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
Overview
- Phase
- Phase 2
- Intervention
- Sonlicromanol
- Conditions
- Mitochondrial Diseases
- Sponsor
- Khondrion BV
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Motor Symptom Severity as assessed with the Gross Motor Function Measure-88 (GMFM-88)
- Status
- Suspended
- Last Updated
- last year
Overview
Brief 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").
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age between 0 months and 17 years
- •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
- •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
- •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%
- •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
- •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.
- •Written informed (patient/parental/caregiver) consent, able and willing to comply with the study requirements of the study protocol.
- •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.
Exclusion Criteria
- Not provided
Arms & Interventions
Sonlicromanol
Paediatric-equivalent dose (as determined by Physiologically Based Pharmacokinetics (PBPK) modelling and the results of the Adaptive PK study) of sonlicromanol twice daily administered as an oral liquid for 26 weeks
Intervention: Sonlicromanol
Placebo
Matching placebo twice daily orally for 26 weeks
Intervention: Placebo
Outcomes
Primary Outcomes
Motor Symptom Severity as assessed with the Gross Motor Function Measure-88 (GMFM-88)
Time Frame: Baseline (Day 1), week 6, week 13, week 27, week 29
Changes from baseline to each assessment of the GMFM-88.The GMFM-88 consists of 88 questions and assesses motor function in 5 domains (lying and rolling; sitting; crawling and kneeling; standing; walking, running, and jumping). 4-point scoring system for each item, item scores ranges from 0-3. Higher scores denote better performance. Scaled score indicates the percentage of total score. Total score ranges from 0-100%
Secondary Outcomes
- Ataxia as assessed with the Scale for the Assessment and Rating of Ataxia (SARA)(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Disability as assessed with the PEDI-CAT (Paediatric Evaluation of Disability Inventory (PEDI-CAT)(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Mitochondrial disease signs and symptoms as assessed with the International Paediatric Mitochondrial Disease Scale (IPMDS)(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Fine manual motor skills as assessed with the 9 Hole Peg Test (NHPT)(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Spasticity as assessed with the Modified Tardieu Scale for spasticity (MTS)(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Caregiver burden as assessed with the ZARIT-12 Burden scale (ZBI-12)(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Dystonia as assessed with Dystonia (Barry-Albright Dystonia scale (BAD)(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Quality of life as assessed with the Neurology Quality of life short Form (NeuroQL-SF)(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Clinician-scored global impression of change (CGIC)(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Patient/Caregiver scored global impression of change (PGIC)(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Patient/Caregiver scored impression of change on patient-identified 3 Most Bothersome Symptoms (MBSA) caused by mitochondrial disease(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Growth as assessed by weight(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Growth as assessed by height(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Growth as assessed by head circumference(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Growth as assessed by Body Mass Index (BMI)(Baseline (Day 1), week 6, week 13, week 27, week 29)
- Temperature(Baseline (Day 1), week 6, week 13, week 27, week 29)
- 10 meter Walk Test (10MWT)(Baseline (Day 1), week 6, week 13, week 27, week 29)