Efficacy of Lithium Sulphate in Preventing Cognitive Processing Speed Impairment Post-CNS Radiotherapy in Pediatric Brain Tumor Patients

The primary objective of this study is to evaluate the **efficacy** of lithium treatment in preventing late-appearing cognitive processing speed impairment (PSI) in children who have undergone central nervous system (CNS) radiotherapy for CNS malignancy. This is clinically relevant as cognitive impairment is a significant long-term side effect of brain radiotherapy, impacting the quality of life and functional outcomes in pediatric patients.

Secondary objectives include:

• Assessing the efficacy of lithium treatment through evaluation of other neuropsychological test scores.
• Evaluating radiological findings after lithium treatment using MRI to further understand its impact.
• Exploring the feasibility of lithium treatment in this patient group.

The clinical trial involves participants diagnosed with a **brain tumor** who have undergone cranial or craniospinal radiation treatment within the last seven years. The study population includes both male and female subjects, aged between 5 and 18 years at the time of radiotherapy. Participants are required to have adequate contraception to prevent pregnancy during the lithium treatment period and for six months thereafter, with a negative pregnancy test at screening, the start of study treatment, and monthly thereafter. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. Written informed consent from the patient and/or caregiver is mandatory for participation.

The clinical trial is designed to evaluate the efficacy of **lithium sulphate, anhydrous** in preventing cognitive impairment following brain radiotherapy in children with a **brain tumor**. This is a Phase IV, randomized, double-blind, placebo-controlled trial. The study will involve the administration of **Lithionit 42 mg (6 mmol) depottablett**, a prolonged-release tablet, and a matching placebo. The trial is expected to last until June 2033, with recruitment having commenced in June 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (5 to 18 years), previous cranial radiation treatment, and negative pregnancy tests. Following the screening, participants will be randomized to receive either the active treatment or placebo. The primary endpoint is the difference in Processing Speed Index (PSI) from baseline compared to two years later. Secondary endpoints include changes in various neuropsychological test scores and brain MRI evaluations at specified intervals.

Study visits will occur at baseline, and approximately 1, 2, and 5 years after the start of treatment, with additional assessments at 3 months, 6 months, 3 years, and 4 years. The end-of-study visit will mark the conclusion of the participant's involvement, which is expected to last up to 5 years. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or adverse events that compromise participant safety.

The clinical trial involves the administration of **Lithionit 42 mg (6 mmol) depottablett**, which is a **prolonged-release tablet** containing the active substance **lithium sulphate, anhydrous**. This medication is manufactured by Karo Pharma AB and is authorized in Sweden. The **route of administration** is **oral use**, and the maximum daily dose is 336 mg, with a total maximum dose of 60 g over the treatment period. The maximum treatment period is 6 months. The primary objective of the trial is to assess the efficacy of lithium treatment in preventing late-appearing cognitive processing speed impairment in children following CNS radiotherapy for CNS malignancy.

In addition to the experimental medication, a **placebo** is used as a comparator in the study. The placebo is designed to match the **42 mg Lithionit** tablets in appearance, being 10 mm, white, and round. The placebo is administered in the same manner as the active medication, ensuring blinding of the study participants and investigators. The placebo does not contain any active substance and serves to evaluate the efficacy of the experimental treatment by comparison.

The efficacy of lithium treatment in preventing late-appearing cognitive processing speed impairment (PSI) after central nervous system (CNS) radiotherapy for CNS malignancy in children will be assessed through a series of primary and secondary endpoints. The primary endpoint is the difference in the **Processing Speed Index (PSI)** from baseline compared to two years later. Secondary endpoints include changes in various neuropsychological test scores, such as the complete set of WPPSI/WISC/WAIS-IV sub-tests (PSI, VCI, VSI, FRI, WMI), Grooved pegboard (motor speed), Beery/Butkenica VMI, Conner's CPT, D-KEFS TMT, and D-KEFS Tower. These tests will be conducted at baseline and approximately 1, 2, and 5 years after the start of the study treatment.

Additional secondary endpoints involve the Pediatric QoL Inventory, PedsQL (health-related quality of life), ULS-3, SDQ, and the Behavior Rating Inventory of Executive Function (executive function: behavior), with assessments scheduled at the same intervals. Changes in the **Processing Speed Index (PSI)** and **Working Memory Index (WMI)** will also be evaluated at 3 months, 6 months, 3 years, and 4 years after the start of the study treatment, compared to baseline. Furthermore, volumetric measures such as hippocampal volume and diffusion tensor imaging (DTI) indices on brain MRI will be evaluated at 6 months, 1 year, 2 years, and 5 years after the start of the study treatment, compared to baseline. These assessments will provide comprehensive data on the efficacy of lithium treatment in this clinical context.