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Trial registered on ANZCTR


Registration number
ACTRN12614000277640
Ethics application status
Approved
Date submitted
10/03/2014
Date registered
17/03/2014
Date last updated
17/03/2014
Type of registration
Retrospectively registered

Titles & IDs
Public title
Role of Testosterone in Prevention of Alzheimer’s Disease
Scientific title
Role of Testosterone in Prevention of Alzheimer’s Disease
Secondary ID [1] 284222 0
NIL
Universal Trial Number (UTN)
U1111-1154-2876
Trial acronym
NA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prevention of Alzheimer's disease 291335 0
Condition category
Condition code
Neurological 291694 291694 0 0
Dementias

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Treatment Group - Testosterone treatment for 24 weeks followed by a wash out period of 4 weeks. Following this step, the participant groups were “crossed over”, such that the testosterone group received placebo and vice versa for a further 24 weeks.

For the testosterone treatment group (n=22), testosterone (50 mg in the form of Andromen(Registered Trademark) 5% FORTE cream obtained from Lawley Pharmaceuticals, Perth, Western Australia) was applied daily to the scrotum, thus using a transdermal route (topically), for 24 weeks.

For all participants, there were a total of 11 clinic visits to Siloam Hospital within the 52-week study period. During the first visit, the participants’ blood pressure, height, weight, body fat percentage and body mass index (BMI) were checked and blood drawn for a baseline reading of blood counts, chemistries, serum testosterone level, LH and SHBG, DHT (dihydrotestosterone) and estradiol, cholesterol, lipid concentrations and plasma beta amyloid levels. The participants’ APOE genotype was also determined. The baseline neuropsychological testing, brain imaging (MRI/MRS) and a CSF sample (for those participants who consented) were collected. CSF samples were collected by lumbar puncture.

At each of the six remaining clinic visits i.e. at 4, 8, 12, 16, 20 and 24 weeks during the first treatment period, blood pressure, weight, body fat percentage and body mass index (BMI) were checked and blood drawn for blood counts, chemistries, measurement of serum testosterone, LH, SHBG, albumin, PSA, DHT, estradiol, insulin, cholesterol, lipid and glucose concentrations and plasma AB levels, while neuropsychological testing were only included at 8, 16 and 24 weeks. At the end of 24 weeks a second CSF sample was collected (from those participants that consented) and MRI/MRS performed, followed by a 4-week washout period.

The placebo and testosterone treatment arms of the study were then crossed-over for a further 24-week treatment period. During this period, the participants were examined every eight weeks (three bleeds in total i.e. at weeks 8, 16 and 24 of the cross-over period); blood collected for analysis as described above and neuropsychological testing performed on all occasions. At the end of the 24-week cross-over period (i.e. week 52 overall, the completion of the trial) a third CSF sample was collected (from those participants that consented) and MRI/MRS performed.

Thus, visits mainly lasted for a maximum of 1.5 hours mainly due to the cognitive testing.

Monitoring adherence mainly comprised of ensuring participants were applying the cream as per the protocol during each of the monitoring visits.
Intervention code [1] 288924 0
Prevention
Intervention code [2] 288925 0
Treatment: Drugs
Comparator / control treatment
Placebo Group - placebo for 24 weeks, followed by a washout period of 4 weeks. Following this step, the participant groups were “crossed over”, such that the placebo group received testosterone and vice versa for a further 24 weeks.

For the placebo group (n=22) the same amount of the cream base [dl-alpha tocopherol acetate (vitamin E), without the testosterone] was applied with the same frequency and in the same manner to that of the treatment group.
Control group
Placebo

Outcomes
Primary outcome [1] 291632 0
Cognition: Neuropsychological Tests/Questionnaires:
1. MMSE
2. Rey Auditory Verbal Learning Test
3. Short form 36 questionnaire
4. Geriatric Depression Scale
5. Depression, Anxiety and Stress Scales
Timepoint [1] 291632 0
Assessed during the following different time points :
1) assessed at baseline
2) assessed at week-8, week-16 and week-24 of the treatment period
3) assessed at the end of washout period (week-28)
4) assessed similarly in the cross-over period (week 28-52)
Secondary outcome [1] 307205 0
Blood Biomarkers:
Serum samples underwent a full blood biochemistry to be measured of the following hormones : LH, estradiol, and insulin . SHBG, albumin, glucose, and PSA levels were also measured. Lipid profile such as HDL, LDL, triglyceride, and cholesterol levels were also performed in plasma heparin samples. Testosterone and DHT levels were measured in serum samples by gas chromatography-mass spectrometry (GC-MS).Plasma underwent analysis for AB 42 and AB 40 levels using ELISAs.
Timepoint [1] 307205 0
Blood sample for bio marker analysis was collected every four weeks starting from baseline.
Secondary outcome [2] 307206 0
Changes in hippocampal volume using Magnetic Resonance Imaging (MRI)
Timepoint [2] 307206 0
MRI was performed on all participants, with or without testosterone treatment, three times i.e.: at the beginning (baseline), at the end of the initial 24-week
treatment period and at the end of the study.
Secondary outcome [3] 307288 0
Measuring levels of the concentration of metabolites in the brain using Magnetic Resonance Spectroscopy (MRS).
Timepoint [3] 307288 0
MRS was performed at baseline, at 24 week and at the end of the study - in all the study participants.

Eligibility
Key inclusion criteria
Male participants: needed to 1) be 50 years of age or older, and have 2) a memory complaint, 3) testosterone levels between 300-600 ng/dL (~10.4 - 20.8 nmol/L), 4) normal levels of PSA, 5) blood pressure within normal limits, 6) no signs of diabetes mellitus, 7) normal liver and kidney enzyme function, and 8) No history of major head injury.

The diagnosis of subjective memory loss (complaint of memory loss but not meeting the criteria for dementia) was reached after a full clinical evaluation including a review of medical and drug history and a physical examination.
Minimum age
50 Years
Maximum age
75 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Any participants meeting the criteria for Dementia were excluded from the study.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation was not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization using procedures like coin-tossing and dice-rolling.

Stratified allocation was employed in the study. In terms of individual memory performance at baseline, assignment to a particular group was random, using stratification to ensure each arm of the study was balanced.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Crossover
Other design features
The clinical investigators and the subjects were blinded.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The mixed model ANOVA analysis consisted of fixed effects for treatment (to compare testosterone with placebo treatment), treatment period (testosterone or placebo), and sequence (testosterone period first or placebo period first), irrespective of the baseline. Carry-over effects were tested from differences from baseline in the first period (week 0) to the end of the washout period (week 24-28), which is the baseline time-point for the second period. When directly comparing two groups based on the presence of APOEe4 genotype, two tailed independent t-tests were performed. All analyses were two-tailed and the alpha level was set at .05.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/09/2006
Actual
2/09/2006
Date of last participant enrolment
Anticipated
1/09/2007
Actual
20/10/2007
Date of last data collection
Anticipated
Actual
Sample size
Target
44
Accrual to date
Final
Recruitment outside Australia
Country [1] 5873 0
Indonesia
State/province [1] 5873 0
Tangerang

Funding & Sponsors
Funding source category [1] 288847 0
Charities/Societies/Foundations
Name [1] 288847 0
McCusker Alzheimer's Research Foundation
Country [1] 288847 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
McCusker Alzheimer's Research Foundation
Address
Suite 22,
Hollywood Medical Centre
85 Monash Avenue
Nedlands WA 6009
Country
Australia
Secondary sponsor category [1] 287542 0
Hospital
Name [1] 287542 0
Siloam Hospitals
Address [1] 287542 0
Jl. Siloam No. 6, Lippo Karawaci 1600, Tangerang 15811
Country [1] 287542 0
Indonesia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290683 0
Human Research Ethics Committee
Ethics committee address [1] 290683 0
270 Joondalup Drive,
Joondalup, WA
6027
Ethics committee country [1] 290683 0
Australia
Date submitted for ethics approval [1] 290683 0
21/05/2005
Approval date [1] 290683 0
21/06/2005
Ethics approval number [1] 290683 0
05-80

Summary
Brief summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss, impairments in behaviour, language and visuo-spatial skills and is ultimately fatal. In the majority of cases, AD onset occurs after the age of 65 (late onset) and is sporadic in origin. Only approximately 5-10% of cases have a disease onset before the age of 65 (early onset). These are often familial forms but only a few that are caused by autosomal dominant mutations in certain AD linked genes. One of the major pathological hallmarks of AD is the presence of neuritic plaques in the brain. These plaques are formed from the build-up of a peptide known as beta-amyloid (AB). There is now evidence to show that sex hormones play an important role in reducing AB levels and so has the potential to protect individuals against developing the disease.

Our laboratory was the first to demonstrate clinically in men a reduction in testosterone levels following chemical castration resulted in increased plasma beta AB levels and subsequently showed that in elderly men a decrease in testosterone levels was associated with increased plasma AB levels. However, the question remains whether changes in plasma testosterone result in changes in AB in the CSF and the brain. In addition, recent research has shown that high levels of the gonadotropin, Luteinizing Hormone (LH), are associated with AD and modulate AB production. However, the relative contribution of LH and testosterone in the pathogenesis of AD remains to be elucidated.

The current study tests the efficacy of testosterone on cognition in high risk men by employing a randomized placebo controlled double blind study and to determine associations with a number of key blood and brain biomarkers. These findings will serve as the basis for the establishment of a larger, multicentre trial for the prevention of AD.





Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 46786 0
Dr Eka J Wahjoepramono
Address 46786 0
5th. Floor - Siloam Hospitals Lippo Village
Jl. Siloam No. 6, Lippo Karawaci 1600, Tangerang 15811, Indonesia
Country 46786 0
Indonesia
Phone 46786 0
+62 811 1461641
Fax 46786 0
Email 46786 0
[email protected]
Contact person for public queries
Name 46787 0
Ralph Martins
Address 46787 0
Suite 22
Hollywood Medical Centre
85 Monash Avenue
Nedlands WA 6009
Country 46787 0
Australia
Phone 46787 0
+61 08 93474200
Fax 46787 0
Email 46787 0
[email protected]
Contact person for scientific queries
Name 46788 0
Ralph Martins
Address 46788 0
Suite 22
Hollywood Medical Centre
85 Monash Avenue
Nedlands WA 6009
Country 46788 0
Australia
Phone 46788 0
+61 08 93474200
Fax 46788 0
Email 46788 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIThe Effects of Testosterone Supplementation on Cognitive Functioning in Older Men2016https://doi.org/10.2174/1871527315666151110125704
N.B. These documents automatically identified may not have been verified by the study sponsor.