The KHENEREXT Study

Khondrion BV11 enrolled

Overview

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.

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Treatment Emergent Adverse Events (TEAE)

Frequency of TEAEs throughout the treatment period.

Time frame: 52 weeks

Secondary Outcomes

Blood Pressure (mmHG)

Changes from baseline to each assessment visit in blood pressure (mmHG)

Time frame: 52 weeks

Safety Outcomes

Changes from baseline to each assessment visit in vital signs, laboratory parameters (chemistry, haematology, urinalysis).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 52 weeks

Test of Attentional Performance (TAP)

Standardised test to evaluate alertness and mental flexibility.

Time frame: 52 weeks

Beck Depression Inventory (BDI)

21-question multiple-choice self-report inventory, for measuring the severity of depression.

Time frame: 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).

Time frame: 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.

Time frame: 52 weeks

Number of headache days

Self report diary.

Time frame: 52 weeks

Pure Tone Audiometry (PTA)

Standardized test to measure individual hearing threshold levels.

Time frame: 52 weeks

University of Penn Smell Identification Test (UPSIT)

Test to measure the individual's ability to detect odors at a suprathreshold level.

Time frame: 52 weeks

Cognitive Failure Questionnaire (CFQ)

Questionnaire to evaluate subjective cognitive functioning.

Time frame: 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.

Time frame: 52 weeks

Five Times Sit to stand test (5XSST)

Test to measure lower limb functional strength.

Time frame: 52 weeks

Handgrip strength

Test to measure upper extremity deficits.

Time frame: 52 weeks

HbA1c

Glucose homeostasis / diabetes control.

Time frame: 52 weeks

Mean daily insulin dose

Glucose homeostasis / diabetes control.

Time frame: 52 weeks

Mean daily oral antidiabetics dose

Glucose homeostasis / diabetes control.

Time frame: 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.

Time frame: 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.

Time frame: 52 weeks

Speech audiometry: Matrix test

Standardized test to measure individual hearing thresholds levels.

Time frame: 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.

Time frame: 52 weeks

Electrocardiogram (ECG): PQ interval (milliseconds)

Changes from baseline to each assessment visit in PQ interval

Time frame: 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)

Time frame: 52 weeks

Electrocardiogram (ECG): QTc

Changes from baseline to each assessment visit in QTc

Time frame: 52 weeks

Electrocardiogram (ECG): T peak - T end interval

Changes from baseline to each assessment visit in T peak - T end interval

Time frame: 52 weeks

Electrocardiogram (ECG): T wave morphology: peak, symmetry

Changes from baseline to each assessment visit in T wave morphology: peak, symmetry

Time frame: 52 weeks

Haematology: haemoglobin (Hb)

Changes from baseline to each assessment visit in haemoglobin (Hb)

Time frame: 52 weeks

Haematology: haematocrit (Ht)

Changes from baseline to each assessment visit in haematocrit (Ht)

Time frame: 52 weeks

Haematology: mean corpuscular haemoglobin (MCH)

Changes from baseline to each assessment visit in mean corpuscular haemoglobin (MCH)

Time frame: 52 weeks

Haematology: mean corpuscular haemoglobin concentration (MCHC)

Changes from baseline to each assessment visit in mean corpuscular haemoglobin concentration (MCHC)

Time frame: 52 weeks

Haematology: red blood cell count (RBC)

Changes from baseline to each assessment visit in red blood cell count (RBC)

Time frame: 52 weeks

Haematology: mean corpuscular volume (MCV)

Changes from baseline to each assessment visit in mean corpuscular volume (MCV)

Time frame: 52 weeks

Haematology: white blood cell (WBC) count

Changes from baseline to each assessment visit in white blood cell (WBC) count

Time frame: 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)

Time frame: 52 weeks

Haematology: thrombocytes

Changes from baseline to each assessment visit in thrombocytes

Time frame: 52 weeks

Chemistry: total protein

Changes from baseline to each assessment visit in total protein

Time frame: 52 weeks

Chemistry: alkaline phosphatase

Changes from baseline to each assessment visit in alkaline phosphatase

Time frame: 52 weeks

Chemistry: aspartate aminotransferase (ASAT)

Changes from baseline to each assessment visit in aspartate aminotransferase (ASAT)

Time frame: 52 weeks

Chemistry: alanine aminotransferase (ALAT)

Changes from baseline to each assessment visit in alanine aminotransferase (ALAT)

Time frame: 52 weeks

Chemistry: gamma-glutamyl transferase (gamma-GT)

Changes from baseline to each assessment visit in gamma-glutamyl transferase (gamma-GT)

Time frame: 52 weeks

Chemistry: total bilirubin

Changes from baseline to each assessment visit in total bilirubin

Time frame: 52 weeks

Chemistry: urea

Changes from baseline to each assessment visit in urea

Time frame: 52 weeks

Chemistry: creatinine

Changes from baseline to each assessment visit in creatinine

Time frame: 52 weeks

Chemistry: creatinine kinase

Changes from baseline to each assessment visit in creatinine kinase

Time frame: 52 weeks

Chemistry: sodium

Changes from baseline to each assessment visit in sodium

Time frame: 52 weeks

Chemistry: potassium

Changes from baseline to each assessment visit in potassium

Time frame: 52 weeks

Chemistry: calcium

Changes from baseline to each assessment visit in calcium

Time frame: 52 weeks

Chemistry: chloride

Changes from baseline to each assessment visit in chloride

Time frame: 52 weeks

Chemistry: lactate

Changes from baseline to each assessment visit in lactate

Time frame: 52 weeks

Chemistry: amylase

Changes from baseline to each assessment visit in amylase

Time frame: 52 weeks

Chemistry: lipase

Changes from baseline to each assessment visit in lipase

Time frame: 52 weeks

Chemistry: uric acid

Changes from baseline to each assessment visit in uric acid

Time frame: 52 weeks

Chemistry: phosphate

Changes from baseline to each assessment visit in phosphate

Time frame: 52 weeks

Chemistry: human serum albumin

Changes from baseline to each assessment visit in human serum albumin

Time frame: 52 weeks

Chemistry: glucose

Changes from baseline to each assessment visit in glucose

Time frame: 52 weeks

Chemistry: HbA1c

Changes from baseline to each assessment visit in HbA1c

Time frame: 52 weeks

Chemistry: thyroid-stimulating hormone (TSH)

Changes from baseline to each assessment visit in thyroid-stimulating hormone (TSH)

Time frame: 52 weeks

Chemistry: free thyroxine (fT4)

Changes from baseline to each assessment visit in free thyroxine (fT4)

Time frame: 52 weeks

Chemistry: C-reactive protein (CRP)

Changes from baseline to each assessment visit in C-reactive protein (CRP)

Time frame: 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)

Time frame: 52 weeks

Heart rate (bpm)

Changes from baseline to each assessment visit in heart rate (bpm)

Time frame: 52 weeks

The KHENEREXT Study

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes