ANZCTR - Registration

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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]

NIL

Universal Trial Number (UTN)

U1111-1154-2876

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Prevention of Alzheimer's disease

Condition category

Condition code

Neurological

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]

Prevention

Intervention code [2]

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]

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]

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]

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]

Blood sample for bio marker analysis was collected every four weeks starting from baseline.

Secondary outcome [2]

Changes in hippocampal volume using Magnetic Resonance Imaging (MRI)

Timepoint [2]

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]

Measuring levels of the concentration of metabolites in the brain using Magnetic Resonance Spectroscopy (MRS).

Timepoint [3]

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

Accrual to date

Final

Recruitment outside Australia

Country [1]

Indonesia

State/province [1]

Tangerang

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

McCusker Alzheimer's Research Foundation

Address [1]

Suite 22
Hollywood Medical Centre
85 Monash Avenue
Nedlands WA 6009

Country [1]

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]

Hospital

Name [1]

Siloam Hospitals

Address [1]

Jl. Siloam No. 6, Lippo Karawaci 1600, Tangerang 15811

Country [1]

Indonesia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Human Research Ethics Committee

Ethics committee address [1]

270 Joondalup Drive, 
Joondalup, WA 
6027

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

21/05/2005

Approval date [1]

21/06/2005

Ethics approval number [1]

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

Dr Eka J Wahjoepramono

Address

5th. Floor - Siloam Hospitals Lippo Village
Jl. Siloam No. 6, Lippo Karawaci 1600, Tangerang 15811, Indonesia

Country

Indonesia

Phone

+62 811 1461641

Fax

ekabrain@gmail.com

Contact person for public queries

Name

Ralph Martins

Address

Suite 22
Hollywood Medical Centre
85 Monash Avenue
Nedlands WA 6009

Country

Australia

Phone

+61 08 93474200

Fax

r.martins@ecu.edu.au

Contact person for scientific queries

Name

Ralph Martins

Address

Suite 22
Hollywood Medical Centre
85 Monash Avenue
Nedlands WA 6009

Country

Australia

Phone

+61 08 93474200

Fax

r.martins@ecu.edu.au

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

Source	Title	Year of Publication	DOI
Dimensions AI	The Effects of Testosterone Supplementation on Cognitive Functioning in Older Men	2016	https://doi.org/10.2174/1871527315666151110125704

N.B. These documents automatically identified may not have been verified by the study sponsor.

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