NT-NOA - Novel Treatment of Some Men With Non-Obstructive Azoospermia

NCT06706414 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: 2024-512996-11-00
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

This clinical interventional study aims to assess whether treatment with denosumab in combination with letrozole can improve sperm production in infertile men with non-obstructive azoospermia selected by serum anti-mullerian hormone (AMH) as a positive predictive biomarker.

Conditions

Infertility, Male

Outcome Measures

Primary Outcomes (1)

• Sperm in the semen sample or TESE on day 90

  Finding of sperm in the semen sample (day 80) or TESE (day 90), that subsequently will be compared with prior TESE if available.

  Day 80 (semen sample) and 90 (TESE) after inclusion

Secondary Outcomes (12)

• The change in expression of proliferation (KI-67, PCNA) and apoptosis (cPARP, TUNEL assay) markers in TESE tissue at day 90 compared to prior TESE if available

  Day 90 after inclusion

• The number of participants with sperm in the ejaculate (sperm pr. milliliter) assessed by semen samples delivered on day 14

  Day 14 after inclusion

• The number of participants with sperm in the ejaculate (sperm pr. milliliter) assessed by semen samples delivered on day 80

  Day 80 after inclusion

• The number of pregnancies achieved by sperm from the ejaculate or by TESE

  Day 180 after inclusion

• The change in serum levels of reproductive hormones (FSH, LH, AMH, Inhibin B og INSL3) on day 14

  Day 14 after inclusion

Other Outcomes (6)

• The change in seminal fluid levels of RANKL, OPG, AMH and Inhibin B on day 14

  Day 14 after inclusion

• The change in seminal fluid levels of RANKL, OPG, AMH and Inhibin B on day 80

  Day 80 after inclusion

• The change in serum levels of minerals (calcium, phosphate, magnesium, zink, bikarbonate, citrate) on day 14

  Day 14 after inclusion

Study Arms (1)

Denosumab

EXPERIMENTAL

Subcutaneous injection with 60 mg Denosumab once

Drug: Denosumab (Prolia); Drug: Letrozole (Aromatase Inhibitors)

Interventions

Letrozole (Aromatase Inhibitors) DRUG

Letrozole oral tablet 2.5 mg once daily

Denosumab

Denosumab (Prolia) DRUG

Subcutaneous injection with 60 mg Denosumab once

Denosumab

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Infertile men ≥ 18 years and \< 60 years of age with azoospermia with normal semen volume (\> 0.9 mL) verified by minimum 2 semen samples.
• No identifiable cause of obstruction.
• Testis size (Prader Orchidometer) ≤ 15 mL on both sides in patients where no prior TESE is available
• Serum AMH levels ≥5 pmol/L.

You may not qualify if:

• Chronic diseases, defined as diagnosis where signs, symptoms, and treatment imply an expected long duration and lack of a cure, such as diabetes mellitus, metabolism disorders, osteoporosis, colitis, etc.
• Chromosome anomalies e.g. Klinefelter Syndrome, XX male
• AZFa/b/c microdeletions besides b2/b3 og gr/gr
• Detected CFTR mutation
• Men with current or previous malignancies, or at potential risk of testicular cancer after baseline examination and ultrasound will be excluded
• Men with hypocalcemia at baseline, defined as albumin corrected calcium \< 2.17 mmol/L or total calcium \< 2.14 mmol/L
• Serum vitamin D (25OHD) levels \< 25 nmol/L
• estimated Glomerular Filtration Rate (eGFR) \< 60 mL/min/1,73 m2
• Insufficient dental status
• Hypersensitivity to latex, Denosumab, or to any of the excipients (acetic acid, sodium hydroxide, Sorbitol (E420), Polysorbate 20) will be excluded.
• Serum Inhibin B \< 5 pg/mL
• Androgen replacement therapy
• Hypogonadotropic hypogonadism
• BMI ≥ 35 kg/m2

Sponsors & Collaborators

• Martin Blomberg Jensen: lead

Study Sites (1)

Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Herlev and Gentofte Hospital

Herlev, 2730, Denmark

Location

Related Publications (22)

• Huynh AL, Baker ST, Stewardson AJ, Johnson DF. Denosumab-associated hypocalcaemia: incidence, severity and patient characteristics in a tertiary hospital setting. Pharmacoepidemiol Drug Saf. 2016 Nov;25(11):1274-1278. doi: 10.1002/pds.4045. Epub 2016 Jun 3.

  PMID: 27255807 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

• 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

• Bone HG, Chapurlat R, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Mellstrom D, Radominski SC, Reginster JY, Resch H, Ivorra JA, Roux C, Vittinghoff E, Daizadeh NS, Wang A, Bradley MN, Franchimont N, Geller ML, Wagman RB, Cummings SR, Papapoulos S. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab. 2013 Nov;98(11):4483-92. doi: 10.1210/jc.2013-1597. Epub 2013 Aug 26.

  PMID: 23979955 BACKGROUND

• Lamy O, Stoll D, Aubry-Rozier B, Rodriguez EG. Stopping Denosumab. Curr Osteoporos Rep. 2019 Feb;17(1):8-15. doi: 10.1007/s11914-019-00502-4. Erratum In: Curr Osteoporos Rep. 2022 Oct;20(5):363. doi: 10.1007/s11914-020-00565-8.

  PMID: 30659428 BACKGROUND

• Uebelhart B, Rizzoli R, Ferrari SL. Retrospective evaluation of serum CTX levels after denosumab discontinuation in patients with or without prior exposure to bisphosphonates. Osteoporos Int. 2017 Sep;28(9):2701-2705. doi: 10.1007/s00198-017-4080-6. Epub 2017 May 24.

  PMID: 28540505 BACKGROUND

• Bekker PJ, Holloway DL, Rasmussen AS, Murphy R, Martin SW, Leese PT, Holmes GB, Dunstan CR, DePaoli AM. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004 Jul;19(7):1059-66. doi: 10.1359/JBMR.040305. Epub 2004 Mar 1.

  PMID: 15176987 BACKGROUND

• Blomberg Jensen M, Andreassen CH, Jorgensen A, Nielsen JE, Juel Mortensen L, Boisen IM, Schwarz P, Toppari J, Baron R, Lanske B, Juul A. RANKL regulates male reproductive function. Nat Commun. 2021 Apr 23;12(1):2450. doi: 10.1038/s41467-021-22734-8.

  PMID: 33893301 BACKGROUND

• Bussiere JL, Pyrah I, Boyce R, Branstetter D, Loomis M, Andrews-Cleavenger D, Farman C, Elliott G, Chellman G. Reproductive toxicity of denosumab in cynomolgus monkeys. Reprod Toxicol. 2013 Dec;42:27-40. doi: 10.1016/j.reprotox.2013.07.018. Epub 2013 Jul 22.

  PMID: 23886817 BACKGROUND

• Sohn W, Lee E, Kankam MK, Egbuna O, Moffat G, Bussiere J, Padhi D, Ng E, Kumar S, Slatter JG. An open-label study in healthy men to evaluate the risk of seminal fluid transmission of denosumab to pregnant partners. Br J Clin Pharmacol. 2016 Feb;81(2):362-9. doi: 10.1111/bcp.12798. Epub 2015 Dec 5.

  PMID: 26447647 BACKGROUND

• Boonen S, Adachi JD, Man Z, Cummings SR, Lippuner K, Torring O, Gallagher JC, Farrerons J, Wang A, Franchimont N, San Martin J, Grauer A, McClung M. Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. J Clin Endocrinol Metab. 2011 Jun;96(6):1727-36. doi: 10.1210/jc.2010-2784. Epub 2011 Mar 16.

  PMID: 21411557 BACKGROUND

• Papapoulos S, Chapurlat R, Libanati C, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Man Z, Mellstrom D, Radominski SC, Reginster JY, Resch H, Roman Ivorra JA, Roux C, Vittinghoff E, Austin M, Daizadeh N, Bradley MN, Grauer A, Cummings SR, Bone HG. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res. 2012 Mar;27(3):694-701. doi: 10.1002/jbmr.1479.

  PMID: 22113951 BACKGROUND

• Polyzos SA, Singhellakis PN, Naot D, Adamidou F, Malandrinou FC, Anastasilakis AD, Polymerou V, Kita M. Denosumab treatment for juvenile Paget's disease: results from two adult patients with osteoprotegerin deficiency ("Balkan" mutation in the TNFRSF11B gene). J Clin Endocrinol Metab. 2014 Mar;99(3):703-7. doi: 10.1210/jc.2013-3762. Epub 2014 Jan 16.

  PMID: 24433001 BACKGROUND

• Schwarz P, Rasmussen AQ, Kvist TM, Andersen UB, Jorgensen NR. Paget's disease of the bone after treatment with Denosumab: a case report. Bone. 2012 May;50(5):1023-5. doi: 10.1016/j.bone.2012.01.020.

  PMID: 22586699 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

• Makras P, Polyzos SA, Papatheodorou A, Kokkoris P, Chatzifotiadis D, Anastasilakis AD. Parathyroid hormone changes following denosumab treatment in postmenopausal osteoporosis. Clin Endocrinol (Oxf). 2013 Oct;79(4):499-503. doi: 10.1111/cen.12188. Epub 2013 Apr 1.

  PMID: 23452098 BACKGROUND

• Anastasilakis AD, Toulis KA, Polyzos SA, Anastasilakis CD, Makras P. Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab. Ther Clin Risk Manag. 2012;8:295-306. doi: 10.2147/TCRM.S24239. Epub 2012 Jun 19.

  PMID: 22767993 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

• 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.

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• Blomberg Jensen M. Vitamin D and male reproduction. Nat Rev Endocrinol. 2014 Mar;10(3):175-86. doi: 10.1038/nrendo.2013.262. Epub 2014 Jan 14.

  PMID: 24419359 BACKGROUND

MeSH Terms

Conditions

Infertility, Male

Interventions

Denosumab; Letrozole; Aromatase Inhibitors

Condition Hierarchy (Ancestors)

Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Infertility; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs

Study Officials

• Christian F.S. Jensen, MD, PhD.

  Department of Urology, Herlev and Gentofte Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head of Research Department Endocrinology

Study Record Dates

• First Submitted: November 19, 2024
• First Posted: November 26, 2024
• Study Start: March 1, 2025
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: April 17, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)