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Trial registered on ANZCTR


Registration number
ACTRN12612000287831
Ethics application status
Approved
Date submitted
7/03/2012
Date registered
12/03/2012
Date last updated
15/11/2019
Date data sharing statement initially provided
15/11/2019
Date results information initially provided
15/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A 2-year, multi-centre double-blind, randomised, placebo-controlled trial to determine in men with total testosterone equal to or less than 14nmol/L the efficacy of testosterone treatment together with a lifestyle program in comparison to a lifestyle program alone, to normalise glucose tolerance in those with newly diagnosed type 2 diabetes (T2DM) or prevent progression to T2DM in those with pre-diabetes.
Scientific title
Will testosterone treatment in combination with a lifestyle program normalise glucose tolerance in men with either pre-diabetes or newly diagnosed type 2 diabetes, in comparison to placebo and a lifestyle program?
Secondary ID [1] 279973 0
Nil
Universal Trial Number (UTN)
Trial acronym
T4DM (www.t4dm.org.au)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes mellitus 285890 0
Condition category
Condition code
Metabolic and Endocrine 286083 286083 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Testosterone treatment comprising 1000mg testosterone undecanoate administered by intramuscular injection at enrolment, 6 weeks and subsequently at 3-monthly intervals for 2-4 years. The trial will have 2 years of recruitment and then a further 2 years of treatment and follow-up. In general, each individual's treatment duration will be determined by when in the recruitment period they join the study. Weight Watchers membership. Weight Watchers is a lifestyle program which involves face-to-face meetings and/or access to the on-line program. It provides guidance on healthly eating and exercise. Participants who choose the meeting option will be requested to attend a weekly meeting. The program also involves diarising of food intake and exercise. Weight Watchers membership will start at enrolment and last for 2 years. Participants will be encouraged to participate in this program and will be asked about their compliance at each study visit. Study visits occur at 6 weeks after enrolment and then every 3 months for 2 to 4 years as described above. For more details see www.t4dm.org.au
T4Bone sub-study: Up to 160 participants enrolled at Austin Hospital will have additional CT scan, DEXA scan and blood sample taken every 12 months for two years to assess the impact of the testosterone intervention on bone density, microarchitecture and turnover.
T4Mood and Behaviour (T4MB)sub-study: All T4DM participants from Fiona Stanley Hospital, Queen Elizabeth Hospital, Austin Hospital and Princess Alexandra Hospital are also enrolled onto the T4MB substudy. This sub-study involves completion of a one-page questionnaire at baseline and every 6 months until 3 months after treatment end.
Reminder sub-study: Up to 540 men who are registered for the T4DM study but do not attend for lab screening within 4 weeks of registration will be randomised to receive a reminder to attend for lab screening by either text message or phone call. A further reminder at 8 weeks will be sent if they have still not attended for lab screening.
Telomere Length sub-study: Up to 900 participants will have an additional whole blood sample collected at the 2 year visit. Telomere length will be measured in whole blood at baseline, and at two years.
Screening process evaluation sub-study: Prospective participants of the T4DM study will be invited to take part in the screening process evaluation sub-study. Participants will be eligible to take part if the they are enrolled in the main study or decline the main study from June - December 2016. Participants who have not completed lab screening at the close of recruitment in December 2016 will also be eligible. Participation in the sub-study will involve completion of a 5-10 minute online questionnaire followed by a 10 minute telephone interview for a sub-group of participants. The sub-group will be selected based on willingness and principles of theoretical sampling. The online questionnaire and phone interviews will collect information participants preferences and feedback with regards to the screening process for the T4DM study.
T4DM Run-off sub-study: Up to 700 participants who are enrolled on the T4DM study and have completed study treatment after January 2015 will attend for 7 visits after completing study treatment. This sub-study involves completion of quality of life questionnaires, collection of serum and whole blood samples and assessment of weight and concomitant medications.
Newsletter sub-study: Up to 950 T4DM study participants (either currently on study treatment or completed study treatment) will be randomly allocated to receive one of eight possible email newsletter messages using a factorial design. Variables to be evaluated are subject line (standard vs enhanced), sender characteristics (generic vs nurse) and addressee (generic vs personalised).
Intervention code [1] 284310 0
Prevention
Intervention code [2] 284432 0
Treatment: Drugs
Intervention code [3] 284433 0
Lifestyle
Comparator / control treatment
Placebo intramuscular injection. The placebo will be identical to testosterone undecanoate but without the active ingredient.

Weight Watchers membership including access to online program and/or group program and follow-up phone calls.
Control group
Placebo

Outcomes
Primary outcome [1] 286561 0
2-hour glucose on OGTT in the non-diabetic range range (<11.1mmol/L on 75g OGTT) at 2 years.
Timepoint [1] 286561 0
2 years from baseline
Primary outcome [2] 305788 0
Change in 2 hour glucose at 2 years from baseline
Timepoint [2] 305788 0
2 years from baseline
Secondary outcome [1] 296392 0
Change in fasting glucose, insulin and HbA1C. These outcomes will be measured by blood analysis.
Timepoint [1] 296392 0
Baseline and approximately every 6 months until 3 months after treatment end.
Secondary outcome [2] 296393 0
Change in body weight and waist circumference. Thes outcomes will be measured by clinical assessment.
Timepoint [2] 296393 0
Baseline and every 3 months until 3 months after treatment end.
Secondary outcome [3] 296394 0
Change in body composition as measured by dual energy X-ray absorptiometry (DEXA).
Timepoint [3] 296394 0
Baseline and after 2 years of treatment
Secondary outcome [4] 296395 0
Change in handgrip strength. This outcome will be measured by a dynamometer which is a piece of medical equipment.
Timepoint [4] 296395 0
Baseline and every 6 months until 3 months after treatment end.
Secondary outcome [5] 296396 0
Change in sexual function and lower urinary tract symptoms. These outcomes will be assessed by patient questionnaire (called the IIEF 15 and the IPSS questionnaires).
Timepoint [5] 296396 0
Baseline and every 6 months until 3 months after treatment end.
Secondary outcome [6] 296397 0
Evaluate biomarkers. This outcome will be assessed by blood analysis.
Timepoint [6] 296397 0
Baseline and every 6 months until 3 months after treatment end.
Secondary outcome [7] 296398 0
Impact on psychosocial factors. This outcome will be assessed by patient questionnaire (called the MacArthur Scale of Subjective Social Status).
Timepoint [7] 296398 0
Baseline and every 6 months until 3 months after treatment end.
Secondary outcome [8] 296399 0
Impact on Weight Watchers compliance. Participants will be questioned about their compliance by the study staff at each visit.
Timepoint [8] 296399 0
Baseline, 6 weeks and then every 3 months until 3 months after treatment end.
Secondary outcome [9] 296400 0
Impact on healthcare expenditure. This outcome will be modeled based on information collected from Medicare about participants healthcare usage.
Timepoint [9] 296400 0
At every third follow-up
Secondary outcome [10] 309499 0
Initiation of anti-diabetic pharmacotherapy
Timepoint [10] 309499 0
Baseline and approximately every 3 months until 3 months after treatment end
Secondary outcome [11] 309500 0
Change in Steroid hormone profile from baseline to end of treatment: Plasma total T, dihydroT, estrone (E1), estradiol (E2), SHBG
Timepoint [11] 309500 0
Baseline, 3 months and then approximately yearly until 3 months after treatment end
Secondary outcome [12] 318999 0
Telomere length at baseline and 2 years, and change in telomere length from baseline to 2 years. By laboratory assay using whole blood for DNA collected at these visits (participants in the Telomere Length Sub-study only)
Timepoint [12] 318999 0
Baseline and after 2 years of treatment
Secondary outcome [13] 325419 0
Bone micro-architecture as assessed by HR-pQCT scan which is a new form of CT scan used to asses bone density and structure (participants in the T4Bone sub-study at Austin Hospital only)
Timepoint [13] 325419 0
Every 12 months until treatment end.
Secondary outcome [14] 325420 0
Bone turnover markers (total osteocalcin, undecarboxylated osteocalcin, P1NP and CTX) as measured by blood test (participants in the T4Bone sub-study at Austin Hospital only)
Timepoint [14] 325420 0
Every 12 months until treatment end
Secondary outcome [15] 325421 0
Impact on motivation and healthy lifestyle behaviour as assessed by the T4DM Mood and Behaviours questionnaire which was designed specifically for this study (only participants of the T4MB (Testosterone for mood and behaviour) sub-study.)
Timepoint [15] 325421 0
Baseline and every 6 months until 3 months after treatment end.
Secondary outcome [16] 325422 0
Response to reminders to attend for lab screening following registration to study (only participants of the Reminder sub-study). Response is measured by reviewing study records to determine the proportion of participants who attend for lab screening by 4, 8 and 12 weeks after study registration
Timepoint [16] 325422 0
4 weeks, 8 weeks and 12 weeks after study registration
Secondary outcome [17] 327081 0
Participant (only those participants who are taking part in the screening evaluation sub-study) views on the T4DM screening process. Both quantitative and qualitative data will be collected using online survey and semi-structured telephone interviews.
Timepoint [17] 327081 0
Screening
Secondary outcome [18] 335209 0
Rate and extent of recovery of endogenous serum testosterone and other reproductive hormone serums (dihydrotestosterone, estradiol, luteinising hormone, follicle stimulating hormone and sex hormone-binding globulin) compared to hormone levels at 12 weeks after final injection (T4DM run-off sub-study only)
Timepoint [18] 335209 0
18 weeks, 24 weeks, 30 weeks, 36 weeks, 12 months and 15 months after final injection
Secondary outcome [19] 346541 0
Normalised blood glucose (2 hour glucose <7.8mmol/L) at 2 years.
Timepoint [19] 346541 0
2 years from baseline
Secondary outcome [20] 351414 0
Change in bone mineral density at the spine and hip as measured by dual-energy X-ray absorptiometry (DXA) scan (T4Bone sub-study)
Timepoint [20] 351414 0
Baseline and after 2 years of treatment
Secondary outcome [21] 353245 0
(Participants in newsletter sub-study only) Emailed newsletter opened by participant (yes/no). The outcome will be assessed using analytics provided by the email distribution application.
Timepoint [21] 353245 0
Within 2 weeks of sending newsletter
Secondary outcome [22] 353246 0
(Participants in newsletter sub-study only) At least one link within email newsletter clicked by participant (yes/no). The outcome will be assessed using analytics provided by the email distribution application.
Timepoint [22] 353246 0
Within 2 weeks of sending newsletter

Eligibility
Key inclusion criteria
Men aged 50 – 74 years
Abdominal obesity (waist circumference greater than or equal to 95cm)
Serum testosterone levels of less than or equal to 14 nmol/L
At screening visit, a 2hr plasma glucose greater than or equal to 7.8 and less than or equal to 15 mmol/L in response to a 75 g oral glucose tolerance test (OGTT)
Willing to participate in a lifestyle program co-ordinated by Weight Watchers
Able and willing to meet all protocol-required procedures and visits
Able to personally read and understand the Participant Information and Consent Form and provide written, signed and dated informed consent to participate in study
Minimum age
50 Years
Maximum age
74 Years
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
Testosterone treatment in the past 12 months
Baseline T less than 8 nmol/L , except where the participant has been assessed by a study investigator and all causes of low testosterone other than obesity have been ruled out.
Previously diagnosed Type 2 Diabetes
Symptoms indicating a requirement for specific pharmacotherapy for diabetes
Use of any medication known to affect testosterone or SHBG within the previous 1 month or with an underlying condition where there is an appreciable possibility that these may be required within the next 2 years. Includes medications which:
Affect the production (e.g. opiates, GnRH agonists) or action (e.g. spironolactone) of androgens
Affect the production of Sex Hormone Binding Globulin (SHBG) (e.g. thyroxine, insulin, growth hormone, antiepileptics):- please note thyroxine permitted if the dose has been stable for at least 3 months and will remain so.
Significant hypothalamo-pituitary gonadal (HPG) pathology likely to require treatment with T, excluding cryptorchidism, torsion, orchitis, well-treated hemochromatosis.
Ongoing episode of major depression or other significant psychiatric disorder
Prior history of prostate cancer or :
Greater than upper limit of normal for age-adjusted PSA values
Clinical suspicion of malignancy on digital rectal examination (DRE)
Score of greater than 19 on the IPSS (Q1-7), indicating severe symptoms of Benign Prostatic Hyperplasia (BPH)
Breast, liver cancer or other malignancy, except for non-melanomatous carcinoma of the skin, which could affect compliance with the protocol or interpretation of study results
Significant personal or first-degree family history of thrombophilia, or taking anticoagulants other than low dose Aspirin (<150mg) and/or clopidogrel
Known to be human immunodeficiency virus ( HIV) positive
Major cardiovascular event within the previous 6 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 6 months
Transient Ischaemic Attack (TIA) or stroke within the previous 3 years
Elevated blood pressure (greater than 160 systolic and greater than 100mmHg diastolic) at screening
Haematocrit greater than 50%
Abnormal liver function: ALT, GGT, Bilirubin or ALP greater than 3 times upper limit of normal (ULN)
Known chronic viral hepatitis
eGFR less than 30 mL/minute
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
Previous or planned bariatric surgery
Treatment with anti-obesity drugs or any investigational medication within 6 months prior to informed consent
Known history of anabolic steroid, drug or alcohol abuse within 6 months prior to the time of screening

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 a centralised web-based randomisation system. 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)
Stratified minimisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 2730 0
Concord Repatriation Hospital - Concord
Recruitment hospital [2] 2731 0
Austin Health - Heidelberg Repatriation Hospital - Heidelberg West
Recruitment hospital [3] 2733 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [4] 2734 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [5] 4688 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [6] 4689 0
Fiona Stanley Hospital - Murdoch

Funding & Sponsors
Funding source category [1] 284843 0
Government body
Name [1] 284843 0
National Health and Medical Research Council
Address [1] 284843 0
GPO Box 1421
Canberra ACT 2601
Country [1] 284843 0
Australia
Funding source category [2] 292423 0
Commercial sector/Industry
Name [2] 292423 0
Bayer Australia Ltd
Address [2] 292423 0
Bayer Australia Ltd
Pharmaceuticals Division
875 Pacific Highway, Pymble, NSW, 2073
Country [2] 292423 0
Australia
Funding source category [3] 292424 0
Commercial sector/Industry
Name [3] 292424 0
Eli Lilly Australia Pty Ltd
Address [3] 292424 0
112 Wharf Rd, West Ryde NSW 2114
Country [3] 292424 0
Australia
Primary sponsor type
University
Name
University of Adelaide
Address
North Terrace
Adelaide SA 5000
Country
Australia
Secondary sponsor category [1] 283721 0
None
Name [1] 283721 0
Address [1] 283721 0
Country [1] 283721 0
Other collaborator category [1] 260604 0
University
Name [1] 260604 0
NHMRC Clinical Trials Centre, University of Sydney
Address [1] 260604 0
Locked Bag 77
Camperdown NSW 1450
Country [1] 260604 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286834 0
Sydney Local Health District Human Research Ethics Committee - CRGH
Ethics committee address [1] 286834 0
1st floor
Building 75
Concord Repatriation General Hospital
Hospital Rd
Concord NSW 2139
Ethics committee country [1] 286834 0
Australia
Date submitted for ethics approval [1] 286834 0
01/04/2012
Approval date [1] 286834 0
03/07/2012
Ethics approval number [1] 286834 0
EC00118

Summary
Brief summary
The T4DM study will investigate whether treatment with testosterone in combination with a lifestyle program normalise glucose tolerance in men with either pre-diabetes or newly diagnosed type 2 diabetes, in comparison to placebo and a lifestyle program in men aged 50-74 years. See www.t4dm.org.au for details
Trial website
www.t4dm.org.au
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 33803 0
Prof Gary Wittert
Address 33803 0
C/O NHMRC Clinical Trials Centre Locked Bag 77 Camperdown NSW 1450
Country 33803 0
Australia
Phone 33803 0
+61295625000
Fax 33803 0
Email 33803 0
t4dm@ctc.usyd.edu.au
Contact person for public queries
Name 17050 0
Ms T4DM Project Manager
Address 17050 0
NHMRC Clinical Trials Centre Locked Bag 77 Camperdown NSW 1450
For more details see www.t4dm.org.au
Country 17050 0
Australia
Phone 17050 0
+61295625000
Fax 17050 0
+61 2 9562 5094
Email 17050 0
t4dm@ctc.usyd.edu.au
Contact person for scientific queries
Name 7978 0
Ms T4DM Project Manager
Address 7978 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 7978 0
Australia
Phone 7978 0
+61295625000
Fax 7978 0
+61 2 9562 5094
Email 7978 0
t4dm@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary