Clinical Trials Register

Summary
EudraCT Number:	2018-001311-79
Sponsor's Protocol Code Number:	JZP080-301
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-11-23
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

Spain - AEMPS

A.2

EudraCT number

2018-001311-79

A.3

Full title of the trial

A Double-blind, Placebo-controlled, Randomized Withdrawal, Multicenter Study of the Efficacy and Safety of JZP-258 in the Treatment of Idiopathic Hypersomnia (IH) with an Open-label Safety Extension

Un estudio multicéntrico, doble ciego, controlado con placebo, aleatorizado, de la eficacia y seguridad de JZP-258 en el tratamiento de la hipersomnia idiopática (IH) con una extensión de seguridad abierta

A.3.1

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

Study on the Effect of JZP-258 in Patients with Idiopathic Hypersomnia

Estudio sobre el efecto de JZP-258 en pacientes con hipersomnia idiopática

A.4.1

Sponsor's protocol code number

JZP080-301

A.5.4

Other Identifiers

Name:

IND

Number:

49,641

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	Jazz Pharmaceuticals
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Jazz Pharmaceuticals
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	Jazz Pharmaceuticals
B.5.2	Functional name of contact point	Ian Foley
B.5.3	Address:
B.5.3.1	Street Address	Wing B, Building 5700,Spires House, John Smith Drive,Oxford Business Park
B.5.3.2	Town/ city	Oxford
B.5.3.3	Post code	OX4 2RW
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+34913303273
B.5.6	E-mail	ian.foley@jazzpharma.com

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	JZP-258, 500 mg/ml oral solution
D.3.2	Product code	JZP-258
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	oxybate (4-hydroxybutanoic acid, γ- hydroxybutyrate, 4-hydroxybutyrate, or GHB)
D.3.9.1	CAS number	502-85-2
D.3.9.3	Other descriptive name	oxybate mixed salt solution: sodium oxybate, potassium oxybate, calcium oxybate,magnezium oxybate
D.3.9.4	EV Substance Code	SUB14731MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/ml gram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment of Idiopathic Hypersomnia

Tratamiento de la Hipersomnia Idiopática

E.1.1.1

Medical condition in easily understood language

Sleep Disorder

Transtorno del sueño

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

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	10040989
E.1.2	Term	Sleep disorder NOS
E.1.2	System Organ Class	100000004873

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	10015595
E.1.2	Term	Excessive daytime sleepiness
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to evaluate the efficacy of JZP-258 in the treatment of IH.

El objetivo principal del este estudio es evaluar la eficacia de JZP-258 en el tratamiento de la HI.

E.2.2

Secondary objectives of the trial

The secondary objective of this study is to evaluate the safety of JZP-258 in the treatment of IH

El objetivo secundario de este estudio es evaluar la seguridad de JZP-258 en el tratamiento de la HI.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Male or female between 18 and 75 years of age, inclusive, at the time of consent.
•Have a primary diagnosis of IH according to the International Classification of Sleep Disorders ICSD-2 or ICSD-3 criteria. If documentation of diagnosis of IH is unavailable or the Investigator deems it necessary to confirm diagnosis, diagnostic testing will be conducted during the Screening Period to confirm the diagnosis of IH according to ICSD-3 criteria. If the Investigator suspects a patient with a previous clinical diagnosis of narcolepsy has IH, a screening PSG and MSLT may be performed to confirm the diagnosis of IH, provided there is no history of cataplexy, no history of SOREMP on nocturnal PSG, and no history of ≥2 SOREMPs on MSLT.
•At the Screening Visit and the Baseline Visit, subjects who are not on Xyrem at study entry must have Epworth Sleepiness Scale (ESS) scores ≥ 11 (as assessed with a look-back period of 1 week). Any subject who will wash out of medications during the Screening Period that could impact ESS score at Screening (eg, stimulant, alerting agent when not taken at a stable dose) will only have to meet the ESS score ≥ 11 requirement at the Baseline visit, after they have washed out of their medication.
•If currently treated with Xyrem, must have documented clinical improvement of EDS after the initiation of Xyrem per Investigator’s clinical judgment.
•Average nightly total sleep time of ≥ 7 hours, per subject history. Average nightly total sleep time will be confirmed by Investigator’s review of sleep diaries collected during the final 2 weeks of the Screening Period.
•If currently treated with stimulants and/or alerting agents or nicotine replacement therapy, must have been taking the same regimen and dose for at least 2 months prior to screening and must agree to take the same dose leading up to and throughout the Double-blind Randomized Withdrawal Period.
•Have used a medically acceptable method of contraception for at least 2 months prior to the first dose of study drug and consent to use a medically acceptable method of contraception from the first dose of study drug, throughout the entire study period, and for 90 days after the last dose of study drug.

•Varones o mujeres entre 18 y 75 años de edad, ambos inclusive, en el momento del consentimiento.
•Tener un diagnóstico primario de HI según los criterios ICSD-2 o ICSD-3 de la Clasificación internacional de los trastornos del sueño. Si no se dispone de la documentación del diagnóstico de HI o el investigador considera que es necesario confirmar el diagnóstico, se llevarán a cabo pruebas de diagnóstico durante el periodo de selección para confirmar el diagnóstico de HI según los criterios ICSD-3. Si el investigador sospecha que un paciente con un diagnóstico clínico previo de narcolepsia padece HI, se podrá realizar una polisomnografía y una prueba de latencia múltiple del sueño para confirmar el diagnóstico de HI, siempre y cuando no haya antecedentes de cataplejía, de periodos de sueño con inicio en la fase REM en polisomnografías nocturnas ni de ≥2 periodos de sueño con inicio en la fase REM en la prueba de latencia múltiple del sueño.
•En la visita de selección y la visita inicial, los sujetos que no tomen Xyrem al inicio del estudio deben contar con puntuaciones ≥11 en la Escala de somnolencia de Epworth (ESS) (según se evalúe en un periodo retroactivo de 1 semana). Todos los sujetos que se sometan a un reposo farmacológico de los medicamentos durante el periodo de selección que pueda afectar a la puntuación de la ESS en la selección (p. ej., estimulante, fármaco para mantener la vigilia cuando no se toma con una dosis estable) solo tendrán que cumplir el requisito de la puntuación ≥11 de la ESS en la visita inicial, tras finalizar el reposo farmacológico de la medicación.
•Si está actualmente en tratamiento con Xyrem, deberá presentar una mejoría clínica documentada de la SDE después del inicio del tratamiento con Xyrem según el criterio clínico del investigador.
•Media del tiempo total de sueño por noche ≥7 horas, según los antecedentes del sujeto. Mediante la revisión por parte del investigador de los diarios del sueño recopilados durante las 2 últimas semanas del periodo de selección se confirmará la media del tiempo total de sueño por noche.
•Si está actualmente en tratamiento con estimulantes, fármacos para mantener la vigilia o una terapia sustitutiva de nicotina, debe haber seguido la misma pauta y dosis durante al menos 2 meses antes de la selección y debe aceptar tomar la misma dosis de manera preliminar y a lo largo del periodo de retirada aleatorizada doble ciego.
•Haber utilizado un método anticonceptivo médicamente aceptable durante al menos 2 meses antes de la primera dosis del fármaco del estudio y aceptar el uso de un método anticonceptivo médicamente aceptable desde la primera dosis del fármaco del estudio, durante todo el periodo del estudio y durante 90 días después de la última dosis del fármaco del estudio.

E.4

Principal exclusion criteria

•Hypersomnia due to another medical, behavioral, or psychiatric disorder condition (eg, narcolepsy, multiple sclerosis, Parkinson’s Disease, stroke).
•Evidence of untreated or inadequately treated sleep-disordered breathing including:
a.Presence of clinically significant and untreated obstructive or central sleep apnea as determined by the Investigator or documented previously;
or documentation of one of the following:
b.Apnea Index > 10 on any historical test (unless a subsequent Apnea Index ≤ 10 was reported after treatment, and the subject agrees to use this treatment throughout the duration of the study) or during the Screening PSG (if done) while on obstructive sleep apnea treatment or untreated; or
c.Clinically significant hypoventilation; or
d.Noncompliance with primary obstructive sleep apnea therapy. (Compliance defined as positive airway pressure use of ≥ 4 hours per night on ≥ 70% of nights [≥ 5 of 7 nights / week], historical report [with Investigator concurrence] of use of an oral appliance on ≥ 70% of nights [≥ 5 of 7 nights/week], or receipt of an effective surgical intervention for obstructive sleep apnea symptoms.)
•Clinically significant parasomnias (eg, sleep walking, rapid eye movement sleep behavior disorder, etc.).
•Current or past (within 1 year) major depressive episode according to DSM-5 criteria. Patients with depression under control are allowed per the judgment of the Investigator or the treating physician and the anti-depressant treatment has to be stable for at least 6 months prior to Screening and remain stable for the duration of the study.
•Current suicidal risk as determined from history, by presence of active suicidal ideation as indicated by positive response to item #4 or #5 on the C-SSRS, or any history of suicide attempt.
•Occupation requiring nighttime shift work or variable shift work with early work start times or other occupations that could affect the safety of the subject per the judgment of the Investigator.
•Treatment or planned treatment with any CNS sedating agents, including but not limited to benzodiazepines or other sedating anxiolytics, sedating antidepressants, hypnotics, sedatives, neuroleptics, opioids, barbiturates, phenytoin, melatonin, ethosuximide, medications containing valproic acid or its sodium salt (eg, depakene and Depakote), or any other medication in which the subject experiences sedation are prohibited during the study. Treatment must have been discontinued within 2 weeks or 5 half-lives, whichever is longer, prior to enrollment. (Discontinuation for the purpose of study enrollment is permitted only if considered safe and medically appropriate by the Investigator, and approved by the Medical Monitor.) The Investigator must ensure that discontinuation from these medications is medically supervised. Subjects must abstain from these medications during the study.
•Current or past substance use disorder (including alcohol) according to DSM-5 criteria, or the subject is unwilling to refrain from consuming alcohol, cannabinoids, or prohibited medications during the study.

•Hipersomnia debida a otra afección médica, conductual o trastorno psiquiátrico (p. ej., narcolepsia, esclerosis múltiple, enfermedad de Parkinson, accidente cerebrovascular).
•Evidencias de trastornos respiratorios del sueño no tratados o tratados de forma inadecuada como:
a.Presencia de apnea obstructiva o central del sueño clínicamente significativa y no tratada según la determinación del investigador o previamente documentada;
o documentación de uno de los siguientes:
b.Índice de apnea >10 en cualquier prueba histórica (a menos que se informara posteriormente de un índice de apnea ≤10 después del tratamiento y el sujeto acepta utilizar este tratamiento a lo largo del estudio) o durante la polisomnografía de selección (si se realiza) mientras esté recibiendo el tratamiento contra la apnea obstructiva del sueño o sin tratamiento; o
c.Hipoventilación clínicamente significativa; o
d.Incumplimiento del tratamiento principal contra la apnea obstructiva del sueño. (El cumplimiento se define como el uso de presión positiva de las vías respiratorias durante ≥4 horas cada noche en ≥70 % de las noches [≥5 de 7 noches/semana], historial clínico [de acuerdo con el investigador] de uso de una aplicación oral en ≥70 % de las noches [≥5 de 7 noches/semana] o realización de una intervención quirúrgica eficaz para los síntomas de la apnea obstructiva del sueño).
•Parasomnias clínicamente significativas (p. ej., sonambulismo, trastorno de la conducta en el sueño paradójico, etc.).
•Episodio depresivo mayor actual o previo (en el año anterior) según los criterios DSM-5. Los pacientes con depresión controlada están permitidos según el criterio del investigador o del médico responsable del tratamiento. El tratamiento antidepresivo ha de ser estable durante al menos 6 meses antes de la selección y mantenerse estable durante todo el estudio.
•Riesgo actual de suicidio, determinado a partir de los antecedentes, por presencia de pensamientos suicidas activos, según indique la respuesta positiva al ítem n.º 4 o n.º 5 en la C-SSRS, o antecedentes de intento de suicidio.
•Empleo en el que se haya de trabajar en el turno de noche o en un turno variable con hora de inicio temprana u otros empleos que pudieran afectar a la seguridad del sujeto, según el criterio del investigador.
•Se prohíbe durante el estudio el tratamiento o tratamiento previsto con cualquier fármaco sedante del SNC, incluidos, entre otros, benzodiacepinas u otros ansiolíticos sedantes, antidepresivos sedantes, hipnóticos, sedantes, neurolépticos, opiáceos, barbitúricos, fenitoína, melatonina, etosuximida, medicamentos que contengan ácido valproico o sus sales de sodio (p. ej., Depakene y Depakote) o cualquier otro medicamento con el que el sujeto experimente sedación. El tratamiento debe haberse interrumpido 2 semanas o 5 semividas antes, lo que dure más, antes de la inscripción. (Se permite la interrupción del tratamiento para la inscripción en el estudio solo si el investigador lo considera seguro y médicamente indicado y el supervisor médico lo aprueba). El investigador debe garantizar que la interrupción de estos medicamentos esté supervisada médicamente. Los sujetos deben abstenerse de tomar estos medicamentos durante el estudio.
•Trastorno por el uso de sustancias actual o pasado (incluido el alcohol) según los criterios DSM-5 o si el sujeto no está dispuesto a abstenerse de consumir alcohol, cannabinoides o los medicamentos prohibidos durante el estudio

E.5 End points

E.5.1

Primary end point(s)

ESS, as assessed by the change in ESS from the end of the Stable
Dose Period to the end of the Double-blind Randomized Withdrawal Period

El criterio de valoración principal de la eficacia es el cambio en la puntuación de la ESS desde el final del periodo de dosis estable hasta el final del periodo de retirada aleatorizada doble ciego.

E.5.1.1

Timepoint(s) of evaluation of this end point

at the end of the Stable Dose Period as fixed effects

Al final del periodo de dosis estable

E.5.2

Secondary end point(s)

Key Efficacy Endpoint:
Patient Global Impression of change assessed by the proportion of subjects reporting worsening of symptoms (minimally, much or very much) at the end of the Double-blind Randomized Withdrawal Period.
Hypersomnolence Severity Scale:Change in total score from the end of the Stable Dose Period to the end of the Double-blind Randomized Withdrawal Period.
Other Secondary Efficacy Endpoints :
Clinical Global Impression of change (CGIc): proportion of subjects reported as worse(minimally, much or very much) at the end of the Double-blind Randomized Withdrawal Period
FOSQ-10: Change in total score from the end of the Stable Dose Period to the end of the Double-blind Randomized Withdrawal Period

Criterios de valoración secundarios clave de la eficacia
•Impresión global del cambio por parte del paciente (PGIc): proporción de sujetos que informan de un empeoramiento de los síntomas (levemente, mucho o muchísimo) en la PGIc al final del periodo de retirada aleatorizada doble ciego.
•Escala de intensidad de la hipersomnolencia (HSS): cambio en la puntuación total desde el final del periodo de dosis estable hasta el final del periodo de retirada aleatorizada doble ciego.
Otros criterios de valoración secundarios de la eficacia
•Impresión clínica global del cambio (CGIc): proporción de sujetos en los que se informa de un empeoramiento (levemente, mucho o muchísimo) al final del periodo de retirada aleatorizada doble ciego.
•FOSQ-10: cambio en la puntuación total desde el final del periodo de dosis estable hasta el final del periodo de retirada aleatorizada doble ciego

E.5.2.1

Timepoint(s) of evaluation of this end point

at the end of Double-blind Randomized Withdrawal Period

Al final del Periodo de retirada aleatorizada doble ciego

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

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

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

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

Belgium

Czech Republic

Finland

France

Germany

Italy

Poland

Spain

United Kingdom

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

last visit of the last subject

Ultima visita del ultimo sujeto

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 years

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:

126

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

140

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)

JZP-258 will not be available to the subject after their participation in
the study has ended

JZP-258 no estará disponible para el sujeto después de que su participación en
el estudio haya terminado

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

2019-02-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-12-18

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