Clinical Trials Register

Summary
EudraCT Number:	2020-004112-10
Sponsor's Protocol Code Number:	PROTECTA
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-11-13
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2020-004112-10

A.3

Full title of the trial

Randomized controlled trial comparing micronized progesterone (Amelgen ®) 400 mg BID versus 400 mg TID for luteal support in artificial vitrified/warmed single blastocyst transfer cycles with low progesterone on day of embryo transfer

A.3.1

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

Study of the effect of an additional administration of Amelgen® 400 mg in women with a low progesterone value on the day of embryo replacement

A.3.2

Name or abbreviated title of the trial where available

PROTECTA

A.4.1

Sponsor's protocol code number

PROTECTA

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	Ghent University Hospital
B.1.3.4	Country	Belgium
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 Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Ghent University Hospital
B.5.2	Functional name of contact point	HIRUZ
B.5.3	Address:
B.5.3.1	Street Address	C. Heymanslaan 10
B.5.3.2	Town/ city	Ghent
B.5.3.3	Post code	9000
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+3293320500
B.5.5	Fax number	+3293320520
B.5.6	E-mail	hiruz.ctu@uzgent.be

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	Amelgen
D.2.1.1.2	Name of the Marketing Authorisation holder	Gedeon Richter Plc.
D.2.1.2	Country which granted the Marketing Authorisation	Hungary
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	Vaginal tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Vaginal 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.3.9.2	Current sponsor code	PROGESTERONE
D.3.9.4	EV Substance Code	SUB10076MIG
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	400
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	Amelgen
D.2.1.1.2	Name of the Marketing Authorisation holder	Gedeon Richter Plc.
D.2.1.2	Country which granted the Marketing Authorisation	Hungary
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	Vaginal tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Vaginal 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.3.9.2	Current sponsor code	PROGESTERONE
D.3.9.4	EV Substance Code	SUB10076MIG
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	400
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

Patients who undergo artificial vitrified/warmed single blastocyst transfer cycles with low progesterone (defined as <10mcg/l) on day of embryo transfer.

E.1.1.1

Medical condition in easily understood language

Patients with a low progesterone level on the day of embryo transfer during an artificial cycle.

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to investigate the effect of an increased dose of vaginal progesterone supplementation (Amelgen ® 400 mg BID vs Amelgen ® 400 mg TID) on the ongoing pregnancy (fetal heartbeat during TVUS between week 6 and 8 of pregnancy) rate for patients undergoing IVF or ICSI treatment with a suboptimal serum progesterone level (defined as <10 mcg/l) on the day of blastocyst transfer in an artificial prepared endometrium cycle.

E.2.2

Secondary objectives of the trial

To assess
- if the degree of endometrial impaction is associated with reproductive outcome
- if progesterone level on the day of blastocyst transfer in an artificial prepared endometrium cycle (< 10 mcg/l versus ≥ 10 mcg/l) is associated with reproductive outcome who are receiving standard of care (hence not Amelgen® 400 mg TID);
- if intercourse frequency (registered by patient diary) is associated with progesterone level on the day of blastocyst transfer in an artificial prepared endometrium cycle and with reproductive outcome who are receiving standard of care (hence not Amelgen® 400 mg TID).

- To evaluate patient comfort and side effects on the day of embryo transfer and day of the initial pregnancy test in patients undergoing IVF or ICSI treatment
- To determine if there are patient characteristics that can predict low progesterone level at day of embryo transfer who are receiving standard of care (hence not Amelgen® 400 mg TID).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

The study population is aimed at a broad population undergoing IVF or ICSI treatment undergoing a single vitrified/warmed single transfer in an artificial prepared endometrium cycle. Subjects who meet all of the following will be considered eligible to participate in the clinical trial:
• Informed consent form (ICF) dated and signed
• Age ≥ 18 and < 43 years old at the time of signing ICF
• Body Mass Index (BMI) ≥ 18.5 kg/m² and < 35 kg/m²
• Less than 5 failed previous Assisted Reproductive Technologies (ART) cycles since live birth or in case of no live birth: since start fertility treatment
• Current pregnancy wish

E.4

Principal exclusion criteria

Subjects who meet any of the following criteria will be excluded from participation in this study:
• Simultaneous participation in another clinical study
• Previous participation in this study
• Known reasons for impaired implantation
(specifically: presence of an hydrosalpinx; presence of a type I, II or III fibroid; Asherman's syndrome; uterine malformations, intrauterine adhesions, ≥ grade 3 endometriosis according to the ASRM classification, endometrial tuberculosis)
• Repeated miscarriages
(> 2 miscarriages)
• Untreated and uncontrolled thyroid dysfunction
• Tumors of the ovary, breast, uterus, pituitary or hypothalamus
• Abnormal vaginal bleeding without a known/diagnosed cause
• Ovarian cysts or enlarged ovaries
• Fibroid tumors of the uterus incompatible with pregnancy
• Malformations of the reproductive organs incompatible with pregnancy
• Previous antibiotic hypersensitivity reactions (streptomycin and/or neomycin)
• Risk factors for thromboembolic events, such as a personal or family history, severe obesity or thrombophilia
• Ongoing pregnancy
• Use of carbamazepine, rifampicin or phenytoin
• Those unable to comprehend the investigational nature of the proposed study

E.5 End points

E.5.1

Primary end point(s)

The primary end point is the ongoing pregnancy rate. The diagnosis of an ongoing pregnancy is made if a fetal heartbeat is documented during TVUS between week 6 and 8 of pregnancy.

E.5.1.1

Timepoint(s) of evaluation of this end point

The diagnosis of an ongoing pregnancy is made if a fetal heartbeat is documented during TVUS between week 6 and 8 of pregnancy.

E.5.2

Secondary end point(s)

The secondary end points are:
- the endometrial impaction as measured with TVUS on the day of the embryo transfer (D5) and possible impact on reproductive outcome (pregnancy rate, clinical pregnancy rate, ongoing pregnancy rate (defined as fetal heartbeat during TVUS between week 6 and 8 of pregnancy), biochemical pregnancy rate, miscarriage rate)
- the comparison of reproductive outcome (pregnancy rate, clinical pregnancy rate, ongoing pregnancy rate (defined as fetal heartbeat during TVUS between week 6 and 8 of pregnancy), biochemical pregnancy rate, miscarriage rate) of subjects with progesterone levels above and below the 10 mcg/L threshold;
- the intercourse frequency (registered by patient diary) and possible impact on progesterone levels and on reproductive outcome (pregnancy rate, clinical pregnancy rate, ongoing pregnancy rate (defined as fetal heartbeat during TVUS between week 6 and 8 of pregnancy), biochemical pregnancy rate, miscarriage rate)

Exploratory endpoints:
- Patient comfort and side effects questionnaire on (1) the day of embryo transfer (D5) and (2) on the day of the initial pregnancy test (D16 (± 2 days)) (separate document) and the patient diary.
Patient-reported perineal irritation
Bleeding/spotting
Other side effects (gastro-intestinal discomfort, headache, …)
Sexual life and intercourse frequency

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints:
- Endometrial impaction as measured with TVUS on the day of the embryo transfer (ET) (D5) and possible impact on reproductive outcome
- Comparison of reproductive outcome (pregnancy rate, clinical pregnancy rate, ongoing pregnancy rate (defined as fetal heartbeat during TVUS between week 6 and 8 of pregnancy), biochemical pregnancy rate, miscarriage rate) of subjects with progesterone levels above and below the 10 mcg/L threshold
- Intercourse frequency (registered by patient diary) and possible impact on progesterone levels and on reproductive outcome

Exploratory endpoints:
- Patient comfort and side effects questionnaire on (1) the day of ET (D5) and (2) on the day of the initial pregnancy test (D16 (± 2 days)) (separate document) and the patient diary

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

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Amelgen

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

LPLV

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:

807

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

Yes

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

807

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.

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

2020-12-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-12-16

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

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