The KHENERGY Study

Study Overview
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Brief Summary
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Mitochondrial Diseases are rare, progressive, multi-system, often-early fatal disorders affecting both children and adults. KH176 is a novel chemical entity currently under development for the treatment of inherited mitochondrial diseases, including MELAS (Mitochondrial Encephalomyopathy, Lactic acidosis, and Stroke-like episodes), MIDD (Maternally Inherited Diabetes and Deafness), Leigh's Disease and LHON (Leber's Hereditary Optic Neuropathy). The current Proof of Concept study aims to explore the effects of treatment with KH176 for 4 weeks on clinical signs and symptoms and biomarkers of mitochondrial disease and to evaluate the safety and pharmacokinetics of KH176 in patients with m.3242A>G related mitochondrial disease.

Detailed Description
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The trial will be a double blind, randomized, placebo-controlled, single-centre, two-way cross-over trial. Twenty patients, with a confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation and with clinical signs of mitochondrial disease, will be randomized over 2 groups (active or placebo first). After a screening period and a training session, each group will have 2 dosing periods of 28 days, with a washout period of at least 28 days in between. On these occasions, patients will receive 100 mg KH176 twice daily (treatment A) or a matching placebo (treatment B) twice daily for 28 days. Clinical assessments will be performed once in a training session prior to baseline, at baseline and in week 4 post dosing during each treatment phase (A and B). Testing conditions and circumstances, with respect to timing of the assessments, hospitalization and meals, will be standardized for each assessement period. Furthermore, assessments of biomarkers for mitochondrial functioning, pharmacokinetics and specific safety assessments will be performed weekly.

Official Title
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An Exploratory, Double-blind, Randomized, Placebo-controlled, Single-center, Two-way Cross-over Study With KH176 in Patients With the Mitochondrial DNA tRNALeu(UUR) m.3243A>G Mutation and Clinical Signs of Mitochondrial Disease

Conditions
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Mitochondrial Diseases, Mitochondrial Myopathies, Mitochondrial Encephalomyopathies, MELAS, MIDD

Intervention / Treatment
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* Drug: KH176
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females aged 18 years or older at screening Ability and willingness to sign the Informed Consent Form prior to screening evaluations. Confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation Heteroplasmy level as measured in urine ≥ 20 %. Body Mass Index (BMI) 18.0-30.0 kg/m2 (extremes included) at screening Clinical evidence of mitochondrial disease, positive NMDAS score (including but not limited to MELAS, MIDD and mixed types). CPEO patients with signs restricted to the eye only are not considered eligible. Disease appropriate physical and mental health as established by medical history, physical examination, electrocardiogram (ECG) and vital signs recording, and results of biochemistry, hematology and urinalysis testing within 3 weeks prior to the first dose as judged by the Investigator. Appropriate cardiac functioning as assessed by medical history, ECG and Echo, evaluated by a cardiologist. Able to comply with the study requirements, including exercise testing and swallowing study medication Willingness to use adequate contraceptive methods (male and female) and negative urine pregnancy test (females) at screening and first baseline assessment. Able and willing to refrain from the use of (multi)vitamins, co-enzyme Q10, Vitamine E, riboflavin, and anti-oxidant supplements (and idebenone/EPI-743), as well as any medication negatively influencing mitochondrial functioning (including but not limited to valproic acid, glitazones, statins, anti-virals, amiodarone, and NSAID's) as well as any strong Cytochrome P450 inhibitors (all 'conazoles-anti-fungals', HIV antivirals, grapefruit) and strong Cytochrome P450 inducers (a.o. carbamazepine, phenobarbital, phenytoin, rifampicine, St Johns wort, pioglitazone, troglitazone) as well as any medication known to affect cardiac repolarization (all anti-psychotics, several anti-depressants: nor/amytriptilline, fluoxetine, anti-emetics: domperidone (motilium) granisetron, ondansetron). Exclusion Criteria: Motoric abnormalities other than related to the mitochondrial disease interfering with the outcome parameters. CPEO patients with clinical signs and symptoms restricted to the eye only Heteroplasmy level as measured in urine < 20% Poor nutritional state as judged by the investigator Body Mass Index (BMI) not within 18.0-30.0 kg/m2 at screening. History of cancer Surgery or active illness of gastro-intestinal tract that might interfere with absorption. Participation in a trial of an investigational product in the preceding 3 months prior to the first dose or during this trial. Positive drug, alcohol or cotinine test at screening and/or admission (Day 1 of the first dosing period). Clinically relevant abnormal laboratory, ECG recordings, cardiac echo (within 1 year prior to screening), vital signs or physical or mental findings at screening as judged by the Investigator. Clinically relevant abnormal ECG or cardiac functioning as judged by a cardiologist. ECG: QTc > 450 ms, abnormal T-wave Symptomatic heart failure or signs of ischemic heart disease Left Ventricular Ejection Fraction <45% History or family history of congenital Long QT syndrome Increased or decreased potassium (local laboratory normal range) Inadequate contraception use, pregnancy or breast feeding (females) Clinically significant presence or history of allergy as judged by the Investigator. History of hypersensitivity or idiosyncrasy to any of the components of the investigational drug. Within 4 weeks prior to dosing, the use of: (multi)vitamins, co-enzyme Q10, Vitamine E, riboflavin, and anti-oxidant supplements (and idebenone/EPI-743), as well as any medication negatively influencing mitochondrial functioning (including but not limited to valproic acid, glitazones, statins, anti-virals, amiodarone, and NSAID's) as well as any strong Cytochrome P450 inhibitors (all 'conazoles-anti-fungals', HIV antivirals, grapefruit) and strong Cytochrome P450 inducers (a.o. carbamazepine, phenobarbital, phenytoin, rifampicin, St Johns wort, pioglitazone, troglitazone) as well as any medication known to affect cardiac repolarization (all anti-psychotics, several anti-depressants: nor/amitriptyline, fluoxetine, anti-emetics: domperidone (motilium) granisetron, ondansetron) as well as any medication metabolized by Cytochrome P450 with a narrow therapeutical width. (for reference: drug interaction table of Indiana University http://medicine.iupui.edu/clinpharm/ddis/clinical-table/)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>Oral administration of 100 mg KH176 twice daily | Drug: KH176<br> <br> |
| Placebo Comparator: Treatment B<br>Oral administration of matching placebo twice daily | Drug: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Movement disorders | Rater assessed change from baseline of motoric abnormalities and movement characteristics | one month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NMDAS | Change from baseline of the Newcastle Mitochondrial Disease Activity Score | one month | 
| Spirometric parameters (FVC,FEV1, PEF) | Change from baseline in spirometric parameters | one month | 
| Spirometric parameters (MIP, MEP) | Change from baseline in spirometric parameters | one month | 
| Sit to Stand Test (30 seconds) | Change from baseline assessment of the maximum number of sit-standings in 30 seconds time | one month | 
| Handgrip Dynamometry | Change from baseline assessment of the maximum grip strenght | one month | 
| 6-min chewing test | Change from baseline assessment in rate of mastication | one month | 
| 6-min chewing test | Change from baseline assessment of pain and tiredness (VAS) during a 6-min chewing test | one month | 
| 6-MWT | Change from baseline assessment of the Distance during a 6-min Walk Test | one month | 
| RAND-SF36 score | Change from baseline in the RAND-SF36 | one month | 
| HAD and BDI | Change from baseline in the Hospital Anxiety and Depression Scale (HAD), supplemented with a Beck Depression Index (BDI) | one month | 
| BDI | Change from baseline in the Beck Depression Index (BDI) | one month | 
| CIS | Change from baseline in the Checklist Individual Strength | one month | 
| TAP | Change from baseline assessment of alertness and mental flexibility during a Test of Attentional Performance (TAP) | one month | 
| Goal Attainment Scale | Assessment of pre-defined goal attainment during each treatment period | one month | 
| Registration of Motor Activity and Sleeping pattern | During each treatment period a continuous registration of Motor Activity and Sleeping pattern by accelerometer, assessing sleep quality, quantity and overall motor activity | one month | 
| Vital Signs | Change from Baseline assessment of vital signs (heart rate, blood pressure) | one month | 
| ECG | Change from Baseline assessment of ECG-intervals | one month | 
| Clinical Laboratory | Change from Baseline assessment of Clinical Laboratory parameters | one month | 
| Pharmacokinetics of KH176 and metabolites | Attainment of steady state and total exposure (AUC) at steady state conditions | one month | 
| Pharmacokinetics of KH176 and metabolites | Attainment of steady state and maximal concentrations (Cmax) at steady state conditions | one month | 
| Glutathione | Change from baseline assessment of the ratio of oxidized/reduced glutathione in blood samples (GSH/GSSG) | one month | 
| Blood biomarker FGF21 | Change from baseline assessment of FGF21 | one month | 
| Blood biomarker GDF15 | Change from baseline assessment of GDF15 | one month | 
| Blood biomarker PRDX1 | Change from baseline assessment of PRDX1 | one month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oxidative phosphorylation (oxphos), MELAS, MIDD, KH176, Proof of Concept, mitochondrial