The KHENERGYZE Study

NCT04165239 | Completed Phase 2

• 1 other identifier: KH-176-202
• Study Type: interventional
• Target: 27
• Locations: 4 countries
• Sites: 4

Brief Summary

Mitochondrial diseases, estimated prevalence 1 in 4,300 adults, is caused by pathogenic mutations in genes finally encoding for mitochondrial proteins of the various enzyme complexes of the OXPHOS. Among these mutations, the 3243A\>G nucleotide change in the mitochondrially encoded transfer RNALeu(UUR) leucine 1 gene (MT TL 1) is the most prevalent one. The OXPHOS dysfunction resulting from such mutations leads to increased production of reactive oxygen species (ROS), ultimately leading to irreversible oxidative damage of macromolecules, or to more selective and reversible redox modulation of cell signaling that may impact (adult) neurogenesis. Despite advances in the understanding of mitochondrial disorders, treatment options are extremely limited and, to date, largely supportive. Therefore, there is an urgent need for novel treatments. KH176, a new active pharmaceutical ingredient (API), is an orally bio-available small molecule under development for the treatment of these disorders (see Section 1.4). The current study will further evaluate the effect of KH176 in various cognitive domains and evaluate the effect of different doses of KH176 (See Section 1.5). In view of the growing recognition of the importance of mitochondrial function in maintaining cognitive processes in the brain, as well as the understanding of the safety profile and pharmacokinetics of KH176 following the two clinical studies described above, a more detailed study is indicated of the effects of KH176 in various cognitive domains, using the confirmed safe and well-tolerated KH176 dose of 100 mg bid, as well as a lower dose of 50 mg bid. The primary objective is an evaluation of KH176 in the attention domain of cognitive functioning, as assessed by the visual identification test score of the Cogstate computerised cognitive testing battery.

Conditions

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

Keywords

Mitochondrial; Oxidative Phosphorylation (OXPHOS); MELAS; MIDD; KH176

Outcome Measures

Primary Outcomes (1)

• Cognitive functioning: Attention

  The attention domain score of cognitive functioning, as assessed by the visual Identification Test of the Cogstate computerised cognitive testing battery

  One month

Secondary Outcomes (14)

• Executive functioning

  One month

• Psychomotor function

  One month

• Working Memeory

  One month

• Visual learning

  One month

• Verbal learning

  One month

Study Arms (3)

Treatment A

EXPERIMENTAL

Oral administration of 50 mg KH176 twice daily

Drug: KH176

Treatment B

EXPERIMENTAL

Oral administration of 100 mg KH176 twice daily

Drug: KH176

Treatment C

PLACEBO COMPARATOR

Oral administration of matching placebo twice daily

Drug: Placebo

Interventions

KH176 DRUG

Oral administration of 50 mg KH176 twice daily

Also known as: Sonlicromanol

Treatment A

Placebo DRUG

Oral administration of matching placebo twice daily

Treatment C

Eligibility Criteria

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

You may not qualify if:

• Surgery of gastro-intestinal tract that might interfere with absorption.
• 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.
• Documented history of ventricular tachycardia (HR\>110 beats/min).
• History of acute heart failure, (family) history of unexplained syncope or congenital long and short QT syndrome or sudden death.
• Clinically relevant abnormal laboratory, vital signs or physical or mental health;
• 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.
• Estimated glomerular filtration rate ≤ 60 mL/min according to the CKD-EPI formula at screening.
• Systolic Blood pressure \> 150 mmHg at screening or baseline.
• All other clinically relevant parameters at screening or baseline as judged by the Investigator.
• 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.
• Serum Hyper-potassium (\> 5.0 mEq/L).
• Serum Hypo-potassium (\< 3.5 mEq/L).
• History of ischemic heart disease.
• Symptomatic heart failure.
• Clinically relevant aorta and/or mitralis valvular defect as judged by the investigator.

Sponsors & Collaborators

• Khondrion BV: lead
• Julius Clinical: collaborator

Study Sites (4)

Rigshospitalet, University of Copenhagen

Copenhagen, DK2100, Denmark

Location

Friedrich-Baur Institut

München, Bavaria, 80336, Germany

Location

Radboud University Medical Center

Nijmegen, Netherlands

Location

Institute for Ageing and Health Newcastle University

Newcastle upon Tyne, United Kingdom

Location

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

Model Details: The study will be a double-blind, randomised, placebo-controlled, multi-centre, three-way cross-over study. Twenty-seven subjects, with a confirmed mitochondrial DNA tRNALeu(UUR) 3243A\>G mutation and with clinical signs of mitochondrial disease including attentional dysfunction, and fulfilling pre-defined cardiac exclusion criteria, will be randomised over three treatment sequences as assigned by Latin-square. Each group will have 3 treatment periods of 28 days each, separated by 14-day washout periods between treatments. During the 28-day treatment periods, subjects will receive bid oral administration of 50 mg KH176,100 mg KH176, or placebo in the sequence as applicable for the group.

Study Record Dates

• First Submitted: November 13, 2019
• First Posted: November 15, 2019
• Study Start: October 30, 2019
• Primary Completion: May 24, 2022
• Study Completion: May 24, 2022
• Last Updated: August 31, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1); NL (1); DE (1); GB (1)