Efficacy and Safety Evaluation of Doxecitine and Doxribtimine in Adults with Thymidine Kinase 2 Deficiency: An Off-Label Single Arm Study

The primary objective of this clinical study is to evaluate the **efficacy** of the combination of doxecitine and doxribtimine (dT+dC) in adult subjects with Thymidine Kinase 2 Deficiency (TK2d). This objective is clinically relevant as TK2d is a mitochondrial disorder that can lead to severe muscle weakness and respiratory failure, and assessing the efficacy of dT+dC could provide insights into potential therapeutic benefits for affected individuals.

Secondary objectives include evaluating the **safety** of dT+dC in adults with TK2d. This is crucial for understanding the risk-benefit profile of the treatment, ensuring that any therapeutic advantages are not outweighed by adverse effects.

The clinical trial involves a study population comprising **adults** diagnosed with TK2 deficiency, a genetic disorder. Participants are both male and female, aged 18 years and older, with no specific upper age limit indicated. The trial does not include a vulnerable population. The total number of participants is not provided by the sponsor. Participants were selected based on their genetic diagnosis of TK2 deficiency and evidence of moderate to severe disease, characterized by motor or respiratory involvement. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include the requirement for participants to provide signed informed consent and, for females of childbearing potential, to use highly effective birth control methods during the study and for 30 days after its conclusion. Male participants with partners of childbearing potential must also adhere to effective contraception methods during the study and for at least 90 days following the last dose of the study medication. The study aims to evaluate the efficacy of dT+dC in this specific population.

The clinical trial is designed to evaluate the **efficacy** and **safety** of the investigational product, doxecitine and doxribtimine, in adult subjects diagnosed with Thymidine Kinase 2 (TK2) deficiency. This is a single-arm, open-label study, which will not include a control group. The trial is set to commence recruitment on June 3, 2024, and is expected to conclude by June 3, 2026. Participants will be administered the investigational product in the form of an **oral solution**. The maximum daily dose is set at 800 mg/kg, with a total maximum dose of 584,000 mg/kg over a treatment period of up to 24 months.

Study visits are structured to ensure comprehensive monitoring and data collection. The initial visit, known as the inclusion or screening visit, will confirm eligibility based on criteria such as age, genetic diagnosis of TK2 deficiency, and specific clinical assessments. Participants must be over 18 years of age and demonstrate moderate to severe disease symptoms. Follow-up visits will occur at regular intervals to assess the primary endpoint of efficacy and the secondary endpoint of safety. These visits will include clinical evaluations, laboratory tests, and assessments of motor and respiratory function. The end-of-study visit will finalize data collection and ensure participant safety post-treatment.

Participant involvement is expected to last for the entire duration of the trial, approximately 24 months, unless early termination is warranted. Conditions for early termination include adverse events, non-compliance with the study protocol, or withdrawal of consent. Participants are required to adhere to the study protocol, including the use of effective contraception for both male and female subjects of childbearing potential, to mitigate any potential risks associated with the investigational product. The trial is conducted in accordance with ethical standards and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of an **experimental medication** composed of two active substances: **doxribtimine** and **doxecitine**. This medication is provided in the form of an **oral solution** and is identified by the sponsor product code MT1621. The pharmaceutical formulation is designed for **oral use**. The maximum daily dose is set at 800 mg/kg, with a total maximum dose of 584,000 mg/kg over the course of the treatment period. The treatment duration is capped at 24 weeks. The medication is not formulated specifically for pediatric use and is classified as a chemical origin product. The trial aims to evaluate the efficacy and safety of this combination in adult subjects diagnosed with Thymidine Kinase 2 (TK2) Deficiency.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on the investigational product, doxecitine and doxribtimine, to assess its therapeutic potential in the specified patient population. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. Participants are required to follow the administration guidelines strictly to maintain the integrity of the study outcomes.

The efficacy of the investigational treatment, **doxecitine and doxribtimine**, will be assessed in a clinical trial involving adult subjects with Thymidine Kinase 2 (TK2) Deficiency. The primary endpoint for evaluating efficacy is the improvement in clinical symptoms associated with TK2 deficiency. This will be measured using specific criteria, including the North Star Ambulatory Assessment Scale (NSAA) with a score of less than 30, a 6-minute walking test covering less than 450 meters, and a Forced Vital Capacity in the sitting position of less than 70% or a significant drop in the decubitus position, or the need for mechanical ventilation.

Data collection will occur at various timepoints throughout the study, with assessments conducted at baseline and at regular intervals during the treatment period, which spans up to 24 weeks. The efficacy parameters will be analyzed using validated scales and tests to ensure accuracy and reliability. The trial is designed as a single-arm study, focusing on the off-label use of the oral solution formulation of the investigational product. The study aims to provide comprehensive data on the efficacy of the treatment in improving the clinical outcomes for patients with TK2 deficiency.