Mitochondrial DiseasesPhase 2NCT04165239
The KHENERGYZE Study
A Phase 2 study testing KH176 in people with Mitochondrial Diseases and Mitochondrial Myopathies, run by Khondrion BV at 4 sites in 4 countries.
Trial summary
Mitochondrial diseases, estimated prevalence 1 in 4,300 adults, is caused by pathogenic mutations in genes finally encoding for mitochondrial proteins of the various enzyme complexes of the OXPHOS. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Mitochondrial Diseases, Mitochondrial Myopathies, Mitochondrial Encephalomyopathies
- What is being tested?
- KH176
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 27 participants
- Where
- 4 sitesin 4 countries
- Study dates
- 30 Oct 2019to 24 May 2022
- 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
None listed.
Who cannot join
- Surgery of gastro-intestinal tract that might interfere with absorption.
- Treatment with an investigational product 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).
- 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;
- 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.
- 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; QTc > 450 ms for male subjects; QTc: > 470ms for female subjects (local, machine read), T-top inversion in >1 consecutive lead.
- Serum Hyper-potassium (> 5.0 mEq/L).
- Serum Hypo-potassium (< 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).
- Poor nutritional state as judged by the investigator.
- 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 anti-oxidant supplements (including, but not limited to idebenone/EPI-743, mitoQ); 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, rifampicin, St. John's wort, pioglitazone, troglitazone).
- any medication known to affect cardiac repolarisation, unless the QTc interval at screening is normal during stable treatment (all anti-psychotics, several anti-depressants, e.g. nor/amitriptyline, fluoxetine, anti-emetics: domperidone (motilium®) granisetron, ondansetron). For a complete list see https://crediblemeds.org.
- any medication metabolised by CYP with a narrow therapeutical width. For reference (Germany and United Kingdom): drug interaction table of Indiana University (http://medicine.iupui.edu/clinpharm/ddis/clinical-table/). For reference (The Netherlands): KNMP Kennisbank (https://www.knmp.nl/producten/knmp-kennisbank/inloggen-knmp-kennisbank. For reference (all other countries): drug interaction table of Indiana University (http://medicine.iupui.edu/clinpharm/ddis/clinical-table/).
Trial locations and contacts
4 sites in 4 countries.
4 sites in 4 countries
United Kingdom1 site
Institute for Ageing and Health Newcastle University
Newcastle upon Tyne
About this study
Official title: A Phase IIb Double-blind, Randomised, Placebo-controlled, Multi-centre, Confirmative Three-way Cross-over Study on Cognitive Function With Two Doses of KH176 in Subjects With a Genetically Confirmed Mitochondrial DNA tRNALeu(UUR) m.3243A>G Mutation.
Mitochondrial diseases, estimated prevalence 1 in 4,300 adults, is caused by pathogenic mutations in genes finally encoding for mitochondrial proteins of the various enzyme complexes of the OXPHOS. Among these mutations, the 3243A>G nucleotide change in the mitochondrially encoded transfer RNALeu(UUR) leucine 1 gene (MT TL 1) is the most prevalent one. The OXPHOS dysfunction resulting from such mutations leads to increased production of reactive oxygen species (ROS), ultimately leading to irreversible oxidative damage of macromolecules, or to more selective and reversible redox modulation of cell signaling that may impact (adult) neurogenesis.
Despite advances in the understanding of mitochondrial disorders, treatment options are extremely limited and, to date, largely supportive. Therefore, there is an urgent need for novel treatments. KH176, a new active pharmaceutical ingredient (API), is an orally bio-available small molecule under development for the treatment of these disorders (see Section 1.4). The current study will further evaluate the effect of KH176 in various cognitive domains and evaluate the effect of different doses of KH176 (See Section 1.5).
In view of the growing recognition of the importance of mitochondrial function in maintaining cognitive processes in the brain, as well as the understanding of the safety profile and pharmacokinetics of KH176 following the two clinical studies described above, a more detailed study is indicated of the effects of KH176 in various cognitive domains, using the confirmed safe and well-tolerated KH176 dose of 100 mg bid, as well as a lower dose of 50 mg bid. The primary objective is an evaluation of KH176 in the attention domain of cognitive functioning, as assessed by the visual identification test score of the Cogstate computerised cognitive testing battery.
Read the detailed description
For this study, a 3 x 3 crossover design will be applied, i.e., with 3 treatments, 3 sequences and 3 periods, employing a Latin square assignment. Using this design, each subject will function as his/her own control. This will reduce variability and thus increase the chances of observing true effects between treatment periods (effects of treatment compared to placebo). In each treatment period, assessments will be performed at baseline prior to dosing and post dosing, enabling a change from baseline analysis and enabling the possibility to compare baseline conditions for each treatment period. The treatment period in each treatment is 28 days (4 weeks), which is supported by the pre-clinical toxicology program. In mouse studies, a 4-week period was sufficient to observe clinically relevant effects.
- Conditions
- Mitochondrial Diseases, Mitochondrial Myopathies, Mitochondrial Encephalomyopathies, MELAS Syndrome, MIDD
- Being tested
- KH176, Placebo
- Keywords
- Mitochondrial, Oxidative Phosphorylation (OXPHOS), MELAS, MIDD, KH176
- Medical subject headings
- Mitochondrial Diseases, Mitochondrial Myopathies, Mitochondrial Encephalomyopathies, MELAS Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
KH176Drug
Also called Sonlicromanol
Oral administration of 50 mg KH176 twice daily
KH176Drug
Also called Sonlicromanol
Oral administration of 100 mg KH176 twice daily
PlaceboDrug
Oral administration of matching placebo twice daily
| Study group | Role | What they receive |
|---|---|---|
| Treatment A | Experimental | Oral administration of 50 mg KH176 twice daily Receives: Drug: KH176 |
| Treatment B | Experimental | Oral administration of 100 mg KH176 twice daily Receives: Drug: KH176 |
| Treatment C | Placebo comparator | Oral administration of matching placebo twice daily Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Cognitive functioning: Attention
The attention domain score of cognitive functioning, as assessed by the visual Identification Test of the Cogstate computerised cognitive testing battery
Measured: One month
Secondary outcomes (14)
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: One month
Psychomotor function
The psychomotor functioning domain score of cognitive functioning, as assessed by the Detection Test of the Cogstate computerised cognitive testing battery
Measured: One month
Working Memeory
The working memory domain score of cognitive functioning, as assessed by the One Back Test of the Cogstate computerised cognitive testing battery
Measured: One month
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: One month
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: One month
Test of Attentional Performance (TAP)
Standardised test to evaluate alertness and mental flexibility
Measured: One month
Beck Depression Inventory
21-question multiple-choice self-report inventory, for measuring the severity of depression
Measured: One month
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: One month
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: One month
Number of headache days
Self report diary
Measured: One month
Pure Tone Audiometry (PTA)
Standardized test measure individual hearing threshold levels
Measured: One month
University of Penn Smell Identification Test (UPSIT)
Test to measure the individual's ability to detect odors at a suprathreshold level.
Measured: One month
Cognitive Failure Questionnaire (CFQ)
Questionnaire to evaluate subjective cognitive functioning.
Measured: One month
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: One month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Nov 2019
- Study start30 Oct 2019
- Primary completion24 May 2022
- Study completion24 May 2022
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
- Randomised
- Intervention model
- Crossover
- Model description
- The study will be a double-blind, randomised, placebo-controlled, multi-centre, three-way cross-over study. Twenty-seven subjects, with a confirmed mitochondrial DNA tRNALeu(UUR) 3243A\>G mutation and with clinical signs of mitochondrial disease including attentional dysfunction, and fulfilling pre-defined cardiac exclusion criteria, will be randomised over three treatment sequences as assigned by Latin-square. Each group will have 3 treatment periods of 28 days each, separated by 14-day washout periods between treatments. During the 28-day treatment periods, subjects will receive bid oral administration of 50 mg KH176,100 mg KH176, or placebo in the sequence as applicable for the group.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 27 participants (actual)
Sponsor and investigators
- Lead sponsor
- Khondrion BV
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Julius Clinical
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04165239
- Sponsor's protocol ID
- KH-176-202
- Status last verified
- Aug 2022
- First submitted
- 13 Nov 2019
- Last updated
- 31 Aug 2022
- Results posted
- No
- Data monitoring committee
- No
- 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 31 Aug 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase IIb Double-blind, Randomised, Placebo-controlled, Multi-centre, Confirmative Three-way Cross-over Study on Cognitive Function With Two Doses of KH176 in Subjects With a Genetically Confirmed Mitochondrial DNA tRNALeu(UUR) m.3243A>G Mutation.
- ClinicalTrials.gov ID
- NCT04165239
- Acronym / sponsor ID
- KH-176-202
- Conditions
- Mitochondrial Diseases, Mitochondrial Myopathies, Mitochondrial Encephalomyopathies, MELAS Syndrome, MIDD
- Keywords
- Mitochondrial, Oxidative Phosphorylation (OXPHOS), MELAS, MIDD, KH176
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 27 participants (actual)
- Lead sponsor
- Khondrion BVIndustry (pharma, biotech, devices)
- Collaborators
- Julius Clinical
- Study start
- 30 Oct 2019 (actual)
- Primary completion
- 24 May 2022 (actual)
- Study completion
- 24 May 2022 (actual)
- First posted
- 15 Nov 2019 (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.
Mitochondrial diseases, estimated prevalence 1 in 4,300 adults, is caused by pathogenic mutations in genes finally encoding for mitochondrial proteins of the various enzyme complexes of the OXPHOS. Among these mutations, the 3243A>G nucleotide change in the mitochondrially encoded transfer RNALeu(UUR) leucine 1 gene (MT TL 1) is the most prevalent one. The OXPHOS dysfunction resulting from such mutations leads to increased production of reactive oxygen species (ROS), ultimately leading to irreversible oxidative damage of macromolecules, or to more selective and reversible redox modulation of cell signaling that may impact (adult) neurogenesis.
Despite advances in the understanding of mitochondrial disorders, treatment options are extremely limited and, to date, largely supportive. Therefore, there is an urgent need for novel treatments. KH176, a new active pharmaceutical ingredient (API), is an orally bio-available small molecule under development for the treatment of these disorders (see Section 1.4). The current study will further evaluate the effect of KH176 in various cognitive domains and evaluate the effect of different doses of KH176 (See Section 1.5).
In view of the growing recognition of the importance of mitochondrial function in maintaining cognitive processes in the brain, as well as the understanding of the safety profile and pharmacokinetics of KH176 following the two clinical studies described above, a more detailed study is indicated of the effects of KH176 in various cognitive domains, using the confirmed safe and well-tolerated KH176 dose of 100 mg bid, as well as a lower dose of 50 mg bid. The primary objective is an evaluation of KH176 in the attention domain of cognitive functioning, as assessed by the visual identification test score of the Cogstate computerised cognitive testing battery.
Detailed description
For this study, a 3 x 3 crossover design will be applied, i.e., with 3 treatments, 3 sequences and 3 periods, employing a Latin square assignment. Using this design, each subject will function as his/her own control. This will reduce variability and thus increase the chances of observing true effects between treatment periods (effects of treatment compared to placebo). In each treatment period, assessments will be performed at baseline prior to dosing and post dosing, enabling a change from baseline analysis and enabling the possibility to compare baseline conditions for each treatment period. The treatment period in each treatment is 28 days (4 weeks), which is supported by the pre-clinical toxicology program. In mouse studies, a 4-week period was sufficient to observe clinically relevant effects.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- The study will be a double-blind, randomised, placebo-controlled, multi-centre, three-way cross-over study. Twenty-seven subjects, with a confirmed mitochondrial DNA tRNALeu(UUR) 3243A>G mutation and with clinical signs of mitochondrial disease including attentional dysfunction, and fulfilling pre-defined cardiac exclusion criteria, will be randomised over three treatment sequences as assigned by Latin-square. Each group will have 3 treatment periods of 28 days each, separated by 14-day washout periods between treatments. During the 28-day treatment periods, subjects will receive bid oral administration of 50 mg KH176,100 mg KH176, or placebo in the sequence as applicable for the group.
| Arm | Type | Receives |
|---|---|---|
| Treatment A | Experimental | Drug: KH176Oral administration of 50 mg KH176 twice daily |
| Treatment B | Experimental | Drug: KH176Oral administration of 100 mg KH176 twice daily |
| Treatment C | Placebo comparator | Drug: PlaceboOral administration of matching placebo twice daily |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (27 listed)
- Surgery of gastro-intestinal tract that might interfere with absorption.
- Treatment with an investigational product 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).
- 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;
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 |
|---|---|---|
| KH176Also: SonlicromanolOral administration of 50 mg KH176 twice daily | Drug | Treatment A |
| KH176Also: SonlicromanolOral administration of 100 mg KH176 twice daily | Drug | Treatment B |
| PlaceboOral administration of matching placebo twice daily | Drug | Treatment C |
Primary outcome
Cognitive functioning: Attention
Time frame: One month
The attention domain score of cognitive functioning, as assessed by the visual Identification Test of the Cogstate computerised cognitive testing battery
14 secondary outcomes
Executive functioning
Time frame: One month
Psychomotor function
Time frame: One month
Working Memeory
Time frame: One month
Visual learning
Time frame: One month
Verbal learning
Time frame: One month
Test of Attentional Performance (TAP)
Time frame: One month
Beck Depression Inventory
Time frame: One month
Hamilton Anxiety and Depression Score (HADS)
Time frame: One month
Newcastle Mitochondrial Disease Scale for Adults (NMDAS)
Time frame: One month
Number of headache days
Time frame: One month
Pure Tone Audiometry (PTA)
Time frame: One month
University of Penn Smell Identification Test (UPSIT)
Time frame: One month
Cognitive Failure Questionnaire (CFQ)
Time frame: One month
Neuro-QoL Fatigue Short Form (quality in life in neurological disorders)
Time frame: One month
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 31 Aug 2022.
- 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 KH176 in people with Mitochondrial Diseases and Mitochondrial Myopathies, 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 0 inclusion and 27 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 31 Aug 2022. 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. Some participants in this study may receive a placebo. 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?
Cognitive functioning: Attention (time frame: One month). 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 31 Aug 2022.