Rec-LH PD and Safety Profile in Hypogonadotropic Hypogonadism Men

NCT04189133 | Unknown Phase 2 DMC

• 1 other identifier: RHYTHM_20-11-2019
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Acquired Hypogonadotropic Hypogonadism

Keywords

luteinising hormone; male infertility; hypogonadotropic hypogonadism; human menopausal gonadotropin

Outcome Measures

Primary Outcomes (4)

• Testosterone

  total testosterone serum levels

  2 weeks after treatment start

• Testosterone

  total testosterone serum levels

  4 weeks after treatment start

• Testosterone

  total testosterone serum levels

  6 weeks after treatment start

• Testosterone

  total testosterone serum levels

  8 weeks after treatment start

Secondary Outcomes (24)

• Inhibin B

  2 weeks after treatment start

• Inhibin B

  4 weeks after treatment start

• Inhibin B

  6 weeks after treatment start

• Inhibin B

  8 weeks after treatment start

• Free testosterone

  2 weeks after treatment start

Other Outcomes (10)

• Steroids

  2 weeks after treatment start

• Steroids

  4 weeks after treatment start

• Steroids

  6 weeks after treatment start

Study Arms (2)

Study group

EXPERIMENTAL

The study group will receive the daily administration sc of Luveris with increasing dosages two weeks (Treatment phase) as follows: Rec-LH 75 IU daily for 2 weeks; Rec-LH 150 IU daily for 2 weeks; Rec-LH 300 IU daily for 2 weeks; Rec-LH 600 IU daily for 2 weeks.

Drug: Lutropin alfa

Control group

ACTIVE COMPARATOR

The control group will receive the administration im of Gonasi HP as follows: hCG 500 IU two times weekly, for 2 weeks; hCG 1000 IU two times weekly, for 2 weeks; hCG 1500 IU two times weekly, for 2 weeks; hCG 2000 IU two times weekly, for 2 weeks.

Drug: Human chorionic gonadotropin

Interventions

Lutropin alfa DRUG

daily increasing dosages of lutropin alfa

Also known as: LH

Study group

Human chorionic gonadotropin DRUG

human chorionic gonadotropin increasing administration

Also known as: hCG

Control group

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Azienda Ospedaliero-Universitaria di Modena: lead

Study Sites (5)

Fondazione IRCCS Ca ' Grande Ospedale Maggiore Policlinico

Milan, Italy

NOT YET RECRUITING

Unit of Endocrinology of Modena

Modena, 41126, Italy

RECRUITING

Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università degli Studi di Napoli "Federico II"

Naples, Italy

NOT YET RECRUITING

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza - University of Rome

Rome, Italy

NOT YET RECRUITING

ivision of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin

Turin, Italy

NOT YET RECRUITING

Related Publications (8)

• 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.

  PMID: 28252213 BACKGROUND

• 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.

  PMID: 23071612 BACKGROUND

• 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.

  PMID: 28452938 BACKGROUND

• 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.

  PMID: 25376649 BACKGROUND

• 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.

  PMID: 28937611 BACKGROUND

• 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.

  PMID: 28424471 BACKGROUND

• 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.

  PMID: 28620352 BACKGROUND

• 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.

  PMID: 28067604 BACKGROUND

MeSH Terms

Conditions

Infertility, Male; Hypogonadism

Interventions

Luteinizing Hormone, beta Subunit; Chorionic Gonadotropin

Condition Hierarchy (Ancestors)

Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Infertility; Male Urogenital Diseases; Gonadal Disorders; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Luteinizing Hormone; Gonadotropins, Pituitary; Gonadotropins; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormones, Anterior; Pituitary Hormones; Peptides; Amino Acids, Peptides, and Proteins; Placental Hormones; Pregnancy Proteins; Proteins

Central Study Contacts

Daniele Santi, MD, PhD

CONTACT

0593961271; daniele.santi@unimore.it

Daniele Santi

CONTACT

0593961271; daniele.santi@unimore.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: November 29, 2019
• First Posted: December 6, 2019
• Study Start: January 19, 2022
• Primary Completion: January 18, 2025
• Study Completion: January 18, 2026
• Last Updated: July 20, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

IT (5)