TNFSF11 Inhibition and Fertility: a Prospective Study

NCT02422108 | Completed Phase 2 DMC

• 2 other identifiers: CBG-study2H-15001992
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

The receptor activator of NF-kB ligand (RANKL) system is considered important for bone homeostasis and comprises three important factors. RANKL exist in three isoforms but the predominant function is mediated by the transmembrane ligand that binds to a specific receptor (receptor activator of NF-KB (RANK)) on a neighbour cell that subsequently activates NFKB and regulates cell cycle OPG is an endogenous secreted protein that binds RANKL and inhibits its signalling. Thus, the RANK/RANKL system is vital for activation of the bone resorbing cells (osteoclasts). In bone the bone synthesizing cells (osteoblasts) express RANKL that signals to RANK on the immature osteoclasts. This induces proliferation and activation of the cells they start to proliferate and resorp bone. OPG is produced by somatic cells in the bone and this production is regulated by sex hormones, TGF-B and various other substances. Today a human made recombinant antibody against RANKL, Denosumab is used to treat osteoporosis as it inhibits RANKL signalling and thus causes less bone resorption in humans. RANKL, RANK and OPG are expressed in the testis and this pathway appears to be a novel regulator of germ cell proliferation. Decreased semen quality is a major factor of male infertility. Semen quality is a measure of the ability of the sperm to accomplish fertilization. Evaluation of male fertility potential is today basically conducted through semen analysis. There is no treatment for men with no sperm in the ejaculate and there exist no drug that can increase sperm counts.Therefore, drugs that can lower RANKL expression/activity for instance an antibody against RANKL such as Denosumab may be used for this new indication: A new treatment option of infertile men with impaired semen quality.

Conditions

Testis; Infertility; Sperm

Keywords

RANKL

Outcome Measures

Primary Outcomes (1)

• Change in sperm production

  evaluated by determining total sperm count and sperm concentration

  after 5, 20, 40, 80, 120, 180 days

Secondary Outcomes (17)

• change in sperm DNA fragmentation index

  after 20 and 120 days

• change in number of motile sperm

  after 5, 20, 40, 80, 120, 180 days

• change in number of morphological normal sperm

  after 5, 20, 40, 80, 120, 180 days

• change in sperm motility

  after 5, 20, 40, 80, 120, 180 days

• change in semen morphology

  after 5, 20, 40, 80, 120, 180 days

Study Arms (1)

intervention

EXPERIMENTAL

Denosumab (Prolia) 60 mg s.c.

Drug: Denosumab

Interventions

Denosumab DRUG

Also known as: Prolia

intervention

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male with an age \> 18 years old
• Referred for male infertility with sperm concentration \>= 0.1 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

You may not qualify if:

• Men with chronic diseases such as
• diabetes mellitus
• Thyroid disease
• endocrine disturbances in need of treatment
• malignant disease
• or diseases known to interfere with calcium homeostasis (such as inflammatory disease with granuloma: sarcoidoses, tuberculosis, Wegeners, vasculitis, inflammatory bowel disease (Crohn's and colitis ulcerosa etc).
• Men with previous testis cancer
• 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
• Serum Calcium ion \< 1,18 or \> 1,35 mmol/l
• Serum OPG \>4 pg/ml
• Serum PTH \<1.6 or \>6 pmol/l
• Inhibin-B \< 50 pg/ml
• Latex Allergy
• no good oral condition or major implants

Sponsors & Collaborators

• Martin Blomberg Jensen: lead

Study Sites (1)

Rigshospitalet

Copenhagen, 2100, Denmark

Location

Related Publications (15)

• Anastasilakis AD, Toulis KA, Goulis DG, Polyzos SA, Delaroudis S, Giomisi A, Terpos E. Efficacy and safety of denosumab in postmenopausal women with osteopenia or osteoporosis: a systematic review and a meta-analysis. Horm Metab Res. 2009 Oct;41(10):721-9. doi: 10.1055/s-0029-1224109. Epub 2009 Jun 17.

  PMID: 19536731 BACKGROUND

• Anastasilakis, A. D., et al.

  BACKGROUND

• Anastasilakis AD, Toulis KA, Polyzos SA, Terpos E. RANKL inhibition for the management of patients with benign metabolic bone disorders. Expert Opin Investig Drugs. 2009 Aug;18(8):1085-102. doi: 10.1517/13543780903048929.

  PMID: 19558335 BACKGROUND

• Blomberg, Jensen M.

  BACKGROUND

• one, H. G., et al.

  BACKGROUND

• Boonen, S., et al.

  BACKGROUND

• Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11.

  PMID: 19671655 BACKGROUND

• Jorgensen, A., et al.

  BACKGROUND

• Kwiecinski GG, Petrie GI, DeLuca HF. Vitamin D is necessary for reproductive functions of the male rat. J Nutr. 1989 May;119(5):741-4. doi: 10.1093/jn/119.5.741.

  PMID: 2723823 BACKGROUND

• Papapoulos, S., et al.

  BACKGROUND

• Polyzos, S. A., et al.

  BACKGROUND

• Schwarz, P., et al.

  BACKGROUND

• Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001 May;16(5):972-8. doi: 10.1093/humrep/16.5.972.

  PMID: 11331648 BACKGROUND

• Toulis KA, Anastasilakis AD. Increased risk of serious infections in women with osteopenia or osteoporosis treated with denosumab. Osteoporos Int. 2010 Nov;21(11):1963-4. doi: 10.1007/s00198-009-1145-1. Epub 2009 Dec 15. No abstract available.

  PMID: 20012939 BACKGROUND

• Uhland AM, Kwiecinski GG, DeLuca HF. Normalization of serum calcium restores fertility in vitamin D-deficient male rats. J Nutr. 1992 Jun;122(6):1338-44. doi: 10.1093/jn/122.6.1338.

  PMID: 1588451 BACKGROUND

MeSH Terms

Conditions

Infertility

Interventions

Denosumab

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Martin M Blomberg Jensen, MD, DMSc

  Rigshospitalet, Denmark

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Senior Researcher

Study Record Dates

• First Submitted: April 6, 2015
• First Posted: April 21, 2015
• Study Start: May 1, 2015
• Primary Completion: February 1, 2017
• Study Completion: January 1, 2019
• Last Updated: March 27, 2019

Record last verified: 2019-03

Locations

DK (1)