Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Vitamin D Supplementation and Male Infertility: The CBG-study a Randomized Clinical Trial

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Martin Blomberg Jensen, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier:
NCT01304927
First received: February 25, 2011
Last updated: November 5, 2014
Last verified: November 2014
  Purpose

Today, it is evident that vitamin D (VD) has more widespread effects than the classical actions related to bone mineralization and calcium homeostasis1. VD deficiency results in impaired reproductive performance in various species of animals, and recently the investigators have shown that the VD receptor (VDR), activating (CYP2R1, CYP27A1, CYP27B1) and inactivating (CYP24A1) enzymes are expressed in the human testis, epididymis, seminal vesicle, prostate and spermatozoa. Our following functional studies showed that VD increases intracellular calcium in mature spermatozoa, and hence may be important not only for spermatogenesis but also for sperm maturation. A new, and yet unpublished cross sectional study of 300 young healthy Danish men showed that men with lower levels of serum VD have significantly lower number of normally developed and motile spermatozoa. Hitherto, most cases of male infertility have been classified as "idiopathic", and infertile couples have been referred to symptomatic treatment at infertility clinics. These fertility treatments are often physically demanding for the female partner as well as expensive for the health care system. Any treatment that might improve semen quality of involuntary infertile men would be beneficial both for the infertile couples and the society in general. Our findings that VD may play a role for human semen quality have not yet been tested clinically. However, if VD supplementation proves efficient this opens for the first time for a causal, safe and cheap treatment of at least some cases of "idiopathic" impaired semen quality. The investigators believe our new human data supported by the results from the VD deficient and VDR KO animal studies and the high proportion of VD deficient Danish men provide sufficient evidence to initiate a randomized clinical trial of VD supplementation to infertile men. Infertile men have also have unfavorable altered levels of sex hormones and higher mortality than fertile men. Since VD deficiency is associated with increased mortality, regulation of aromatase, immune system, bone metabolism, glucose metabolism, cardiovascular system etc. our suggested clinical trial may also be able to evaluate several secondary endpoints in addition to the potential effect on semen quality.


Condition Intervention Phase
Male Infertility
Drug: Cholecalciferol and calcium
Other: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Vitamin D Supplementation and Male Infertility: The Copenhagen Bone-Gonadal Study a Double Blinded Randomized Clinical Trial

Resource links provided by NLM:


Further study details as provided by Rigshospitalet, Denmark:

Primary Outcome Measures:
  • semen quality [ Time Frame: 150 days ] [ Designated as safety issue: No ]
    difference in semen quality (semen variables total sperm count, sperm concentration, sperm motility, sperm morphology and semen volume) between VD and placebo treated men after 150 days of treatment.

  • sperm motility [ Time Frame: 150 days ] [ Designated as safety issue: No ]
    Differences in Sperm motility (ABC) and progressive sperm motility (AB) between placebo and VD group, supported by other motility measures such as length of penetration in egg media and difference in motility over time (3-5 hours from ejaculation)between VD and placebo treated men

  • sperm morphology [ Time Frame: 150 days ] [ Designated as safety issue: No ]
    Differences in percentage of spermatozoa with normal morphology assessed according to strict criteria between placebo and VD group.

  • sperm concentration [ Time Frame: 150 days ] [ Designated as safety issue: No ]
    Differences in sperm concentration between placebo and VD group.

  • total sperm count [ Time Frame: 150 days ] [ Designated as safety issue: No ]
    Differences in total sperm count between placebo and VD group.

  • semen volume [ Time Frame: 150 days ] [ Designated as safety issue: No ]
    Differences in semen volume between placebo and VD group.


Secondary Outcome Measures:
  • Inhibin-B [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    Difference in serum levels of Inhibin B between placebo and VD group after 90 and/or 150 days

  • Testosterone [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    Difference in serum levels of total and free testosterone between placebo and VD group after 90 and/or 150 days

  • AMH [ Time Frame: 90 and 150 ] [ Designated as safety issue: No ]
    Difference in serum levels of anti-müellerian hormone (AMH) between placebo and VD group after 90 and/or 150 days

  • estrogen [ Time Frame: 90 and 150 ] [ Designated as safety issue: No ]
    Difference in serum levels of estrogen (estradiol) between placebo and VD group after 90 and/or 150 days

  • LH [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    Difference in serum levels of lh (luteinizing hormone) between placebo and VD group after 90 and/or 150 days

  • FSH [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in FSH (follicle stimulating hormone) between placebo and VD group after 90 and/or 150 days

  • SHBG [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in SHBG (sex hormone binding hormone) between placebo and VD group after 90 and/or 150 days

  • DXA scan [ Time Frame: 150 days ] [ Designated as safety issue: No ]
    difference in fat mass, fat free mass, muscle mass and bone mineral density evaluated by full body DXA scan between placebo and VD group after 150 days

  • Circulating metabolites of Vitamin D [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following VD metabolites inactive VD2 and VD3,25-hydroxy-VD2, 25-hydroxy-VD3, 1,25(OH)2D3, 24,25(OH)2D3, and 1,24,25(OH)2D3 between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • PTH [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of PTH (parathyroid hormone between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • alkaline phosphatase [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of alkaline phosphatase (also bone specific subtype) between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • calcium [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of calcium ( meaning total calcium, calcium ion and albumin corrected calcium) between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • phosphate [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of phosphate between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • FGF23 [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of FGF23 (both intact and fragmented) between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • Klotho [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of klotho (also subtypes) between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • osteocalcin [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of osteocalcin between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • osteopontin [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of osteopontin between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • Rank-L [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of Rank-L between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • calcitonin [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of calcitonin between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • bone markers [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of bone markers such as procollagen III between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • change in the method of assisted reproductive technique or number of pregnancies [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the type of method used IUI, IVF, ICSI and in the number of achieved pregnancies between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • change in the number of spontaneous pregnancies [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the number of spontaneous achieved pregnancies between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • blood pressure [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in systolic and/or diastolic blood pressure between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • CYP24A1 expression at the annulus [ Time Frame: 150 days ] [ Designated as safety issue: No ]
    difference CYP24A1 expression at the annulus of human spermatozoa between placebo and VD group after 150 days and between the initial level (day 0) and 150 days in both arms.

  • Bone and calcium regulators in seminal fluid [ Time Frame: 150 days ] [ Designated as safety issue: No ]
    difference in seminal fluid concentration of pH, HCO3-, calcium, zinc, phosphate, VD, 1,25(OH)2D3, 25-OHD3, 24,25(OH)2D3, 1,24,25(OH)2D3, FGF23, Klotho, osteocalcin, osteopontin between placebo and VD group after 150 days and between the initial level (day 0) and 150 days in both arms.

  • weight and BMI [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in weight and BMI between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • Glucose metabolism [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in serum level of glucose, Hb1Ac, cholesterol, lipid profile, insulin, leptin, adiponectin, C-peptid, HOMA, insulin sensitivity, incretin hormones (such as GLP1 and 2)between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • Growth and IGF axis [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in serum level of GH, IGF-I, IGFBP-3 between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • tumor markers [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in PSA (prostate specific antigen both free and bound) and CEA ( carcino embryonic antigen)between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • stress hormones [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in serum level of cortisol, ACTH and copeptin between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • prolactin [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in serum level of prolactin between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • kidney and cardiovascular markers [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in serum level of creatinin, albumin, urea, urea acid (urat), creatinine clearance, renin, aldosteron, angiotensinogen, B2-microglobulin, and angiotensin 2 between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • liver markers [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in serum level of aminotransferases (ALAT, ASAT, GGT), LDH, amylase, bilirubin between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • infectious disease [ Time Frame: 28, 90 and 150 days ] [ Designated as safety issue: No ]
    difference in frequency and severity of infectious diseases such as cold, sinusitis, tonsillitis, laryngitis, pneumonia, UVI, gastroenteritis, skin infections. between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • fever [ Time Frame: 28, 90 and 150 days ] [ Designated as safety issue: No ]
    difference in frequency and severity of fever episodes between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • inflammatory markers [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of acute phase reactants such as CRP (C reactive peptide), Ferritin, procalcitonin, leukocytes, thrombocytes, reticulocytes, RBC, haematocrit, complement, immunoglobulins, auto-antibodies such as ANA, antiphopholipantibody, rheumafactor and coagulation factors between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • natriuretic peptides [ Time Frame: 90 and 150 days ] [ Designated as safety issue: No ]
    difference in the following serum levels of ANP and BNP between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.

  • DNA Fragmentation [ Time Frame: 0-150 ] [ Designated as safety issue: No ]
    DNA fragmentation index will be investigated on 75-100 randomly selected individuals prior to and following the intervention with either placebo or vitamin D

  • Predefined Subgroup analyses [ Time Frame: day 90 and 150 ] [ Designated as safety issue: No ]
    Predefined subgroups. Vitamin D levels: a. deficient< 25 nM, b. insufficient 25-50 nM Season: a. Winter, b. spring, c. summer and d. autumn or x. Winter(October-March)and y.Summer(April to September) Serum calcium ion: a. =/<1.20 nM , b. > 1.20 nM Sperm concentration: a. < 5 million/ml, b. 5-20 million/ml,c. > 20 million/ml Inhibin B: a. < 100 pg/ml ,b. 100-150 pg/ml, c. > 150 pg/ml BMI: a. < 25 , b. 25-30, c. > 30 Cryptorchidism: a. YES/NO


Estimated Enrollment: 300
Study Start Date: February 2011
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Cholecalciferol + calcium
Group of intervention: Each man will receive 300,000 IU (7500 ug) Cholecalciferol (VD3) orally once after blood and semen sampling and performed DXA scan. Thereafter they will receive VD tablets of 1,400 IU (35 ug) + 500 mg calcium daily for 3 months. At 3 months a clinical control and blood sampling will be performed, followed by continued daily intake of 1400 IU VD3 + 500 mg calcium. At end of treatment at five months after inclusion the men deliver two semen samples, have a blood sample drawn and a DEXA scan performed.
Drug: Cholecalciferol and calcium
Initial one dose oral mixture of 300.000 IU Cholecalciferol followed by 5 months treatment with one tablet daily containing 35 ug Cholecalciferol and 500 mg calcium
Other Name: Inactive vitamin D
Placebo Comparator: placebo
Group receiving placebo: Each man will receive placebo oral mixture once after blood- and semen sampling and performed DXA scan. Thereafter they will receive placebo tablets daily for 3 months. At 3 months a clinical control and blood sampling will be performed, followed by continued daily intake of placebo. At end of treatment at five months after inclusion the men deliver two semen samples, have a blood sample drawn and a DEXA scan performed.
Other: Placebo
microcrystalline cellulose maltodextrin Arachidis oil

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male with an age > 18 years old
  • Referred for male infertility with sperm concentration >= 0.01 million/ml. Additionally, all men must have either sperm concentration < 20 million/ml or < 50% progressive motile spermatozoa or < 12% morphological normal spermatozoa using strict criteria

Exclusion Criteria:

  • Men with chronic diseases (such as diabetes mellitus, Thyroid disease, endocrine disturbances in need of treatment, malignant disease, or diseases known to interfere with VD intake or very sensitive to VD intake (such as inflammatory disease with granuloma: sarcoidoses, tuberculosis, Wegeners, vasculitis, inflammatory bowel disease (Crohn's and colitis ulcerosa etc).
  • Men with present or previous malignant disease
  • If there is an indication for testis biopsy and it is planned or conducted within the next 6 months
  • Serum 25-hydroxy-D3 > 50 nmol/l at the time of inclusion
  • Serum Calcium ion > 1,35 mmol/l
  • Inhibin-B < 30 pg/ml
  • Intake of vitamin D above 15 ug daily
  • Allergy towards vitamin D or arachidis oil (peanuts)
  • Men with total or partly obstructive oligospermia and men who had vasectomy performed

Criteria for drop out:

  • Abrogation of the treatment
  • Newly diagnosed endocrine, calcium metabolic disease, parathyroid, thyroid, diabetes or other endocrine disease in need of treatment
  • New malignant disease
  • Treatment with chemotherapy, immunomodulating therapy, salazopyrin
  • Oral or iv treatment with steroid hormones
  • Treatment with diuretics, antihypertensive treatment, treatment the heart, calcium channel blockers
  • Development of vitamin d intoxication
  • If testis biopsy is performed or other surgery in the genital region during the trial
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01304927

Locations
Denmark
Rigshospitalet
Copenhagen, Denmark, 2100
Sponsors and Collaborators
Rigshospitalet, Denmark
Investigators
Principal Investigator: Martin Blomberg Jensen, MD Department of growth and reproduction, Rigshospitalet
  More Information

No publications provided

Responsible Party: Martin Blomberg Jensen, MD, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT01304927     History of Changes
Other Study ID Numbers: 2010124801, 2010-024588-42, H-4-2010-138
Study First Received: February 25, 2011
Last Updated: November 5, 2014
Health Authority: Denmark: Danish Dataprotection Agency
Denmark: Danish Medicines Agency
Denmark: The Regional Committee on Biomedical Research Ethics

Keywords provided by Rigshospitalet, Denmark:
Reproduction
Sex hormones
Glucose metabolism
Bone metabolism
Calcium
Sperm
testis
bone
endocrinology

Additional relevant MeSH terms:
Infertility
Infertility, Male
Genital Diseases, Female
Genital Diseases, Male
Calcium, Dietary
Cholecalciferol
Ergocalciferols
Vitamin D
Vitamins
Bone Density Conservation Agents
Growth Substances
Micronutrients
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 25, 2014