The KHENERGY Study

NCT02909400 | Completed Phase 2

• 1 other identifier: KH176-201
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Mitochondrial Diseases; Mitochondrial Myopathies; Mitochondrial Encephalomyopathies; MELAS; MIDD

Keywords

mitochondrial; oxidative phosphorylation (oxphos); MELAS; MIDD; KH176; Proof of Concept

Outcome Measures

Primary Outcomes (1)

• Movement disorders

  Rater assessed change from baseline of motoric abnormalities and movement characteristics

  one month

Secondary Outcomes (24)

• NMDAS

  one month

• Spirometric parameters (FVC,FEV1, PEF)

  one month

• Spirometric parameters (MIP, MEP)

  one month

• Sit to Stand Test (30 seconds)

  one month

• Handgrip Dynamometry

  one month

Study Arms (2)

Treatment A

EXPERIMENTAL

Oral administration of 100 mg KH176 twice daily

Drug: KH176

Treatment B

PLACEBO COMPARATOR

Oral administration of matching placebo twice daily

Drug: placebo

Interventions

KH176 DRUG

Treatment A

placebo DRUG

Treatment B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• Khondrion BV: lead
• Radboud University Medical Center: collaborator

Study Sites (1)

Radboud University Medical Center

Nijmegen, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 30058726 DERIVED

MeSH Terms

Conditions

Mitochondrial Diseases; Mitochondrial Myopathies; Mitochondrial Encephalomyopathies; MELAS Syndrome

Interventions

6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Brain Diseases, Metabolic, Inborn; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 13, 2016
• First Posted: September 21, 2016
• Study Start: September 1, 2016
• Primary Completion: July 1, 2017
• Study Completion: July 1, 2017
• Last Updated: February 23, 2018

Record last verified: 2018-02

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)