A study to evaluate the efficacy of KH176 in patients with a genetically confirmed mitochondrial DNA mutation. Patients to be allocated randomly to placebo or investigational drug in different periods; meaning each patient will receive both placebo as well as the investigational drug. Assignment of actual treatment order will be unknown to patient and doctor.
- Conditions
- A genetically confirmed mitochondrial desoxyribonucleic acid (DNA) transfer ribonucleic acid (tRNA)Leu(UUR) m.3243A>G mutation (including but not limited to MELAS, MIDD and mixed compositions).MedDRA version: 22.0Level: PTClassification code 10052641Term: Mitochondrial DNA mutationSystem Organ Class: 10010331 - Congenital, familial and genetic disordersTherapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]
- Registration Number
- EUCTR2019-000599-40-DK
- Lead Sponsor
- Khondrion B.V.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 27
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.Confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation (heteroplasmy = 20%, urinary epithelial cells).
4.Positive NMDAS score >10 at Screening.
5. Three or more clinical features, with no other causative unifying diagnosis, found to commonly occur in subjects with a m.3243A>G mutation:
- Deafness
- Developmental delay
- Diabetes Mellitus
- Epilepsy
- Gastrointestinal complaints
- Progressive External Ophtalmoplegia (PEO) and retinopathy
- Ataxia
- Exercise intolerance
- Fatigue
- Migraine (with or without aura), specified by at least five attacks fulfilling diagnostic criteria B-D:
B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)
C. Headache has at least two of the following four characteristics:
1. unilateral location
2. pulsating quality
3. moderate or severe pain intensity
4. aggravation or causing avoidance of routine physical activity (e.g. walking or climbing stairs)
D. During headache at least one of the following:
1. nausea and/or vomiting
2. photophobia and phonophobia
6.Attentional dysfunction score (Cogstate Identification test) = 0.2 standard deviations poorer than healthy controls at Screening.
7.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.
8.Objectified Left Ventricular Ejection Fraction (LVEF) =45% (echocardiography, or otherwise).
9.Left Ventricular (LV) wall thickness =15 mm.
10.Left atrium dilatation = 40 mL/m2.
Note: No need to test LV parameters (criteria #7, #8, #9) if favorable echocardiography (or otherwise) results dated less than 6 months prior to Screening are available.
11.Women of childbearing potential 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. Sexual abstinence is an acceptable contraceptive method only as true abstinence: when this is in line with the preferred and usual lifestyle of the patient. [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: 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 childb
1. Surgery of gastro-intestinal tract that might interfere with absorption.
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. Documented history of ventricular tachycardia (HR>110 beats/min).
4. History of acute heart failure, (family) history of unexplained syncope or congenital long and short QT syndrome or sudden death.
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 < 3.5 x ULN, re-assessment is allowed at the investigator’s discretion.
b) Estimated glomerular filtration rate = 60 mL/min according to the CKD-EPI formula at screening.
c) Systolic Blood pressure > 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 for male subjects; QTc: > 470ms for female subjects (local, machine read), T-top inversion in >1 consecutive lead.
7. Serum Hyper-potassium (> 5.0 mmol/L).
8. Serum Hypo-potassium (< 3.5 mmol/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. Poor nutritional state as judged by the investigator.
14. History of hypersensitivity or idiosyncrasy to any of the components of the investigational drug.
15. Medical history of drug abuse (illegal drugs such as cannabinoids, amphetamines, cocaine, opiates or problematic use of prescription drugs such as benzodiazepines, opiates).
16. 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.
c. any strong CYP3A4 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 QTc interval at screening is normal during stable treatment (all anti-psychotics, several anti-depressants: e.g. nor/amitriptyline, fluoxetine, anti-emetics: domperidone (motilium) granisetron, ondansetron). For a complete list see https://crediblemeds.org.
f. any medication metabolised by CYP with a narrow therapeutical width. For reference (Germany and United Kingdom): drug interaction table of Indiana University (http://medicine.iupui.edu/
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method