A randomized placebo controlled, double-blind phase II study to explore the safety, efficacy and pharmacokinetics of sonlicromanol in children with genetically confirmed mitochondrial disease.

1. Age between birth and 17 years
2. Genetically confirmed mitochondrial disease, of which the gene defect is
known to decrease one or more oxidative phosphorylation system enzymes and who
suffer from motor symptoms, based on investigator judgement.
3. Abnormal gross motor function and/or presence of at least one clinically
significant motor symptom (ataxia, dystonia, chorea and/or spasticity) based on
investigator judgement
4. Before enrollment in the adaptive PK phase and before randomization into the
double-blind placebo-controlled phase: GMFM-88 Total Score <=96%
5. Before enrollment in the adaptive PK phase and before randomization into the
double-blind placebo-controlled phase: IMPDS Score >=10
6. Stable disease symptoms since the previous routine control visit (consistent
with a score of *stable* on the item *disease course since previous IPMDS* of
the IPMDS) in the opinion of the investigator.
7. Written informed (patient/parental/caregiver) assent/consent, able and
willing to comply with the study requirements of the study protocol.
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 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 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 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 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.

1. Surgery of the gastro-intestinal tract with removal of piece(s) of stomach,
duodenum or jejunum that might interfere with absorption. Feeding through
gastrostomy tube is however allowed.
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. Clinically relevant cardiovascular disease or risk factors for arrythmia:
a. Abnormal ECG (including QTcF exceeding the 95th percentile for the age- and
sex-dependent QTc interval (https://www.qtcalculator.org) and/or abnormal
structural of functional 2D ECHO
b. Systolic Blood Pressure (SBP) above the 95th percentile for the sex, age
group and height percentile at screening or baseline on single measurement (see
appendix 1)
c. History of acute or chronic heart failure, (family history of unexplained
syncope or congenital long and short QT syndrome or sudden death
d. Hyperkalemia or hypokalemia; hypomagnesemia or hypermagnesemia; hypocalcemia
or hypercalcemia (local laboratory normal values; to be judged by investgator)
4. Clinically relevant abnormal laboratory results:
a. Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) > 3
times upper limit of normal (ULN), or bilirubin > 3 x ULN. 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 below age-appropriate limits (according
to the 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
> 1 year: < 60 ml/min/1.73 m2
c. All other clinically relevant parameters at screening or baseline as judged
by the investigator.
5. History of hypersensitivity or idiosyncrasy to any of the components of the
investigational product.
6. Medical history of drug abuse (illegal drugs such as cannabinoids,
amphetamines, cocaine, opiates or problematic use of prescription drugs such as
benzodiazepines, opiates).
7. 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, rifampicin, St. John*s wort, pioglitazone,
troglitazone).
e. any medication known to affect cardiac repolarisation, unless the QTc
interval at screening is normal during stable treatment for a period of two
weeks, or 5 half-lives of the medication and its major metabolite(s), whichever
period is the shortest (all anti-psychotics, several anti-depressants:
nor/amytriptyline, fluoxetine, anti-emetics: domperidone (Motilium®),
granisetron, ondansetron).
f. any medication metabolised by CYP3A4 with a narrow therapeutic width.