An open-label clinical trial to investigate the efficacy and safety of corifollitropin alfa combined with hCG in adult men with hypogonadotropic hypogonadism

Eberhard Nieschlag, Pierre-Marc G Bouloux, Barbara J Stegmann, R Ravi Shankar, Yanfen Guan, Anjela Tzontcheva, Christine McCrary Sisk, Hermann M Behre, Eberhard Nieschlag, Pierre-Marc G Bouloux, Barbara J Stegmann, R Ravi Shankar, Yanfen Guan, Anjela Tzontcheva, Christine McCrary Sisk, Hermann M Behre

Abstract

Background: Hypogonadotropic hypogonadism (HH) in men results in insufficient testicular function and deficiencies in testosterone and spermatogenesis. Combinations of human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) have been successful in the treatment of HH. Corifollitropin alfa is a long-acting FSH-analog with demonstrated action in women seeking infertility care. The aim of this study was to investigate the efficacy and safety of corifollitropin alfa combined with hCG to increase testicular volume and induce spermatogenesis in men with HH.

Methods: This was a Phase III, multi-center, open-label, single-arm trial of corifollitropin alfa in azoospermic men aged 18 to 50 years with HH. After 16 weeks of pretreatment of 23 subjects with hCG alone, 18 subjects with normalized testosterone (T) levels who remained azoospermic entered the 52-week combined treatment phase with hCG twice-weekly and 150 μg corifollitropin alfa every other week. The increase in testicular volume (primary efficacy endpoint) and induction of spermatogenesis resulting in a sperm count ≥1 × 106/mL (key secondary efficacy endpoint) during 52 weeks of combined treatment were assessed. Safety was evaluated by the presence of anti-corifollitropin alfa antibodies and the occurrence of adverse events (AEs).

Results: Mean (±SD) testicular volume increased from 8.6 (±6.09) mL to 17.8 (±8.93) mL (geometric mean fold increase, 2.30 [95% CI: 2.03, 2.62]); 14 (77.8%) subjects reached a sperm count ≥1 × 106/mL. No subject developed confirmed anti-corifollitropin alfa antibodies during the trial. Treatment was generally well tolerated.

Conclusions: Corifollitropin alfa 150 μg administrated every other week combined with twice-weekly hCG for 52 weeks increased testicular volume significantly, and induced spermatogenesis in >75% of men with HH who had remained azoospermic after hCG treatment alone.

Trial registration: ClinicalTrials.gov: NCT01709331 .

Keywords: Corifollitropin alfa; Gonadotropin deficiency; Hypogonadotropic hypogonadism; Male infertility; Testis.

Figures

Fig. 1
Fig. 1
Mean (±SD) testicular volume at each study visit from pretreatment baseline to Week 52 of the combined treatment phase
Fig. 2
Fig. 2
a Mean (±SD) sperm concentration (×106) from Day 1 to Week 52 of the combined treatment phase; b Total sperm count (×106/ejaculate) during the combined treatment phase
Fig. 3
Fig. 3
a Mean (±SD) percentage of progressively motile sperm during the combined treatment phase; b Mean (±SD) percentage of normal morphology sperm during the combined treatment phase
Fig. 4
Fig. 4
a–f Mean (±SD) hormone levels from pretreatment baseline to Week 52 of the combined treatment phase

References

    1. Fraietta R, Zylberstejn DS, Esteves SC. Hypogonadotropic hypogonadism revisited. Clinics (Sao Paulo) 2013;68(Suppl 1):81–8. doi: 10.6061/clinics/2013(Sup01)09.
    1. Rohayem J, Zitzmann M, Nieschlag E. Congenital hypogondotropic hypogonadism and Kallmann’s syndrome. Reference Module in Biomedical Sciences. Elsevier 12-Dec-15; doi:10.1016/B978-0-12-801238%E2%80%933.98874%E2%80%933.
    1. Lytton B, Kase N. Effects of human menopausal gonadotrophin on a eunuchoidal male. N Engl J Med. 1966;274:1061–4. doi: 10.1056/NEJM196605122741905.
    1. Buechter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol. 1998;139:298–303. doi: 10.1530/eje.0.1390298.
    1. Kliesch S, Behre HM, Nieschlag E. Recombinant human follicle-stimulating hormone and human chorionic gonadotropin for induction of spermatogenesis in a hypogonadotropic male. Fertil Steril. 1995;63:1326–8. doi: 10.1016/S0015-0282(16)57619-5.
    1. Bouloux PMG, Nieschlag E, Burger HG, Skakkebaek NE, Wu FCW, Handelsman DJ. Induction of spermatogenesis by recombinant follicle-stimulating hormone (Puregon) in hypogonadotropic azoospermic men who failed to respond to human chorionic gonadotropin alone. J Androl. 2003;24:604–11. doi: 10.1002/j.1939-4640.2003.tb02712.x.
    1. Corifollitropin alfa Ensure Study Group Corifollitropin alfa for ovarian stimulation in IVF: a randomized trial in lower-body-weight women. Reprod Biomed Online. 2010;21:66–76. doi: 10.1016/j.rbmo.2010.03.019.
    1. Devroey P, Boostanfar R, Koper NP, Mannaerts BM, Ijzerman-Boon PC, Fauser BC. A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol. Hum Reprod. 2009;24:3063–72. doi: 10.1093/humrep/dep291.
    1. Boostanfar R, Shapiro B, Levy M, Rosenwaks Z, Witjes H, Stegmann BJ, et al. Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization. Fertil Steril. 2015;104:94–103. doi: 10.1016/j.fertnstert.2015.04.018.
    1. Fauser BCJM, Mannaerts BMJL, Devroey P, Leader A, Boime I, Baird DT. Advances in recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency. Hum Reprod Update. 2009;15:309–21. doi: 10.1093/humupd/dmn065.
    1. Bouloux PMG, Handelsman DJ, Jockenhövel F, Nieschlag E, Rabinovici J, Frasa WLH. First human exposure to FSH-CTP in hypogonadotropic hypogonadal males. Hum Reprod. 2001;16:1592–7. doi: 10.1093/humrep/16.8.1592.
    1. WHO Laboratory Manual for the Examination and Processing of Human Sperm, 5th edition. Geneva: World Health Organisation; 2010.
    1. Burgués S, Calderón MD, the Spanish Collaborative Group on Male Hypogonadotropic Hypogonadism Subcutaneous self-administration of highly purified follicle stimulating hormone and human chorionic gonadotrophin for the treatment of male hypogonadotrophic hypogonadism. Hum Reprod. 1997;12:980–6. doi: 10.1093/humrep/12.5.980.
    1. European Metrodin HP Study Group Efficacy and safety of highly purified urinary follicle-stimulating hormone with human chorionic gonadotropin for treating men with isolated hypogonadotropic hypogonadism. Fertil Steril. 1998;70:256–62. doi: 10.1016/S0015-0282(98)00156-3.
    1. Liu PY, Turner L, Rushford D, McDonald J, Gordon Baker HW, Conway AJ, et al. Efficacy and safety of recombinant human follicle stimulating hormone (Gonal-F) with urinary human chorionic gonadotrophin for induction of spermatogenesis and fertility in gonadotrophin-deficient men. Hum Reprod. 1999;14:1540–5. doi: 10.1093/humrep/14.6.1540.
    1. Rohayem J, Hauffa BP, Zacharin M, Kliesch S, Zitzmann M, German Adolescent Hypogonadotropic Hypogonadism Study Group Testicular growth and spermatogenesis: new goals for pubertal hormone replacement in boys with hypogonadotrophic hypogonadism? A multicentre prospective study of hCG/rFSH treatment outcomes during adolescence. Clin Endocrinol (Oxf) 2017;86:75–87. doi: 10.1111/cen.13164.
    1. Rocchietti March M, Isidori A. New frontiers in the treatment of male sterility. Contraception. 2002;65:279–81.
    1. Rohayem J, Sinthofen N, Nieschlag E, Kliesch S, Zitzmann Causes of hypogonadotropic hypogonadism predict response to gonadotropin substitution in adults. Andrology. 2016;4:87–94. doi: 10.1111/andr.12128.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir