Clinical Trials Register

Summary
EudraCT Number:	2020-001177-78
Sponsor's Protocol Code Number:	APHP191008
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-04-09
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

France - ANSM

A.2

EudraCT number

2020-001177-78

A.3

Full title of the trial

Certolizumab to Prevent Pregnancy Complications in High-Risk Patients with APS or SLE

Certolizumab en prévention de complications de la grossesse chez les patientes à haut risque atteintes d’un Syndrome des Antiphospholipides (SAPL) et/ou d’un Lupus Erythémateux Systémique et porteuse de l’anticorps Anticoagulant circulant (ACC) de type lupique (IMPACT)

A.3.1

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

Certolizumab to Prevent Pregnancy Complications in High-Risk Patients with Antiphospholipid syndrome (APS) or systemic lupus erythematosus (SLE)

A.3.2

Name or abbreviated title of the trial where available

IMPACT

A.4.1

Sponsor's protocol code number

APHP191008

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03152058

A.5.4

Other Identifiers

Name:

IND Number

Number:

130908

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	University of Utah
B.1.3.4	Country	United States
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	University of Utah
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Utah
B.5.2	Functional name of contact point	Dr Ware Branch
B.5.3	Address:
B.5.3.1	Street Address	30 North 1900 East
B.5.3.2	Town/ city	Salt Lake City
B.5.3.3	Post code	UT 84132
B.5.3.4	Country	United States
B.5.4	Telephone number	+1801 581 8995
B.5.6	E-mail	ware.branch@hsc.utah.edu

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	CIMZIA
D.2.1.1.2	Name of the Marketing Authorisation holder	UCB Pharma S.A.
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Certolizumab
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CERTOLIZUMAB PEGOL
D.3.9.1	CAS number	428863-50-7
D.3.9.4	EV Substance Code	SUB25423
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	200
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	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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

Pregnant women with Antiphospholipid Syndrom (APS) and Lupus Antocoagulant (LAC)

Patientes enceintes atteintes d’un Syndrome des Antiphospholipides (SAPL) et/ou d’un Lupus Erythémateux Systémique et porteuse de l’anticorps Anticoagulant circulant (ACC) de type lupique

E.1.1.1

Medical condition in easily understood language

Pregnant women with Antiphospholipid Syndrom (APS) and Lupus Antocoagulant (LAC)

Patientes enceintes atteintes d’un Syndrome des Antiphospholipides (SAPL) et/ou d’un Lupus Erythémateux Systémique et porteuse de l’anticorps Anticoagulant circulant (ACC) de type lupique

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	PT
E.1.2	Classification code	10002817
E.1.2	Term	Antiphospholipid syndrome
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10058347
E.1.2	Term	Lupus anticoagulant positive
E.1.2	System Organ Class	100000004848

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	10058355
E.1.2	Term	Lupus anticoagulant
E.1.2	System Organ Class	100000004848

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine whether TNF-α blockade added to a regimen of heparin and low dose aspirin during pregnancy reduces the rate of APOs in women with APS1 (prior vascular thrombosis and/or pregnancy morbidity) and LAC

Déterminer si un traitement anti-TNF ajouté à un traitement standard d’héparine et d’aspirine à faible dose pendant la grossesse réduit le taux de morbi-mortalité périnatale chez les femmes atteintes de SAPL associé ou non à un Lupus systémique et porteuses d’un ACC.

E.2.2

Secondary objectives of the trial

To determine whether TNF-α blockade during pregnancy favorably alters angiogenic markers of poor placental vascularization in women with APS and LAC

Déterminer si le traitement par anti-TNFα pendant la grossesse modifie favorablement les marqueurs angiogéniques d’une mauvaise vascularisation placentaire chez les femmes atteintes de SAPL associé ou non à un Lupus systémique et porteuses d’un ACC.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Pregnant as defined by positive test for elevated ß-HCG and having a live, appropriate-size embryo by ultrasound, but < 8 weeks gestation;
2. Antiphospholipid syndrome (APS)
3. Positive LAC, on two or more occasions greater than 12 weeks apart, one of which must be within the previous 18 months. If a candidate for the study is newly diagnosed (<12 weeks) with APS, meets clinical criteria for APS and has one positive LAC confirmed by review of the medical record, she may be consented and screened. At baseline, LAC will be measured at the study core lab and she will be enrolled if it is found to be positive. The LAC measurement will be repeated 12 weeks after the initial determination and, if positive, she will remain in the study.
4. Age 18-40 (+364 days) years of age and able to give informed consent;
5. Laboratory hematocrit > 26% at time of screening.

1. Grossesse confirmée par un test positif avec une concentration de ß-HCG élevée ou par échographie, mais <8 semaines d’aménorrhées (SA);
2. Syndrome des antiphospholipides (SAPL) (et/ou Lupus)
3. Anticorps anticoagulant circulant de type lupique (ACC) positif, confirmé à deux reprises et à plus de 12 semaines d'intervalle, dont l'une doit se situer dans les 18 mois précédant l’inclusion. Si une patiente est nouvellement diagnostiquée pour un SAPL (moins de 12 semaines), et l’ACC positif, elle peut être incluse. La mesure de l’ACC sera répétée 12 semaines après la première évaluation. Si la détermination est à nouveau positive, elle restera dans l'étude.
4. Etre âgée de 18 à 40 ans (+364 jours) et pouvoir donner son consentement éclairé;
5. Hématocrite > 26% au moment du dépistage.
Le diagnostic de SAPL avec ACC sera confirmé par l'investigateur principal du centre par un examen des dossiers médicaux.

E.4

Principal exclusion criteria

1. Hypertension (BP >140/90) present at screening;
2. Multifetal gestation;
3. Type 1 or type 2 diabetes antedating pregnancy;
4. SLE patients requiring prednisone >10 mg/day;
5. Platelet count <100,000 per microliter;
6. Women currently taking prednisone greater than 10 mg daily for an autoimmune disorder, other than immune thrombocytopenia; More than 60 mg once daily in a tapering regimen or 20 mg once daily in a maintenance regimen for immune thrombocytopenia
7. Women with urinary excretion with greater than 500 mg (0.5 g) per day (spot urine protein/creatinine ratio 0.5);
8. Serum creatinine >1.2 mg/dL;
9. History of tuberculosis or untreated positive PPD;
10. Women with a tuberculin skin test induration of 5 mm or greater; or positive quantiFERON-gold test
11. Women with HIV, Hepatitis B or Hepatitis C positive status;
12. Concomitant participation in another interventional research study;
13. Known contraindications or relative contraindications to certolizumab :
a. Active infection, e.g., chronic hepatitis B.
b. History of recurrent infection, e.g., recurrent cellulitis, or opportunistic infection.
c. History of prior active/treated endemic mycoses in the last two years (including coccidioidomycosis, blastomycosis, or histoplasmosis).
d. History of heart failure.
e. History of peripheral demyelinating disease or Guillian-Barré syndrome.
f. History of hematologic malignancy.
g. Prior adverse reaction to certolizumab or other anti-TNF-α agent.

1. Hypertension (PA> 140/90)
2. Grossesse multiple
3. Diabète de type 1 ou de type 2 précédant la grossesse
4. Femmes avec un Lupus Erythémateux Systémique nécessitant plus de 10mg/jour de prednisone
5. Taux de plaquettes <100 000 par microlitre à l’inclusion
6. Femmes prenant actuellement :
a. Plus de 10 mg par jour de prednisone pour une maladie auto-immune autre que le Purpura Thrombopénique Immunologique (PTI);
b. Plus de 60 mg/jour dans le cadre d'un traitement d’attaque ou 20 mg/jour dans un régime d'entretien en cas de PTI;
7. Protéinurie > 500 mg (0,5 g) par jour (ratio urinaire protéinurie/créatinurie : 0,5 g/g);
8. Créatinine sérique> 1,2 mg / dL;
9. Antécédents de tuberculose ou d’IdR anormalement positive non traitée
10. Femmes présentant une induration au test cutané de à la tuberculine de 5 mm ou plus; ou test quantiFERON-gold positif
11. Femmes ayant le statut positif au VIH, à l'hépatite B ou à l'hépatite C;
12. Contre-indications connues ou relatives au certolizumab
a) Infection active, par exemple l'hépatite B chronique.
b) Antécédents d'infection récurrente, par exemple, cellulite récurrente ou infection opportuniste.
c) Antécédents de mycoses endémiques actives / traitées antérieurement au cours des deux dernières années (dont coccidioïdomycose, blastomycose ou histoplasmose).
d) Antécédents médicaux d'insuffisance cardiaque.
e) Antécédents de démyélinisation périphérique ou de syndrome de Guillian-Barré.
f) Antécédents de malignité hématologique.
g) Réaction indésirable au certolizumab ou à un autre agent anti-TNFα.
13. Participation dans une autre recherche clinique

E.5 End points

E.5.1

Primary end point(s)

The primary outcome will be a composite of two APOs associated with poor placentation in women with APS and LAC:
(1) fetal death (>10 wks gestation)
(2) severe PE or PI requiring delivery prior to 34 wks gestation. PE and severe PE will be diagnosed according to U.S. criteria. PI as an antenatal diagnosis requiring delivery will be defined as (1) abnormal or non-reassuring fetal surveillance test(s), e.g. a non-reactive non-stress test or biophysical profile score <6, suggestive of fetal hypoxemia, (2) abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia, e.g. absent or reverse end-diastolic flow in the umbilical artery, (3) oligohydramnios, e.g. an amniotic fluid index of <5 cm or single deepest vertical pocket less than 2 cm, or (4) ultrasound estimated fetal weight ≤5th percentile

Critère composite (mort fœtale, pré-éclampsie sévère <34 SA, oligohydramnios, retard de croissance intra-uterin (RCIU) <5ème percentile)

E.5.1.1

Timepoint(s) of evaluation of this end point

10 weeks gestation
34 weeks gestation

10 SA
34SA

E.5.2

Secondary end point(s)

Secondary clinical outcomes will include :
(1) neonatal death due to complications of prematurity because of preterm delivery for PE or PI,
(2) preterm labor or preterm rupture of membranes resulting in delivery prior to 36 weeks gestation,
(3) PE or PI not requiring delivery prior to 34 weeks gestation,
(4) gestational age at delivery,
(5) maternal thrombosis,
(6) small-for-gestational age birthweight (<10th percentile)
(7) known adverse reactions to certolizumab.
(8) biomarkers of APOs : impact of TNF- α blockade on angiogenic factors and their relationship to PE and PI.

Mort néonatale, prématurité avant 36SA,
Pré-éclampsie >= 34 SA,
Terme de naissance,
Retard de croissance <10ème percentile,
Effets secondaires du Certolizumab,
Thrombose maternelle

E.5.2.1

Timepoint(s) of evaluation of this end point

36 weeks gestation
Delivery Time

36SA
Date accouchement

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

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

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

United States

E.8.7

Trial has a data monitoring committee

Yes

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

LVLS

Dernière visite du dernier patient inclus

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 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:

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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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

Aucun

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

2020-05-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-02-25

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

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