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

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ClinicalTrials.gov Identifier: NCT06051240
Recruitment Status : Recruiting
First Posted : September 22, 2023
Last Update Posted : April 12, 2024
Sponsor:
Collaborator:
Rigshospitalet, Denmark
Information provided by (Responsible Party):
Region Stockholm

Study Description
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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.


Condition or disease Intervention/treatment Phase
Cognitive Impairment Cognitive Decline Radiotherapy Side Effect Radiotherapy; Complications Brain Tumor Memory Impairment Late Effect of Radiation Drug: Lithium Drug: Placebo Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Quadruple (Participant, Care Provider, 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.
Primary Purpose: Prevention
Official Title: Lithium Treatment to Prevent Cognitive Impairment After Brain Radiotherapy
Actual Study Start Date : February 16, 2024
Estimated Primary Completion Date : August 31, 2030
Estimated Study Completion Date : August 31, 2033

Resource links provided by the National Library of Medicine


Arms and Interventions
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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)


Outcome Measures
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Primary Outcome Measures :
  1. Processing Speed Index (PSI) [ Time Frame: 2 years after start of study treatment ]
    Cognitive processing speed. Normed score min 45, max 155. Higher = better.


Secondary Outcome Measures :
  1. Fractional anisotropy (FA) index [ Time Frame: Baseline (before treatment) - 5 years after start of study treatment ]
    White matter integrity on MRI brain.

  2. Other Wechsler Intelligence scale scores (except PSI): [ Time Frame: 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.


  3. Grooved pegboard [ Time Frame: Baseline (before treatment) - 5 years after start of study treatment ]
    Motor speed / manual dexterity. Unit: time in seconds to complete all pegs. Lower=better.

  4. Beery/Buktenica visual motor integration (VMI) [ Time Frame: Baseline (before treatment) - 5 years after start of study treatment ]
    Visual motor integration. Normed score min 1, max 19. Higher = better.

  5. Conner´s Continous Performance Test (CPT) III [ Time Frame: Baseline (before treatment) - 5 years after start of study treatment ]
    Sustained attention. Multiple T-scores, min 0, max 80. Higher = better.

  6. Delis-Kaplan Executive Function System Trail Making Test (D-KEFS TMT) [ Time Frame: 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.

  7. Delis-Kaplan Executive Function System Color-Word Interference Test (D-KEFS CWT), age 8 years and above. [ Time Frame: Baseline (before treatment) - 5 years after start of study treatment ]
    Executive function and inhibition. Normed score min 1, max 19. Higher = better.

  8. Nepsy II: Inhibition, Verbal Fluency, [ Time Frame: 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.

  9. Pediatric QoL Inventory (PedsQL) [ Time Frame: Baseline (before treatment) - 5 years after start of study treatment ]
    Health related quality of life. Score min 0, max 100. Higher=better.

  10. University of California Los Angeles (UCLA) 3-Item Loneliness Scale (ULS-3) [ Time Frame: Baseline (before treatment) - 5 years after start of study treatment ]
    Loneliness scale. Score min 3, max 9. Lower = better.

  11. Strengths and Difficulties Questionnaire (SDQ) [ Time Frame: Baseline (before treatment) - 5 years after start of study treatment ]
    Psychosocial strengths and difficulties. Score min 0, max 40.

  12. Behavior Rating Inventory of Executive Function (BRIEF). [ Time Frame: Baseline (before treatment) - 5 years after start of study treatment ]
    Executive function. Score min 20, max 80.


Other Outcome Measures:
  1. Feasibility of recruitment and retention, numerical data [ Time Frame: 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)

  2. Feasibility of recruitment and retention, qualitative data [ Time Frame: 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.

  3. Feasibility of treatment - IMP treatment duration [ Time Frame: During study treatment (appx 6 months) ]
    Duration of IMP treatment, measured in total number of days where IMP was taken

  4. Feasibility of treatment - number of IMP reductions and stops [ Time Frame: During study treatment (appx 6 months) ]
    • Numbers of IMP dose reductions
    • Number of IMP temporary stops

  5. Feasibility of treatment - reasons for IMP reductions and stops [ Time Frame: 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.

  6. Feasibility of treatment - lithium serum concentration within target range [ Time Frame: 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

  7. Feasibility of treatment - adverse events [ Time Frame: During study treatment (appx 6 months) + 1 month ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.


Eligibility Criteria
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Ages Eligible for Study:   5 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06051240


Contacts
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Contact: Klas Blomgren, MD, Professor 0046703233353 klas.blomgren@regionstockholm.se
Contact: Gustaf Hellspong, MD, PhD Student 0707308144 gustaf.hellspong@regionstockholm.se

Locations
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Sweden
Karolinska Universitetssjukhuset Not yet recruiting
Solna, Stockholm, Sweden, 171 64
Contact: Klas Blomgren, MD, Professor    0046703233353    klas.blomgren@regionstockholm.se   
Contact: Gustaf Hellspong, MD, PhD Student    0046707308144    gustaf.hellspong@regionstockholm.se   
HOPE Recruiting
Stockholm, Sweden, 17176
Contact: Gustaf Hellspong, MD    +46812371594    gustaf.hellspong@regionstockholm.se   
Contact: Klas Blomgren, MD, professor    +46703233353    klas.blomgren@regionstockholm.se   
Sponsors and Collaborators
Region Stockholm
Rigshospitalet, Denmark
More Information
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Responsible Party: Region Stockholm
ClinicalTrials.gov Identifier: NCT06051240    
Other Study ID Numbers: 2023-504071-24-00
2023-504071-24-00 ( Other Identifier: EudraCT )
First Posted: September 22, 2023    Key Record Dates
Last Update Posted: April 12, 2024
Last Verified: June 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Region Stockholm:
lithium
neuroprotection
neuroprotective
regenerative
prevention
 radiation
pediatric brain tumor
brain tumor
cognition
cognitive
Additional relevant MeSH terms:
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Brain Neoplasms
Cognitive Dysfunction
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Brain Diseases
Central Nervous System Diseases
 Nervous System Diseases
Lithium Carbonate
Antidepressive Agents
Psychotropic Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs