Background
Methods/design
Study subjects
Inclusion criteria
- Age > 18 years and <65 years - Previous treatment for testicular cancer - No signs of relapse 1 year after the last treatment (orchiectomy, radiotherapy, chemotherapy) - Serum free testosterone < the age-adjusted mean value and >2 standard deviations (SD) below the age-adjusted mean value - Serum luteinizing hormone (LH) > 2 SD above the age-adjusted mean value |
Exclusion criteria
- Testosterone treatment within the last 6 months - Contraindications to testosterone treatment: (prostate cancer, prostate specific antigen (PSA) > 4 ng/mL), malignancy suspect prostate by digital rectal examination (ALT) > 1.5 upper limit of normal, erythrocyte volume fraction (EVF) > 50%, breast cancer - Symptomatic obstructive sleep apnoea syndrome - Heart failure > New York Heart Association class II - Uncontrolled hypertension: (Systolic blood pressure > 160 mmHg despite antihypertensive treatment, measured at two separate occasions) - Inability to understand information about the trial - Participation in any other clinical trial - Allergy for the active substance or additives in Tostran or placebo. - Known diabetes mellitus, or diabetes mellitus detected at screening or at baseline - Paternity wish at the time of inclusiona
|
Recruitment and informed consent
Randomization and procedures for breakage of randomization code
Blinding
Intervention
Dose adjustment | Dose modifications | Follow-up |
---|---|---|
Starting dose: 10 mg daily (one depression of the piston) | ||
Week 2: 20 mg daily (two depressions of the piston) | ||
Week 4: 30 mg daily (three depressions of the piston) | ||
Week 8: 40 mg daily (four depressions of the piston) | ||
52 weeks: End of treatment | ||
Safety issues | ||
Increase in free testosterone to >3 SD above the age-adjusted mean | Dose adjustment to previous treatment step | Measurement of free testosterone and LH after 14 days and dose adjustment accordingly |
Decrease in LH to < −2 SD below the age-adjusted mean | Dose adjustment to previous treatment step | Measurement of free testosterone and LH after 14 days and dose adjustment accordingly |
Increase in EVF to >52% | Dose adjustment to previous treatment step | Measurement of EVF after 14 days and dose adjustment accordingly |
Plasma PSA > 4 ng/mL at any visit. A PSA increase of >1 ng/mL at visit 7 or visit 8, using plasma PSA at visit 6 as baseline | Referral for urological consultation | According to urological consultation: Stop treatment if increased risk of prostate cancer. Continue treatment at the same treatment step if there is no increased risk of prostate cancer |
An increase in systolic blood pressure > 20 mmHg confirmed at two separate measurements despite antihypertensive therapy, if not due to free testosterone being >3 SD from the age-adjusted mean | Stop treatment | Measurement of blood pressure after 14 days. If still elevated referral to general practitioner |
ALT increase >1.5 upper reference level | Stop treatment | Measurement of ALT after 14 days. If still elevated referral for hepatological consultation |
Any other exclusion criteria becoming apparent during treatment | Stop treatment |
Dose modifications
Planned inclusion
Measurements
Data assessment | Screening | Baseline Week 0 | Dose adjustment 1 Week 2 | Dose adjustment 2 Week 4 | Dose adjustment 3 Week 8 | On treatment Week 26 | Last dose Week 52 | Follow-up Week 64 |
---|---|---|---|---|---|---|---|---|
hCG-stimulation test | x | |||||||
Blood pressure | x | x | x | x | x | x | x | x |
Blood samples | x | x | x | x | x | x | x | x |
Waist circumference | x | x | x | x | ||||
DXA scan | x | x | x | x | ||||
Oral glucose tolerance test | x | x | x | x | ||||
Questionnaires | x | x | x | x | ||||
Anogenital distance | x | x | ||||||
Randomization | x | |||||||
On treatment | x | x | x | x | x | x | ||
Dose adjustment | x | x | x | |||||
Evaluation of side effects | x | x | x | x | x | x | x |
Systemic effects
- Glucose metabolism (fasting glucose, 2 h glucose, insulin, hemoglobin a1c, HOMA-index) - Cholesterol (high density lipoprotein-cholesterol, low density lipoprotein-cholesterol, total cholesterol) - Inflammatory markers (interleukin 1-β, interleukin-6, interleukin-8, tumour necrotic factor-alpha) - Adipocytokines (adiponectin, leptin) - Reproductive hormones (total testosterone, free testosterone, luteinizing hormone) |
Body composition and bone mineral density
- Whole body bone mineral density, whole body t-score, t-score of the lumbar spine and proximal femoral bone - Lean body mass - Whole body fat percent (Z-score) - Visceral adiposity, android fat distribution, gynoid fat distribution |
Anthropomorphic measures
- Waist circumference - Hip circumference - Body mass index - Anogenital distance |
Patient reported outcomes
- Health related quality of Life (EORTC QLQ-C30) - Anxiety and Depression: (Hospital Depression and Anxiety Scale) - Fatigue: (Multiple Fatigue Inventory-20) - Symptoms of testosterone deficiency and erectile dysfunction: (International Index of Erectile Function-15) |