the khenergyc study

Conditions: Mitochondrial Diseases; Mitochondrial DNA tRNALeu(UUR) m.3243A<G Mutation; MELAS; Subacute Necrotizing Encephalomyelopathy

Summary: this a randomized placebo controlled, double-blind phase ii study to explore the pharmacokinetics, safety and efficacy of sonlicromanol in children (from birth to 17 years) with 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 ("khenergyc").

mitochondrial diseases (md) are rare progressive, multi-system, often early onset and fatal disorders affecting both children and adults. despite advances in the understanding of mitochondrial disorders, treatment options are extremely limited and, to date, largely supportive. therefore, there is an urgent need for novel treatments. sonlicromanol (kh176) is an orally bio-available small molecule under development for the treatment of these disorders. the current study will explore the pharmacokinetics, safety and efficacy of sonlicromanol in children (from birth to 17 years) with 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. the primary objective of the study is to evaluate the effect of sonlicromanol on motor symptom severity in children with genetically confirmed mitochondrial disease affecting oxidative phosphorylation during a 6 month treatment period (gmfm). the trial consists of 2 phases, with the main phase being a randomized placebo controlled, double-blind, phase ii parallel group study to explore the efficacy and safety of sonlicromanol in twenty-four (24) children with mitochondrial disease and motor symptoms,. the first phase is an adaptive pharmacokinetics (pk) study with 4 days treatment (to expected steady state in most subjects) in the following age-groups: birth - 1 year, 1-2 years, 2- 6 years, 6-12 years, and 12 - 17 years. an age group should have at least 3 subjects before being analysed. subjects will take 4 days of open-label sonlicromanol orally at the anticipated adult-equivalent dose. after completion of enrolment in an age group, the pk data from that age group will be analysed to confirm the adult-equivalent dose that will be used thereafter in the second phase of the trial. older age groups will be studied before younger age groups. in the second phase subjects will be randomized (by age group) over 2 groups. group 1 will receive an adult-equivalent dose of sonlicromanol twice daily orally for 26 weeks. group 2 will receive matching placebo twice daily for 26 weeks. a final follow-up visit is scheduled 2 weeks after the intake of the last dose of the treatment period. duration of subject participation: the overall study duration of the trial for a eligible subject is estimated to be approximately 7 months, consisting of up to 4 weeks screening, 26 weeks (6 months) of treatment and 2 week post-treatment follow-up. at the end of the study treatment all participants will be offered to continue treatment with sonlicromanol during a open label extension (ole) trial for 12 months.

Eligibility criteria:
inclusion criteria: 1. age between 0 months 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 (hypotonia, decreased muscle strength, 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: gross motor function measure-88 (gmfm-88) total score ≤96% 5. before enrollment in the adaptive pk phase and before randomization into the double-blind placebo-controlled phase: international paediatric mitochondrial disease scale ipmds 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) 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. exclusion criteria: 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: 1. abnormal ecg (including qtcf exceeding the 95th percentile for the age- and sex-dependent qtc interval (https://www.qtcalculator.org) and/or abnormal structural or functional 2d echo 2. 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) 3. history of acute or chronic heart failure, (family) history of unexplained syncope or congenital long and short qt syndrome or sudden death 4. hyperkalemia or hypokalemia; hypomagnesemia or hypermagnesemia; hypocalcemia or hypercalcemia (local laboratory normal values; to be judged by investigator) 4. clinically relevant abnormal laboratory results: 1. 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. 2. estimated glomerular filtration rate below age-appropriate limits (according to the formula: 40.9\* ((1.8 / cystatine c)0.93): \ 1 year: \< 60 ml/min/1.73 m2 3. 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: 1. (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. 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 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- / amitriptyline, fluoxetine, anti-emetics: domperidone (motilium®), granisetron, ondansetron). 6. any medication metabolised by cyp3a4 with a narrow therapeutic width.

Keywords: kh176 sonlicromanol melas leigh syndrome oxidative phosphorylation (oxphos) phase ii