MitBrain

An exploratory randomised clinical trial to assess the safety and efficacy of sildenafil treatment in paediatric patients with mitochondrial disease presenting with neurological symptoms

Project name: An exploratory randomised clinical trial to assess the safety and efficacy of sildenafil treatment in paediatric patients with mitochondrial disease presenting with neurological symptoms

Acronim: MitBrain

Total project cost: 15 384 738,17 PLN
Value of co-financing: 15 384 738,17 PLN
Project duration: 01.03.2026 – 29.02.2032

Project objective: MitBrain is an exploratory clinical trial with randomised initiation of treatment. It aims to evaluate the safety and efficacy of sildenafil treatment in paediatric patients with mitochondrial disease presenting with neurological symptoms. Mitochondrial diseases (MD) (ORPHA code: 223713) are a highly diverse group of disorders resulting from abnormalities in the structure or function of mitochondria, leading to energy production deficits. MDs are progressive diseases, often leading to developmental disorders and disability. They carry a risk of premature death. There is no effective and causal treatment for most MDs, and symptomatic treatment does not slow the progression of the disease. Sildenafil is a phosphodiesterase type 5 inhibitor (PDE5i) used to treat pulmonary hypertension and erectile dysfunction. Its efficacy and safety have been demonstrated in the treatment of pulmonary hypertension in adults and children, including newborns. PDE5i has been identified in drug screening studies on neural progenitor cells with Leigh syndrome (the most common MD phenotype in children) as the most effective drug for improving mitochondrial function. Despite promising experimental results, little is known about the use of PDE5i in this patient group. The study will include paediatric patients with MD (diagnosed using the Nijmegen scale and/or genetic testing) who exhibit neurological symptoms. Patients will be recruited from among IPCZD centre patients and newly registered patients.

Patients will be randomly assigned to one of two groups:

• group 1: patients treated with sildenafil (n=15),
• group 2: patients receiving placebo (n=15). After 6 months, all patients will continue treatment with sildenafil for another 18 months. After 12 months (V4), patients will be unblinded to conduct a preliminary analysis of treatment efficacy. The observation period for each patient is planned to be 25 months (24 months of treatment + 1 month of observation after the end of treatment). The drug will be administered at the Centre during a 4-day hospitalisation. Visits to the Centre will take place every 6 months with an assessment of the safety and efficacy of the treatment, and there will be telephone visits between visits to the Centre.

The overall assessment of the survey results will consist of an analysis of:

• the incidence of adverse events in both groups;
• MD progression assessed according to IPMDS (International Paediatric Mitochondrial Disease Severity Scale) in both groups;
• assessment of quality of life and disease severity and improvement/deterioration in the opinion of the patient’s parents/legal guardians;
• concentration of light neurofilament chain, biochemical biomarkers of MD and their correlation with the severity of mitochondrial disease according to IPMDS;
• mitochondrial function by assessing the rate of ATP production by peripheral blood monoclonal cells before and during treatment with sildenafil, using Seahorse XF technology.