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Effect of Lithium and Divalproex in Alzheimer's Disease

Primary Purpose

Alzheimer Disease

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Divalproex
Lithium
Sponsored by
National Institute of Neurological Disorders and Stroke (NINDS)
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alzheimer Disease focused on measuring Tau, T181, T231, Amyloid Beta, Beta-Catenin, Alzheimer Disease, AD

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA: Patient is between the ages of 40 and 90 (inclusive). Patient will have a diagnosis of AD; the study will be confined to patients who are able to provide consent (pass a capacity assessment). The modified Hachinski Ischemia Score must be less than 4. Brain MRI performed within 15 months of enrollment must be compatible with the diagnosis of AD. Patient and/or caregiver are willing to adhere to protocol requirements as evidenced by written, informed consent. EXCLUSION CRITERIA: Patients meeting any of the following exclusion criteria during screening or during the study will not be enrolled or will be immediately excluded from the study, as appropriate: Patient has a history of any medical condition that can reasonably be expected to subject the patient to unwarranted risk. Patient has clinically significant laboratory abnormalities that would preclude administration of lithium and divalproex. Patient is taking a prohibited concomitant medication. The following medications are forbidden for at least one month prior to the treatment phase (unless otherwise noted) and during the course of the study: Any investigational drugs; Anti-depressants (eligibility will be considered as long as dosage remains stable throughout the study); Anticonvulsants and other mood stabilizing drugs; Treatment that may provoke lithium toxicity due to reduced renal clearance, including metronidazole, spectinomycin, tetracycline; Treatment that may substantially increase steady-state plasma lithium levels resulting in lithium toxicity, including angiotensin-converting enzyme inhibitors, NSAIDS, diuretics; Treatment that may increase the risk of neurotoxicity, including calcium channel blocking agents; Drugs that may increase urinary lithium excretion resulting in lower serum lithium concentrations, such as acetazolamide, urea, xanthine preparations, alkalinizing agents such as sodium bicarbonate, theophylline; Drugs that interact with lithium, including methyldopa; Neuroleptics (eligibility will be considered as long as dosage remains stable throughout the study). If patient is on existing atypical neuroleptic drugs, these will be continued at the same dose. Patients will not start a new prescription for atypical antipsychotics during the study; Drugs that may prolong the effects of lithium, including neuromuscular blocking agents; Digoxin, warfarin. Patient has not been using an adequate contraceptive method for the last 30 days or unwilling to continue contraception throughout the study, or is not at least one year post-menopausal (if female). Patient is pregnant or breastfeeding. Patient has participated in a clinical study with an investigational drug within the last 30 days. Patient has a condition (such as active drug or alcohol abuse) that, in the opinion of the investigators, would interfere with compliance or safety. Patient has known hypersensitivity to lithium or divalproex. Patient's inability to swallow tablets or to comply with medication schedule. Patient has no adequate caregiver. Patient and/or caregiver are unwilling to sign an informed consent or to comply with protocol requirements. Patient is unwilling to have lumbar puncture.

Sites / Locations

  • National Institute of Neurological Disorders and Stroke (NINDS)

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

First Posted
July 23, 2004
Last Updated
March 3, 2008
Sponsor
National Institute of Neurological Disorders and Stroke (NINDS)
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1. Study Identification

Unique Protocol Identification Number
NCT00088387
Brief Title
Effect of Lithium and Divalproex in Alzheimer's Disease
Official Title
Glycogen Synthetase Kinase 3 (GSK-3) Inhibition in Alzheimer's Disease
Study Type
Interventional

2. Study Status

Record Verification Date
March 2005
Overall Recruitment Status
Completed
Study Start Date
July 2004 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
March 2005 (undefined)

3. Sponsor/Collaborators

Name of the Sponsor
National Institute of Neurological Disorders and Stroke (NINDS)

4. Oversight

5. Study Description

Brief Summary
This study will examine the effect of the drugs lithium and divalproex (Depakote) on tau proteins, a type of protein in the brain and spinal fluid that are altered in patients with Alzheimer's disease. Both drugs are approved by the Food and Drug Administration to treat mood disorders, and both have been shown in animal studies to decrease the amount of altered tau protein. This study will determine whether lithium alone or in combination with divalproex reduces the altered tau protein in the spinal fluid of patients with Alzheimer's disease. Patients with Alzheimer's disease who are between 40 and 90 years of age may be eligible for this study. Candidates are screened with a medical history and physical examination, neurologic and neuropsychological evaluation, blood and urine tests, electrocardiogram (EKG), and, if needed, a magnetic resonance imaging (MRI) scan of the brain. Participants undergo the following tests and procedures: Drug treatment: Patients take study drugs for 6 weeks. Weekly clinic visits: Patients come to the clinic once a week for a physical examination, blood and urine tests, a review of drug side effects, and to receive the next week's supply of medications. Lumbar puncture (spinal tap): Patients have a lumbar puncture at study weeks 2, 4, and 6 to measure various brain chemicals and tau proteins in the cerebrospinal fluid (CSF), which bathes the brain and spinal cord. For this test, a local anesthetic is given and a needle is inserted in the space between the bones in the lower back where the CSF circulates below the spinal cord. A small amount of fluid is collected through the needle. Follow-up visit: Two weeks after completing the study medication, patients return to the clinic for a final evaluation, including a physical examination and blood and urine tests.
Detailed Description
The overall objective of this study is to examine the acute effects of lithium alone and/or in combination with divalproex on surrogate measures of neuroprotective activity in patients with Alzheimer's disease. It is hypothesized that at safe and tolerable doses these drugs will inhibit glycogen synthase kinase-3 activity and reduce the phosphorylated tau epitopes threonine-181 and threonine-231 implicated in the pathogenesis of this disorder. In this proof-of-principle study, efficacy on reducing tau phosphorylated epitopes will be assessed through cerebrospinal fluid (CSF) measurements. Safety will be monitored by means of frequent clinical evaluations and laboratory tests.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer Disease
Keywords
Tau, T181, T231, Amyloid Beta, Beta-Catenin, Alzheimer Disease, AD

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Enrollment
35 (false)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Divalproex
Intervention Type
Drug
Intervention Name(s)
Lithium

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: Patient is between the ages of 40 and 90 (inclusive). Patient will have a diagnosis of AD; the study will be confined to patients who are able to provide consent (pass a capacity assessment). The modified Hachinski Ischemia Score must be less than 4. Brain MRI performed within 15 months of enrollment must be compatible with the diagnosis of AD. Patient and/or caregiver are willing to adhere to protocol requirements as evidenced by written, informed consent. EXCLUSION CRITERIA: Patients meeting any of the following exclusion criteria during screening or during the study will not be enrolled or will be immediately excluded from the study, as appropriate: Patient has a history of any medical condition that can reasonably be expected to subject the patient to unwarranted risk. Patient has clinically significant laboratory abnormalities that would preclude administration of lithium and divalproex. Patient is taking a prohibited concomitant medication. The following medications are forbidden for at least one month prior to the treatment phase (unless otherwise noted) and during the course of the study: Any investigational drugs; Anti-depressants (eligibility will be considered as long as dosage remains stable throughout the study); Anticonvulsants and other mood stabilizing drugs; Treatment that may provoke lithium toxicity due to reduced renal clearance, including metronidazole, spectinomycin, tetracycline; Treatment that may substantially increase steady-state plasma lithium levels resulting in lithium toxicity, including angiotensin-converting enzyme inhibitors, NSAIDS, diuretics; Treatment that may increase the risk of neurotoxicity, including calcium channel blocking agents; Drugs that may increase urinary lithium excretion resulting in lower serum lithium concentrations, such as acetazolamide, urea, xanthine preparations, alkalinizing agents such as sodium bicarbonate, theophylline; Drugs that interact with lithium, including methyldopa; Neuroleptics (eligibility will be considered as long as dosage remains stable throughout the study). If patient is on existing atypical neuroleptic drugs, these will be continued at the same dose. Patients will not start a new prescription for atypical antipsychotics during the study; Drugs that may prolong the effects of lithium, including neuromuscular blocking agents; Digoxin, warfarin. Patient has not been using an adequate contraceptive method for the last 30 days or unwilling to continue contraception throughout the study, or is not at least one year post-menopausal (if female). Patient is pregnant or breastfeeding. Patient has participated in a clinical study with an investigational drug within the last 30 days. Patient has a condition (such as active drug or alcohol abuse) that, in the opinion of the investigators, would interfere with compliance or safety. Patient has known hypersensitivity to lithium or divalproex. Patient's inability to swallow tablets or to comply with medication schedule. Patient has no adequate caregiver. Patient and/or caregiver are unwilling to sign an informed consent or to comply with protocol requirements. Patient is unwilling to have lumbar puncture.
Facility Information:
Facility Name
National Institute of Neurological Disorders and Stroke (NINDS)
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
12677073
Citation
Bloom BS, de Pouvourville N, Straus WL. Cost of illness of Alzheimer's disease: how useful are current estimates? Gerontologist. 2003 Apr;43(2):158-64. doi: 10.1093/geront/43.2.158.
Results Reference
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PubMed Identifier
12671529
Citation
Knopman D. Pharmacotherapy for Alzheimer's disease: 2002. Clin Neuropharmacol. 2003 Mar-Apr;26(2):93-101. doi: 10.1097/00002826-200303000-00009.
Results Reference
background
PubMed Identifier
7574462
Citation
Arai H, Terajima M, Miura M, Higuchi S, Muramatsu T, Machida N, Seiki H, Takase S, Clark CM, Lee VM, et al. Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer's disease. Ann Neurol. 1995 Oct;38(4):649-52. doi: 10.1002/ana.410380414.
Results Reference
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Effect of Lithium and Divalproex in Alzheimer's Disease

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