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

April 16, 2026 updated by: Martin Blomberg Jensen

Novel Treatment of Some Men With Non-Obstructive Azoospermia (NT-NOA): A Clinical Interventional Study

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Infertility is a health issue worldwide with more than 15% of couples experiencing infertility. Male factors contribute in 50% of all cases and is the sole cause in 30% of all infertile couples . Treatment options for the male infertility are limited and only specific conditions like varicocele and hypogonadotropic hypogonadism can be effectively treated with surgery and hormonal stimulation, respectively. However, for the remaining 90% of infertile men, no treatment options exist. Instead, their female partners must undergo fertility treatment.

Men with the most pronounced impairment of semen quality, men with azoospermia, have no sperm in the ejaculate and are classically divided into obstructive azoospermia (OA) and non-obstructive azoospermia (NOA), with the ladder being the most common. These men needs to have surgery performed for sperm retrieval with either testicular sperm aspiration (TESA), testicular sperm extraction (TESE) or micro testicular sperm extraction (microTESE) in order to have a chance of becoming biological fathers. The chance of successful sperm retrieval in men with OA is close to 100%, whereas men with NOA have a significantly lower chance with only around 10-40% being successful. This is due to the vast difference in etiology between men with OA and NOA. Even with a successful surgical intervention only half of the cases will result in a live birth, leaving the majority of men with NOA no chance of becoming biological fathers. Therefore, novel treatment options for even a minor sub-group of these men are warranted.

RANKL is a ligand for the receptor activator of nuclear factor kappa beta (RANK), and their pathway plays a prominent role in the regulation of bone metabolism. The binding of RANKL to RANK on osteoclast precursors induces osteoclast maturation and activation, thereby stimulating bone resorption, and regulates cell cycle i.e., proliferation, differentiation, and apoptosis. Osteoprotegerin (OPG) is a secreted decoy receptor that controls RANKL-RANK interaction by binding RANKL and inhibits activation of RANK and preventing osteoclast differentiation and activation.

Denosumab, a drug used in millions of patients worldwide under trade names Prolia® and Xgeva®, inhibits the RANKL pathway and is used to treat osteoporosis and bone metastases. The drug's mechanism of action inhibits RANKL and thus inhibits bone resorption through reduced osteoclast activation. This reduces the loss of bone mineral density (BMD), which reduces the risk of bone loss and thereby the risk of fracture and osteoporosis. Denosumab has been shown in several clinical studies to be a safe and effective drug in both women and men and has been in clinical use in both sexes for many years. As Denosumab has a teratogenic effect, pharmacokinetic studies in both monkeys and healthy men were performed before approval of the drug as a treatment for osteoporosis in men. These studies showed that Denosumab concentration in semen does not pose a risk to the fetus during sexual intercourse with the pregnant woman and therefore is safe to use for the suggested infertility indication as there is no risk of fetal transmission.

The investigators have also shown that RANKL also influences germ cell apoptosis, differentiation, and proliferation in mice and humans. This indicates that the RANKL system could be a potential direct regulator of spermatogenesis, and thus highlighting that the drug Denosumab, a RANKL inhibitor, commonly used to treat osteoporosis, may be used for medical treatment of men with decreased sperm production. The effects of denosumab in vitro were supported by a pilot intervention study in 12 infertile men, which showed that denosumab either had a highly beneficial or detrimental effect on sperm production. This implies that only a sub-group of infertile men should be offered this treatment and these men should be identified by, preferably, a simple and accessible biomarker.

Therefore, the investigators are currently conducting two randomized clinical trials "First In Treating Infertility (FITMI)" and "Novel Approach for Oligospermia (NAPO) to explore whether denosumab can improve semen quality in infertile men selected by serum AMH, but already have sperm concentration between 2 mio/mL - 20 mio/mL (FITMI) and 0.01 mio/mL - 2 mio/mL (NAPO). These are both important studies, but still leaves out men with no sperm in the ejaculate, azoospermic patients. Therefore, there is a need for a trial adressing these patients for a potential novel treatment option.

NT-NOA is a single-center, sponsor-investigator-initiated, interventional trial, Following successful completion of screening procedures, subjects will all receive denosumab 60 mg s.c. and Letrozole oral tablet 2.5 mg once daily. Participants will all initiate letrozole treatment 14 days prior to the denosumab injection and will continue until the TESE procedure. The study will be carried out at the Division of Translational Endocrinology, Copenhagen University Hospital, Herlev, Copenhagen, Denmark.

The investigators believe it is of clinical relevance to treat 10 patients with denosumab in combination with letrozole for 1 of them to achieve sperm production, however, it is difficult to estimate. Ideally 50% of the treated participants will have sperm suitable for ART post intervention. By including 16 patients, there will be sufficient power to determine if combination therapy with denosumab and letrozole induces a clinically relevant effect on spermatogenesis.

Study Type

Interventional

Enrollment (Estimated)

16

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Herlev, Denmark, 2730
        • Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Herlev and Gentofte Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Denosumab
Subcutaneous injection with 60 mg Denosumab once
Drug: Denosumab (Prolia)
Subcutaneous injection with 60 mg Denosumab once
Drug: Letrozole (Aromatase Inhibitors)
Letrozole oral tablet 2.5 mg once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Sperm in the semen sample or TESE on day 90
Time Frame: Day 80 (semen sample) and 90 (TESE) after inclusion
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Time Frame: Day 90 after inclusion
TESE
Day 90 after inclusion
The number of participants with sperm in the ejaculate (sperm pr. milliliter) assessed by semen samples delivered on day 14
Time Frame: Day 14 after inclusion
Semen sample
Day 14 after inclusion
The number of participants with sperm in the ejaculate (sperm pr. milliliter) assessed by semen samples delivered on day 80
Time Frame: Day 80 after inclusion
Semen sample
Day 80 after inclusion
The number of pregnancies achieved by sperm from the ejaculate or by TESE
Time Frame: Day 180 after inclusion
Survey
Day 180 after inclusion
The change in serum levels of reproductive hormones (FSH, LH, AMH, Inhibin B og INSL3) on day 14
Time Frame: Day 14 after inclusion
Serum sample
Day 14 after inclusion
The change in serum levels of reproductive hormones (FSH, LH, AMH, Inhibin B og INSL3) on day 80
Time Frame: Day 80 after inclusion
Serum sample
Day 80 after inclusion
The change in serum levels of sex steroids (Testosterone, Estradiol and SHBG) on day 14
Time Frame: Day 14 after inclusion
Serum sample
Day 14 after inclusion
The change in serum levels of sex steroids (Testosterone, Estradiol and SHBG) on day 80
Time Frame: Day 80 after inclusion
Serum sample
Day 80 after inclusion
The change in seminal fluid levels of reproductive hormones (AMH, Inhibin B, INSL3) on day 14
Time Frame: Day 14 after inclusion
Seminal fluid
Day 14 after inclusion
The change in seminal fluid levels of reproductive hormones (AMH, Inhibin B, INSL3) on day 80
Time Frame: Day 80 after inclusion
Seminal fluid
Day 80 after inclusion
The change in the endocrine gonadal function (Inhibin B/FSH ratio, Testosterone/LH ratio and AMH/testosterone ratio) on day 14
Time Frame: Day 14 after inclusion
Serum sample
Day 14 after inclusion
The change in the endocrine gonadal function (Inhibin B/FSH ratio, Testosterone/LH ratio and AMH/testosterone ratio) on day 80
Time Frame: Day 80 after inclusion
Serum sample
Day 80 after inclusion

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
The change in seminal fluid levels of RANKL, OPG, AMH and Inhibin B on day 14
Time Frame: Day 14 after inclusion
Seminal fluid
Day 14 after inclusion
The change in seminal fluid levels of RANKL, OPG, AMH and Inhibin B on day 80
Time Frame: Day 80 after inclusion
Seminal fluid
Day 80 after inclusion
The change in serum levels of minerals (calcium, phosphate, magnesium, zink, bikarbonate, citrate) on day 14
Time Frame: Day 14 after inclusion
Serum
Day 14 after inclusion
The change in serum levels of minerals (calcium, phosphate, magnesium, zink, bikarbonate, citrate) on day 80
Time Frame: Day 80 after inclusion
Serum
Day 80 after inclusion
The change in seminal fluid levels of minerals (calcium, phosphate, magnesium, zink, bikarbonate, citrate) on day 14
Time Frame: Day 14 after inclusion
Seminal fluid
Day 14 after inclusion
The change in seminal fluid levels of minerals (calcium, phosphate, magnesium, zink, bikarbonate, citrate) on day 80
Time Frame: Day 80 after inclusion
Seminal fluid
Day 80 after inclusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Martin Blomberg Jensen

Investigators

  • Principal Investigator: Christian F.S. Jensen, MD, PhD., Department of Urology, Herlev and Gentofte Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2025

Primary Completion (Estimated)

August 1, 2026

Study Completion (Estimated)

August 1, 2026

Study Registration Dates

First Submitted

November 19, 2024

First Submitted That Met QC Criteria

November 22, 2024

First Posted (Actual)

November 26, 2024

Study Record Updates

Last Update Posted (Actual)

April 17, 2026

Last Update Submitted That Met QC Criteria

April 16, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2024-512996-11-00 (Ctis)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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