The KHENERGYZE Study

NCT ID: NCT04165239

Last Updated: 2022-08-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 27 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-30
• Study Completion Date: 2022-05-24

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.

Detailed Description

For this study, a 3 x 3 crossover design will be applied, i.e., with 3 treatments, 3 sequences and 3 periods, employing a Latin square assignment. Using this design, each subject will function as his/her own control. This will reduce variability and thus increase the chances of observing true effects between treatment periods (effects of treatment compared to placebo). In each treatment period, assessments will be performed at baseline prior to dosing and post dosing, enabling a change from baseline analysis and enabling the possibility to compare baseline conditions for each treatment period. The treatment period in each treatment is 28 days (4 weeks), which is supported by the pre-clinical toxicology program. In mouse studies, a 4-week period was sufficient to observe clinically relevant effects.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Treatment A

Oral administration of 50 mg KH176 twice daily

Group Type: EXPERIMENTAL

KH176

Intervention Type: DRUG

Oral administration of 50 mg KH176 twice daily

Treatment B

Oral administration of 100 mg KH176 twice daily

Group Type: EXPERIMENTAL

KH176

Intervention Type: DRUG

Oral administration of 100 mg KH176 twice daily

Treatment C

Oral administration of matching placebo twice daily

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Oral administration of matching placebo twice daily

Interventions

KH176

Oral administration of 50 mg KH176 twice daily

Intervention Type: DRUG

KH176

Oral administration of 100 mg KH176 twice daily

Intervention Type: DRUG

Placebo

Oral administration of matching placebo twice daily

Intervention Type: DRUG

Other Intervention Names

Sonlicromanol; Sonlicromanol

Eligibility Criteria

Exclusion Criteria

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;

1. 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.

2. Estimated glomerular filtration rate ≤ 60 mL/min according to the CKD-EPI formula at screening.

3. Systolic Blood pressure > 150 mmHg at screening or baseline.

4. 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 mEq/L).

8. Serum Hypo-potassium (< 3.5 mEq/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:

1. (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.

2. 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.

Note: thus, mitoQ and any medication negatively influencing mitochondrial functioning are allowed as long as the dose has been stable for at least one month prior to first dosing and remains stable throughout the study.

3. any strong Cytochrome P450 (CYP)3A4 inhibitors (all 'conazoles-anti-fungals', HIV antivirals, grapefruit).

4. strong CYP3A4 inducers (including HIV antivirals, carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort, pioglitazone, troglitazone).

5. any medication known to affect cardiac repolarisation, unless the 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.

6. 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/clinpharm/ddis/clinical-table/). For reference (The Netherlands): KNMP Kennisbank (https://www.knmp.nl/producten/knmp-kennisbank/inloggen-knmp-kennisbank. For reference (all other countries): drug interaction table of Indiana University (http://medicine.iupui.edu/clinpharm/ddis/clinical-table/).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Julius Clinical

INDUSTRY

Sponsor Role: collaborator

Khondrion BV

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Rigshospitalet, University of Copenhagen

Copenhagen, , Denmark

Friedrich-Baur Institut

München, Bavaria, Germany

Radboud University Medical Center

Nijmegen, , Netherlands

Institute for Ageing and Health Newcastle University

Newcastle upon Tyne, , United Kingdom

Countries

Denmark; Germany; Netherlands; United Kingdom

Other Identifiers

KH-176-202

Identifier Type: -

Identifier Source: org_study_id