The KHENERGYC Study

NCT04846036 | Suspended Phase 2 DMC

• 1 other identifier: KH176-204
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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").

Conditions

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

Keywords

KH176; Sonlicromanol; MELAS; Leigh syndrome; Oxidative phosphorylation (oxphos); Phase II

Outcome Measures

Primary Outcomes (1)

• Motor Symptom Severity as assessed with the Gross Motor Function Measure-88 (GMFM-88)

  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%

  Baseline (Day 1), week 6, week 13, week 27, week 29

Secondary Outcomes (17)

• 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

• Dystonia as assessed with Dystonia (Barry-Albright Dystonia scale (BAD)

  Baseline (Day 1), week 6, week 13, week 27, week 29

• 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

Other Outcomes (57)

• Mortality

  Up to 29 weeks

• Health Utility Index (HUI)

  Baseline (Day 1), week 6, week 13, week 27, week 29

• EQ-5D-Y Proxy

  Baseline (Day 1), week 6, week 13, week 27, week 29

Study Arms (2)

Sonlicromanol

EXPERIMENTAL

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

Drug: Sonlicromanol

Placebo

PLACEBO COMPARATOR

Matching placebo twice daily orally for 26 weeks

Drug: Placebo

Interventions

Sonlicromanol DRUG

Oral administration of sonlicromanol twice daily

Also known as: KH176

Sonlicromanol

Placebo DRUG

Oral administration of matching placebo twice daily

Placebo

Eligibility Criteria

• Age: 0 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.
• Clinically relevant cardiovascular disease or risk factors for arrythmia:
• 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
• 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)
• History of acute or chronic heart failure, (family) history of unexplained syncope or congenital long and short QT syndrome or sudden death
• Hyperkalemia or hypokalemia; hypomagnesemia or hypermagnesemia; hypocalcemia or hypercalcemia (local laboratory normal values; to be judged by investigator)
• Clinically relevant abnormal laboratory results:
• 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.
• 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
• All other clinically relevant parameters at screening or baseline as judged by the investigator
• History of hypersensitivity or idiosyncrasy to any of the components of the investigational product.
• Medical history of drug abuse (illegal drugs such as cannabinoids, amphetamines, cocaine, opiates or problematic use of prescription drugs such as benzodiazepines, opiates).
• 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:

Sponsors & Collaborators

• Khondrion BV: lead
• Julius Clinical: collaborator
• ProPharma Group: collaborator
• Europees Fonds voor Regionale Ontwikkeling (EFRO): collaborator
• Ardena: collaborator
• Certara: collaborator

Study Sites (1)

Radboud University Medical Center

Nijmegen, Gelderland, 6525 EX, Netherlands

Location

Related Publications (1)

• Smeitink J, van Maanen R, de Boer L, Ruiterkamp G, Renkema H. A randomised placebo-controlled, double-blind phase II study to explore the safety, efficacy, and pharmacokinetics of sonlicromanol in children with genetically confirmed mitochondrial disease and motor symptoms ("KHENERGYC"). BMC Neurol. 2022 Apr 27;22(1):158. doi: 10.1186/s12883-022-02685-3.

  PMID: 35477351 DERIVED

MeSH Terms

Conditions

Mitochondrial Diseases; MELAS Syndrome; Leigh Disease

Interventions

6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Muscular Diseases; Musculoskeletal Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Neuromuscular Diseases; Vascular Diseases; Cardiovascular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pyruvate Metabolism, Inborn Errors; Carbohydrate Metabolism, Inborn Errors

Study Officials

• Lonneke de Boer, MD

  Radboud University Medical Center Nijmegen, Netherlands

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Randomized, placebo controlled, double-blind

Study Record Dates

• First Submitted: February 5, 2021
• First Posted: April 15, 2021
• Study Start: February 1, 2021
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: January 10, 2025

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)