Cognitive ImpairmentPhase 2NCT01055392
Disease-modifying Properties of Lithium in the Neurobiology of Alzheimer's Disease
A Phase 2 study testing Lithium Carbonate in people with Cognitive Impairment and Alzheimer Disease, run by University of Sao Paulo at 1 site in Brazil.
Trial summary
Lithium salts have been used for the treatment of psychiatric disorders for over five decades, mostly as a mood-stabilizing drug. Recent evidence points to the inhibition of the enzyme glycogen synthase kinase-3beta (GSK3) as one of its mechanisms of action. Read more about this study
- Who is it for?
- Ages 60 to 80 years
- Conditions the study is for
- Cognitive Impairment, Alzheimer Disease
- What is being tested?
- Lithium Carbonate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 80 participants
- Where
- 1 siteBrazil
- Study dates
- Mar 2007to Mar 2009
- 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 60 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- patients with amnestic mild cognitive impairment;
- age: 60 to 80 years-old;
Who cannot join
- sensory deficiencies that might preclude the administration of cognitive tests;
- active major psychiatry disorder;
- unstable clinical conditions such as cardiac insufficiency, uncontrolled diabetes mellitus, renal failure;
- previous use of lithium salts;
- concurrent participation in other clinical trial or intervention studies;
Trial locations and contacts
1 site in 1 country.
Brazil1 site
Institute of Psychiatry, Faculty of Medicine - University of Sao Paulo
São Paulo, São Paulo, 05403-010
About this study
Official title: Disease-modifying Properties of Lithium in the Neurobiology of Alzheimer's Disease: a Double-blind, Placebo-controlled Prevention Study in Elderly Patients With Mild Cognitive Impairment
Lithium salts have been used for the treatment of psychiatric disorders for over five decades, mostly as a mood-stabilizing drug. Recent evidence points to the inhibition of the enzyme glycogen synthase kinase-3beta (GSK3) as one of its mechanisms of action. The overactivity of this enzyme has been implicated in the pathogenesis of Alzheimer's disease (AD), given its involvement in mechanisms related to the hyperphosphorylation of Tau protein and the production of beta-amyloid peptide. These are key events leading respectively to the formation of neurofibrillary tangles and senile plaques, which are the neuropathological hallmarks of the disease. Several in vitro and animal studies have shown that the inhibition of GSK3 by lithium and other agents attenuates these pathological processes, reinforcing the notion that GSK3 is a likely target for future disease-modifying therapies for AD. Indeed, a recent study published by our group showed that chronic lithium use is associated with a decrement in the expected prevalence of dementia, in a sample of elderly individuals with bipolar disorder. To investigate this putative neuroprotective effect in a prospective way, the investigators started 24-month randomized, double-blinded controlled trial of lithium for the prevention of dementia in a sample of elderly individuals with amnestic mild cognitive impairment (MCI), a condition associated with increased risk for the development of AD. The clinical and biological outcomes of this trial include the attenuation of cognitive deficits, and the modification of certain biological markers of the disease (as measured in the cerebrospinal fluid, leukocytes and platelets). The objective of the present application is to enable the extension of this ongoing trial to an additional 2-year follow-up. A longer follow-up (48 months) will increase the statistical power to ascertain the primary outcome variables of this study, particularly the con-version from MCI to Alzheimer's disease. This will warrant a more consistent conclusion about the potential of lithium treatment in the prevention of dementia, in addition to a better evaluation of safety and tolerability profiles of the long-term use of lithium in older individuals.
- Conditions
- Cognitive Impairment, Alzheimer Disease
- Being tested
- Lithium Carbonate, Placebo
- Keywords
- mild cognitive impairment, Alzheimer's disease, Lithium, disease-modification, cognition, early Alzheimer's disease
- Medical subject headings
- Cognitive Dysfunction, Alzheimer Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lithium CarbonateDrug
lithium carbonate tablets, 150 mg to 450 mg (target serum lithium level 0.25 mEq/L - 0.5 mEq/L), divided in two doses, two years.
PlaceboDrug
Identical placebo tablets were administered twice-a-day for two years.
| Study group | Role | What they receive |
|---|---|---|
| Lithium | Experimental | Patients received low doses of lithium salts (from 150 mg to 450 mg of lithium salts daily) to achieve sub-therapeutic lithium levels (target serum lithium level of 0,25 - 0,5 mEq/L). Lithium doses were administered twice a day. Lithium doses were titrated to achieve the target serum lithium levels within the first two weeks after study recruitment. After achieving the target serum lithium level, lithium salts doses remained stable until the end of the study. Receives: Drug: Lithium Carbonate |
| Placebo | Placebo comparator | Identical placebo tablets were administered twice-a-day for two years. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
effect of lithium to delay progression of cognitive deficits in patients with amnestic MCI
Measured: two year
Secondary outcomes (2)
effect of lithium on CSF levels of Total Tau, Phosphorylated Tau and Amyloid-beta42
Measured: one year
the effect of lithium on the activity of GSK3β in platelets and leukocytes drawn from peripheral blood.
Measured: one year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jan 2010 (estimated)
- Study startMar 2007
- Primary completionMar 2009
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 Cognitive ImpairmentStudies of the same condition, open and under way.
- More trials run by University of Sao PauloThe 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
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Sao Paulo
- Sponsor type
- University, hospital or other
- Investigators
- Orestes V Forlenza, Ph.D., Principal investigator, Department and Institute of Psychiatry, Faculty of Medicine - University of Sao PauloWagner F Gattaz, Ph.D., Study director, Department and Institute of Psychiatry, Faculty of Medicine - University of Sao Paulo
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01055392
- Sponsor's protocol ID
- OVForlenza-Lithium
- Other IDs
- 554535/2005-0
- Status last verified
- Dec 2009
- First submitted
- 22 Jan 2010
- Last updated
- 25 Jan 2010
- Results posted
- No
- Data monitoring committee
- No
Publications
Forlenza OV, Radanovic M, Talib LL, Gattaz WF. Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial. Br J Psychiatry. 2019 Nov;215(5):668-674. doi: 10.1192/bjp.2019.76.
PubMed 30947755Aprahamian I, Santos FS, dos Santos B, Talib L, Diniz BS, Radanovic M, Gattaz WF, Forlenza OV. Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension. J Clin Psychiatry. 2014 Jul;75(7):e672-8. doi: 10.4088/JCP.13m08741.
PubMed 25093483Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011 May;198(5):351-6. doi: 10.1192/bjp.bp.110.080044.
PubMed 21525519
Study at a glance
From the registry record, last updated by the sponsor on 25 Jan 2010. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Disease-modifying Properties of Lithium in the Neurobiology of Alzheimer's Disease: a Double-blind, Placebo-controlled Prevention Study in Elderly Patients With Mild Cognitive Impairment
- ClinicalTrials.gov ID
- NCT01055392
- Acronym / sponsor ID
- OVForlenza-Lithium
- Conditions
- Cognitive Impairment, Alzheimer Disease
- Keywords
- mild cognitive impairment, Alzheimer's disease, Lithium, disease-modification, cognition, early Alzheimer's disease
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- University of Sao PauloUniversity, hospital or other
- Study start
- Mar 2007
- Primary completion
- Mar 2009 (actual)
- First posted
- 25 Jan 2010 (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.
Lithium salts have been used for the treatment of psychiatric disorders for over five decades, mostly as a mood-stabilizing drug. Recent evidence points to the inhibition of the enzyme glycogen synthase kinase-3beta (GSK3) as one of its mechanisms of action. The overactivity of this enzyme has been implicated in the pathogenesis of Alzheimer's disease (AD), given its involvement in mechanisms related to the hyperphosphorylation of Tau protein and the production of beta-amyloid peptide. These are key events leading respectively to the formation of neurofibrillary tangles and senile plaques, which are the neuropathological hallmarks of the disease. Several in vitro and animal studies have shown that the inhibition of GSK3 by lithium and other agents attenuates these pathological processes, reinforcing the notion that GSK3 is a likely target for future disease-modifying therapies for AD. Indeed, a recent study published by our group showed that chronic lithium use is associated with a decrement in the expected prevalence of dementia, in a sample of elderly individuals with bipolar disorder. To investigate this putative neuroprotective effect in a prospective way, the investigators started 24-month randomized, double-blinded controlled trial of lithium for the prevention of dementia in a sample of elderly individuals with amnestic mild cognitive impairment (MCI), a condition associated with increased risk for the development of AD. The clinical and biological outcomes of this trial include the attenuation of cognitive deficits, and the modification of certain biological markers of the disease (as measured in the cerebrospinal fluid, leukocytes and platelets). The objective of the present application is to enable the extension of this ongoing trial to an additional 2-year follow-up. A longer follow-up (48 months) will increase the statistical power to ascertain the primary outcome variables of this study, particularly the con-version from MCI to Alzheimer's disease. This will warrant a more consistent conclusion about the potential of lithium treatment in the prevention of dementia, in addition to a better evaluation of safety and tolerability profiles of the long-term use of lithium in older individuals.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Lithium | Experimental | Drug: Lithium CarbonatePatients received low doses of lithium salts (from 150 mg to 450 mg of lithium salts daily) to achieve sub-therapeutic lithium levels (target serum lithium level of 0,25 - 0,5 mEq/L). Lithium doses were administered twice a day. Lithium doses were titrated to achieve the target serum lithium levels within the first two weeks after study recruitment. After achieving the target serum lithium level, lithium salts doses remained stable until the end of the study. |
| Placebo | Placebo comparator | Drug: PlaceboIdentical placebo tablets were administered twice-a-day for two years. |
Who may qualify
- Ages
- 60 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- patients with amnestic mild cognitive impairment;
- age: 60 to 80 years-old;
Key exclusion criteria (5 listed)
- sensory deficiencies that might preclude the administration of cognitive tests;
- active major psychiatry disorder;
- unstable clinical conditions such as cardiac insufficiency, uncontrolled diabetes mellitus, renal failure;
- previous use of lithium salts;
- concurrent participation in other clinical trial or intervention studies;
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 |
|---|---|---|
| Lithium Carbonatelithium carbonate tablets, 150 mg to 450 mg (target serum lithium level 0.25 mEq/L - 0.5 mEq/L), divided in two doses, two years. | Drug | Lithium |
| PlaceboIdentical placebo tablets were administered twice-a-day for two years. | Drug | Placebo |
Primary outcome
effect of lithium to delay progression of cognitive deficits in patients with amnestic MCI
Time frame: two year
2 secondary outcomes
effect of lithium on CSF levels of Total Tau, Phosphorylated Tau and Amyloid-beta42
Time frame: one year
the effect of lithium on the activity of GSK3β in platelets and leukocytes drawn from peripheral blood.
Time frame: one year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jan 2010.
- Derived from this study: PubMed 30947755Forlenza OV, Radanovic M, Talib LL, Gattaz WF. Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial. Br J Psychiatry. 2019 Nov;215(5):668-674. doi: 10.1192/bjp.2019.76.
- Derived from this study: PubMed 25093483Aprahamian I, Santos FS, dos Santos B, Talib L, Diniz BS, Radanovic M, Gattaz WF, Forlenza OV. Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension. J Clin Psychiatry. 2014 Jul;75(7):e672-8. doi: 10.4088/JCP.13m08741.
- Derived from this study: PubMed 21525519Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011 May;198(5):351-6. doi: 10.1192/bjp.bp.110.080044.
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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.
Orestes V Forlenza, Ph.D. principal investigator
Department and Institute of Psychiatry, Faculty of Medicine - University of Sao Paulo
Wagner F Gattaz, Ph.D. study director
Department and Institute of Psychiatry, Faculty of Medicine - University of Sao Paulo
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 Lithium Carbonate in people with Cognitive Impairment and Alzheimer Disease, run by University of Sao Paulo at 1 site in Brazil.
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 2 inclusion and 5 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: status not confirmed, as of the sponsor's last update on 25 Jan 2010. 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 Brazil. 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. Some participants in this study may receive a placebo. 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?
Results are not available in the source record.
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.
What does the primary outcome measure?
effect of lithium to delay progression of cognitive deficits in patients with amnestic MCI (time frame: two year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01055392, 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 25 Jan 2010.