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| Name | Class |
|---|---|
| Alzheimer's Drug Discovery Foundation | OTHER |
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Frontotemporal dementia (FTD) is a progressive neurodegenerative illness that affects the frontal and anterior temporal lobes of the brain. Changes in behavior, including agitation, aggression, and repetitive behaviors, are common symptoms in FTD. The investigators currently do not have good medications to treat these symptoms in FTD, and the medications the investigators use often have side effects. In this project, the investigators will test the use of low-dose lithium, compared to a placebo pill, for the treatment of behavioral symptoms in FTD. Lithium greatly reduces the behavioral symptoms of bipolar disorder, and many have found low-dose lithium to be well-tolerated in patients with dementia. Lithium appears to inhibit the creation of a protein involved in many cases of FTD called tau.
Behavioral symptoms of Frontotemporal dementia (FTD), including agitation, aggression, and inappropriate repetitive behaviors are common, distressing to patients and caregivers, often lead to institutionalization, and can be very difficult and expensive to treat. There is a dearth of medication for treating these symptoms in FTD. Typically, antidepressants and antipsychotic medications are prescribed - which low efficacy and, with the latter class, carry serious adverse effects such as parkinsonism and increased cardiovascular-related mortality. The investigators propose a study of the efficacy of lithium carbonate compared to placebo in the treatment of agitation, aggression, and inappropriate repetitive behaviors in 60 patients with FTD in a randomized, double-blind, two-arm parallel 12-week trial. Lithium is a highly effective treatment for mania and symptoms of agitation or aggression in bipolar disorder. It also inhibits tau aggregation and phosphorylation, leading to considerable interest in its use as a disease-modifying treatment for tauopathies such as FTD and Alzheimer's disease. Unfortunately, earlier trials using typical doses (i.e., doses prescribed for treatment of bipolar disorder) showed high incidence of serious adverse effects (including confusion and delirium). For this proposed study the investigators will: 1) use lower doses and lower target serum concentrations than have preceding trials (shown in preliminary data from a Columbia study and data from other labs to be well-tolerated) and 2) target behavioral symptoms rather than cognitive outcomes.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lithium carbonate | Experimental | Lithium will be prescribed starting at 150 mg/day, with subsequent dose titration to 300, 450, and 600 mg/day as tolerated according to side effects and blood lithium level. |
|
| Placebo | Placebo Comparator | Placebo will be prescribed starting at 1 pill per day, with subsequent dose titration to 2,3, and 4 pills per day as tolerated by sham blood lithium levels provided by an unblinded study team member. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lithium Carbonate | Drug | Lithium will be prescribed starting at 150 mg/day, with subsequent dose titration to 300, 450, and 600 mg/day as tolerated according to side effects and blood lithium level. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Agitation and Aggression as Measured by the Neuropsychiatric Inventory Scale (NPI) | The NPI is a scale designed to assess behavioral changes due to neurological illness. It uses a standardized caregiver interview to rate patient symptoms in a variety of domains, including "Agitation/Aggression." Each domain includes a number of questions about potential specific symptoms, and then asks the caregiver to rate symptom frequency (1, occasionally, to 4, very frequently) as well as symptom severity (1, mild, to 3, severe). Scores range from from 0-12, with 0 being no symptoms and 12 being very frequent and severe symptoms. The study aims to test the effect of lithium on agitation/aggression as compared to placebo by testing whether participants taking lithium show a greater reduction in their NPI "Agitation/Aggression" domain score over the course of the trial. | 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Responders in the Lithium and Placebo Groups | Responder defined as a 30% decrease in NPI core score (sum of domain scores for "Agitation/Aggression" and "Aberrant Motor Behavior") plus a Clinical Global Impression (CGI) Change score of much improved or very much improved (CGI based on these behavioral symptoms only). | 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Motor Symptoms as Measured by the NPI | NPI domain "Aberrant Motor Behaviors" will be observed to test the effect of lithium on repetitive behaviors as compared to placebo, by examining whether participants taking lithium show a greater reduction in their "Aberrant Motor Behaviors" NPI domain score. Scores range from from 0-12, with 0 being no symptoms and 12 being very frequent and severe symptoms. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Edward Huey, MD | Brown University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Columbia University Irving Medical Center | New York | New York | 10032 | United States |
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A total of 17 participants signed a consent form. One participant was a screen failure, resulting in randomization of 16 participants.
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| ID | Title | Description |
|---|---|---|
| FG000 | Lithium Carbonate | Lithium will be prescribed starting at 150 mg/day, with subsequent dose titration to 300, 450, and 600 mg/day as tolerated according to side effects and blood lithium level. Lithium Carbonate: Lithium will be prescribed starting at 150 mg/day, with subsequent dose titration to 300, 450, and 600 mg/day as tolerated according to side effects and blood lithium level. |
| FG001 | Placebo | Placebo will be prescribed starting at 1 pill per day, with subsequent dose titration to 2,3, and 4 pills per day as tolerated by sham blood lithium levels provided by an unblinded study team member. Placebo: Placebo will be prescribed starting at 1 pill per day, with subsequent dose titration to 2,3, and 4 pills per day as tolerated by sham blood lithium levels. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Lithium Carbonate | Lithium will be prescribed starting at 150 mg/day, with subsequent dose titration to 300, 450, and 600 mg/day as tolerated according to side effects and blood lithium level. Lithium Carbonate: Lithium will be prescribed starting at 150 mg/day, with subsequent dose titration to 300, 450, and 600 mg/day as tolerated according to side effects and blood lithium level. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Agitation and Aggression as Measured by the Neuropsychiatric Inventory Scale (NPI) | The NPI is a scale designed to assess behavioral changes due to neurological illness. It uses a standardized caregiver interview to rate patient symptoms in a variety of domains, including "Agitation/Aggression." Each domain includes a number of questions about potential specific symptoms, and then asks the caregiver to rate symptom frequency (1, occasionally, to 4, very frequently) as well as symptom severity (1, mild, to 3, severe). Scores range from from 0-12, with 0 being no symptoms and 12 being very frequent and severe symptoms. The study aims to test the effect of lithium on agitation/aggression as compared to placebo by testing whether participants taking lithium show a greater reduction in their NPI "Agitation/Aggression" domain score over the course of the trial. | Posted | Mean | Standard Error | score on a scale | 12 weeks |
|
12 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Lithium Carbonate | Lithium will be prescribed starting at 150 mg/day, with subsequent dose titration to 300, 450, and 600 mg/day as tolerated according to side effects and blood lithium level. Lithium Carbonate: Lithium will be prescribed starting at 150 mg/day, with subsequent dose titration to 300, 450, and 600 mg/day as tolerated according to side effects and blood lithium level. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fall | Injury, poisoning and procedural complications | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Edward Huey, MD | Brown University | 401-455-6403 | edward_huey@brown.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 31, 2021 | Dec 6, 2023 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D057180 | Frontotemporal Dementia |
| ID | Term |
|---|---|
| D057174 | Frontotemporal Lobar Degeneration |
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D016651 | Lithium Carbonate |
| ID | Term |
|---|---|
| D002254 | Carbonates |
| D000468 | Alkalies |
| D007287 | Inorganic Chemicals |
| D002255 | Carbonic Acid |
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|
| Placebo | Drug | Placebo will be prescribed starting at 1 pill per day, with subsequent dose titration to 2,3, and 4 pills per day as tolerated by sham blood lithium levels. |
|
| 12 weeks |
| Presence of Adverse Events as Measured by the Treatment Emergent Symptoms Scale (TESS) | The tolerability of low-dose lithium by assessing emergent side effects over the course of the 12-week trial will be assessed. The side effects will be captured with TESS in which 30 symptoms are rated either "Absent," "Mild," "Moderate," or "Severe." The change in TESS score from baseline to week 12 will be observed. Total scores range from 0 to 96 with a higher score indicating a worse outcome. | 12 weeks |
| The Relationship Between Changes in Brain-derived Neurotropic Factor (BDNF) Serum Levels and Changes in NPI "Agitation/Aggression" Score | The baseline serum BDNF levels as a potential baseline predictor of lithium treatment response and an increase from pre to post-treatment BDNF levels as a potential biomarker correlate of improvement in symptoms (as measured by the NPI) will be explored. The mean change of NPI "Agitation/Aggression" score as a function of BDNF level change from baseline to 12 weeks will be reported. Scores range from from 0-12, with 0 being no symptoms and 12 being very frequent and severe symptoms. | Baseline and 12 weeks |
| The Relationship Between Changes in Brain-derived Neurotropic Factor (BDNF) Serum Levels and Changes in NPI "Aberrant Motor Behavior" Score | The baseline serum BDNF levels as a potential baseline predictor of lithium treatment response and an increase from pre to post-treatment BDNF levels as a potential biomarker correlate of improvement in symptoms (as measured by the NPI) will be explored. Aberrant motor behavior is characterized by repetitive movements and inability to sit still. The mean change of NPI Aberrant Motor Behavior score as a function of BDNF level change from baseline to 12 weeks will be reported. Scores range from from 0-12, with 0 being no symptoms and 12 being very frequent and severe symptoms. | Baseline and 12 weeks |
| BG001 | Placebo | Placebo will be prescribed starting at 1 pill per day, with subsequent dose titration to 2,3, and 4 pills per day as tolerated by sham blood lithium levels provided by an unblinded study team member. Placebo: Placebo will be prescribed starting at 1 pill per day, with subsequent dose titration to 2,3, and 4 pills per day as tolerated by sham blood lithium levels. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Lithium will be prescribed starting at 150 mg/day, with subsequent dose titration to 300, 450, and 600 mg/day as tolerated according to side effects and blood lithium level.
Lithium Carbonate: Lithium will be prescribed starting at 150 mg/day, with subsequent dose titration to 300, 450, and 600 mg/day as tolerated according to side effects and blood lithium level.
| OG001 | Placebo | Placebo will be prescribed starting at 1 pill per day, with subsequent dose titration to 2,3, and 4 pills per day as tolerated by sham blood lithium levels provided by an unblinded study team member. Placebo: Placebo will be prescribed starting at 1 pill per day, with subsequent dose titration to 2,3, and 4 pills per day as tolerated by sham blood lithium levels. |
|
|
| Secondary | Number of Responders in the Lithium and Placebo Groups | Responder defined as a 30% decrease in NPI core score (sum of domain scores for "Agitation/Aggression" and "Aberrant Motor Behavior") plus a Clinical Global Impression (CGI) Change score of much improved or very much improved (CGI based on these behavioral symptoms only). | Posted | Number | participants | 12 weeks |
|
|
|
| Other Pre-specified | Change in Motor Symptoms as Measured by the NPI | NPI domain "Aberrant Motor Behaviors" will be observed to test the effect of lithium on repetitive behaviors as compared to placebo, by examining whether participants taking lithium show a greater reduction in their "Aberrant Motor Behaviors" NPI domain score. Scores range from from 0-12, with 0 being no symptoms and 12 being very frequent and severe symptoms. | Posted | Mean | Standard Error | score on a scale | 12 weeks |
|
|
|
| Other Pre-specified | Presence of Adverse Events as Measured by the Treatment Emergent Symptoms Scale (TESS) | The tolerability of low-dose lithium by assessing emergent side effects over the course of the 12-week trial will be assessed. The side effects will be captured with TESS in which 30 symptoms are rated either "Absent," "Mild," "Moderate," or "Severe." The change in TESS score from baseline to week 12 will be observed. Total scores range from 0 to 96 with a higher score indicating a worse outcome. | Posted | Mean | Standard Error | score on a scale | 12 weeks |
|
|
|
| Other Pre-specified | The Relationship Between Changes in Brain-derived Neurotropic Factor (BDNF) Serum Levels and Changes in NPI "Agitation/Aggression" Score | The baseline serum BDNF levels as a potential baseline predictor of lithium treatment response and an increase from pre to post-treatment BDNF levels as a potential biomarker correlate of improvement in symptoms (as measured by the NPI) will be explored. The mean change of NPI "Agitation/Aggression" score as a function of BDNF level change from baseline to 12 weeks will be reported. Scores range from from 0-12, with 0 being no symptoms and 12 being very frequent and severe symptoms. | Posted | Mean | Standard Error | score on a scale | Baseline and 12 weeks |
|
|
|
| Other Pre-specified | The Relationship Between Changes in Brain-derived Neurotropic Factor (BDNF) Serum Levels and Changes in NPI "Aberrant Motor Behavior" Score | The baseline serum BDNF levels as a potential baseline predictor of lithium treatment response and an increase from pre to post-treatment BDNF levels as a potential biomarker correlate of improvement in symptoms (as measured by the NPI) will be explored. Aberrant motor behavior is characterized by repetitive movements and inability to sit still. The mean change of NPI Aberrant Motor Behavior score as a function of BDNF level change from baseline to 12 weeks will be reported. Scores range from from 0-12, with 0 being no symptoms and 12 being very frequent and severe symptoms. | Posted | Mean | Standard Error | score on a scale | Baseline and 12 weeks |
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|
| 0 |
| 9 |
| 2 |
| 9 |
| 0 |
| 9 |
| EG001 | Placebo | Placebo will be prescribed starting at 1 pill per day, with subsequent dose titration to 2,3, and 4 pills per day as tolerated by sham blood lithium levels provided by an unblinded study team member. Placebo: Placebo will be prescribed starting at 1 pill per day, with subsequent dose titration to 2,3, and 4 pills per day as tolerated by sham blood lithium levels. | 0 | 7 | 0 | 7 | 0 | 7 |
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| D009422 | Nervous System Diseases |
| D057177 | TDP-43 Proteinopathies |
| D019636 | Neurodegenerative Diseases |
| D057165 | Proteostasis Deficiencies |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D017554 |
| Carbon Compounds, Inorganic |
| D018020 | Lithium Compounds |