Lithium Treatment to Prevent Cognitive Impairment After Brain Radiotherapy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Lithium Treatment to Prevent Cognitive Impairment After Brain Radiotherapy

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

Intervention / Treatment
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* Drug: Lithium
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lithium<br>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. | Drug: Lithium<br>* Lithium sulphate, 42 mg (6 mmol lithium)<br>* Other names: Lithium sulphate;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* White round tablet, 10 mm. Identical to experimental drug (lithium)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Processing Speed Index (PSI) | Cognitive processing speed. Normed score min 45, max 155. Higher = better. | 2 years after start of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fractional anisotropy (FA) index | White matter integrity on MRI brain. | Baseline (before treatment) - 5 years after start of study treatment | 
| Other Wechsler Intelligence scale scores (except PSI): | Verbal Comprehension Index (VCI) Visual Spatial Index (VSI) Fluid Reasoning Index (FRI) Working Memory Index (WMI) Normed score min 45, max 155. Higher = better. | Baseline (before treatment) - 5 years after start of study treatment | 
| Grooved pegboard | Motor speed / manual dexterity. Unit: time in seconds to complete all pegs. Lower=better. | Baseline (before treatment) - 5 years after start of study treatment | 
| Beery/Buktenica visual motor integration (VMI) | Visual motor integration. Normed score min 1, max 19. Higher = better. | Baseline (before treatment) - 5 years after start of study treatment | 
| Conner´s Continous Performance Test (CPT) III | Sustained attention. Multiple T-scores, min 0, max 80. Higher = better. | Baseline (before treatment) - 5 years after start of study treatment | 
| Delis-Kaplan Executive Function System Trail Making Test (D-KEFS TMT) | Executive function and inhibition, age 8 years and above. Normed score min 1, max 19. Higher = better. | Baseline (before treatment) - 5 years after start of study treatment | 
| Delis-Kaplan Executive Function System Color-Word Interference Test (D-KEFS CWT), age 8 years and above. | Executive function and inhibition. Normed score min 1, max 19. Higher = better. | Baseline (before treatment) - 5 years after start of study treatment | 
| Nepsy II: Inhibition, Verbal Fluency, | Executive function and inhibition, age below 8 years. Normed score min 1, max 19. Higher = better. | Baseline (before treatment) - 5 years after start of study treatment | 
| Pediatric QoL Inventory (PedsQL) | Health related quality of life. Score min 0, max 100. Higher=better. | Baseline (before treatment) - 5 years after start of study treatment | 
| University of California Los Angeles (UCLA) 3-Item Loneliness Scale (ULS-3) | Loneliness scale. Score min 3, max 9. Lower = better. | Baseline (before treatment) - 5 years after start of study treatment | 
| Strengths and Difficulties Questionnaire (SDQ) | Psychosocial strengths and difficulties. Score min 0, max 40. | Baseline (before treatment) - 5 years after start of study treatment | 
| Behavior Rating Inventory of Executive Function (BRIEF). | Executive function. Score min 20, max 80. | Baseline (before treatment) - 5 years after start of study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lithium, neuroprotection, neuroprotective, regenerative, prevention, radiation, pediatric brain tumor, brain tumor, cognition, cognitive