Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000761268
Ethics application status
Approved
Date submitted
21/03/2018
Date registered
7/05/2018
Date last updated
27/04/2023
Date data sharing statement initially provided
16/04/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
A study investigating whether testosterone and omega 3 from fish oil has an effect on the accumulation of protein plaques linked to Alzheimer’s disease in older men concerned about their memories
Scientific title
A 56 week, Double-Blind, Randomised Study to Evaluate the Efficacy of Testosterone, With and without DHA Supplementation on Cerebral Amyloid Load in Men with Subjective Memory Complaints
Secondary ID [1] 294410 0
nil
Universal Trial Number (UTN)
U1111-1137-8841
Trial acronym
TotAL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Subjective Memory Complaints 307140 0
Age-related cognitive decline 307576 0
Dementia 307577 0
Cognitive Impairment 307710 0
Condition category
Condition code
Neurological 306261 306261 0 0
Dementias

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

(Note that the DHA component of this study was completed on May 28, 2021. Participants enrolled after this date are randomised to one of two arms: 1) Testosterone 1000mg/4 ml or 2) placebo-testosterone)


Intramuscular injections will be administered by a study doctor or nurse

There will be a maximum of 8 injections (1 on day one of treatment and then one every 8 weeks for 56 weeks)

Injections will be administered at the study site; there will be no need for ensuring adherence

For those randomised prior to the cessation of DHA assignment on 28/08/2021, 2 capsules were taken in the morning and 2 were taken in the evening. Participants were advised that these should be taken after food.

A diary card was used to monitor adherence to SHA. At drug return/redispensing, the number being returned was determined and compared to the expected number in order to identify any missed doses or overdoses. Non-compliance was discussed with the participant by a study doctor
Intervention code [1] 300697 0
Treatment: Drugs
Intervention code [2] 300698 0
Prevention
Comparator / control treatment
Control treatment group is arm 3, consisting of placebo injections given intramuscularly every 8 weeks & placebo capsules taken orally (4 capsules per day) for 56 weeks. After cessation of DHA assignment on 28/05/2021, the placebo arm received placebo injections only.

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

Placebo REANDRON® 1000 will be presented in an identical 5 mL glass ampoule and it has similar appearance as a clear, yellowish oily solution. Ingredients include benzyl benzoate and castor oil.
The placebo capsules matched the EPAX1050TG capsules in appearance (same colour and shape), weight and texture. They were transparent soft capsules, oblong size 20 and filled with corn oil.
Control group
Placebo

Outcomes
Primary outcome [1] 305268 0
Change from baseline in brain amyloid levels as measured by 18F-Flutemetamol positron emission tomography (PET) scans
Timepoint [1] 305268 0
Baseline and then every 8 weeks until the end of treatment (56 weeks).
Secondary outcome [1] 344663 0
A change from baseline in a composite score of cognitive functioning derived from scores on California Verbal Learning Test –Second Edition (CVLT-II), Brief Visuospatial Memory Test – Revised (BVMT-R), Logical Memory subtest of the Wechsler Memory Scale-R, Executive Abilities: Methods and Instruments for Neurobehavioral Evaluation and Research Battery (NIH EXAMINER), Boston Naming Test (BNT), Controlled Oral Word Association Test (COWAT), and the WAIS-III Digit Span and Digit Symbol Coding Tasks; as well as a change in global cognition measured by the Montreal Cognitive Assessment (MoCA).
Timepoint [1] 344663 0
Week 56 (visit 10) scores will be compared to baseline.
Secondary outcome [2] 344666 0
Change from baseline in CSF amyloid concentration as measured by Abeta 1-42 (Aß42) in CSF.
Timepoint [2] 344666 0
Beta amyloid levels will as assessed at week 56 and compared to baseline.
Secondary outcome [3] 344683 0
Change from baseline of neurodegeneration by assessing changes in imaging biomarkers.
Neurodegeneration will be assessed based on changes in imaging biomarkers. PET-determined brain glucose metabolism and MRI. The MRI will be used to exclude people based on any structural findings that may affect cognition and to assess the effect of treatment on hippocampal volume (via pre and post-treatment measurement).

Timepoint [3] 344683 0
Baseline to End of Treatment (56 weeks)

Eligibility
Key inclusion criteria
1. Men aged 60 – 80 years at the time of signing the consent
2. Able to personally read and understand the Participant Information and Consent Form and provide written, signed and dated informed consent to participate in the study
3. Able and willing to meet all protocol-required procedures and visits
4. Must have an available project partner who has sufficient contact (at least 5 hours per week) with the participant to provide reliable information on the cognitive and functional abilities of the participant
5. Must have Global PiB-like SUVR score of 1.3 - 2.0 on PET (completed within 12 months of Day 1)
6. A MoCA score of 23 to 30 at the Screening Visit dependant on age and education, see appendix III
7. A score of greater than or equal to 25 on Memory Complaints Questionnaire (MAC-Q) at Screening Visit
8. General cognition and functional performance are preserved to the extent that that no suspected or possible Mild Cognitive Impairment or AD with dementia exists based on the results of neuropsychological testing at Screening IV. Note: If a comparable neuropsychological battery (as determined by the lead neuropsychologist) has been performed
within 4 months of screening, the data collected can be used to assess this criterion.
9. Visual and auditory acuity to perform the cognitive tests (eyeglasses and hearing aids permitted)
10. Be willing to provide a blood sample for Apolipoprotein E (APOE) genotyping
Minimum age
60 Years
Maximum age
80 Years
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pathological androgen deficiency (< 8 nmol/L) in accordance with current Pharmaceutical Benefits Scheme guidelines requiring testosterone replacement, or testosterone supplementation during the previous 2 years
2. Serum testosterone measurement greater than or equal to 18 nmol/L within 6 months of study or at the Screening Visit
3. Use of any medication known to:
• Affect testosterone or SHBG within the previous 1 month or with an underlying condition where there is any possibility that permanent usage may be required within the next 12 months
• Affect the production (e.g. opiates, GnRH agonists) or action (e.g. spironolactone) of androgens
• Affect the production [e.g. opiates, GnRH agonists] or action [e.g. spironolactone, Duodart (combination of Tamsulosin and Dutasteride), Avodart (Dutasteride)] of androgens
4. Known to have hypothalamo-pituitary or significant testis pathology (excl. cryptorchidism)
5. Known clinically significant folic acid or B12 deficiency
6. Diagnosed with severe untreated Obstructive Sleep Apnoea (OSA) or commenced CPAP within the previous 6 months
7. Type 1 diabetes mellitus
8. Clinically significant systemic illness or serious infection (e.g., pneumonia, septicemia) within 30 days prior to or during Screening
9. Known to be Human Immunodeficiency Virus (HIV) positive
10. 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] – If any of these drugs are taken intermittently (no more than three times a week) there should be no use within 2 days of any cognitive testing *In the case of low dose corticosteroids, if in the opinion of the investigator the dose of the drug is sufficiently low to not represent a significant anti-cholinergic burden, then the subject can be included in the study
11. Ongoing episode of major depression, or current diagnosis or history of schizophrenia, bipolar disorder or any other psychiatric condition which could significantly interfere with their cooperation in participating in the study
12. Significant neurological or medical disorders that in the opinion of the investigator may impair cognitive performance such as epilepsy, Parkinson’s disease, clinical episode of stroke/TIA. In these instances, consensus agreement with the sponsor regarding participant eligibility should be sought
13. History of malignancy of any organ treated within the past 2 years, regardless of whether there is evidence of local recurrence or metastases. However localised basal cell carcinoma or localised squamous cell of the skin are permitted
14. Prior history of prostate cancer or:
• > ULN for age-adjusted PSA values
• Clinical suspicion of malignancy on digital rectal examination (DRE) o Except where the participants have been assessed by an urologist and all causes for high PSA/abnormal size on DRE other than Benign Prostatic Hyperplasia /Prostatitis have been ruled out
• High risk of prostate cancer according to family history (men with one or more first-degree relatives diagnosed <65yo, or men with a first-degree relative with familial breast cancer (BRCA1 or BRCA2))
15. Personal or family history of thrombophilia, or personal history of deep vein thrombosis (DVT) / pulmonary embolism (PE) diagnosed in the last 12 months; or taking anticoagulants or antiplatelet medications other than low dose aspirin (< 300 mg) for cardio-vascular prophylaxis.
16. IPSS score greater than or equal to 19, as it is regarded a contra-indication for Testosterone therapy
17. Major cardiovascular event within the previous 12 months, or active cardiac disease defined as one or more of the following:
• New York Heart Association Functional Classification of heart failure greater than or equal to 2 (See Appendix II) or symptomatic angina
• Uncontrolled arrhythmias, or arrhythmias deemed clinically significant by the investigator
• Myocardial infarction, cardiac stenting or angioplasty in past 12 months
• Significant ECG finding
18. Uncontrolled hypertension (elevated blood pressure greater than or equal to 160/100 mmHg)
19. Significant abnormal laboratory results (in the opinion of the investigator) or meeting any of the following criteria (Note: if the abnormal finding is a result of a temporary condition, the laboratory test may be repeated once at least 7 days after the initial blood draw):
• Haematocrit > 54% (2 consecutive readings at least 7 days apart) and Haemoglobin > 18.5 g/dL, or platelet counts < 100,000 cells/uL
• ALT, GGT, Bilirubin or ALP 2 > Upper Limit of Normal (ULN)
• > 1.5 ULN coagulation profile (COAG) includes INR, APTT and fibrinogen)
• eGFR < 50 mL/minute (using CKD-EPI algorithm)
20. Known chronic viral hepatitis
21. Received any other investigational medication within 2 months of consent or 5 half-lives of the used IP, whichever is longer
22. Current evidence or history of drug or alcohol abuse within 2 years as determined by the investigator. A record of usage in the past 3 months and/or previous significant abuse should be documented in the medical history
23. BMI > 35kg/m2
24. Lumbar spinal surgery within the last 6 months prior to screening, or any lumbar deformity or prior spinal surgery that in the opinion of the investigator would contraindicate lumbar puncture (this exclusion criteria only relevant if participant consents to having a Lumbar Puncture)
25. History of chronic or repeat CSF leakage following previous lumbar puncture (this exclusion criteria only relevant if participant consents to having a Lumbar Puncture)
26. Currently taking fish oil supplement. Note, individual will be eligible if they enter a 30 day wash out period prior to PET.
27. Unable to have an MRI due to:
• Pacemakers
• Electronically, magnetically, and mechanically activated implants
• Metallic splinters in the eye
• Ferromagnetic haemostatic clips in the CNS or any other circumstance that would contradict an MRI scan
28. Depression and anxiety specific signs and symptoms as indicated by the investigator’s clinical judgement. A Hospital Anxiety Depression Scale score greater than or equal to 8 must always be discussed with the participant and will be exclusionary unless ruled not clinically significant by the investigator.
29. Brain MRI results showing findings unrelated to AD that, in the opinion of the investigator might be a leading cause of cognition decline, might pose a risk to the participant or might prevent a satisfactory MRI assessment during the study
30. Hypersensitivity to any of the investigational products or any of the excipient, including fish or fish products
31. Any other severe or unstable medical condition that in the opinion of the investigator could be expected to progress, recur or change to the extent that it could put the participant at risk or bias the clinical and cognitive assessments to a significant degree. Consensus agreement with the sponsor should be sought if required
32. Participants, who intend to father a child, will be advised not to take part in this study
33. Enrolment in another clinical trial within 30 days prior to Randomisation
34. Exposure to any cognitive assessments included in the study within 6 months of the Screening Visit, with the exception of MoCA.

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)
Randomised controlled trial - We are using an automatic randomisation (pin assess) through fax/email - external provider of NMHRC CTC Randomisation Team. Also includes Kit number for IVRS assignment and allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The stratification variables:
1. Site (2 sites)
2. SUVR score (2 groups: 1.40 – 1.70, vs 1.71 – 2.00)
3. APOE genotype combinations:
2/2
2/3 or 3/2 (the same thing)
3/3
2/4 or 4/2 (the same thing)
3/4 or 4/3 (the same thing)
4/4

Stratification is being conducted by an external provider-NMHRC Randomisation team through computerised system.
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
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
For this phase II study, the proportion reaching primary and secondary outcomes 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 arms (because of the nature of the study design), exploratory comparisons may be conducted to obtain estimates of the plausible range reaching primary and secondary outcomes 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 outcomes will be described using the Kaplan-Meier method 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 amyloid readings is approximately 5% and based on an absolute improvement in the amyloid load score of between 4% and 6% would still be considered as reaching primary outcome (as no amyloid deterioration is considered clinically worthwhile). Currently, it is anticipated that 1% of untreated (placebo control) participants would demonstrate a change 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 measured by a 6% improvement in the baseline cerebral amyloid load and the primary endpoint for the study will be the proportion of individuals reaching this threshold.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
16/04/2018
Date of last participant enrolment
Anticipated
31/10/2023
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
120
Accrual to date
60
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA
Recruitment hospital [1] 10440 0
Australian Alzheimer’s Research Foundation - Nedlands
Recruitment postcode(s) [1] 22145 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 297881 0
Charities/Societies/Foundations
Name [1] 297881 0
Australian Alzheimer's Research Foundation Inc
Country [1] 297881 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Australian Alzheimer's Research Foundation Inc
Address
8 Verdun Street Nedlands WA 6009
Country
Australia
Secondary sponsor category [1] 296930 0
None
Name [1] 296930 0
None
Address [1] 296930 0
None
Country [1] 296930 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298930 0
Ramsay Healthcare HREC WA|SA
Ethics committee address [1] 298930 0
Ethics committee country [1] 298930 0
Australia
Date submitted for ethics approval [1] 298930 0
14/11/2016
Approval date [1] 298930 0
22/03/2017
Ethics approval number [1] 298930 0
HPH480
Ethics committee name [2] 299975 0
Macquarie University Human Research Ethics Committee
Ethics committee address [2] 299975 0
Ethics committee country [2] 299975 0
Australia
Date submitted for ethics approval [2] 299975 0
13/10/2016
Approval date [2] 299975 0
12/12/2016
Ethics approval number [2] 299975 0
5201600795

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

Contacts
Principal investigator
Name 78690 0
A/Prof Roger Clarnette
Address 78690 0
Australian Alzheimers Research Foundation,
Sarich Neuroscience Research Institute,
8 Verdun Street, Nedlands WA 6009
Country 78690 0
Australia
Phone 78690 0
+61 8 6304 3966
Fax 78690 0
618 6389 2033
Email 78690 0
[email protected]
Contact person for public queries
Name 78691 0
Kevin Taddei
Address 78691 0
Australian Alzheimers Research Foundation,
Sarich Neuroscience Research Institute,
8 Verdun Street, Nedlands WA 6009
Country 78691 0
Australia
Phone 78691 0
+618 6304 3966
Fax 78691 0
Email 78691 0
[email protected]
Contact person for scientific queries
Name 78692 0
Kevin Taddei
Address 78692 0
Australian Alzheimers Research Foundation,
Sarich Neuroscience Research Institute,
8 Verdun Street, Nedlands WA 6009
Country 78692 0
Australia
Phone 78692 0
+618 6304 3966
Fax 78692 0
Email 78692 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
No additional documents have been identified.