Clinical Trials Register

Summary
EudraCT Number:	2018-001137-41
Sponsor's Protocol Code Number:	666
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-04-25
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

2018-001137-41

A.3

Full title of the trial

Use of Omalizumab will increase the pregnancy rate, proof of concept study, where women with asthma and infertility will be treated three times with weight and IgE balanced dosis at the sixth day of their period bleeding.

Brug af omalizumab vil øge graviditets raten, koncept studie, hvor kvinder med astma og infertilitet vil blive behandlet 3 gange med vægt og IgE balanceret dosis ved deres 6 dag af menstruation.

A.3.1

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

Brug af omalizumab vil øge graviditets raten, koncept studie, hvor kvinder med astma og infertilitet vil blive behandlet 3 gange med vægt og IgE balanceret dosis ved deres 6 dag af menstruation.

A.3.2

Name or abbreviated title of the trial where available

Use of Omalizumab will increase the pregnancy rate, proof of concept study, where women with asthma

A.4.1

Sponsor's protocol code number

666

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	Hvidovre Hospital. Dep of Respiratory Medicine
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	Hvidovre Hospital. Dep of Respiratory Medicin
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	Hvidovre Hospital. Dep of Respiratory Medicin
B.5.2	Functional name of contact point	Hvidovre Hospital
B.5.3	Address:
B.5.3.1	Street Address	Kettegård Alle 30
B.5.3.2	Town/ city	Hvidovre
B.5.3.3	Post code	2650
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004538623825
B.5.6	E-mail	csulrik@dadlnet.dk

D. IMP Identification
D.IMP: 1
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	Xolair
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Healthcare A/S
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.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OMALIZUMAB
D.3.9.1	CAS number	242138-07-4
D.3.9.2	Current sponsor code	omalizumab
D.3.9.3	Other descriptive name	xolair
D.3.9.4	EV Substance Code	SUB12543MIG
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	150
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	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	Injection
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

infertility within female asthma patients as a result of systemic inflamation.

infertilitet hos kvindelige astma patienter som følge af systemisk betændelse.

E.1.1.1

Medical condition in easily understood language

infertility within female asthma patients as a result of systemic inflamation

infertilitet hos kvindelige astma patienter som følge af systemisk betændelse.

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

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

To compare, pregnancy rates in asthma patients undergoing IVF/ICSI treatment when treated with either omalizumab or placebo in up to three consecutive fertility treatments with embryo transfer. The primary endpoint is pregnancy confirmed by ultra sound in week 7.

Sammenligne graviditets rate (positiv blod-hCG) og pågående graviditet ultra lyds bekræftet i uge 7 ved astma patienter under IVF/ICSI som bliver behandlet med enten omalizumab eller placebo ved 3 påfølgende menstruations cyklusser og fulgt til fødsel eller graviditetstab.

E.2.2

Secondary objectives of the trial

A) Change in Sputum and blood Eosinophilic cell count (before treatment and after treatment).
B) Change in VEGF, CRP, IL6, IL8, IgE, TNFa, ECP in blood, sputum and uterus secretion (before treatment, and after treatment).
C) Changes in the microbiota in sputum (before treatment and after treatment).
D) Change in airway inflammation, the inflammatory markers in the blood, the inflammation in the uterus and the sex hormones before and after treatment.
E) Rate of pregnancy loss: Difference between positive s-hCG and ongoing pregnancy week 7, week 12, and birth – number of malformation , preterm, preeclampsia, perinatal death, SGA, birth weight in both groups.
F) Primary outcome in relation to length of infertility prior to referral and TTP

A) Ændring i sputum og blod Eosinofili (før behandling vs efter behandling)
B) Ændring i VEGF, CRP, IL6, IL8, IgE, TNFa, ECP i blod, sputum slimhinder (før behandling vs efter behandling)
C) Ændring i microbiota i sputum, (før behandling vs efter behandling).
D) Ændring i luftvejs inflammation, inflammations markører I blod, inflammation i uterus og sex hormoner.
E) Rate af aborter (positive s-hCG og ongoing graviditet uge 7, uge 12, og fødsel), antal malformationer , preterm, preeclampsia, SGA, fødselsvægt i begge grupper.
F) Primary outcome i relation til længden af infertilitet før henvisning og TTP.

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

Sub-study - Follow-up study of children born by main study participants

For all children born by main study participants (PRO_ART study) medical record entry will be done up to five years after birth of the individual child to collect information regarding malformations and/or other conditions of the children born in the study in both groups together with the children born by women in the screening cohort.

Delstudie - Opfølgende undersøgelse af børn født af hovedundersøgelsesdeltagere

For alle børn født af hovedundersøgelsesdeltagere (PRO_ART undersøgelsen) vil journalopslag ske op til fem år efter det enkelte barns fødsel for at indsamle oplysninger om misdannelser og/eller andre tilstande hos de børn født i undersøgelsen i begge grupper sammen med de børn født af kvinder i screeningskohorten.

E.3

Principal inclusion criteria

* 18-40 years old
• Informed consent
• Diagnosis of asthma with or without allergy
• Infertility due to male factor infertility, tubal factor infertility or unexplained infertility.
• Referred to IVF treatment with or without ICSI
• Willingness to receive treatment with biologic drugs during menstruation period
• Controlled disease with an ACQ ≤ 1.5

•18-40 år
•Informeret samtykke
•Astma diagnose med eller uden allergi
•Infertilitet på baggrund af mandlig faktor infertilitet, tuba faktor infertilitet eller uforklaret infertilitet.
•Henvist til IVF behandling med eller uden ICSI
•Samtykke til at modtage biologisk eller antibiotika under menstruations periode.
• Kontrolleret sygdom, med ACQ ≤ 1.5

E.4

Principal exclusion criteria

• Other respiratory diseases than asthma
• Other inflammatory disease or a disease that affects fertility.
• Allergy to the investigational drugs
• Respiratory infections requiring antibiotics or anti-viral treatment within 30 days
• TESA / TESE, Endometriosis
• Infertility due to other reasons than male factor, tubal factor or unexplained infertility

•Anden lungesygdom end astma.
•Anden inflammatorisk sygdom eller anden sygdom der påvirker fertiliteten.
•Allergi for medicin der bruges I studiet.
•Infektion i lungen der krævede antibiotika eller anti-viral behandling indenfor de sidste 30 dage.
• TESA/ TESE, endometriosis.
• Infertilitet på baggrund af andet end mandlig faktor, tuba faktor eller uforklaret infertilitet.

E.5 End points

E.5.1

Primary end point(s)

The pregnancy rate, measured as birt or loss of pregnancy after three consecutive IVF cycles

Graviditets rate, målt som fødsel eller graviditetstab efter tre påfølgende IVF cyklusser.

E.5.1.1

Timepoint(s) of evaluation of this end point

31 december 2024

E.5.2

Secondary end point(s)

1st day of menstruation, 6th day of
menstruation, at time of ovulation (both treatments).
A) Change in Sputum and blood Eosinophilic cell count (before treatment and after treatment)

B) Change in VEGF, CRP, IL6, IL8, IgE, TNFa, ECP in blood, sputum and uterus secretion (before treatment, and after treatment). No collections will be done during the menstruation period.

C) Changes in the microbiota in sputum (before treatment and after treatment). No collections will be done during menstruation period.

D) Change in airway inflammation, the inflammatory markers in the blood, the inflammation in the uterus secretion and the sex hormones before and after treatment.

E) Rate of miscarriages: ongoing s-hCG week 7, ongoing s-hCG week 12, and birth. – number of malformation , preterm, preeclampsia, perinatal death, SGA, birth weight in both groups.

F) Total time from first attempt at conceiving to first treatment day, adjusted TTP.

End points sub-study:
A) Number of malformations and/or other conditions of the children born in the study
B) Descriptive information about sex, weight, height
C) Information from (if any) lab samples etc.

1 dag oaf menstruation, 6 dag af
menstruation, vedovulation (begge behandlinger).
A) Ændring i Sputum and blod Eosinophilic celle tal (før behandlig og efter behandling)

B) ændring i VEGF, CRP, IL6, IL8, IgE, TNFa, ECP in blod, sputum and uterus secretion (før behandling og efter behandling). Ingen indsamling under menstrations periode

C) Ændring i microbiota i sputum (før behandling og efter behandling).

D) ændring i luftvejs inflammation, blod markører for inflamation, inflammation i uterus secretion og kønshormom før og effter behandling.

E) Rate af graviditets tab: pågående blod-hCG uge 7, pågående blod-hCG week 12, and fødsel. – antal misdannelser, for tidlig fødte, preeclampsia, perinatal død, SGA, fødselsvægt i begge grupper.

F) Total tid fra første førsøg på at undfange til første behandlings dag justeret "tid til graviditet.

Slutpunkter delundersøgelse:
A) Antal misdannelser og/eller andre tilstande hos de børn, der er født i undersøgelsen
B) Beskrivende information om køn, vægt, højde
C) Oplysninger fra (hvis nogen) laboratorieprøver mv.

E.5.2.1

Timepoint(s) of evaluation of this end point

31 december 2029

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

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

End of trial 365 days after frist day of treatment.

Endt studie 365 dage efter første dag med behandling.

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:

180

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

180

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

Ingen

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

2018-06-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-06-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-12-31

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