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

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ClinicalTrials.gov Identifier: NCT02862210
Recruitment Status : Recruiting
First Posted : August 10, 2016
Last Update Posted : August 19, 2019
Sponsor:
Collaborator:
Alzheimer's Drug Discovery Foundation
Information provided by (Responsible Party):
Edward D Huey, MD, Columbia University

Tracking Information
First Submitted Date  ICMJE August 7, 2016
First Posted Date  ICMJE August 10, 2016
Last Update Posted Date August 19, 2019
Actual Study Start Date  ICMJE January 27, 2017
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 15, 2019)
Change in agitation and aggression as measured by the Neuropsychiatric Inventory Scale (NPI) [ Time Frame: 12 weeks ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 9, 2016)
  • Reduction in agitation as measured by the NPI scale [ Time Frame: 12 weeks ]
  • Reduction in aggression as measured by the NPI scale [ Time Frame: 12 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 18, 2017)
Proportion of responders in the lithium and placebo groups [ Time Frame: 12 weeks ]
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).
Original Secondary Outcome Measures  ICMJE
 (submitted: August 9, 2016)
Number of adverse events [ Time Frame: 12 weeks ]
Current Other Pre-specified Outcome Measures
 (submitted: August 15, 2019)
  • Change in motor symptoms as measured by the NPI [ Time Frame: 12 weeks ]
    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.
  • Presence of adverse events as measured by the Treatment Emergent Symptoms Scale (TESS) [ Time Frame: 12 weeks ]
    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.
  • The relationship between changes in brain-derived neurotropic factor (BDNF) serum levels and changes in NPI "Agitation/Aggression" score and "Aberrant Motor Behavior" score [ Time Frame: 12 weeks ]
    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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia
Official Title  ICMJE Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Frontotemporal Dementia (FTD)
Intervention  ICMJE
  • Drug: 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.
    Other Name: Lithobid
  • Drug: 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.
Study Arms  ICMJE
  • Experimental: 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.
    Intervention: Drug: Lithium Carbonate
  • Placebo Comparator: 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.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 9, 2016)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Hannah Silverman 212-305-6284 hs2971@cumc.columbia.edu
Contact: Edward D. Huey, MD 212-305-1134 edh2126@columbia.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02862210
Other Study ID Numbers  ICMJE NYSPI 7310
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Edward D Huey, MD, Columbia University
Study Sponsor  ICMJE Columbia University
Collaborators  ICMJE Alzheimer's Drug Discovery Foundation
Investigators  ICMJE
Principal Investigator: Edward Huey, MD Columbia University
PRS Account Columbia University
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP