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

Phase 3RecruitingNCT06451757

Khondrion BV220 enrolled

Overview

The KHENERFIN study aims to determine whether the study medicine, sonlicromanol, is able to reduce symptoms of fatigue and the impact of fatigue on daily life, and whether sonlicromanol is able to improve physical abilities of people like balance control and lower limb skeletal muscle strength in people with mitochondrial disease. In this study, the effects of sonlicromanol are compared against a placebo, a tablet identical in appearance and taste but without the active drug. Participants take either sonlicromanol or placebo twice daily for a treatment duration of 52 weeks. In addition to these primary objectives, the study evaluates the efficacy of sonlicromanol on secondary and exploratory outcomes, as well as its safety and tolerability after one year of treatment.

The KHENERFIN study is investigating the medicine sonlicromanol. The study aims to see if sonlicromanol can reduce symptoms of fatigue and reduce the impact of fatigue on daily life. The study also investigates if sonlicromanol improves physical abilities like balance control and lower limb skeletal muscle strength in people with mitochondrial disease. In addition to these primary objectives, the study evaluates the efficacy of sonlicromanol on selected secondary and exploratory outcomes. It also assesses 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. Participants cannot change their assigned rreatment. During the screening period, which lasts a maximum of 4 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. Sonlicromanol will be supplied in tablet form, containing 90 mg of sonlicromanol (equivalent to 100 mg of sonlicromanol.HCl), with the tablets embossed accordingly or provided as a placebo. The study medication must be taken twice daily during the treatment period of 52 weeks. Up to 220 subjects with a confirmed mitochondrial DNA tRNALeu(UUR) 3243A\>G mutation will be randomly assigned in a 1:1 ratio to receive either sonlicromanol or placebo.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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): 1. Patient self-reported chronic fatigue for at least 3 months prior to the Screening Visit and recorded in the clinical patient files; AND 2. Presence of fatigue (raw total score \>22), assessed by Neuro-QoL SFv1-F at Screening. 5. 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: 1. First degree atrioventricular (AV)-block 2. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type) 3. Right bundle branch block. 9. History of acute heart failure (within the last 3 months). 10. Higher degree of AV-blocks (AVB II° or III°). 11. Other exclusion criteria per protocol

Locations (10)

Massachusetts General Hospital

Boston, Massachusetts, United States

NOT_YET_RECRUITING

Cleveland Clinic Neurological Institute Mellen Center

Cleveland, Ohio, United States

NOT_YET_RECRUITING

The University of Texas Health Science Center at Houston

Houston, Texas, United States

NOT_YET_RECRUITING

Rigshospitalet, University of Copenhagen

Kopenhagen, Region Sjælland, Denmark

NOT_YET_RECRUITING

CHU de Bordeaux - Hôpital Pellegrin Service Gynecologie Obstetrique

Bordeaux, Gironde, France

NOT_YET_RECRUITING

Groupe Hospitalier Pitie-Salpetriere - Charles-Foix Clinical Investigation Center Paris-Est

Paris, Paris, France

NOT_YET_RECRUITING

Klinikum der Universität München Friedrich-Baur-Institut

München, Germany

NOT_YET_RECRUITING

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, Milano, Italy

NOT_YET_RECRUITING

Radboud University Medical Center

Nijmegen, Gelderland, Netherlands

RECRUITING

University College London Hospitals NHS Foundation Trust National Hospital for Neurology and Neurosurgery

London, Greater London, United Kingdom

RECRUITING

Outcomes

Primary Outcomes

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.

Time frame: Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

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.

Time frame: Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

Secondary Outcomes

36-Item Short Form Survey (SF-36)

Change from Baseline at week 52 and at other relevant study visits of the 36-item Short Form Survey Instrument (SF-36). 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.

Time frame: Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

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.

Time frame: Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

Beck Depression Inventory-2 (BDI-2)

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.

Time frame: Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

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.

Time frame: Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

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.

Time frame: Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

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

Overview

Conditions

Interventions

Eligibility

Locations (10)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts