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| A randomised, single-blinded, placebo-controlled, multicentre study to investigate the pharmacodynamic effects of lithium on glycogen synthase kinase-3 (GSK-3) activity in patients with Alzheimer's disease |
| ISRCTN | ISRCTN72046462 |
| ClinicalTrials.gov identifier | |
| Public title | A randomised, single-blinded, placebo-controlled, multicentre study to investigate the pharmacodynamic effects of lithium on glycogen synthase kinase-3 (GSK-3) activity in patients with Alzheimer's disease |
| Scientific title | |
| Acronym | N/A |
| Serial number at source | D0200C00001 |
| Study hypothesis | Ten-week treatment with lithium affects glycogen synthase kinase-3 (GSK-3) activity and cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) in patients with mild Alzheimer's disease. |
| Lay summary | |
| Ethics approval |
Ethics approval received from:
1. Ethics Committee of the Medical Faculty of the Ludwig-Maximilians University of Munich (Ethikkommission der Medizinischen Fakultät der Ludwig-Maximilians Universität München) on the 10th September 2004 (ref: 208/04) 2. Ethics Commitee of the Ruprecht-Karl University of Heidelberg (Ethikkommission der Ruprecht-Karl-Universität Heidelberg) on the 12th November 2004 (ref: 366/2004) 3. Ethics Committee of the Ruprecht-Karl University of Heidelberg, Faculty for Clinical Medicine Mannheim on the 18th November 2004 (ref: 220/04) 4: Ethics Committee of Charité Berlin (Ethikkommission der Charité Berlin) on the 11th November 2004 (ref: EA4/036/04) 5: Ethics Committee of the University of Tübingen (Ethikkommission der Universität Tübingen) on the 12th October 2004 (ref: 341/2004G) 6. Ethics Committee of the Faculty for Medicine of the Technical University of Munich (Ethikkommission der Fakultät für Medizin der Technischen Universität München) on the 3rd November (ref: 1191/04) |
| Study design | Randomised, single-blind, placebo controlled, parallel-group multicentre study |
| Countries of recruitment | Germany |
| Disease/condition/study domain | Alzheimer's disease |
| Participants - inclusion criteria |
1. Provision of informed consent
2. Female, without child bearing potential (post-menopausal for at least one year or surgically sterile) or male, aged 50 - 85 years 3. Clinical diagnosis of mild Alzheimer's disease 4. Diagnosis of Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for primary degenerative dementia of the Alzheimer's type 5. National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for Alzheimer's disease 6. Stable dose of cholinesterase inhibitors (ChEI) for at least six months or no prior treatment with ChEI. Limited treatment periods with ChEI such as days or weeks after which treatment was stopped, not regarded as having any effects on the disease. 7. Willingness and ability to complete all study-related procedures and to understand patient information |
| Participants - exclusion criteria |
1. Any other clinically significant condition or laboratory abnormality that may interfere with the patient's ability to participate in the study or the study results, as judged by the investigator
2. Electrocardiogram (ECG) changes and/or signs indicative of significant cardiovascular disease, or other conditions in which lithium treatment is contraindicated, as judged by the investigator 3. Untreated hypothyroidism 4. Concomitant use of valproic acid, memantine, neuroleptics, coumarin, anticoagulants, or non-steroidal non-inflammatory drugs (NSAIDs) 5. Salt-restricted diet 6. Clinically significant liver disease or an elevation in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) or total bilirubin of 1.5 times the upper limit of the reference range 7. Known or suspected drug or alcohol abuse 8. Contraindications as detailed in the country-specific prescribing information for lithium 9. Participation in another drug trial within four weeks prior enrolment into this study or longer in accordance with local requirements 10. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the investigational sites) 11. Previous enrolment or randomisation of treatment in the present study |
| Anticipated start date | 22/11/2004 |
| Anticipated end date | 29/07/2005 |
| Status of trial | Completed |
| Patient information material | |
| Target number of participants | 70 |
| Interventions |
Following enrolment visit and baseline assessments, eligible patients were randomised to receive lithium sulphate (Lithionit®) or placebo (randomised 1:1), and entered into a titration phase of six weeks. During the titration phase, there were weekly visits to adjust the lithium dose to the target serum lithium concentration of 0.5 - 0.8 mmol/L. The starting dose of lithium sulphate, 42 mg (6 mmol Li+), was 1 + 1 tablets daily (one tablet in the morning and one tablet in the evening approximately 12 hours apart). Dosages were escalated at weekly intervals until the target serum lithium concentration of 0.5 - 0.8 mmol/L (measured 12 hours from last dose) was reached, with 4 + 4 tablets taken during the maintenance phase.
Total duration of treatment: 10 weeks Follow-up: at baseline and end of treatment (10 weeks) |
| Primary outcome measure(s) |
The following were assessed at baseline and the end of treatment (10 weeks):
1. Change in GSK-3 activity in lymphocytes 2. Change in p-tau181 and p-tau231 in CSF |
| Secondary outcome measure(s) |
The following were assessed at baseline and the end of treatment (10 weeks):
1. Change in beta-amyloid (1-42) in CSF and blood 2. Change in tau in CSF 3. Change in cognitive function as measured by cognitive subscore of the Alzheimer's Disease Assessment Scale (ADAScog) and Neuropsychiatric Inventory (NPI) 4. To monitor safety and tolerability |
| Sources of funding | AstraZeneca (Sweden) |
| Trial website | |
| Publications | 2009 results in http://www.ncbi.nlm.nih.gov/pubmed/19573486 |
| Contact name | Prof Harald Hampel |
| Address |
Discipline of Psychiatry
School of Medicine and Trinity College Institute of Neuroscience (TCIN) Trinity College University of Dublin The Adelaide and Meath Hospital Incorporating The National Children's Hospital (AMiNCH) Tallaght |
| City/town | Dublin |
| Zip/Postcode | 24 |
| Country | Ireland |
| Tel | +353 (0)1 896 3706 |
| Fax | +353 (0)1 896 1313 |
| harald.hampel@tcd.ie | |
| Sponsor | AstraZeneca (Sweden) |
| Address |
c/o Dr Peter Annas
Senior Research Scientist AstraZeneca R & D Södertälje |
| City/town | Södertälje |
| Zip/Postcode | SE-15185 |
| Country | Sweden |
| Tel | +46 8 553 290 35 |
| Fax | +46 8 553 274 91 |
| peter.annas@astrazeneca.com | |
| Sponsor website: | http://www.astrazeneca.com |
| Date applied | 19/05/2008 |
| Last edited | 28/07/2009 |
| Date ISRCTN assigned | 02/07/2008 |
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| © 2012 ISRCTN unless otherwise stated. | |
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