A Novel Aromatase Inhibitor, Leflutrozole, for Treatment of Non-Obstructive Azoospermia (NOVA-NOA)

The NOVA-NOA Trial A Novel Aromatase Inhibitor, Leflutrozole, for Treatment of Non-Obstructive Azoospermia A Prospective Interventional Study

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

Study Overview

• Status: Not yet recruiting
• Conditions: Infertility, Male; Infertility Due to Azoospermia
• Intervention / Treatment: Drug: Leflutrozole, Dose 2

Detailed Description

Non-obstructive azoospermia (NOA) is the most severe form of male factor infertility and reflects a profound impairment of spermatogenesis. Men with NOA typically require surgical sperm retrieval procedures, such as testicular sperm aspiration (TESA), testicular sperm extraction (TESE), or micro-TESE, followed by intracytoplasmic sperm injection (ICSI). Even with surgical retrieval, sperm recovery rates remain limited and live birth rates are modest. At present, no pharmacological treatments are approved for male infertility, underscoring a substantial unmet clinical need.

Aromatase inhibitors reduce the conversion of testosterone to estradiol by inhibiting the CYP19A1 enzyme, thereby increasing the testosterone-to-estradiol ratio and stimulating gonadotropin secretion. Letrozole and anastrozole have been used off-label in infertile men, including selected patients with NOA, with small studies demonstrating that aromatase inhibition may induce the appearance of spermatozoa in the ejaculate. Leflutrozole is a novel, non-steroidal aromatase inhibitor and a derivative of letrozole with an extended half-life, allowing once-weekly oral dosing at substantially lower doses than conventional daily aromatase inhibitor regimens. Previous clinical studies in men with obesity-associated functional hypogonadism have demonstrated that once-weekly leflutrozole improves serum testosterone concentrations and semen parameters with an acceptable safety profile.

The NOVA-NOA trial is a single-center, prospective, interventional study designed to evaluate the efficacy and safety of leflutrozole in men with non-obstructive azoospermia. The study investigates whether 20 weeks of treatment with oral leflutrozole 0.3 mg administered once weekly can induce the presence of spermatozoa in the ejaculate and thereby potentially reduce the need for surgical sperm retrieval.

Following informed consent and confirmation of azoospermia at screening and baseline, eligible participants receive oral leflutrozole 0.3 mg once weekly for a total treatment duration of 20 weeks. Semen samples are collected prior to treatment and during therapy at predefined visits (Weeks 12, 16, and 20) to evaluate spermatogenic response. If spermatozoa are identified in any semen sample during treatment, participants are offered repeat semen sampling and referral to a fertility clinic for cryopreservation according to standard clinical practice. Participants continue study treatment until Week 20 irrespective of early detection of spermatozoa.

Blood and urine samples are collected longitudinally to characterize changes in reproductive hormones, metabolic parameters, mineral homeostasis, bone turnover markers, and circulating concentrations of leflutrozole. Seminal fluid is additionally analyzed for leflutrozole concentrations when sufficient ejaculate volume permits. These assessments are intended to describe the endocrine and systemic effects of sustained aromatase inhibition in men with NOA and to support mechanistic interpretation of any spermatogenic response.

Safety is evaluated throughout the study using repeated clinical assessments, laboratory monitoring, and systematic recording of adverse events. Key safety measures include monitoring of hematocrit, hemoglobin, prostate-specific antigen, liver biochemistry, and cardiovascular parameters. Participants are followed until Week 24 for on-site safety assessments, corresponding to more than five half-lives of the investigational medicinal product, and complete an additional safety and pregnancy outcome follow-up by telephone at Week 36.

Statistical analyses are conducted on an intention-to-treat basis. The primary efficacy analysis evaluates whether treatment with leflutrozole induces the presence of spermatozoa in the ejaculate, using an exact binomial testing framework under the assumption that untreated men with NOA would not spontaneously develop spermatozoa during the observation period. Secondary analyses describe within-participant changes in hormonal, metabolic, and exploratory semen parameters over time.

The overall objective of the NOVA-NOA trial is to determine whether, once-weekly leflutrozole administered without concomitant medication can induce spermatogenesis sufficient for the appearance of spermatozoa in the ejaculate of men with non-obstructive azoospermia, thereby offering a potential non-surgical pathway to biological fatherhood for a subset of this patient population.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Mads Joon Jorsal, MD; Phone Number: +45 38686364; Email: mads.joon.jorsal@regionh.dk
• Study Contact Backup: Name: Emil Brink Wriedt, MD; Phone Number: +45 38686364; Email: emil.brink.wriedt@regionh.dk

Study Locations

• Denmark
  • Herlev, Denmark, 2100
    • Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Copenhagen University Hospital Herlev., Herlev,
    • Contact: Mads Joon Jorsal, MD; Phone Number: +45 38 68 63 64; Email: mads.joon.jorsal@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed informed consent by participant
• Signed informed consent by participant's partner (must just be obtained before the par-ticipant starts treatment at Visit 1), if applicable, regarding blood samples, data collec-tion about fertility treatment as well as pregnancy and pregnancy outcome
• 18-55 years
• Azoospermia verified by at least 2 semen samples, average semen volume >= 1,0 ml with no identifiable sign of obstruction (samples taken at Visit -1 and at Visit 0 prior to confirmation of eligibility and dosing).
• Serum AMH or Inhibin B level above the lower limit of quantification (LLOQ) at screening or within 6 months prior to screening
• Testosterone < 15 nmol/L at screening or within 6 months prior to screening
• Serum estradiol above the lower limit of normal range (48 pmol/L) at screening or within 6 months prior to screening

Exclusion Criteria:

• Klinefelter or other major genetic conditions including large deletions on sex chromosomes
• Average testis size > 20 mL unless obstruction has been excluded
• TESE procedure < ½ year ago
• LH concentration > 15 IU/L at screening
• Current abuse of steroids
• BMI > 45 kg/m2
• Severe chronic diseases requiring daily medication
• Prior thromboembolic event within the last 24 months
• Cardiovascular event within the last 6 months judged as significant by the investigator
• Osteoporosis requiring medical treatment

• Use of any prescription or non-prescription medication (apart from routine vitamins, occasional use of paracetamol, acetylsalicylic acid, or ibuprofen) which could interfere with pharmacokinetic or pharmacodynamic results, as judged by the investigator, such as:

  • Herbal products and non-routine vitamins
  • Insulin
  • Medication such as systemic corticosteroids, tricyclic antidepressants, and atypical antipsychotics
• Surgery scheduled for the trial duration period, except for minor, non-gastrointestinal surgical procedures at the discretion of the investigator
• Cancer (past or present, except basal cell skin cancer or squamous cell skin cancer), which in the investigator's opinion could interfere with the results of the trial
• Serum prostate specific antigen (PSA) > 3 ng/mL at screening or within 6 months prior to screening
• Hematocrit >50% at screening or within 6 months prior to screening
• Mental incapacity, language barriers or unwillingness to comply with the requirements of the protocol, which may preclude adequate understanding or co-operation during the trial, as judged by the investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Leflutrozole; once-weekly oral Leflutrozole capsule 0.3 mg	Drug: Leflutrozole, Dose 2; Leflutrozole capsule 0.3 mg once weekly administered orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with spermatozoa in the ejaculate at Week 12-20.	The primary endpoint is proportion of patients with spermatozoa in the ejaculate at Week 20 (end-of-treatment).	From enrollment to Week 20 (end-of-treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in serum reproductive hormones	Change in serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, estradiol, inhibin B, anti-Müllerian hormone (AMH), and sex hormone-binding globulin (SHBG).	Change from baseline to week 20 (end-of-treatment)
Change in seminal fluid reproductive biomarkers	Change in concentrations of RANK ligand (RANKL), osteoprotegerin (OPG), anti-Müllerian hormone (AMH), and inhibin B measured in seminal	Change from baseline to week 20 (end-of-treatment)
Change in reproductive hormone ratios	Change in serum inhibin B/FSH ratio, testosterone/LH ratio, testosterone/estradiol ratio, and AMH/testosterone ratio.	Change from baseline to week 20 (end-of-treatment)
Change in body mass index	Change in body mass index (BMI) weight and height will be combined to calculate BMI in kg/m^2	Change from baseline to week 20 (end-of-treatment)
Change in glycemic and insulin resistance markers	Change in HbA1c, fasting plasma glucose, fasting insulin, C-peptide, and homeostatic model assessment for insulin resistance (HOMA-IR)	Change from baseline to week 20 (end-of-treatment)
Change in lipid profile	Change in total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides.	Change from baseline to week 20 (end-of-treatment)
Change in hematocrit	Change in hematocrit measured as a safety-related secondary outcome	Change from baseline to week 20 (end-of-treatment)
Change in markers of bone turnover	Change in serum procollagen type 1 N-terminal propeptide (PINP) and C-terminal telopeptide of type I collagen (CTX).	Change from baseline to week 20 (end-of-treatment)
Change in urinary mineral homeostasis	Change in spot urine concentrations of albumin, calcium, magnesium, iron, ferritin, phosphate, zinc, bicarbonate, and citrate.	Change from baseline to week 20 (end-of-treatment)
Change in serum mineral homeostasis	Change in serum concentrations of albumin, calcium, phosphate, magnesium, iron, ferritin, transferrin, hepcidin, and zinc	Change from baseline to week 20 (end-of-treatment)
Change in seminal fluid mineral concentrations	Change in seminal fluid concentrations of albumin, calcium, phosphate, magnesium, iron, ferritin, and zinc	Change from baseline to week 20 (end-of-treatment)
Change in calciotropic hormones	Change in serum parathyroid hormone (PTH), fibroblast growth factor-23 (FGF-23), and α-Klotho.	Change from baseline to week 20 (end-of-treatment)
Change in vitamin D metabolites	Change in serum concentrations of cholecalciferol, 25-hydroxyvitamin D (25-OHD), 24,25-dihydroxyvitamin D, 1,25-dihydroxyvitamin D, and derived vitamin D metabolite ratios	Change from baseline to week 20 (end-of-treatment)
Change in adrenal and androgen precursor hormones	Change in serum concentrations of androstenedione, cortisone, and dehydroepiandrosterone sulfate (DHEAS).	Change from baseline to week 20 (end-of-treatment)
Leflutrozole concentrations in serum in participants	Plasma concentration of Leflutrozole in participants	From enrollment to the end of trial at 24 weeks
Leflutrozole concentration in seminal fluid	Leflutrozole concentration in seminal fluid	From enrollment to the end-of-treatment at 20 weeks
Leflutrozole concentration in partners	Plasma Leflutrozole concentration in the female partner	From enrollment to week 16 after inclusion
Change in sperm parameters when measurable	Change in sperm count, concentration, motility, and morphology in participants with detectable spermatozoa in the ejaculate.	Change from baseline to week 20 (end-of-treatment)
Change in height	Change in height (centimeters)	Change from baseline to week 20 (end-of-treatment)
Change in weight	Change in weight (kilograms)	Change from baseline to week 20 (end-of-treatment)

Collaborators and Investigators

• Sponsor: Martin Blomberg Jensen
• Collaborators: ReproNovo SA
• Investigators: Principal Investigator: Martin Blomberg Jensen, D.M.Sc., Herlev Hospital

Publications and helpful links

General Publications

• Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015 Apr 26;13:37. doi: 10.1186/s12958-015-0032-1.
• Pundir J, Achilli C, Bhide P, Sabatini L, Legro RS, Rombauts L, Teede H, Coomarasamy A, Zamora J, Thangaratinam S. Risk of foetal harm with letrozole use in fertility treatment: a systematic review and meta-analysis. Hum Reprod Update. 2021 Apr 21;27(3):474-485. doi: 10.1093/humupd/dmaa055.
• Wickramasinghe LC, Tsantikos E, Kindt A, Raftery AL, Gottschalk TA, Borger JG, Malhotra A, Anderson GP, van Wijngaarden P, Hilgendorff A, Hibbs ML. Granulocyte Colony-Stimulating Factor is a Determinant of Severe Bronchopulmonary Dysplasia and Coincident Retinopathy. Am J Pathol. 2023 Dec;193(12):2001-2016. doi: 10.1016/j.ajpath.2023.07.006. Epub 2023 Sep 9.
• Yang Y, Chen S, Chen H, Guo Y, Teng X. The efficacy of anastrozole in subfertile men with and without abnormal testosterone to estradiol ratios. Transl Androl Urol. 2022 Sep;11(9):1262-1270. doi: 10.21037/tau-22-95.
• Cavallini G, Beretta G, Biagiotti G. Preliminary study of letrozole use for improving spermatogenesis in non-obstructive azoospermia patients with normal serum FSH. Asian J Androl. 2011 Nov;13(6):895-7. doi: 10.1038/aja.2011.44. Epub 2011 Jun 27.
• Helo S, Ellen J, Mechlin C, Feustel P, Grossman M, Ditkoff E, McCullough A. A Randomized Prospective Double-Blind Comparison Trial of Clomiphene Citrate and Anastrozole in Raising Testosterone in Hypogonadal Infertile Men. J Sex Med. 2015 Aug;12(8):1761-9. doi: 10.1111/jsm.12944. Epub 2015 Jul 14.
• Eisenberg ML, Lathi RB, Baker VL, Westphal LM, Milki AA, Nangia AK. Frequency of the male infertility evaluation: data from the national survey of family growth. J Urol. 2013 Mar;189(3):1030-4. doi: 10.1016/j.juro.2012.08.239. Epub 2012 Sep 23.
• Schlegel PN, Sigman M, Collura B, De Jonge CJ, Eisenberg ML, Lamb DJ, Mulhall JP, Niederberger C, Sandlow JI, Sokol RZ, Spandorfer SD, Tanrikut C, Treadwell JR, Oristaglio JT, Zini A. Diagnosis and treatment of infertility in men: AUA/ASRM guideline part II. Fertil Steril. 2021 Jan;115(1):62-69. doi: 10.1016/j.fertnstert.2020.11.016. Epub 2020 Dec 9.
• Thonneau P, Marchand S, Tallec A, Ferial ML, Ducot B, Lansac J, Lopes P, Tabaste JM, Spira A. Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989). Hum Reprod. 1991 Jul;6(6):811-6. doi: 10.1093/oxfordjournals.humrep.a137433.

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): August 31, 2027

Study Registration Dates

• First Submitted: April 16, 2026
• First Submitted That Met QC Criteria: April 30, 2026
• First Posted (Actual): May 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Diseases, Male; Male Urogenital Diseases; Infertility; Infertility, Male; leflutrozole
• Other Study ID Numbers: 2025-524774-42-00

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