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Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia (Lithium)

Primary Purpose

Frontotemporal Dementia (FTD)

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Lithium Carbonate

Placebo

About this trial

This is an interventional treatment trial for Frontotemporal Dementia (FTD) focused on measuring Lithium, Lithium Carbonate

Eligibility Criteria

40 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age 40-85
A diagnosis of behavioral variant FTD (bv-FTD) or semantic variant Primary Progressive Aphasia (sv-PPA, which is generally accompanied by a behavioral syndrome), or agrammatic/non-fluent Primary Progressive Aphasia (nfv-PPA) with behavioral symptoms
Neuropsychiatric Inventory (NPI) agitation/aggression subscale score ≥4 or disinhibition subscale score ≥ 4 or repetitive behavior subscale ≥ 4 or total score ≥ 6. On each subscale, a score higher than 4 represents moderate to severe symptoms
Folstein Mini-Mental State Examination (MMSE) score 5-26/30
An study partner (usually a family member) is required to provide information during interviews about the patient
Capacity to consent. Subjects without capacity to consent must have capacity to appoint a surrogate
Structural MRI or CT scan after symptom onset

Exclusion Criteria:

Medical contraindication or history of intolerability to lithium, falls in the last month, current abnormal thyroid functions (T3, T4 or thyroid stimulating hormone (TSH); treated hypothyroidism with normal thyroid function tests will not lead to exclusion), creatinine level > 1.5 mg/100 ml or glomerular filtration rate < 44 ml/min/1.73m2 will also lead to exclusion
The diagnosis of bipolar disorder or schizophrenia or schizoaffective disorder
Alcohol or substance use disorder in the prior 6 months
Current diagnosis of other major neurological disorder, e.g., Alzheimer's Disease (AD), stroke with residual clinical deficits, multiple sclerosis, Parkinson's disease. Subjects with MRI or CT evidence of cerebrovascular disease but without clinical signs of stroke will be included
Sitting blood pressure > 150/90 mm Hg, unstable cardiac disease, severe or unstable medical illness
Use of medications, including diuretics, known to have adverse effects when combined with lithium. Use of antipsychotic medications will be permitted
Current major depression or suicidality or dangerous behavior with risk of harm to self and others
Corrected QT interval (QTc) interval > 460 ms at the time of baseline electrocardiogram (EKG)
Woman of child-bearing potential

Sites / Locations

Columbia University Irving Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Lithium carbonate

Placebo

Arm Description

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 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.

Outcomes

Primary Outcome Measures

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). Thus, in each domain a patient can score from 0-12, with 0 being no symptoms and 12 being very frequent and severe symptoms. The study aims to test that lithium will significantly reduce 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.

Secondary Outcome Measures

Proportion of responders in the lithium and placebo groups

Response requires 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).

Full Information

NCT ID

NCT02862210

First Posted

August 7, 2016

Last Updated

December 15, 2022

Sponsor

Columbia University

Collaborators

Alzheimer's Drug Discovery Foundation

1. Study Identification

Unique Protocol Identification Number

NCT02862210

Brief Title

Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia

Acronym

Lithium

Official Title

Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Completed

Study Start Date

January 27, 2017 (Actual)

Primary Completion Date

November 20, 2022 (Actual)

Study Completion Date

November 20, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Columbia University

Collaborators

Alzheimer's Drug Discovery Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed Description

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 the study 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Frontotemporal Dementia (FTD)

Keywords

Lithium, Lithium Carbonate

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

17 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Lithium carbonate

Arm Type

Experimental

Arm Description

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.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Lithium Carbonate

Other Intervention Name(s)

Lithobid

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

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.

Primary Outcome Measure Information:

Title

Change in agitation and aggression as measured by the Neuropsychiatric Inventory Scale (NPI)

Description

Time Frame

12 weeks

Secondary Outcome Measure Information:

Title

Proportion of responders in the lithium and placebo groups

Description

Time Frame

12 weeks

Other Pre-specified Outcome Measures:

Title

Change in motor symptoms as measured by the NPI

Description

NPI domain "Aberrant Motor Behaviors" will be observed to test that lithium will significantly reduce repetitive behaviors as compared to placebo, by examining whether participants taking lithium show a greater reduction in their "Aberrant Motor Behaviors" NPI domain score.

Time Frame

12 weeks

Title

Presence of adverse events as measured by the Treatment Emergent Symptoms Scale (TESS)

Description

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.

Time Frame

12 weeks

Title

The relationship between changes in brain-derived neurotropic factor (BDNF) serum levels and changes in NPI "Agitation/Aggression" score and "Aberrant Motor Behavior" score

Description

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.

Time Frame

12 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age 40-85 A diagnosis of behavioral variant FTD (bv-FTD) or semantic variant Primary Progressive Aphasia (sv-PPA, which is generally accompanied by a behavioral syndrome), or agrammatic/non-fluent Primary Progressive Aphasia (nfv-PPA) with behavioral symptoms Neuropsychiatric Inventory (NPI) agitation/aggression subscale score ≥4 or disinhibition subscale score ≥ 4 or repetitive behavior subscale ≥ 4 or total score ≥ 6. On each subscale, a score higher than 4 represents moderate to severe symptoms Folstein Mini-Mental State Examination (MMSE) score 5-26/30 An study partner (usually a family member) is required to provide information during interviews about the patient Capacity to consent. Subjects without capacity to consent must have capacity to appoint a surrogate Structural MRI or CT scan after symptom onset Exclusion Criteria: Medical contraindication or history of intolerability to lithium, falls in the last month, current abnormal thyroid functions (T3, T4 or thyroid stimulating hormone (TSH); treated hypothyroidism with normal thyroid function tests will not lead to exclusion), creatinine level > 1.5 mg/100 ml or glomerular filtration rate < 44 ml/min/1.73m2 will also lead to exclusion The diagnosis of bipolar disorder or schizophrenia or schizoaffective disorder Alcohol or substance use disorder in the prior 6 months Current diagnosis of other major neurological disorder, e.g., Alzheimer's Disease (AD), stroke with residual clinical deficits, multiple sclerosis, Parkinson's disease. Subjects with MRI or CT evidence of cerebrovascular disease but without clinical signs of stroke will be included Sitting blood pressure > 150/90 mm Hg, unstable cardiac disease, severe or unstable medical illness Use of medications, including diuretics, known to have adverse effects when combined with lithium. Use of antipsychotic medications will be permitted Current major depression or suicidality or dangerous behavior with risk of harm to self and others Corrected QT interval (QTc) interval > 460 ms at the time of baseline electrocardiogram (EKG) Woman of child-bearing potential

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Edward Huey, MD

Organizational Affiliation

Columbia University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Columbia University Irving Medical Center

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia

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