The KHENERGYC Study

Inclusion Criteria:

1. Age between 0 months and 17 years

2. Genetically confirmed mitochondrial disease, of which the gene defect is known todecrease one or more oxidative phosphorylation system enzymes and who suffer frommotor symptoms, based on investigator judgement

3. Abnormal gross motor function and/or presence of at least one clinically significantmotor symptom (hypotonia, decreased muscle strength, ataxia, dystonia, chorea and/orspasticity) based on investigator judgement

4. Before enrollment in the adaptive PK phase and before randomization into thedouble-blind placebo-controlled phase: Gross Motor Function Measure-88 (GMFM-88)Total Score ≤96%

5. Before enrollment in the adaptive PK phase and before randomization into thedouble-blind placebo-controlled phase: International Paediatric MitochondrialDisease Scale IPMDS Score ≥10

6. Stable disease symptoms since the previous routine control visit (consistent with ascore of "stable" on the item "disease course since previous IPMDS" of the IPMDS) inthe opinion of the investigator.

7. Written informed (patient/parental/caregiver) consent, able and willing to complywith the study requirements of the study protocol.

8. Women of childbearing potential must be willing to use highly effectivecontraceptive methods during the entire study, i.e. combined (estrogen andprogestogen containing) oral, intravaginal or transdermal hormonal contraceptionassociated with inhibition of ovulation; oral, injectable, or or implantableprogestogen-only hormonal contraception associated with inhibition of ovulation; useof an intrauterine device; an intrauterine hormone releasing system, bilateral tubalocclusion and vasectomy of the partner. Any hormonal contraception method must besupplemented with a barrier method (preferably male condom). Vasectomised partner isconsidered a highly effective birth control method provided that partner is the solesexual partner of the subject and that the vasectomised partner has received medicalassessment of the surgical success. Sexual abstinence is considered a highlyeffective method only if defined as refraining from heterosexual intercourse duringthe entire period of risk associated with the study treatments. Reliability ofsexual abstinence needs to be evaluated in in relation to the duration of theclinical trial and the preferred and usual lifestyle of the subject. Periodicabstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) andwithdrawal 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 have been surgically sterilized (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 usecondoms during the entire study.

• female partners of childbearing potential of male subjects must be willing to useadequate contraceptive methods during the entire study, i.e., a hormonalcontraceptive method (pill, vaginal ring, patch, implant, injectable,hormone-medicated intrauterine device) or an intrauterine device.

Exclusion criteria:

1. Surgery of the gastro-intestinal tract with removal of piece(s) of stomach, duodenumor jejunum that might interfere with absorption. Feeding through gastrostomy tube ishowever allowed.

2. Treatment with an investigational product within 3 months or 5 times the half-lifeof the investigational product (whichever is longer) prior to the first dose of thestudy medication.

3. Clinically relevant cardiovascular disease or risk factors for arrythmia:

4. Abnormal ECG (including QTcF exceeding the 95th percentile for the age- andsex-dependent QTc interval (https://www.qtcalculator.org) and/or abnormalstructural or functional 2D ECHO

5. Systolic Blood Pressure (SBP) above the 95th percentile for the sex, age groupand height percentile at screening or baseline on single measurement (seeappendix 1)

6. History of acute or chronic heart failure, (family) history of unexplainedsyncope or congenital long and short QT syndrome or sudden death

7. Hyperkalemia or hypokalemia; hypomagnesemia or hypermagnesemia; hypocalcemia orhypercalcemia (local laboratory normal values; to be judged by investigator)

8. Clinically relevant abnormal laboratory results:

9. Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) > 3 timesupper limit of normal (ULN), or bilirubin > 3 x ULN. If a patient has ASAT orALAT > 3 x ULN but < 3.5 x ULN, re-assessment is allowed at the investigator'sdiscretion.

10. Estimated glomerular filtration rate below age-appropriate limits (according tothe formula: 40.9* ((1.8 / Cystatine C)0.93): < 2 months: < 25 ml/min/1.73 m2 2 months to 1 year: < 35 ml/min/1.73 m2 > 1year: < 60 ml/min/1.73 m2

11. All other clinically relevant parameters at screening or baseline as judged bythe investigator

12. History of hypersensitivity or idiosyncrasy to any of the components of theinvestigational product.

13. Medical history of drug abuse (illegal drugs such as cannabinoids, amphetamines,cocaine, opiates or problematic use of prescription drugs such as benzodiazepines,opiates).

14. The use of any of the following medication and/or supplements within 4 weeks or 5times the half-life (whichever is longer) prior to the first dosing of the studymedication:

15. (multi)vitamins, co-enzyme Q10, Vitamin E, riboflavin, and antioxidantsupplements (including, but not limited to idebenone/EPI-743, mitoQ); unlessstable for at least one month before first dosing and remaining stablethroughout the study.

16. any medication negatively influencing mitochondrial functioning (including butnot limited to valproic acid, glitazones, statins, anti-virals, amiodarone, andnon-steroidal anti- inflammatory drugs (NSAIDs)), unless stable for at leastone month before first dosing and remaining stable throughout the study.Note: thus, mitoQ and any medication negatively influencing mitochondrialfunctioning are allowed as long as the dose has been stable for at least onemonth prior to first dosing and remains stable throughout the study.

17. any strong Cytochrome P450 (CYP)3A4 inhibitors (all 'conazoles-anti-fungals',HIV antivirals, grapefruit).

18. strong CYP3A4 inducers (including HIV antivirals, carbamazepine, phenobarbital,phenytoin, rifampicin, St. John's wort, pioglitazone, troglitazone).

19. any medication known to affect cardiac repolarisation, unless the QTc intervalat screening is normal during stable treatment for a period of two weeks, or 5half-lives of the medication and its major metabolite(s), whichever period isthe shortest (all anti-psychotics, several anti-depressants: nor- /amitriptyline, fluoxetine, anti-emetics: domperidone (Motilium®), granisetron,ondansetron).

20. any medication metabolised by CYP3A4 with a narrow therapeutic width.