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.

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 #8, #9, #10) 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, 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.

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:
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 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:
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, unless the QTc
interval at screening is normal during stable treatment (all anti-psychotics,
several anti-depressants, e.g. nor/amytriptiline, fluoxetine, anti-emetics:
domperidone (motilium) granisetron, ondansetron). For a complete list see
https://crediblemeds.org.
f. 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.