A Phase III, Randomised, Double-blind, Placebo-controlled, Parallel-group, Pivotal Trial to Assess the Efficacy and Safety of Sonlicromanol in Adult Subjects With a Genetically Confirmed Mitochondrial DNA tRNALeu(UUR) m.3243A>G Variant
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- Khondrion BV
- 入组人数
- 220
- 试验地点
- 10
- 主要终点
- Neuro-QoL Fatigue Short Form v1
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Trial personnel and subjects will be blinded to treatment until the database is locked. Investigators will contact the Sponsor prior to unblinding any subject's treatment unless in the instance of a medical emergency.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
- •6. Other Inclusion criteria per protocol.
排除标准
- •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.
- •QTcF > 450 msec (men) or QTcF > 470 msec (women).
- •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.
- •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:
- •First degree atrioventricular (AV)-block
- •Second 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
研究组 & 干预措施
Matching Placebo
Administration of 100 mg matching placebo twice daily
干预措施: Placebo (Drug)
Sonlicromanol (KH176)
Administration of 90 mg sonlicromanol (equivalent to 100 mg sonlicromanol.HCl) twice daily
干预措施: Sonlicromanol (Drug)
结局指标
主要结局
Neuro-QoL Fatigue Short Form v1
时间窗: Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
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)
时间窗: Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)
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.
次要结局
- Patient-scored Global Impression of Severity scale (PGI-S)(Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit))
- Clinician-scored Global Impression of Severity (CGI-S)(Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit))
- 36-Item Short Form Survey (SF-36)(Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit))
- The PROMIS Fatigue Primary Mitochondrial Disease Short Form (PROMIS) Fatigue PMD SF)(Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit))
- Beck Depression Inventory-2 (BDI-2)(Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit))
- Patient-scored Global Impression of Severity scale (PGI-S)(Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit))
- Clinician-scored Global Impression of Severity (CGI-S)(Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit))