| Eligibility |
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.
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) = 0.5 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 #8, #9, #10) if favourable echocardiography
(or otherwise) results dated less than 6 months prior to Screening are available.
11. 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, hormone-medicated intrauterine
device) or an intrauterine device.
12. Able to comply with the study requirements, including swallowing study medication.
Exclusion Criteria
1. Surgery of gastro-intestinal tract that might interfere with absorption.
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. Documented history of ventricular tachycardia (HR>110 beats/min).
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;
1. 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.
2. Estimated glomerular filtration rate = 60 mL/min according to the CKD-EPI formula
at screening.
3. Systolic Blood pressure > 150 mmHg at screening or baseline.
4. 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 for male subjects; QTc: > 470ms for female subjects (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. Medical history of drug abuse (illegal drugs such as cannabinoids, amphetamines,
cocaine, opiates or problematic use of prescription drugs such as benzodiazepines,
opiates).
16. 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:
1. (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.
2. 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.
3. any strong Cytochrome P450 (CYP)3A4 inhibitors (all 'conazoles-anti-fungals', HIV
antivirals, grapefruit).
4. strong CYP3A4 inducers (including HIV antivirals, carbamazepine, phenobarbital,
phenytoin, rifampicin, St. John's wort, pioglitazone, troglitazone).
5. any medication known to affect cardiac repolarisation, unless the QTc interval at
screening is normal during stable treatment (all anti-psychotics, several
anti-depressants, e.g. nor/amitriptyline, fluoxetine, anti-emetics: domperidone
(motilium®) granisetron, ondansetron). For a complete list see
https://crediblemeds.org.
6. any medication metabolised by CYP with a narrow therapeutical 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. For
reference (all other countries): drug interaction table of Indiana University
(http://medicine.iupui.edu/clinpharm/ddis/clinical-table/).
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