Clinical trial NCT04604548: The KHENEREXT Study
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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)
Lead sponsor: Khondrion BV
Sponsor class: INDUSTRY
Collaborators: name: Julius Clinical
name: ProPharma Group
name: Certara
First posted: 2020-10-27
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open Label
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Treatment Emergent Adverse Events (TEAE)
timeFrame: 52 weeks
Secondary outcomes:
measure: Blood Pressure (mmHG)
timeFrame: 52 weeks
measure: Safety Outcomes
timeFrame: 52 weeks
measure: Cognitive functioning: Attention
timeFrame: 52 weeks
measure: Executive functioning
timeFrame: 52 weeks
measure: Psychomotor functioning
timeFrame: 52 weeks
measure: Visual learning
timeFrame: 52 weeks
measure: Working Memory
timeFrame: 52 weeks
measure: Verbal learning
timeFrame: 52 weeks
measure: Test of Attentional Performance (TAP)
timeFrame: 52 weeks
measure: Beck Depression Inventory (BDI)
timeFrame: 52 weeks
measure: Hamilton Anxiety and Depression Score (HADS)
timeFrame: 52 weeks
measure: Newcastle Mitochondrial Disease Scale for Adults (NMDAS)
timeFrame: 52 weeks
measure: Number of headache days
timeFrame: 52 weeks
measure: Pure Tone Audiometry (PTA)
timeFrame: 52 weeks
measure: University of Penn Smell Identification Test (UPSIT)
timeFrame: 52 weeks
measure: Cognitive Failure Questionnaire (CFQ)
timeFrame: 52 weeks
measure: Neuro-QoL Fatigue Short Form (quality in life in neurological disorders)
timeFrame: 52 weeks
measure: Five Times Sit to stand test (5XSST)
timeFrame: 52 weeks
measure: Handgrip strength
timeFrame: 52 weeks
measure: HbA1c
timeFrame: 52 weeks
measure: Mean daily insulin dose
timeFrame: 52 weeks
measure: Mean daily oral antidiabetics dose
timeFrame: 52 weeks
measure: Short Form-36 (SF-36)
timeFrame: 52 weeks
measure: EQ-5Dimension-5Level (EQ-5D-5L)
timeFrame: 52 weeks
measure: Speech audiometry: Matrix test
timeFrame: 52 weeks
measure: Short Form McGill Pain Questionnaire (SF-MPQ)
timeFrame: 52 weeks
measure: Electrocardiogram (ECG): PQ interval (milliseconds)
timeFrame: 52 weeks
measure: Electrocardiogram (ECG): QRS duration (milliseconds) and morphology (peak, axis)
timeFrame: 52 weeks
measure: Electrocardiogram (ECG): QTc
timeFrame: 52 weeks
measure: Electrocardiogram (ECG): T peak - T end interval
timeFrame: 52 weeks
measure: Electrocardiogram (ECG): T wave morphology: peak, symmetry
timeFrame: 52 weeks
measure: Haematology: haemoglobin (Hb)
timeFrame: 52 weeks
measure: Haematology: haematocrit (Ht)
timeFrame: 52 weeks
measure: Haematology: mean corpuscular haemoglobin (MCH)
timeFrame: 52 weeks
measure: Haematology: mean corpuscular haemoglobin concentration (MCHC)
timeFrame: 52 weeks
measure: Haematology: red blood cell count (RBC)
timeFrame: 52 weeks
measure: Haematology: mean corpuscular volume (MCV)
timeFrame: 52 weeks
measure: Haematology: white blood cell (WBC) count
timeFrame: 52 weeks
measure: Haematology: white blood cell differential (WBC differential: neutrophils, lymphocytes, monocytes, eosinophils, basophils)
timeFrame: 52 weeks
measure: Haematology: thrombocytes
timeFrame: 52 weeks
measure: Chemistry: total protein
timeFrame: 52 weeks
measure: Chemistry: alkaline phosphatase
timeFrame: 52 weeks
measure: Chemistry: aspartate aminotransferase (ASAT)
timeFrame: 52 weeks
measure: Chemistry: alanine aminotransferase (ALAT)
timeFrame: 52 weeks
measure: Chemistry: gamma-glutamyl transferase (gamma-GT)
timeFrame: 52 weeks
measure: Chemistry: total bilirubin
timeFrame: 52 weeks
measure: Chemistry: urea
timeFrame: 52 weeks
measure: Chemistry: creatinine
timeFrame: 52 weeks
measure: Chemistry: creatinine kinase
timeFrame: 52 weeks
measure: Chemistry: sodium
timeFrame: 52 weeks
measure: Chemistry: potassium
timeFrame: 52 weeks
measure: Chemistry: calcium
timeFrame: 52 weeks
measure: Chemistry: chloride
timeFrame: 52 weeks
measure: Chemistry: lactate
timeFrame: 52 weeks
measure: Chemistry: amylase
timeFrame: 52 weeks
measure: Chemistry: lipase
timeFrame: 52 weeks
measure: Chemistry: uric acid
timeFrame: 52 weeks
measure: Chemistry: phosphate
timeFrame: 52 weeks
measure: Chemistry: human serum albumin
timeFrame: 52 weeks
measure: Chemistry: glucose
timeFrame: 52 weeks
measure: Chemistry: HbA1c
timeFrame: 52 weeks
measure: Chemistry: thyroid-stimulating hormone (TSH)
timeFrame: 52 weeks
measure: Chemistry: free thyroxine (fT4)
timeFrame: 52 weeks
measure: Chemistry: C-reactive protein (CRP)
timeFrame: 52 weeks
measure: Chemistry: Lipids: cholesterol, triglycerides, low density lipoproteins (LDL), high density lipoproteins (HDL)
timeFrame: 52 weeks
measure: Heart rate (bpm)
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Kopenhagen
country: Denmark
facility: Rigshospitalet, University of Copenhagen
city: München
country: Germany
facility: Klinikum der Universität München Friedrich-Baur-Institut
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Newcastle upon Tyne
country: United Kingdom
facility: Institute for Ageing and Health Newcastle University
Study officials:
References: