KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases

Mitochondrial Diseases Clinical Trial

— KH176-301  

Official title:

A Phase III, Randomised, Double-blind, Placebo-controlled, Parallel-group, Pivotal Trial to Assess the Efficacy and Safety of Sonlicromanol in Adult Subjects With a Genetically Confirmed Mitochondrial DNA tRNALeu(UUR) m.3243A>G Variant

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06451757
• Other study ID #: Khondrion B.V.
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: January 2, 2025
• Est. completion date: July 2, 2027

Study information

• Verified date: June 2024
• Source: Khondrion BV
• Contact: Jan Smeitink, MD, PhD, MAE
• Phone: +31 24 7635000
• Email: smeitink[@]khondrion.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The KHENERFIN study is investigating whether the study medicine, sonlicromanol, is able to improve symptoms of fatigue and the impact of fatigue on daily life, and whether sonlicromanol is able improve physical abilities of people living with mitochondrial disease, such as balance control and lower limb skeletal muscle strength.

For this study, the effects of sonlicromanol are compared with those from a placebo (study medication that looks like the actual study medicine but contains no active medicine). The study medicine (or placebo) is a powder that is dissolved in water and must be taken twice daily during the treatment period of 52 weeks.

Additionally, the study evaluates the efficacy of sonlicromanol on selected secondary and exploratory outcome measures, as well as the safety and tolerability of sonlicromanol after 52 weeks of treatment with sonlicromanol.

Description:

The KHENERFIN study is investigating whether the study medicine, sonlicromanol, is able to improve symptoms of fatigue and the impact of fatigue on daily life, and whether sonlicromanol is able improve physical abilities of people living with mitochondrial disease such as balance control and lower limb skeletal muscle strength. Additionally, the study evaluates the efficacy of sonlicromanol on selected secondary and exploratory outcome measures, as well as the safety and tolerability of sonlicromanol. This study is a placebo controlled, double blind study; the effects of sonlicromanol will be compared with a placebo (study medication that looks like the actual study medicine but contains no active medicine). Neither the participants nor the study team know who is receiving the study medicine or placebo and participants are not able to change which treatment they are assigned.

During the screening period, which lasts a maximum of 6 weeks, it is assessed whether the potential participant meets all requirements to participate in the study. Patients who complete the screening phase and are enrolled in the study are randomly (by chance) assigned to receive either the study medicine sonlicromanol or placebo (no active medication). Participants have an equal chance of receiving either sonlicromanol or a placebo. A final follow-up visit is scheduled 2 weeks after taking the last dose of study medication. Total study duration is approximately 60 weeks. The study medicine (as well as placebo) is a powder that is dissolved in water and must be taken twice daily during the treatment period of 52 weeks. A total of 150 patients with a confirmed mitochondrial DNA tRNALeu(UUR) 3243A>G mutation will participate in this study.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 150
• Est. completion date: July 2, 2027
• Est. primary completion date: July 2, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Males and females aged =18 years.

• A confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation plus a heteroplasmy percentage = 20% in white blood cells, or urine (urinary epithelial cells), or buccal smear or skeletal muscle (results must be available prior to the subject being randomized).

• Presence of chronic fatigue (not attributable to otherwise treatable or reversible etiologies):

• Complaints of patient self-reported chronic fatigue for at least 3 months prior to the Screening Visit and recorded in the clinical patient files AND

• Presence of fatigue (raw total score >22 being a T-score >50), assessed by Neuro-QoL SFv1-F at Screening.

• Presence of mitochondrial myopathy defined as:

• 5XSST at Screening and Baseline = 9.1 seconds.

• Myopathy (proximal muscle weakness), NMDAS Section III Clinical Assessment at Screening, item 5 score =1, which reads: "mild but clear proximal weakness in hip flexion and shoulder abduction - MRC 4/5". For the inclusion only hip flexion, but not shoulder abduction, should be taken into account.

• The patient is able and willing to provide written Informed Consent prior to screening evaluations and to attend study appointments within the specified time windows.

• The patient is, in the investigator's opinion, likely to comply with the protocol and able to adhere to the study requirements for the length of the study, and swallowing study medication, as well as the use of digital applications (ability to complete electronic patient reported outcomes (PROs).

• Clinically stable (apart from PMD symptoms) at screening as determined by medical history, physical examination, vital signs measurements, 12-lead ECG, and clinical laboratory evaluations at Screening, and as assessed by the Investigator.

• The patient has been on stable exercise regimen for at least 4 weeks prior to randomization and willing to not change their exercise regimen for the duration of the study treatment period.

• Left Ventricular wall thickness =15 mm at screening if not explained by cardiac involvement of mitochondrial disease (e.g., by cardiovascular magnetic resonance [CMR]).

• Women of childbearing potential must be willing to use highly effective contraceptive methods during the entire study. To be considered not of childbearing potential, potential female participants 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. Sonlicromanol 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 sonlicromanol 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.

Exclusion Criteria:

• Progressive External Ophthalmoplegia (PEO) as the single clinical manifestation associated with m.3243A>G.

• Treatment with an IMP for PMD within 3 months (or 5 times the half-life of the IMP, whichever is longer) prior to screening or plans to use an IMP (other than the study intervention) during the study.

• Bone deformities or motor abnormalities of PMD or other than those related to mitochondrial myopathy or significant other medical conditions that in the opinion of the PI may interfere with and confound the interpretation the participant's performance during the 5 times sit to stand test (5XSST).

• Surgery of gastrointestinal tract that might interfere with drug absorption. Or severe GI dysmotility, chronic diarrhea, bouts of pseudo-obstruction which will impair appropriate IMP absorption in the opinion of the investigator.

• Documented history of sustained ventricular tachycardia (HR >110 beats/min) at rest and absence of an implanted cardioverter-defibrillator (ICD). In case of non-sustained ventricular tachycardia, myocardial ischemia must be excluded.

• History of ischemic heart disease with reduced left ventricular ejection fraction (<45%) and/or severe valvular heart disease.

• Symptomatic heart failure with reduced ejection-fraction with LVEF to 40% (HFrEF); in case of heart failure with preserved ejection-fraction (HFpEF) or only mildly reduced ejection-fraction (HFmrEF) (defined as LVEF =40%) patients may be included if the clinical symptoms are stable for at least 3 months as judged by the Investigator.

• History of acute heart failure (within the last 3 months), (family) history of unexplained syncope or congenital long and short QT syndrome or sudden death.

• Higher degree of AV-blocks (AVB II° or III°) in the absence of a pacemaker or ICD.

• In case QTcFridericia is >450ms (male) and >470ms (female) and a simultaneous bundle-branch-block (LBBB or RBBB) is not present at screening then QTcF will be calculated using regular QT interval (three cycles averaged). In case LBBB or RBBB is present, the modified QT interval (QTm) should be calculated by subtracting 50% of the length of the BBB-QRS from the measured QT interval (QTm = QTBBB - 50% QRSBBB). Subsequently, a rate-correction formula should be applied as usual. For QTcF = QTm / (RR_Interval/1000)1/3.

• Novel and/or dynamic ECG abnormalities (including ST-segment elevation or depression of >1 mm in at least two contiguous leads and/or T-wave inversions) within the last 3 months suggestive of myocardial ischemia. In this case the presence of myocardial ischemia must be excluded to include the patient to this study.

• Recent history of unstable disease, inadequately controlled neurological manifestations or not recovered from stroke-like episodes including but not limited to stroke-like episodes within the last 6 months, hospitalized for status epilepticus within the last 6 months.

• Blood pressure >160/90 mmHg at screening or baseline confirmed by re-testing (3x; supine position; first measure after 20 minutes of rest).

• =1 clinical laboratory test value outside the reference range, based on the blood and urine samples taken at the screening visit, that are of potential risk to the patient's safety, or the patient has, at the screening visit:

• Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2.

• Serum potassium >5.0 mEq/L or <3.5 mEq/L).

• AST, ALT or total bilirubin (TBL) >3 x ULN at Screening. Patients who have a slightly elevated TBL and/or ALT and/or AST and are suitable candidates for the study, can be enrolled in the study if the Investigator can rule out any underlying liver dysfunction by running additional tests and after discussing the case with the medical monitor.

• Medical history of drug abuse (illegal drugs such as cannabinoids, amphetamines, cocaine, opiates, or problematic use of prescription drugs such as benzodiazepines, opiates).

• Within 4 weeks prior to screening, the use of:

• (multi)vitamins, co-enzyme Q10, Vitamin E, riboflavin, amino acids, 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 screening and willing to remain 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 the dose has been stable for at least one month before screening and the dose is to remain stable throughout the study (1).

• 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 metabolized by CYP3A4 with a narrow therapeutic index.

• medication known to be substrate of Organic Cation Transporter 1 (OCT1) and organic cation transporter 2 (OCT2) with a narrow therapeutic index.

• strong P-glycoprotein inhibitors (including amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tariquidar, and verapamil).

• any medication known to affect cardiac repolarisation unless QTcF 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-/amitriptyline, fluoxetine, anti-emetics: domperidone, granisetron, ondansetron). For a complete list see https://crediblemeds.org.

• Patient has psychiatric conditions such as schizophrenia, bipolar disorder or major depressive disorder that has not been under control within 3 months prior to screening.

• Patient has severe behavioral or cognitive problems that preclude participation in the study.

• Patient has undergone an inpatient hospitalization that precludes participation in the study, within the 30 days prior to the randomization.

• Patient has a planned hospitalization or a surgical procedure during the study, which may affect the study assessments.

• Patient has clinically significant and unstable respiratory disease and/or cardiac disease (medical history or current clinical findings), or prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to randomization.

• Patient requires any ventilator support, including CPAP or BiPAP at night.

• Patient has severe vision impairment that may interfere with their ability to complete all study requirements.

• Patient has an active malignancy or any other cancer from which the Patient has been disease-free for <5 years, except for curative treated localized non-melanoma skin cancer (e.g., basal cell or squamous cell carcinoma).

• Patient has a solid organ transplant and/or is currently receiving treatment with therapy for immunosuppression.

• Patient has a history of active human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection.

• The patient has an immediate family member (defined as family members residing at the same address) who participates in the study or the continuation protocol (to avoid potential mix up / switch of medications during participation).

• Patient has BMI below 18.5 kg/m2 or above 35 kg/m2 at screening.

• Patient has any active viral or bacterial infection at the time of randomization.

• Patient is pregnant or breast feeding.

Related Conditions & MeSH terms

• Acidosis
• Acidosis, Lactic
• Deafness
• Diabetes Mellitus, Type 2
• Hearing Loss
• Maternally Inherited Diabetes and Deafness (MIDD)
• MELAS Syndrome
• Mitochondrial Diseases
• Mitochondrial DNA tRNALeu(UUR) m.3243A<G Mutation
• Mitochondrial Encephalomyopathies

Intervention

Drug:
• Sonlicromanol
Oral administration of 100 mg sonlicromanol (KH176) twice daily during 52 weeks
• Placebo
Oral administration of 100 mg placebo twice daily during 52 weeks

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Khondrion BV

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Newcastle Mitochondrial Disease Adult Scale (NMDAS)	Change from Baseline compared to placebo at week 52 and at other relevant study visits of the Newcastle Mitochondrial Disease Scale for Adults (NMDAS). The NMDAS is a semi-quantitative clinical rating scale designed specifically for all forms of mitochondrial disease. The rating scale encompasses all aspects of mitochondrial disease by exploring several domains: current function, system specific involvement, and current clinical assessment. Each question/item in the NMDAS has a possible score from 0-5. Each of the three section scores are calculated by simply summing the scores obtained for each question in that section, with the higher the score the more severe the disease. Thus, scores can range from 0 to 50 for Sections I and III, and from 0 to 45 for Section II, and from 0 to 145 for Sections I through III. Higher scores indicate a higher level of disease severity.	Baseline (Day 1), Weeks 26, 52 (End of Trial Visit)
Other	Brief Pain Inventory Short Form (BPI-SF)	Change from Baseline compared to placebo at week 52 and at other relevant study visits of the Brief Pain Inventory-Short Form (BPI-SF). The BPI-SF is a validated (33) self-administered questionnaire to assess the severity of pain and the impact of pain on the patient's daily functions. BPI-SF evaluates pain severity at its worst, least, and average during the last 24 hours, as well as current pain level, with 0 representing no pain and 10 the worst pain imaginable. Seven items measuring interference with daily functioning (general activity, walking, work, mood, relations with others, sleep, and enjoyment of life) are also assessed on an 11-point scale, where 0 represents no interference and 10 complete interferences. The scores can be averaged to the two components of the BPI SF score, the Pain Severity Index and the Pain Interference Index. Higher scores indicate a higher level of severity and impact of pain.	Baseline (Day 1), Weeks 26, 52 (End of Trial Visit)
Other	Health Economics and Outcomes Research (HEOR) Assessments: EQ-5D-5L	Change from Baseline compared to placebo at week 52 and at other relevant study visits of the EQ-5Dimension-5 Level (EQ-5D-5L). The EQ-5D-5L is a self-report health-related quality of life (HRQoL) instrument consisting a descriptive system and a visual analogue scale (EQ-VAS). The descriptive system that defines health in five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response categories (levels): no problems, slight problems, moderate problems, severe problems and extreme problems. The EQ-VAS records the respondent's self-rated health on a vertical VAS. The respondents can report their perceived health status with a grade ranging from 0 ('the worst health you can imagine') to 100 ('the best health you can imagine'). A higher score denotes a worse health state.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit) and at week 52 (Follow-up)
Other	Columbia-Suicide Severity Rating Scale (C-SSRS)	Change from Baseline compared to placebo at week 52 and at other relevant study visits of the Columbia-Suicide Severity Rating Scale (C-SSRS). The instrument assesses severity of suicidal ideation ("severity subscale"), rated on a 5-point ordinal scale, the intensity of ideation subscale ("intensity subscale"), comprising 5 items, rated on a 5-point ordinal scale: frequency, duration, controllability, deterrents, and reason for ideation, resulting in 0-25 score range summed from five items, with higher scores indicating more severe suicidal ideation. A score of 0 indicates that no suicide ideation is present. The behaviour subscale is a nominal scale including actual, aborted, and interrupted attempts; preparatory behaviour; and self-injurious behaviour. The lethality subscale assesses actual attempts; actual lethality rated on a 6-point ordinal scale. Higher scores indicate a higher level of severity.	Baseline (Day 1), Weeks 26, 52 (End of Trial Visit)
Other	Gastro-Intestinal symptoms.	Change from Baseline compared to placebo on the number of gastro-intestinal complaints, intensity and duration. The number of gastro-intestinal complaints/month will be captured, starting at screening until (and including) the week 52 visit. For this purpose the Gastro-Intestinal symptoms questionnaire will be used.	Through week 52
Other	Seizure episodes	Change from Baseline compared to placebo on the number of seizures, intensity and duration and on the use of medication. Seizure data (e.g., occurrence, duration, intensity severity; and any use of migraine medication) are captured daily through a daily headache-diary.	Through week 52
Other	Safety and tolerability assessed by nature, frequency and severity of treatment emergent adverse events (TEAEs)	Safety and tolerability assessed by nature, frequency and severity of treatment emergent adverse events (TEAEs) Treatment emergent adverse events will be coded using medical dictionary for regulatory activities (MedDRA). A TEAE is defined as an adverse event (AE) observed after starting administration of the investigational product (IP) to 14 days after last dose of IP. An AE is any untoward medical occurrence in a participant, temporally associated with the use of IP, whether or not considered related to the IP. An AE can therefore be any unfavourable and unintended, symptom, or disease (new or exacerbated) temporally associated with the use of IP.	Through Week 52
Other	Safety: Clinically significant body weight changes and/or AEs	Incidence of clinically significant body weight changes.	Baseline (Day 1), Weeks 26, 52 (End of Trial Visit)
Other	Safety: 12 lead ECG parameters: QRS duration (milliseconds)	12 lead ECG parameter data QRS duration (milliseconds) will be summarised.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
Other	Safety: 12 lead ECG parameters: QRS morphology (peak, axis)	12 lead ECG parameter data QRS morphology (peak, axis) will be summarised.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
Other	Safety: 12 lead ECG parameters: QTcB (Bazett)	12 lead ECG parameter data QTcB (Bazett) will be summarised.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
Other	Safety: 12 lead ECG parameters: QTcF (Fridericia)	12 lead ECG parameter data QTcF (Fridericia) will be summarised.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
Other	Safety: 12 lead ECG parameters: PQ interval: milliseconds (ms))	12 lead ECG parameter data PQ intervals (milliseconds) will be summarised.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
Other	Safety: 12 lead ECG parameters: Heart rate: beats per minute (bpm)	12 lead ECG parameter data Heart rate (beats per minute (bpm) be summarised.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
Other	Safety: 12 lead ECG parameters: Tpeak-Tend interval	12 lead ECG parameter data (Tpeak-Tend interval) will be summarised.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
Other	Safety: 12 lead ECG parameters: T wave morphology (peak, symmetry)	12 lead ECG parameter data T-wave morphology (symmetry) will be summarised.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
Other	Safety: Incidence of laboratory abnormalities, based on haematology, clinical chemistry, and urinalysis test results	Incidence of laboratory abnormalities outside the clinical reference ranges based on haematology, serum biochemistry, and urinalysis test	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
Other	Safety: Vital signs abnormalities and/or AEs	Incidence of clinically significant vital sign values.	Baseline (Day 1), Weeks 26, 52 (End of Trial Visit)
Other	Pharmacokinetics: Tmax (hours)	Tmax: Time to reach maximum (peak) plasma concentration following drug administration (hours)	pre-dose, and at 1, 2, 3, 4, 6, 12 hours post dosing.
Other	Pharmacokinetics: Cmax (ng/mL)	Maximum (peak) plasma drug concentration in ng/mL	pre-dose, and at 1, 2, 3, 4, 6, 12 hours post dosing.
Other	Pharmacokinetics: Ctrough (ng/mL)	Plasma concentration (measured concentration at the end of a dosing interval at steady state in ng/mL	pre-dose, and at 1, 2, 3, 4, 6, 12 hours post dosing.
Other	Pharmacokinetics: AUCinf (h*ng/mL)	Area under the plasma concentration time curve from time zero to infinity in h*ng/mL	pre-dose, and at 1, 2, 3, 4, 6, 12 hours post dosing.
Other	Pharmacokinetics: AUCtau (h*ng/mL)	Area under the plasma concentration time curve in h*ng/mL	pre-dose, and at 1, 2, 3, 4, 6, 12 hours post dosing.
Other	Pharmacokinetics: T1/2 (hours)	Terminal Elimination Half-life	pre-dose, and at 1, 2, 3, 4, 6, 12 hours post dosing.
Primary	Neuro-QoL Fatigue Short Form v1	Change from baseline compared to placebo at week 52 and at other relevant study visits of the Quality of Life in Neurological Disorders Fatigue Short Form version 1 (Neuro-QoL Fatigue - SF v1): The Neuro-QoL Fatigue SF v1 is an 8-item self-assessment questionnaire evaluating the perception of fatigue and its impact in daily life activities. Each question is scored as following: 1=Never, 2=Rarely, 3=Sometimes, 4=Often, and 5=Always. Total raw scores range from 8-40. T-scores are calculated from the short form scoring table provided in the instruments´manual. T-score distributions rescale raw scores into standardized scores with a mean of 50 and a standard deviation (SD) of 10. Change from baseline: Negative numbers mean less fatigue, better outcome, positive score means more fatigue, worse outcome.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
Primary	Five Times Sit-To-Stand Test (5XSST)	Change from Baseline compared to placebo at week 52 and at other relevant study visits of the 5xSST in total time (in seconds) to complete the 5xSTS. The 5xSST scoring is based on the amount of time (to the nearest decimal in seconds a subject is able to transfer from a seated to a standing position and back to sitting five times. Inability to complete five repetitions without assistance or use of upper extremity support indicates 'failure to perform of test, any modifications should be documented. Participant is directed to stand up straight as quickly as possible 5 times, without stopping in between, keeping arms folded across the chest. When 5xSST is not reached within 30.0 seconds the test is stopped and the actual number of sit to stands reached within those 30 seconds is recorded. Faster times (in sec) denotes better performance.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
Secondary	RAND 36-Item Short Form Survey (SF-36)	Change from Baseline at week 52 and at other relevant study visits of the RAND 36-item Short Form Survey Instrument (RAND SF-36). RAND-SF36 is a 36-item multidimensional self-report health related quality of life (HRQoL) questionnaire, containing 36 items measuring eight dimensions of HRQoL: 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, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. To score the SF-36, scales are standardized with a scoring algorithm to obtain a score ranging from 0 to 100. Standard scoring algorithms yield two distinct, higher-order summary scores: Physical Component Summary (PCS) and Mental Component Summary (MCS). Higher scores on all subscales represent better health and functioning.	Baseline (Day 1), Weeks 26, 52 (End of Trial Visit)
Secondary	The PROMIS Fatigue Primary Mitochondrial Disease Short Form (PROMIS) Fatigue PMD SF)	Change from baseline at week 52 and at other relevant study visits of the Patient-Reported Outcomes Measurement Information System (PROMIS®) Fatigue Primary Mitochondrial Disease Short Form (PROMIS Fatigue PMD SF). The PROMIS Fatigue Primary Mitochondrial Disease Short Form is a nine-item self-report inventory to assess fatigue symptoms and impacts on daily living measured in PMD. The PROMIS Fatigue PMD SF asks the respondent to rate the experience and impact of fatigue symptoms by asking how often they feel or experienced specific fatigue symptoms in the past seven days on a 5-point rating scale scored as: "never" (1), "rarely" (2), "sometimes" (3), "often" (4), "always" (5). Higher scores indicate greater fatigue severity.	Baseline (Day 1), Weeks 26, 52 (End of Trial Visit)
Secondary	Beck Depression Inventory (BDI)	Change from Baseline compared to placebo at week 52 and at other relevant study visits of the Beck Depression Inventory (BDI). The Beck Depression Inventory (BDI) is a 21-question multiple-choice self-report inventory, for measuring the severity of depression. It is composed of items relating to symptoms of depression such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms such as fatigue, weight loss, and lack of interest in sex. Each answer is scored on a scale value of 0 to 3; higher scores indicate more severe depressive symptoms.	Baseline (Day 1), Weeks 26, 52 (End of Trial Visit)
Secondary	Patient-scored Global Impression of Severity scale (PGI-S)	Change from Baseline compared to placebo at week 52 and at other relevant study visits of the Patient Global Impression of Severity (PGI-S).The Patient scored Global Impression - Severity questionnaire assesses patient's impression of disease severity. The PGI-S item asks the respondent to rate the severity of their PMD symptoms at the time of assessment ("Please choose the response that best describes the severity of your Primary Mitochondrial Disease (PMD) symptoms today") on a 7-point scale scored as: "none" (1), "very mild" (2), "mild" (3), "moderate" (4), "moderately severe" (5), "severe", (6), or "extremely severe" (7). Higher scores indicate a higher level of severity.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
Secondary	Clinician-scored Global Impression of Severity (CGI-S)	Change from Baseline compared to placebo at week 52 and at other relevant study visits of the Clinician Global Impression of Severity (CGI-S). The Clinician scored Global Impression - Severity (CGI-S) scale is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. The CGI-S asks the clinician one question: "Considering your total clinical experience with this particular population, how ill is the patient at this time?" which is rated on the following seven-point scale: "normal, not at all ill" (1), "borderline" (2), "mild" (3), "moderate" (4), or "marked" (5), "severe" (6), and "among the most extremely affected patients" (7). This rating is based upon observed and reported symptoms, behaviour, and function at the time of the assessment.Higher scores indicate a higher level of severity.	Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)