khenerfin study: a trial to evaluate the efficacy and safety of sonlicromanol in primary mitochondrial diseases

Conditions: Mitochondrial Diseases; Maternally Inherited Diabetes and Deafness (MIDD); Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes (MELAS); Mitochondrial DNA tRNALeu(UUR) m.3243A<G Mutation

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.

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.

Eligibility criteria:
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.

Keywords: mitochondrial diseases oxidative phosphorylation (oxphos) maternally inherited diabetes and deafness (midd) mitochondrial dna trnaleu(uur) m.3243a<g mutation mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (melas) sonlicromanol kh176