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

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.

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.

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.

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.

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.

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.

Newcastle Mitochondrial Disease Adult Scale (NMDAS)

Change from Baseline compared to placebo at week 52 and at other relevant study visits of the Newcastle Mitochondrial Disease Scale for Adults (NMDAS). The NMDAS is a semi-quantitative clinical rating scale designed specifically for all forms of mitochondrial disease. The rating scale encompasses all aspects of mitochondrial disease by exploring several domains: current function, system specific involvement, and current clinical assessment. Each question/item in the NMDAS has a possible score from 0-5. Each of the three section scores are calculated by simply summing the scores obtained for each question in that section, with the higher the score the more severe the disease. Thus, scores can range from 0 to 50 for Sections I and III, and from 0 to 45 for Section II, and from 0 to 145 for Sections I through III. Higher scores indicate a higher level of disease severity.

Brief Pain Inventory Short Form (BPI-SF)

Change from Baseline compared to placebo at week 52 and at other relevant study visits of the Brief Pain Inventory-Short Form (BPI-SF). The BPI-SF is a validated (33) self-administered questionnaire to assess the severity of pain and the impact of pain on the patient's daily functions. BPI-SF evaluates pain severity at its worst, least, and average during the last 24 hours, as well as current pain level, with 0 representing no pain and 10 the worst pain imaginable. Seven items measuring interference with daily functioning (general activity, walking, work, mood, relations with others, sleep, and enjoyment of life) are also assessed on an 11-point scale, where 0 represents no interference and 10 complete interferences. The scores can be averaged to the two components of the BPI SF score, the Pain Severity Index and the Pain Interference Index. Higher scores indicate a higher level of severity and impact of pain.

Health Economics and Outcomes Research (HEOR) Assessments: EQ-5D-5L

Change from Baseline compared to placebo at week 52 and at other relevant study visits of the EQ-5Dimension-5 Level (EQ-5D-5L). The EQ-5D-5L is a self-report health-related quality of life (HRQoL) instrument consisting a descriptive system and a visual analogue scale (EQ-VAS). The descriptive system that defines health in five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response categories (levels): no problems, slight problems, moderate problems, severe problems and extreme problems. The EQ-VAS records the respondent's self-rated health on a vertical VAS. The respondents can report their perceived health status with a grade ranging from 0 ('the worst health you can imagine') to 100 ('the best health you can imagine'). A higher score denotes a worse health state.

Columbia-Suicide Severity Rating Scale (C-SSRS)

Change from Baseline compared to placebo at week 52 and at other relevant study visits of the Columbia-Suicide Severity Rating Scale (C-SSRS). The instrument assesses severity of suicidal ideation ("severity subscale"), rated on a 5-point ordinal scale, the intensity of ideation subscale ("intensity subscale"), comprising 5 items, rated on a 5-point ordinal scale: frequency, duration, controllability, deterrents, and reason for ideation, resulting in 0-25 score range summed from five items, with higher scores indicating more severe suicidal ideation. A score of 0 indicates that no suicide ideation is present. The behaviour subscale is a nominal scale including actual, aborted, and interrupted attempts; preparatory behaviour; and self-injurious behaviour. The lethality subscale assesses actual attempts; actual lethality rated on a 6-point ordinal scale. Higher scores indicate a higher level of severity.