EUCTR2019-000599-40-DE进行中（未招募）1 期
A Phase IIb double-blind, randomised, placebo-controlled, multi-centre, confirmative three-way cross-over study on cognitive function with two doses of KH176 in subjects with a genetically confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation. - KHENERGYZE
Khondrion B.V.0 个研究点目标入组 27 人开始时间: 2019年9月10日最近更新:
适应症
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 27
研究概览
简要总结
暂无简介。
研究设计
- 研究类型
- Interventional clinical trial of medicinal product
入排标准
- 性别
- All
入选标准
- •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
- •- Exercise intolerance
- •- 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 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 pote
排除标准
- •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/
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