Clinical Trials Register

Summary
EudraCT Number:	2020-000256-35
Sponsor's Protocol Code Number:	CNPOBC2020
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-09-14
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

Denmark - DHMA

A.2

EudraCT number

2020-000256-35

A.3

Full title of the trial

Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a randomised, double-blind, placebo-controlled trial

Et randomiseret placebo-kontrolleret studie af intravenøs immunglobulin og prednisolon i behandlingen af gentagne graviditetstab efter IVF/ICSI

A.3.1

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

Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a randomised, double-blind, placebo-controlled trial

Et randomiseret placebo-kontrolleret studie af intravenøs immunglobulin og prednisolon i behandlingen af gentagne graviditetstab efter IVF/ICSI

A.4.1

Sponsor's protocol code number

CNPOBC2020

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04701034

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1273-8585

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	Aalborg University Hospital
B.1.3.4	Country	Denmark
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	Aalborg University Hospital
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Ole B. Christiansen
B.5.2	Functional name of contact point	Ole B. Christiansen
B.5.3	Address:
B.5.3.1	Street Address	Reberbansgade 15
B.5.3.2	Town/ city	Aalborg
B.5.3.3	Post code	9000
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4526821960
B.5.6	E-mail	olbc@rn.dk

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	Privigen
D.2.1.1.2	Name of the Marketing Authorisation holder	CSL Behring
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Privigen
D.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Human normal immunoglobulin
D.3.9.2	Current sponsor code	IVIg
D.3.9.3	Other descriptive name	HUMAN NORMAL IMMUNOGLOBULIN
D.3.9.4	EV Substance Code	SUB14196MIG
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	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
D.3.11.7	Plasma derived medicinal product	Yes
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	Prednisolone
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Prednisolone
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Enteral use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PREDNISOLONE
D.3.9.2	Current sponsor code	Prednisolone
D.3.9.4	EV Substance Code	SUB10018MIG
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: 3
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	Human Albumin "CSL Behring" 5%
D.2.1.1.2	Name of the Marketing Authorisation holder	CSL Behring
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Human Albumin "CSL Behring"
D.3.2	Product code	Human Albumin
D.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Human Albumin
D.3.9.2	Current sponsor code	Human Albumin
D.3.9.3	Other descriptive name	HUMAN PLASMA PROTEINS WITH NOT LESS THAN 96% ALBUMIN
D.3.9.4	EV Substance Code	SUB22285
D.3.10	Strength
D.3.10.1	Concentration unit	mg/l milligram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50.000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Recurrent pregnancy loss after assisted reproductive technology treatment

E.1.1.1

Medical condition in easily understood language

Recurrent pregnancy loss after assisted fertility treatment

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10078356
E.1.2	Term	Recurrent pregnancy loss
E.1.2	System Organ Class	100000004868

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 a randomized, double-blinded placebo-controlled trial we aim to investigate whether treatment with prednisolone and IVIg before and in early pregnancy improves the chance of a live birth in women undergoing treatment with artificial reproductive technologies (ART) after previous recurrent pregnancy losses after ART.

E.2.2

Secondary objectives of the trial

The study aims to investigate if treatment with IVIg combined with prednisolone is associated with adverse events to the women or her child, and whether the drugs can modulate leucocyte subsets in pheripheral blood.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Women with ≥ 2 consecutive pregnancy losses (miscarriages or biochemical pregnancies) ≤ gestational week 10 after ART with the present partner

E.4

Principal exclusion criteria

BMI ≥35
Age ≥41 years
Significant uterine malformation(s)
Known parental balanced chromosomal translocations
≥2 previous pregnancies with fetuses with known abnormal karyotype
Patients with IgA deficiency, IgA-autoantibodies or hyperprolinaemia
Anti-Müllerian hormone (AMH) <4 pmol/l if the planned IVF/ICSI cycle does not imply the use of donor egg. If IVF/ICSI with egg donation is planned, a low AMH value is not an exclusion criterion.
Treatment with medication interacting with prednisolone:
CYP3A4-inhibitors (fx erythromycin, itraconazol, ritonavir, lopinavir), CYP3A4-inductors (fx phenobarbital, phenytoin og rifampicin), loop diuretics, thiazides, amphotericin B, beta2-agonists, antidiabetics (metformin is acceptable), interleukin-2, somatropins, anticholinergics and regular treatment with NSAIDs.
Patients with moderate/severe hypertension, diabetes mellitus, heart insufficiency, severe mental disorders, Cushing syndrome, myasthenia gravis, ocular herpes simplex, pheochromocytoma, systemic sclerosis, and moderate/severe renal dysfunction.
Patients with a clinical or biochemical profile indicating need for heparin or levothyroxine treatment during pregnancy (see the description below)
Previous treatment with IVIg
Allergy to prednisolone and/or IVIg

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the percentage of participants with ≥1 normal, viable fetus at NT scan among all participants in each treatment group, and subsequently among participants with a positive pregnancy test after embryo transfer and among all participants except participants pregnant with a fetus having a confirmed chromosomal abnormality. Furthermore, the relative risk, absolute risk reduction, and adjusted risk ratio for this primary outcome will describe the primary outcome. The primary endpoint is also measured in subgroups based on diagnosis of primary and secondary RPL, respectively, i.e., no prior birth or a history of ≥1 previous birth after 22 weeks prior to RPL diagnosis.

The primary analyses will be undertaken as
1. an Intention-to-Treat (ITT) analysis, including all patients who were allocated to either active or placebo treatment at the start of the ART cycle, even if they did not receive infusion with IVIg or albumin due to cancellation of embryo/blastocyst transfer.
2. a per-protocol (PP) analysis including patients who were randomized and received the allocated infusion of study medicine at embryo/blastocyst transfer and had this transfer performed. (excluded: : A verified complete or partial mola or ectopic pregnancy or an induced abortion after ET for social or genetic reason)

E.5.1.1

Timepoint(s) of evaluation of this end point

The true measure for success in this trial is the birth of a healthy child at term with no significant adverse effects for the mother. However, the randomization code will be broken and the trial unblinded already when the last participant has completed the questionnaire after the nuchal scan in gestational week 14. This allows the research group to start data analysis, but final publication will await last delivery in order to include Intention-to-Treat and Per Protocol analyses with full perinatal data.

E.5.2

Secondary end point(s)

The secondary outcome is the frequency of maternal and fetal serious and non-serious adverse events/reactions, other reproductive outcomes (miscarriages with and without confirmed chromosomal abnormality, negative pregnancy tests, stillbirths, live births), perinatal outcomes (sex, birth weight, gestational age, admission to neonatal unit, congenital deformities, prematurity (<37 weeks of gestation), small for gestational age (SGA = birthweight <10th percentile), birth weight <2500 g), and pregnancy complications (preeclampsia, gestational hypertension, gestational diabetes, and instrumental delivery) in each two treatment groups. The secondary endpoint is the relative difference between groups in each of the secondary outcomes.
Maternal adverse reactions and fetal adverse reactions that might be associated with the study medicine will be assessed continuously during treatment of the participants and until after birth for pregnant participants.

And lastly, the effect of study medicine on immune cells and microvesicles in the participants' blood.

E.5.2.1

Timepoint(s) of evaluation of this end point

The same as in the primary outcome; at the time when all patients, who become pregnant after their ART treatment, have ended their pregnancy.

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

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

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

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

The study ends and randomisation code will be disclosed when the last included patient has had a miscarriage or has passed gestational week 12-13 (time of nuchal scan) with a viable foetus.This allows the research group to start data analysis, but final publication will await last delivery in order to include ITT and PP analyses with full perinatal data.

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)

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

Yes

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)

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

2020-11-11

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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