The KHENEREXT Study

A Phase IIb Open-label, Multi-centre, Extension Study to Explore the Long-term Safety and Efficacy of KH176 in Subjects With a Genetically Confirmed Mitochondrial DNA tRNALeu(UUR) m.3243A>G Mutation Who Have Completed the KHENERGYZE Study KH176-202.

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.

Study Overview

• Status: Completed
• Conditions: Mitochondrial Diseases; Mitochondrial DNA tRNALeu(UUR) m.3243A; Maternally Inherited Diabetes and Deafness (MIDD); Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke Like Episodes (MELAS); Chronic Progressive External Ophthalmoplegia (CPEO)
• Intervention / Treatment: Drug: Oral administration of 100 mg KH176 twice daily

Detailed Description

Mitochondrial diseases, estimated prevalence 1 in 4,300 adults, are caused by pathogenic mutations in genes that ultimately encode mitochondrial proteins of the different enzyme complexes of the oxidative phosphorylation system (OXPHOS). Of these mutations, the 3243> G nucleotide change in the mitochondrially encoded transfer RNALeu (UUR) leucine 1 gene (MT TL 1) is the most prevalent one. When mitochondria are defective, it can result in a wide variety of serious and debilitating diseases, especially in energy-demanding tissues such as the muscles and brain. Therefore, signs and symptoms of mitochondrial disease can include a variety of symptoms such as fatigue, exercise tolerance, muscle weakness, and ataxia, heart failure, deafness, blindness, stunted growth, and cognitive learning disabilities.

Despite advances in understanding mitochondrial disease, treatment options are extremely limited and largely supportive to date. Therefore, there is an urgent need for new treatments. KH176, a pharmaceutical ingredient (API), is an orally bioavailable small molecule under development for the treatment of these conditions. KH176 acts as a potent intracellular redox modulating agent targeting the reactive oxygen species as demonstrated in a number of in vitro and in vivo assays. An earlier phase II study showed positive effects of KH176 on alertness and mood.

The main objective of the current study is to enable continued treatment with KH176-202 for patients who have completed the KH176-202 study. Since KH176 is expected to be a chronic treatment for mitochondrial diseases, this study will examine long-term safety and explore long-term efficacy. To this end, the highest dose of 100 mg KH176 twice daily (safe and well tolerated by the target group in study KH176-201) will be used as the initial dose, to be administered over 1 year (minimum 365 days). Study KH176-202 uses doses of 50 mg twice daily and 100 mg twice daily. Currently, this study is still blinded, but a review of blinded safety data suggests that these doses are well tolerated.

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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jan Smeitink, MD, PhD, MAE; Phone Number: +31247635000; Email: smeitink@khondrion.com
• Study Contact Backup: Name: Gerrit Ruiterkamp; Phone Number: +31612805425 +31612805425; Email: ruiterkamp@khondrion.com

Study Locations

• Denmark
  • Kopenhagen, Denmark, DK2100
    • Rigshospitalet, University of Copenhagen
• Germany
  • München, Germany, 80336
    • Klinikum der Universität München Friedrich-Baur-Institut
• Netherlands
  • Nijmegen, Netherlands
    • Radboud University Medical Center
• United Kingdom
  • Newcastle upon Tyne, United Kingdom
    • Institute for Ageing and Health Newcastle University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Males and females aged 18 years or older at screening.
2. Ability and willingness to provide written Informed Consent prior to screening evaluations.
3. Having fulfilled all inclusion and exclusion criteria and completed the full treatment period of study KH176-202.
4. 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.
5. Objectified Left Ventricular Ejection Fraction (LVEF) ≥45% (echocardiography, or otherwise).
6. Left Ventricular (LV) wall thickness ≤15 mm.
7. 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.

8. 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.
9. Able to comply with the study requirements, including swallowing study medication.

Exclusion criteria:

In order to be eligible to participate in this study, a subject must not meet any of the following criteria:

1. Surgery of gastro-intestinal tract that might interfere with absorption.
2. 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.
3. 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.
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; e) 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.

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

   g) Systolic blood pressure > 150 mmHg at screening or baseline. h) 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; mean QTc of triplicate ECG recording > 450 ms for male subjects; mean QTc of triplicate ECG recording > 470ms for female subjects (Diagram-read), T-top inversion in >1 consecutive lead.
7. Serum hyperkalemia (> 5.0 mEq/L).
8. Serum hypokalemia (< 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. History of hypersensitivity or idiosyncrasy to any of the components of the investigational drug.
14. Medical history of drug abuse (illegal drugs such as cannabinoids, amphetamines, cocaine, opiates or problematic use of prescription drugs such as benzodiazepines, opiates).

15. 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 antioxidant supplements (including, but not limited to idebenone/EPI-743, mitoQ or alternative names for similar products); 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, rifampicine, St. John's wort, pioglitazone, troglitazone).
    5. any medication known to affect cardiac repolarisation, unless QTc interval at screening is normal during stable treatment for a period of two weeks, or 5 half-lives of the medication and its major metabolite(s), whichever period is the shortest (all anti-psychotics, several anti-depressants, e.g. nor-/amytriptiline, fluoxetine, anti-emetics: domperidone, granisetron, ondansetron). For a complete list see https://crediblemeds.org.
    6. any medication metabolised by CYP3A4 with a narrow therapeutic width

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open Label treatment; Oral administration of 100 mg KH176 twice daily	Drug: Oral administration of 100 mg KH176 twice daily; Drug: KH176

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Emergent Adverse Events (TEAE)	Frequency of TEAEs throughout the treatment period.	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Pressure (mmHG)	Changes from baseline to each assessment visit in blood pressure (mmHG)	52 weeks
Safety Outcomes	Changes from baseline to each assessment visit in vital signs, laboratory parameters (chemistry, haematology, urinalysis).	52 weeks
Cognitive functioning: Attention	The attention domain score of cognitive functioning, as assessed by the Identification Test of the Cogstate computerised cognitive testing battery.	52 weeks
Executive functioning	The executive functioning domain score of cognitive functioning, as assessed by the Groton Maze Learning Test of the Cogstate computerised cognitive testing battery.	52 weeks
Psychomotor functioning	The psychomotor functioning domain score of cognitive functioning, as assessed by the Detection Test of the Cogstate computerised cognitive testing battery.	52 weeks
Visual learning	The visual learning domain score of cognitive functioning, as assessed by the One Card Learning Test of the Cogstate computerised cognitive testing battery.	52 weeks
Working Memory	The working memory domain score of cognitive functioning, as assessed by the One Back Test of the Cogstate computerised cognitive testing battery.	52 weeks
Verbal learning	The verbal learning functioning domain score of cognitive functioning, as assessed by the International Shopping List Test of the Cogstate computerised cognitive testing battery.	52 weeks
Test of Attentional Performance (TAP)	Standardised test to evaluate alertness and mental flexibility.	52 weeks
Beck Depression Inventory (BDI)	21-question multiple-choice self-report inventory, for measuring the severity of depression.	52 weeks
Hamilton Anxiety and Depression Score (HADS)	Subject-reported outcome measure and comprises 14 items equally divided over the two subscales anxiety (HADS-A) and depression (HADS-D).	52 weeks
Newcastle Mitochondrial Disease Scale for Adults (NMDAS)	Semi-quantitative clinical rating scale designed for mitochondrial disease. The rating scale explores several domains: current function, system specific involvement, current clinical assessment and quality of life.	52 weeks
Number of headache days	Self report diary.	52 weeks
Pure Tone Audiometry (PTA)	Standardized test to measure individual hearing threshold levels.	52 weeks
University of Penn Smell Identification Test (UPSIT)	Test to measure the individual's ability to detect odors at a suprathreshold level.	52 weeks
Cognitive Failure Questionnaire (CFQ)	Questionnaire to evaluate subjective cognitive functioning.	52 weeks
Neuro-QoL Fatigue Short Form (quality in life in neurological disorders)	8-item self assessment questionnaire evaluating the perception of fatigue and its impact in daily life activities.	52 weeks
Five Times Sit to stand test (5XSST)	Test to measure lower limb functional strength.	52 weeks
Handgrip strength	Test to measure upper extremity deficits.	52 weeks
HbA1c	Glucose homeostasis / diabetes control.	52 weeks
Mean daily insulin dose	Glucose homeostasis / diabetes control.	52 weeks
Mean daily oral antidiabetics dose	Glucose homeostasis / diabetes control.	52 weeks
Short Form-36 (SF-36)	36-item self report health related quality of life questionnaire evaluating of functional health and well-being, physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, general health perceptions, and perceived change in health.	52 weeks
EQ-5Dimension-5Level (EQ-5D-5L)	Self-report health-related quality of life (HRQoL) instrument evaluating mobility, self-care, usual activities, pain/discomfort, anxiety/depression and perceived health.	52 weeks
Speech audiometry: Matrix test	Standardized test to measure individual hearing thresholds levels.	52 weeks
Short Form McGill Pain Questionnaire (SF-MPQ)	Self-rating questionnaire assessing severity, affective, and evaluative dimensions of subjective pain experience using a sensory and affective subscales and a visual analogue scale (VAS) to record the patient's present pain intensity.	52 weeks
Electrocardiogram (ECG): PQ interval (milliseconds)	Changes from baseline to each assessment visit in PQ interval	52 weeks
Electrocardiogram (ECG): QRS duration (milliseconds) and morphology (peak, axis)	Changes from baseline to each assessment visit in QRS duration (milliseconds) and morphology (peak, axis)	52 weeks
Electrocardiogram (ECG): QTc	Changes from baseline to each assessment visit in QTc	52 weeks
Electrocardiogram (ECG): T peak - T end interval	Changes from baseline to each assessment visit in T peak - T end interval	52 weeks
Electrocardiogram (ECG): T wave morphology: peak, symmetry	Changes from baseline to each assessment visit in T wave morphology: peak, symmetry	52 weeks
Haematology: haemoglobin (Hb)	Changes from baseline to each assessment visit in haemoglobin (Hb)	52 weeks
Haematology: haematocrit (Ht)	Changes from baseline to each assessment visit in haematocrit (Ht)	52 weeks
Haematology: mean corpuscular haemoglobin (MCH)	Changes from baseline to each assessment visit in mean corpuscular haemoglobin (MCH)	52 weeks
Haematology: mean corpuscular haemoglobin concentration (MCHC)	Changes from baseline to each assessment visit in mean corpuscular haemoglobin concentration (MCHC)	52 weeks
Haematology: red blood cell count (RBC)	Changes from baseline to each assessment visit in red blood cell count (RBC)	52 weeks
Haematology: mean corpuscular volume (MCV)	Changes from baseline to each assessment visit in mean corpuscular volume (MCV)	52 weeks
Haematology: white blood cell (WBC) count	Changes from baseline to each assessment visit in white blood cell (WBC) count	52 weeks
Haematology: white blood cell differential (WBC differential: neutrophils, lymphocytes, monocytes, eosinophils, basophils)	Changes from baseline to each assessment visit in WBC differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils)	52 weeks
Haematology: thrombocytes	Changes from baseline to each assessment visit in thrombocytes	52 weeks
Chemistry: total protein	Changes from baseline to each assessment visit in total protein	52 weeks
Chemistry: alkaline phosphatase	Changes from baseline to each assessment visit in alkaline phosphatase	52 weeks
Chemistry: aspartate aminotransferase (ASAT)	Changes from baseline to each assessment visit in aspartate aminotransferase (ASAT)	52 weeks
Chemistry: alanine aminotransferase (ALAT)	Changes from baseline to each assessment visit in alanine aminotransferase (ALAT)	52 weeks
Chemistry: gamma-glutamyl transferase (gamma-GT)	Changes from baseline to each assessment visit in gamma-glutamyl transferase (gamma-GT)	52 weeks
Chemistry: total bilirubin	Changes from baseline to each assessment visit in total bilirubin	52 weeks
Chemistry: urea	Changes from baseline to each assessment visit in urea	52 weeks
Chemistry: creatinine	Changes from baseline to each assessment visit in creatinine	52 weeks
Chemistry: creatinine kinase	Changes from baseline to each assessment visit in creatinine kinase	52 weeks
Chemistry: sodium	Changes from baseline to each assessment visit in sodium	52 weeks
Chemistry: potassium	Changes from baseline to each assessment visit in potassium	52 weeks
Chemistry: calcium	Changes from baseline to each assessment visit in calcium	52 weeks
Chemistry: chloride	Changes from baseline to each assessment visit in chloride	52 weeks
Chemistry: lactate	Changes from baseline to each assessment visit in lactate	52 weeks
Chemistry: amylase	Changes from baseline to each assessment visit in amylase	52 weeks
Chemistry: lipase	Changes from baseline to each assessment visit in lipase	52 weeks
Chemistry: uric acid	Changes from baseline to each assessment visit in uric acid	52 weeks
Chemistry: phosphate	Changes from baseline to each assessment visit in phosphate	52 weeks
Chemistry: human serum albumin	Changes from baseline to each assessment visit in human serum albumin	52 weeks
Chemistry: glucose	Changes from baseline to each assessment visit in glucose	52 weeks
Chemistry: HbA1c	Changes from baseline to each assessment visit in HbA1c	52 weeks
Chemistry: thyroid-stimulating hormone (TSH)	Changes from baseline to each assessment visit in thyroid-stimulating hormone (TSH)	52 weeks
Chemistry: free thyroxine (fT4)	Changes from baseline to each assessment visit in free thyroxine (fT4)	52 weeks
Chemistry: C-reactive protein (CRP)	Changes from baseline to each assessment visit in C-reactive protein (CRP)	52 weeks
Chemistry: Lipids: cholesterol, triglycerides, low density lipoproteins (LDL), high density lipoproteins (HDL)	Changes from baseline to each assessment visit in Lipids: cholesterol, triglycerides, low density lipoproteins (LDL), high density lipoproteins (HDL)	52 weeks
Heart rate (bpm)	Changes from baseline to each assessment visit in heart rate (bpm)	52 weeks

Collaborators and Investigators

• Sponsor: Khondrion BV
• Collaborators: Julius Clinical; ProPharma Group; Certara

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 2021
• Primary Completion (Actual): June 1, 2023
• Study Completion (Actual): June 1, 2023

Study Registration Dates

• First Submitted: June 19, 2020
• First Submitted That Met QC Criteria: October 21, 2020
• First Posted (Actual): October 27, 2020

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: MELAS; MIDD; KH176; Open Label Extension; CPEO; oxidative phosphorylation (oxphos)
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Disease Attributes; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Otorhinolaryngologic Diseases; Ear Diseases; Metabolism, Inborn Errors; Cranial Nerve Diseases; Sensation Disorders; Brain Diseases, Metabolic; Ocular Motility Disorders; Brain Diseases, Metabolic, Inborn; Hearing Disorders; Cerebral Small Vessel Diseases; Paralysis; Acid-Base Imbalance; Mitochondrial Myopathies; Hearing Loss; Chronic Disease; Mitochondrial Diseases; Deafness; MELAS Syndrome; Mitochondrial Encephalomyopathies; Ophthalmoplegia, Chronic Progressive External; Ophthalmoplegia; Acidosis; Acidosis, Lactic; 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: KH176-203

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No