Behaviors and Mental Disorders

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Cognitive Dysfunction

Brain Neoplasms

Cognition Disorders

Neurocognitive Disorders

Mental Disorders

Psychotic Disorders

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Brain Tumor, Childhood

Central Nervous System Depressants

Psychotropic Drugs

All Drugs and Chemicals

Lithium Carbonate

Antidepressive Agents

Enzyme Inhibitors

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.

Lithium

White round tablet, 10 mm. Identical to experimental drug (lithium)

Placebo

Klas Blomgren, MD, Professor

Gustaf Hellspong, MD, PhD Student

Gustaf Hellspong, MD

Klas Blomgren, MD, professor

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.

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.

Lithium Treatment to Prevent Cognitive Impairment After Brain Radiotherapy

* 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.

Duration of IMP treatment, measured in total number of days where IMP was taken

* Numbers of IMP dose reductions
* Number of IMP temporary 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.

* 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

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.

Cognitive processing speed. Normed score min 45, max 155. Higher = better.

* Verbal Comprehension Index (VCI)
* Visual Spatial Index (VSI)
* Fluid Reasoning Index (FRI)
* Working Memory Index (WMI)

Normed score min 45, max 155. Higher = better.

Motor speed / manual dexterity. Unit: time in seconds to complete all pegs. Lower=better.

Visual motor integration. Normed score min 1, max 19. Higher = better.

Sustained attention. Multiple T-scores, min 0, max 80. Higher = better.

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

Executive function and inhibition. Normed score min 1, max 19. Higher = better.

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

Health related quality of life. Score min 0, max 100. Higher=better.

Loneliness scale. Score min 3, max 9. Lower = better.

Psychosocial strengths and difficulties. Score min 0, max 40.

Executive function. Score min 20, max 80.

Rigshospitalet, Denmark

Region Stockholm

Skin and Connective Tissue Diseases

Breast Neoplasms

Nootropic Agents

Donepezil

Cholinesterase Inhibitors

Cholinergic Agents

Neurotransmitter Agents

Participants will be asked to take one 5 mg tablet of donepezil daily for 6 weeks followed by two 5 mg tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.

Participants will be asked to take one tablet of matching placebo daily for 6 weeks followed by two tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.

Participants will be asked to take one 5 mg tablet of donepezil daily for 6 weeks followed by two 5mg tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.

Donepezil 5 mg

Stephen R Rapp, PhD

This study is to compare the safety and effects of donepezil (Aricept) for patients reporting cognitive or memory issues after receiving chemotherapy for breast cancer. Patients will receive either donepezil or placebo for 24 weeks. The primary objective is to see if memory improves with the use of donepezil during the study.

Randomized, double-blind, placebo-controlled study with 24 weeks of exposure to drug or placebo followed by a 12 week wash-out period. Patients who meet the eligibility criteria will be stratified by age (\<50, 50-59, 60-69, ≥70) and randomized to donepezil or placebo with equal probability. A total of 276 patients will be enrolled (138 per arm). We expect an accrual rate of 7-10 participants per month based on our prior feasibility study. We expect the study to be complete within 40 months.

Participants will be asked to take one 5mg tablet of donepezil or one tablet of matching placebo orally once a day for 6 weeks followed by two 5mg tablets (10mg total) of donepezil or two placebo tablets orally once a day for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.

Time points for performing study assessments. Participants will be administered the cognitive battery of tests and questionnaires at baseline, week 12, week 24 and week 36. In addition, a single vial of blood will be drawn at baseline for apolipoprotein E (APOE) genotyping and subsequent bioassays (pending supplemental funding).

Phase 3 Randomized Placebo Controlled Clinical Trial of Donepezil

A Phase 3 Randomized Placebo Controlled Clinical Trial of Donepezil in Chemotherapy Exposed Breast Cancer Survivors With Cognitive Impairment

Wake Forest National Cancer Institute Community Oncology Research Program (NCORP) Research Base is committed to following the NIH Statement on Sharing Research Data. As of July 2018, the Wake Forest (WF) NCORP Research Base (RB) signed an agreement with NCI to contribute de-identified data and data dictionaries from clinical trials conducted through our RB to the NCI National Clinical Trials Network (NCTN)/NCORP data archive within 6 months of primary and non-primary publications of phase II/III and phase III trials. This will become the primary means for sharing raw data, and we will adhere to the guidelines spelled out in the NCTN/NCORP Data Archive Usage Guide.

Hopkins Verbal Learning Test-Revised (HVLT-R): The HVLT-R measures verbal learning and memory. It consists of a 12-item word list which is read to patients on three successive learning trials. Free recall scores are recorded for each learning trial. After a 20-minute interval during which patients complete other non-interfering tasks and questionnaires they are asked to recall the target words. Range is 0-36 with higher values representing better verbal learning and memory.

The digit symbol coding (DSC) test measures processing speed, working memory, visuospatial processing, and attention. The DSC test measures processing speed. It requires respondents to transcribe symbols (e.g., \>) associated with a number (0-9) into empty boxes beneath a series of randomly ordered numbers. Total score is number of correctly transcribed symbols in 2 minutes. Scores range from 0 to 100, with higher scores indicating higher cognitive function.

This self-report scale assesses fatigue. Scale ranges from 7 to 35 converted to T-scale ranging 29.4 to 83.2 Higher scores representing more fatigue.

The FACT-Cog is a patient-reported outcome (PRO) that includes subscales to measure Perceived Cognitive Impairment (PCI, n = 20 items, score range 0-80). Higher FACT-Cog PCI scores are better and indicate less cognitive impairment.

The Controlled Oral Word Association Test from the Halstead-Reitan Neuropsychological Battery is a verbal fluency test in which participants are asked to say as many words as possible from a given category and in a specified timeframe (typically 60 seconds). Scores are the sum of all acceptable words. Minimum is 0 with no specified maximum; higher values represent better verbal fluency.

TMT Part A consists of 25 circles on a piece of paper with the numbers 1 to 25 written randomly in each. For Part A, the person is tasked with drawing a line from one circle to the next in ascending numerical order, from 1 to 25, as quickly as possible. The lines between the circles are referred to as the "trail." Range 1-300 in seconds. Lower values indicate completing task faster with less difficulty. It is a measure of executive functioning with lower values being better.

TMT Part B also consists of 25 circles on a piece of paper, But, rather than all of the circles containing numbers, they contain numbers (1 to 12) and letters (A through L). For Part B, the person is tasked with connecting the circles in ascending order, alternating back and forth from numbers to letters. In other words, the "trail" would be connected like this:1-A-2-B-3-C-4-D-5-E-6-F-7-G-8-H-9-I-10-J-11-K-12-L-13. The range 1-300 seconds. Higher values indicate worse executive functioning.

The Digit Span Task (Backwards-Only Version) measures working memory. On each question the participant repeats the numbers in reverse order of that presented aloud by the examiner (e.g., If the examiner says "5-6", the correct response would be "6-5"; If the examiner says "5-1-7-4-2-3-8", the correct response would be "8-3-2-4-7-1-5"). Score is 0 to 16 with higher scores representing better working memory.

National Cancer Institute (NCI)

Wake Forest University Health Sciences

Each adverse event will include the date of onset, date of resolution, severity, and the relationship to the study agent or intervention, and any action taken with respect to the study agent or intervention. Grade 1 and 2 adverse events (AEs), expected grade 3 or grade 4 AEs will not be collected. Unexpected grade 3 AEs that are unrelated or unlikely will also not be collected.

Participants will be asked to take one 5 mg tablet of donepezil daily for 6 weeks followed by two 5 mg tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.

Donepezil 5 mg: Participants will be asked to take one 5 mg tablet of donepezil daily for 6 weeks followed by two 5mg tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.

Participants will be asked to take one tablet of matching placebo daily for 6 weeks followed by two tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.

Placebo: Participants will be asked to take one tablet of matching placebo daily for 6 weeks followed by two tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.

Total

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Body Mass Index (BMI)

Chemotherapy Received

Menopausal Status

Participant reported use of hormonal therapies (for their breast cancer treatment) at time of study enrollment.

Currently taking hormonal therapy

Time since completed chemotherapy (months)

The Shipley Institute of Living Scale-Version 2 Vocabulary subtest was used to estimate premorbid cognitive function (score range, 0-40). Higher values represent better cognitive function.

Shipley Institute of Living Scale-2 Vocabulary

Highest level of Education Completed

Hopkins Verbal Learning Test- Revised (HVLT-R): Total

Measure Description: Hopkins Verbal Learning Test-Revised (HVLT-R): The HVLT-R measures verbal learning and memory. It consists of a 12-item word list which is read to patients on three successive learning trials. Free recall scores are recorded for each learning trial. After a 20-minute interval during which patients complete other non-interfering tasks and questionnaires they are asked to recall the target words. Delayed Recall range is 0-12 with higher values representing better verbal learning and memory.

Hopkins Verbal Learning Test- Revised (HVLT-R): Delayed Recall

Measure Description: Hopkins Verbal Learning Test-Revised (HVLT-R): The HVLT-R measures verbal learning and memory. It consists of a 12-item word list which is read to patients on three successive learning trials. Free recall scores are recorded for each learning trial. After a 20-minute interval during which patients complete other non-interfering tasks and questionnaires they are asked to recall the target words. Recognition memory range is 0-12 with higher values representing better verbal learning and memory.

Hopkins Verbal Learning Test- Revised (HVLT-R): Recognition

Measure Description: Hopkins Verbal Learning Test-Revised (HVLT-R): The HVLT-R measures verbal learning and memory. It consists of a 12-item word list which is read to patients on three successive learning trials. Free recall scores are recorded for each learning trial. After a 20-minute interval during which patients complete other non-interfering tasks and questionnaires they are asked to recall the target words. Discrimination range is -12 to 12 with higher values representing better verbal learning and memory.

Hopkins Verbal Learning Test- Revised (HVLT-R): Discrimination

TMT Part A consists of 25 circles on a piece of paper with the numbers 1 to 25 written randomly in each. For Part A, the person is tasked with drawing a line from one circle to the next in ascending numerical order, from 1 to 25, as quickly as possible. The lines between the circles are referred to as the "trail." Range 1-300 in seconds. Lower values indicate completing task faster with less difficulty. It is a measure of executive functioning with lower values being better.

Trail Making Test (TMT) - A

TMT Part B also consists of 25 circles on a piece of paper, But, rather than all of the circles containing numbers, they contain numbers (1 to 12) and letters (A through L). For Part B, the person is tasked with connecting the circles in ascending order, alternating back and forth from numbers to letters. In other words, the "trail" would be connected like this:1-A-2-B-3-C-4-D-5-E-6-F-7-G-8-H-9-I-10-J-11-K-12-L-13. The range 1-300 seconds. Higher values indicate worse executive functioning.

Trail Making Test (TMT) - B

Controlled Oral Word Association (COWA)

The Digit Span Task (Backwards-Only Child Version) measures working memory. On each question the participant repeats the numbers in reverse order of that presented aloud by the examiner (e.g., If the examiner says "5-6", the correct response would be "6-5"; If the examiner says "5-1-7-4-2-3-8", the correct response would be "8-3-2-4-7-1-5"). Score is 0 to 16 with higher scores representing better working memory.

Digit Span Test Backward

The digit symbol test measures processing speed, working memory, visuospatial processing, and attention. Scores range from 0 to 100, with higher scores indicating higher cognitive function.

Digit Symbol Coding

The Functional Assessment of Cancer Therapy (FACT)-Cognition is a patient-reported outcome (PRO) that includes subscales to measure Perceived Cognitive Impairment (PCI, n = 20 items, score range 0-80). Higher FACT-Cog PCI scores are better and indicate less cognitive impairment.

The Functional Assessment of Cancer Therapy (FACT)-Cognition: Perceived Cognitive Impairment

This self-report scale assesses fatigue. Scores range from 7 to 35 and are converted to a T-scale with ranges from 29.4 to 83.2. Higher scores representing more fatigue.

Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue - Short Form 7a

All participants that were enrolled and randomized completed baseline assessments.

Our mainly non-Hispanic, white sample of breast cancer survivors, while geographically diverse, is not representative of all survivors. A lack of validated alternate forms of most of our tests may have contributed to a practice effect. We did not collect estrogen receptor, progesterone receptor or human epidermal growth factor receptor 2 (HER2) status.

Lead Biostatistician (Emily Dressler, PhD)

With a sample size of 266, there was 90% power to detect a treatment difference of 2 words for HVLT-R total recall score (SD=4.26, effect size=0.47) with a two-sided 5% level of significance. This calculation assumed an ANCOVA model analysis with 25% dropout and 2% missing data at end of treatment. A single interim analysis for futility occurred after 138 participants, with stopping rule of two-sided p-value \< 0.0154. This design required 3.5% more than fixed design, increasing total to 276.

12 Weeks

24 Weeks

36 Weeks

Intent to treat analysis. Considered and utilized all data available at each timepoint.

Hopkins Verbal Learning Test-Revised (HVLT-R) - Total

Intent to treat analysis. All available data from all participants utilized in models.

Digit Symbol Coding Results

Intent to treat: all participants and timepoints available were utilized.

PROMIS 7-item Fatigue Scale Converted to T-scale Results

Intent to treat analyses: all available timepoints and participant data utilized.

FACT-Cognition (Version 3): Perceived Cognitive Impairment

Intent to treat analysis. All available timepoints from all participants utilized.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Lithium Treatment to Prevent Cognitive Impairment After Brain Radiotherapy	NCT06051240	Cognitive Impai... Cognitive Decli... Radiotherapy Si... Radiotherapy; C... Brain Tumor Memory Impairme... Late Effect of ...	Lithium Placebo	5 Years -	Region Stockholm
Lithium Treatment to Prevent Cognitive Impairment After Brain Radiotherapy	NCT06051240	Cognitive Impai... Cognitive Decli... Radiotherapy Si... Radiotherapy; C... Brain Tumor Memory Impairme... Late Effect of ...	Lithium Placebo	5 Years -	Region Stockholm
Lithium Treatment to Prevent Cognitive Impairment After Brain Radiotherapy	NCT06051240	Cognitive Impai... Cognitive Decli... Radiotherapy Si... Radiotherapy; C... Brain Tumor Memory Impairme... Late Effect of ...	Lithium Placebo	5 Years -	Region Stockholm
Phase 3 Randomized Placebo Controlled Clinical Trial of Donepezil	NCT02822573	Cognitive Dysfu... Memory Impairme...	Donepezil 5 mg Placebo	18 Years - 75 Years	Wake Forest University Health Sciences

Spots Global Cancer Trial Database for memory impairment