Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000071527
Ethics application status
Approved
Date submitted
9/01/2015
Date registered
27/01/2015
Date last updated
20/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Testosterone for Androgen Deficiency-Like Symptoms
Scientific title
Testosterone for Androgen Deficiency-Like Symptoms: A three phase, placebo-controlled, double-blind crossover study for males 40 years or older who believe they have androgen-like deficiency to assess whether testosterone gel treatment is superior to a placebo gel.
Secondary ID [1] 285934 0
Nil known
Universal Trial Number (UTN)
Trial acronym
T4ADS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Androgen deficiency 293862 0
Condition category
Condition code
Metabolic and Endocrine 294165 294165 0 0
Other metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Eligible participants will visit the study centre 11 times over a 27 week period. They will be randomised to receive either daily Testosterone gel 1% (Androgel) or a placebo gel in the first 6 week treatment period and the alternative gel in the second treatment period. The men will chose which gel they prefer to use for the third treatment period. There will be a 3 week washout period between each treatment period.
The gel is delivered in a pump pack. Pushing the pump 6 times will deliver 7.5 mg of gel (i.e. 50mgs testosterone) and is to be applied at about the same time each day preferably in the morning to clean, dry healthy skin on the trunk.
Treatment period 1 -. He will receive 3 containers of the gel which he will apply daily for 6 weeks. During this time he will return for 2 visits at 3 and 6 weeks which will involve blood collection for safety and research purposes and completion of health questionnaires. At the 6 week visit the empty gel bottles are returned
Wash out period 1 – 3 weeks of no treatment
Treatment period 2 - he will receive 3 containers of the alternate gel which he will apply daily for 6 weeks. During this time he will return for 2 visits at 3 and 6 weeks which will involve blood collection for safety and research purposes and completion of health questionnaires. At the 6 week visit the empty gel bottles are returned.
Wash out period 2 – 3 weeks of no treatment
Treatment period 3 – participant will choose which gel he preferred in the first or second treatment period and will be given his choice of gel to use for another 6 week period. As at the other treatment visits there will be blood collection for safety and research purposes and completion of health questionnaires.
Intervention code [1] 290912 0
Treatment: Drugs
Comparator / control treatment
Placebo gel. The gel is delivered in a pump pack. Pushing the pump 6 times will deliver 7.5 mg of matching gel (i.e. no testosterone) and is to be applied at about the same time each day preferably in the morning to clean, dry healthy skin on the trunk.
Control group
Placebo

Outcomes
Primary outcome [1] 293959 0
To evaluate whether androgen deficiency-like symptoms improve following 6 weeks of testosterone gel application significantly more than 6 weeks of placebo gel treatment.

SF36 Health Survey; IIEF - 15 Questionnaire; International Prostate Symptom Score; Physical Activity (Active Australia); WHO Well being Index 5 scale; Personal mastery scale (PC-SAD; Perlin & Schooler 1978); Aging Male Symptoms Scale questionnaires will be completed every 3 weeks from baseline to completion of treatment period three to assess this outcome.

Every 3 weeks from baseline to completion of treatment period 3 hormone levels will be collected. These hormones will be T - Testosterone, DHT - Dihydrotestosterone, E2 - Estradiol, SHBG - Sex Hormone Binding Globulin, LH - Luteinizing Hormone, FSH - Follicle Stimulating Hormone
Timepoint [1] 293959 0
Quality of Life questionnaires and serum hormone levels will be collected every 3 weeks from baseline to completion of treatment period three to assess this outcome.
Secondary outcome [1] 312234 0
To determine whether pre-treatment (baseline) blood testosterone levels predict a superior response to testosterone compared with placebo.

SF36 Health Survey; IIEF - 15 Questionnaire; International Prostate Symptom Score; Physical Activity (Active Australia); WHO Well being Index 5 scale; Personal mastery scale (PC-SAD; Perlin & Schooler 1978); Aging Male Symptoms Scale questionnaires will be completed every 3 weeks from baseline to completion of treatment period three to assess this outcome.

Every 3 weeks from baseline to completion of treatment period three hormone levels will be collected. These hormones will be T - Testosterone, DHT - Dihydrotestosterone, E2 - Estradiol, SHBG - Sex Hormone Binding Globulin, LH - Luteinizing Hormone, FSH - Follicle Stimulating Hormone
Timepoint [1] 312234 0
Quality of Life questionnaires and serum hormone levels will be collected every 3 weeks from baseline to completion of treatment period three to assess this outcome.

Secondary outcome [2] 312235 0
To determine the response to the preferred treatment (testosterone or placebo) is reproducible where the preferred treatment remains blinded

SF36 Health Survey; IIEF - 15 Questionnaire; International Prostate Symptom Score; Physical Activity (Active Australia); WHO Well being Index 5 scale; Personal mastery scale (PC-SAD; Perlin & Schooler 1978); Aging Male Symptoms Scale questionnaires will be completed every 3 weeks from baseline to completion of treatment period three to assess this outcome.

Every 3 weeks from baseline to completion of treatment period three hormone levels will be collected. These hormones will be T - Testosterone, DHT - Dihydrotestosterone, E2 - Estradiol, SHBG - Sex Hormone Binding Globulin, LH - Luteinizing Hormone, FSH - Follicle Stimulating Hormone
Timepoint [2] 312235 0
Quality of Life questionnaires and serum hormone levels will be collected every 3 weeks from baseline to completion of treatment period three to assess this outcome.

Eligibility
Key inclusion criteria
Men aged 40 years or older
Believed to have androgen deficiency (AD)
Symptoms consistent with AD (according to US clinical guidelines)
Provides written, informed consent and is willing to comply with study requirements
Minimum age
40 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
Pathologically-based AD
Major chronic illness causing serious disability or with life expectancy less then 2 years in the opinion of the investigator
Major cardiovascular event (new or worsened angina, infarction, angioplasty, uncontrolled arrhythmia or hypertension) within the last 6 months
Contraindication to testosterone including prostate or breast cancer.
History of androgen or other drug abuse within last year.
History of HIV or viral hepatitis.
Skin disease that may interfere with transdermal drug administration.
History of major psychiatric disease or psychological condition that may limit understanding and compliance with study requirements.
Regular use of medications that interfere with absorption, metabolism or action of testosterone and may require dosage change during the study.
Haematocrit over 0.50 or history of polycythaemia

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated randomised list
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
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Analysis of Variance - ANOVA for cross-over studies allowing for post-hoc stratification into symptom cluster (sexual versus energy symptoms)

Due to the powerful with-subject, cross-over design, the principal determinant of sample size will be to have sufficient power to determine an important goal of the study, that is whether pre-treatment blood T will predict the magnitude of the specific net T effect (ie T minus placebo effect) on the primary and secondary endpoints. Because the study is the first to adopt the design feature of not requiring any pre-entry blood T threshold, there is no prior data on which to base a formal sample size determination for this endpoint.

The proposed sample size is based on the following background and estimates:
*Objective dose-response characteristics were established for testosterone in studies of older men (1,2) using muscle and fat endpoints. This study included 60 men with suppressed endogenous serum testosterone who were administered one of 5 testosterone doses (ranging from sub- to supra- physiological, 25-600 mg weekly) creating tightly dose-dependent serum testosterone levels with clear dose-dependent effects on muscle mass and strength, and fat mass. For muscle mass, the correlation between testosterone dose (and hence serum testosterone) and increase in muscle strength was 0.40.
*Our previous data on serum testosterone in similar aged but healthy men (3) has a mean serum testosterone of 16.7 (SD 5.4) nmol/L and a 95% CI of 8.2 – 28.2. Given the non-healthy state we expect a range of serum testosterone of 6 – 24 nmol/L in our study participants. The only useful guide to magnitude (and timescale) of symptom responses to testosterone administration in men with AD is a study of 40 AD-deficient men aged 18- 65 yr where linear analog scale responses increased from 10-30% (between-person SD ~10%) before treatment to peak at 50-60% by 3-6 weeks (4).
*We assume a range of 20% to 60% for baseline LSS score and a doubling of LSS score (mean 40% to 80%) to represent the minimum worthwhile clinical improvement. Over a range of baseline serum testosterone from 6-24 nmol/L, this is equivalent to a slope of 2.2 % per nmol/L.
*Using a linear regression of LSS score on serum testosterone, a sample size of 100 will have >80% power to detect at least a doubling of LSS score even if expected correlation of 0.40 drops to 0.30 (PASS software, linear regression module, two-sided a test of slope=2.2 vs null hypothesis (slope=0) with SDx=5.4, residual variance=correlation).

1. Storer TW, Woodhouse L, Magliano L, Singh AB, Dzekov C, Dzekov J, Bhasin S.Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men. J Am Geriatr Soc. 2008.
2. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, Lee M, Yarasheski KE, Sinha-
Hikim I, Dzekov C, Dzekov J, Magliano L, Storer TW. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle.
J Clin Endocrinol Metab. 2005;90(2):678-688.
3. Sartorius G, Spasevska S, Idan A, Turner L, Forbes E, Zamojska A, Allan C, Ly L, Conway A, McLachlan R, Handelsman D. Serum Testosterone, Dihydrotestosterone and Estradiol Concentrations in Older Men Self-Reporting Very Good Health:The Healthy Man Study. Clin Endocrinol (Oxf). 2012;77(7):755-763.
4. Jockenhovel F, Minnemann T, Schubert M, Freude S, Hubler D, Schumann C, Christoph A, Gooren L, Ernst M. Timetable of effects of testosterone administration to hypogonadal men on variables of sex and mood. Aging Male. 2009;12(4):113-118.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
18/01/2016
Actual
16/02/2016
Date of last participant enrolment
Anticipated
Actual
7/07/2016
Date of last data collection
Anticipated
28/02/2017
Actual
25/01/2017
Sample size
Target
40
Accrual to date
Final
43
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 3308 0
Concord Repatriation Hospital - Concord
Recruitment postcode(s) [1] 9090 0
2139 - Concord Repatriation Hospital

Funding & Sponsors
Funding source category [1] 290521 0
Hospital
Name [1] 290521 0
Department of Andrology, Concord Repatriation General Hospital
Country [1] 290521 0
Australia
Primary sponsor type
Hospital
Name
Department of Andrology, Concord Repatriation General Hospital
Address
Department of Andrology, Building 22
Concord Repatriation General Hospital
Hospital Road
CONCORD, NSW 2139
Country
Australia
Secondary sponsor category [1] 289216 0
None
Name [1] 289216 0
Address [1] 289216 0
Country [1] 289216 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292171 0
Sydney Local Health District - CRGH (EC00118)
Ethics committee address [1] 292171 0
Human Research Ethics Committee - CRGH
Concord Repatriation General Hospital
Building 75, Hospital Road
CONCORD NSW 2139
Ethics committee country [1] 292171 0
Australia
Date submitted for ethics approval [1] 292171 0
Approval date [1] 292171 0
07/10/2014
Ethics approval number [1] 292171 0
HREC/14/CRGH/140

Summary
Brief summary
The T4ADS study will investigate whether androgen deficiency-like symptoms, such as decreased sense of well-being, energy, libido, motivation, improve following 6 weeks of testosterone (T) gel application significantly more than during 6 weeks of placebo gel treatment.
The study will run at the Department of Andrology, CRGH and will aim to recruit 40 men with possible androgen deficiency-like symptoms from the local community.
Men 40 and over will be invited to join the study if they or their own doctor believe they have androgen deficiency.
Volunteers interested in participation will be screened for eligibility by medical history, physical examination and blood tests.
Eligible and consenting participants will be randomised at enrolment to receive either T or placebo gel as their first 6 week treatment and the alternative gel in the second treatment period. The third 6 week treatment period will let the men chose which gel they prefer to use. Study visits will be over a total of 27 weeks.
It is hoped that androgen deficiency-like symptoms improve significantly following 6 weeks of T gel application than during 6 weeks of placebo gel treatment. We would also like to determine whether pre-treatment blood T levels predict a superior response to T compared to placebo and whether the participants preferred treatment, either T or placebo is reproducible when the preferred treatment remains blinded.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 53890 0
Prof David Handelsman
Address 53890 0
Department of Andrology, Building 22
Hospital Road
Concord Repatriation General Hospital
CONCORD NSW 2139
Country 53890 0
Australia
Phone 53890 0
+61 2 97677222
Fax 53890 0
Email 53890 0
[email protected]
Contact person for public queries
Name 53891 0
Prof David Handelsman
Address 53891 0
Department of Andrology, Building 22
Hospital Road
Concord Repatriation General Hospital
CONCORD NSW 2139
Country 53891 0
Australia
Phone 53891 0
+61 2 97677222
Fax 53891 0
Email 53891 0
[email protected]
Contact person for scientific queries
Name 53892 0
Prof David Handelsman
Address 53892 0
Department of Andrology, Building 22
Hospital Road
Concord Repatriation General Hospital
CONCORD NSW 2139
Country 53892 0
Australia
Phone 53892 0
+61 2 97677222
Fax 53892 0
Email 53892 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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