The KHENEREXT Study

• ClinicalTrials.gov Identifier: NCT04604548
• Recruitment Status: Active, not recruiting
• First Posted: October 27, 2020
• Last Update Posted: March 8, 2023
• Sponsor: Khondrion BV
• Collaborators: Julius Clinical; ProPharma Group; Certara
• Information provided by (Responsible Party): Khondrion BV

Study Description

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.

Condition or disease	Intervention/treatment	Phase
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)	Drug: Oral administration of 100 mg KH176 twice daily	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open Label
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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.
• Actual Study Start Date: August 9, 2021
• Estimated Primary Completion Date: September 2023
• Estimated Study Completion Date: September 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Treatment Emergent Adverse Events (TEAE) [ Time Frame: 52 weeks ]
   Frequency of TEAEs throughout the treatment period.

Secondary Outcome Measures :

1. Blood Pressure (mmHG) [ Time Frame: 52 weeks ]
   Changes from baseline to each assessment visit in blood pressure (mmHG)
2. Safety Outcomes [ Time Frame: 52 weeks ]
   Changes from baseline to each assessment visit in vital signs, laboratory parameters (chemistry, haematology, urinalysis).
3. Cognitive functioning: Attention [ Time Frame: 52 weeks ]
   The attention domain score of cognitive functioning, as assessed by the Identification Test of the Cogstate computerised cognitive testing battery.
4. Executive functioning [ Time Frame: 52 weeks ]
   The executive functioning domain score of cognitive functioning, as assessed by the Groton Maze Learning Test of the Cogstate computerised cognitive testing battery.
5. Psychomotor functioning [ Time Frame: 52 weeks ]
   The psychomotor functioning domain score of cognitive functioning, as assessed by the Detection Test of the Cogstate computerised cognitive testing battery.
6. Visual learning [ Time Frame: 52 weeks ]
   The visual learning domain score of cognitive functioning, as assessed by the One Card Learning Test of the Cogstate computerised cognitive testing battery.
7. Working Memory [ Time Frame: 52 weeks ]
   The working memory domain score of cognitive functioning, as assessed by the One Back Test of the Cogstate computerised cognitive testing battery.
8. Verbal learning [ Time Frame: 52 weeks ]
   The verbal learning functioning domain score of cognitive functioning, as assessed by the International Shopping List Test of the Cogstate computerised cognitive testing battery.
9. Test of Attentional Performance (TAP) [ Time Frame: 52 weeks ]
   Standardised test to evaluate alertness and mental flexibility.
10. Beck Depression Inventory (BDI) [ Time Frame: 52 weeks ]
    21-question multiple-choice self-report inventory, for measuring the severity of depression.
11. Hamilton Anxiety and Depression Score (HADS) [ Time Frame: 52 weeks ]
    Subject-reported outcome measure and comprises 14 items equally divided over the two subscales anxiety (HADS-A) and depression (HADS-D).
12. Newcastle Mitochondrial Disease Scale for Adults (NMDAS) [ Time Frame: 52 weeks ]
    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.
13. Number of headache days [ Time Frame: 52 weeks ]
    Self report diary.
14. Pure Tone Audiometry (PTA) [ Time Frame: 52 weeks ]
    Standardized test to measure individual hearing threshold levels.
15. University of Penn Smell Identification Test (UPSIT) [ Time Frame: 52 weeks ]
    Test to measure the individual's ability to detect odors at a suprathreshold level.
16. Cognitive Failure Questionnaire (CFQ) [ Time Frame: 52 weeks ]
    Questionnaire to evaluate subjective cognitive functioning.
17. Neuro-QoL Fatigue Short Form (quality in life in neurological disorders) [ Time Frame: 52 weeks ]
    8-item self assessment questionnaire evaluating the perception of fatigue and its impact in daily life activities.
18. Five Times Sit to stand test (5XSST) [ Time Frame: 52 weeks ]
    Test to measure lower limb functional strength.
19. Handgrip strength [ Time Frame: 52 weeks ]
    Test to measure upper extremity deficits.
20. HbA1c [ Time Frame: 52 weeks ]
    Glucose homeostasis / diabetes control.
21. Mean daily insulin dose [ Time Frame: 52 weeks ]
    Glucose homeostasis / diabetes control.
22. Mean daily oral antidiabetics dose [ Time Frame: 52 weeks ]
    Glucose homeostasis / diabetes control.
23. Short Form-36 (SF-36) [ Time Frame: 52 weeks ]
    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.
24. EQ-5Dimension-5Level (EQ-5D-5L) [ Time Frame: 52 weeks ]
    Self-report health-related quality of life (HRQoL) instrument evaluating mobility, self-care, usual activities, pain/discomfort, anxiety/depression and perceived health.
25. Speech audiometry: Matrix test [ Time Frame: 52 weeks ]
    Standardized test to measure individual hearing thresholds levels.
26. Short Form McGill Pain Questionnaire (SF-MPQ) [ Time Frame: 52 weeks ]
    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.
27. Electrocardiogram (ECG): PQ interval (milliseconds) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in PQ interval
28. Electrocardiogram (ECG): QRS duration (milliseconds) and morphology (peak, axis) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in QRS duration (milliseconds) and morphology (peak, axis)
29. Electrocardiogram (ECG): QTc [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in QTc
30. Electrocardiogram (ECG): T peak - T end interval [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in T peak - T end interval
31. Electrocardiogram (ECG): T wave morphology: peak, symmetry [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in T wave morphology: peak, symmetry
32. Haematology: haemoglobin (Hb) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in haemoglobin (Hb)
33. Haematology: haematocrit (Ht) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in haematocrit (Ht)
34. Haematology: mean corpuscular haemoglobin (MCH) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in mean corpuscular haemoglobin (MCH)
35. Haematology: mean corpuscular haemoglobin concentration (MCHC) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in mean corpuscular haemoglobin concentration (MCHC)
36. Haematology: red blood cell count (RBC) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in red blood cell count (RBC)
37. Haematology: mean corpuscular volume (MCV) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in mean corpuscular volume (MCV)
38. Haematology: white blood cell (WBC) count [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in white blood cell (WBC) count
39. Haematology: white blood cell differential (WBC differential: neutrophils, lymphocytes, monocytes, eosinophils, basophils) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in WBC differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils)
40. Haematology: thrombocytes [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in thrombocytes
41. Chemistry: total protein [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in total protein
42. Chemistry: alkaline phosphatase [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in alkaline phosphatase
43. Chemistry: aspartate aminotransferase (ASAT) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in aspartate aminotransferase (ASAT)
44. Chemistry: alanine aminotransferase (ALAT) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in alanine aminotransferase (ALAT)
45. Chemistry: gamma-glutamyl transferase (gamma-GT) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in gamma-glutamyl transferase (gamma-GT)
46. Chemistry: total bilirubin [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in total bilirubin
47. Chemistry: urea [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in urea
48. Chemistry: creatinine [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in creatinine
49. Chemistry: creatinine kinase [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in creatinine kinase
50. Chemistry: sodium [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in sodium
51. Chemistry: potassium [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in potassium
52. Chemistry: calcium [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in calcium
53. Chemistry: chloride [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in chloride
54. Chemistry: lactate [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in lactate
55. Chemistry: amylase [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in amylase
56. Chemistry: lipase [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in lipase
57. Chemistry: uric acid [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in uric acid
58. Chemistry: phosphate [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in phosphate
59. Chemistry: human serum albumin [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in human serum albumin
60. Chemistry: glucose [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in glucose
61. Chemistry: HbA1c [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in HbA1c
62. Chemistry: thyroid-stimulating hormone (TSH) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in thyroid-stimulating hormone (TSH)
63. Chemistry: free thyroxine (fT4) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in free thyroxine (fT4)
64. Chemistry: C-reactive protein (CRP) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in C-reactive protein (CRP)
65. Chemistry: Lipids: cholesterol, triglycerides, low density lipoproteins (LDL), high density lipoproteins (HDL) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in Lipids: cholesterol, triglycerides, low density lipoproteins (LDL), high density lipoproteins (HDL)
66. Heart rate (bpm) [ Time Frame: 52 weeks ]
    Changes from baseline to each assessment visit in heart rate (bpm)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Denmark

Rigshospitalet, University of Copenhagen

Kopenhagen, Denmark, DK2100

Germany

Klinikum der Universität München Friedrich-Baur-Institut

München, Germany, 80336

Netherlands

Radboud University Medical Center

Nijmegen, Netherlands

United Kingdom

Institute for Ageing and Health Newcastle University

Newcastle upon Tyne, United Kingdom

Sponsors and Collaborators

Khondrion BV

Julius Clinical

ProPharma Group

Certara

More Information

• Responsible Party: Khondrion BV
• ClinicalTrials.gov Identifier: NCT04604548
• Other Study ID Numbers: KH176-203
• First Posted: October 27, 2020
• Last Update Posted: March 8, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Khondrion BV:

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

Additional relevant MeSH terms:

Mitochondrial Encephalomyopathies; Ophthalmoplegia, Chronic Progressive External; MELAS Syndrome; Deafness; Ophthalmoplegia; Acidosis; Mitochondrial Diseases; Acidosis, Lactic; Hearing Loss; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Acid-Base Imbalance; Metabolic Diseases; Ocular Motility Disorders; Cranial Nerve Diseases; Paralysis; Eye Diseases; Mitochondrial Myopathies; Muscular Diseases; Musculoskeletal Diseases; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Neuromuscular Diseases; Brain Diseases, Metabolic, Inborn; Cerebral Small Vessel Diseases