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
DOI	https://doi.org/10.1186/ISRCTN72046462
Secondary identifying numbers	D0200C00001

Submission date: 19/05/2008
Registration date: 02/07/2008
Last edited: 28/07/2009

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Nervous System Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Prof Harald Hampel
Scientific

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
Dublin
24
Ireland

Phone	+353 (0)1 896 3706
Email	harald.hampel@tcd.ie

Study information

Study design	Randomised, single-blind, placebo controlled, parallel-group multicentre study
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Scientific title
Study objectives	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.
Ethics approval(s)	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)
Health condition(s) or problem(s) studied	Alzheimer's disease
Intervention	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)
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Specified
Drug / device / biological / vaccine name(s)	Lithium
Primary outcome measure	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 measures	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
Overall study start date	22/11/2004
Completion date	29/07/2005

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Both
Target number of participants	70
Key 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
Key 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
Date of first enrolment	22/11/2004
Date of final enrolment	29/07/2005

Locations

Countries of recruitment

Germany
Ireland

Study participating centre

Discipline of Psychiatry

Dublin
24
Ireland

Sponsor information

AstraZeneca (Sweden)
Industry

c/o Dr Peter Annas
Senior Research Scientist
AstraZeneca R & D Södertälje
Södertälje
SE-15185
Sweden

Phone	+46 8 553 290 35
Email	peter.annas@astrazeneca.com
Website	http://www.astrazeneca.com
"ROR"	https://ror.org/04wwrrg31

Funders

Funder type

Industry

AstraZeneca (Sweden)
Government organisation / For-profit companies (industry)

Alternative name(s): AstraZeneca PLC, Pearl Therapeutics
Location: United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/06/2009		Yes	No