SONLICROMANOL for Primary mitochondrial disease (m.3243A>G) | MELAS | MIDD

Inclusion criteria

• {"criterion_text":"- 1. Males and females aged ≥18 years with a multi-system primary mitochondrial disease."}
• {"criterion_text":"- 10.\tWomen of child-bearing potential, defined as all women physiologically capable of becoming pregnant, should be using highly effective/adequate methods of contraception during study treatment. Highly effective contraception methods include: o\tTotal sexual abstinence: if defined as refraining from heterosexual intercourse during the entire period of risk associated with study treatment up to a minimum of 7 days after treatment discontinuation. 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. o \tCombined oral, intravaginal, transdermal, implanted, injected (estrogen and progestogen containing) hormonal contraception or progesterone only hormonal contraception associated with inhibition of ovulation. o\tPlacement of an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) o\tFemale sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment. o\tVasectomy of the partner; vasectomized partner is considered a highly effective birth control method if partner is the sole sexual partner of the subject and that the vasectomized partner has received medical assessment of the surgical success."}
• {"criterion_text":"- 2. A confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation (m.3243A>G PMD) plus an age adjusted heteroplasmy percentage ≥ 20% in white blood cells [=blood heteroplasmy/0.977(age+12)], or , not age adjusted in urine (urinary epithelial cells), or buccal smear or skeletal muscle (results (obtained per local guidance) ≥ 20% must be available prior to the subject being randomized)."}
• {"criterion_text":"- 3. Presence of chronic fatigue (not attributable to other aetiologies than PMD): a. Patient self-reported chronic fatigue for at least 3 months prior to the Screening Visit and recorded in the clinical patient files; AND b. Presence of fatigue (raw total score >22), assessed by Neuro-QoL SFv1-F at Screening."}
• {"criterion_text":"- 4. Presence of mitochondrial myopathy defined as: 5xSST at Screening and Baseline should be ≥11 seconds and participant must demonstrate the ability to complete the test at baseline (i.e., complete the 5 times sit to stand ≤ 30 seconds)."}
• {"criterion_text":"- 5. The participant is able and willing to provide written Informed Consent prior to screening evaluations and to attend study appointments within the specified time windows."}
• {"criterion_text":"- 6. The participant 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, and to use the digital applications (ability to complete electronic patient reported outcomes (e-PROs))."}
• {"criterion_text":"- 7. 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."}
• {"criterion_text":"- 8. The participant has been on stable, no matter what, 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."}
• {"criterion_text":"- 9. Left Ventricular septal or posterior wall thickness ≤15 mm at screening as measured by standard ECHO cardiography or cardiac MRI."}

Exclusion criteria

• {"criterion_text":"- 1. Treatment with any IMP 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."}
• {"criterion_text":"- 25. Participant 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)."}
• {"criterion_text":"- 26. Participant has a solid organ transplant and/or is currently receiving treatment with therapy for immunosuppression."}
• {"criterion_text":"- 10. Higher degree of AV-blocks (AVB II° or III°)."}
• {"criterion_text":"- 27. Participant has a history of active human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection."}
• {"criterion_text":"- 28.\tParticipant has BMI below 10.0 kg/m2 or above 35 kg/m2 at screening"}
• {"criterion_text":"- 29.\tParticipant has any active viral or bacterial infection at screening or randomization or suffers from post-COVID Lyme or Q fever."}
• {"criterion_text":"- 3. Surgery of gastrointestinal tract that might interfere with drug absorption. Or severe GI dysmotility, chronic vomiting, diarrhea, bouts of pseudo-obstruction which will impair appropriate IMP absorption in the opinion of the investigator."}
• {"criterion_text":"- 30.\tParticipant is pregnant or breast feeding."}
• {"criterion_text":"- 4. Clinically significant respiratory disease and/or cardiac disease (medical history or current clinical findings) in the opinion of the investigator."}
• {"criterion_text":"- 5. Prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to screening."}
• {"criterion_text":"- 18. Participant has psychiatric conditions such as schizophrenia, bipolar disorder or major depressive disorder that has not been under control within 3 months prior to screening."}
• {"criterion_text":"- 6.\tQTcF > 450 msec (men) or QTcF > 470 msec (women). In case QTc Fridericia is >450ms (men) and >470ms (women) and a simultaneous bundle-branch-block (LBBB or RBBB) is not present 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, the Fridericia formula should be applied as usual; QTcF = QTm / (RR_Interval/1000)1/3."}
• {"criterion_text":"- 7. Structural heart disease based on cardiac MRI or Echocardiography (e.g., clinically significant valve disease; i.e., aortic or mitral valve stenosis or regurgitation) and/or abnormal conduction (QRS >120 msec, PR < 120 msec), and/or repolarization (QTcF > 450 msec (men) or QTcF > 470 msec (women)). QTcF must be measurable in all subjects; for patients with QRS duration >120 msec, alternative QT correction formulas should be considered to ensure accurate assessment. Myocardial function (LVEF <52% in men and < 54% in women), symptomatic ischemic heart disease (inducible ischemia or coronary obstruction), and/or pathologic hypertrophy (e.g. > 15mm septal or posterior wall thickness), that is not well controlled under current specialized care. Subjects with congestive heart failure class II and above should also be excluded."}
• {"criterion_text":"- 8.\tFamily history of unexplained/ not investigated syncope or congenital long and short QT syndrome or sudden death (under the age of 60). ECG evidence of acute or recent ischemia, acute or Recent Myocardial Infraction, atrial fibrillation, high grade AV Blocks (Second Degree AV Block Type II or Third-degree AV Block), complete Heart Block or active conduction system abnormalities except for any of the following: a.\tFirst degree atrioventricular (AV)-block b.\tSecond degree AV-block Type 1 (Mobitz Type 1/Wenckebach type) c.\tRight bundle branch block."}
• {"criterion_text":"- 11. ECG confirmed active acute coronary syndrome criteria as described by the American Heart Association."}
• {"criterion_text":"- 9. 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."}
• {"criterion_text":"- 12. Pacemaker or automated implantable defibrillator (AICD)."}
• {"criterion_text":"- 13. 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 prior to screening, hospitalized for status epilepticus within the last 6 months prior to screening."}
• {"criterion_text":"- 14. Participants with a blood pressure >160/90 mmHg at both screening and baseline will be excluded if elevated values are confirmed upon repeat measurement (3x with at least 2 minutes in between; supine position; first measure after 10 minutes of rest)."}
• {"criterion_text":"- 15.\t≥1 clinically significant (in the opinion of the investigator) clinical laboratory test value outside the reference range, based on the blood samples taken at the screening visit, that are of potential risk to the patient's safety, or the patient has, at the screening visit: a.\tEstimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. b.\tSerum potassium >5.0 mmol/L or <3.5 mmol/L). Potassium determinations might be repeated if slightly elevated or lowered compared to reference range and in case of doubt of sampling issues. c.\tAbnormal hepatic laboratory parameters, unless the following specific conditions are met: •\tTotal bilirubin: Elevations above the upper limit of normal (ULN) are only permissible in the context of a confirmed diagnosis of Gilbert syndrome. In such cases: a)\tTotal bilirubin may be up to 1.5 × ULN b)\tDirect (conjugated) bilirubin must remain within normal limits c)\tThere must be no clinical or laboratory evidence of hepatic dysfunction •\tALT and AST: No exceptions will be made for alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels in participants with Gilbert syndrome. These values must remain within protocol-defined limits. •\tSuspected Mitochondrial Disease: If elevations in ALT and/or AST are suspected to be attributable to underlying primary mitochondrial disease, eligibility may be considered on a case-by-case basis, contingent upon: a)\tDocumentation of suspected mitochondrial etiology by a qualified specialist b)\tExclusion of alternative causes for transaminase elevations (e.g., viral hepatitis, alcohol use, drug-induced liver injury) c)\tApproval of the Sponsor CMO"}
• {"criterion_text":"- 16. Medical history of drug abuse (such as amphetamines, cocaine, opiates, or problematic use of prescription drugs such as benzodiazepines, opiates) at screening."}
• {"criterion_text":"- 19.\tParticipants who, in the judgement of the investigator, pose a suicidal risk, or participants with a history of suicidal attempts, or having answered Yes (for the past 6 months) to question number 4 or question number 5 of the Suicidal Ideation section of the C-SSRS at baseline and screening."}
• {"criterion_text":"- 17.\tWithin 4 weeks prior to screening (for amiodarone this should be 12 months), the use of: a.\t(multi)vitamins, co-enzyme Q10, arginine, citrulline, Vitamin E, riboflavin, amino acids, antioxidant supplements (including, but not limited to idebenone/EPI-743, mitoQ or alternative names for similar products) and mito-cocktails; unless stable for at least one month prior to first dose and willing to remain stable throughout the study. b.\tany medication negatively influencing mitochondrial functioning (including but not limited to valproic acid, glitazones, statins, anti-virals, amiodarone, and nonsteroidal anti-inflammatory drugs (NSAIDs)), unless the dose has been stable for at least one month prior to first dose and the dose is to remain stable throughout the study (for reference see a.o. doi: 10.1002/jimd.12196). c.\tany moderate or strong Cytochrome P450 (CYP)3A4 inhibitors (all ‘conazoles-antifungals’, HIV antivirals, grapefruit) (for reference see http://go.drugbank.com). d.\tstrong CYP3A4 inducers (including HIV antivirals, carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort, pioglitazone, troglitazone). (for reference see http://go.drugbank.com). e.\tany medication metabolized by CYP3A4 with a narrow therapeutic index e.g., tacrolimus, cyclosporine), unless medically necessary and reviewed by the Sponsor or designated medical monitor for information/advice only (for reference see http://go.drugbank.com). f.\tmedication known to be substrate of Organic Cation Transporter 1 (OCT1) and organic cation transporter 2 (OCT2) with a narrow therapeutic index, unless medically necessary and reviewed by the Sponsor or designated medical monitor for information/advice only (for reference see http://go.drugbank.com). g.\tP-glycoprotein inhibitors (including amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tariquidar, and verapamil) (for reference see http://go.drugbank.com). h.\tany 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 longest (all anti-psychotics, several anti-depressants, e.g. nor-/amitriptyline, fluoxetine, anti-emetics: domperidone, granisetron, ondansetron). For a complete list see https://crediblemeds.org."}
• {"criterion_text":"- 31.\tParticipant has progressive external ophthalmoplegia (PEO) and no other mitochondrial disease organ involvement."}
• {"criterion_text":"- 2. Bone deformities, motor abnormalities or chronic ulcers that in the opinion of the PI may interfere with and/or confound the interpretation of the subject's performance during the 5 times sit to stand test (5XSST)."}
• {"criterion_text":"- 20. Participant has severe behavioural or cognitive problems that preclude participation in the study."}
• {"criterion_text":"- 21. Participant has undergone an inpatient hospitalization that precludes participation in the study, within the 30 days prior to screening."}
• {"criterion_text":"- 22. Participant has a planned hospitalization or a surgical procedure during the study, which may affect the study assessments."}
• {"criterion_text":"- 23. Participant requires any ventilator support, including CPAP (continuous positive airway pressure) or BiPAP (bilevel positive airway pressure) at night."}
• {"criterion_text":"- 24. Participant has severe vision impairment that may interfere with their ability to complete all study requirements."}

Primary endpoints

• {"endpoint_text":"- Change from baseline at Week 52 in the: 1. NeuroQoL Fatigue SF v1 score","definition_or_measurement_approach":"Change from baseline at Week 52 assessed using the Neuro-QoL Fatigue SF v1 instrument (NeuroQoL Fatigue SF v1 score)."}
• {"endpoint_text":"- Change from baseline at Week 52 in the: 2. Duration of the 5 Times Sit-to-Stand Test (5xSST)","definition_or_measurement_approach":"Change from baseline at Week 52 in duration (seconds) of the 5 Times Sit-to-Stand Test (5xSST) measured per protocol."}

Secondary endpoints

• {"endpoint_text":"- Change from baseline at Week 52 in the: 1. 36-Item Short Form Survey (SF-36): sub-score physical functioning","definition_or_measurement_approach":"Change from baseline at Week 52 assessed by the SF-36 physical functioning subscore."}
• {"endpoint_text":"- Change from baseline at Week 52 in the: 2. Fatigue Severity Scale (FSS)","definition_or_measurement_approach":"Change from baseline at Week 52 assessed using the Fatigue Severity Scale (FSS)."}
• {"endpoint_text":"- Change from baseline at Week 52 in the: 3. Beck Depression Inventory (BDI-2) total score","definition_or_measurement_approach":"Change from baseline at Week 52 assessed using the Beck Depression Inventory (BDI-2) total score."}
• {"endpoint_text":"- Change from baseline at Week 52 in the: 4. Patient reported global impression of severity (PGI-S)","definition_or_measurement_approach":"Change from baseline at Week 52 assessed by the Patient Global Impression of Severity (PGI-S)."}
• {"endpoint_text":"- Change from baseline at Week 52 in the: 5. Clinician reported global impression of severity (CGI-S)","definition_or_measurement_approach":"Change from baseline at Week 52 assessed by the Clinician Global Impression of Severity (CGI-S)."}

Methods

• K2_Recruitment material_Dr-to-Patient Letter (Doctor-to-patient letters) - recruitment material documents present (associated with specific Member State submissions).
• K2_Recruitment material_Patient Brochure (Patient brochures) - informational materials for potential participants.
• K1_Recruitment arrangements / K1_Recruitment Arrangements_public / K1_Recruitment material_Fact Sheet / K2_Recruitment material_Referral Letter - recruitment arrangements documents and referral letters available (country-specific versions present for Italy, Netherlands, France, Denmark, Germany).

Italy

Earliest CTIS Part Ii Submission Date

17-09-2025

Latest Decision Or Authorization Date

08-01-2026

Processing Time Days

113

Number Of Sites

1

Number Of Participants

15

Netherlands

Earliest CTIS Part Ii Submission Date

09-12-2025

Latest Decision Or Authorization Date

19-12-2025

Processing Time Days

10

Number Of Sites

1

Number Of Participants

60

France

Earliest CTIS Part Ii Submission Date

24-11-2025

Latest Decision Or Authorization Date

13-05-2026

Processing Time Days

170

Number Of Sites

2

Number Of Participants

35

Denmark

Earliest CTIS Part Ii Submission Date

08-12-2025

Latest Decision Or Authorization Date

13-05-2026

Processing Time Days

156

Number Of Sites

1

Number Of Participants

6

Germany

Earliest CTIS Part Ii Submission Date

28-11-2025

Latest Decision Or Authorization Date

15-05-2026

Processing Time Days

168

Number Of Sites

1

Number Of Participants

24

Primary sponsor

Full Name

Khondrion B.V.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Netherlands

Contract research organisations

Name

Iqvia Biotech Limited

Responsibilities

Clinical monitoring, eCOA, Connected Devices - ECG, CEVA - DSMB management, Site contracting and payments (as listed under sponsor duties).

Name

IQVIA Limited

Responsibilities

ECG reading and data storage.

Name

IQVIA Laboratories LLC / Iqvia Laboratories Limited

Responsibilities

Laboratory services, sample storage and related laboratory activities.

Name

Medidata Solutions Inc.

Responsibilities

Electronic data capture / vendor platform services.

Name

Greenphire LLC

Responsibilities

Patient concierge / patient support services.

Third parties

• {"country":"Netherlands","full_name":"Manufacturing Packaging Farmaca (MPF) B.V.","duties_or_roles":"QP release, drug supply; sponsor duty codes: 15, 3","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Clinical Outcomes Solutions LLC","duties_or_roles":"Patient Exit interviews (sponsor duty code 15)","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United Kingdom","full_name":"Clinical Outcomes Solutions Limited","duties_or_roles":"Patient Exit interviews (sponsor duty code 15)","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Ardena Bioanalysis B.V.","duties_or_roles":"Analytical laboratory services (sponsor duty code 4)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"Sponsor duty code 7 (electronic data capture/vendor services)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Iqvia Laboratories Limited","duties_or_roles":"Sample storage (value), laboratory services (code 4)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Patient Concierge (value)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Quest Diagnostics Nichols Institute Inc.","duties_or_roles":"Laboratory services (sponsor duty code 4)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Finland","full_name":"Nadmed Oy","duties_or_roles":"Laboratory services (sponsor duty code 4)","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Veramed Limited","duties_or_roles":"Regulatory or related support (sponsor duty code 10)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"IQVIA Laboratories LLC","duties_or_roles":"Laboratory services (sponsor duty code 4)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"ECG reading and data storage (value)","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Iqvia Biotech Limited","duties_or_roles":"Multiple operational roles including Clinical monitoring, eCOA, Connected Devices - ECG, CEVA - DSMB management, Site contracting and payments; sponsor duty codes: 11,12,15,5,6,8","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Universiteit Leiden","duties_or_roles":"Research support / laboratory services (sponsor duty code 4)","organisation_type":"Educational Institution"}