The KHENERGY Study (KHENERGY)

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

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.

Study Overview

• Status: Completed
• Conditions: Mitochondrial Diseases; Mitochondrial Myopathies; MELAS; Mitochondrial Encephalomyopathies; MIDD
• Intervention / Treatment: Drug: placebo; Drug: KH176

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands
    • Radboud University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males and females aged 18 years or older at screening
2. Ability and willingness to sign the Informed Consent Form prior to screening evaluations.
3. Confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation
4. Heteroplasmy level as measured in urine ≥ 20 %.
5. Body Mass Index (BMI) 18.0-30.0 kg/m2 (extremes included) at screening
6. 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.
7. 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.
8. Appropriate cardiac functioning as assessed by medical history, ECG and Echo, evaluated by a cardiologist.
9. Able to comply with the study requirements, including exercise testing and swallowing study medication
10. Willingness to use adequate contraceptive methods (male and female) and negative urine pregnancy test (females) at screening and first baseline assessment.
11. 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:

1. Motoric abnormalities other than related to the mitochondrial disease interfering with the outcome parameters.
2. CPEO patients with clinical signs and symptoms restricted to the eye only
3. Heteroplasmy level as measured in urine < 20%
4. Poor nutritional state as judged by the investigator
5. Body Mass Index (BMI) not within 18.0-30.0 kg/m2 at screening.
6. History of cancer
7. Surgery or active illness of gastro-intestinal tract that might interfere with absorption.
8. Participation in a trial of an investigational product in the preceding 3 months prior to the first dose or during this trial.
9. Positive drug, alcohol or cotinine test at screening and/or admission (Day 1 of the first dosing period).
10. 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.
11. Clinically relevant abnormal ECG or cardiac functioning as judged by a cardiologist.
12. ECG: QTc > 450 ms, abnormal T-wave
13. Symptomatic heart failure or signs of ischemic heart disease
14. Left Ventricular Ejection Fraction <45%
15. History or family history of congenital Long QT syndrome
16. Increased or decreased potassium (local laboratory normal range)
17. Inadequate contraception use, pregnancy or breast feeding (females)
18. Clinically significant presence or history of allergy as judged by the Investigator.
19. History of hypersensitivity or idiosyncrasy to any of the components of the investigational drug.

20. 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/)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment A; Oral administration of 100 mg KH176 twice daily	Drug: KH176
PLACEBO_COMPARATOR: Treatment B; Oral administration of matching placebo twice daily	Drug: placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Khondrion BV
• Collaborators: Radboud University Medical Center

Publications and helpful links

General Publications

• Janssen MCH, Koene S, de Laat P, Hemelaar P, Pickkers P, Spaans E, Beukema R, Beyrath J, Groothuis J, Verhaak C, Smeitink J. The KHENERGY Study: Safety and Efficacy of KH176 in Mitochondrial m.3243A>G Spectrum Disorders. Clin Pharmacol Ther. 2019 Jan;105(1):101-111. doi: 10.1002/cpt.1197. Epub 2018 Sep 3.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2016
• Primary Completion (ACTUAL): July 1, 2017
• Study Completion (ACTUAL): July 1, 2017

Study Registration Dates

• First Submitted: September 13, 2016
• First Submitted That Met QC Criteria: September 16, 2016
• First Posted (ESTIMATE): September 21, 2016

Study Record Updates

• Last Update Posted (ACTUAL): February 23, 2018
• Last Update Submitted That Met QC Criteria: February 22, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: MELAS; MIDD; KH176; mitochondrial; oxidative phosphorylation (oxphos); Proof of Concept
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Brain Diseases, Metabolic; Mitochondrial Diseases; Mitochondrial Myopathies; Mitochondrial Encephalomyopathies; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Antioxidants; 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
• Other Study ID Numbers: KH176-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO