Lithium Treatment to Prevent Cognitive Impairment After Brain Radiotherapy (LiBRA)

Randomized, placebo-controlled, double-blinded, parallel group clinical trial to investigate if 6 months of oral lithium tablets (S-lithium 0,5-1,0 mmol/l) will prevent cognitive decline after brain radiotherapy in pediatric brain tumor survivors. Primary outcome measure is Processing Speed Index (PSI) 2 years after start of study treatment.

Late-appearing cognitive side effects after brain radiotherapy is a potential disabling condition in pediatric brain tumor survivors. It can have profound negative effects on education, career options and quality of life. There is no current interventional drug treatment to prevent this intellectual impairment after brain tumor treatment. Primary objective: To assess the efficacy of lithium treatment (up to 7 years) after brain radiotherapy (both whole brain and focal) for central nervous system malignancy in preventing late-appearing cognitive processing speed impairment in children aged 5 or older. Secondary objectives: To assess the efficacy of lithium treatment through evaluation of other neuropsychological/quality of life test scores. To assess the efficacy of lithium treatment through evaluation of radiological findings after lithium treatment using Magnetic Resonance Imaging (MRI) of the brain. Exploratory objectives: To explore the feasibility, safety and tolerability of lithium treatment in this patient group, using side effect forms/adverse events (AE) reporting and laboratory measures.

Cognitive Impairment, Cognitive Decline, Radiotherapy Side Effect, Radiotherapy; Complications, Brain Tumor, Memory Impairment, Late Effect of Radiation

lithium, neuroprotection, neuroprotective, regenerative, prevention, radiation, pediatric brain tumor, brain tumor, cognition, cognitive

Randomization is based on whether or not the study participant had received radiotherapy to the whole brain (CSI) or only part of it (focal irradiation). Within each of these two arms there is a predetermined block randomization with a 2:1 lithium:placebo ratio.

Identical-looking placebo is used. S-lithium levels are masked by using a separate lab service and sham values for placebo group.

Lithionit 42 mg (lithium sulphate, 6 mmol), start dose 1x1, then slow dose escalation using therapeutic drug monitoring (TDI) to establish a target serum level of 0.5-1.0 mmol/liter.

Identical looking placebo (white round tablet, 10 mm diameter) will be dose escalated and monitored the same way as lithium, with sham values guiding the dosing.

Verbal Comprehension Index (VCI) Visual Spatial Index (VSI) Fluid Reasoning Index (FRI) Working Memory Index (WMI) Normed score min 45, max 155. Higher = better.

Executive function and inhibition, age 8 years and above. Normed score min 1, max 19. Higher = better.

Delis-Kaplan Executive Function System Color-Word Interference Test (D-KEFS CWT), age 8 years and above.

Number of potentially eligible patients identified Number of patients screened Number of patients randomized Number of patients completing the study per protocol Number of patients terminating study during IMP treatment period (6 months). Number of patients terminating study during follow-up period (up 5 years post IMP treatment)

Description of reason why eligle patient declined screening Description of reason why screened patient was not randomized/included Description of reason(s) for early study termination.

Descriptions of reason(s) for IMP dose reductions Descriptions of reason(s) for IMP temporary stops Descriptions of reason(s) for IMP premature (before per protocol) permanent stop.

Number of target serum concentration measurements within target range (0.5-1.0 mmol/liter) divided by total number of measurements. Number of target serum concentration measurements above target range (0.5-1.0 mmol/liter) divided by total number of measurments Number of target serum concentration measurements below target range (0.5-1.0 mmol/liter) divided by total number of measurments

Inclusion Criteria: Age >5 years. Age <18 years at time of radiotherapy. Has received cranial/craniospinal radiation treatment of brain tumor within the last 7 years. Adequate contraceptive method to prevent pregnancy* during the entire lithium treatment period and six months thereafter. Negative pregnancy test* at screening, at start of study treatment, and monthly thereafter. Written informed consent from patient and/or caregiver. Exclusion Criteria: Allergy/hypersensitivity to lithium or any of the excipients Renal failure (Cystatin C derived Glomerular Filtration Rate < 60). Cardiac failure or heart disease, including Brugada syndrome (or family history thereof). Uncontrolled hypothyroidism. Pregnancy or breast feeding. Severe fluid or electrolyte imbalance. Karnofsky-Lansky score < 60. Other condition deemed incompatible with inclusion in this study (estimated 2 year survival prognosis less than 25 %, expected poor protocol compliance, inability to swallow tablets, language difficulties). Inclusion in other study protocol precluding inclusion in this study.