E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Male hypogonadism (total testosterone <3ng/ml) |
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E.1.1.1 | Medical condition in easily understood language |
low total testosterone levels in men |
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E.1.1.2 | Therapeutic area | Diseases [C] - Male diseases of the urinary and reproductive systems [C12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10000193 |
E.1.2 | Term | Male sex hormone abnormalities |
E.1.2 | System Organ Class | 100000004872 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to evaluate whether vitamin D supplementation with 20,000 weekly over 12 weeks significantly increases TT levels when compared to placebo. |
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E.2.2 | Secondary objectives of the trial |
In addition, we also aim to test the hypothesis that vitamin D supplementation improves endocrine parameters (e.g. FT, SHBG, LH, FSH, and estradiol), metabolic parameters as well as sexual, physical and psychological symptoms.
Moreover, we will evaluate whether vitamin D supplementation with 20,000 weekly over 12 weeks improves endocrine parameters (e.g. TT, FT, SHBG, LH, FSH, and estradiol) and metabolic parameters when compared to placebo in eugonadal men.
Further, we will perform genotyping of vitamin D-related polymorphisms to evaluate a possible genetic background of the association of vitamin D with androgen levels. In addition, gene expression analyses of relevant candidate genes in association with pathways of vitamin D and testosterone will be performed at each visit in order to analyze functional changes during vitamin D treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Hypogonadal men:
- TT levels below 3.0 ng/ml (measured at the baseline visit and confirmed at study visit 1)
- 25(OH)D levels below 30 ng/ml (measured at the baseline visit)
- Male, age of ≥ 18 and <70 years
- Written informed consent before entered into study
COntrol group
- TT levels ≥3.0 ng/ml (measured at the baseline visit and confirmed at study visit 1)
- 25(OH)D levels below 30 ng/ml (measured at the baseline visit)
- Male, age of ≥ 18 and <70 years
- Written informed consent before entered into study
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E.4 | Principal exclusion criteria |
- Hypercalcemia defined as a serum calcium > 2,7 mmol/L
- Oral or transdermal testosterone supplementation in the last 2 months before entering the study
- IM testosterone supplementation 6 months before entering the study
- Regular intake of vitamin D supplements before study entry
- Men with chronic diseases (such as diabetes mellitus, thyroid disease, endocrine disturbances in need of treatment (except hypogonadism), or diseases known to interfere with vitamin D intake or very sensitive to vitamin D intake (such as inflammatory disease with granuloma: sarcoidoses, tuberculosis, Mb Wegener, vasculitis, inflammatory bowel disease
- Intake of medication influencing metabolic or endocrine parameters (insulin sensitizers, insulin, glucocorticoids,…) in the last 3 months before study entry
- PSA >4 ng/ml (or >3 ng/ml in men at high risk for prostate cancer) (see state of the art)
- Palpable prostate nodule or induration
- Hematocrit >50%
- Untreated severe obstructive sleep apnea
- Severe lower urinary tract symptoms
- Uncontrolled or poorly controlled heart failure
- A history of prostate cancer, breast cancer, orchidectomy, chromosomal disorders (e.g. Klinefelter Syndrome)
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E.5 End points |
E.5.1 | Primary end point(s) |
Changes in total testosterone levels after vitamin D supplementation. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Changes in
- Endocrine parameters including FT, SHBG, LH, FSH, and estradiol
- Insulin resistance and insulin sensitivity assessed by homeostatic model assessment-insulin resistance (HOMA-IR), HOMA-beta, MATSUDA, and Quantitative Insulin-sensitivity Check Index (QUICKI)
- AUCins and AUCgluc derived from the oral glucose tolerance test
- Lipid levels (total cholesterol, HDL, LDL, triglycerides)
- Fat and lean mass assessed via dual-energy X-ray absorptiometry (DXA)
- Sexual, physical and psychological symptoms
after vitamin D supplementation.
Moreover, we will perform genotyping of vitamin D-related polymorphisms (VDR Cdx-2, Bsm-I, Fok-I, Apa-I, Taq-I, GC, DHCR7 and CYP2R1). In addition, gene expression analyses will be done for biosynthesis and metabolism of male (and female) sex hormones, e.g. androgen receptor (AR), estrogen receptor (ER), aromatase (Cyp19A1), FOXL2 (Forkhead Box Protein L2), hydroxysteroid dehydrogenase 3β (HSD3β), STAR (Steroidogenic acute regulatory protein), Cytochrom-P11 (CYP11), cytochrome P17 (CYP17A1), receptors for follicle stimulating hormone (FSHR) and luteotropic hormone (LHR), SHBG (Sex-hormon binding globulin),…), important anti- and proinflammatoric genes (interleukins, interferon, FOXP3 (forkhead box P3),…), genes of glucose metabolism (IGF-1 (Insulin-like growth factor 1), IGF-1R (Insulin-like growth factor 1 Rezeptor), IGF-BP (Insulin-like growth factor binding proteins), INSL (Insulin-like peptides), insulin rezeptor (IR),…), genes of the vitamin D metabolism (vitamin D rezeptor (VDR), 25-Hydroxylasen (Cyp2R1, Cyp27A1), 24-Hydroxylase (Cyp24A1), 1-alpha-hydroxylase (Cyp27B1),…), genes of the TGF-beta superfamily (inhibins, activins and their receptos, follistatin, transforming growth factors (TGF) and their receptors, bone morphogenetic proteins (BMPs), anti müllerian hormone (AMH), growth and differentiation factor 9 (GDF9),…), as well as genes out ofbone metabolism, such as parathyrin (PTH), klotho, osteocalcin, and GPRC6A. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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the last visit of the last subject undergoing the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 36 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |