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

Inclusion criteria

1. Signed Informed Consent

2. Males and females aged ≥18 years with a multi-system primary mitochondrial disease.

3. 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 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).

4. Presence of chronic fatigue (not attributable to other etiologies than PMD):

5. Patient self-reported chronic fatigue for at least 3 months prior to the Screening Visit and recorded in the clinical patient files; AND

6. Presence of fatigue (raw total score >22), assessed by Neuro-QoL SFv1-F at Screening.

7. 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 test within 30 seconds).

6. Other Inclusion criteria per protocol.

Exclusion criteria

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.

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).

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.

4. Clinically significant respiratory disease and/or cardiac disease (medical history or current clinical findings) in the opinion of the investigator.

5. Prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to screening.

6. QTcF > 450 msec (men) or QTcF > 470 msec (women).

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)). 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.

8. Family history of unexplained/uninvestigated 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 with the exception of any of the following:

9. First degree atrioventricular (AV)-block

10. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type)

11. Right bundle branch block.

12. History of acute heart failure (within the last 3 months).

13. Higher degree of AV-blocks (AVB II° or III°).

14. Other exclusion criteria per protocol