Clinical Trials Register

Summary
EudraCT Number:	2014-001185-10
Sponsor's Protocol Code Number:	14I/Prg02
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-07-03
Trial results	View 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

2014-001185-10

A.3

Full title of the trial

Effect of a progesterone 25 mg solution (Pleyris, IBSA Farmaceutici Italia, srl) administered by oral route compared to an oral progesterone 200 mg capsule (Prometrium, Rottapharm SpA) on the endometrial thickness of post-menopausal women under hormone replacement therapy. A pilot, prospective, open-label, randomised, three arm, parallel-group, single centre, phase II clinical trial.

Effetto di progesterone 25 mg soluzione (Pleyris, IBSA Farmaceutici Italia, srl) somministrato per via orale comparato con un progesterone 200 mg in capsule (Prometrium, Rottapharm SpA) sullo spessore dell’endometrio in donne in post-menopausa sotto terapia ormonale sostitutiva. Studio clinico pilota, prospettico, in aperto, randomizzato, a tre braccia, a gruppi paralleli, singolo centro, di fase II

A.3.1

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

Effect on the endometrial thickness of progesterone 25 mg solution administered by oral route in post-menopausal women under treatment with estrogens, compared to progesterone 200 mg capsules.

Effetto sullo spessore dell’endometrio di progesterone 25 mg soluzione somministrato per via orale in donne in post-menopausa in trattamento con estrogeni, in confronto con progesterone 200 mg capsule.

A.4.1

Sponsor's protocol code number

14I/Prg02

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	IBSA Institut Biochimique SA
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	IBSA Institut Biochimique SA
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IBSA Institut Biochimique SA
B.5.2	Functional name of contact point	Clinical Research Manager
B.5.3	Address:
B.5.3.1	Street Address	Via del Piano
B.5.3.2	Town/ city	Pambio-Noranco
B.5.3.3	Post code	6915
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41583601000
B.5.5	Fax number	+41583601655
B.5.6	E-mail	claudia.scarsi@ibsa.ch

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	PLEYRIS 25 mg solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	IBSA Farmaceutici Italia, srl
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	PLEYRIS 25 mg solution for injection (in the protocol also designated Progesterone 25 mg solution)
D.3.4	Pharmaceutical form	Solution for injection
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	PROGESTERONE
D.3.9.1	CAS number	57-83-0
D.3.9.3	Other descriptive name	Pregn-4-ene-3,20-dione, Δ4-pregnone-3,20-dione
D.3.9.4	EV Substance Code	SUB10076MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	22.35
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	PROMETRIUM 200 mg soft capsules for oral and vaginal use
D.2.1.1.2	Name of the Marketing Authorisation holder	Rottapharm S.p.A
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	PROMETRIUM 200 mg soft capsules for oral and vaginal use
D.3.4	Pharmaceutical form	Capsule, soft
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	progesterone
D.3.9.3	Other descriptive name	PROGESTERONE, MICRONISED, Pregn-4-ene-3,20-dione, Δ4-pregnone-3,20-dione
D.3.9.4	EV Substance Code	SUB45084
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	200
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

hormone replacement therapy of menopause (as progestin therapy in association to estrogen replacement therapy)

terapia ormonale sostitutiva della menopausa (come terapia progestinica da associare alla terapia estrogenica sostitutiva)

E.1.1.1

Medical condition in easily understood language

hormone replacement therapy of menopause

terapia ormonale sostitutiva della menopausa

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	PT
E.1.2	Classification code	10020388
E.1.2	Term	Hormone replacement therapy
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

to evaluate the protective effect of progesterone on the endometrium of post-menopausal women under HRT, assessed by measurement of endometrial thickness, upon administration of two dosing schemes (continuous sequential and combined continuous) of progesterone 25 mg solution administered by oral route, compared to an oral progesterone 200 mg capsule (Prometrium).

Valutare l’effetto protettivo del progesterone sull’endometrio di donne in post menopausa sottoposte a terapia ormonale sostitutiva con estrogeno. La valutazione viene fatta per mezzo della misurazione dello spessore endometriale in seguito a due differenti schemi di assunzione (continuo sequenziale e combinato continuo) del progesterone 25 mg soluzione somministrato per via orale comparato a progesterone orale 200 mg in capsule (Prometrium).

E.2.2

Secondary objectives of the trial

Histological assessment of the endometrium; Incidence of withdrawal bleeding and/or irregular bleeding; Safety evaluation (adverse events).

Valutazione istologica dell'endometrio; incidenza di sanguinamento vaginale regolare o irregolare; valutazione della sicurezza (eventi avversi).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Signed written informed consent prior to inclusion in the study.
- Post-menopausal women defined as:
* 12 months of spontaneous amenorrhea
* or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/ml
* and since maximum 2 years, with intact uterus.
- Climateric symptoms.
- Age 40-65.
- BMI: 18<BMI<30 kg/m2.
- Negative mammogram and normal clinical breast examination.
- Negative Pap test.
- Normal pelvic examination.
- Evaluable screening endometrial biopsy (i.e., endometrial tissue sufficient for diagnosis) displaying no findings of endometrial hyperplasia or cancer.
- Endometrium thickness < 5 mm at screening.

- Donne in post-menopausa definite come:
*12 mesi di amenorrea spontanea,
*oppure 6 mesi di amenorrea spontanea con livelli di FSH nel siero > 40 mIU/ml,
*e fino ad un massimo di 2 anni, con utero intatto
- Sintomi della menopausa.
- Età 40-65.
- BMI: 18<BMI<30 kg/m2.
- Mammogramma negativo e normale valutazione clinica del seno.
- Pap test negativo.
- Esame pelvico normale.
- Biopsie endometriali di screening valutabili (vale a dire con tessuto sufficiente per la diagnosi) che non mostrano segni di iperplasia o cancro endometriale
- Spessore endometriale < 5 mm allo screening.

E.4

Principal exclusion criteria

- Estrogen, progestin or estrogen/progestin drug products during the past 3 months.
- Contraindications to HRT:
*known hypersensitivity to the active substances or to any of the excipients;
*acute or history of severe liver disease;
*porphyria;
*undiagnosed genital bleeding;
*known, past or suspected breast cancer;
*known, past or suspected estrogen-dependent malignant tumors or pre-cancerous conditions (e.g. endometrial cancer);
*known, past or suspected hepatic tumors (benign or malign);
*severe hypertriglyceridemia;
*endometrial hyperplasia;
*previous or current venous thromboembolism (e.g. deep venous thrombosis, pulmonary embolism, thrombophlebitis);
*high risk of arterial or venous thrombosis;
*known thrombophilic disorders;
*active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction, stroke).
*active or history of leiomyomas (uterine fibroids) or endometriosis;
*risk factors for estrogen-dependent tumors;
- Presence of uterine fibroids or polyps or other factors affecting endometrial thickness measurement.
- Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption, fructose intolerance or sucrose isomaltase deficiency (because of the excipients contained in Progynova, i.e. lactose and saccharose).
- Allergy to peanuts (because of the excipient contained in Prometrium, i.e. arachis oil).
- Participation in a concurrent clinical trial or another trial within the past 2 months.
- Use of concomitant medications, including OTC, that might interfere with the study evaluation (see section 7.4).
- Intake of phytoestrogens through food or natural products.
- Presence of any medical condition or other circumstances which would significantly decrease the chance of obtaining reliable data, achieving study objectives or completing the study.
- Serious psychiatric problems (whether or not receiving treatment) or in any case such as to compromise the patient’s reliability.
- Presumption of poor reliability/cooperation.
- Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.

- Estrogeni, progestinici o terapia estro-progestinica durante i precedenti 3 mesi.
- Controindicazioni alla Terapia Ormonale Sostitutiva:
*Ipersensibilità ai principi attivi o ad uno qualsiasi degli eccipienti
*Grave disfunzione o malattia epatica
*Porfiria
*Emorragia vaginale non diagnosticata
*Cancro noto o presunto della mammella
*Conosciuti o sospetti tumori maligni o condizioni pre-cancerose (es. cancro endometriale) estrogeno-dipendenti;
*Tumore al fegato noto o presunto (benigno o maligno)
*Ipertrigliceridemia severa
*Iperplasia endometriale
*precedente o corrente tromboembolia venosa (es. trombosi venosa profonda, embolia polmonare, tromboflebite)
*alto rischio di trombosi arteriosa o venosa.
*trombofilia conosciuta
*malattia tromboembolica arteriosa attiva o recente (es. angina, infarto miocardico, ictus)
*problema in corso o storia di leiomiomi (fibromi uterini) o endometriosi;
*fattori di rischio per tumori estrogeno-dipendenti;
- Presenza di fibromi uterini o polipi o di altri fattori che influenzano la misurazione dello spessore endometriale .
- Rari problemi ereditari di intolleranza al galattosio, deficit di Lapp lattasi o malassorbimento di glucosio- galattosio , intolleranza al fruttosio o saccarosio isomaltasi (a causa degli eccipienti contenuti in Progynova , cioè lattosio e saccarosio) .
- Allergia alle arachidi (a causa dell’eccipiente contenuto in Prometrium, cioè olio di arachidi).
- Partecipazione ad uno studio clinico concomitante o un altro studio clinico negli ultimi 2 mesi
- Uso di farmaci concomitanti, tra cui OTC, che potrebbero interferire con la valutazione dello studio.
- Assunzione di fitoestrogeni attraverso il cibo o prodotti naturali
- Presenza di qualsiasi condizione medica o altre circostanze che potrebbero ridurre in modo significativo la possibilità di ottenere dati affidabili, il raggiungimento degli obiettivi di studio o di completare lo studio .
- Problemi psichiatrici gravi (anche a ricevere il trattamento) o comunque tali da compromettere l'affidabilità del paziente.
- Presunzione di scarsa affidabilità / cooperazione.
- Qualsiasi motivo che, a giudizio dello sperimentatore, potrebbe impedire al soggetto di partecipare allo studio.

E.5 End points

E.5.1

Primary end point(s)

evolution of the endometrial thickness after treatment with estrogen and progesterone

evoluzione dello spessore endometriale dopo trattamento con estrogeno e progesterone

E.5.1.1

Timepoint(s) of evaluation of this end point

3 months (90 days)

3 mesi (90 giorni)

E.5.2

Secondary end point(s)

evolution of the endometrial thickness after treatment with estrogen and progesterone; hystological evalutaion of the endometrium; incidence of regular or irregular vaginal bleeding; safety evaluation (adverse events)

evoluzione dello spessore endometriale dopo trattamento con estrogeno e progesterone; valutazione istologica dell'endometrio; incidenza di sanguinamento vainale regolare o irregolare; valutazione della sicurezza (eventi avversi)

E.5.2.1

Timepoint(s) of evaluation of this end point

depending on the end-point: day 17, 1 month (day 34), 3 months (day 90) or throughout the whole study duration

a seconda dell'end-point: 17 giorni, 1 mese (giorno 34), 3 mesi (giorno 90) o durante tutto il corso dello studio

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

Yes

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)

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)

Yes

E.8.2.2

Placebo

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

Yes

E.8.4

The trial involves multiple sites in the 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.1.1.1

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)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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)

expected normal treatment of that condition

normale pratica clinica prevista per la patologia in 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

2014-09-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2016-01-31

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