Efficacy of Calcium Folinate in Kearns-Sayre Syndrome with Cerebral Folate Deficiency: A Randomized Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of folinic acid administration compared to no treatment on the clinical outcome in patients with Kearns-Sayre syndrome (KSS). This is clinically relevant as KSS is a rare mitochondrial disorder characterized by progressive external ophthalmoplegia, retinopathy, and cardiac conduction defects, and finding effective treatments could significantly improve patient outcomes.

Secondary objectives include assessing the efficacy of folinic acid administration compared to no treatment on:

• Changes in 5-methyltetrahydrofolate (5MTHF) concentrations in cerebrospinal fluid (CSF)
• Changes in brain volume
• White matter alterations
• Changes in concentrations of choline and myo-inositol
• Correlation of folinic acid, 5MTHF, and clinical outcomes

The clinical trial involves a study population comprising **children and adolescents** aged 6 to 17 years diagnosed with **Kearns-Sayre syndrome** (KSS). Both male and female participants are included, and the trial specifically targets a vulnerable population. The sponsor has not provided the total number of participants. Participants were selected based on specific criteria, including disease onset before 12 years of age and a 5MTHF concentration of less than 20 nM in cerebrospinal fluid at screening. Additionally, participants must have a symptom complex that includes progressive external ophthalmoplegia, ptosis, and pigmentary retinopathy, along with either cardiac conduction defects, cerebellar syndrome, or elevated cerebrospinal fluid protein levels. Genetic identification of a single large-scale mitochondrial DNA deletion or duplication, or the mtDNA m.3243A>G mutation, is required in at least two different cell types. The trial also necessitates written informed consent from legally designated representatives and a willingness to use contraception to prevent pregnancy during the trial period. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **folinic acid** administration in patients with **Kearns-Sayre syndrome** (KSS) and cerebral folate deficiency. This is a Phase IV, randomized, controlled, parallel-group, observer-blinded, interventional trial with a delayed-start study design. The trial aims to compare the clinical outcomes of folinic acid treatment against no treatment. The study is expected to run from August 1, 2023, to December 31, 2026, with a maximum treatment period of 12 months for each participant.

Participants will be children and adolescents aged 6 to 17 years diagnosed with KSS, with disease onset before 12 years of age, and a 5-methyltetrahydrofolate (5MTHF) concentration of less than 20 nM in cerebrospinal fluid (CSF) at screening. The inclusion criteria also require the presence of a symptom complex including progressive external ophthalmoplegia, ptosis, and pigmentary retinopathy, along with either cardiac conduction defects, cerebellar syndrome, or elevated CSF protein levels. Genetic confirmation of a single large-scale mitochondrial DNA deletion or mutation is also necessary.

The trial will involve several study visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria. Following randomization, participants will undergo baseline assessments, and subsequent follow-up visits will occur at months 3, 6, 9, 12, 15, and 18. The primary endpoint will be assessed by the International Pediatric Mitochondrial Disease Scale (IPMDS) at these time points, with the primary analysis focusing on the baseline-adjusted mean difference between the treatment and control groups after 6 months. Secondary endpoints include biomarker concentrations, regional brain volume, and other neuroimaging assessments.

Participants are expected to be involved in the study for up to 18 months, with the possibility of early termination if they experience adverse events, withdraw consent, or fail to comply with the study protocol. The trial will utilize both oral and intravenous routes for the administration of folinic acid, with a maximum daily dose of 250 mg. The study is not classified as a low-intervention trial, and it does not involve a pediatric formulation of the investigational product.

The clinical trial involves the administration of **Calcium Folinate**, a pharmaceutical agent classified under the ATC code V03AF03. The medication is provided in a pharmaceutical form designated as PHF00169MIG. The maximum daily dose of Calcium Folinate is 250 mg, with the same amount being the maximum total dose permissible within a 24-hour period. The treatment is administered either orally or intravenously, depending on the clinical requirements and patient condition. The maximum treatment period is set at 12 weeks, during which the efficacy of the medication will be evaluated in patients diagnosed with Kearns-Sayre syndrome and cerebral folate deficiency.

In this study, the experimental treatment with Calcium Folinate is compared against a control group receiving no treatment. This design aims to assess the clinical outcomes associated with folinic acid therapy in the specified patient population. The trial does not include any additional non-experimental treatments such as standard-of-care therapy or placebo. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol and to accurately assess the treatment's efficacy.

The efficacy of folinic acid therapy in patients with Kearns-Sayre syndrome (KSS) and cerebral folate deficiency will be assessed using both primary and secondary endpoints. The primary endpoint involves the International Pediatric Mitochondrial Disease Scale (IPMDS), which will be measured at seven time points: baseline, and months 3, 6, 9, 12, 15, and 18. The primary analysis will focus on the baseline-adjusted mean difference between the experimental treatment group and the no-treatment control group after 6 months. Additionally, changes from baseline to months 6, 12, and 18 will be analyzed.

Secondary endpoints include the concentration of the biomarker **5-methyltetrahydrofolate (5MTHF)** in cerebrospinal fluid (CSF), regional brain volume, size and extension of white matter alterations, and myelination assessed by magnetic resonance imaging (MRI). Furthermore, concentrations of choline and myo-inositol will be evaluated using 1H magnetic resonance spectroscopy (MRS). Baseline-adjusted mean differences will also be assessed using the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS).