Acquired Hypogonadotropic Hypogonadism Clinical Trial
— RHYTHMOfficial title:
Pharmacodynamics and Safety of Human Recombinant Luteinising Hormone in Hypogonadotropic Hypogonadal Men
Objectives: The overall clinical question is whether LH supplementation to men in indication for FSH according to the AIFA note 74, or with HH, will improve spermatogenesis and pregnancy rate (spontaneous or after ART) over FSH alone or FSH+hCG. However, since LH has never been used in men so far, the first, specific object of this study is the assessment of pharmacodynamics and safety profile of LH in HH men. To this end, this study will evaluate the pharmacodynamics and safety profile of recombinant LH (Luveris) and compare the response to Luveris and urinary hCG (Gonasi HP) in HH men. The pharmacodynamics will be assessed primarily for testosterone levels in response to increasing doses of LH and the comparison of the response to a fix dose of hCG, and later for more extend steroid profile. Methods: Multicentre longitudinal, interventional, randomized, open-label, phase II, clinical trial, assessing pharmacodynamics of LH in acquired HH men. The statistical hypothesis is non-inferiority of the highest LH dose employed compared to a fix hCG dose. Primary endpoint: serum testosterone levels evaluated by liquid-chromatography, tandem mass spectrometry (LC-MS/MS). Secondary endpoints: Safety and tolerability as determined by AE reporting, vital signs, and ECG, stereognosis (inhibin B, free testosterone, sex hormone binding globulin (SHBG), estradiol, whole steroid profile provided by LC-MS/MS) and testicular volume. Patients: 32 men with acquired HH, including HH after neurosurgery for tumours or HH due to pituitary adenoma-related mass effect. Patients will be randomized (1:1) according to a permuted- blocks randomization list, to the study group, treated with Luveris (increasing doses at two weekly intervals), or to the control group treated with Gonasi HP (2000 IU twice/week). In the study group, increasing LH dosages will be administered to obtain a testosterone dose-response curve, starting with the minimum expected efficient dose (75 IU/d, sc) for two weeks followed by 150, 225 and 300 IU at two-weekly interval, respectively. The control group will be treated by the standard approach, i.e. hCG 2000 IU IM twice-weekly for 8 weeks. Patients will be further followed up for 4 weeks after treatment withdrawal. During the study, the patients will be evaluated two times per week during the treatment phase and every two weeks in the follow-up phase.
Status | Recruiting |
Enrollment | 32 |
Est. completion date | January 18, 2026 |
Est. primary completion date | January 18, 2025 |
Accepts healthy volunteers | No |
Gender | Male |
Age group | 18 Years to 45 Years |
Eligibility | Inclusion Criteria: - Male sex - Age between 18 and 45 years - Acquired HH forms - HH after neurosurgery for tumors (i.e. pituitary adenoma, including prolactinoma, craniopharyngioma, germinomas, meningiomas, gliomas, and astrocytomas). Infiltrative disease (hemochromatosis, granulomatous disease, histiocytosis, and sarcoidosis), OR - HH due to pituitary adenoma-related mass effect, in case of cured or controlled hormone hypersecretion - Total testosterone serum levels below the normal ranges (lower than 3 ng/mL) - No androgen replacement therapies in the last three months before enrolment - No hyper-secretion of other pituitary hormones Exclusion Criteria: HH forms, such as: - Combined pituitary hormone deficiency - Genetic syndromes (e.g., Prader-Labhart-Willi, CHARGE, Lawrence-Moon- Bardet-Biedl) - Iatrogenic HH forms, such as traumatic pituitary stalk interruption syndrome, irradiation, high dose corticosteroids, and anabolic steroids - Drug abuse and major systemic diseases - Chronic severe liver disease - Concomitant illnesses which could interfere with the study participation - Active malignancy diseases - Known or possible androgen-dependent tumors for example male breast carcinoma or prostatic carcinoma - Cardiac failure, hypertension, renal dysfunction, migraines, or epilepsy. (since aggravation or recurrence may occasionally be induced as a result of increased androgen production) - Haematocrit <40% or >54% - Congenital HH are excluded since these genetic forms of HH could be related to other systemic or pituitary diseases, which could bias the selection of patients. |
Country | Name | City | State |
---|---|---|---|
Italy | Fondazione IRCCS Ca ' Grande Ospedale Maggiore Policlinico | Milan | |
Italy | Unit of Endocrinology of Modena | Modena | |
Italy | Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita` degli Studi di Napoli "Federico II" | Naples | |
Italy | Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza - University of Rome | Rome | |
Italy | ivision of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin | Turin |
Lead Sponsor | Collaborator |
---|---|
Azienda Ospedaliero-Universitaria di Modena |
Italy,
Althunian TA, de Boer A, Groenwold RHH, Klungel OH. Defining the noninferiority margin and analysing noninferiority: An overview. Br J Clin Pharmacol. 2017 Aug;83(8):1636-1642. doi: 10.1111/bcp.13280. Epub 2017 Apr 6. — View Citation
Casarini L, Lispi M, Longobardi S, Milosa F, La Marca A, Tagliasacchi D, Pignatti E, Simoni M. LH and hCG action on the same receptor results in quantitatively and qualitatively different intracellular signalling. PLoS One. 2012;7(10):e46682. doi: 10.1371/journal.pone.0046682. Epub 2012 Oct 5. — View Citation
Casarini L, Riccetti L, De Pascali F, Gilioli L, Marino M, Vecchi E, Morini D, Nicoli A, La Sala GB, Simoni M. Estrogen Modulates Specific Life and Death Signals Induced by LH and hCG in Human Primary Granulosa Cells In Vitro. Int J Mol Sci. 2017 Apr 28;18(5):926. doi: 10.3390/ijms18050926. — View Citation
Nardelli AA, Stafinski T, Motan T, Klein K, Menon D. Assisted reproductive technologies (ARTs): evaluation of evidence to support public policy development. Reprod Health. 2014 Nov 7;11(1):76. doi: 10.1186/1742-4755-11-76. — View Citation
Nwabuobi C, Arlier S, Schatz F, Guzeloglu-Kayisli O, Lockwood CJ, Kayisli UA. hCG: Biological Functions and Clinical Applications. Int J Mol Sci. 2017 Sep 22;18(10):2037. doi: 10.3390/ijms18102037. — View Citation
Riccetti L, Yvinec R, Klett D, Gallay N, Combarnous Y, Reiter E, Simoni M, Casarini L, Ayoub MA. Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors. Sci Rep. 2017 Apr 19;7(1):940. doi: 10.1038/s41598-017-01078-8. — View Citation
Santi D, Casarini L, Alviggi C, Simoni M. Efficacy of Follicle-Stimulating Hormone (FSH) Alone, FSH + Luteinizing Hormone, Human Menopausal Gonadotropin or FSH + Human Chorionic Gonadotropin on Assisted Reproductive Technology Outcomes in the "Personalized" Medicine Era: A Meta-analysis. Front Endocrinol (Lausanne). 2017 Jun 1;8:114. doi: 10.3389/fendo.2017.00114. eCollection 2017. — View Citation
Santi D, Spaggiari G, Casarini L, Fanelli F, Mezzullo M, Pagotto U, Granata ARM, Carani C, Simoni M. Central hypogonadism due to a giant, "silent" FSH-secreting, atypical pituitary adenoma: effects of adenoma dissection and short-term Leydig cell stimulation by luteinizing hormone (LH) and human chorionic gonadotropin (hCG). Aging Male. 2017 Jun;20(2):96-101. doi: 10.1080/13685538.2016.1276161. Epub 2017 Jan 9. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Steroids | Other steroids provided by the LC-MS/MS methodology | 2 weeks after treatment start | |
Other | Steroids | Other steroids provided by the LC-MS/MS methodology | 4 weeks after treatment start | |
Other | Steroids | Other steroids provided by the LC-MS/MS methodology | 6 weeks after treatment start | |
Other | Steroids | Other steroids provided by the LC-MS/MS methodology | 8 weeks after treatment start | |
Other | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | This was evaluated considering red blood cell count, marker of liver function, markers of coagulation. | 2 weeks after treatment start | |
Other | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | This was evaluated considering red blood cell count, marker of liver function, markers of coagulation. | 4 weeks after treatment start | |
Other | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | This was evaluated considering red blood cell count, marker of liver function, markers of coagulation. | 6 weeks after treatment start | |
Other | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | This was evaluated considering red blood cell count, marker of liver function, markers of coagulation. | 8 weeks after treatment start | |
Other | Testicular volume | Testicular volume will be assessed locally at each visit by a physician blind to the patient group allocation | Baseline | |
Other | Testicular volume | Testicular volume will be assessed locally at each visit by a physician blind to the patient group allocation | 8 weeks after treatment start | |
Primary | Testosterone | total testosterone serum levels | 2 weeks after treatment start | |
Primary | Testosterone | total testosterone serum levels | 4 weeks after treatment start | |
Primary | Testosterone | total testosterone serum levels | 6 weeks after treatment start | |
Primary | Testosterone | total testosterone serum levels | 8 weeks after treatment start | |
Secondary | Inhibin B | Inhibin B serum levels | 2 weeks after treatment start | |
Secondary | Inhibin B | Inhibin B serum levels | 4 weeks after treatment start | |
Secondary | Inhibin B | Inhibin B serum levels | 6 weeks after treatment start | |
Secondary | Inhibin B | Inhibin B serum levels | 8 weeks after treatment start | |
Secondary | Free testosterone | Free testosterone serum levels | 2 weeks after treatment start | |
Secondary | Free testosterone | Free testosterone serum levels | 4 weeks after treatment start | |
Secondary | Free testosterone | Free testosterone serum levels | 6 weeks after treatment start | |
Secondary | Free testosterone | Free testosterone serum levels | 8 weeks after treatment start | |
Secondary | SHBG | sex hormone binding globulin (SHBG) | 2 weeks after treatment start | |
Secondary | SHBG | sex hormone binding globulin (SHBG) | 4 weeks after treatment start | |
Secondary | SHBG | sex hormone binding globulin (SHBG) | 6 weeks after treatment start | |
Secondary | SHBG | sex hormone binding globulin (SHBG) | 8 weeks after treatment start | |
Secondary | Estradiol | Estradiol serum levels by LC-MS/MS evaluation | 2 weeks after treatment start | |
Secondary | Estradiol | Estradiol serum levels by LC-MS/MS evaluation | 4 weeks after treatment start | |
Secondary | Estradiol | Estradiol serum levels by LC-MS/MS evaluation | 6 weeks after treatment start | |
Secondary | Estradiol | Estradiol serum levels by LC-MS/MS evaluation | 8 weeks after treatment start | |
Secondary | LH | Serum LH | 2 weeks after treatment start | |
Secondary | LH | Serum LH | 4 weeks after treatment start | |
Secondary | LH | Serum LH | 6 weeks after treatment start | |
Secondary | LH | Serum LH | 8 weeks after treatment start | |
Secondary | FSH | Serum FSH | 2 weeks after treatment start | |
Secondary | FSH | Serum FSH | 4 weeks after treatment start | |
Secondary | FSH | Serum FSH | 6 weeks after treatment start | |
Secondary | FSH | Serum FSH | 8 weeks after treatment start |
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT02651688 -
A Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene
|
Phase 2 |