Alzheimer DiseasePhase 2NCT00088387
Effect of Lithium and Divalproex in Alzheimer's Disease
A Phase 2 study testing Divalproex and Lithium in people with Alzheimer Disease, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Alzheimer Disease
- What is being tested?
- Divalproex and Lithium
- How many people
- 35 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2004to Mar 2005
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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);
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institute of Neurological Disorders and Stroke (NINDS)
Bethesda, Maryland, 20892
About this study
Official title: Glycogen Synthetase Kinase 3 (GSK-3) Inhibition in Alzheimer's Disease
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.
Read more
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.
Read the 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.
- Conditions
- Alzheimer Disease
- Being tested
- Divalproex, Lithium
- Keywords
- Tau, T181, T231, Amyloid Beta, Beta-Catenin, Alzheimer Disease, AD
- Medical subject headings
- Alzheimer Disease, Pick Disease of the Brain, Plaque, Amyloid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DivalproexDrug
LithiumDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jul 2004 (estimated)
- Study startJul 2004
- Study completionMar 2005
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Alzheimer DiseaseStudies of the same condition, open and under way.
- More trials run by National Institute of Neurological Disorders and Stroke (NINDS)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Enrolment
- 35 participants
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00088387
- Sponsor's protocol ID
- 040243
- Other IDs
- 04-N-0243
- Status last verified
- Mar 2005
- First submitted
- 23 Jul 2004
- Last updated
- 4 Mar 2008
- Results posted
- No
Publications
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.
PubMed 12677073Knopman D. Pharmacotherapy for Alzheimer's disease: 2002. Clin Neuropharmacol. 2003 Mar-Apr;26(2):93-101. doi: 10.1097/00002826-200303000-00009.
PubMed 12671529Arai 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.
PubMed 7574462
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Glycogen Synthetase Kinase 3 (GSK-3) Inhibition in Alzheimer's Disease
- ClinicalTrials.gov ID
- NCT00088387
- Acronym / sponsor ID
- 040243
- Conditions
- Alzheimer Disease
- Keywords
- Tau, T181, T231, Amyloid Beta, Beta-Catenin, Alzheimer Disease, AD
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 35 participants
- Lead sponsor
- National Institute of Neurological Disorders and Stroke (NINDS)US National Institutes of Health
- Study start
- Jul 2004
- Study completion
- Mar 2005
- First posted
- 26 Jul 2004 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (24 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Divalproex | Drug | – |
| Lithium | Drug | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Mar 2008.
- Background: PubMed 12677073Bloom 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.
- Background: PubMed 12671529Knopman D. Pharmacotherapy for Alzheimer's disease: 2002. Clin Neuropharmacol. 2003 Mar-Apr;26(2):93-101. doi: 10.1097/00002826-200303000-00009.
- Background: PubMed 7574462Arai 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Divalproex and Lithium in people with Alzheimer Disease, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Mar 2008. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00088387, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Mar 2008.