None listed
Conditions
Brief summary
In this study we propose to identify a cohort of 200 men who have a higher-than-normal amyloid in the brain, who are experiencing Subjective Memory Complaints but are not symptomatic for Alzheimer's disease. These men will be treated with testosterone (intramuscular injection), with and without DHA (oral administration) over 56 weeks. The study will evaluate the ability of testosterone & DHA to reduce the levels of LH, beta amyloid levels and subsequent impact on amyloid PIB-like load in the brain. This study will look at the effects of study treatment on brain images (MRI, PET scans), participants’ scores on psychometric tasks, neuropsychological questionnaires (measurement of memory loss and thinking ability) tests and the effect of treatment on different blood biomarkers. This study will look at the effects of study treatment on brain images (MRI, PET scans), participants’ scores on psychometric tasks, neuropsychological questionnaires (measurement of memory loss and thinking ability) tests and the effect of treatment on different blood biomarkers.
Interventions
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
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
Sponsors
Australian Alzheimer's Research Foundation Inc
Study design
Allocation
Randomised controlled trial
Primary purpose
Prevention
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
Male
Age
60 Years to 80 Years
Healthy volunteers
No
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
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.
Outcome results
None listed