Clinical Trials Register

Summary
EudraCT Number:	2021-005564-21
Sponsor's Protocol Code Number:	SIRAVA
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-11-09
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

Netherlands - Competent Authority

A.2

EudraCT number

2021-005564-21

A.3

Full title of the trial

Five-year boostability after single-visit single-dose intramuscular rabies pre-exposure prophylaxis.

Anamnestische antistofrespons vijf jaar na een enkele rabiesvaccinatie als pre-exposure profylaxe.

A.3.1

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

How well does the immune system remember vaccination against rabies five years after a single shot?

Hoe goed herinnert het afweersysteem een inenting tegen hondsdolheid vijf jaar na een enkele injectie?

A.3.2

Name or abbreviated title of the trial where available

SIRAVA

A.4.1

Sponsor's protocol code number

SIRAVA

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	Leiden University Medical Center
B.1.3.4	Country	Netherlands
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	Bavarian Nordic A/S
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	Leiden University Medical Center
B.5.2	Functional name of contact point	Department of Infectious Diseases
B.5.3	Address:
B.5.3.1	Street Address	Albinusdreef 2
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333ZA
B.5.3.4	Country	Netherlands
B.5.6	E-mail	L.G.Visser@lumc.nl

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	Rabipur
D.2.1.1.2	Name of the Marketing Authorisation holder	Bavarian Nordic A/S
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Rabipur
D.3.4	Pharmaceutical form	Lyophilisate and solvent for solution 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	Rabies vaccine
D.3.9.3	Other descriptive name	RABIES VIRUS (INACTIVATED) STRAIN FLURY LEP
D.3.9.4	EV Substance Code	SUB25746
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	2.5
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

Healthy volunteers

Gezonde vrijwilligers

E.1.1.1

Medical condition in easily understood language

Rabies vaccination

Vaccinatie tegen hondsdolheid

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10069589
E.1.2	Term	Rabies immunization
E.1.2	System Organ Class	100000004865

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 demonstrate the presence of a rapid and adequate anamnestic antibody response against rabies virus vaccine five years after primary vaccination with a single intramuscular dose (1.0 mL) of rabies vaccine. The rate of increase in geometric mean concentrations of RVNA observed at day 8 after a standard 2-dose PEP vaccination schedule should be non-inferior to that of the reference group who received primary vaccination with 2-dose PrEP.

We vergelijken de langdurige werking en veiligheid van een enkele vaccinatie tegen hondsdolheid met twee vaccinaties tegen hondsdolheid. Vijf jaar na pre-exposure profylaxe kijken we of de stijging in RVNA titers op dag 8 na post-exposure profylaxe non-inferior is bij mensen die 1 vaccinatie hebben ontvangen vergeleken met mensen die 2 vaccinaties hebben ontvangen.

E.2.2

Secondary objectives of the trial

1. To describe the kinetics of rabies virus neutralizing antibody levels in healthy young adults, who received single-visit single-dose rabies PrEP or two-visit PrEP, during a five-year follow-up.

2. To describe the kinetics of rabies-specific memory B-cells in healthy young adults, who received single-visit single-dose rabies PrEP or two-visit PrEP, during a five-year follow-up.

1. De kinetiek beschrijven van RVNA titers in gezonde jongvolwassenen gedurende een follow-up van vijf jaar na ofwel een enkele ofwel twee vaccinaties tegen hondsdolheid.

2. De kinetiek beschrijven van rabies-specifieke B-geheugencellen in gezonde jongvolwassenen gedurende een follow-up van vijf jaar na ofwel een enkele ofwel twee vaccinaties tegen hondsdolheid.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age ≥18 years and ≤40 years
• Good health according to investigator
• Willingness and ability to adhere to the study regimen
• Able to provide informed consent
• Naïve to rabies exposure or vaccination
• Willing to comply to a follow-up of 5 years
• Unlikely to require rabies PrEP in next 5 years

• Minimaal 18 en maximaal 40 jaar oud
• Goede gezondheid
• Bereid en in staat tot het volhouden van de studieplanning
• In staat om informed consent te verlenen
• Niet eerder blootgesteld aan of gevaccineerd tegen rabies
• Bereid om aan een follow-up van vijf jaar deel te nemen
• Waarschijnlijk geen PEP nodig in de komende vijf jaar

E.4

Principal exclusion criteria

• History of previous rabies vaccination
• Suspected previous vaccination against rabies
• Known or suspected severe allergy against egg protein
• Known or suspected allergy against any of the other vaccine components
• History of unusual or severe reactions to any previous vaccination
• History of (pre)syncope associated with medical procedures involving needles
• Immunocompromized state due to illness or medication
• Administration of plasma or blood products three months prior to inclusion
• (hydroxy)chloroquine or mefloquine use
• History of any neurological disorder including epilepsy
• Pregnancy during study visits in which the participant is vaccinated
• Breastfeeding during and up to 4 weeks after study visits in which the participant is vaccinated
• Any current infectious disease other than seasonal cold
• Bleeding disorders or use of anticoagulants

• Eerder gevaccineerd tegen rabies
• Vermoeden van eerdere vaccinatie tegen rabies
• Bekende of vermoede ernstige allergie tegen eiwit
• Bekende of vermoede allergie tegen overige vaccincomponenten
• Voorgeschiedenis van ongebruikelijke of ernstige reacties op eerdere vaccinaties
• Voorgeschiedenis van (pre)syncope bij medische procedures met naalden
• Immunogecompromitteerd door ziekte of medicatie
• Toedeniening van plasma of bloedproducten in de drie maanden voor inclusie
• Gebruik van (hydroxy)chloroquine of mefloquine
• Voorgeschiedenis van een neurologische aandoening, waaronder epilepsie
• Zwangerschap tijdens studiebezoeken waarbij de deelnemer gevaccineerd wordt
• Borstvoeding geven tijdens en tot 4 weken na studiebezoeken waarbij de deelnemer gevaccineerd wordt
• Elke andere infectieziekte dan seizoensverkoudheid
• Bloedziekten of het gebruik van anticoagulantia

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the rate of increase of geometric mean concentrations (GMC) of rabies neutralizing antibodies between day 1 and day 8 after revaccination.

De stijging van geometrisch gemiddelde concentraties (GMC) van rabies-neutraliserende antistoffen tussen dag 1 en 8 na revaccinatie.

E.5.1.1

Timepoint(s) of evaluation of this end point

5 years after pre-exposure immunization.

Vijf jaar na pre-exposure profylaxe.

E.5.2

Secondary end point(s)

Percentage of subjects with RVNA titer >0.5 IU/mL at D1, D57 or D64, Y1, Y2 and Y5 after primary vaccination.
Percentage of subjects with RVNA titers>0.5 IU/mL at D1, D8 and D15, after the simulated post-exposure vaccination.
Percentage of subjects with RVNA titers>3 IU/mL, and percentage of subjects with RVNA titers >5 IU/mL at day 8 after simulated PEP.
GMCs at D1, D57 or D64, Y1, Y2 and Y5 after primary vaccination, and at D1, D8 and D15 after the simulated post-exposure vaccination.

Percentage proefpersonen met RVNA titer >0.5 IU/mL op D1, D57 of D64, Y1, Y2 en Y5 na primaire vaccinatie.
Percentage proefpersonen met RVNA titers>0.5 IU/mL op D1, D8 en D15, na gesimuleerde post-exposure vaccinatie.
Percentage proefpersonen met RVNA titers>3 IU/mL, en percentage proefpersonen met >5 IU/mL op dag 8 na gesimuleerde post-exposure post-exposure vaccinatie.
GMCs op D1, D57 of D64, Y1, Y2 en Y5 na primaire vaccinatie, en op D1, D8 en D15 na gesimuleerde post-exposure vaccinatie.

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

E.8.1.7.1

Other trial design description

Laboratorium (analyse) geblindeerd betreft allocatie

Laboratory blinded from allocation

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

Standaard pre-exposure profylaxe (2 vaccinaties)

Standard pre-exposure prophylaxis (2 vaccinations)

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

LVLS

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:

240

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

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception