A genetically confirmed mitochondrial desoxyribonucleic acid (DNA) tRNALeu(UUR) m.3243A>G mutation (including but not limited to MELAS. MIDD and mixed phenotypes.
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. Males and females aged 18 years or older at screening. 2. Ability and willingness to provide written Informed Consent prior to screening evaluations. 3. Having fulfilled all inclusion and exclusion criteria and completed the full treatment period of study KH176-202. 4. Disease appropriate physical and mental health as established at Screening by medical history, physical examination, ECG and vital signs recording, and results of clinical chemistry and haematology testing as judged by the investigator. 5. Objectified Left Ventricular Ejection Fraction (LVEF) =45% (echocardiography, or otherwise). 6. Left Ventricular (LV) wall thickness =15 mm. 7. Left atrium dilatation = 40 mL/m2. Note: No need to test LV parameters (criteria #5, #6, #7) if favourable echocardiography (or otherwise) results dated less than 13 months prior to Screening are available. 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 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 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 be post-menopausal for at least two years, or have been surgically sterilised (bilateral tubal ligation, hysterectomy or bilateral oophorectomy) for at least 6 months prior to Screening. Note 3: Sonlicromanol (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, injec
Exclusion criteria
Exclusion criteria: 1. Surgery of gastro-intestinal tract that might interfere with absorption. 2. Treatment with an investigational product (except sonlicromanol (KH176)) 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. Documented history of ventricular tachycardia (HR>110 beats/min). 4. (Family) history of acute heart failure, unexplained syncope or congenital long QT syndrome. 5. Clinically relevant abnormal laboratory, vital signs or physical or mental health; a) Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) > 3 x upper limit of normal (ULN), or bilirubin > 3 x ULN at screening. If a patient has ASAT or ALAT > 3 x ULN but 150 mmHg at screening or baseline. d) All other clinically relevant parameters at screening or baseline as judged by the Investigator. 6. Clinically relevant abnormal ECG or cardiac functioning, defined as ST-segment elevation > 1 mm in I, II, III, aVL ,aVF ,V3 ,V4 ,V5 ,V6; > 2 mm in V1, V2; QTc > 450 ms (local, machine read), T-top inversion in >1 consecutive lead. 7. Serum hyperkalemia (> 5.0 mEq/L). 8. Serum hypokalemia (< 3.5 mEq/L). 9. History of ischemic heart disease. 10. Symptomatic heart failure. 11. Clinically relevant aorta and/or mitralis valvular defect as judged by the investigator. 12. Pregnancy or breast feeding (females). 13. History of hypersensitivity or idiosyncrasy to any of the components of the investigational drug. 14. 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, rifampicine, St. John’s wort, pioglitazone, troglitazone). e. any medication known to affect cardiac repolarisation (all anti-psychotics, several anti-depressants, e.g. anti-emetics: domperidone, granisetron, ondansetron). f. any medication metabolised by CYP3A4 with a narrow therapeutic width. For reference (The Netherlands): KNMP Kennisbank (https://www.knmp.nl/producten/knmp-kennisbank/inloggen-knmp-kennisbank).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the long-term safety of sonlicromanol (KH176) during an 18-months treatment period, including: 1.The tolerability and safety of sonlicromanol 100 mg BID (potentially reduced to 50 mg BID) following 18 months of oral administration 2.Electrocardiogram (ECG) intervals, rhythm and morphology ;Secondary Objective: Secondary objectives To explore the effect of sonlicromanol (KH176) on cognitive domains To explore the effect of sonlicromanol during an 18 months treatment period on: 1.Test of Attentional Performance 2.Beck Depression Inventory 3.Hospital Anxiety and Depression Scale 4.Newcastle Mitochondrial Disease Scale for Adults 5.Number of headache days, intensity and duration, and use of medication 6.Hearing 7.Smell identification 8.Cognitive Failure Questionnaire 9.Neuro-QoL Fatigue 10.Five times Sit to Stand Test 11.Mini-Balance Evaluation Systems-Test 12.Handgrip Strength ( 13.Glucose homeostasis / diabetes control 14.Short Form McGill Pain Questionnaire 15.RAND SF-36 16.Clinician-scored Global Impression of Change 17.Patient-scored Global Impression of Change 18.Patient-scored Impression of Change Additional objectives •Pharmacokinetic parameters of KH176/KH183 •Health Economics and Outcomes Research information •Biomarker/metabolomics analysis ;Primary end point(s): •Frequency of TEAEs throughout the treatment period. •Changes from baseline to each assessment visit in vital signs, ECG parameters, laboratory parameters (chemistry, haematology, urinalysis). ;Timepoint(s) of evaluation of this end point: From first intake of the study medication until the Follow-up Visit scheduled 28 days after the last intake of study medication. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary efficacy endpoints: Changes from baseline to each assessment visit in the following domains of cognitive functioning: • the attention domain score of cognitive functioning, as assessed by the visual identification test of the Cogstate computerised cognitive testing battery • executive functioning • working memory • psychomotor function • visual learning • verbal learning Changes from baseline to each visit in: • TAP: Alertness • HADS, supplemented with a Beck Depression Index (BDI) • NMDAS Score • Number of headache days, intensity and duration and use of medication to relieve headache • Hearing (Pure Tone Audiometry (PTA) and speech audiometry) • Smell identification test (University of Pennsylvania Smell Identification Test (UPSIT)) • CFQ (overall score and 4 sub scores) • Neuro-QoL Fatigue Short Form • Five Times Sit to Stand test (5XSST) • Mini-Balance Evaluation Systems Test (Mini-BESTest) • Handgrip strength (HS) • HbA1c • Mean daily insulin dose (weighted average daily dose over periods 0-3, 3-6, 6-9, 9-12, 12-15 and 15-18 months) • Mean daily oral antidiabetics dose (weighted average daily dose over periods 0-3, 3-6, 6-9, 9-12, 12-15 and 15-18 months) • Short Form McGill Pain Questionnaire (SF-MPQ) • RAND SF-36 • Clinician-scored Global Impression of Change (CGIC) • Patient-scored Global Impression of Change (PGIC) • Patient-scored Impression of Change on patient-identified three most bothersome symptoms caused by mitochondrial disease (Most Bothersome Symptom Assessment (MBSA)) Other endpoints • Proportion of patients with post-baseline termination of 1 or more anti-diabetics • Proportion of patients with post-baseline starting of 1 or more anti-diabetics • Metabolomics and biomarker in plasma and urine • EQ-5D-5L ;Timepoint(s) of evaluation of this end point: Pre-dose day 1 (baseline, week 13, week 26, week 39, week 52, week 65, week 78 and Follow up (day 28 after last drug intake. | — |
Countries
Denmark, Germany, Netherlands, United Kingdom
Contacts
Public ContactMarcel Bootsma
Julius Clinical
Outcome results
None listed