Clinical Trials Register

Summary
EudraCT Number:	2016-001022-34
Sponsor's Protocol Code Number:	AVX012-CT-001
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:	2016-07-05
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

Spain - AEMPS

A.2

EudraCT number

2016-001022-34

A.3

Full title of the trial

A phase I/II, double-blind, placebo-controlled study assessing the safety and efficacy of AVX-012 ophthalmic solution in subjects with mild-to-moderate dry eye syndrome

Ensayo clínico fase I/II, doble ciego, controlado con placebo para evaluar la seguridad y eficacia de la solución oftálmica AVX-012, en sujetos con síndrome de ojo seco leve a moderado.

A.3.1

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

A phase I/II, double-blind, placebo-controlled study assessing the safety and efficacy of AVX-012 ophthalmic solution in subjects with mild-to-moderate dry eye syndrome

Ensayo clínico fase I/II, doble ciego, controlado con placebo para evaluar la seguridad y eficacia de la solución oftálmica AVX-012, en sujetos con síndrome de ojo seco leve a moderado

A.3.2

Name or abbreviated title of the trial where available

A phase I/II, double-blind, placebo-controlled study assessing the safety and efficacy of AVX-012

Estudio fase I/II doble ciego controlado con placebo para evaluar la seguridad y eficacia de AVX-012

A.4.1

Sponsor's protocol code number

AVX012-CT-001

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	AVIZOREX PHARMA, S.L.
B.1.3.4	Country	Spain
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	AVIZOREX PHARMA, S.L.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AVIZOREX PHARMA, S.L.
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Parc Científic de Barcelona. C/Baldiri Reixac 4-8
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08028
B.5.3.4	Country	Spain
B.5.4	Telephone number	3493 402 90 26
B.5.6	E-mail	patrick.tresserras@avxpharma.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.3.2	Product code	AVX-012
D.3.4	Pharmaceutical form	Eye drops, solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AVX-012 Ophthalmic Solution
D.3.9.1	CAS number	AVX012001
D.3.9.2	Current sponsor code	AVX-012
D.3.9.3	Other descriptive name	AVX-012
D.3.9.4	EV Substance Code	SUB182641
D.3.10	Strength
D.3.10.1	Concentration unit	µmole/l micromole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
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.IMP: 2
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.3.2	Product code	AVX-012
D.3.4	Pharmaceutical form	Eye drops, solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AVX-012 Ophthalmic Solution
D.3.9.1	CAS number	AVX012001
D.3.9.2	Current sponsor code	AVX-012
D.3.9.3	Other descriptive name	AVX-012
D.3.9.4	EV Substance Code	SUB182641
D.3.10	Strength
D.3.10.1	Concentration unit	µmole/l micromole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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	Eye drops, solution
D.8.4	Route of administration of the placebo	Ocular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Dry eye syndrome

Síndrome de ojo seco

E.1.1.1

Medical condition in easily understood language

Dry eye syndrome

Síndrome de ojo seco

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

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	10013777
E.1.2	Term	Dry eye syndrome
E.1.2	System Organ Class	100000004853

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part A of the study, assessing the safety of AVX-012 ophthalmic solution in subjects with dry eye syndrome.

Part B of the study, to evaluate the efficacy of the ophthalmic solution AVX-012 in the treatment of symptoms of dry eye syndrome.

Parte A del estudio, evaluar la seguridad de la solución oftálmica AVX-012 en sujetos con síndrome de ojo seco.

Parte B del estudio, evaluar la eficacia de la solución oftálmica AVX-012 en el tratamiento de síntomas del síndrome de ojo seco.

E.2.2

Secondary objectives of the trial

Part B of the study:

Confirm the safety of AVX-012 ophthalmic solution in subjects with dry eye syndrome.
Assess the efficacy of AVX-012 ophthalmic solution in terms of corneal staining, Schirmer I test, tear film break up time, and conjunctival staining findings.

Parte B del estudio:

Confirmar la seguridad de la solución oftálmica AVX-012 en sujetos con síndrome de ojo seco.
Evaluar la eficacia de la solución oftálmica AVX-012 en términos de tinción corneal, prueba de Schirmer I, tiempo de ruptura de la película lagrimal y los resultados de la tinción de la conjuntiva.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients will be included in the study if all of the following criteria are met:
Male or female subjects of at least 18 years of age.
Diagnosis of dry eye (by a health care professional) for at least 3 months prior to screening visit.
Normal lid anatomy.
Intraocular pressure less than 22 mmHg (inclusive) in each eye.
Best-corrected visual acuity measured by ETDRS in each eye of 20/200 (logMAR 1.0) or better.
Schirmer I test score of ≥ 3 mm to ≤ 9 mm/ 5 min (with anesthesia).
SANDE symptom score of 50 or more.
Total ocular staining of minimum 1 in Oxford scale with fluorescein and/or green lissamine.
Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements.

Los criterios de inclusión serán definidos con el objetivo de seleccionar a una población homogénea de pacientes con síndrome de ojo seco leve a moderado.
Los pacientes serán incluidos en el estudio si cumplen todos los siguientes criterios:
1. Hombres y mujeres adultos de >= 18 años
2. Diagnóstico de ojo seco (por un profesional de la salud) al menos 3 meses antes de la visita de selección.
3. Anatomía del párpado normal.
4. Presión intraocular inferior a 22 mmHg (incluido) en cada ojo.
5. La mejor agudeza visual corregida medida en cada ojo por el test ETDRS, de 20/200 (log MAR 1.0) o mejor.
6. Test de Schirmer I >= 3 mm a <= 9 mm / 5 min (con anestesia).
7. Cuestionario de síntomas SANDE de 50 o más.
8. Tinción ocular total en la Escala de Oxford de mínimo 1 con fluoresceína y / o verde lisamina
9. Disposición y capacidad de proporcionar el consentimiento informado por escrito antes de cualquier procedimiento relacionado con el estudio y para cumplir con todos los requisitos del estudio.

E.4

Principal exclusion criteria

Exclusion criteria will be defined ensuring that both ophthalmic and systemic criteria disqualify inappropriate subjects from inclusion in the clinical study.
Patients will be excluded for participating in this study if 1 or more of the following criteria are met:

•Ophthalmic criteria:
1.History of other than dry eye, ocular surface of moderate to severe Meibomian gland disease (grades +++ to ++++ [moderately to severely altered expressibility and secretion quality]: moderate symptoms with mild to moderate corneal staining, mainly peripheral; or marked symptoms with marked corneal staining, central in addition), chronic, or acute ophthalmic disease in either eye, including glaucoma, macular degeneration, clinically significant cataract (primary or secondary).
2.Best-corrected visual acuity score of 55 letters read or lower in each eye as measured by ETDRS (letters read method).
3.Any hypersensitivity to the use of the study product formulations or an allergy to any ingredient(s) contained within product formulations or products required while participating in the study, such as sodium fluorescein.
4.Intraocular, strabismus, or palpebral surgery or surgery in the orbit or glaucoma laser surgery within the previous 6 months.
5.History of refractive surgery in either eye (e.g., radial keratotomy, PRK, LASIK, etc.).
6.Ocular trauma within the past 6 months.
7.Ocular surgery or laser treatment within the past 3 months.
8.Evidence of ocular abnormalities in either eye that could adversely affect the safety or efficacy outcome such as:
 Eyelid anomalies that affect proper lid closure or proper blink function (e.g., ectropion or entropion).
 Corneal disorders or abnormality such as active corneal ulcer, current corneal abrasion, keratoconus, or corneal dystrophies which are actively changing or affect vision.
 Metaplasia of the ocular surface.
 Current filamentous keratitis.
 Evidence of corneal neovascularization.
 Any history of herpes simplex or herpes zoster keratitis.
 Ocular infection (bacterial, viral, or fungal), inflammation not associated with dry eye such as uveitis, iritis, active blepharitis, active allergic conjunctivitis, etc., cystoid macular edema.
9.Ocular medication of any kind, with the exception of artificial tears/gels/lubricants within the past 2 weeks of screening. Note: a minimum 90-day washout period from use of Restasis® or Ikervis® will be required.
10.Use of systemic medication that might cause dryness in the eye as a secondary effect (such as antihistaminics, hormone replacing therapies, etc.).
11.Contact lens use within 2 weeks prior to screening visit and/or unwilling to avoid contact lens use during the course of the study.
12.Unwilling to avoid use of additional artificial tears (other than study treatments) throughout the study, starting at screening visit.
13.Participation in an investigational drug or device trial within the 30 days previous to screening visit.
14.Any abnormality preventing reliable applanation tonometry of either eye.
15.Central corneal thickness greater than 600 µm by conventional pachymetry.
16.Signs of severe ocular surface diseases including corneal or conjunctival staining judged as severe by the investigator.
•Systemic criteria:
1.Clinically significant systemic disease (e.g., uncontrolled diabetes, myasthenia gravis, hepatic, renal, cardiovascular, or endocrine disorders), previous cerebrovascular accident with a significant residual motor or sensory defect, progressive neurologic disorders (Parkinsonism, dementias, multiple sclerosis, unstable acquired seizure disorders) which might interfere with the study as judged by the investigator.
2.Any systemic disease or medication that might course with known dryness in the eye.
3.Changes of systemic medication that could have a substantial effect on intraocular pressure within 30 days prior to screening or anticipated during the study.
4.Any medical condition (systemic or ophthalmic) that may, in the opinion of the investigator, preclude the safe administration of the investigational product or safe participation in this study.
5.Women of childbearing potential (those who are not surgically sterilized or postmenopausal for at least 2 years) who do not agree to abstain from sexual intercourse with a male partner or use a medically acceptable method of birth control (such as condom, diaphragm or cervical/vault cap with spermicide) until 28 days post-treatment, or those who meet any of the following conditions:

Pacientes que cumplan 1 o más de los siguientes criterios serán excluidos:
*Oftalmológicos:
1.Historia de enfermedad distinta al ojo seco, enfermedad moderada a grave de las glándulas de Meibomio, enfermedad oftálmica aguda o crónica en cualquier ojo, incluyendo glaucoma, degeneración macular, catarata clínicamente significativa (primaria o secundaria)
2.Mejor agudeza visual corregida de 55 letras leídas o menos en cada ojo medida por ETDRS (método letras leídas)
3.Cualquier hipersensibilidad a las formulaciones de los productos utilizados en el estudio, o alergia a cualquier producto o ingrediente(s) contenido dentro de las formulaciones de los productos utilizados durante su participación en el estudio, como fluoresceína sódica
4.Cirugía de estrabismo, intraocular o cirugía láser para glaucoma en los 6 meses previos
5.Historia de cirugía refractiva en cualquier ojo (queratotomía radial, PRK, LASIK)
6.Trauma ocular en los últimos 6 meses
7.Cirugía ocular o tratamiento con láser dentro de los últimos 3 meses
8.Evidencia de anormalidades oculares en cualquiera de los ojos, que puedan afectar negativamente los resultados de seguridad o eficacia, tales como:
-Anormalidades en los párpados que puedan afectar el cierre o función (ectropión o entropión)
-Trastornos corneales o anormalidades como úlcera corneal activa, abrasión corneal, queratocono o distrofia corneal que estén cambiando activamente o que afecten la visión
-Metaplasia de la superficie ocular
-Queratitis filamentosa actual
-Evidencia de neovascularización corneal
-Historia de herpes simple o de queratitis por herpes zóster
-Infección ocular (bacteriana, viral o fúngica), inflamación no asociada con ojo seco tal como: uveítis, iritis, blefaritis activa, conjuntivitis alérgica activa, etc., edema macular cistoide
9.Medicación ocular de cualquier tipo, a excepción de lágrimas artificiales/geles/lubricantes durante las últimas 2 semanas a la selección. Nota: se requerirá un mínimo de 90 días de periodo de lavado tras uso de Restasis® o Ikervis®
10.Medicación sistémica que pueda causar sequedad de ojos como efecto secundario (antihistamínicos, terapia de reemplazo hormonal)
11.Uso de lentes de contacto dentro de las 2 semanas previas a la visita de selección y/o rechazo a evitar el uso de lentes de contacto durante el estudio
12.No estar dispuesto a evitar el uso de lágrimas artificiales (distintas de los tratamientos del estudio) durante el estudio, desde la visita de selección
13.Participación en un ensayo con medicamento o dispositivo de investigación, dentro de los 30 días previos a la visita de selección
14.Prevención de cualquier anormalidad confiable por tonometría de aplanación para cualquier ojo
15.Espesor corneal central superior a 600 micras por paquimetría convencional
16.Signos de gravedad de enfermedades de la superficie ocular incluyendo tinción corneal o conjuntival juzgada de grave por el investigador
*Sistémicos:
1.Enfermedad sistémica clínicamente significativa (diabetes no controlada, miastenia gravis, trastornos hepáticos, renales, cardiovasculares o endocrinológicos), accidente cerebrovascular previo con secuelas motoras o sensitivas residuales significativas, trastorno neurológico progresivo (parkinsonismo, demencia, esclerosis múltiple, trastorno convulsivo adquirido inestable) que podrían interferir con el estudio a juicio del investigador
2.Enfermedad sistémica o medicación que pueda cursar con sequedad conocida de ojos
3.Cambios en la medicación sistémica que pueda tener efecto sustancial sobre la presión intraocular dentro de los 30 días previos a la selección o de manera prevista durante el estudio
4.Cualquier condición médica (sistémica u oftálmica) que en opinión del investigador pueda ser un obstáculo para la administración segura del producto en investigación o para la seguridad en el estudio
5.Mujeres en edad fértil (aquellas no esterilizadas quirúrgicamente o con postmenopausia de al menos 2 años) que no estén de acuerdo en abstención de relaciones sexuales con una pareja masculina o en utilizar algún método aceptado para el control de natalidad (condón, diafragma,capuchón cervical con agente espermicida), hasta 28 días después del tratamiento, o en su defecto, aquellas que cumplan culaquiera de las siguientes condiciones:
-Embarazo actual o
-Resultado positivo en el test de embarazo (en orina) en la visita de selección, o
-En período de lactancia
6.Las mujeres en edad fértil deberán tener un resultado negativo en la prueba de embarazo en orina en la selección, y estar de acuerdo en abstenerse de tener relaciones sexuales con una pareja masculina o utilizar algún método aceptado para el control de la natalidad (condón, diafragma o capuchón cervical con un agente espermicida) hasta 28 días después del tratamiento. Los hombres deben estar de acuerdo en abstenerse de tener relaciones sexuales con una pareja femenina o usar condón con espermicida hasta 28 días después del tratamiento.

E.5 End points

E.5.1

Primary end point(s)

Study part A:
The primary endpoint for the study part A will be the percentage of patients with adverse events from baseline (treatment period and post-treatment safety follow-up). They will include adverse events reported over the medical interview or evidenced on any of the following assessments:

* Vital signs: systolic blood pressure, diastolic blood pressure, and heart rate.

* Laboratory analyses:

• Hematology: hemoglobin, hematocrit, erythrocyte count, leukocyte count, and platelet count.
• Biochemistry: glucose, creatinine, bilirubin, aspartate transferase (AST), alanine transferase (ALT), gamma glutamyl transferase (GGT), total cholesterol, sodium, and potassium.
• Urine pregnancy test, for women of childbearing potential.

* Best-corrected visual acuity (ETDRS)
* Corneal anesthesia (Cochet-Bonnet)
* Intraocular pressure
* Biomicroscopy/staining (fluorescein), and ophthalmoscopy (dilated).

An independent safety committee will be in charge of assessing the tolerability of study treatments to proceed to part B.

Study part B
The primary endpoint for the study part B will be the percentage of patients achieving an improvement ≥ 20 points in the Symptom Assessment iN Dry Eye (SANDE) questionnaire according to the different dosing frequencies (TID and BID).

Estudio parte A:

La variable principal de evaluación de la parte A del estudio será el porcentaje de pacientes con eventos adversos desde la línea basal (periodo de tratamiento y seguimiento de seguridad post-tratamiento). Se incluirán eventos adversos informados durante la entrevista médica o documentados en cualquiera de las siguientes evaluaciones:

* Signos vitales: presión arterial sistólica, presión arterial diastólica y la frecuencia cardíaca.

* Análisis de laboratorio:
• Hematología: hemoglobina, hematocrito, recuento de eritrocitos, recuento de leucocitos y recuento de plaquetas.
• Bioquímica: glucosa, creatinina, bilirrubina, aspartato aminotransferasa (AST), alanino aminotransferasa (ALT), gamma-glutamil-transferasa (GGT), colesterol total, sodio y potasio.
• Prueba de embarazo en orina, para las mujeres en edad fértil.

* Mejor agudeza visual corregida (ETDRS)
* Anestesia corneal (Cochet-Bonnet)
* Presión intraocular, biomicroscopía / tinción (fluoresceína), y oftalmoscopia (dilatadas).

Un comité independiente de seguridad será el encargado de evaluar la tolerabilidad de los tratamientos del estudio para proceder a la parte B.

Estudio de la parte B:

La variable principal de evaluación de la parte B será el porcentaje de pacientes que alcanzaron una mejoría > = 20 puntos en el cuestionario de evaluación de los síntomas de ojo seco (SANDE) en relación a las diferentes pautas de administración (dos veces al día y tres veces al día).

E.5.1.1

Timepoint(s) of evaluation of this end point

Part A
Safety endpoints will be collected:

• Screening visit 0 (days -5 to 0)
• Start of treatment visit 1 (day 1 of treatment +/-2 days)
• End of treatment/early termination visit 2 (day 7 of treatment +/-2 days or early termination)
• Post-treatment safety follow-up visit 3 (1 day after the end of treatment):

Part B
Efficacy endpoints will be collected:

• Screening visit (visit 0): within the 5 days prior to starting the study treatment.
• Visits over the treatment period: at the beginning of the study treatment (visit 1: day 1 of treatment), after 7 days (visit 2) and 14 days (visit 3) of starting the treatment, and at the end of treatment (visit 4: 28 days after starting the treatment or early termination).

Las variables de seguridad se recogerán:
• Visita de selección (Días -5 a 0)
• Inicio del tratamiento visita 1 (día 1 del tratamiento +/- 2 días)
• Final del tratamiento / terminación anticipada visita 2 (día 7 de tratamiento +/- 2 días o terminación anticipada)
• Visita de seguimiento de seguridad post-tratamiento visita 3 (1 día después del final del tratamiento)

Parte B
Las variables de eficacia se recogerán:
• Visita de selección (visita 0): dentro de los 5 días antes de comenzar el tratamiento
• Las visitas durante el período de tratamiento: al comienzo del tratamiento del estudio (visita 1: día 1 de tratamiento), a los 7 (visita 2) y 14 días (visita 3) de iniciar el tratamiento y al final del tratamiento ( visita 4: 28 días después del inicio o terminación anticipada)

E.5.2

Secondary end point(s)

Study part B

Secondary endpoints will include:
• The percentage of patients with adverse events from baseline (treatment period and post-treatment safety follow-up) according to the different dosing frequencies (TID and BID).
• Changes in corneal staining, Shirmer I test, tear film break up time, and conjunctival staining over the study treatment according to the different dosing frequencies (TID and BID).

Estudio parte B:

Las variables secundarias de evaluación de la parte B incluyen:
• El porcentaje de pacientes con eventos adversos desde la línea basal (periodo de tratamiento y seguimiento de seguridad post-tratamiento) en base a las diferentes pautas de administración (dos veces al día y tres veces al día).
• Los cambios en la tinción corneal, Test de Schirmer I, el tiempo de ruptura de la película lagrimal y la tinción conjuntival durante el tratamiento del estudio de acuerdo con las diferentes pautas de administración (dos veces al día y tres veces al día).

E.5.2.1

Timepoint(s) of evaluation of this end point

Study part B

Secondary endpoints will be collected:

•AEs, changes in corneal staining and conjunctival staining:
- Screening visit (visit 0)
- Visits over the treatment period: visit 1, visit 2, visit 3 and visit 4
- Post-treatment safety follow-up (visit 5)

•Shirmer I test and tear film break up time:
- Screening visit (visit 0)
- Visits over the treatment period: visit 1, visit 2, visit 3 and visit 4

Estudio parte B

Los objetivos secundarios serán recogidos de la siguiente manera:

•AA, cambios en la tinción corneal y conjuntival:
- Visita de selección (visita 0)
- Visitas durante el período de tratamiento: visita 1, 2, 3 y 4
- Visita de seguimiento de seguridad post-tratamiento (visita 5)

•Test de Schirmer I y tiempo de ruptura de la película lagrima:
- Visita de selección (visita 0)
- Visitas durante el período de tratamiento: visita 1, 2, 3 y 4

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

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)

Yes

E.7.1.1

First administration to humans

Yes

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

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

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

Última visita última muestra

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

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:

172

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

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

172

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)

None

Ninguno

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Unolab Manufacturing
G.4.3.4	Network Country	Spain
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	OCASA
G.4.3.4	Network Country	Spain

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-10-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-08-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-12-21

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