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.

Study Overview

• Status: Not yet recruiting
• Conditions: Cognitive Impairment; Brain Tumor; Cognitive Decline; Memory Impairment; Radiotherapy Side Effect; Radiotherapy; Complications; Late Effect of Radiation
• Intervention / Treatment: Drug: Lithium; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 84
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Klas Blomgren, MD, Professor; Phone Number: 0046703233353; Email: klas.blomgren@regionstockholm.se
• Study Contact Backup: Name: Gustaf Hellspong, MD, PhD Student; Phone Number: 0707308144; Email: gustaf.hellspong@regionstockholm.se

Study Locations

• Sweden
  • Stockholm
    • Solna, Stockholm, Sweden, 171 64
      • Karolinska Universitetssjukhuset
      • Contact: Klas Blomgren, MD, Professor; Phone Number: 0046703233353; Email: klas.blomgren@regionstockholm.se
      • Contact: Gustaf Hellspong, MD, PhD Student; Phone Number: 0046707308144; Email: gustaf.hellspong@regionstockholm.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lithium; 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; Lithium sulphate, 42 mg (6 mmol lithium); Other Names: Lithionit; Lithium sulphate
Placebo Comparator: Placebo; 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; White round tablet, 10 mm. Identical to experimental drug (lithium)

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of recruitment and retention, numerical data	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)	From screening - end of study (5 years)
Feasibility of recruitment and retention, qualitative data	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.	From screening - end of study (5 years)
Feasibility of treatment - IMP treatment duration	Duration of IMP treatment, measured in total number of days where IMP was taken	During study treatment (appx 6 months)
Feasibility of treatment - number of IMP reductions and stops	Numbers of IMP dose reductions; Number of IMP temporary stops	During study treatment (appx 6 months)
Feasibility of treatment - reasons for IMP reductions and stops	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.	During study treatment (appx 6 months)
Feasibility of treatment - lithium serum concentration within target range	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	During study treatment (appx 6 months)
Feasibility of treatment - adverse events	Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.	During study treatment (appx 6 months) + 1 month

Collaborators and Investigators

• Sponsor: Region Stockholm
• Collaborators: Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Estimated): November 30, 2023
• Primary Completion (Estimated): August 31, 2030
• Study Completion (Estimated): August 31, 2033

Study Registration Dates

• First Submitted: June 12, 2023
• First Submitted That Met QC Criteria: September 20, 2023
• First Posted (Actual): September 22, 2023

Study Record Updates

• Last Update Posted (Actual): September 22, 2023
• Last Update Submitted That Met QC Criteria: September 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: cognition; prevention; lithium; radiation; brain tumor; neuroprotection; cognitive; pediatric brain tumor; regenerative; neuroprotective
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Neurocognitive Disorders; Central Nervous System Neoplasms; Nervous System Neoplasms; Cognition Disorders; Cognitive Dysfunction; Brain Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Antimanic Agents; Lithium Carbonate
• Other Study ID Numbers: 2023-504071-24-00 (Other Identifier: EudraCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No