Clinical Trials Register

Summary
EudraCT Number:	2012-000036-26
Sponsor's Protocol Code Number:	PGL11-006
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-04-11
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2012-000036-26

A.3

Full title of the trial

A Phase III, multicentre, randomized, double-blind clinical study, investigating the efficacy and safety of repeated 12-week courses of daily 5mg or 10mg doses of PGL4001 for the long-term management of symptomatic uterine fibroids

A.3.1

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

Assessment of the efficacy and safety of PGL4001 of repeated 12-week courses for the long-term management of symptomatic uterine fibroids

A.3.2

Name or abbreviated title of the trial where available

PEARL IV (PGL4001 Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata)

A.4.1

Sponsor's protocol code number

PGL11-006

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	PregLem S.A.
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	PregLem S.A.
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	PregLem S.A.
B.5.2	Functional name of contact point	General Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Chemin du Pré-Fleuri 3,
B.5.3.2	Town/ city	Plan-Les-Ouates, Geneva
B.5.3.3	Post code	1228
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41(0)228840340
B.5.5	Fax number	+41(0)228840349
B.5.6	E-mail	info@preglem.com

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	No
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	ulipristal acetate
D.3.2	Product code	PGL4001
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	ulipristal (INN) acetate
D.3.9.1	CAS number	126784-99-4
D.3.9.2	Current sponsor code	PGL4001
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	10
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	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	No
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	ulipristal acetate
D.3.2	Product code	PGL4001
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	ulipristal (INN) acetate
D.3.9.1	CAS number	126784-99-4
D.3.9.2	Current sponsor code	PGL4001
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.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	Tablet
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

Uterine myomas are benign, monoclonal, hormone-sensitive, smooth
muscle tumours of the uterus. They are the most common tumour of the
female reproductive tract in pre-menopausal women and mostly
asymptomatic affecting approximately 40% of women between 35 and
55 years. When symptomatic, the main symptoms are heavy uterine
bleeding, abdominal pressure, abdominal pain, increased urinary
frequency and infertility.

E.1.1.1

Medical condition in easily understood language

Uterine fibroid

E.1.1.2

Therapeutic area

Body processes [G] - Reproductive physiologi cal processes [G08]

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	10046801
E.1.2	Term	Uterine myoma
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

Part I Primary Objective:
To compare and assess the sustained efficacy of two repeated 12-week treatment courses of daily administration of 5mg and 10mg doses of PGL4001 on uterine bleeding in women with uterine fibroids.

Part II Primary Objective:
To compare and assess the sustained efficacy of four repeated 12-week treatment courses of daily administration of 5mg and 10mg doses of PGL4001 on uterine bleeding in women with uterine fibroids.

E.2.2

Secondary objectives of the trial

Part I Secondary Objectives:
Efficacy objective:
• To compare and assess the sustained efficacy of two repeated 12-week treatment courses of daily administration of 5mg and 10mg doses of PGL4001 on myoma volume, uterus volume, Quality of Life (QoL), and pain.
Safety objective:
• To assess the overall safety of two repeated 12-week treatment courses of daily administration of 5mg or 10mg of PGL4001.
Part II Secondary Objectives:
Efficacy objective:
• To compare and assess the sustained efficacy of four repeated 12-week treatment courses of 5mg and 10mg doses of PGL4001 on myoma volume, uterus volume, Quality of Life (QoL), and pain.
Safety objective:
• To assess the overall safety of four repeated 12-week treatment courses of daily administration of 5mg or 10mg doses of PGL4001.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

To be eligible for inclusion into this study, the subjects must fulfil all of the following criteria:
1. Provision of written informed consent prior to any study related procedures.
2. Pre-menopausal women between 18 and 50 years inclusive.
3. Subject with a Body Mass Index ≥18 and ≤40.
4. Subject with hormonal levels FSH ≤ 20 mIU/mL (measured at screening 2 visit).
5. Subject with myomatous uterus < 16 weeks (compared to a uterus of 16 weeks of pregnancy)
6. Subject with a largest uterine myoma between 3 cm and 12 cm diameter inclusive.
7. Subject with menstrual cycle ≥22 and ≤35 days. The menstrual cycle between screening 1 visit and visit 2 should be the one considered for eligibility.
8. PBAC score >100 as measured during screening over the first 8 days of the menstrual bleed
9. Subject has no significant findings at breast examination at the screening visit.
10. Females of childbearing potential are advised to practice a non-hormonal method of contraception among one of the following:
o Sexual abstinence
o Diaphragm
o Condom
o Or having a partner with a vasectomy with either confirmed azoospermia or performed at least 6 months prior to the study.

Females of non-childbearing potential are defined as women with tubal ligation sterilisation at least two months before the start.

E.4

Principal exclusion criteria

To be eligible for inclusion in this study the subjects must not meet any of the following criteria:
1. The subject has a history of uterus surgery that would interfere with the study endpoints. The investigator must assess whether a previous surgery is likely to interfere with the study. Subjects who had a uterine artery embolization may be included in the study ≥ 6 months after the procedure.
2. The subject has a history of or current uterus cervix, ovarian or breast cancer.
3. The subject has had a significant and persisting finding on Papanikolaou test (PAP) smear within the past 12 months.
4. The subject has a history of endometrium hyperplasia or adenocarcinoma or similar lesions in the screening biopsy. If by exception the endometrium biopsy results are only made available after subject’s visit 2, the Investigator will follow the instructions listed in Appendix G.
5. Subject has a large uterine polyp (> 2cm).
6. Subject has extensively calcified myomas and/or uterus.
7. Subject has a known severe coagulation disorder.
8. Subject has one or more ovarian cysts ≥ 4cm diagnosed by ultrasound.
9. The subject has a history of treatment for myoma with a SPRM.
10. The subject has been taking prohibited medication :
o Treatments with progestins (systemic or progestin releasing intra-uterine system) or an oral contraceptive: within the month before the screening visit.
o Acetylsalicylic acid, mefenamic acid, anticoagulants such as cumarins and/or antifibrinolytic drugs such as tranexemic acid within one week before the screening visit
o Systemic glucocorticoid treatments and/or systemic depot glucocorticoid treatments within one week or two months before the screening visit, respectively.
o GnRH agonist and antagonist:
 Immediate or monthly sustained release depot preparation or immediate release form within 6 months of screening visit
 3 or 6 months sustained release depot preparation within 12 months before the screening visit.
11. The subject is likely to require treatment during the study with drugs that are not permitted by the study protocol: progestins (systemic or progestin releasing intra-uterine system), hormonal contraceptives, systemic glucocorticoids (oral and injectable), GnRH agonist and GnRH antagonists.
12. The subject requires treatment with a medication which includes potent inhibitors of CYP3A4 (such as ketoconazole)
13. The subject requires treatment with a medication which includes potent inducers of CYP3A4 (such as rifampicin).
14. The subject has abnormal hepatic function at study entry (defined as aspartate transaminase [AST], alanine transaminase [ALT], gamma glutamyl transferase [GGT], hepatic alkaline phosphatase, or total bilirubin above twice the upper limit of normal). In case of isolated elevated GGT, the subject may be enrolled if the re-test is within the allowed limits.
15. The subject has a positive pregnancy test at baseline, is nursing or planning a pregnancy during the course of the study.
16. The subject has a problem with alcohol or drug abuse.
17. The subject has a mental condition rendering her unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.
18. The subject has abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardise the subject’s safety or interfere with study evaluations.
19. The subject has an allergy to SPRMs or progestins or any of the ingredients of the study drug tablet (see list of ingredients in the investigator’s brochure).
20. The subject is currently enrolled in an investigational drug or device study or participated in such a study within the previous 30 days and is still in exclusion period.

E.5 End points

E.5.1

Primary end point(s)

PART I
Primary Efficacy Endpoint:
Percentage of subjects who are in amenorrhea at the end of both treatment courses 1 and 2.
Amenorrhea is defined as no more than 1 day of spotting within a 35 day interval.

PART II
Primary Efficacy Endpoint:
Percentage of subjects who are in amenorrhea at the end of all four treatment courses.

E.5.1.1

Timepoint(s) of evaluation of this end point

As soon as the last subject has completed Part I of the protocol and all data have been cleaned, the treatment groups will be unblinded, and the results up to and including the visit following the second course of treatment (visit 8) will be analysed (Full integrated Clinical Study Report [CSR]). As soon as the last subject has completed Part II of the protocol and all data have been cleaned, the results of the second part of the study will be analysed (separate Full CSR).

E.5.2

Secondary end point(s)

Secondary Endpoints Part 1:
Efficacy:
• Percentage of subjects who are in amenorrhea at the end of treatment course 1 and at the end of treatment course 2.
• Percentage of subjects in amenorrhea in the last 56 days of both treatment courses 1 and 2.
• Percentage of subjects in amenorrhea in the last 56 days of treatment course 1 and in the last 56 days of treatment course 2.
• Percentage of subjects with controlled bleeding in the last 56 days of both treatment courses 1 and 2. Controlled bleeding is defined as no episodes of heavy bleeding and a maximum of 8 days of bleeding during the last 56 days of a course of treatment.
• Percentage of subjects with controlled bleeding in the last 56 days of treatment course 1 and in the last 56 days of treatment course 2.
• Proportion of days with uterine bleeding between visit 2 and visit 8.
• Proportion of days with heavy uterine bleeding between visit 2 and visit 8.
• Median time to amenorrhea during treatment course 1 and during treatment course 2.
• Change from baseline to visits 6, 7 and 8 in the volume of the 3 largest myomas, measured by transvaginal ultrasound.
• Change from baseline to visits 6, 7 and 8 in uterus volume, measured by transvaginal ultrasound.
• Change from baseline to end of treatment course 1 and to end of treatment course 2 in quality of life, measured with the UFS- QoL questionnaire.
• Change from baseline to end of treatment course 1 and to end of treatment course 2 in quality of life, measured with the EQ-5D questionnaire.
• Change from baseline to end of treatment course 1 and to end of treatment course 2 in pain, measured using a Visual Analog Scale (VAS).

Safety:
• Number and proportion of subjects withdrawing from treatment early for safety reasons related to study drug.
• Number and proportion of subjects experiencing treatment-emergent adverse events including subject-reported adverse events and clinically significant changes in the following parameters (change from baseline: in gynaecological examination, in ECG, in laboratory parameters, observed in vital signs measurements, in endometrial thickness assessed by transvaginal ultrasound, of the ovary observed by transvaginal ultrasound, in endometrium biopsy).

Secondary Endpoints Part 2:
Efficacy:
• Percentage of subjects who are in amenorrhea at the end of treatment course 3 and at the end of treatment course 4.
• Percentage of subjects in amenorrhea in the last 56 days of all four treatment courses.
• Percentage of subjects in amenorrhea in the last 56 days of treatment course 3 and in the last 56 days of treatment course 4.
• Percentage of subjects with controlled bleeding in the last 56 days of all four treatment courses.
• Percentage of subjects with controlled bleeding in the last 56 days of treatment course 3 and in the last 56 days of treatment course 4.
• Proportion of days with uterine bleeding between visit 2 and visit 11.
• Proportion of days with heavy uterine bleeding between visit 2 and visit 11.
• Median time to amenorrhea during treatment course 3 and during treatment course 4.
• Change from baseline to visits 9, 10, 11 and 12 in the volume of the 3 largest myomas, measured by transvaginal ultrasound.
• Change from baseline to visits 9, 10, 11 and 12 in uterus volume, measured by transvaginal ultrasound.
• Change from baseline to end of treatment course 3 and to end of treatment course 4 in quality of life, measured with the UFS- QoL questionnaire.
• Change from baseline to end of treatment course 4 in quality of life, measured with the EQ-5D questionnaire.
• Change from baseline to end of treatment course 3 and to end of treatment course 4 in pain, measured using a Visual Analogue Scale (VAS).

Safety:
• Number and proportion of subjects withdrawing from treatment early for safety reasons related to study drug.
• Number and proportion of subjects experiencing treatment-emergent adverse events including subject-reported adverse events and clinically significant changes in the following parameters (change from baseline: in gynaecological examination, in ECG, in laboratory parameters, observed in vital signs measurements, in endometrial thickness assessed by transvaginal ultrasound, of the ovary observed by transvaginal ultrasound, in endometrium biopsy).

E.5.2.1

Timepoint(s) of evaluation of this end point

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)

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

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

Yes

E.8.2.3.1

Comparator description

2 doses are studied, each dose arm is the control of the other.Placebo is used for maintaning blind.

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Russian Federation

Ukraine

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

Final clinical database lock

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

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:

500

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

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

450

F.4.2.2

In the whole clinical trial

500

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)

back to usual care

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

2012-05-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-06-11

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

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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