2025-522361-30-00尚未招募3 期
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.
Khondrion B.V.4 个研究点 分布在 3 个国家目标入组 97 人开始时间: 2025年12月19日最近更新:
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 97
- 试验地点
- 4
- 主要终点
- Change from baseline at Week 52 in the: 1. NeuroQoL Fatigue SF v1 score
研究概览
简要总结
To evaluate the efficacy of sonlicromanol during a 52-week treatment period on:
- Physical fatigue symptoms and impact on daily living/quality of life
- Lower limb skeletal muscle strength and dynamic balance control
研究设计
- 分配方式
- Randomized
- 主要目的
- Wave 2
- 盲法
- None
入排标准
- 年龄范围
- 18 years 至 64 years（18-64 Years）
- 接受健康志愿者
- 否
入选标准
- •Males and females aged ≥18 years with a multi-system primary mitochondrial disease.
- •Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, should be using highly effective/adequate methods of contraception during study treatment. Highly effective contraception methods include: o Total sexual abstinence: if defined as refraining from heterosexual intercourse during the entire period of risk associated with study treatment up to a minimum of 3 months of treatment discontinuation. Reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. o Combined oral, intravaginal, transdermal, implanted, injected (estrogen and progestogen containing) hormonal contraception or progesterone only hormonal contraception associated with inhibition of ovulation. o Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) o Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment. o Vasectomy of the partner; vasectomized partner is considered a highly effective birth control method provided that partner is the sole sexual partner of the subject and that the vasectomized partner has received medical assessment of the surgical success.
- •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 ≥ 20% in urine (urinary epithelial cells), or buccal smear or skeletal muscle (results (obtained per local guidance) must be available prior to the subject being randomized).
- •Presence of chronic fatigue (not attributable to other etiologies than PMD): a. Patient self-reported chronic fatigue for at least 3 months prior to the Screening Visit and recorded in the clinical patient files; AND b. 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 at least at or above 11 seconds and patients must demonstrate the ability to complete the test at baseline.
- •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, and to use the digital applications (ability to complete electronic patient reported outcomes (e-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, no matter what, 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 septal or posterior wall thickness ≤15 mm at screening as measured by standard ECHO cardiography or cardiac MRI.
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.
- •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.
- •Participants who, in the judgement of the investigator, pose a suicidal risk, or participants with a history of suicidal attempts, or having answered Yes (for the past 6 months) to question number 4 or question number 5 of the Suicidal Ideation section of the C-SSRS.
- •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).
- •Patient has severe behavioural 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 screening.
- •Patient has a planned hospitalization or a surgical procedure during the study, which may affect the study assessments.
- •Patient requires any ventilator support, including CPAP (continuous positive airway pressure) or BiPAP (bilevel positive airway pressure) 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.
- •Higher degree of AV-blocks (AVB II° or III°).
- •Patient has a history of active human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection.
- •Patient has BMI below 18.5 kg/m2 or above 35 kg/m2 at screening.
- •Patient has any active viral or bacterial infection at screening and randomization or suffers from post-COVID Lyme or Q fever.
- •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.
- •Patient is pregnant or breast feeding.
- •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). In case QTc Fridericia is >450ms (men) and >470ms (women) and a simultaneous bundle-branch-block (LBBB or RBBB) is not present 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/
- •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)). QTcF must be measurable in all subjects; for patients with QRS duration >120 msec, alternative QT correction formulas should be considered to ensure accurate assessment. 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: a. First degree atrioventricular (AV)-block b. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type) c. Right bundle branch block.
- •ECG confirmed active acute coronary syndrome criteria as described by the American Heart Association.
- •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.
- •Pacemaker or automated implantable defibrillator (AICD).
- •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 prior to screening, hospitalized for status epilepticus within the last 6 months prior to screening.
- •Participants with a blood pressure >160/90 mmHg at both screening and baseline will be excluded if elevated values are confirmed upon repeat measurement (3x with at least 2 minutes in between; supine position; first measure after 10 minutes of rest).
- •≥1 clinically significant (in the opinion of the investigator) 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: a. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m
- •b. Serum potassium >5.0 mEq/L or <3.5 mEq/L). Potassium determinations might be repeated if slightly elevated or lowered compared to reference range and in case of doubt of sampling issues....
- •Medical history of drug abuse (such as amphetamines, cocaine, opiates, or problematic use of prescription drugs such as benzodiazepines, opiates) at screening.
- •Within 4 weeks prior to screening and first administration of sonlicromanol (for amiodarone this should be 12 months), the use of: a. (multi)vitamins, co-enzyme Q10, arginine, citrulline, Vitamin E, riboflavin, amino acids, antioxidant supplements (including, but not limited to idebenone/EPI-743, mitoQ or alternative names for similar products) and mito-cocktails; unless stable for at least one month before screening and willing to remain stable throughout the study. b. any medication negatively influencing mitochondrial functioning (including but not limited to valproic acid, glitazones, statins, anti-virals, and nonsteroidal 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 (for reference see a.o. doi: 10.1002/jimd.12196). c. any moderate or strong Cytochrome P450 (CYP)3A4 inhibitors (all ‘conazoles-antifungals’, HIV antivirals, grapefruit) (for reference see http://go.drugbank.com). d. strong CYP3A4 inducers (including HIV antivirals, carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort, pioglitazone, troglitazone). (for reference see http://go.drugbank.com). e. any medication metabolized by CYP3A4 with a narrow therapeutic index e.g., tacrolimus, cyclosporine), unless medically necessary and reviewed by the Sponsor or designated medical monitor for information/advice only (for reference see http://go.drugbank.com). f. medication known to be substrate of Organic Cation Transporter 1 (OCT1) and organic cation transporter 2 (OCT2) with a narrow therapeutic index, unless medically necessary and reviewed by the Sponsor or designated medical monitor for information/advice only (for reference see http://go.drugbank.com). g. P-glycoprotein inhibitors (including amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tariquidar, and verapamil) (for reference see http://go.drugbank.com). h. 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 halflives of the medication and its major metabolite(s), whichever period is the longest (all anti-psychotics, several anti-depressants, e.g. nor-/amitriptyline, fluoxetine, anti-emetics: domperidone, granisetron, ondansetron). For a complete list see https://crediblemeds.org.
结局指标
主要结局
Change from baseline at Week 52 in the: 1. NeuroQoL Fatigue SF v1 score
Change from baseline at Week 52 in the: 1. NeuroQoL Fatigue SF v1 score
Change from baseline at Week 52 in the: 2. Duration of the 5 Times Sit-to-Stand Test (5xSST)
Change from baseline at Week 52 in the: 2. Duration of the 5 Times Sit-to-Stand Test (5xSST)
次要结局
- Change from baseline at Week 52 in the: 1. 36-Item Short Form Survey (SF-36): sub-score physical functioning
- Change from baseline at Week 52 in the: 2. Fatigue Severity Scale (FSS)
- Change from baseline at Week 52 in the: 3. Beck Depression Inventory (BDIII) total score
- Change from baseline at Week 52 in the: 4. Patient reported global impression of severity (PGI-S)
- Change from baseline at Week 52 in the: 5. Clinician reported global impression of severity (CGI-S)
研究者
Jan Smeitink, MD, PhD, MAE
Scientific
Khondrion B.V.
研究点 (4)
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