Clinical Trials Register

Summary
EudraCT Number:	2016-002724-83
Sponsor's Protocol Code Number:	iHIVARNA-01
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-04-19
Trial results	View 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

2016-002724-83

A.3

Full title of the trial

A phase IIa randomized, placebo controlled, double blinded study to evaluate the safety and immunogenicity of iHIVARNA-01 in chronically HIV-infected patients under stable combined antiretroviral therapy.

Een fase II gerandomiseerde, placebo gecontroleerde studie naar de veiligheid en immunogeniciteit van intranodale vaccinatie met TriMix/mRNA in chronisch HIV geïnfecteerde patiënten tijdens cART

A.3.1

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

Phase II vaccination trial in HIV-1 infected subjects

Fase II vaccinatie trial in HIV-1 geïnfecteerde patiënten

A.3.2

Name or abbreviated title of the trial where available

iHIVARNA phase II

iHIVARNA fase II

A.4.1

Sponsor's protocol code number

iHIVARNA-01

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	Erasmus MC
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	European Union
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IDIBAPS
B.5.2	Functional name of contact point	Hospital Clínic
B.5.3	Address:
B.5.3.1	Street Address	Villarroel 170
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08036
B.5.3.4	Country	Spain
B.5.4	Telephone number	349322754002884
B.5.6	E-mail	fgarcia@clinic.cat

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	No
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	iHIVARNA-01
D.3.2	Product code	iHIVARNA-01.3
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intralymphatic use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TriMix
D.3.9.3	Other descriptive name	Mixture of mRNAs of human CD40L, TLR4ca and human CD70
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	HIVACAT
D.3.9.3	Other descriptive name	mRNA encoding different HIV antigens
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	900
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.IMP: 2
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	No
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	TriMix
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intralymphatic use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TriMix
D.3.9.3	Other descriptive name	Mixture of mRNAs of human CD40L, TLR4ca and human CD70
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intralymphatic use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic HIV-1 infection

Chronische HIV-1 infectie

E.1.1.1

Medical condition in easily understood language

Vaccine against HIV-1 infection

Vaccin tegen HIV-1 infectie

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	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10068341
E.1.2	Term	HIV-1 infection
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

• safety and tolerability, as measured by the total number of adverse events.
• immunogenicity of an immunization schedule with HIV-TriMix-mRNA as measured by the increase in frequency of the HIV-specific T-cell responses between baseline and 2 weeks after the last injection as compared to both control groups, immunized with TriMix-mRNA only or WFI only

veiligheid en verdraagbaarheid gemeten door het totale aantal adverse voorvallen
• immunogeniciteit van een immunisatie schema met HIV-TriMix-mRNA (iHIVARNA-01) om de frequentie van HIV-specifieke T-cel responsen te verhogen tussen baseline en 2 weken na de laatste injectie in vergelijking met de controle groepen, geïmmuniseerd met alleen TriMix-mRNA of alleen WFI.

E.2.2

Secondary objectives of the trial

• magnitude and kinetics of the HIV-specific CD4+ and CD8+ T cell responses after immunization (ELISPOT, ICS).
• time until plasma viral rebound after cART interruption at week 6.
• plasma viral load suppression in vivo after interruption of cART
• functional cure: proportion of patients with pVL below the lower level of detectability level after cART interruption.
• primary immune response against vaccine.
• CD8+ T-cell HIV suppressive capacity.
• effect on reservoir as measured by proviral DNA and the intracellular viral RNA.
• viral immune escape
• host protein mRNA expression profiles in whole blood

• omvang en kinetiek van de HIV-specifieke CD4+ and CD8+ T cel responsen opgewekt immunisatie s(ELISPOT, ICS).
• tijd tot virale rebound, na therapie onderbreking (ATI) op week 6,
• Bepaling van het deel van de patiënten met controle van viral load (ondetecteerbaar) na cART onderbreking.
• primaire immuunrespons tegen het vaccin.
• CD8+ T-cel HIV suppressive capaciteit.
• effect op het reservoir gemeten door proviraal DNA en intracellulair viraal RNA
• virale immuun escape
• mRNA expressie profielen van gastheer eiwitten in volbloed
•

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. ≥ 18 years of age;
2. Voluntarily signed informed consent;
3. Proven HIV-1 infection (with documented antibodies against HIV-1 and a detectable plasma HIV-1 RNA before initiation of therapy);
4. On stable treatment with cART regimen (antiretroviral therapy consisting of at least three registered antiretroviral agents) for at least 3 years;
5. Nadir CD4+ ≥ 350 cells/μl (up to 2 occasional determinations ≤ 350 cells/μl are allowed);
6. Current CD4+ cell count ≥ 450 cells/μl;
7. HIV-RNA below 50 copies/mL in the last 6 months prior to randomization, during at least two measurements (occasional so called ‘blips’ ≤ 500 copies/mL are permitted);
8. If sexually active, willing to use a reliable method of reducing the risk of transmission to their sexual partners during treatment interruption (including PrEP).
a. For heterosexually active female, using an effective method of contraception with partner (combined oral contraceptive pill; injectable or implanted contraceptive; IUD/IUS; consistent record with condoms; physiological or anatomical sterility (in self or partner) from 14 days prior to the first vaccination until 4 months after the last vaccination.
b. For heterosexually active male, using an effective method of contraception with their partner from the first day of vaccination until 4 months after the last vaccination.

1. ≥ 18 jaar oud;
2. Vrijwillig ondertekend toestemmingsformulier;
3. Bewezen HIV-1 infectie (met gedocumenteerde antilichamen tegen HIV-1 en detecteerbaar plasma HIV-1 RNA voor begin van therapie);
4. Op stabiele behandeling met een cART regime (antiretrovirale therapie bestaande ten minste drie geregistreerde antiretrovirale middelen) voor ten minste drie jaar;
5. Nadir CD4+ ≥ 350 cellen/μl (tot 2 occasionele uitslagen ≤ 350 cellen/μl zijn toegestaan);
6. Huidig CD4+ cel aantal ≥ 450 cellen/μl;
7 HIV-RNA onder 50 kopieën/mL in de laatste 6 maanden voorafgaand aan randomisatie, tijdens ten minste twee bepalingen (occasionele zogenaamde ‘blips’ ≤ 500 kopieën/mL zijn toegestaan)
8. Indien seksueel actief, bereidheid tot het gebruik van een betrouwbare methode voor het reduceren van het risico van transmissie naar de seksuele partner tijdens de onderbreking van de cART behandeling (inclusief PrEP)
a. Voor heteroseksueel actieve vrouwen, het gebruik van een effectieve methode van contraceptie met de partner (gecombineerde orale contraceptie pil, geïnjecteerde of geïmplementeerde contraceptie, consistent gebruik van condooms, fysiologische of anatomische steriliteit (zelf of van partner) vanaf 14 dagen voor de eerste vaccinatie tot vier maanden na de laatste vaccinatie.
b. Voor heteroseksueel actieve mannen, gebruik van een effectieve voor contraceptie met hun partner vanaf de eerste dag van vaccinatie tot vier maanden na de laatste vaccinatie.

E.4

Principal exclusion criteria

1. Treatment with non-cART regimen prior to cART regimen;
2. Previous failure to antiretroviral and/or mutations conferring genotypic resistance to antiretroviral therapy;
3. Non-subtype B HIV infection;
4. Active Hepatitis B virus and/or Hepatitis C virus co-infection;
5. History of a CDC class C event (see appendix A);
6. Pregnant female (screened with a positive pregnancy test), lactating or intending to become pregnant during the study;
7. Active malignancy ≤ 30 days (extended period on the clinical assessment of the investigator) prior to screening;
8. Active infection with fever (38°C or above) ≤ 10 days of screening and/or first vaccination;
9. Therapy with immunomodulatory agents (e.g. systemic corticosteroids), including cytokines (e.g. IL-2), immunoglobulins and/or cytostatic chemotherapy ≤ 90 days prior to screening. This does not include seasonal influenza, hepatitis B and/or other travel related vaccines;
10. Congenital, acquired or induced coagulation disorders, such as thrombocytopenia (thrombocytes < 150x109/L) and/or current use of anti-coagulant medication (e.g. coumarins, inhibitors of Xa); Usage of NSAIDs (including acetylsalicylic acid) is allowed, however it is advised to interrupt therapy 10 days ahead of vaccination;
11. Usage of any investigational drug ≤ 90 days prior to study entry;
12. An employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, or is a family member of an employee or the investigator
13. Any other condition, which, in the opinion of the investigator, may interfere with the evaluation of the study objectives

1. Behandeling met niet-cART regime voorafgaand aan cART regime;
2. Eerder falen op antiretrovirale therapie en/of mutaties die resistentie tegen antiretroviral therapie geven;
3. Niet-subtype B HIV infectie;
4. Eerdere HIV vaccinatie behandeling;
5. Actieve Hepatitis B virus en/of Hepatitis C virus co-infectie;
6. Geschiedenis van een CDC class C voorval;
7. Zwangere vrouw (bewezen met een positieve zwangerschapstest), borstvoeding gevend of de intentie om zwanger te worden tijdens de studie;
8. Actieve infectie (38°C of hoger) ≤ 10 dagen voorafgaand aan de screening visite en/of eerste vaccinatie;
9. Therapie met immunomodulatoire agentia (bijv. systemische corticosteroïden), inclusief cytokinen (bijv. IL-2), immunoglobulinen en/of cytostatische chemotherapie ≤ 90 dagen voor screening. Dit omvat niet de seizoensgriep, hepatitis B en/of andere reis gerelateerde vaccins;
10. Congenitale, verworven of geïnduceerde stollingsafwijkingen, zoals thrombocytopenie (thrombocyten < 150x109/L) en/of huidig gebruik van anti-coagulant medicatie (bijv. coumarinen, remmers van Xa); Gebruik van NSAID (inclusief acetylsalicylzuur) is toegestaan, maar het wordt geadviseerd deze behandeling 10 dagen voor vaccinatie te onderbreken;
11. Gebruik van enig ander onderzoeksgeneesmiddel ≤ 90 days voorafgaand aan studie entree;
12. Een werknemer van de onderzoeker of onderzoeksplek, met directe betrokkenheid bij de voorgestelde studie of andere studies onder leiding van de onderzoeker of studieplek of een familielid van een werknemer van de onderzoeker
13. Enige andere gesteldheid die naar mening van de onderzoeker de evaluatie van de studiedoelen kan beïnvloeden.

E.5 End points

E.5.1

Primary end point(s)

• safety and tolerability, as measured by the total number of adverse
events.
• immunogenicity of an immunization schedule with HIV-TriMix-mRNA
as measured by the increase in frequency of the HIV-specific T-cell
responses between baseline and 2 weeks after the last injection as
compared to both control groups, immunized with TriMix-mRNA only or WFI only

• veiligheid en verdraagbaarheid gericht op de aard, frequentie en ernst van lokale adverse voorvallen en systemische bijwerkingen
• immunogeniciteit van een immunisatie schema met HIV-TriMix-mRNA (iHIVARNA-01) om de frequentie van HIV-specifieke T-cel responsen te verhogen tussen baseline en 2 weken na de laatste injectie in vergelijking met de controle groepen, geïmmuniseerd met alleen TriMix-mRNA of alleen WFI.

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety will be reported 6 weeks after the first vaccination.

Immunogenicity will be determined by an Elipsot assay at week 6, two
week after the last vaccination

Veiligheid wordt gemeten 6 weken na de eerste vaccinatie

Immunogeniciteit wordt gemeten op 6 weken, twee weken na de laatste vaccinatie

E.5.2

Secondary end point(s)

• Evaluatie van de omvang en kinetiek van de HIV-specifieke CD4+ and CD8+ T cel responsen opgewekt door het immunisatie schema in de 3 groepen, m.b.v. twee methodes (ELISPOT, intra-cellulaire cytokine kleuring - ICS).
• Evaluatie van het vermogen van het immunisatie schema om de tijd tot virale rebound, na therapie onderbreking (ATI) op week 6, te verlengen.
• Evaluatie van het suppressieve effect op plasma viral load in vivo na ATI van W6 tot W18 in vergelijking met twee controle groepen, die alleen TriMix of alleen WFI krijgen toegediend.
• Bepaling van het deel van de patiënten met controle van virale load below (ondetecteerbaar) 12 and 24 weken nar start ATI (functional cure).
• Evaluatie van het percentage patiënten die een primaire immuun respons heeft ontwikkeld tegen eerder niet herkende HIV peptiden.
• Analyze van de inductie of versterking van de CD8+ T-cel HIV suppressive capaciteit.
• Evaluatie van het effect op het reservoir gemeten door proviraal DNA en intracellulair viraal RNA (niet gespliced en multiple spliced viraal RNA).
• Detectie van virale immuun escape d.m.v. sequencing van HIV en het uitvoering van zeef effect analyses op virus dat terugkomt na cART onderbreking.
• Evaluatie van de gastheer eiwit mRNA expressie profielen in volledig bloed bij baseline en W6 en W18.
• Opslag van samples voor toekomstige bepaling van darm microbiota samenstelling en diversiteit in relatie tot HIV immuun status.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary end point will be determined after the analytical treatment
interruption 18 and 30 weeks after the first vaccination.

De secundaire endpoints worden gemeten na de analytical treatment interruption (ATI), 18 en 30 weken na de eerste vaccinatie

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)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

TriMix combinación (adjuvante)

TriMix stimulatory mix (cf adjuvants alone)

E.8.2.4

Number of treatment arms in the trial

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

LVLS

Laatste visite van laatste patiënt

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

E.8.9.2

In all countries concerned by the trial 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

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

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

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)

Not different from normal HIV cART treatment

Niet anders dan normale HIV behandeling met cART

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-04-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-06

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-11-27

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