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Infertility, MalePhase 1/2NAPONCT06300229

NAPO - Novel Approach for Oligospermia

A Phase 1/2 study testing Denosumab and sodium chloride in people with Infertility, Male, run by Martin Blomberg Jensen at 1 site in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This randomized controlled trial aims to assess whether treatment with denosumab can improve semen quality in infertile men selected by serum anti-mullerian hormone (AMH) as a positive predictive biomarker, and with severely impaired semen quality (concentrations between 0.01 million/mL to 2 million/mL). Read more about this study

Who is it for?
Ages 18 to 60 years, men only
Conditions the study is for
Infertility, Male
What is being tested?
Denosumab and sodium chloride
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
42 participants
Where
1 siteDenmark
Study dates
1 Mar 2024to 31 Aug 2025
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • Men only
  • No healthy volunteers
  • Adult

Who may be able to join

  • Infertile men ≥ 18 years and < 60 years of age
  • Sperm concentration ≤ 2 million pr. mL
  • Serum AMH levels ≥28 pmol/L.
  • The participants must have appropriate Danish or English language skills and give written informed consent.

Who cannot join

  • 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.
  • Sperm concentration <0.01 million pr. mL
  • 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
Show all 12Show fewer
  • Insufficient dental status
  • Vasectomy
  • Hypersensitivity to latex, Denosumab, or to any of the excipients (acetic acid, sodium hydroxide, Sorbitol (E420), Polysorbate 20) will be excluded.
  • Serum FSH <3 IU/L
  • Testis size > 17 mL
  • BMI ≥ 35 kg/m2

Trial locations and contacts

1 site in 1 country.

Denmark1 site

  • Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine

    Copenhagen

Other trials in Denmark

About this study

Official title: Novel Approach for Oligospermia (NAPO): A Randomized Controlled Trial

This randomized controlled trial aims to assess whether treatment with denosumab can improve semen quality in infertile men selected by serum anti-mullerian hormone (AMH) as a positive predictive biomarker, and with severely impaired semen quality (concentrations between 0.01 million/mL to 2 million/mL).

Read the detailed description

Infertility is a common problem globally and impaired semen quality is responsible for up to 40% of all cases. Despite the high prevalence there are currently only very limited treatment options to improve semen quality for infertile men. Instead, almost all infertile couples are treated with inseminations or assisted reproductive techniques (ARTs) independently of the etiology of infertility. ARTs are very successful but expensive and associated with a significant treatment burden of the female partner due to the invasive methodology and the need for hormonal treatment often for several months.

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.

In light of this, our research group has investigated the effect of denosumab in human testicular germ cell lines as well as in human testicular tissue ex vivo "hanging drop" cultures. Treatment with denosumab did in both cases increase the proliferation of the germinal cells, which is an indicator that denosumab treatment potential beneficial effect on sperm production by reducing apoptosis in the germ cells. This led to a pilot intervention study of 12 infertile men who were overall healthy and without comorbidities. The men were treated with a single-dose of 60 mg of denosumab subcutaneous (s.c.). The study showed that the response to RANKL inhibition was either bad or highly beneficial. This was an interesting finding and indicates that only a fraction of infertile men should be offered denosumab treatment and this fraction of beneficial responders should ideally be identified based on an easily accessible biomarker before initiation of treatment. On this knowledge, a randomized controlled trial, "First In Treating Male Infertility" (FITMI), is being conducted to explore whether treatment with denosumab can improve semen quality in infertile men who are selected by serum AMH, but already have a sperm concentration that is at least 2 million/mL. This is an important study, but unfortunately, it leaves out a solution for those with sperm concentration under 2 million/mL, who are the most vulnerable in this regard. Therefore, there is a need for a randomized controlled trial that addresses the specific concerns of individuals with sperm concentrations below 2 million/mL to provide a valuable option in an otherwise hopeless situation.

NAPO is a single-center, sponsor-investigator-initiated, placebo-controlled, double-blinded randomized trial. Following successful completion of screening procedures, subjects will be randomized in a 2:1 fashion to receive either denosumab 60 mg s.c. or a placebo. The study will be carried out at the Division of Translational Endocrinology, Copenhagen University Hospital, Herlev, Copenhagen, Denmark.

With the power to avoid a type II error set to 80% (1-β) at a two-sided 5% significance level, 42 men allocated 2:1 in each of the investigation arms are needed to detect a difference in sperm concentration of 100% between intervention and placebo group in the primary outcome. The primary analysis will be a covariance analysis in which day 80 measurements are analyzed, initially as crude values but also adjusted on baseline.

Being tested
Denosumab, sodium chloride
Medical subject headings
Infertility, Male

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DenosumabDrug

    Also called Prolia

    Subcutaneous injection with 60 mg Denosumab once

  • sodium chlorideDrug

    Also called sodium chloride (NaCl)

    Subcutaneous injection with NaCl once

Study groups in NCT06300229
Study groupRoleWhat they receive
DenosumabActive comparatorSubcutaneous injection with 60 mg Denosumab once
Receives: Drug: Denosumab
PlaceboPlacebo comparatorSubcutaneous injection with NaCl once
Receives: Drug: sodium chloride

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The difference in sperm concentration (million pr. mL) on day 80

    Semen analysis - The average concentration of two semen samples delivered on day 80 and day 83 after inclusion is used.

    Measured: Day 80 and day 83 after inclusion

Secondary outcomes (7)

  1. The difference in semen quality (total sperm count, motile sperm, progressive motile sperm and morphologically normal sperm) between baseline and two semen samples delivered at day 80 and day 83 after inclusion

    Semen analysis

    Measured: Day 80 and day 83 after inclusion

  2. The change/differences in number of pregnancies achieved before day 180

    Survey

    Measured: Day 180 after inclusion

  3. The difference in the number of miscarriages throughout the trial before day 180

    Survey

    Measured: Day 450 after inclusion]

  4. The change/difference in serum levels of follicle stimulating hormone (FSH) on day 80

    Serum sample

    Measured: Day 80 after inclusion

  5. The change/difference in serum levels of reproductive hormone luteinizing hormone (LH) on day 80

    Serum sample

    Measured: Day 80 after inclusion

  6. The change/difference in serum levels of reproductive hormone AMH on day 80

    Serum sample

    Measured: Day 80 after inclusion

  7. The change/difference in serum levels of reproductive hormone Inhibin B on day 80

    Serum sample

    Measured: Day 80 after inclusion

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Mar 2024
  2. Study start1 Mar 2024
  3. Primary completion29 Jan 2025
  4. Study completion31 Aug 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
42 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06300229
Sponsor's protocol ID
2023-508325-27-00
Other IDs
2023
Acronym
NAPO
Status last verified
Dec 2025
First submitted
2 Mar 2024
Last updated
19 Dec 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Huynh T, Mollard R, Trounson A. Selected genetic factors associated with male infertility. Hum Reprod Update. 2002 Mar-Apr;8(2):183-98. doi: 10.1093/humupd/8.2.183.

    PubMed 12099633

  • Krausz C. Male infertility: pathogenesis and clinical diagnosis. Best Pract Res Clin Endocrinol Metab. 2011 Apr;25(2):271-85. doi: 10.1016/j.beem.2010.08.006.

    PubMed 21397198

  • Skakkebaek NE, Rajpert-De Meyts E, Buck Louis GM, Toppari J, Andersson AM, Eisenberg ML, Jensen TK, Jorgensen N, Swan SH, Sapra KJ, Ziebe S, Priskorn L, Juul A. Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility. Physiol Rev. 2016 Jan;96(1):55-97. doi: 10.1152/physrev.00017.2015.

    PubMed 26582516

  • Blomberg Jensen M, Lawaetz JG, Petersen JH, Juul A, Jorgensen N. Effects of Vitamin D Supplementation on Semen Quality, Reproductive Hormones, and Live Birth Rate: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2018 Mar 1;103(3):870-881. doi: 10.1210/jc.2017-01656.

    PubMed 29126319

  • Bollehuus Hansen L, Kaludjerovic J, Nielsen JE, Rehfeld A, Poulsen NN, Ide N, Skakkebaek NE, Frederiksen H, Juul A, Lanske B, Blomberg Jensen M. Influence of FGF23 and Klotho on male reproduction: Systemic vs direct effects. FASEB J. 2020 Sep;34(9):12436-12449. doi: 10.1096/fj.202000061RR. Epub 2020 Jul 30.

    PubMed 32729975

  • Juel Mortensen L, Lorenzen M, Jorgensen N, Andersson AM, Nielsen JE, Petersen LI, Lanske B, Juul A, Hansen JB, Blomberg Jensen M. Possible link between FSH and RANKL release from adipocytes in men with impaired gonadal function including Klinefelter syndrome. Bone. 2019 Jun;123:103-114. doi: 10.1016/j.bone.2019.03.022. Epub 2019 Mar 23.

    PubMed 30914274

  • 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.

    PubMed 24419359

  • Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008 Apr;29(2):155-92. doi: 10.1210/er.2007-0014. Epub 2007 Dec 5.

    PubMed 18057140

  • Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998 Apr 17;93(2):165-76. doi: 10.1016/s0092-8674(00)81569-x.

    PubMed 9568710

  • Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997 Apr 18;89(2):309-19. doi: 10.1016/s0092-8674(00)80209-3.

    PubMed 9108485

  • Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001 Dec;142(12):5050-5. doi: 10.1210/endo.142.12.8536.

    PubMed 11713196

  • 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.

    PubMed 19558335

  • 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.

    PubMed 23452098

  • 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.

    PubMed 22586699

  • 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.

    PubMed 24433001

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Denosumab and sodium chloride in people with Infertility, Male, run by Martin Blomberg Jensen at 1 site in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The difference in sperm concentration (million pr. mL) on day 80 (time frame: Day 80 and day 83 after inclusion). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06300229, which also lists 31 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2025.

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