Clinical Trials Register

Summary
EudraCT Number:	2021-002966-41
Sponsor's Protocol Code Number:	APHP210639
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:	2021-06-28
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

2021-002966-41

A.3

Full title of the trial

Anti-Covid-19 vaccine protection in immunocompromised children (1-15 years) with acute leukemia and their siblings (≥ 12 years). Phase I-II trial evaluating safety and post-vaccination humoral and cellular immunogenicity / PACIFIC STUDY

Protection vaccinale Anti-Covid-19 portant sur les enfants Immunodéprimés (1 à 15 ans) atteints de leucémie aiguë et leur Fratrie (≥ 12 ans). Essai de Phase I-II évaluant la tolérance et l’Immunogénicité humorale et Cellulaire post-vaccinale / Etude PACIFIC

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

PACIFIC

A.4.1

Sponsor's protocol code number

APHP210639

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	Assistance Publique – Hôpitaux de Paris / DRCI
B.1.3.4	Country	France
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	Assistance Publique – Hôpitaux de Paris
B.4.2	Country	France
B.4.1	Name of organisation providing support	Ministère de la Santé
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Assistance Publique – Hôpitaux de Paris
B.5.2	Functional name of contact point	Elodie SOLER
B.5.3	Address:
B.5.3.1	Street Address	Hôpital Saint-Louis, 1 avenue Claude Vellefaux
B.5.3.2	Town/ city	PARIS
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.4	Telephone number	01 44 84 17 35
B.5.6	E-mail	elodie.soler@aphp.fr

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	COMIRNATY®
D.2.1.1.2	Name of the Marketing Authorisation holder	BioNTech Manufacturing GmbH
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.3.4	Pharmaceutical form	Concentrate for dispersion for 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	COVID-19 mRNA vaccine (nucleoside-modified)
D.3.9.3	Other descriptive name	COVID-19 mRNA vaccine (nucleoside-modified)
D.3.10	Strength
D.3.10.1	Concentration unit	ml millilitre(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.45
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	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

- Children aged 1-15 years with LA undergoing chemotherapy or whose last chemotherapy session date is less than or equal to 12 months.
- Siblings of children with LA (living in the same household > 50% of the time): 12-15 years old.

- Enfants de 1 à 15 ans atteints de LA en cours de chimiothérapie ou dont la date de dernière séance de chimiothérapie est inférieure ou égale à 12 mois.
- Fratrie des enfants atteints de LA (vivant sous le même toit > 50% du temps) : de 12 à 15 ans.

E.1.1.1

Medical condition in easily understood language

children (1-15 years) with acute leukemia

Enfants de 1 à 15 ans atteints de Leucémie aigüe

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10000835
E.1.2	Term	Acute leukemia
E.1.2	System Organ Class	100000004864

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 evaluate the safety and immunogenicity of COMIRNATY® (BNT162b2) vaccine (two injections 21-28 days apart) in children with LA (1-15 years) and their siblings (≥12 years)

Evaluer la tolérance et l’immunogénicité du vaccin COMIRNATY® (BNT162b2) (deux injections à 21-28 jours d’intervalle) chez les enfants atteints de LA (1 à 15 ans) et leur fratrie (≥12 ans)

E.2.2

Secondary objectives of the trial

- To evaluate the level of anti-S IgG at incl., between D21 and D28, 6 and 12 months after the 1st dose.
- Study the level of anti-N IgG at incl., between D21 and D28, 2 , 6 and 12 months of the 1st dose.
- Anti-Spike IgG neutralization capacity (if anti-Spike IgG is detected) measured at D0, 2, 6 and 12 months after the 1st inj.
- Specific T-cell response (Elispot) to SARS-CoV-2 at D0, 2, 6 and 12 months after the 1st inj.
- SARS-CoV-2 PCR positivity in the nasopharynx at D8, D15 and D28 in case of infection
- Incidence of symptomatic SARS-CoV-2 infections, AND a positive SARS-CoV-2 PCR, within 12 months of vaccination
- Genotype of the SARS-CoV-2 strain in case of infection
- Time between planned and actual date of chemotherapy in case of infection
- 10-item WHO COVID-19 scale in case of infection
- In case of infection in a vaccinated child, PCR SARS-CoV-2 of the entourage as soon as the diagnosis is made and within 7 d. of contact (if the 1st PCR is neg.)

- Evaluer le taux des IgG anti-S à l’inclusion, entre J21 et J28, à 6 et 12 mois de la 1ère dose.
- Etudier le taux des IgG anti-N à l’inclusion, entre J21 et J28, 2, 6 et 12 mois de la 1ère dose.
- Capacité de neutralisation des IgG anti-Spike (en cas de détection d’IgG anti-Spike) mesurée à J0, 2, 6 et 12 mois de la 1ère inj.
- Réponse cellulaire T spécifique (Elispot) anti-SARS-CoV-2 à J0, 2, 6 et 12 mois de la 1ère inj.
- Positivité de la PCR SARS-CoV-2 dans le naso-pharynx à J8, J15 et J28 en cas d’infection
- Incidence d’infections à SARS-CoV-2 symptomatiques, ET une PCR SARS-CoV-2 positive, dans les 12 mois après vaccination
- Génotype de la souche de SARS-CoV-2 en cas d’infection
- Délai entre date prévue et date effective de chimio en cas d’infection
- Echelle OMS COVID-19 en 10 items en cas d’infection
- En cas d’infection chez un enfant vacciné, PCR SARS-CoV-2 de l’entourage dès diagnostic et dans les 7 j suivant le contage (si 1ère PCR négative)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Children 1-15 years of age:
• With acute lymphoblastic leukemia undergoing chemotherapy (minimum 2 weeks after the last PEG-ASPARAGINASE injection) or whose last chemotherapy is less than or equal to 12 months.
• With acute myeloid leukemia within 12 months after the end of treatment
- Brother or sister between 12 and 15 years of age living in the same household as the child with ALL more than 50% of the time
- Informed consent of parents
- Patient affiliated to a social security plan

- Enfant de 1 à 15 ans :
• Atteint de leucémie aiguë lymphoblastique en cours de chimiothérapie (2 semaines au minimum après la dernière injection de PEG-ASPARAGINASE) ou dont la dernière chimiothérapie est inférieure ou égale à 12 mois.
• Atteint de leucémie aiguë myéloïde dans les 12 mois après la fin du traitement
- Frère ou sœur de 12 à 15 ans vivant sous le même toit que l’enfant atteint de LA plus de 50% du temps
- Consentement éclairé des parents
- Patient affilié à un régime de sécurité sociale

E.4

Principal exclusion criteria

- Documented SARS-CoV-2 infection in progress or within the last three months
- Known clinical allergy to polyethylene glycol (PEG)
- Pregnant in the first trimester or breastfeeding
- Platelet count < 50 G/L or PNN count < 0.5G/L at time of vaccination
- Vaccinated within 4 weeks prior to the first injection or scheduled to receive a licensed vaccine 4 weeks after the last injection.
- Any bleeding disorder considered a contraindication to intramuscular injection
- History of severe adverse events following vaccine administration including anaphylactic reaction and associated symptoms such as rash, difficulty breathing, angioedema, and abdominal pain, or a history of allergic reaction that may be exacerbated by a vaccine component
- Participant who has been vaccinated with BCG within the past year.

- Infection documentée au SARS-CoV-2 en cours ou datant de moins de trois mois
- Allergie clinique connue au polyéthylène glycol (PEG)
- Femme enceinte au premier trimestre de grossesse ou allaitante
- Taux de plaquettes < 50 G/L ou taux de PNN < 0.5G/L au moment de la vaccination
- Vaccination dans les 4 semaines précédant la première injection ou ayant prévu de recevoir un vaccin homologué 4 semaines après la dernière injection.
- Tout trouble hémorragique considéré comme une contre-indication à l'injection intramusculaire
- Antécédents d’effets indésirables sévères après l’administration d’un vaccin incluant une réaction anaphylactique et les symptômes associés, comme un rash, une difficulté respiratoire un angio-oedème et une douleur abdominale, ou des antécédents de réaction allergique pouvant être exacerbée par un composant du vaccin
- Participant ayant été vacciné contre le BCG au cours de l'année précédente.

E.5 End points

E.5.1

Primary end point(s)

Primary co-criteria
In children under 12 years of age:
- Dose-limiting toxicity (DLT) defined on the presence within 7 days after vaccine injection of a vaccine-attributable adverse event of grade 3 or higher (detailed below)
- Significant increase in anti-Spike IgG titer AND positive anti-S IgG neutralization test 2 months after the 1st injection

1) Tolerance criteria
Dose-limiting toxicity (DLT) is defined according to the criteria listed in Table 1. They are derived from the CTCAE V5.0 (37) and the FDA guidance "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials" (38).
Any other CTCAE V5.0 grade 3-4 unexpected clinical adverse events related to vaccination.
A Critical Event and LDT Review Committee will validate whether the reported grade 3-4 AEs are attributable to vaccines.

2) Immunogenicity criteria
- 4-fold or more increase in anti-Spike IgG titer AND positive neutralization test (from 1/5 dilution) 2 months after the first injection.
- If both of these efficacy criteria are present, the patient is considered to have "significant seroconversion" to vaccination.

Co-critères primaires
Chez les enfants de moins de 12 ans :
- Toxicité dose limitante (TDL) définie sur la présence dans les 7 jours après injection vaccinale d’un événement indésirable imputable au vaccin de grade 3 ou plus (détaillés ci-dessous)
- Elévation significative du titre d’IgG anti-Spike ET test de neutralisation des IgG anti-S positif 2 mois après la 1ère injection

1) Critères de tolérance
La Toxicité dose limitante (TDL) est définie selon les critères mentionnés dans le Tableau 1. Ils sont dérivés de la CTCAE V5.0 (37) et du guide FDA « Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials » (38).
Tout autre événement indésirable clinique de grade 3-4 inattendu selon le CTCAE V5.0 en lien avec la vaccination.
Un comité de relecture des évènements critiques et TDL validera si les EIG de grade 3-4 déclarés sont imputables aux vaccins.

2) Critères d’immunogénicité
− Elévation d’un facteur 4 ou plus du titre d’IgG anti-Spike ET test de neutralisation positif (à partir de la dilution 1/5) 2 mois après la 1ère injection.
− Si ces deux critères d’efficacité sont présents, le patient est considéré comme ayant une « séroconversion significative » à la vaccination.

E.5.1.1

Timepoint(s) of evaluation of this end point

7 days after vaccine injection and 2 month after the first injection

7 jours après injection vaccinale et 2 mois après la 1ère injection

E.5.2

Secondary end point(s)

- To evaluate the level of anti-S IgG at inclusion, between D21 and D28, 6 months and 12 months after the 1st dose.
- Study the level of anti-N IgG at inclusion, between D21 and D28, 2 months, 6 months and 12 months of the 1st dose.
- Anti-Spike IgG neutralization capacity (if anti-Spike IgG is detected) measured at D0, 2, 6 and 12 months after the 1st injection
- Specific T-cell response (Elispot) to SARS-CoV-2 at D0, 2, 6 and 12 months after the first injection
- SARS-CoV-2 PCR positivity in the nasopharynx at D8, D15 and D28 in case of infection
- Incidence of symptomatic SARS-CoV-2 infections, defined as the presence of at least one of fever, dyspnea, cough, chest pain, anosmia, agueusia, diarrhea, or vomiting, AND a positive SARS-CoV-2 PCR, within 12 months of vaccination
- Genotype of the SARS-CoV-2 strain in case of infection
- Time between planned and actual date of chemotherapy in case of infection
- 10-item WHO COVID-19 scale in case of infection
- In case of infection in a vaccinated child, PCR SARS-CoV-2 of the entourage (contact cases) as soon as the diagnosis is made and within 7 days of contact (if the first PCR is negative)

- Evaluer le taux des IgG anti-S à l’inclusion, entre J21 et J28, à 6 mois et 12 mois de la 1ère dose.
- Etudier le taux des IgG anti-N à l’inclusion, entre J21 et J28, 2 mois, 6 mois et 12 mois de la 1ère dose.
- Capacité de neutralisation des IgG anti-Spike (en cas de détection d’IgG anti-Spike) mesurée à J0, 2, 6 et 12 mois de la 1ère injection
- Réponse cellulaire T spécifique (Elispot) anti-SARS-CoV-2 à J0, 2, 6 et 12 mois de la 1ère injection
- Positivité de la PCR SARS-CoV-2 dans le naso-pharynx à J8, J15 et J28 en cas d’infection
- Incidence d’infections à SARS-CoV-2 symptomatiques, définies par la présence d’au moins un symptôme parmi fièvre, dyspnée, toux, douleurs thoraciques, anosmie, agueusie, diarrhée ou vomissement, ET une PCR SARS-CoV-2 positive, dans les 12 mois après vaccination
- Génotype de la souche de SARS-CoV-2 en cas d’infection
- Délai entre date prévue et date effective de chimiothérapie en cas d’infection
- Echelle OMS COVID-19 en 10 items en cas d’infection
- En cas d’infection chez un enfant vacciné, PCR SARS-CoV-2 de l’entourage (cas contacts) dès diagnostic et dans les 7 jours suivant le contage (si 1ère PCR négative)

E.5.2.1

Timepoint(s) of evaluation of this end point

At inclusion, between D21 and D28, at 6 months and 12 months of the 1st dose.

A l’inclusion, entre J21 et J28, à 6 mois et 12 mois de la 1ère dose.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

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

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)

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

Yes

E.8.1.7.1

Other trial design description

Recherche de dose avec schéma Bayesien

dose surch trial with Bayesian scheme

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

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

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

LVLP

DVDP

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

Yes

F.1.1

Number of subjects for this age range:

150

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

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

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Children from 1 to 15 years old.

Enfant de1 à 15 ans

F.4 Planned number of subjects to be included

F.4.1

In the member state

150

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)

Not different from the expected normal treatment of that condition

Pas différent du traitement normal attendu de cette condition

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

2021-08-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-08-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-01-03

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