Clinical Trials Register

Summary
EudraCT Number:	2014-002832-15
Sponsor's Protocol Code Number:	49916
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-10-01
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

Netherlands - Competent Authority

A.2

EudraCT number

2014-002832-15

A.3

Full title of the trial

Ulipristal versus Gonadotropin-releasing hormone agonists prior to laparoscopic myomectomy: a double blind randomized controlled trial

Ulipristal versus Gonadotropine-releasing hormoon agonists voorafgaand aan laparoscopische myoomenucleatie: een dubbelblind gerandomiseerd onderzoek

A.3.1

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

Ulipristal versus Gonadotropin-releasing hormone agonists prior to laparoscopic fibroid removal: a double blind randomized controlled trial

Ulipristal versus Gonadotropine-releasing hormoon agonists voorafgaand aan laparoscopische myoom verwijdering: een dubbelblind gerandomiseerd onderzoek

A.4.1

Sponsor's protocol code number

49916

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	VU university medical center
B.1.3.4	Country	Netherlands
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	Gedeon Richter
B.4.2	Country	Hungary
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	VU university medical center
B.5.2	Functional name of contact point	Dept of gynaecology
B.5.3	Address:
B.5.3.1	Street Address	de Boelelaan 1117
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081 HZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031204444444
B.5.6	E-mail	w.hehenkamp@vumc.nl

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	Esmya
D.2.1.1.2	Name of the Marketing Authorisation holder	Gedeon Richter
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	ulipristalacetate
D.3.9.1	CAS number	126784-99-4
D.3.9.3	Other descriptive name	ULIPRISTAL ACETATE
D.3.9.4	EV Substance Code	SUB30470
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	5
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	Lucrin
D.2.1.1.2	Name of the Marketing Authorisation holder	AbbVie B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Powder and solvent for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LEUPRORELIN ACETATE
D.3.9.1	CAS number	74381-53-6
D.3.9.4	EV Substance Code	SUB02900MIG
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	11.25
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.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	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Uterine fibroids are very common during reproductive years in women. Minimally invasive treatments are emerging. Myomectomy is the gold standard which removes the fibroids entirely, preferably laparoscopically because of a faster recovery and cosmetical benefits, although the succes of a laparoscopic approach is dependent on the size of the fibroid(s) and the difficulty of dissection.

Myomen van de uterus komen veel voor. Het toepassen van een myoomenucleatie is de gouden standaard: alleen hiermee worden het myoom (de myomen) volledig verwijderd. Minimaal invasieve behandelingen worden steeds vaker toegepast. De laparoscopische myoomenucleatie wordt bij voorkeur uitgevoerd ivm het voordeel voor de patient ten aanzien van herstel en cosmetisch resultaat. Het succes van laparoscopisch opereren wordt echter bepaald door de grootte van het myoom en het chirurgische klievingsvlak.

E.1.1.1

Medical condition in easily understood language

Uterine fibroids are very common. Sometimes removal is necessary, preferably by laparoscopy, although this is only possible when the fibroids are not too big.

Myomen (vleesbomen) van de baarmoeder komen veel voor. Soms is het noodzakelijk om deze myomen te verwijderen, bij voorkeur met een kijkoperatie, maar dan kan alleen als de myomen niet te groot zijn.

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	LLT
E.1.2	Classification code	10046784
E.1.2	Term	Uterine fibroids
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

In order to increase the success rate of a laparoscopic procedure pre-treatment to decrease the volume might be beneficial. Gonadotropin-releasing hormone agonists (GnRHa) are used for this purpose with good results in terms of volume reduction, but sometimes resulting in loss of distinction of the right surgical planes and side effects (hot flushes) for the patient. Ulipristal is a new pre-operative treatment option for symptomatic fibroids, which has demonstrated good results in terms of volume reduction. The effect on cleavage planes is unknown. In this study Ulipristal will be compared to the gold standard: GnRH analogues in order to pre-treat fibroids that will be removed by laparoscopic myomectomy.

Om een laparoscopische benadering mogelijk te maken, danwel te vergemakkelijken is voorbehandeling raadzaam. Hiervoor werd altijd GnRH analogen gebruikt. Nadeel van dit middel is echter de bijwerkingen (opvliegers) en het mogelijk bemoeilijkte klievingsvlak. Sinds kort is een nieuw geneesmiddel voor deze indicatie geregistreerd: Ulipristal acetaat waarbij minder bijwerkingen zijn beschreven. Het effect op chirurgische uitkomsten en de vergelijking met GnRH is echter nog niet bekend. Dit onderzoek vergelijkt Ulipristal met de gouden standaard GnRH analogen als voorbehandeling voor een laparoscopische myoomenucleatie.

E.2.2

Secondary objectives of the trial

Furthermore the following outcomes will be investigated: volume reduction, surgical time, surgical ease, complications, quality of life, satisfaction and costs.

Naast de primaire uitkomst zullen de volgende uitkomsten worden onderzocht: volumereductie van de myomen, operatie duur, chirurgisch gemak, complicaties, kwaliteit van leven, tevredenheid en kosten.

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

Title: pre-treatment versus no pre-treatment prior to laparoscopic myomectomy: a non-randomized comparison.
Date: same as general protocol
Version: 1
Objectives: same objectives as main study (pre-treatment versus no-pre-treatment)
Methods: Eligible patients that are not willing to participate in the trial will not be pre-treated, or will be treated with the gold standard: GnRHa. Those patients that choose not to be pre-treated will be asked to participate in the untreated, not-randomized control group and will (after informed consent) follow the same study flow as the randomized patients. This way, pre-treatment in general can be compared to no pre-treatment.

Titel: voorbehandeling versus geen voorbehandeling voor laparoscopische myoomenucleatie: een niet-gerandomiseerde vergelijking.
datum: zelfde als algemeen protocol
Versie: 1
Obejctive: zelfde objectives als primaire studie (maar dan wel voorbehandeling versus geen voorbehandeling).
Methode: Geschikte patienten die niet willen deelnemen aan de studie zullen ofwel geen voorbehandeling krijgen, ofwelk behandeld worden met de gouden standaard: GnRHa. De patienten die ervoor kiezen helemaal geen voorbehandeling te krijgen zullen gevraagd worden om deel te nemen aan de studie in de niet-voorbehandelde, niet-gerandomiseerde controle groep. Zij zullen (na tekenen van informed consent) dezelfde studie-flow volgen als de gerandomiseerde patienten (met uitzondering van de voorbehandeing). Op deze manier kan voorbehandeling in het algemeen ook worden vergeleken met geen voorbehandeling.

E.3

Principal inclusion criteria

Women visiting the gynecological outpatient department with symptomatic fibroids will be screened for eligibility. In order to be eligible to participate in this trial, a subject must meet all of the following criteria:
 provide written consent prior to any study related procedures
 pre-menopausal
 a planned resection of a maximum of 2 FIGO (PALM-COEIN classification)
type 3, 4, 5, 6 or 2-5 fibroids of >5 cm
 the(se) fibroid(s) should be between 5 and 12 cm (maximum diameter)
 other fibroids should be small (<2 cm), not clinically relevant, or not resectable
(e.g. difficult position), or type 7 (any size)
 eligible for laparoscopic myomectomy

Vrouwen met symptomatische myomen gezien op de polikliniek gynaecologie die in aanmerking komen voren een myoomenucleatie worden gescreend op geschiktheid.
Inclusie criteria zijn voor deelname aan het onderzoek zijn:
 geschreven en mondeling consent kunnen geven voor deelname
 pre-menopauzaal
 geplande myoom enucleatie laparoscopisch van maximaal 2 myomen FIGO
(PALM-COEIN classification) type 3, 4, 5, 6 or 2-5 fibroids of >5 cm
 diameter tussen de 5 en 12 cm (maximum diameter)
andere myomen mogen niet groter zijn dan 2 cm, niet klinisch relevant of
niet reseceerbaar (moeilijke positie of type 7 (any size)
 geschikt voor laparoscopische myoom enucleatie

E.4

Principal exclusion criteria

A potential subject who meets any of the following criteria will be excluded from participation in this trial:
 pregnancy
 (suspicion of) malignancy
 any type 0-2 fibroids smaller than 5 cm
 more than 2 type 3-6 fibroids > 5 cm that need to be removed (except type 7
fibroids of any size)
 use of any hormonal agents and not willing to discontinue their use
 use of anticoagulants
 coagulopathy
 Use of NSAIDs impacting bleeding before surgery
 Contraindication to laparoscopy procedure or causes of complications
(multiple laparotomies, frozen pelvis, severe endometriosis)
 allergy to leuprolide acetate/comparable nonapeptides or Ulipristal

Voornaamste exclusie criteria:
 zwangerschap
 (verdenking op) maligniteit
 aanwezigheid ype 0-2 myoom <5 cm
 meer dan 2 type 3-6 myomen >5 cm die verwijderd moeten worden, behalve type
7 myoom ongeacht de afmeting
 gebruik van hormonale medicatie en onbereidheid deze te staken
 gebruik anti-stolling
 coagulopathie
 gebruik van NSAIDs (bloedings neiding beinvloedend) voorafgaand aan de operatie
contra-indicatie voor laparoscopie (meerder laparotomieen in VG, frozen
pelvis, graad IV endometriose)
 allergie leuprolide acetate/comparable nonapeptides or Ulipristal

E.5 End points

E.5.1

Primary end point(s)

In this study it will be investigated if Ulipristal is non-inferior to GnRH in terms of intra-operative blood-loss (primary outcome).

Dit onderzoek wordt uitgevoerd om te beoordelen of voorbehandeling met ulipristal non-inferior is ten op zichte van GnRHa met betrekking tot per-operatief bloedverlies (primaire uitkomst maat).

E.5.1.1

Timepoint(s) of evaluation of this end point

This endpoint will be reached when the last patient is operated on. This will be around 4 months after inclusion of the last patient, since pre-treatment takes 3 months, after which surgery will take place within a month.

Dit eindpunt zal bereikt worden wanneer de laatste patient is geopereerd. Dat zal ongeveer 4 maanden na de laatste randomisatie zijn, aangezien de voorbehandeling 3 maanden in beslag neemt en de operatie binnen een maand na het einde van de voorbehandeling zal plaatsvinden.

E.5.2

Secondary end point(s)

Furthermore the following outcomes will be investigated: volume reduction, surgical time, surgical ease, complications, quality of life, satisfaction and costs.

Naast de primaire uitkomst zullen de volgende uitkomsten worden onderzocht: volumereductie van de myomen, operatie duur, chirurgisch gemak, complicaties, kwaliteit van leven, tevredenheid en kosten.

E.5.2.1

Timepoint(s) of evaluation of this end point

The last endpoint will be obtained with the last questionnaire 6 months after treatment.

Het laatste eindpunt zal 6 maanden na de behandeling worden verkregen door een vragenlijst.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

De trial is officially ended when the last questionnaire at six months follow up is returned.

De studie is beeindigd wanneer de laatste vragenlijst 6 maanden na de behandeling is teruggestuurd.

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

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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)

none

geen

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

2014-10-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-12-17

P. End of Trial
P.	End of Trial Status	Completed

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