Genetically confirmed mitochondrial disease
Conditions
Interventions
Product Name: Sonlicromanol
Product Code: KH176
Pharmaceutical Form: Oral solution
INN or Proposed INN: sonlicromanol
Current Sponsor code: KH176
Other descriptive name: KH176
Concentration unit: mg/m
Sponsors
Khondrion B.V.
Eligibility
Sex/Gender
All
Inclusion 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. 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. For randomization into the double blind placebo-controlled phase: GMFM Score =96 5. For 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) 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,
Exclusion criteria
Exclusion criteria: 1. Surgery of 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 above the 95th percentile for the sex, age group and height percentile at screening or baseline on single measurement 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; hypomagnesiemia or hypermagnesieamia; hypocalcemia or hypercalcemia (local laboratory normal values) 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 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 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. 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-depr
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the effect of sonlicromanol on motor symptom severity (GMFM-88) in children with genetically confirmed mitochondrial defect known to affect oxidative phosphorylation during a 6 month treatment period.;Secondary Objective: To evaluate the effect of Sonlicromanol on: •Fine manual motor skills •Physical performance •Spasticity •Dystonia •Ataxia •Disability •Mitochondrial disease signs and symptoms •Caregiver burden •Quality of Life •Clinician-scored global impression of change •Patient/Caregiver scored global impression of change •Patient/Caregiver scored impression of change on patient-identified 3 most bothersome symptoms caused by mitochondrial disease •Growth •Evaluation of safety and tolerability of sonlicromanol following 6 months of oral administration on TEAEs, vitals , ECG , Lab •Confirm the pediatric-equivalent dose (PED) of sonlicromanol and investigate the multiple dose pharmacokinetics of sonlicromanol and its active metabolite KH183 •Biomarker/metabolomics analysis •Explore mortality •Health Economics and Outcomes Research information •Explore the acceptability and palatability of sonlicromanol ;Primary end point(s): Change from baseline (measured at pre-dose Day 1) to end of treatment in the Gross Motor Function Measure-88 ;Timepoint(s) of evaluation of this end point: Baseline (measured at pre-dose Day 1), week 5, week 13, week 27 (end of treatment), and week 29 (Follow-up) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Changes from baseline (measured at pre-dose Day 1) to end of treatment of: 1. 9 Hole Peg Test 2. 10 meter walk test 3. Modified Tardieu Scale for spasticity 4. Barry-Albright Dystonia scale (BAD) 5. Scale for the Assessment and Rating of Ataxia (SARA) 6. Pediatric Evaluation of Disability Inventory (PEDI-CAT) 7. International Paediatric Mitochondrial Disease Scale (IPMDS) (total and for each domain and individual item). 8. Zarit-12 Burden scale 9. NeuroQL-SF 10. Clinician-scored global impression of change (7-point Likert scale) 11. Patient/Caregiver scored global impression of change (7-point Likert scale) 12. Patient/Caregiver scored impression of change on patient-identified 3 most bothersome symptoms caused by mitochondrial disease (7-point Likert scale) 13. Growth and Weight Other endpoints: 14. Proportion of responders on Clinician-scored and Patient/Caregiver scored global impression of change (defined as patients with any improvement from baseline) 15. Pharmacokinetic endpoints (Tmax, Cmax, Ctrough, AUCinf, AUCtau, T1/2, and CL/F) 16. Safety / tolerability endpoints (TEAEs, change from baseline in vital signs (SBP, DBP, PR), ECG and laboratory parameters) 17. Overall survival 18. Metabolomics and biomarkers in plasma and urine 19. Palatability / acceptability endpoints: children self-report scales; parent report 20. EQ-5D-Y (proxy version 1), Health Utilities Index (HUI) ;Timepoint(s) of evaluation of this end point: Baseline (measured at pre-dose Day 1), week 5, week 13, week 27 (end of treatment), and week 29 (Follow-up) | — |
Countries
Czechia, Netherlands
Contacts
Public ContactGerrit Ruiterkamp
Khondrion B.V.
Outcome results
None listed