Clinical Trials Register

Summary
EudraCT Number:	2017-004982-28
Sponsor's Protocol Code Number:	FFIS/PG/2017/03
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-03-14
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

2017-004982-28

A.3

Full title of the trial

Phase IIb prospective, unicentric, randomized, parallel, double-blind, placebo-controlled clinical trial to evaluate the intravenous infusion of prostaglandins as therapy in patients with non-arteritic anterior ischemic optic neuropathy.

Ensayo clínico en fase IIb prospectivo, unicéntrico, aleatorizado, paralelo, doble ciego, controlado con placebo para evaluar la infusión intravenosa de prostaglandinas como terapia en pacientes con neuropatía óptica isquémica anterior no arterítica.

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

PG-NAION

A.4.1

Sponsor's protocol code number

FFIS/PG/2017/03

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	Fundación para la Formación e Investigación Sanitarias de la Región de Murcia
B.1.3.4	Country	Spain
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	FFIS
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	Fundación para la Formación e Investigación Sanitaria de la Región de Murcia
B.5.2	Functional name of contact point	UICEC
B.5.3	Address:
B.5.3.1	Street Address	Luis Fontes Pagan 9, 1 planta
B.5.3.2	Town/ city	Murcia
B.5.3.3	Post code	30003
B.5.3.4	Country	Spain
B.5.4	Telephone number	34968359763
B.5.5	Fax number	34968359777
B.5.6	E-mail	lola.serna@carm.es

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Alprostadil
D.2.1.1.2	Name of the Marketing Authorisation holder	GENFARMA LABORATORIO, S.L.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Prostaglandin E1
D.3.9.1	CAS number	UK82077500
D.3.9.3	Other descriptive name	PROSTAGLANDIN E1, LIPID-ENCAPSULATED
D.3.9.4	EV Substance Code	SUB121290
D.3.10	Strength
D.3.10.1	Concentration unit	µg/kg microgram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Non-arteritic anterior ischemic optic neuropathy (NOIANA).

Neuropatía óptica isquémica anterior no arterítica (NOIANA).

E.1.1.1

Medical condition in easily understood language

Sudden loss of vision due to a decrease or interruption of blood flow to the optic nerve.

Pérdida repentina de la visión debido a una disminución o interrupción del flujo sanguíneo hacia el nervio óptico.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the efficacy of the intravenous infusion of PGE1 (Alprostadil) to improve the visual function of patients with NOIANA.
• Visual acuity assessed with ETDRS (Early Treatment Diabetic Retinopathy Study) test

Determinar la eficacia de la infusión intravenosa de PGE1 (Alprostadil) para mejorar la función visual de pacientes con NOIANA.
•Agudeza visual valorada con test ETDRS (Early Treatment Diabetic Retinopathy Study)

E.2.2

Secondary objectives of the trial

To assess the safety of the intravenous infusion of PGE1 (Alprostadil) in patients with NOIANA.
• Serious adverse events with possible, probable or safe relationship with the procedure.
• Non-serious adverse events with possible, probable or safe relationship with the procedure.
To analyze the effects of intravenous infusion of PGE1 (Alprostadil) in the evolution of patients with NOIANA based on the following criteria.
• Intraocular pressure assessed with applanation tonometry
• Visual field valued with Humphrey campimetry.
• Thickness of the layer of nerve fibers and ganglion cells of the retina assessed with optical coherence tomography.
• Fund of eye valued with biomicroscopy.
• Hemodynamic indices of the ocular arteries assessed with transorbital Doppler ultrasound.
Study the characteristics of the optic disc of the affected eye and the contralateral:
• Optical disc area and cup / disc ratio assessed with optical coherence tomography.

Evaluar la seguridad de la infusión intravenosa de PGE1 (Alprostadil) en pacientes con NOIANA.
•Acontecimientos adversos graves con relación posible, probable o segura con el procedimiento.
•Acontecimientos adversos no graves con relación posible, probable o segura con el procedimiento.
Analizar los efectos de la infusión intravenosa de PGE1 (Alprostadil) en la evolución de los pacientes con NOIANA en base a los siguientes criterios.
•Presión intraocular valorada con tonometría de aplanación
•Campo visual valorado con campimetría Humphrey.
•Grosor de la capa de fibras nerviosas y de células ganglionares de la retina valorados con tomografía de coherencia óptica.
• Fondo de ojo valorado con biomicroscopía.
• Índices hemodinámicos de las arterias oculares valorados con ecografía doppler transorbitaria.
Estudiar las características del disco óptico del ojo afecto y el contralateral:
• Área del disco óptico y relación copa/disco valorado con tomografía de coherencia óptica.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patients of both sexes between the ages of 50 and 80, both inclusive.
• Patients with the first episode of NOIANA.
• Patients with NOIANA with a time of evolution from the beginning of the clinic less than or equal to 15 days.
• Potentially fertile patients should have a negative pregnancy test in serum or urine.
• Patients who offer sufficient guarantees of adherence to the protocol.
• Patients who give written informed consent to participate in the study.

•Pacientes de ambos sexos con edad comprendida entre los 50 y los 80 años, ambas inclusive.
•Pacientes con primer episodio de NOIANA.
•Pacientes con NOIANA con un tiempo de evolución desde el inicio de la clínica menor o igual a 15 días.
•Pacientes potencialmente fértiles deberán tener una prueba de embarazo negativo en suero u orina.
•Pacientes que ofrezcan garantías suficientes de adhesión al protocolo.
•Pacientes que otorguen su consentimiento informado por escrito para participar en el estudio.

E.4

Principal exclusion criteria

• Patients with previous optic neuropathy of any etiology in the affected eye.
• Patients with previous diagnosis or signs / symptoms at the time of arteritis of the temporal artery.
• Patients with optic neuropathy with bilateral clinical presentation of any etiology.
• Patients with loss of vision due to acute hypotension in the context of a surgical intervention, acute hemorrhage or hemodynamic shock.
• Patients with severe loss of previous vision in the eye affected by ophthalmologic causes: severe cataract, glaucoma or intraocular pressure greater than 30 mmHg, severe diabetic retinopathy, macular degeneration associated with severe age.
• Patients with clinical onset in the month following major non-ocular or intraocular surgery, except phakectomy.
• Patients with abnormal elevation of ESR or CRP (> 2 times the upper limit of normal)
• Patients with creatinine levels above 1.5 mg / dL.
• Patients on steroid treatment in the month prior to the episode.
• Patients under treatment with oral anticoagulants.
• Patients on treatment with hydroxychloroquine, ethambutol, vigabatrin at any time before the episode.
• Patients in whom the use of PGE1 (Alprostadil) is contraindicated:
- Hypersensitivity to Alprostadil or to any of the excipients.
- Cardiac insufficiency grade III-IV of the NYH.
- Inadequately treated heart failure or coronary artery disease.
- Alteration of the hemodynamically relevant cardiac rhythm.
- Myocardial infarction or stroke in the 6 months prior to the start of treatment.
- Severe hypotension.
- Clinical or radiological signs of acute pulmonary edema or patients with a history of heart failure who have developed pulmonary edema.
- Severe chronic obstructive pulmonary disease (COPD) or pulmonary veno-occlusive disease (PVOD).
- Signs of acute liver injury (elevated transaminases and gamma GT) or with a history of severe liver injury.
- Patients in whom complications due to bleeding can be expected (eg, recent gastrointestinal ulcer, multiple trauma.
- Stenosis and / or insufficiency of the aortic valve or miter.
• Patients with participation in a clinical trial in the last 6 months.
• Patients with inability to understand informed consent.
• Pregnant patients, in postpartum period or during active lactation period.
• Physically fertile patients, defined as all women physiologically capable of becoming pregnant, including women whose track record, lifestyle or sexual orientation excludes intercourse with a male and women whose partners have been sterilized with vasectomy or other methods, NOT TO BE WHO are using a reliable contraceptive method (see Appendix C). This contraceptive method can be:
- Complete abstinence from sexual intercourse
- Surgical sterilization (tubal ligation)
- Surgical sterilization of the couple (vasectomy)
- Oral implanted or injectable hormonal contraceptives *

* Because hormonal contraceptives present a risk of thrombosis, other effective contraceptive methods should be considered.

These reliable contraceptive methods must be maintained during your participation in the study.

•Pacientes con neuropatía óptica previa de cualquier etiología en el ojo afecto.
•Pacientes con diagnóstico previo o signos/síntomas en el momento de arteritis de la arteria temporal.
•Pacientes con neuropatía óptica con presentación clínica bilateral de cualquier etiología.
•Pacientes con pérdida de visión por hipotensión aguda en el contexto de una intervención quirúrgica, hemorragia aguda o shock hemodinámico.
•Pacientes con pérdida severa de visión previa en el ojo afecto de causa oftalmológica: catarata severa, glaucoma o presión intraocular mayor de 30 mmHg, retinopatía diabética de grado severo, degeneración macular asociada a la edad de grado severo.
•Pacientes con inicio de clínica en el mes siguiente a una cirugía mayor no-ocular o intraocular, excepto faquectomía.
•Pacientes con elevación anormal de VSG o PCR (>2 veces el límite superior de la normalidad)
•Pacientes con niveles de creatinina por encima de 1.5 mg/dL.
•Pacientes en tratamiento con esteroides en el mes previo del episodio.
•Pacientes en tratamiento con anticoagulantes orales.
•Pacientes en tratamiento con hidroxicloroquina, etambutol, vigabatrina en cualquier momento antes del episodio.
•Pacientes en los que el uso de PGE1 (Alprostadil) está contraindicado:
-Hipersensibilidad al Alprostadil o a alguno de los excipientes.
-Insuficiencia cardiaca grado III-IV de la NYH.
-Insuficiencia cardiaca inadecuadamente tratada o enfermedad arterial coronaria.
-Alteración del ritmo cardiaco relevante hemodinámicamente.
-Infarto de miocardio o derrame cerebral en los 6 meses previos al comienzo del tratamiento.
-Hipotensión severa.
-Signos clínicos o radiológicos de edema pulmonar agudo o pacientes con historia de insuficiencia cardiaca que hayan desarrollado edema pulmonar.
-Enfermedad pulmonar obstructiva crónica severa (EPOC) o enfermedad veno-oclusiva pulmonar (EPVO).
-Signos de lesión hepática aguda (transaminasas y gamma GT elevadas) o con una historia de lesión hepática severa.
-Pacientes en los que se pueda esperar complicaciones por sangrado (ej. úlcera gastrointestinal reciente, politraumatismo.
-Estenosis y/o insuficiencia de la válvula aórtica o mitra.
•Pacientes con participación en un ensayo clínico en los últimos 6 meses.
•Pacientes con incapacidad para comprender el consentimiento informado.
•Pacientes embarazadas, en periodo postparto o en periodo de lactancia activa.
•Pacientes físicamente fértiles, definidas como todas las mujeres fisiológicamente capaces de quedarse embarazadas, incluyendo las mujeres cuya trayectoria, estilo de vida u orientación sexual excluya el coito con un varón y mujeres cuyas parejas hayan sido esterilizados con vasectomía u otros métodos, A NO SER QUE estén utilizando un método anticonceptivo fiable (véase Apéndice C). Dicho método anticonceptivo puede ser:
-Abstinencia completa de coito sexual
-Esterilización quirúrgica (ligadura de trompas)
-Esterilización quirúrgica de la pareja (vasectomía)
-Anticonceptivos hormonales implantados o inyectables, orales*

* Debido a que los anticonceptivos hormonales presentan un riesgo de trombosis, deberían considerarse otros métodos anticonceptivos eficaces.

Dichos métodos anticonceptivos fiables deberán mantenerse durante su participación en el estudio.

E.5 End points

E.5.1

Primary end point(s)

Efficacy assessment:
•Visual acuity
ETDRS (Early Treatment Diabetic Retinopathy Study) Test: It allows to determine the best monocular visual acuity in mesopic conditions, for it the illuminated box ESV-3000, which allows the photopic and mesopic illumination (85 cd / m2 or 3 cd / m2) will be used. . It will be done at 4 m and 1 m when the patient read less than 15 letters at 4 m. The test will end when the patient is unable to read all the letters of a line (5), collecting the total number of letters correctly identified until that moment. Subsequently, the AV will be moved from the number of letters read to the LogMar Scale (+1.0, -0.3) for far vision with correction.
- Visual acuity with correction (AVcc) - distant vision: Nº letters, LogMar.

Valoración de eficacia:

•Agudeza visual
Test ETDRS (Early Treatment Diabetic Retinopathy Study): Permite determinar la mejor agudeza visual monocular en condiciones mesópicas, para ello se utilizará la caja iluminada ESV-3000, que permite la iluminación fotópica y mesópica (85 cd/ m2 o 3 cd/m2). Se realizará a 4 m y a 1 m cuando el paciente lea menos de 15 letras a 4 m. El test finalizará cuando el paciente sea incapaz de leer la totalidad de letras de una línea (5), recogiéndose el total de letras correctamente identificadas hasta ese momento. Posteriormente se trasladará la AV desde nº de letras leídas a Escala LogMar (+1.0, -0.3) para visión lejana con corrección.
- Agudeza visual con corrección (AVcc) - visión lejana: Nº letras, LogMar.

E.5.1.1

Timepoint(s) of evaluation of this end point

It will be performed on all patients at the times specified in the protocol: at the screening visit, the day after the end of treatment, at 30 days and at 3 months.

Se realizará en todos los pacientes en los tiempos que quedan especificados en el protocolo: en la visita de selección, al día siguiente de finalizar el tratamiento, a los 30 días y a los 3 meses.

E.5.2

Secondary end point(s)

Security assessment:
• Rate of serious adverse events with possible, probable or defined relationship with the procedure.
• Rate of non-serious adverse events with possible, probable or defined relationship with the procedure.
Assessment of the evolution of the disease:
• Optical disc area and cup / disc ratio
•Visual field
• Thickness of the layer of nerve fibers and ganglion cells of the retina
• Fund of eye
• Hemodynamic indices of the ocular arteries
•Intraocular pressure

Valoración de seguridad:
•Tasa de Acontecimientos adversos graves con relación posible, probable o definida con el procedimiento.
•Tasa de Acontecimientos adversos no graves con relación posible, probable o definida con el procedimiento.
Valoración de la evolución de la enfermedad:
•Área del disco óptico y relación copa/disco
•Campo visual
•Grosor de la capa de fibras nerviosas y de células ganglionares de la retina
•Fondo de ojo
•Índices hemodinámicos de las arterias oculares
•Presión intraocular

E.5.2.1

Timepoint(s) of evaluation of this end point

Safety assessment: AA and AAG
In all study visits once the informed consent has been signed.
Assessment of the evolution of the disease:
• Intraocular pressure: It will be done at the screening visit, at 30 days and at 3 months.
• Visual field: It will be done at the screening visit, at 30 days and at 3 months.
• Thickness of the layer of nerve fibers and ganglion cells of the retina: This will be done at the screening visit, at 30 days and at 3 months.
• Fund of eye: It will be realized in the visit of selection, to the 30 days and to the 3 months.
• Hemodynamic indices of the ocular arteries: This will be done during the screening visit and the day after finishing the treatment.
• Area of the optical disc and cup / disc ratio: It will be done in the selection visit.

Valoración de seguridad:AA y AAG
En todas las visitas del estudio una vez firmado el consentimiento informado.
Valoración de la evolución de la enfermedad:
•Presión intraocular :Se realizará en la visita de selección, a los 30 días y a los 3 meses.
•Campo visual :Se realizará en la visita de selección, a los 30 días y a los 3 meses.
•Grosor de la capa de fibras nerviosas y de células ganglionares de la retina:Se realizará en la visita de selección, a los 30 días y a los 3 meses.
•Fondo de ojo:Se realizará en la visita de selección, a los 30 días y a los 3 meses.
•Índices hemodinámicos de las arterias oculares:Se realizará en la visita de selección y al día siguiente de finalizar el tratamiento.
•Área del disco óptico y relación copa/disco:Se realizará en en la visita de selección.

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

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

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS: last visit of the last subject undergoing the trial

Última visita del último paciente reclutado

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

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.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

Ninguna

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

2018-05-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-18

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
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