Clinical Trials Register

Summary
EudraCT Number:	2019-004677-12
Sponsor's Protocol Code Number:	RHYTHM
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-10-07
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2019-004677-12

A.3

Full title of the trial

Pharmacodynamics and safety of human recombinant luteinising hormone in hypogonadotropic hypogonadal men.

Farmacodinamica e Sicurezza dell’ormone luteinizzante umano in maschi con ipogonadismo ipogonadotropo

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Evaluation of luteinizing hormone effect in men

Valutazione dell'azione dell'ormone luteinizzante nell'uomo

A.3.2

Name or abbreviated title of the trial where available

Rec-LH PD and safety profile in hypogonadotropic hypogonadism Men

A.4.1

Sponsor's protocol code number

RHYTHM

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	UNIVERSITA' DEGLI STUDI DI MODENA E REGGIO EMILIA - DIPARTIMENTO DI SCIENZE BIOMEDICHE, METABOLICHE E NEUROSCIENZE
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Merck Serono
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Comitato Etico dell'Area Vasta Emilia Nord
B.5.2	Functional name of contact point	Comitato Etico
B.5.3	Address:
B.5.3.1	Street Address	Policlinico di Modena, Via Largo del Pozzo 71
B.5.3.2	Town/ city	Modena
B.5.3.3	Post code	41124
B.5.3.4	Country	Italy
B.5.6	E-mail	bianchi.anna@aou.mo.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	LUVERIS - 75 IU/ML POLVERE E SOLVENTE PER SOLUZIONE INIETTABILE 1 FLACONCINO + 1 FIALA USO SOTTOCUTANEO
D.2.1.1.2	Name of the Marketing Authorisation holder	MERCK SERONO EUROPE LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Luveris
D.3.2	Product code	[034951]
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LUTROPINA ALFA
D.3.9.1	CAS number	152923-57-4
D.3.9.2	Current sponsor code	G03GA07
D.3.9.3	Other descriptive name	Lutropin alpha
D.3.10	Strength
D.3.10.1	Concentration unit	IU/l international unit(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	75
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	GONASI HP - 2000 UI/1 ML POLVERE E SOLVENTE PER SOLUZIONE INIETTABILE 1 FLACONCINO POLVERE+1 SIRINGA PRERIEMPITA DI SOLVENTE CON 2 AGHI
D.2.1.1.2	Name of the Marketing Authorisation holder	IBSA FARMACEUTICI ITALIA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Gonasi HP
D.3.2	Product code	[003763]
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GONADOTROPINA CORIONICA
D.3.9.1	CAS number	61489-71-2
D.3.9.2	Current sponsor code	G03GA02
D.3.9.3	Other descriptive name	Gonadotropin chorionic
D.3.10	Strength
D.3.10.1	Concentration unit	IU/l international unit(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	Yes
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Aquired hypogonadotropic hypogonadism

Ipogonadismo Ipogonadotropo aquisito

E.1.1.1

Medical condition in easily understood language

Hypogonadism

Ipogonadismo

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10021012
E.1.2	Term	Hypogonadotrophic hypogonadism
E.1.2	System Organ Class	100000004860

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The objective of this study is to assess the pharmacodynamics of recombinant LH, comparing the response to LH and hCG in hypogonadotropic hypogonadism patients and to evaluate LH safety profile. The results of this study are necessary for future clinical trials to test the hypothesis that, being the physiological hormone, the addition of LH improves the stimulation of spermatogenesis compared to FSH alone in infertile men and compared to FSH+hCG in HH. The patients with hypogonadotropic hypogonadism object of this study are simultaneously the best model for pharmacodynamics of LH/hCG and are representative of both male infertility and hypogonadism.
The pharmacodynamics of LH and the comparison of response to LH and hCG will be assessed by measuring serum steroid levels by liquid-chromatography, tandem mass spectrometry (LC-MS/MS).

L'obiettivo di questo studio è quello di valutare la farmacodinamica di LH ricombinante, confrontando la risposta a LH e hCG nei pazienti con ipogonadismo ipogonadotropo e valutare il profilo di sicurezza dell'LH. I risultati di questo studio sono necessari per futuri studi clinici per testare l'ipotesi che, essendo l'ormone fisiologico, l'aggiunta di LH migliora la stimolazione della spermatogenesi rispetto al solo FSH negli uomini sterili e rispetto a FSH + hCG in HH. I pazienti con ipogonadismo ipogonadotropo oggetto di questo studio sono il miglior modello per la farmacodinamica di LH / hCG e sono rappresentativi sia dell'infertilità maschile che dell'ipogonadismo.
La farmacodinamica di LH e il confronto della risposta a LH e hCG saranno valutati misurando i livelli sierici di steroidi mediante cromatografia liquida, spettrometria di massa tandem (LC-MS / MS).

E.2.2

Secondary objectives of the trial

1. Full Safety profile
2. Identification of the LH dosages needed to restore normal testosterone production in men with acquired hypogonadotropic hypogonadism and of the relationship between LH administered and testosterone increase, e.g. in terms of % serum testosterone increase per IU of r-hLH. This parameter will be useful for future clinical studies based on LH.
3. Comparison of steroid profiles, hormone related profiles and serum levels of testicular steroids upon stimulation by LH or hCG by immunoassay and by LC-MS/MS technique when available as validated method.
4. Testicular size

1. Profilo di sicurezza completo
2. Identificazione dei dosaggi di LH necessari per ripristinare la normale produzione di testosterone negli uomini con ipogonadismo ipogonadotropico acquisito e della relazione tra LH somministrato e aumento del testosterone, ad es. in termini di aumento del testosterone% per UI di r-hLH. Questo parametro sarà utile per futuri studi clinici basati su LH.
3. Confronto dei profili steroidei, dei profili ormonali correlati e dei livelli sierici di steroidi testicolari al momento della stimolazione mediante LH o hCG mediante test immunologico e mediante tecnica LC-MS / MS quando disponibile come metodo convalidato.
4. Volume testicolare

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male sex
• Age between 18 and 45 years
• Acquired hypogonadotropic hypogonadism forms:
o Hypogonadotropic hypogonadism after neurosurgery for tumors (i.e. pituitary adenoma, including prolactinoma, craniopharyngioma, germinomas, meningiomas, gliomas, and astrocytomas). OR
o Hypogonadotropic hypogonadism 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. On the other hand, when the patient was treated with intramuscular testosterone formulations, they must be changed into gel formulations at least in the six months before enrolment. When the patient was treated with androgens in gel formulations, they must be stopped 15 days before enrolment.
• No current hyper-secretion of other pituitary hormones

888/5000
• Sesso maschile
• Età compresa tra 18 e 45 anni
• Forme di ipogonadismo ipogonadotropo acquisiti:
o Ipogonadismo ipogonadotropo dopo neurochirurgia per tumori (ad es. adenoma ipofisario, incluso prolattinoma, craniofaringioma, germinomi, meningiomi, gliomi e astrocitomi). O
o Ipogonadismo ipogonadotropo dovuto all'effetto di massa correlato all'adenoma ipofisario, in caso di ipersecrezione di ormone indurito o controllato
• Livelli sierici totali di testosterone al di sotto degli intervalli normali (inferiori a 3 ng / mL)
• Nessuna terapia sostitutiva con androgeni negli ultimi tre mesi prima dell'arruolamento. D'altra parte, quando il paziente è stato trattato con formulazioni intramuscolari di testosterone, devono essere cambiate in formulazioni di gel almeno nei sei mesi precedenti l'arruolamento. Quando il paziente è stato trattato con androgeni in formulazioni di gel, devono essere interrotti 15 giorni prima dell'arruolamento.
• Nessuna iper-secrezione attuale di altri ormoni ipofisari

E.4

Principal exclusion criteria

• Congenital hypogonadotropic hypogonadism forms, such as: Congenital combined pituitary hormone deficiency; Genetic syndromes (e.g., Prader-Labhart-Willi, CHARGE, Lawrence-Moon-Bardet-Biedl)
• Acquired HH forms due to Infiltrative disease (hemochromatosis, granulomatous disease, histiocytosis, and sarcoidosis)
• Use of anabolic steroids and/or chronic non-replacement steroid therapies
• Drug and alcohol abuse
• Major systemic diseases, such as chronic severe liver disease, active malignancy diseases, cardiac failure, hypertension, renal dysfunction, migraines, or epilepsy (since aggravation or recurrence may occasionally be induced as a result of increased androgen production)
• Concomitant illnesses which could interfere with the study participation
• Medical history of androgen-dependent tumors (i.e. male breast carcinoma or prostatic carcinoma)
• Haematocrit <40% or >54%

• forme congenite di ipogonadismo ipogonadotropo, come: deficit congenito di ormone ipofisario combinato; Sindromi genetiche (ad es. Prader-Labhart-Willi, CHARGE, Lawrence-Moon-Bardet-Biedl)
• Forme HH acquisite a causa di malattia infiltrativa (emocromatosi, malattia granulomatosa, istiocitosi e sarcoidosi)
• Uso di steroidi anabolizzanti e / o terapie steroidee non sostitutive croniche
• Abuso di droghe e alcol
• Principali patologie sistemiche, come gravi patologie epatiche croniche, patologie maligne attive, insufficienza cardiaca, ipertensione, disfunzione renale, emicrania o epilessia (poiché l'aggravamento o la recidiva possono occasionalmente essere indotti a seguito di una maggiore produzione di androgeni)
• Malattie concomitanti che potrebbero interferire con la partecipazione allo studio
• Anamnesi di tumori androgeni-dipendenti (es. Carcinoma mammario maschile o carcinoma prostatico)
• Ematocrito <40% o> 54%

E.5 End points

E.5.1

Primary end point(s)

The primary outcome measure of the study will be the total testosterone serum levels increase, centrally measured by LC-MS/MS at each visit. Indeed, the primary endpoint of the study will be the comparison of total testosterone increase during LH administration to what obtained by hCG treatment. Moreover, primary endpoint will be the detection of a dose-response curve of testosterone increase during LH administration.

L'outcome primario dello studio sarà l'aumento totale dei livelli sierici di testosterone, misurato centralmente da LC-MS / MS ad ogni visita. Infatti, l'endpoint primario dello studio sarà il confronto tra l'aumento totale del testosterone durante la somministrazione di LH e quello ottenuto dal trattamento con hCG. Inoltre, l'endpoint primario sarà il rilevamento di una curva dose-risposta dell'aumento del testosterone durante la somministrazione di LH.

E.5.1.1

Timepoint(s) of evaluation of this end point

Two times weekly during the treatment phase and one time every two weeks in the washout phase

Due volte alla settimana durante la fase di trattamento e una volta ogni due settimane nella fase di washout del trattamento

E.5.2

Secondary end point(s)

Inhibin B, free testosterone, LH, FSH, estradiol, anti-Mullerian hormone (AMH); Safety and tolerability as determined by AE, SAE reporting, vital signs, ECG, Concomitant medication, laboratory parameters should be included in each panel (e.g., for haematology, chemistry, urinalysis) and evaluation of anti-Human-LH Antibodies formation in the serum.; • Red blood cell count
• Markers of liver and renal function
• Markers of coagulation
• 1,25 and 25 Hydroxy-vitamin D serum levels, INSL-3; Testicular volume

Inibina B, testosterone libero, LH, FSH, estradiolo, ormone anti-Mulleriano (AMH); Sicurezza e tollerabilità determinate da AE, segnalazione SAE, segni vitali, ECG, farmaci concomitanti, parametri di laboratorio devono essere inclusi in ciascun pannello (ad es. Per ematologia, chimica, analisi delle urine) e valutazione della formazione di anticorpi anti-LH nel siero .; • Emocromo
• Marker di funzione epatica e renale
• Markers di coagulazione
• 1,25 and 25 Hydroxy-vitamina D e INSL-3; Volume testicolare

E.5.2.1

Timepoint(s) of evaluation of this end point

Two times weekly during the treatment phase and one time every two weeks in the washout phase; Two times weekly during the treatment phase and one time every two weeks in the washout phase; Two times weekly during the treatment phase and one time every two weeks in the washout phase; Baseline, at the end of treatment phase, at the end of washout phase

Due volte alla settimana durante la fase di trattamento e una volta ogni due settimane nella fase di washout del trattamento; Due volte alla settimana durante la fase di trattamento e una volta ogni due settimane nella fase di washout del trattamento; Due volte alla settimana durante la fase di trattamento e una volta ogni due settimane nella fase di washout del trattamento; al baseline, alla fine della fase di trattamento e alla fine della fase di washout del farmaco

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

IMP 2

IMP2

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

111/5000
The trial will be completed upon enrollment and the two study phases in 32 patients

La sperimentazione sarà terminata al raggiungimento dell'arruolamento e delle due fasi di studio in 32 pazienti

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Subjects enrolled in the trial will be followed by the enrolling centre after the study

I soggetti arruolati nella sperimentazione saranno seguiti dal centro di iscrizione dopo lo studio

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-01-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-02-09

P. End of Trial
P.	End of Trial Status	Ongoing

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