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Trial registered on ANZCTR


Registration number
ACTRN12613000034730
Ethics application status
Not yet submitted
Date submitted
10/01/2013
Date registered
14/01/2013
Date last updated
23/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Intervention of Testosterone & Fish Oil as a possible strategy for the Prevention of Alzheimer’s Disease
Scientific title
A 56 week, double-blind, randomised, placebo-controlled trial to determine the efficacy of testosterone, with and without DHA supplementation in PiB positive men with Subjective Memory Complaints as a strategy to prevent the development of Alzheimer’s Disease.
Secondary ID [1] 281654 0
nil
Universal Trial Number (UTN)
U1111-1137-8841
Trial acronym
InTrePad
Linked study record

Health condition
Health condition(s) or problem(s) studied:
In men with Subjective Memory Complaints 287942 0
Condition category
Condition code
Neurological 288321 288321 0 0
Alzheimer's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
testosterone undecanoate 1000mg/ 4ml (intramuscular injection) every 8 weeks, for 56 weeks

Docosahexaenoic acid (DHA) capsules, 4 capsules per day (total daily dose of 1720mg of DHA) for 56 weeks


There are 3 treatment arms:
Arm 1: Testosterone 1000mg/4 ml plus 1720 mg of DHA
Arm 2: Testosterone 1000mg/4 ml plus placebo-DHA
Arm 3: placebo-testosterone plus placebo-DHA
Intervention code [1] 286190 0
Treatment: Drugs
Intervention code [2] 286191 0
Prevention
Comparator / control treatment
Control treatment group is arm 3, comprising of placebo injections given intramuscular every 8 weeks & placebo capsules, 4 capsules per day for 56 weeks

The placebo treatments will be identical to active treatment but without the active ingredients.
Control group
Placebo

Outcomes
Primary outcome [1] 288493 0
The primary outcome of the study will be a decrease in Pittsburgh compound B (PiB) score at 13 months of at least 4% from the baseline score.
Timepoint [1] 288493 0
The primary endpoint of the study will be the proportion of participants achieving a success at 13 months.
Secondary outcome [1] 300307 0
A comprehensive battery of questionnaires & structured interviews will be used to access the neuropsychological, mood, and daily functioning measures to assess the efficacy of treatment interventions in comparison to placebo on cognitive functions.
Questionnaires will include: Mini Mental State Examination, Memory for Intentions Screening Test, Benton Visual Retention Test, Stroop Neuropsychological Screening Test, Memory Complaints Questionnaire and Prospective and Retrospective Memory Questionnaire, World Health Organization Quality of Life measure, Activities of Daily Living Questionnaire
Timepoint [1] 300307 0
Week 28 & 56 scores will be compared to baseline.
Secondary outcome [2] 300308 0
To evaluate the treatment interventions on plasma and/or cerebrospinal fluid (CSF) beta amyloid levels compared to placebo.
Timepoint [2] 300308 0
Beta amyloid levels will as assessed at week 56 and compared to baseline.
Secondary outcome [3] 300309 0
Fluorodeoxyglucose (FDG) PET scans will evaluate the efficacy of treatment interventions at improving brain glucose metabolism compared to the placebo control group.
Timepoint [3] 300309 0
Changes in brain glucose metabolism will be assessed at week 56 and compared to baseline scans.
Secondary outcome [4] 300310 0
Evaluate the treatment intervention on inflammatory & oxidative exploratory biomarkers.
Timepoint [4] 300310 0
These will be assessed at week 28 & 56 and compared to baseline.
Secondary outcome [5] 300311 0
Brain Magnetic Resonance Imaging (MRI) will be used to measure change in hippocampal volume to evaluate treatment intervention in the different groups.
Timepoint [5] 300311 0
Assesments will be made at week 56 and compared to baseline.
Secondary outcome [6] 300312 0
The treatment impact on Quality of Life (QoL) using the following Q of L questionnaires (WHO Qol & SF-36) will be assessed.
Timepoint [6] 300312 0
Q of L will be assessed at week 28, 56 and compared to baseline.
Secondary outcome [7] 300313 0
The safety and tolerability of the treatment interventions compared to placebo will be assessed.
Timepoint [7] 300313 0
Safety and tolerability will be assessed at each study visit e.g. every 8 weeks over the 56 week study period. Adverse Event reporting, vital signs, safety bloods, physical examination and treatment compliance will be assessed.
The most frequently reported side effects of intramuscular administration of testosterone undeconate are acne or pain at the injection site. Side effects reported in less than 10% of patients treated with testosterone undeconate included: an increase in red blood cells, weight increase, an increase in prostate specific antigen value (prostate hyperplasia) and the occurrence of hot flushes.

Eligibility
Key inclusion criteria
1. Men aged 60 years or over
2. Able to personally read and understand the Participant Information and Consent Form and provide written, signed and dated informed consent to participate in study
3. Able and willing to meet all protocol-required procedures and visits
4. Must have an available informant who is knowledgeable about the participant, who has a minimum of 5 hours contact per week and can provide a reliable way to determine cognitive status of the participant
5. Participants must be PiB-PET positive based on cut-off level of greater than 1.5 SUVR and PET scan done within 6 months at time of commencement of treatment if deemed eligible to participate
6. Mini Mental State Examination (MMSE) greater than 24 as stratified by age and education (i.e. cognitively normal), with inclusion at the discretion of the investigator team (after taking into consideration, age, education, medical, neurological and psychiatric condition)
7. A score of greater than 25 on Memory Complaints Questionnaire (MACQ) to ensure the participants are SMCs
8. Mini- International Neuropsychiatric Interview (depression and anxiety specific) (MINI), Consistent with the absence of major depression at the screening visit according to DSM-IV TR
Minimum age
60 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pathological androgen deficiency (< 8 nmol/L)
2. Baseline serum testosterone measurement >18 nmol/L within 6 months of study screening visit
3. Use of any medication known to: affect testosterone or Sex Hormone Binding Globulin (SHBG) within the previous 1 month or with an underlying condition where there is any possibility that these may be required within the next 12 months
4. Known to have hypothalamo-pituitary or testis pathology (excl. cryptorchidism)
5. Screening ECG that shows evidence of a serious and/or unstable clinical significant condition as determined by the Investigator
6. Laboratory or clinical signs of untreated, clinically significant abnormal thyroid function as deemed by the Investigator
7. Clinically significant folic acid or vitamin B12 deficiency detected within 1 year prior to study consent
8. Diagnosed with severe untreated Obstructive Sleep Apnoea or commenced Continuous positive airway pressure (CPAP) within the previous 6 months
9. Type 1 diabetes mellitus
10. Current clinically significant infection requiring systemic antibiotics
11. Known to be human immunodeficiency virus (HIV) positive
12. Participants should not be included in the study if they are taking chronic narcotic analgesic treatment (including codeine) anti-psychotics, tricyclic antidepressants, dopamine agonists, benzodiazepines, lithium, oral corticosteroids, other anti-cholinergics, cholinesterase inhibitors, paroxetine [an SSRI that is anticholinergic]
13. Clinically significant non-malignant disease that is likely to lead to serious illness or death within 2 years, or in the opinion of the Clinical Investigator, requires other intervention
14. Ongoing episode of major depression or other significant psychiatric or neurological disorders that may have an impact on cognitive performance such as schizophrenia, epilepsy, Parkinson’s disease or clinical episode of stroke.
15. Breast, liver cancer or other malignancy within the last 5 years. Non-melanoma skin cancer (s) treated with curative intent are eligible if disease-free for at least 2 years
16. Prior history of prostate cancer, above Upper Limit of Normal (ULN) for age-adjusted Prostate Specific Antigen (PSA) values or abnormal prostate on digital rectal examination (DRE)
17. Personal or family history of thrombophilia, or taking anticoagulants, other than low dose Aspirin (100mg) for cardiovascular prophylaxis
18. > 1.5 X Upper Limit of Normal coagulation profile
19. Major cardiovascular event within the previous 6 months, or active cardiac disease
20. Elevated blood pressure (above 160/100mmHg) at screening
21. Haematocrit > 52% and Haemoglobin > 18.5 g/dL, or platelet counts <100,000 cells/uL
22. ALT, GGT, Bilirubin or ALP > 3 times upper limit of normal (ULN)
23. Known chronic viral hepatitis
24. eGFR < 50 mL/minute
25. Treatment with investigational medication within 2 months prior to informed consent
26. Known history of drug or alcohol abuse within 6 months prior to the time of screening
27. BMI > 35
28. Lumbar spinal surgery within the last 6 months prior to screening, or any lumbar spinal surgery that interferes with anatomy of the inter-vertebral spaces
29. History of chronic or repeat cerebrospinal fluid leakage following previous lumbar puncture
30. Unable to have an MRI




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)
After confirming eligibility, participants will be enrolled and randomised using Interactive Voice Response System (IVRS). Treatments will be allocated using stratified minimisation. Treatment allocation is double-blind.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised using IVRS into one of three treatment groups and stratified according to:
Age
APOE genotype
PIB load
Memory performance at baseline
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
For this phase II study, the proportion of successes in each of the randomised groups, together with the 95% confidence intervals will be reported. While there is no intention to make formal comparisons between the groups, exploratory comparisons may be conducted to obtain estimates of the plausible range of success rates in order to better inform any subsequent studies. For continuous variables, comparisons will be made using the t-test, and chi-squared tests will be used for categorical variables. Time-to-event will be described using the Kaplan-Meier and comparisons made using the logrank test. Exploratory analyses examining the impact of other variables will be performed using multiple regression (linear, logistic and proportional hazards) techniques.

The variability of PiB readings is approximately 5% and based and an absolute improvement in the PiB score of between 2% and 4% would still be considered a success (as no PiB deterioration is considered clinically worthwhile). Currently, it is anticipated that 1% of untreated (placebo control) participants would demonstrate a success at 13 months. For the intervention to be considered worthwhile to evaluate further in a broader population or larger study, this proportion would be required to be at least 7%. The primary outcome of this study will be a success as measured by a 4% improvement in the baseline PiB score and the primary endpoint for the study will be the proportion of successes.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
study never went ahead, due to funding issues.
Date of first participant enrolment
Anticipated
28/02/2013
Actual
Date of last participant enrolment
Anticipated
28/02/2014
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
200
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 321 0
Hollywood Private Hospital - Nedlands
Recruitment postcode(s) [1] 6124 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 286468 0
Charities/Societies/Foundations
Name [1] 286468 0
McCusker Alzheimer's Research Foundation Inc
Country [1] 286468 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Lawley Pharmaceuticals
Address
Unit 2 / 15A Harrogate Street
West Ledderville
WA 6007
Country
Australia
Secondary sponsor category [1] 285257 0
None
Name [1] 285257 0
Address [1] 285257 0
Country [1] 285257 0
Other collaborator category [1] 277223 0
Charities/Societies/Foundations
Name [1] 277223 0
McCusker Alzheimer's Research Foundation Inc
Address [1] 277223 0
Suite 22, Hollywood Medical Centre
85 Monash Ave
Nedlands WA 6009
Country [1] 277223 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 288544 0
Hollywood Private Hospital Research Ethics Committee
Ethics committee address [1] 288544 0
Ethics committee country [1] 288544 0
Australia
Date submitted for ethics approval [1] 288544 0
12/11/2012
Approval date [1] 288544 0
Ethics approval number [1] 288544 0
HPH351

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 36546 0
Prof Professor Ralph Martins
Address 36546 0
Sir James McCusker Alzheimer's Disease Research Unit,
Hollywood Medical Centre
85 Monash Avenue
Nedlands WA 6009
Country 36546 0
Australia
Phone 36546 0
+618 9347 4200
Fax 36546 0
Email 36546 0
[email protected]
Contact person for public queries
Name 36547 0
Kevin Taddei
Address 36547 0
McCusker Alzheimer's Research Foundation Inc,
Suite 22, Hollywood Medical Centre,
85 Monash Ave,
Nedlands WA 6009
Country 36547 0
Australia
Phone 36547 0
+618 6304 5107
Fax 36547 0
Email 36547 0
[email protected]
Contact person for scientific queries
Name 36548 0
Kevin Taddei
Address 36548 0
McCusker Alzheimer's Research Foundation Inc,
Suite 22, Hollywood Medical Centre,
85 Monash Ave,
Nedlands WA 6009
Country 36548 0
Australia
Phone 36548 0
+618 6304 5107
Fax 36548 0
Email 36548 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

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