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

Inclusion criteria

• Signed Informed Consent
• Males and females aged ≥18 years with a multi-system primary mitochondrial disease.
• 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).
• Presence of chronic fatigue (not attributable to other etiologies than PMD):

• 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), assessed by Neuro-QoL SFv1-F at Screening.
• 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).

• Other Inclusion criteria per protocol.

Exclusion criteria

• 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.
• 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).
• 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.
• Clinically significant respiratory disease and/or cardiac disease (medical history or current clinical findings) in the opinion of the investigator.
• Prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to screening.
• 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 Left ventricular dysfunction (LVEF \<52% in men and \< 54% in women) and / or congestive cardiac failure (more severe than grade II) and / or Maximum left-ventricular septal or posterior wall thickness > 15 mm and / or Evidence of active myocardial ischaemia, ECG evidence and / or recent history of myocardial infarction (\< 6-months) and / or coronary angioplasty / coronary bypass surgery (\< 12 months).
• Family history of unexplained/uninvestigated syncope or congenital long and short QT syndrome or sudden death (under the age of 60) and / or Abnormal QTcF interval [QTcF > 450 msec (men) or QTcF > 470 msec (women) = abnormally long QTcF or QTcF \< QT \< 320ms = abnormally short QtcF] and / or Intermittent or persistent WPW (pre-excitation) syndrome on ECG [ie: abnormally wide QRS > 120ms with slurred up-stroke ('delta' wave) and PR-interval \< 120ms] and / or ECG evidence of atrial fibrillation (permanent, persistent or paroxysmal) and / or

High grade AV Block [2nd-degree AV block Type II (ie: 2:1) or complete AV block (3rd degree) or intermittent conduction system abnormalities with the exception of any of the following:

• 1st degree atrioventricular (AV)-block
• 2nd degree AV-block Type 1 (Mobitz Type 1 / Wenckebach type)
• Right bundle branch block.
• History of acute heart failure (within the last 3 months).
• Higher degree of AV-blocks (AVB II° or III°).
• Other exclusion criteria per protocol