Mitochondrial Diseases are rare, progressive, multi-system, often-early fatal disorders affecting both children and adults. KH176 is a novel chemical entity currently under development for the treatment of inherited mitochondrial diseases, including MELAS (Mitochondrial Encephalomyopathy, Lactic acidosis, and Stroke-like episodes), MIDD (Maternally Inherited Diabetes and Deafness), Leigh's Disease and LHON (Leber's Hereditary Optic Neuropathy). The current Proof of Concept study aims to explore the effects of treatment with KH176 for 4 weeks on clinical signs and symptoms and biomarkers of mitochondrial disease and to evaluate the safety and pharmacokinetics of KH176 in patients with m.3242A>G related mitochondrial disease.

The trial will be a double blind, randomized, placebo-controlled, single-centre, two-way cross-over trial. Twenty patients, with a confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation and with clinical signs of mitochondrial disease, will be randomized over 2 groups (active or placebo first). After a screening period and a training session, each group will have 2 dosing periods of 28 days, with a washout period of at least 28 days in between. On these occasions, patients will receive 100 mg KH176 twice daily (treatment A) or a matching placebo (treatment B) twice daily for 28 days.

Clinical assessments will be performed once in a training session prior to baseline, at baseline and in week 4 post dosing during each treatment phase (A and B). Testing conditions and circumstances, with respect to timing of the assessments, hospitalization and meals, will be standardized for each assessement period. Furthermore, assessments of biomarkers for mitochondrial functioning, pharmacokinetics and specific safety assessments will be performed weekly.

Inclusion Criteria:

1. Males and females aged 18 years or older at screening
2. Ability and willingness to sign the Informed Consent Form prior to screening evaluations.
3. Confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation
4. Heteroplasmy level as measured in urine ≥ 20 %.
5. Body Mass Index (BMI) 18.0-30.0 kg/m2 (extremes included) at screening
6. Clinical evidence of mitochondrial disease, positive NMDAS score (including but not limited to MELAS, MIDD and mixed types). CPEO patients with signs restricted to the eye only are not considered eligible.
7. Disease appropriate physical and mental health as established by medical history, physical examination, electrocardiogram (ECG) and vital signs recording, and results of biochemistry, hematology and urinalysis testing within 3 weeks prior to the first dose as judged by the Investigator.
8. Appropriate cardiac functioning as assessed by medical history, ECG and Echo, evaluated by a cardiologist.
9. Able to comply with the study requirements, including exercise testing and swallowing study medication
10. Willingness to use adequate contraceptive methods (male and female) and negative urine pregnancy test (females) at screening and first baseline assessment.
11. Able and willing to refrain from the use of (multi)vitamins, co-enzyme Q10, Vitamine E, riboflavin, and anti-oxidant supplements (and idebenone/EPI-743), as well as any medication negatively influencing mitochondrial functioning (including but not limited to valproic acid, glitazones, statins, anti-virals, amiodarone, and NSAID's) as well as any strong Cytochrome P450 inhibitors (all 'conazoles-anti-fungals', HIV antivirals, grapefruit) and strong Cytochrome P450 inducers (a.o. carbamazepine, phenobarbital, phenytoin, rifampicine, St Johns wort, pioglitazone, troglitazone) as well as any medication known to affect cardiac repolarization (all anti-psychotics, several anti-depressants: nor/amytriptilline, fluoxetine, anti-emetics: domperidone (motilium) granisetron, ondansetron).

Exclusion Criteria:

1. Motoric abnormalities other than related to the mitochondrial disease interfering with the outcome parameters.

2. CPEO patients with clinical signs and symptoms restricted to the eye only

3. Heteroplasmy level as measured in urine < 20%

4. Poor nutritional state as judged by the investigator

5. Body Mass Index (BMI) not within 18.0-30.0 kg/m2 at screening.

6. History of cancer

7. Surgery or active illness of gastro-intestinal tract that might interfere with absorption.

8. Participation in a trial of an investigational product in the preceding 3 months prior to the first dose or during this trial.

9. Positive drug, alcohol or cotinine test at screening and/or admission (Day 1 of the first dosing period).

10. Clinically relevant abnormal laboratory, ECG recordings, cardiac echo (within 1 year prior to screening), vital signs or physical or mental findings at screening as judged by the Investigator.

11. Clinically relevant abnormal ECG or cardiac functioning as judged by a cardiologist.

12. ECG: QTc > 450 ms, abnormal T-wave

13. Symptomatic heart failure or signs of ischemic heart disease

14. Left Ventricular Ejection Fraction <45%

15. History or family history of congenital Long QT syndrome

16. Increased or decreased potassium (local laboratory normal range)

17. Inadequate contraception use, pregnancy or breast feeding (females)

18. Clinically significant presence or history of allergy as judged by the Investigator.

19. History of hypersensitivity or idiosyncrasy to any of the components of the investigational drug.

20. Within 4 weeks prior to dosing, the use of:

    • (multi)vitamins, co-enzyme Q10, Vitamine E, riboflavin, and anti-oxidant supplements (and idebenone/EPI-743),
    • as well as any medication negatively influencing mitochondrial functioning (including but not limited to valproic acid, glitazones, statins, anti-virals, amiodarone, and NSAID's)
    • as well as any strong Cytochrome P450 inhibitors (all 'conazoles-anti-fungals', HIV antivirals, grapefruit)
    • and strong Cytochrome P450 inducers (a.o. carbamazepine, phenobarbital, phenytoin, rifampicin, St Johns wort, pioglitazone, troglitazone)
    • as well as any medication known to affect cardiac repolarization (all anti-psychotics, several anti-depressants: nor/amitriptyline, fluoxetine, anti-emetics: domperidone (motilium) granisetron, ondansetron)
    • as well as any medication metabolized by Cytochrome P450 with a narrow therapeutical width. (for reference: drug interaction table of Indiana University http://medicine.iupui.edu/clinpharm/ddis/clinical-table/)