| Eligibility |
Inclusion Criteria:
- Age 18 years or older.
- A confirmed PMD diagnosis caused by a known pathogenic gene mutation or deletion of
the mitochondrial genome (category 6 of the International Classification of Inborn
Metabolic Disorders [ICIMD])12 according to American College of Medical Genetics
(ACMG)/Association of Molecular Pathology (AMP) criteria1, with multisystemic disease
expressions, including:
1. m.3243A>G associated MELAS-MIDD spectrum disorders,
2. single large scale mtDNA deletion associated KSS-CPEO spectrum disorders,
3. other multisystemic mtDNA-related disease (including MERRF).
- Presence of chronic mitochondrial fatigue:
- History of mitochondrial fatigue for at least 3 months prior to the Screening
Visit AND
- Presence of at least moderate level of fatigue, assessed by PROMIS® Fatigue PMD
Short form raw score = 27 at Screening and Baseline
- Presence of mitochondrial myopathy defined as:
- Myopathy (proximal muscle weakness), NMDAS Section III Clinical Assessment, item
5 score = 1, which reads: "minimal reduction in hip flexion and/or shoulder
abduction only (e.g. MRC 4+/5)". For the inclusion only hip flexion, but not
shoulder abduction, should be taken into account. AND / OR
- Exercise Tolerance: NMDAS Section I, item 9 score = 1, which reads: "unlimited on
flat - symptomatic on inclines or stairs".
- Patients must be able to perform at least 2 repetitions and the maximal capacity must
not exceed 17 repetitions in males or 16 repetitions in females in a 30s STS test at
screening.
- Clinically stable, apart from symptoms associated with the diagnosis of mitochondrial
disease, at Screening and Baseline, as determined by medical history, physical
examination, 12-lead ECG, vital signs measurements, and clinical laboratory
evaluations at Screening, as assessed by the investigator.
- The patient is willing and able to attend study appointments within the specified time
windows.
- Willingness and ability to complete electronic PROs.
- Willingness to maintain a stable diet during the Screening and study periods.
- Patients who take any mitochondrial disease-focused vitamins or supplemental
therapies, including coenzyme Q10 (CoQ10), niacin/nicotinamide (vitamin B3), and
L-arginine, has been on a stable dose regimen of these for 3 months prior to
randomisation and intends to stay on a stable dose for the duration of the study
period.
- Willingness to suspend treatment with idebenone during the study.
- Female patient is not pregnant and at least one of the following conditions apply:
1. Not a woman of childbearing potential (WOCBP)
2. WOCBP must agree not to try and become pregnant and use a highly effective method
of contraception from the time of informed consent through at least 36 days (~5
half-lives of KL1333 plus 30 days) after the last dose of investigational
medicinal product (IMP) administration.
- Male patients with female partner(s) of childbearing potential must agree to use a
male condom in addition to using highly effective contraception throughout the
treatment period and for 96 days after the last dose of IMP administration. The
requirement to use a male condom also applies to male patients with a pregnant or
breastfeeding partner.
- Female patients must agree not to breastfeed starting at Screening and throughout the
study period and for 36 days after the last dose of IMP administration.
- Female patients must agree to not donate ova throughout the study period and for 36
days after the last dose of IMP administration, and male patients must agree to not
donate sperm throughout the study period and for 96 days after the last dose of IMP
administration.
Exclusion Criteria:
- Primary mitochondrial disease with predominant neurodegenerative phenotypes, such as,
but not limited to, Leigh syndrome, Leber hereditary optic neuropathy (LHON) and
Neuropathy ataxia-retinitis pigmentosa syndrome (NARP).
- Primary mitochondrial disease nuclear DNA mutations or mutations causing mtDNA
destabilisation. Genetic mtDNA variants of uncertain significance, likely pathogenic,
or pathogenic mutations with degrees of heteroplasmy below what can be considered to
definitely cause PMD.
- General fatigue or muscle weakness due to causes other than mitochondrial disease, in
the opinion of the investigator.
- Significant cardiovascular disease (e.g., sustained or symptomatic arrhythmia; dilated
heart chambers or reduced function; Mobitz II atrioventricular block or greater) OR
abnormal ECG that is clinically significant, as determined by the investigator. Any
QTcF > 450 msec for male patients and > 470 msec for female patients is exclusionary.
In the case of an exclusionary QTcF, the ECG can be repeated twice and the average of
3 QTcF intervals should be used to determine the QTcF eligibility.
- Recent history of unstable disease, inadequately controlled neurological
manifestations or not recovered from stroke-like episodes including but not limited
to:
1. stroke-like episodes within the last 6 months
2. more than 1 seizure/month within the last 6 months
3. hospitalised for Status Epilepticus within the last 6 months
4. more than 4 days of migraine episodes/month within the last 6 months
- History of inflammatory bowel disease, gastric erosions, peptic ulcer disease, or
gastrointestinal bleeding episodes. Gastroesophageal reflux disease diagnosed by
objective endoscopic or radiographic means, and clinically symptomatic at any point
over the last 6 months.
- The patient has one or more clinical laboratory test values 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) calculated by the Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI) creatinine equation <30 mL/min/1.73
m2
- a serum total bilirubin value > 1.5 times the upper limit of the reference range
unless elevation is related to Gilbert's syndrome and the investigator can rule
out any underlying liver dysfunction based on other tests, the patient has a
Child-Pugh score =6, and after discussing the case with the medical monitor
- a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value
> 2 times the upper limit of the reference range. Values between 2 and 3 times
the upper limit of the reference range may be allowed if concomitant to elevation
in creatine kinase as long as the investigator can rule out any underlying liver
dysfunction based on other tests, the patient has a Child-Pugh score =6, and
after discussing the case with the medical monitor
- The patient has, in the investigator's opinion, severe ataxia, neuropathy, balance
problems or other medical condition that would interfere the evaluation of the 30s STS
test.
- Untreated or undertreated sleep apnoea, in the opinion of the investigator.
- Use of idebenone within 14 days prior to the first dose.
- Patients have a history of unstable or severe pulmonary, immunological, oncological,
hepatic disease, renal disease, or another medically significant illness other than
PMD or takes medication that could, in the investigator's opinion, interfere with the
assessments of safety, tolerability, or efficacy, or interfere with the conduct or
interpretation of the study.
- The patient is, in the investigator's opinion, unlikely to comply with the protocol
e.g. due to cognitive impairment or is unsuitable for any reason.
- The patient has an immediate family member (defined as family members residing at the
same address) who participates in the study.
- Female patients with a positive pregnancy result at Screening or at Baseline.
- A patient cannot participate if they received an investigational drug 30 days or 5
half-lives prior to the Screening Visit (whichever is longer), or plans to use an
investigational drug (other than the study intervention) during the study
- Hypersensitivity to the active substance or to any of the excipients or placebo.
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