Brain Tumor, Cognitive Decline, Cognitive Impairment, Late Effect of Radiation, Memory Impairment, Radiotherapy; Complications, Radiotherapy Side Effect
Conditions
Keywords
lithium, neuroprotection, neuroprotective, regenerative, prevention, radiation, pediatric brain tumor, brain tumor, cognition, cognitive
Brief summary
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
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.
Interventions
DRUGLithium
Lithium sulphate, 42 mg (6 mmol lithium)
DRUGPlacebo
White round tablet, 10 mm. Identical to experimental drug (lithium)
Sponsors
Rigshospitalet, Denmark
Region Stockholm
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Identical-looking placebo is used. S-lithium levels are masked by using a separate lab service and sham values for placebo group.
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Processing Speed Index (PSI) | 2 years after start of study treatment | Cognitive processing speed. Normed score min 45, max 155. Higher = better. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Beery/Buktenica visual motor integration (VMI) | Baseline (before treatment) - 5 years after start of study treatment | Visual motor integration. Normed score min 1, max 19. Higher = better. |
| Delis-Kaplan Executive Function System Trail Making Test (D-KEFS TMT) | Baseline (before treatment) - 5 years after start of study treatment | 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. | Baseline (before treatment) - 5 years after start of study treatment | Executive function and inhibition. Normed score min 1, max 19. Higher = better. |
| Nepsy II: Inhibition, Verbal Fluency, | Baseline (before treatment) - 5 years after start of study treatment | Executive function and inhibition, age below 8 years. Normed score min 1, max 19. Higher = better. |
| Pediatric QoL Inventory (PedsQL) | Baseline (before treatment) - 5 years after start of study treatment | Health related quality of life. Score min 0, max 100. Higher=better. |
| University of California Los Angeles (UCLA) 3-Item Loneliness Scale (ULS-3) | Baseline (before treatment) - 5 years after start of study treatment | Loneliness scale. Score min 3, max 9. Lower = better. |
| Strengths and Difficulties Questionnaire (SDQ) | Baseline (before treatment) - 5 years after start of study treatment | Psychosocial strengths and difficulties. Score min 0, max 40. |
| Behavior Rating Inventory of Executive Function (BRIEF). | Baseline (before treatment) - 5 years after start of study treatment | Executive function. Score min 20, max 80. |
| Fractional anisotropy (FA) index | Baseline (before treatment) - 5 years after start of study treatment | White matter integrity on MRI brain. |
| Other Wechsler Intelligence scale scores (except PSI): | Baseline (before treatment) - 5 years after start of study treatment | * Verbal Comprehension Index (VCI) * Visual Spatial Index (VSI) * Fluid Reasoning Index (FRI) * Working Memory Index (WMI) Normed score min 45, max 155. Higher = better. |
| Grooved pegboard | Baseline (before treatment) - 5 years after start of study treatment | Motor speed / manual dexterity. Unit: time in seconds to complete all pegs. Lower=better. |
| Conner´s Continous Performance Test (CPT) III | Baseline (before treatment) - 5 years after start of study treatment | Sustained attention. Multiple T-scores, min 0, max 80. Higher = better. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of treatment - IMP treatment duration | During study treatment (appx 6 months) | Duration of IMP treatment, measured in total number of days where IMP was taken |
| Feasibility of treatment - number of IMP reductions and stops | During study treatment (appx 6 months) | * Numbers of IMP dose reductions * Number of IMP temporary stops |
| Feasibility of treatment - reasons for IMP reductions and stops | During study treatment (appx 6 months) | * 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. |
| Feasibility of treatment - lithium serum concentration within target range | During study treatment (appx 6 months) | * 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 |
| Feasibility of treatment - adverse events | During study treatment (appx 6 months) + 1 month | Number of participants with treatment-related adverse events as assessed by CTCAE v5.0. |
| Feasibility of recruitment and retention, qualitative data | From screening - end of study (5 years) | * 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. |
| Feasibility of recruitment and retention, numerical data | From screening - end of study (5 years) | * 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) |
Countries
Sweden
Contacts
Primary ContactKlas Blomgren, MD, Professor
Backup ContactGustaf Hellspong, MD, PhD Student
Outcome results
None listed