Mitochondrial DiseasesPhase 2KHENERGYNCT02909400
The KHENERGY Study
A Phase 2 study testing KH176 in people with Mitochondrial Diseases and Mitochondrial Myopathies, run by Khondrion BV at 1 site in Netherlands.
Trial summary
Mitochondrial Diseases are rare, progressive, multi-system, often-early fatal disorders affecting both children and adults. KH176 is a novel chemical entity currently under development for the treatment of inherited mitochondrial diseases, including MELAS (Mitochondrial Encephalomyopathy, Lactic acidosis, and… 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
- 20 participants
- Where
- 1 siteNetherlands
- Study dates
- Sep 2016to Jul 2017
- 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 sign the Informed Consent Form prior to screening evaluations.
- Confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation
- Heteroplasmy level as measured in urine ≥ 20 %.
- Body Mass Index (BMI) 18.0-30.0 kg/m2 (extremes included) at screening
- Clinical evidence of mitochondrial disease, positive NMDAS score (including but not limited to MELAS, MIDD and mixed types). CPEO patients with signs restricted to the eye only are not considered eligible.
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- Disease appropriate physical and mental health as established by medical history, physical examination, electrocardiogram (ECG) and vital signs recording, and results of biochemistry, hematology and urinalysis testing within 3 weeks prior to the first dose as judged by the Investigator.
- Appropriate cardiac functioning as assessed by medical history, ECG and Echo, evaluated by a cardiologist.
- Able to comply with the study requirements, including exercise testing and swallowing study medication
- Willingness to use adequate contraceptive methods (male and female) and negative urine pregnancy test (females) at screening and first baseline assessment.
- Able and willing to refrain from the use of (multi)vitamins, co-enzyme Q10, Vitamine E, riboflavin, and anti-oxidant supplements (and idebenone/EPI-743), as well as any medication negatively influencing mitochondrial functioning (including but not limited to valproic acid, glitazones, statins, anti-virals, amiodarone, and NSAID's) as well as any strong Cytochrome P450 inhibitors (all 'conazoles-anti-fungals', HIV antivirals, grapefruit) and strong Cytochrome P450 inducers (a.o. carbamazepine, phenobarbital, phenytoin, rifampicine, St Johns wort, pioglitazone, troglitazone) as well as any medication known to affect cardiac repolarization (all anti-psychotics, several anti-depressants: nor/amytriptilline, fluoxetine, anti-emetics: domperidone (motilium) granisetron, ondansetron).
Who cannot join
- Motoric abnormalities other than related to the mitochondrial disease interfering with the outcome parameters.
- CPEO patients with clinical signs and symptoms restricted to the eye only
- Heteroplasmy level as measured in urine < 20%
- Poor nutritional state as judged by the investigator
- Body Mass Index (BMI) not within 18.0-30.0 kg/m2 at screening.
- History of cancer
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- Surgery or active illness of gastro-intestinal tract that might interfere with absorption.
- Participation in a trial of an investigational product in the preceding 3 months prior to the first dose or during this trial.
- Positive drug, alcohol or cotinine test at screening and/or admission (Day 1 of the first dosing period).
- Clinically relevant abnormal laboratory, ECG recordings, cardiac echo (within 1 year prior to screening), vital signs or physical or mental findings at screening as judged by the Investigator.
- Clinically relevant abnormal ECG or cardiac functioning as judged by a cardiologist.
- ECG: QTc > 450 ms, abnormal T-wave
- Symptomatic heart failure or signs of ischemic heart disease
- Left Ventricular Ejection Fraction <45%
- History or family history of congenital Long QT syndrome
- Increased or decreased potassium (local laboratory normal range)
- Inadequate contraception use, pregnancy or breast feeding (females)
- Clinically significant presence or history of allergy as judged by the Investigator.
- History of hypersensitivity or idiosyncrasy to any of the components of the investigational drug.
- Within 4 weeks prior to dosing, the use of:
- (multi)vitamins, co-enzyme Q10, Vitamine E, riboflavin, and anti-oxidant supplements (and idebenone/EPI-743),
- as well as any medication negatively influencing mitochondrial functioning (including but not limited to valproic acid, glitazones, statins, anti-virals, amiodarone, and NSAID's)
- as well as any strong Cytochrome P450 inhibitors (all 'conazoles-anti-fungals', HIV antivirals, grapefruit)
- and strong Cytochrome P450 inducers (a.o. carbamazepine, phenobarbital, phenytoin, rifampicin, St Johns wort, pioglitazone, troglitazone)
- as well as any medication known to affect cardiac repolarization (all anti-psychotics, several anti-depressants: nor/amitriptyline, fluoxetine, anti-emetics: domperidone (motilium) granisetron, ondansetron)
- as well as any medication metabolized by Cytochrome P450 with a narrow therapeutical width. (for reference: drug interaction table of Indiana University http://medicine.iupui.edu/clinpharm/ddis/clinical-table/)
Trial locations and contacts
1 site in 1 country.
About this study
Official title: An Exploratory, Double-blind, Randomized, Placebo-controlled, Single-center, Two-way Cross-over Study With KH176 in Patients With the Mitochondrial DNA tRNALeu(UUR) m.3243A>G Mutation and Clinical Signs of Mitochondrial Disease
Mitochondrial Diseases are rare, progressive, multi-system, often-early fatal disorders affecting both children and adults. KH176 is a novel chemical entity currently under development for the treatment of inherited mitochondrial diseases, including MELAS (Mitochondrial Encephalomyopathy, Lactic acidosis, and Stroke-like episodes), MIDD (Maternally Inherited Diabetes and Deafness), Leigh's Disease and LHON (Leber's Hereditary Optic Neuropathy). The current Proof of Concept study aims to explore the effects of treatment with KH176 for 4 weeks on clinical signs and symptoms and biomarkers of mitochondrial disease and to evaluate the safety and pharmacokinetics of KH176 in patients with m.3242A>G related mitochondrial disease.
Read the detailed description
The trial will be a double blind, randomized, placebo-controlled, single-centre, two-way cross-over trial. Twenty patients, with a confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation and with clinical signs of mitochondrial disease, will be randomized over 2 groups (active or placebo first). After a screening period and a training session, each group will have 2 dosing periods of 28 days, with a washout period of at least 28 days in between. On these occasions, patients will receive 100 mg KH176 twice daily (treatment A) or a matching placebo (treatment B) twice daily for 28 days.
Clinical assessments will be performed once in a training session prior to baseline, at baseline and in week 4 post dosing during each treatment phase (A and B). Testing conditions and circumstances, with respect to timing of the assessments, hospitalization and meals, will be standardized for each assessement period. Furthermore, assessments of biomarkers for mitochondrial functioning, pharmacokinetics and specific safety assessments will be performed weekly.
- Conditions
- Mitochondrial Diseases, Mitochondrial Myopathies, Mitochondrial Encephalomyopathies, MELAS, MIDD
- Being tested
- KH176, placebo
- Keywords
- mitochondrial, oxidative phosphorylation (oxphos), MELAS, MIDD, KH176, Proof of Concept
- 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
placeboDrug
| Study group | Role | What they receive |
|---|---|---|
| Treatment A | Experimental | Oral administration of 100 mg KH176 twice daily Receives: Drug: KH176 |
| Treatment B | 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.
Movement disorders
Rater assessed change from baseline of motoric abnormalities and movement characteristics
Measured: one month
Secondary outcomes (24)
NMDAS
Change from baseline of the Newcastle Mitochondrial Disease Activity Score
Measured: one month
Spirometric parameters (FVC,FEV1, PEF)
Change from baseline in spirometric parameters
Measured: one month
Spirometric parameters (MIP, MEP)
Change from baseline in spirometric parameters
Measured: one month
Sit to Stand Test (30 seconds)
Change from baseline assessment of the maximum number of sit-standings in 30 seconds time
Measured: one month
Handgrip Dynamometry
Change from baseline assessment of the maximum grip strenght
Measured: one month
6-min chewing test
Change from baseline assessment in rate of mastication
Measured: one month
6-min chewing test
Change from baseline assessment of pain and tiredness (VAS) during a 6-min chewing test
Measured: one month
6-MWT
Change from baseline assessment of the Distance during a 6-min Walk Test
Measured: one month
RAND-SF36 score
Change from baseline in the RAND-SF36
Measured: one month
HAD and BDI
Change from baseline in the Hospital Anxiety and Depression Scale (HAD), supplemented with a Beck Depression Index (BDI)
Measured: one month
BDI
Change from baseline in the Beck Depression Index (BDI)
Measured: one month
CIS
Change from baseline in the Checklist Individual Strength
Measured: one month
TAP
Change from baseline assessment of alertness and mental flexibility during a Test of Attentional Performance (TAP)
Measured: one month
Goal Attainment Scale
Assessment of pre-defined goal attainment during each treatment period
Measured: one month
Registration of Motor Activity and Sleeping pattern
During each treatment period a continuous registration of Motor Activity and Sleeping pattern by accelerometer, assessing sleep quality, quantity and overall motor activity
Measured: one month
Vital Signs
Change from Baseline assessment of vital signs (heart rate, blood pressure)
Measured: one month
ECG
Change from Baseline assessment of ECG-intervals
Measured: one month
Clinical Laboratory
Change from Baseline assessment of Clinical Laboratory parameters
Measured: one month
Pharmacokinetics of KH176 and metabolites
Attainment of steady state and total exposure (AUC) at steady state conditions
Measured: one month
Pharmacokinetics of KH176 and metabolites
Attainment of steady state and maximal concentrations (Cmax) at steady state conditions
Measured: one month
Glutathione
Change from baseline assessment of the ratio of oxidized/reduced glutathione in blood samples (GSH/GSSG)
Measured: one month
Blood biomarker FGF21
Change from baseline assessment of FGF21
Measured: one month
Blood biomarker GDF15
Change from baseline assessment of GDF15
Measured: one month
Blood biomarker PRDX1
Change from baseline assessment of PRDX1
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 posted21 Sep 2016 (estimated)
- Study startSep 2016
- Primary completionJul 2017
- Study completionJul 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- 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
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Khondrion BV
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Radboud University Medical Center
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02909400
- Sponsor's protocol ID
- KH176-201
- Acronym
- KHENERGY
- Status last verified
- Feb 2018
- First submitted
- 13 Sep 2016
- Last updated
- 23 Feb 2018
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Janssen MCH, Koene S, de Laat P, Hemelaar P, Pickkers P, Spaans E, Beukema R, Beyrath J, Groothuis J, Verhaak C, Smeitink J. The KHENERGY Study: Safety and Efficacy of KH176 in Mitochondrial m.3243A>G Spectrum Disorders. Clin Pharmacol Ther. 2019 Jan;105(1):101-111. doi: 10.1002/cpt.1197. Epub 2018 Sep 3.
PubMed 30058726
Study at a glance
From the registry record, last updated by the sponsor on 23 Feb 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Exploratory, Double-blind, Randomized, Placebo-controlled, Single-center, Two-way Cross-over Study With KH176 in Patients With the Mitochondrial DNA tRNALeu(UUR) m.3243A>G Mutation and Clinical Signs of Mitochondrial Disease
- ClinicalTrials.gov ID
- NCT02909400
- Acronym / sponsor ID
- KHENERGY / KH176-201
- Conditions
- Mitochondrial Diseases, Mitochondrial Myopathies, Mitochondrial Encephalomyopathies, MELAS, MIDD
- Keywords
- mitochondrial, oxidative phosphorylation (oxphos), MELAS, MIDD, KH176, Proof of Concept
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Khondrion BVIndustry (pharma, biotech, devices)
- Collaborators
- Radboud University Medical Center
- Study start
- Sep 2016 (actual)
- Primary completion
- Jul 2017 (actual)
- Study completion
- Jul 2017 (actual)
- First posted
- 21 Sep 2016 (estimated)
- 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 are rare, progressive, multi-system, often-early fatal disorders affecting both children and adults. KH176 is a novel chemical entity currently under development for the treatment of inherited mitochondrial diseases, including MELAS (Mitochondrial Encephalomyopathy, Lactic acidosis, and Stroke-like episodes), MIDD (Maternally Inherited Diabetes and Deafness), Leigh's Disease and LHON (Leber's Hereditary Optic Neuropathy). The current Proof of Concept study aims to explore the effects of treatment with KH176 for 4 weeks on clinical signs and symptoms and biomarkers of mitochondrial disease and to evaluate the safety and pharmacokinetics of KH176 in patients with m.3242A>G related mitochondrial disease.
Detailed description
The trial will be a double blind, randomized, placebo-controlled, single-centre, two-way cross-over trial. Twenty patients, with a confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation and with clinical signs of mitochondrial disease, will be randomized over 2 groups (active or placebo first). After a screening period and a training session, each group will have 2 dosing periods of 28 days, with a washout period of at least 28 days in between. On these occasions, patients will receive 100 mg KH176 twice daily (treatment A) or a matching placebo (treatment B) twice daily for 28 days.
Clinical assessments will be performed once in a training session prior to baseline, at baseline and in week 4 post dosing during each treatment phase (A and B). Testing conditions and circumstances, with respect to timing of the assessments, hospitalization and meals, will be standardized for each assessement period. Furthermore, assessments of biomarkers for mitochondrial functioning, pharmacokinetics and specific safety assessments will be performed weekly.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment A | Experimental | Drug: KH176Oral administration of 100 mg KH176 twice daily |
| Treatment B | 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 (11 listed)
- Males and females aged 18 years or older at screening
- Ability and willingness to sign the Informed Consent Form prior to screening evaluations.
- Confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation
- Heteroplasmy level as measured in urine ≥ 20 %.
- Body Mass Index (BMI) 18.0-30.0 kg/m2 (extremes included) at screening
Key exclusion criteria (26 listed)
- Motoric abnormalities other than related to the mitochondrial disease interfering with the outcome parameters.
- CPEO patients with clinical signs and symptoms restricted to the eye only
- Heteroplasmy level as measured in urine < 20%
- Poor nutritional state as judged by the investigator
- Body Mass Index (BMI) not within 18.0-30.0 kg/m2 at screening.
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 |
|---|---|---|
| KH176 | Drug | Treatment A |
| placebo | Drug | Treatment B |
Primary outcome
Movement disorders
Time frame: one month
Rater assessed change from baseline of motoric abnormalities and movement characteristics
24 secondary outcomes
NMDAS
Time frame: one month
Spirometric parameters (FVC,FEV1, PEF)
Time frame: one month
Spirometric parameters (MIP, MEP)
Time frame: one month
Sit to Stand Test (30 seconds)
Time frame: one month
Handgrip Dynamometry
Time frame: one month
6-min chewing test
Time frame: one month
6-min chewing test
Time frame: one month
6-MWT
Time frame: one month
RAND-SF36 score
Time frame: one month
HAD and BDI
Time frame: one month
BDI
Time frame: one month
CIS
Time frame: one month
TAP
Time frame: one month
Goal Attainment Scale
Time frame: one month
Registration of Motor Activity and Sleeping pattern
Time frame: one month
Vital Signs
Time frame: one month
ECG
Time frame: one month
Clinical Laboratory
Time frame: one month
Pharmacokinetics of KH176 and metabolites
Time frame: one month
Pharmacokinetics of KH176 and metabolites
Time frame: one month
Glutathione
Time frame: one month
Blood biomarker FGF21
Time frame: one month
Blood biomarker GDF15
Time frame: one month
Blood biomarker PRDX1
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 23 Feb 2018.
- Derived from this study: PubMed 30058726Janssen MCH, Koene S, de Laat P, Hemelaar P, Pickkers P, Spaans E, Beukema R, Beyrath J, Groothuis J, Verhaak C, Smeitink J. The KHENERGY Study: Safety and Efficacy of KH176 in Mitochondrial m.3243A>G Spectrum Disorders. Clin Pharmacol Ther. 2019 Jan;105(1):101-111. doi: 10.1002/cpt.1197. Epub 2018 Sep 3.
- 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.
1 site in 1 country: 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 1 site in Netherlands.
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 11 inclusion and 26 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 23 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. 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?
Movement disorders (time frame: one month). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02909400, which also lists 1 linked publication.
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 23 Feb 2018.