The KHENEREXT Study

NCT04604548 | Completed Phase 2 DMC

• 1 other identifier: KH176-203
• Study Type: interventional
• Target: 11
• Locations: 4 countries
• Sites: 4

Brief Summary

This is an open-label, multi-centre study in subjects with a genetically confirmed mitochondrial deoxyribonucleic acid (DNA) transfer ribonucleic acid (tRNA)Leu(UUR) m.3243A\>G mutation who completed study KH176-202. In the KH176-203 study subjects will be receiving KH176 100 mg BID or KH176 50 mg bid in die (BID) (as determined by the investigator based on safety / tolerability considerations) for a year, thereby ensuring continued treatment with KH176 after study KH176-202. A final follow-up visit is scheduled 4 weeks after the intake of the last dose of study medication for patients not rolling over into the compassionate use program. Primary safety data and secondary efficacy (endpoint) data will be monitored and reviewed every three months by an independent Data Safety Monitoring Board (DSMB) to evaluate potential risks and benefits.

Conditions

Mitochondrial Diseases; Mitochondrial DNA tRNALeu(UUR) m.3243A<G Mutation; Maternally Inherited Diabetes and Deafness (MIDD); Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke Like Episodes (MELAS); Chronic Progressive External Ophthalmoplegia (CPEO)

Keywords

KH176; Open Label Extension; MELAS; MIDD; CPEO; oxidative phosphorylation (oxphos)

Outcome Measures

Primary Outcomes (1)

• Treatment Emergent Adverse Events (TEAE)

  Frequency of TEAEs throughout the treatment period.

  52 weeks

Secondary Outcomes (66)

• Blood Pressure (mmHG)

  52 weeks

• Safety Outcomes

  52 weeks

• Cognitive functioning: Attention

  52 weeks

• Executive functioning

  52 weeks

• Psychomotor functioning

  52 weeks

Study Arms (1)

Open Label treatment

EXPERIMENTAL

Oral administration of 100 mg KH176 twice daily

Drug: Oral administration of 100 mg KH176 twice daily

Interventions

Oral administration of 100 mg KH176 twice daily DRUG

Drug: KH176

Open Label treatment

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 provide written Informed Consent prior to screening evaluations.

You may not qualify if:

• Disease appropriate physical and mental health as established at Screening by medical history, physical examination, ECG and vital signs recording, and results of clinical chemistry and haematology testing as judged by the investigator.
• Objectified Left Ventricular Ejection Fraction (LVEF) ≥45% (echocardiography, or otherwise).
• Left Ventricular (LV) wall thickness ≤15 mm.
• Left atrium dilatation ≤ 40 mL/m2. Note: No need to test LV parameters (criteria #5, #6, #7) if favourable echocardiography (or otherwise) results dated less than 13 months prior to Screening are available.
• Women of childbearing potential must be willing to use highly effective contraceptive methods during the entire study, i.e., combined (estrogen and progestogen containing) oral, intravaginal or transdermal hormonal contraception associated with inhibition of ovulation;, oral, injectable or implantable progestogen-only hormonal contraception associated with inhibition of ovulation; use of an intrauterine device; an intrauterine hormone releasing system, bilateral tubal occlusion and vasectomy of the partner. Any hormonal contraception method must be supplemented with a barrier method (preferably male condom). Vasectomised partner is considered a highly effective birth control method provided that partner is the sole sexual partner of the subject and that the vasectomised partner has received medical assessment of the surgical success. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. Reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Note 1: Natural family planning methods, female condom, cervical cap or diaphragm are not considered adequate contraceptive methods in the context of this study.
• Note 2: To be considered not of childbearing potential, potential female subjects must be post-menopausal for at least two years, or have been surgically sterilised (bilateral tubal ligation, hysterectomy or bilateral oophorectomy) for at least 6 months prior to Screening.
• Note 3: KH176 has been shown non-genotoxic judged from the Ames test, Chromosomal Aberration test and in vivo Micronucleus test. Moreover, appreciable systemic exposure from the exposure to (\~2.5 mL) semen is extremely unlikely. However, until reproductive toxicology studies have confirmed that KH176 does not adversely affect normal reproduction in adult males and females, as well as causing developmental toxicity in the offspring, the following contraceptive precautions must be adhered to:
• male subjects with female partners of childbearing potential must be willing to use condoms during the entire study.
• female partners of childbearing potential of male subjects must be willing to use adequate contraceptive methods during the entire study, i.e., a hormonal contraceptive method (pill, vaginal ring, patch, implant, injectable, hormone-medicated intrauterine device) or an intrauterine device.
• Able to comply with the study requirements, including swallowing study medication.
• In order to be eligible to participate in this study, a subject must not meet any of the following criteria:
• Surgery of gastro-intestinal tract that might interfere with absorption.
• Treatment with an investigational product (except KH176) 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), PVC burden ≥5% or daytime Mobitz II AV block on any of the Holter assessments in the KH176-202 study or in the medical history.

Sponsors & Collaborators

• Khondrion BV: lead
• Julius Clinical: collaborator
• ProPharma Group: collaborator
• Certara: collaborator

Study Sites (4)

Rigshospitalet, University of Copenhagen

Copenhagen, DK2100, Denmark

Location

Klinikum der Universität München Friedrich-Baur-Institut

München, 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; Noninsulin-dependent diabetes mellitus with deafness; MELAS Syndrome; Ophthalmoplegia, Chronic Progressive External

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Muscular Diseases; Musculoskeletal Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Neuromuscular Diseases; Vascular Diseases; Cardiovascular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Ophthalmoplegia; Ocular Motility Disorders; Cranial Nerve Diseases; Paralysis; Neurologic Manifestations; Eye Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open Label

Study Record Dates

• First Submitted: June 19, 2020
• First Posted: October 27, 2020
• Study Start: August 9, 2021
• Primary Completion: June 1, 2023
• Study Completion: June 1, 2023
• Last Updated: March 6, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

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