Clinical Trials Register

Summary
EudraCT Number:	2013-005348-28
Sponsor's Protocol Code Number:	ARD-3150-1201(ORBIT-3)
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:	2014-04-11
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

2013-005348-28

A.3

Full title of the trial

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Pulmaquin® in the Management of Chronic Lung Infections with Pseudomonas aeruginosa in Subjects with Non-Cystic Fibrosis Bronchiectasis, including 28 Day Open-Label Extension and Pharmacokinetic Substudy (ORBIT-3)

Estudio multicéntrico, aleatorizado, doble ciego y controlado con placebo para evaluar la seguridad y eficacia de Pulmaquin® en el tratamiento de infecciones pulmonares crónicas con Pseudomonas aeruginosa en sujetos con bronquiectasia no asociada a la fibrosis quística, que incluye una extensión abierta de 28 días y un subestudio farmacocinético (ORBIT-3)

A.3.1

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

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Pulmaquin® (ARD-3150, Dual Release Ciprofloxacin for Inhalation) in subjects who have a lung infection that includes the bacteria Pseudomonas aeruginosa due to non-cystic fibrosis bronchiectasis

Estudio multicéntrico, aleatorizado, y controlado con placebo doble ciego para evaluar la seguridad y eficacia de Pulmaquin ® (ARD-3150, liberación dual de ciprofloxacino para inhalación) en sujetos que tienen una infección pulmonar que incluye la bacteria Pseudomonas aeruginosa, debido a la bronquiectasia no asociada a fibrosis quística

A.3.2

Name or abbreviated title of the trial where available

Pulmaquin® with Non-Cystic Fibrosis Bronchiectasis (ORBIT 3)

Pulmaquin® con bronquiectasia no asociada a fibrosis quística (ORBIT 3)

A.4.1

Sponsor's protocol code number

ARD-3150-1201(ORBIT-3)

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01515007

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	Aradigm Corporation
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	Aradigm Corporation
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	Aradigm Corporation
B.5.2	Functional name of contact point	Chief Medical Officer
B.5.3	Address:
B.5.3.1	Street Address	3929 Point Eden Way
B.5.3.2	Town/ city	Hayward, California
B.5.3.3	Post code	CA 94545
B.5.3.4	Country	United States
B.5.4	Telephone number	0015102658838
B.5.5	Fax number	0015102658878
B.5.6	E-mail	froehlichj@aradigm.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	Pulmaquin®
D.3.2	Product code	ARD-3150
D.3.4	Pharmaceutical form	Nebuliser solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ciprofloxacin Hydrochloride
D.3.9.1	CAS number	86483-48-9
D.3.9.2	Current sponsor code	Ciprofloxacin for Inhalation (CFI)
D.3.9.3	Other descriptive name	CIPROFLOXACIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ciprofloxacin Hydrochloride
D.3.9.1	CAS number	86483-48-9
D.3.9.2	Current sponsor code	Free Ciprofloxacin for Inhalation (FCI)
D.3.9.3	Other descriptive name	CIPROFLOXACIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	AS2
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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	Nebuliser solution
D.8.4	Route of administration of the placebo	Inhalation use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic lung infections with Pseudomonas aeruginosa in subjects with
non-cystic fibrosis bronchiectasis.

Infecciones pulmonares crónicas con Pseudomonas aeruginosa en sujetos con bronquiectasia no asociada a fibrosis quística

E.1.1.1

Medical condition in easily understood language

Lung infection that includes the bacteria Pseudomonas aeruginosa due
to non-cystic fibrosis bronchiectasis.

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	PT
E.1.2	Classification code	10057582
E.1.2	Term	Lung infection pseudomonal
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10006446
E.1.2	Term	Bronchiectasis NOS
E.1.2	System Organ Class	100000004855

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 main objective of this study is to evaluate the efficacy of Pulmaquin compared to placebo in the management of chronic lung infections with P. aeruginosa (a type of bacteria) in subjects with non-cystic fibrosis bronchiectasis by evaluating the time to first pulmonary exacerbation (worsening).

El objetivo principal de este estudio es evaluar la eficacia de Pulmaquin en comparación con el placebo en el tratamiento de las infecciones pulmonares crónicas con P. aeruginosa en sujetos con bronquiectasia no asociada a la fibrosis quística mediante la evaluación del tiempo transcurrido hasta la primera exacerbación pulmonar.

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are to evaluate:
? Efficacy of Pulmaquin compared to placebo as assessed by clinical outcomes (including pulmonary exacerbations), pulmonary function, patient-reported outomes, and exercise testing in the Double-Blind Phase.
? Microbiological response.
? Safety and tolerability of Pulmaquin compared to placebo in the Double-Blind Phase.
? Safety and tolerability of Pulmaquin in the Open-Label Extension.

Los objetivos secundarios son:
-la eficacia de Pulmaquin, en comparación con el placebo, según la evaluación de los resultados clínicos (incluidas las exacerbaciones pulmonares), la función pulmonar, los resultados notificados por los pacientes y la prueba de esfuerzo en la fase doble ciega.
-la respuesta microbiológica
-la seguridad y tolerabilidad de Pulmaquin, en comparación con el placebo, en la fase doble ciega
-la seguridad y la tolerabilidad de Pulmaquin en la extensión abierta

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

A pharmacokinetic substudy to be conducted as part of study ARD-3150-1201 (ORBIT 3) open label extension.
Objective: to assess the PK of Pulmaquin in blood and sputum in subjects with non-CF bronchiectasis.

Un subestudio farmacocinético se llevará a cabo como parte del estudio de ARD-3150-1201 (ORBIT 3) extensión abierta.
Objetivo: evaluar la farmacocinética de Pulmaquin en sangre y esputo en pacientes con bronquiectasias no debidas a fibrosis quística

E.3

Principal inclusion criteria

Subjects will be entered into this study only if they meet all of the following criteria:
1. Are willing and able to provide written informed consent.
2. Are males or females who are 18 year of age or older and are able to
walk.
3. Have had a confirmed diagnosis of non-CF bronchiectasis per
computerized tomography showing bronchial wall dilatation (internal
bronchial lumen diameter greater than accompanying pulmonary artery
or lack of tapering) with or without bronchial wall thickening.
4. Have a documented history of at least 2 pulmonary exacerbations
treated with courses of antibiotics within the last 12 months.
5. Have been off any antibiotic treatment for a minimum of 28 days prior
to Visit 1, except for macrolides (azithromycin or erythromycin) used
chronically at a stable dose.
6. Have forced expiratory volume in 1 second (FEV1) ? 25% of predicted
values at the Screening Visit (Visit 0).
7. Have positive documented P. aeruginosa in a sputum/deep-throat
swab culture (or bronchoalveolar lavage [BAL] or bronchoscopic
specimen) prior to the Screening Visit (Visit 0).
8. Have positive P. aeruginosa in the sputum/deep-throat swab culture
collected at the Screening Visit (Visit 0). If sputum sample is negative,
sputum/swab culture can be repeated on up to 3 occasions during
Screening to document P. aeruginosa presence.
9. Are clinically stable and capable of performing the 6mwt without
supplemental oxygen.
10. Are willing and able to comply with the requirements for
participation in the study.
11. Female subjects of childbearing potential must have a negative
pregnancy test at the Screening Visit and must use an acceptable
method of contraception for at least 3 months prior to the first dose of
study drug and for 28 days after the last dose of study drug. Acceptable
methods of contraception for women are orally administered or
implantable hormonal contraceptives, surgical intervention, intrauterine
device (IUD), and sexual abstinence. To be considered "not of
childbearing potential", female subjects must be postmenopausal for at
least 1 year as confirmed by an elevated follicle-stimulating hormone
(FSH) level (? 30 mIU/mL) at Screening and 1 year of amenorrhea, or
have been irreversibly surgically sterilized by hysterectomy,
oophorectomy, or bilateral tubal ligation for at least 3 months prior to
the first dose of study drug. Male subjects whose female partners are of
childbearing potential (definition as above) must agree to use an
acceptable method of birth control for the duration of study treatment
and for 28 days after the last dose of study drug.

Únicamente se incluirá a los pacientes en el estudio si cumplen todos los criterios siguientes:
1.estén dispuestos y son capaces de otorgar su consentimiento informado por escrito
2.son hombres o mujeres con 18 años de edad o más y son capaces de caminar
3.han tenido un diagnóstico confirmado de bronquiectasia no asociada a la fibrosis quística por tomografía computerizada que muestra la dilatación de la pared bronquial (diámetro interno del lumen bronquial mayor que la arteria pulmonar que lo acompaña o falta de disminución gradual ) con o sin engrosamiento de la pared bronquial.
4.tienen un historial documentado de al menos 2 exacerbaciones pulmonares tratadas con ciclos de antibióticos en los últimos 12 meses
5.han suspendido un tratamiento con antibióticos durante un mínimo de 28 días antes de la visita 1, a excepción de los macrólidos (azitromicina o eritromicina)utilizados crónicamente con una dosis estable
6.tienen un volumen de espiración forzada en i segundo (VEF) mayor o igual al 25%, respecto a los valores previstos, en la visita de selección (visita 0)
7.tienen un resultado positivo documentado de P. aeruginosa en el cultivo de esputo/exudado faríngeo profundo ( o lavado broncoalveolar LBA oo muestra de broncoscopia) antes de la visita de selección (visita 0)
8.tienen un resultado positivo P. aeruginosa en el cultivo de esputo/exudado faríngeo profundo recogido en la visita de selección (visita 0). Si la muestra de esputo es negativa, el cultivo de esputo/exudado se puede repetir hasta en 3 ocasiones durante la selecciónpara documentar la presencia de P. aeruginosa
9.son crónicamente estables y capaces de realizar la prueba de caminata de 6 minutos (6mpc) sin oxígeno suplementario
10.están dispuestos y son capaces de cumplir con los requisitos para participar en el estudio.
11.los sujetos femeninos en edad fértil deben presentar una prueba de embarazo negativa en la visita de selección y deben utilizar un método anticnceptivo aceptable durante al menos 3 meses antes de la primera dosis del fármaco del estudio y durante 28 días después de la última dosis del fármaco del estudio.. Los métodos anticonceptivos aceptables para las mujeres son los que se administran pofr via oral o los implantes anticonceptivos hormonales, la intervención quirúrgica, el dispositivo intrauterino (DIU) y la abstinencia sexual.
Para que se considere que "no están en edad fértil" debe haberse confirmado que las mujeres han sido posmenopáusicas durante al menos 1 añoscon un elevado nivel de hormona foliculoestimulantte (mayor o igual a30 mUI/ml en la selección y 1 año de amenorrea, o se han esterilizado quirúrgicamente de forma irreversible por histerectomía, ooforectomia o ligadura de trompas bilateral durante al menos 3 meses antes de la primera dosis del fármaco del estudio.
Los varones cuyas parejas estén en edad fértil deben aceptar utilizar un método anticonceptivo aceptable durante el tratamiento del estudio y durante 28 días después de la última dosis del fármaco del estudio

E.4

Principal exclusion criteria

Subjects will be randomized into this study only if they meet none of the following criteria:
1. Have a pulmonary exacerbation during the Screening Phase (between
Visit 0 and randomization), defined as requiring acute treatment with
inhaled, oral, or intravenous antibiotics prior to the first dose of study
drug.
2. Have a clinical diagnosis of CF.
3. Have primary diagnosis of Chronic Obstructive Pulmonary Disease
(COPD) related to smoking history of greater than 10 pack years.
4. Have a current diagnosis of active allergic bronchopulmonary
aspergillosis.
5. Have received any intravenous, oral, or inhaled anti-pseudomonal
antibiotic (except chronic macrolides erythromycin or azithromycin with
a stable dose) within 28 days prior to Visit 1.
6. Have an allergy to ciprofloxacin, gemifloxacin, levofloxacin,
moxifloxacin, or norfloxacin.
7. Have a known allergy to soy products.
8. Have used tizanidine within 28 days prior to Visit 1 and would need to
use tizanidine during the study (because tizanidine is contraindicated
due to a PK interaction with ciprofloxacin).
9. Have initiated supplemental oxygen within 28 days prior to Visit 1.
10. Have used any intravenous or intramuscular corticosteroid or have
used oral corticosteroid > 10 mg/day or > 20 mg every other day within
28 days of Visit 1.
11. Have had changes in either the treatment regimen or initiation of
treatment with any of the following medications within 28 days prior to
Visit 1:
a. Macrolides, e.g., azithromycin or erythromycin
b. Inhaled hypertonic saline or inhaled mannitol
c. Mucolytics
d. Bronchodilator medications
e. Oral corticosteroid
12. Have had changes in physiotherapy technique or frequency within 28
days prior to Visit 1.
13. Have a history of solid organ (e.g., lung) transplantation.
14. Have a non-tuberculosis mycobacterial infection requiring treatment.
15. Have active tuberculosis.
16. Have serum creatinine levels ? 2.0x upper limit of normal (ULN) at
the Screening Visit (Visit 0).
17. Have serum transaminase levels > 3x ULN at the Screening Visit
(Visit 0).
18. Have a febrile illness within 1 week prior to Visit 1.
19. Have had massive hemoptysis (greater than or equal to 300 mL or
requiring blood transfusion) within 6 months prior to Visit 1.
20. Have received an investigational drug or device within 28 days prior
to Visit 1.
21. Have any serious or active medical or psychiatric illness, which in the
opinion of the Investigator, would interfere with subjects' treatment,
assessment, or compliance with the protocol.
22. Have a history or suspicion of unreliability, poor cooperation, or noncompliance
with medical treatment.
23. Are unable to use nebulizers.
24. Are unable either to understand the instruction for use of the study
drug or to complete the Quality of Life Questionnaire-Bronchiectasis
(QoL-B) at Visit 1.
25. Have previously been enrolled in this study.
26. Are pregnant, plan to become pregnant during this study, are nursing
mothers or are unwilling to use an acceptable method of contraception
for the duration of the study.
27. Have any other condition that, in the opinion of the Investigator,
would prohibit the subject from participating in the study.

Únicamente se incluirá a los pacientes en el estudio si no cumplen ninguno de los criterios siguientes:
1.haber sufrido una exacerbación pulmonar durante la fase de selección (entre la visita 0 y la visita de aleatorización), definida como la necesidad de tratamiento agudo con antibióticos inhalados , orales o intravenosos antes de la primera dosis del fármaco del estudio.
2.haber recibido un diagnóstico clínico de fibrosis quística
3.haber recibido un diagnóstico primario de enfermedad pulmonar obstructiva crónica en relación con antecedentes de tabaquismo de más de 10 paquetes por año.
4.tener un diagnóstico actual de aspergilosis broncopulmonar alérgica activa.
5.haber recibido cualquier antibiótico contra pseudomonas intravenoso, oral o inhalado (excepto los macrólidos crónicos con una dosis estable) en los 28 días previos a la visita 1
6.tener alergia al ciprofloxacino, gemifloxacino, levofloxacino, moxifloxacino,o norfloxacino
7.tener una alergia conocida a los productos de soja
8.haber utilizado tizanidina en los 28 días previos a la visita 1 y necesitar el uso de tizanidina durante el estudio
9.haber iniciado tratamiento con oxígeno suplementario en los 28 días previos a la visita 1
10.haber utilizado cualquier corticoesteroide por via intravenosa o intramuscular o corticoides orales superior a 10mg/dia o superior a 20mg cada dos días en los 28 días posteriores a la visita1
11.haber aplicado cambios en el régimen de tratamiento o haber iniciado un tratamiento con cualquiera de los siguientes medicamentos los 28 días anteriores a la visita 1: macrólidos, solución salina hipertónica inhalada o manitol inhalado, mucolíticos, fármacos broncodilatadores, corticoesteroides orales
12.haber realizado cambios en la técnica o la frecuencia de la fisioterapia durante los 28 días anteriores a la visita 1
13.tener antecedentes de transplante de órganos sólidos
14.tener una infección por micobacterias no tuberculosas que requieren tratamiento
15.tener tuberculosis activa
16.tener niveles de creatinina sérica superior o igual a 2 veces el límite superior de la normalidad en la visita de selección
17.tener niveles de transaminasas séricas superior a 3 veces el LSN en la visita de selección
18.tener una enfermedad febril en el plazo de 1 semana antes de la visita1
19.haber sufrido hemoptisis masiva en los 6 meses previos a la visita 1
20.haber sido tratado con un fármaco o un dispositivo en investigación en los 28 días anteriores a la visita 1
21.sufrir alguna enfermedad médica o psiquiátrica grave o activa, que en opinión del investigador, interferiría con el tratamiento, la evaluación o el cumplimiento del protocolo
22.tener antecedentes o sospecha de falta de fiabilidad, poca cooperación o incumplimiento con el tratamiento médico
23.ser incapaz de utilizar nebulizadores
24.ser incapaz de entender bien las instrucciones de uso del fármaco del estudio o de completar el cuestionario de calidad de vida en la visita 1
25.haber sido inscrito anteriormente en este ensayo
26.estar embarazada, tener previsto quedarse embarazada durante este estudio, ser madre lactante o no estar dispuesto a utilizar un método anticonceptivo aceptable durante el estudio.
27.cualquier otra enfermedad que, a criterio del investigador, prohibiría al sujeto participar en el estudio

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint of this study is the time to first pulmonary
exacerbation from baseline (Day 1) to Week 48.

La variable principal de eficacia de este estudio es el tiempo hasta la primera exacerbación pulmonar de la línea de base (día 1) a la semana 48.

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline (Day 1) to Week 48.

Desde la línea de base (día 1) hasta la semana 48

E.5.2

Secondary end point(s)

- Number of pulmonary exacerbations from baseline (Day 1) to Week 48.
- Number of severe pulmonary exacerbations from baseline (Day 1) to
Week 48.
- Change in Respiratory Symptoms Domain score of Qol-B from baseline
(Day 1) to Week 48.

-Número de exacerbaciones pulmonares desde la línea de base (día 1) hasta la semana 48
-número de exacerbaciones pulmonares severas desde la línea de base (día 1) hasta la semana 48
-Cambio en los síntomas de dominio respiratorio con puntuación del Qol-B de la línea de base(Día 1) a la semana 48.

E.5.2.1

Timepoint(s) of evaluation of this end point

From baseline (Day 1) to Week 48.

desde la línea de base (día 1) hasta la semana 48

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

Yes

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

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

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

Australia

Canada

Germany

Hungary

Israel

Italy

Netherlands

New Zealand

Poland

Romania

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

The study will close when all subjects have completed the follow-up telephone call at Day 394(+- 2 days), which will take place 30 days after the subject receives the last dose of open-label study drug at Visit 15 (Day 364).
Therefore End of Study is defined as when the last patient completes Visit 16 (Study Day 394) ? or the last early withdrawal visit, whichever is later.

El estudio se cerrará cuando todos los sujetos hayan finalizado la llamada telefónica de seguimiento en el día 394 (+ - 2 días), que tendrá lugar 30 días después de que el sujeto reciba la última dosis del fármaco del estudio en la visita 15 (Día 364 ).
Por lo tanto Fin del Estudio se define como cuando el último paciente complete Visita 16 (Estudio Día 394) - o la última visita retirada anticipada, lo que ocurra después.

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

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