RECRUITING

Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease

Conditions

Primary Mitochondrial Disease Chronic fatigue Myopathy Muscle weakness Exercise intolerance Diabetes

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

The primary objective of the FALCON study is to evaluate the efficacy of KL1333 on selected disease manifestations of primary mitochondrial disease (PMD) following 48 weeks of treatment. This objective involves evaluating the efficacy of KL1333 versus placebo on fatigue symptoms and impacts on daily living as well as on functional lower extremity strength and endurance. Additionally, the study evaluates the safety and tolerability of KL1333.

Official Title

An Interventional, Randomised, Double-blind, Parallel-group, Placebo-controlled, Flexible-dose, Adaptive Study of the Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease

Quick Facts

Study Start:2022-12-13

Study Completion:2027-11

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT05650229

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion 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.	* 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.

Inclusion Criteria

Exclusion 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.

* 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.

Contacts and Locations

Study Contact

Communication Manager

CONTACT

+46462756220

clinicaltrialinfo@abliva.com

Principal Investigator

Amel Karaa, MD

PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Grainne Gorman, MD, PhD

PRINCIPAL_INVESTIGATOR

Wellcome Centre for Mitochondrial Research, Newcastle University

Study Locations (Sites)

Akron Children's Hospital

Akron, Ohio, 44307

United States

The University of Texas Health Science Center at Houston

Houston, Texas, 77030

United States

Collaborators and Investigators

Sponsor: Abliva AB

Amel Karaa, MD, PRINCIPAL_INVESTIGATOR, Massachusetts General Hospital
Grainne Gorman, MD, PhD, PRINCIPAL_INVESTIGATOR, Wellcome Centre for Mitochondrial Research, Newcastle University

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2022-12-13

Study Completion Date2027-11

Study Record Updates

Study Start Date2022-12-13

Study Completion Date2027-11

Terms related to this study

Keywords Provided by Researchers

Chronic fatigue
Myopathy
Muscle weakness
Exercise intolerance
Diabetes

Additional Relevant MeSH Terms

Primary Mitochondrial Disease