Clinical Trials Register

Summary
EudraCT Number:	2011-000439-10
Sponsor's Protocol Code Number:	UOE/01-2011
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:	2012-03-29
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

2011-000439-10

A.3

Full title of the trial

Effect of metformin and clomiphene in obese hypogonadal men with or without type 2 diabetes on plasma levels of testosterone and metabolic parameters

Effetto della terapia con metformina e clomifene in maschi obesi ipogonadici con o senza diabete di tipo 2 sui livelli plasmatici del testosterone e sui parametri metabolici

A.3.1

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

Effect of metformin and clomiphene in obese hypogonadal men with or without type 2 diabetes on plasma levels of testosterone and metabolic parameters

Effetto della terapia con metformina e clomifene in maschi obesi ipogonadici con o senza diabete di tipo 2 sui livelli plasmatici del testosterone e sui parametri metabolici

A.4.1

Sponsor's protocol code number

UOE/01-2011

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	AZIENDA OSPEDALIERA DI BOLOGNA POLICLINICO S. ORSOLA M. MALPIGHI
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	AUSL Bari (fornitura di clomifene citrato)
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	AOU di Bologna
B.5.2	Functional name of contact point	U.O. Endocrinologia - Prof.Pasquali
B.5.3	Address:
B.5.3.1	Street Address	Via Albertoni 15
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40138
B.5.3.4	Country	Italy
B.5.4	Telephone number	051/6364147
B.5.5	Fax number	051/6363080
B.5.6	E-mail	renato.pasquali@unibo.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	SEROFENE*30CPR 50MG
D.2.1.1.2	Name of the Marketing Authorisation holder	MERCK SERONO SpA
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.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLOMIFENE CITRATE
D.3.9.1	CAS number	50-41-9
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	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.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	GLUCOPHAGE*60CPR RIV 1000MG
D.2.1.1.2	Name of the Marketing Authorisation holder	MERCK SERONO SpA
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.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METFORMIN HYDROCHLORIDE
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

obese subjects with type 2 diabetes and hypogonadism

Obesità, diabete di tipo 2 e ipogonadismo

E.1.1.1

Medical condition in easily understood language

obese subjects with type 2 diabetes and hypogonadism

Obesità, diabete di tipo 2 e 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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10049746
E.1.2	Term	Insulin-requiring type II diabetes mellitus
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10021011
E.1.2	Term	Hypogonadism male
E.1.2	System Organ Class	10014698 - Endocrine disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10033307
E.1.2	Term	Overweight
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

evaluate the effect of the therapy with metformin and clomiphene citrate on plasma levels of testosterone in obese subjects with type 2 diabetes or glucose intolerance, and hypogonadism

Effetto della terapia con metformina e clomifene citrato sui livelli plasmatici di testosterone

E.2.2

Secondary objectives of the trial

evaluate the effect of the therapy with metformin and clomiphene citrate on:
• metabolic parameters (plasma glucose, HbA1c, insulin and C-peptide, HOMA-IR, free fatty acids (FFA), total cholesterol, HDL, LDL, triglycerides);
• circulating levels of markers of chronic inflammation (fibrinogen, CRP) and inflammatory cytokines (TNF-a, IL-6);
• on the plasma levels of hormones secreted by adipose tissue (adiponectin, leptin);
• on the plasma levels of endocannabinoids.

Effetto della terapia con metformina e clomifene citrato sui parametri metabolici, su markers di infiammazione cronica , sui livelli plasmatici di ormoni secreti dal tessuto adiposo e degli endocannabinoidi.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

OTHER SUBSTUDIES:
Substudy forsees the deternmination of CAG polimorfism. Substudy is integrated in the core study UOE/01-2011.

ALTRI SOTTOSTUDI:
Sottostudio prevede la determinazione del polimorfismo CAG. Sottostudio è parte integrante del protocollo sperimentale core UOE/01-2011.

E.3

Principal inclusion criteria

males aged between 35 and 55 years
• Obesity, defined according to the WHO criteria for body mass index (BMI)superior to 30 kg/m2
• diagnosis of diabetes or impaired glucose tolerance according to the criteria defined by the American Diabetes Association (ADA) in 2009: in particular will be considered to have impaired glucose tolerance subjects with glucose at the second hour after oral glucose tolerance test (OGTT ) between 140 and 199 mg /dl, and diabetic subjects with fasting glucose superior to 126 mg /dl or blood glucose at the second hour after oral glucose tolerance test (OGTT)superior to 200 mg /dl
• HbA1c inferior to 8.5%
• metabolic syndrome, defined according to ATP III guidelines, or to the simultaneous presence of three or more of the following disorders: central obesity (waist circumference superior/egual to 102 cm), hypertension (SBP superior/egual to 130 mmHg or DBP superior/egual to 85 mmHg or pharmacological therapy for hypertension), hypertriglyceridemia (superior/egual to 150 mg /dl or pharmacological therapy hypertriglyceridemia), low HDL cholesterol (inferior to 40 mg /dl or pharmacological therapy for low HDL cholesterol
• hypogonadism, defined for circulating levels of total testosterone inferior/egual to 3 ng /ml
• signature of informed consent.

• maschi di età compresa tra 35 e 55 anni
• obesità, definita in accordo con i criteri della WHO per un indice di massa corporea (BMI) superiore a 30 kg/m2
• diagnosi di diabete o di alterata tolleranza glucidica, secondo i criteri definiti dall’American Diabetes Association (ADA) nel 2009: in particolare saranno considerati affetti da alterata tolleranza glucidica i soggetti con glicemia alla seconda ora dopo carico orale di glocosio (OGTT) compresa tra 140 e 199 mg/dl, e affetti da diabete i soggetti con glicemia a digiuno superiore a 126 mg/dl o con glicemia alla seconda ora dopo carico orale di glocosio (OGTT) superiore a 200 mg/dl
• HbA1c inferiore a 8.5%
• sindrome metabolica, definita secondo le linee guida ATP III, ovvero per la presenza contemporanea di 3 o più dei seguenti disordini: obesità centrale (circonferenza vita maggiore/uguale a 102 cm); ipertensione arteriosa (PAS maggiore/uguale a 130 mmHg o PAD maggiore/uguale a 85 mmHg o terapia farmacologica per ipertensione); ipertrigliceridemia (maggiore/uguale a 150 mg/dL o terapia farmacologica ipertrigliceridemia); ridotto colesterolo HDL (minore a 40 mg/dL o terapia farmacologica per basso colesterolo HDL)
• ipogonadismo, definito per livelli circolanti di testosterone totale minore/uguale a 3 ng/ml
• firma del consenso informato.

E.4

Principal exclusion criteria

• Patients with primary or secondary hypogonadism associated with genetic diseases or infiltrative or destructive disease of endocrine organs (testis, hypothalamus-pituitary)
• Patients on oral hypoglycemic agents treatment or in the 3 months preceding the start of the study
• Patients on lipid-lowering drug therapy or in the 3 months preceding the start of the study
• Known or suspected hypersensitivity to the drug or drug class in the study;
• Patients with serious medical conditions that, in the opinion of the investigator, contraindicate the patient's participation in the study;
• Use of systemic experimental drugs in the last 3 months before inclusion in the study.
• Patients unable to follow the procedures of the Protocol.

• Pazienti con ipogonadismo di natura primitiva o secondaria associato a malattie genetiche o a processi infiltrativi o distruttivi a carico degli organi endocrini (testicolo, ipotalamo-ipofisi)
• Pazienti in terapia farmacologica con ipoglicemizzanti orali in atto o nei 3 mesi precedenti l’inizio dello studio
• Pazienti in terapia farmacologica con ipolipemizzanti in atto o nei 3 mesi precedenti l’inizio dello studio
• Nota o sospetta ipersensibilità al farmaco od alla classe farmacologica in studio;
• Pazienti con gravi condizioni cliniche che, a giudizio dello sperimentatore, controindicano la partecipazione del paziente allo studio;
• Utilizzo di farmaci sperimentali per via sistemica negli ultimi 3 mesi prima dell’inclusione nello studio.
• Pazienti non in grado di seguire le procedure previste dal protocollo.

E.5 End points

E.5.1

Primary end point(s)

The primary goal of the study is to evaluate the effect of metformin and clomiphene on plasma levels of testosterone.

L’ obiettivo primario dello studio è valutare l’effetto della terapia con metformina e con clomifene sui livelli plasmatici di testosterone.

E.5.1.1

Timepoint(s) of evaluation of this end point

30 weeks

30 settimane

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

30 weeks

30 settimane

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

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

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

Yes

E.8.2.3

Other

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

E.8.7

Trial has a data monitoring committee

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

LVLS

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

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.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)

Not applicable.
Study population: male subjects age 35-55 years.

Non applicabile.
Popolazione: maschi età 35-55 anni.

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

2011-07-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-05-10

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

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