knmp-kennisbank).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Frequency of TEAEs throughout the treatment period.
• Changes from baseline to each assessment visit in vital signs, ECG parameters, laboratory parameters (chemistry, haematology, urinalysis).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From first intake of the study medication until the Follow-up Visit scheduled 28 days after the last intake of study medication. |
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| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
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, 9-12, 12-15 and 15-18 months)
• Mean daily oral antidiabetics dose (weighted average daily dose over periods 0-3, 3-6, 6-9, 9-12, 12-15 and 15-18 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))
Other endpoints
• Proportion of patients with post-baseline termination of 1 or more anti-diabetics
• Proportion of patients with post-baseline starting of 1 or more anti-diabetics
• Metabolomics and biomarker in plasma and urine
• EQ-5D-5L
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Pre-dose day 1 (baseline, week 13, week 26, week 39, week 52, week 65, week 78 and Follow up (day 28 after last drug intake. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Open label, long-term Follow-up |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Netherlands |
| Germany |
| Denmark |
| United Kingdom |
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| E.8.7 | Trial 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
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| The end of the study as a whole is met when all subjects have completed all assessments (LVLS), and all subject data have been cleaned and all study sites have been closed. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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