Clinical Trials Register

Summary
EudraCT Number:	2010-019497-32
Sponsor's Protocol Code Number:	PGL09-027
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-09-14
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

Austria - BASG

A.2

EudraCT number

2010-019497-32

A.3

Full title of the trial

A Phase III, multicentre, clinical study investigating the efficacy and safety of three successive periods of 3-month open-label PGL4001 treatment, each followed by ten days of double-blind treatment with progestin or placebo and a drug-free period until return of menses, in subjects with myomas and heavy uterine bleeding.

A.3.1

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

Assessment of the efficacy of PGL4001 in repeated treatment courses on reducing symptoms of uterine fibroids causing heavy menstrual periods

A.3.2

Name or abbreviated title of the trial where available

PEARL III extension

A.4.1

Sponsor's protocol code number

PGL09-027

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	Audrey Osouf
B.5.3	Address:
B.5.3.1	Street Address	Chemin du Pré-Fleuri 3, Plan-Les-Ouates
B.5.3.2	Town/ city	Geneva
B.5.3.3	Post code	1228
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+ 41 (0) 22 884 03 20
B.5.5	Fax number	+41 (0) 22 884 03 49
B.5.6	E-mail	audrey.osouf@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	Information not present in EudraCT
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
D.3.9.1	CAS number	126784-99-4
D.3.9.2	Current sponsor code	PGL4001
D.3.9.3	Other descriptive name	VA2914 (HRA), CDB-2914 (NICHD), RTI 3021-012 (RTI), HRP-2000 (WHO)
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)	Information not present in EudraCT
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	Yes
D.2.1.1.1	Trade name	Primolut-Nor® 10mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Quimica Farmaceutica Bayer S.L.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Information not present in EudraCT
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	NORETHISTERONE ACETATE
D.3.9.1	CAS number	51-98-9
D.3.9.3	Other descriptive name	NORETHISTERONE ACETATE
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.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

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	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 assess the sustained efficacy of three 3-month treatment cycles of ulipristal acetate on myoma symptoms, specifically uterine bleeding.

E.2.2

Secondary objectives of the trial

Efficacy:
• To assess the sustained efficacy of three 3-month treatment cycles of ulipristal acetate on myoma symptoms other than uterine bleeding (i.e. myoma size, pain, quality of life (QoL)).
Safety:
• To assess the overall safety of the on-off 3-month administration of PGL4001 for up to a total of four treatment cycles (including PGL09-026 PEARL III treatment cycle).
Exploratory:
• To assess, recruitment permitting, the long-term clinical efficacy and safety benefit of following each of the three 3-month treatment cycles with ulipristal acetate by a ten-day course of norethisterone acetate or placebo

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 PGL09-027 study related procedures.
2. Subject completed visit 6 of PGL09-026 study, 10 to 18 days after menstruation following end of treatment with PGL4001, and did not take medications forbidden by the protocol.
3. Subject has no contraindication to enter the extension study, based on the responsible investigator’s judgment.

E.4

Principal exclusion criteria

To be eligible for inclusion in this study the subjects must not meet any of the following criteria:
1. Subject has a large uterine polyp (> 2cm).
2. Subject has one or more ovarian cysts ≥ 4cm diagnosed by ultrasound at visit 6 of PGL09-026.
3. 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), acetylsalicylic acid, mefenamic acid, anticoagulants such as cumarins, antifibrynolytic drugs such as tranexamic acid, treatments containing PgP substrates (digoxin, fexofenadine), and/or treatments containing moderate or potent inhibitors or inducers of CYP3A4.
4. Subject has abnormal hepatic function at re-test (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). A re-test will be performed if hepatic function test values are above twice the upper limit of normal at visit 5 of PGL09-026 study. If the second test result is still above twice the upper limit of normal, the subject cannot be included. In case of isolated GGT, the subject may be enrolled if the re-test is within the allowed limits.
5. Subject has a lactose or galactose intolerance (i.e. lapp lactase deficiency or glucose-galactose malabsorption)
6. Subject has a positive pregnancy test or is planning a pregnancy during the course of the study.
7. Subject has a current problem with alcohol or drug abuse.
8. 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.
9. Subject has clinically significant abnormal findings at visit A or any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the subject’s safety or interfere with study evaluations.

E.5 End points

E.5.1

Primary end point(s)

Primary efficacy endpoint:

•Percentage of subjects in amenorrhea at the end of each course of PGL4001 treatment received.

E.5.2

Secondary end point(s)

Secondary endpoints:

Efficacy:
•Change from baseline (measured at baseline in PGL09-026 study) to approximately 14 days after start of menses following each of the three PGL4001 and norethisterone acetate or placebo treatment periods and at follow-up (respectively visit B, visit C, visit D and visit F), in myoma size, measured on the three largest myomas identified at visit 1 of PGL09-026, by transvaginal ultrasound.
•Change from baseline to visit B, visit C, visit D and to visit F in patient-reported pain using the short-form McGill Pain Questionnaire.
•Change from baseline to visit B, visit C, visit D and to visit F in quality of life measured using the specific UFS-QoL questionnaire.
•Change from baseline to visit B, visit C, visit D and to visit F in quality of life measured using the general EQ-5D questionnaire.

Safety:
•Changes from baseline observed during a physical examination
•Changes from baseline observed during a gynaecological and/or breast examination.
•Changes from baseline observed in vital sign measurements, ECG.
•Changes from baseline observed in endometrial thickness assessed by transvaginal ultrasound.
•Changes from baseline of the ovary observed by transvaginal ultrasound.
•Serum levels of estradiol (E2).
•Changes from baseline in serum Adrenocorticotropic hormone (ACTH), Thyroid Stimulating Hormone (TSH) and prolactin levels.
•Change from baseline in the following laboratory parameters: haematology, coagulation, biochemistry and lipids.
•Changes from baseline in endometrium biopsy (i.e. hyperplasia, adenocarcinoma).
•Number and proportion of subjects experiencing treatment-emergent adverse events including patient-reported adverse events and clinically significant changes in the parameters listed above.

Exploratory:
•Assessment of the strength of the first menstrual bleed after each PGL4001 treatment, using the Pictorial Bleeding Assessment Chart (PBAC).
•Time to return of menstruation following each PGL4001 treatment discontinuation.
•Frequency of Progesterone receptor modulator associated endometrial changes (PAEC) observed in the endometrial biopsy at visit E, approximately 14 days after last treatment cycle with PGL4001 followed by norethisterone acetate or placebo.

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

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)

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

Yes

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)

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

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

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	200
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	No
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	20
F.4.2	For a multinational trial
F.4.2.1	In the EEA	200
F.4.2.2	In the whole clinical trial	200

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

2010-10-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-10-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-02-27

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