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Trial record 5 of 6 for:    "Alzheimer Disease" | "Lithium carbonate"

Lithium As a Treatment to Prevent Impairment of Cognition in Elders (LATTICE)

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ClinicalTrials.gov Identifier: NCT03185208
Recruitment Status : Recruiting
First Posted : June 14, 2017
Last Update Posted : January 31, 2019
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Ariel Gildengers, University of Pittsburgh

Brief Summary:
Alzheimer's disease (AD) is the most common cause of dementia in adults 65 years and older. AD leads to a complete loss of memory and independent function, and presently there is no cure. Many studies suggest that lithium treatment may delay dementia onset or slow its progression. However, more research is needed to understand the extent of its anti-dementia properties if it will be deployed broadly in the general population. This study will examine whether lithium has anti-dementia properties in older adults who have mild cognitive impairment and are at risk of becoming demented.

Condition or disease Intervention/treatment Phase
Mild Cognitive Impairment Drug: Lithium Carbonate Drug: Placebo oral capsule Phase 4

Detailed Description:
Alzheimer's disease (AD) is the most common cause of dementia in adults 65 years and older. Unchecked, the disease will reach epidemic proportions in the United States and worldwide by 2050, and presently, there is no intervention that has shown a clear effect on AD progression. Over the past several years, there has been increasing interest in re-purposing the use of lithium for diseases involving neurodegeneration. Lithium treatment has been associated with neurogenesis in the hippocampus, up-regulation of important neurotrophic factors such as B-cell lymphoma 2 (Bcl-2) and brain-derived neurotrophic factor (BDNF), and inhibition of glycogen synthase kinase 3 (GSK-3) isoforms α and β. In particular, GSK-3α interacts with gamma-secretase playing a critical role in the conversion of amyloid precursor protein (APP) to amyloid-beta (Aβ); lithium has been shown to reduce Aβ production and memory deficits in AD transgenic mouse models. GSK-3β phosphorylates tau, a critical step in the formation of neurofibrillary tangles, and lithium has been shown to reduce tau phosphorylation in vivo and in vitro. That lithium may alter the AD trajectory is supported by numerous observational reports showing delay of dementia onset in those treated with it. However, the results of the few human lithium trials conducted have been mixed. Additional research is needed to determine whether lithium has a role as an anti-dementia agent. In contrast to previous studies, we will implement an Randomized Controlled Trial (RCT) with a more integrative, comprehensive approach than done before involving state-of-the-art ultra-high field (7T) human Magnetic Resonance Imaging (MRI), neurocognitive assessment, and blood- and Cerebrospinal Fluid (CSF)- based biomarker measurement to investigate the role of lithium as an anti-dementia agent. The specific aim of this pilot-feasibility study is to examine the potential disease modifying properties of lithium in individuals with mild cognitive impairment (MCI) in delaying conversion to dementia. The study will enroll and randomly assign 80 individuals 60 years and older with MCI to take lithium, titrated to a maximally tolerated blood level (0.5 to 0.8 meq/L), or placebo for two years to assess lithium's effects on preserving cognition and delaying conversion to dementia. Participants will receive annual neurocognitive assessment, blood- and CSF-based biomarker measurement, and 7T MRI of structural brain volumes (e.g., hippocampal, total cortical gray). At baseline, all subjects who are able will undergo Positron Emission Tomography (PET) imaging for Aβ. The following hypotheses will be tested: H1: a) Participants randomized to take lithium for two years, compared to placebo, will better maintain cognitive function, primarily in memory, which b) will be associated with changes in biomarkers (e.g., GSK-3β, BDNF). H2: a) Participants randomized to take lithium, compared to placebo, will have larger hippocampal volumes and lower total gray matter thinning, which b) will be associated with changes in biomarkers and c) better cognitive function, primarily in memory. The exploratory aim examines whether lithium is related to additional markers of enhanced brain integrity (e.g., lower level of microbleeds, higher white matter integrity, better network connectivity, or decreased CSF phospho tau levels).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Longitudinal, randomized, double-blind, placebo-controlled experimental trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Participants, investigators (who will also be prescribers/care providers), and both clinical and cognitive raters will be blind to treatment. A non-blind physician not providing care or ratings will receive real and generate false blood levels to communicate to other investigators for the purpose of titration of the lithium/placebo. Measures for emergency unblinding will be available as well for safety.
Primary Purpose: Prevention
Official Title: Evaluation of Brain and Cognitive Changes in Older Adults With MCI Taking Lithium to Prevent Alzheimer Type Dementia
Actual Study Start Date : September 1, 2017
Estimated Primary Completion Date : March 31, 2022
Estimated Study Completion Date : March 31, 2022


Arm Intervention/treatment
Experimental: Lithium carbonate
Lithium carbonate will be initiated at 150 mg per day and increased based on blood levels until a steady blood level between 0.6 and 0.8 meq/L is achieved. Participants will continue at the dose achieved for 2 years with quarterly monitoring.
Drug: Lithium Carbonate
See lithium carbonate arm

Placebo Comparator: placebo
Matching placebo will be initiated and increased based on pretend blood levels. Participants will take placebo for 2 years with quarterly monitoring.
Drug: Placebo oral capsule
See placebo arm




Primary Outcome Measures :
  1. Change from baseline cognitive testing measures over 2 years [ Time Frame: At baseline and annually for 2 years ]
    Preclinical Alzheimer Cognitive Composite composed of Memory and other cognitive tests

  2. Change from baseline biomarker values over 2 years [ Time Frame: At baseline and annually for 2 years ]
    GSK-3β activity, BDNF

  3. Change from baseline brain volume values over 2 years as measured by structural imaging (7T MRI) [ Time Frame: At baseline and annually for 2 years ]
    Total volume, Grey & White matter volume, regional volumes


Secondary Outcome Measures :
  1. Change from baseline brain integrity measures over 2 years as measured by structural imaging (7T MRI) [ Time Frame: At baseline and annually for 2 years ]
    lower level of microbleeds, higher white matter integrity, better network connectivity

  2. Change from baseline cerebrospinal phospho tau levels over 2 years [ Time Frame: At baseline and annually for 2 years ]
    CSF



Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 60 years or older
  2. Diagnosis of Mild Cognitive Impairment

Exclusion Criteria:

  1. Major psychiatric illness (mild psychiatric illness may be included)
  2. Major neurologic illness (e.g., multiple sclerosis)
  3. Contraindication to lithium (e.g., renal insufficiency)
  4. Unable to complete neuropsychological testing due to non-remediable impairment (e.g., blindness)

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): NCT03185208


Contacts
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Contact: James Emanuel 412-246-6004 emanuelje@upmc.edu
Contact: Isaac Delozier 412-246-6487 delozierij@upmc.edu

Locations
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United States, Pennsylvania
University of Pittsburgh Medical Center Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: James Emanuel    412-246-6004    emanuelje@upmc.edu   
Contact: Isaac Delozier    412-246-6487    delozierij@upmc.edu   
Principal Investigator: Ariel Gildengers, MD         
Sponsors and Collaborators
Ariel Gildengers
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Ariel Gildengers, MD University of Pittsburgh

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Responsible Party: Ariel Gildengers, Associate Professor of Psychiatry, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT03185208     History of Changes
Other Study ID Numbers: PRO17030527
R01AG055389-01 ( U.S. NIH Grant/Contract )
First Posted: June 14, 2017    Key Record Dates
Last Update Posted: January 31, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Deidentified participant data will be shared with the National Cell Repository for Alzheimer's Disease (NCRAD).

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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.: Yes
Keywords provided by Ariel Gildengers, University of Pittsburgh:
Lithium
Alzheimer's Disease
Mild Cognitive Impairment
MCI
Dementia
Alzheimer
Cognition
Memory
Thinking
Prevention
amyloid
imaging
MRI
PET
tau
plaques
tangles
Additional relevant MeSH terms:
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Lithium Carbonate
Cognitive Dysfunction
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Antidepressive Agents
Psychotropic Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs