Mitochondrial DiseasesPhase 2NCT04604548
The KHENEREXT Study
A Phase 2 study testing Oral administration of 100 mg KH176 twice daily in people with Mitochondrial Diseases and Mitochondrial DNA tRNALeu(UUR) m.3243A<G Mutation, run by Khondrion BV at 4 sites in 4 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Mitochondrial Diseases, Mitochondrial DNA tRNALeu(UUR) m.3243A<G Mutation, Maternally Inherited Diabetes and Deafness (MIDD)
- What is being tested?
- Oral administration of 100 mg KH176 twice daily
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 4 sitesin 4 countries
- Study dates
- 9 Aug 2021to 1 Jun 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Males and females aged 18 years or older at screening.
- Ability and willingness to provide written Informed Consent prior to screening evaluations.
- Having fulfilled all inclusion and exclusion criteria and completed the full treatment period of study KH176-202.
- 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.
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- 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.
Who cannot join
- 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.
- History of acute heart failure, (family) history of unexplained syncope or congenital long and short QT syndrome or sudden death.
- 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.
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- Estimated glomerular filtration rate ≤ 60 mL/min according to the CKD-EPI formula at screening.
- Systolic blood pressure > 150 mmHg at screening or baseline. h) All other clinically relevant parameters at screening or baseline as judged by the Investigator.
- 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.
- Serum hyperkalemia (> 5.0 mEq/L).
- Serum hypokalemia (< 3.5 mEq/L).
- History of ischemic heart disease.
- Symptomatic heart failure.
- Clinically relevant aorta and/or mitralis valvular defect as judged by the investigator.
- Pregnancy or breast feeding (females).
- History of hypersensitivity or idiosyncrasy to any of the components of the investigational drug.
- Medical history of drug abuse (illegal drugs such as cannabinoids, amphetamines, cocaine, opiates or problematic use of prescription drugs such as benzodiazepines, opiates).
- 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:
- (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.
- 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.
- any strong Cytochrome P450 (CYP)3A4 inhibitors (all 'conazoles-anti-fungals', HIV antivirals, grapefruit).
- strong CYP3A4 inducers (including HIV antivirals, carbamazepine, phenobarbital, phenytoin, rifampicine, St. John's wort, pioglitazone, troglitazone).
- 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.
- any medication metabolised by CYP3A4 with a narrow therapeutic width
Trial locations and contacts
4 sites in 4 countries.
4 sites in 4 countries
Germany1 site
Klinikum der Universität München Friedrich-Baur-Institut
München, 80336
United Kingdom1 site
Institute for Ageing and Health Newcastle University
Newcastle upon Tyne
About this 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.
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.
Read the 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.
- 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)
- Being tested
- Oral administration of 100 mg KH176 twice daily
- Keywords
- KH176, Open Label Extension, MELAS, MIDD, CPEO, oxidative phosphorylation (oxphos)
- Medical subject headings
- Mitochondrial Diseases, Noninsulin-dependent diabetes mellitus with deafness, MELAS Syndrome, Ophthalmoplegia, Chronic Progressive External
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Oral administration of 100 mg KH176 twice dailyDrug
Drug: KH176
| Study group | Role | What they receive |
|---|---|---|
| Open Label treatment | Experimental | Oral administration of 100 mg KH176 twice daily Receives: Drug: Oral administration of 100 mg KH176 twice daily |
What is being measured
The primary outcome is the main question the study is designed to answer.
Treatment Emergent Adverse Events (TEAE)
Frequency of TEAEs throughout the treatment period.
Measured: 52 weeks
Secondary outcomes (66)
Blood Pressure (mmHG)
Changes from baseline to each assessment visit in blood pressure (mmHG)
Measured: 52 weeks
Safety Outcomes
Changes from baseline to each assessment visit in vital signs, laboratory parameters (chemistry, haematology, urinalysis).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 52 weeks
Test of Attentional Performance (TAP)
Standardised test to evaluate alertness and mental flexibility.
Measured: 52 weeks
Beck Depression Inventory (BDI)
21-question multiple-choice self-report inventory, for measuring the severity of depression.
Measured: 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).
Measured: 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.
Measured: 52 weeks
Number of headache days
Self report diary.
Measured: 52 weeks
Pure Tone Audiometry (PTA)
Standardized test to measure individual hearing threshold levels.
Measured: 52 weeks
University of Penn Smell Identification Test (UPSIT)
Test to measure the individual's ability to detect odors at a suprathreshold level.
Measured: 52 weeks
Cognitive Failure Questionnaire (CFQ)
Questionnaire to evaluate subjective cognitive functioning.
Measured: 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.
Measured: 52 weeks
Five Times Sit to stand test (5XSST)
Test to measure lower limb functional strength.
Measured: 52 weeks
Handgrip strength
Test to measure upper extremity deficits.
Measured: 52 weeks
HbA1c
Glucose homeostasis / diabetes control.
Measured: 52 weeks
Mean daily insulin dose
Glucose homeostasis / diabetes control.
Measured: 52 weeks
Mean daily oral antidiabetics dose
Glucose homeostasis / diabetes control.
Measured: 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.
Measured: 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.
Measured: 52 weeks
Speech audiometry: Matrix test
Standardized test to measure individual hearing thresholds levels.
Measured: 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.
Measured: 52 weeks
Electrocardiogram (ECG): PQ interval (milliseconds)
Changes from baseline to each assessment visit in PQ interval
Measured: 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)
Measured: 52 weeks
Electrocardiogram (ECG): QTc
Changes from baseline to each assessment visit in QTc
Measured: 52 weeks
Electrocardiogram (ECG): T peak - T end interval
Changes from baseline to each assessment visit in T peak - T end interval
Measured: 52 weeks
Electrocardiogram (ECG): T wave morphology: peak, symmetry
Changes from baseline to each assessment visit in T wave morphology: peak, symmetry
Measured: 52 weeks
Haematology: haemoglobin (Hb)
Changes from baseline to each assessment visit in haemoglobin (Hb)
Measured: 52 weeks
Haematology: haematocrit (Ht)
Changes from baseline to each assessment visit in haematocrit (Ht)
Measured: 52 weeks
Haematology: mean corpuscular haemoglobin (MCH)
Changes from baseline to each assessment visit in mean corpuscular haemoglobin (MCH)
Measured: 52 weeks
Haematology: mean corpuscular haemoglobin concentration (MCHC)
Changes from baseline to each assessment visit in mean corpuscular haemoglobin concentration (MCHC)
Measured: 52 weeks
Haematology: red blood cell count (RBC)
Changes from baseline to each assessment visit in red blood cell count (RBC)
Measured: 52 weeks
Haematology: mean corpuscular volume (MCV)
Changes from baseline to each assessment visit in mean corpuscular volume (MCV)
Measured: 52 weeks
Haematology: white blood cell (WBC) count
Changes from baseline to each assessment visit in white blood cell (WBC) count
Measured: 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)
Measured: 52 weeks
Haematology: thrombocytes
Changes from baseline to each assessment visit in thrombocytes
Measured: 52 weeks
Chemistry: total protein
Changes from baseline to each assessment visit in total protein
Measured: 52 weeks
Chemistry: alkaline phosphatase
Changes from baseline to each assessment visit in alkaline phosphatase
Measured: 52 weeks
Chemistry: aspartate aminotransferase (ASAT)
Changes from baseline to each assessment visit in aspartate aminotransferase (ASAT)
Measured: 52 weeks
Chemistry: alanine aminotransferase (ALAT)
Changes from baseline to each assessment visit in alanine aminotransferase (ALAT)
Measured: 52 weeks
Chemistry: gamma-glutamyl transferase (gamma-GT)
Changes from baseline to each assessment visit in gamma-glutamyl transferase (gamma-GT)
Measured: 52 weeks
Chemistry: total bilirubin
Changes from baseline to each assessment visit in total bilirubin
Measured: 52 weeks
Chemistry: urea
Changes from baseline to each assessment visit in urea
Measured: 52 weeks
Chemistry: creatinine
Changes from baseline to each assessment visit in creatinine
Measured: 52 weeks
Chemistry: creatinine kinase
Changes from baseline to each assessment visit in creatinine kinase
Measured: 52 weeks
Chemistry: sodium
Changes from baseline to each assessment visit in sodium
Measured: 52 weeks
Chemistry: potassium
Changes from baseline to each assessment visit in potassium
Measured: 52 weeks
Chemistry: calcium
Changes from baseline to each assessment visit in calcium
Measured: 52 weeks
Chemistry: chloride
Changes from baseline to each assessment visit in chloride
Measured: 52 weeks
Chemistry: lactate
Changes from baseline to each assessment visit in lactate
Measured: 52 weeks
Chemistry: amylase
Changes from baseline to each assessment visit in amylase
Measured: 52 weeks
Chemistry: lipase
Changes from baseline to each assessment visit in lipase
Measured: 52 weeks
Chemistry: uric acid
Changes from baseline to each assessment visit in uric acid
Measured: 52 weeks
Chemistry: phosphate
Changes from baseline to each assessment visit in phosphate
Measured: 52 weeks
Chemistry: human serum albumin
Changes from baseline to each assessment visit in human serum albumin
Measured: 52 weeks
Chemistry: glucose
Changes from baseline to each assessment visit in glucose
Measured: 52 weeks
Chemistry: HbA1c
Changes from baseline to each assessment visit in HbA1c
Measured: 52 weeks
Chemistry: thyroid-stimulating hormone (TSH)
Changes from baseline to each assessment visit in thyroid-stimulating hormone (TSH)
Measured: 52 weeks
Chemistry: free thyroxine (fT4)
Changes from baseline to each assessment visit in free thyroxine (fT4)
Measured: 52 weeks
Chemistry: C-reactive protein (CRP)
Changes from baseline to each assessment visit in C-reactive protein (CRP)
Measured: 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)
Measured: 52 weeks
Heart rate (bpm)
Changes from baseline to each assessment visit in heart rate (bpm)
Measured: 52 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Oct 2020
- Study start9 Aug 2021
- Primary completion1 Jun 2023
- Study completion1 Jun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Mitochondrial DiseasesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Open Label
- Masking
- None (open label)
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- Khondrion BV
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Julius Clinical, ProPharma Group, Certara
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04604548
- Sponsor's protocol ID
- KH176-203
- Status last verified
- Mar 2024
- First submitted
- 19 Jun 2020
- Last updated
- 6 Mar 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT04604548
- Acronym / sponsor ID
- KH176-203
- 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)
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 11 participants (actual)
- Lead sponsor
- Khondrion BVIndustry (pharma, biotech, devices)
- Collaborators
- Julius Clinical, ProPharma Group, Certara
- Study start
- 9 Aug 2021 (actual)
- Primary completion
- 1 Jun 2023 (actual)
- Study completion
- 1 Jun 2023 (actual)
- First posted
- 27 Oct 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Open Label
| Arm | Type | Receives |
|---|---|---|
| Open Label treatment | Experimental | Drug: Oral administration of 100 mg KH176 twice dailyOral administration of 100 mg KH176 twice daily |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Males and females aged 18 years or older at screening.
- Ability and willingness to provide written Informed Consent prior to screening evaluations.
- Having fulfilled all inclusion and exclusion criteria and completed the full treatment period of study KH176-202.
- 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).
Key exclusion criteria (25 listed)
- 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.
- History of acute heart failure, (family) history of unexplained syncope or congenital long and short QT syndrome or sudden death.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Oral administration of 100 mg KH176 twice dailyDrug: KH176 | Drug | Open Label treatment |
Primary outcome
Treatment Emergent Adverse Events (TEAE)
Time frame: 52 weeks
Frequency of TEAEs throughout the treatment period.
66 secondary outcomes
Blood Pressure (mmHG)
Time frame: 52 weeks
Safety Outcomes
Time frame: 52 weeks
Cognitive functioning: Attention
Time frame: 52 weeks
Executive functioning
Time frame: 52 weeks
Psychomotor functioning
Time frame: 52 weeks
Visual learning
Time frame: 52 weeks
Working Memory
Time frame: 52 weeks
Verbal learning
Time frame: 52 weeks
Test of Attentional Performance (TAP)
Time frame: 52 weeks
Beck Depression Inventory (BDI)
Time frame: 52 weeks
Hamilton Anxiety and Depression Score (HADS)
Time frame: 52 weeks
Newcastle Mitochondrial Disease Scale for Adults (NMDAS)
Time frame: 52 weeks
Number of headache days
Time frame: 52 weeks
Pure Tone Audiometry (PTA)
Time frame: 52 weeks
University of Penn Smell Identification Test (UPSIT)
Time frame: 52 weeks
Cognitive Failure Questionnaire (CFQ)
Time frame: 52 weeks
Neuro-QoL Fatigue Short Form (quality in life in neurological disorders)
Time frame: 52 weeks
Five Times Sit to stand test (5XSST)
Time frame: 52 weeks
Handgrip strength
Time frame: 52 weeks
HbA1c
Time frame: 52 weeks
Mean daily insulin dose
Time frame: 52 weeks
Mean daily oral antidiabetics dose
Time frame: 52 weeks
Short Form-36 (SF-36)
Time frame: 52 weeks
EQ-5Dimension-5Level (EQ-5D-5L)
Time frame: 52 weeks
Speech audiometry: Matrix test
Time frame: 52 weeks
Short Form McGill Pain Questionnaire (SF-MPQ)
Time frame: 52 weeks
Electrocardiogram (ECG): PQ interval (milliseconds)
Time frame: 52 weeks
Electrocardiogram (ECG): QRS duration (milliseconds) and morphology (peak, axis)
Time frame: 52 weeks
Electrocardiogram (ECG): QTc
Time frame: 52 weeks
Electrocardiogram (ECG): T peak - T end interval
Time frame: 52 weeks
Electrocardiogram (ECG): T wave morphology: peak, symmetry
Time frame: 52 weeks
Haematology: haemoglobin (Hb)
Time frame: 52 weeks
Haematology: haematocrit (Ht)
Time frame: 52 weeks
Haematology: mean corpuscular haemoglobin (MCH)
Time frame: 52 weeks
Haematology: mean corpuscular haemoglobin concentration (MCHC)
Time frame: 52 weeks
Haematology: red blood cell count (RBC)
Time frame: 52 weeks
Haematology: mean corpuscular volume (MCV)
Time frame: 52 weeks
Haematology: white blood cell (WBC) count
Time frame: 52 weeks
Haematology: white blood cell differential (WBC differential: neutrophils, lymphocytes, monocytes, eosinophils, basophils)
Time frame: 52 weeks
Haematology: thrombocytes
Time frame: 52 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Mar 2024.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
4 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Oral administration of 100 mg KH176 twice daily in people with Mitochondrial Diseases and Mitochondrial DNA tRNALeu(UUR) m.3243A<G Mutation, run by Khondrion BV at 4 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Denmark, Germany, Netherlands, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Treatment Emergent Adverse Events (TEAE) (time frame: 52 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Mar 2024.