Clinical Trials Register

Summary
EudraCT Number:	2017-002660-41
Sponsor's Protocol Code Number:	NVG14L127
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-06-18
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-002660-41

A.3

Full title of the trial

A Phase IIIb, prospective, interventional, multicentre, three-year study to explore the long-term evolution of sign and symptoms, and occurrence of complications in Dry Eye Disease patients with severe keratitis receiving IKERVIS® (1mg/ml ciclosporin) eye drops

Studio di fase IIIb, prospettico, interventistico, multicentrico, della durata di tre anni volto a valutare l’evoluzione a lungo termine dei segni e sintomi, e l’insorgenza di complicanze in pazienti affetti da sindrome dell’occhio secco associata a cheratite grave trattati con il collirio IKERVIS® (ciclosporina 1 mg/ml)

A.3.1

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

A three-year study to explore the long-term evolution of sign and symptoms of severe Dry Eye Disease in patients receiving IKERVIS® (1mg/ml ciclosporin) eye drops.

Studio di tre anni volto a valutare l’evoluzione a lungo termine dei segni e sintomi associati alla sindrome dell’occhio secco grave in pazienti trattati con il collirio IKERVIS® (ciclosporina 1 mg/ml)

A.3.2

Name or abbreviated title of the trial where available

Studio di tre anni volto a valutare l’evoluzione a lungo termine dei segni e sintomi associati alla

A.4.1

Sponsor's protocol code number

NVG14L127

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	SANTEN SAS
B.1.3.4	Country	France
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	SANTEN SAS
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	SANTEN SAS
B.5.2	Functional name of contact point	Global Regulatory Affairs Europe
B.5.3	Address:
B.5.3.1	Street Address	Genavenir IV, 1 Rue Pierre Fontaine
B.5.3.2	Town/ city	Evry
B.5.3.3	Post code	91058
B.5.3.4	Country	France
B.5.6	E-mail	regulatoryaffairs@santen.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	Yes
D.2.1.1.1	Trade name	IKERVIS 1 mg/mL eye drops, emulsion
D.2.1.1.2	Name of the Marketing Authorisation holder	SANTEN Oy
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	N.A.
D.3.2	Product code	[N.A.]
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	CICLOSPORINA
D.3.9.1	CAS number	59865-13-3
D.3.9.2	Current sponsor code	DE-076B
D.3.9.3	Other descriptive name	NOVA22007
D.3.9.4	EV Substance Code	SUB06250MIG
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	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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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 DISEASE WITH SEVERE KERATITIS

Sindrome dell'occhio secco associata a cheratite grave

E.1.1.1

Medical condition in easily understood language

Dry Eye Disease with a severly inflamed cornea

Sindrome dell'occhio secco associata a infiammazione della cornea

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	PT
E.1.2	Classification code	10023332
E.1.2	Term	Keratitis
E.1.2	System Organ Class	10015919 - Eye disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1) To evaluate the long-term efficacy of a continuous treatment of IKERVIS® (1mg/mL ciclosporin) eye drops in adult dry eye disease (DED) patients with severe keratitis on corneal sign and DED symptoms,
and to estimate the lag time (if any) to improvement in symptoms (if any)
2) To assess the ocular surface complications over the three-year study period.

1) Valutare l’efficacia a lungo termine di un trattamento continuo con il collirio IKERVIS® (ciclosporina 1 mg/ml) in pazienti adulti affetti da sindrome dell’occhio secco (dry eye disease, DED) associata a cheratite grave con segni e sintomi corneali e di DED, e stimare il tempo di latenza (se presente) al miglioramento dei sintomi.
•2) Valutare le complicanze a livello della superficie oculare nell’arco del periodo di studio di tre anni.

E.2.2

Secondary objectives of the trial

1) To evaluate the efficacy parameters (signs and symptoms), the ocular surface complications, and the quality of life over treatment Periods 1 and 2.
2) To evaluate the safety and tolerability of IKERVIS® (1mg/mL ciclosporin) eye drops treatment over the three-year study period.

1) Valutare, i parametri di efficacia (segni e sintomi), le complicanze a livello della superficie oculare e la qualità della vita nell’arco dei Periodi 1 e 2 di trattamento.
2) Valutare la sicurezza e la tollerabilità del trattamento con il collirio IKERVIS® (ciclosporina 1 mg/ml) nell’arco del periodo di studio di tre anni.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) In the opinion of the investigator, the patient is capable of understanding and complying with protocol requirements.
2) The patient has signed and dated a written informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3) Male or female patient is aged 18 years or above.
4) At least 4 weeks of use of tear substitutes prior to the Baseline Visit.
5) DED patients with severe keratitis
6) Patient must be willing and able to undergo and return for scheduled study-related examinations.

1) Secondo il parere dello sperimentatore, il paziente è in grado di comprendere e rispettare i requisiti del protocollo.
2)Il paziente ha firmato e datato un modulo di consenso informato scritto ed eventuali autorizzazioni sulla privacy richieste prima dell’avvio di qualsiasi procedura dello studio.
3) Il paziente di sesso maschile o femminile ha età pari o superiore a 18 anni.
4)Il paziente ha usato sostituti lacrimali per almeno 4 settimane prima della Visita di basale.
5) Il paziente è affetto da DED associata a cheratite grave
6)Il paziente deve essere disposto e in grado di sottoporsi agli esami correlati allo studio in programma e di ritornare presso la struttura sanitaria ai fini dell’esecuzione di tali esami.

E.4

Principal exclusion criteria

1) Best corrected distance visual acuity (BCDVA) score = 20/200 Snellen in each eye.
2) Presence or history of any systemic or ocular disorder, condition or disease that could possibly interfere with the conduct of the required study procedures or the interpretation of study results or judged by the investigator to be incompatible with the study (e.g., diabetes with glycemia out of range, thyroid malfunction, uncontrolled autoimmune disease, current systemic infections, ocular infection…).
3) Known hypersensitivity to one of the components of the study or procedural medications (e.g., fluorescein, etc...).
4) History of ophthalmic malignancy.
5) History of malignancy (other than ophthalmic) in the last 5 years
6) Any change in systemic immunosuppressant drugs within 30 days before the Baseline Visit or anticipated change during the course of the study.
7) Pregnancy or lactation at the Baseline Visit.8
8) Women of childbearing potential not using a medically acceptable, highly effective method of birth control (such as hormonal implants, injectable or oral contraceptives together with condoms, some intrauterine devices, sexual abstinence or vasectomised partner) from the Baseline Visit throughout the conduct of the study treatment periods and up to 2 weeks after the study end. Post-menopausal women (two years without menstruation) do not need to use any method of birth control.
9) Participation in a clinical trial with an investigational substance within the past 30 days prior to Baseline Visit.
10)Participation in another clinical study at the same time as the present study.

1) Punteggio della migliore acuità visiva corretta a distanza (Best Corrected Distance Visual Acuity, BCDVA) = 20/200 punteggio Snellen in ciascun occhio.
2) Presenza o anamnesi di qualsiasi disturbo, condizione o patologia oculare o sistemica che potrebbe potenzialmente interferire con la conduzione delle procedure dello studio previste o con l’interpretazione dei risultati dello studio o, a giudizio dello sperimentatore, incompatibile con lo studio (ad esempio, diabete con glicemia non compresa nel range, problemi alla tiroide, malattia autoimmune incontrollata, infezioni sistemiche in corso, infezione oculare...).
3) Ipersensibilità nota a uno dei componenti dei farmaci procedurali o di studio (ad es. la fluoresceina, ecc.).
4) Anamnesi di neoplasie maligne oftalmiche.
5) Anamnesi di neoplasie maligne (non oftalmiche) negli ultimi 5 anni.
6) Modifiche di eventuali farmaci immunosoppressori sistemici entro 30 giorni dalla Visita basale o modifiche previste nel corso dello studio.
7) Gravidanza o allattamento alla Visita basale.
8) Donne potenzialmente fertili che non fanno uso di un metodo anticoncezionale altamente efficace ed accettabile sotto il profilo medico (quali impianti ormonali, contraccettivi orali o iniettabili abbinati a preservativi, alcuni dispositivi intrauterini, astinenza sessuale o partner sottoposto a vasectomia) a partire dalla Visita basale, per tutta la durata dei periodi di trattamento dello studio e sino a 2 settimane dopo la conclusione della ricerca. Le donne in post-menopausa (due anni senza mestruazioni) non sono tenute ad usare alcun metodo anticoncezionale.
9) Partecipazione a una sperimentazione clinica con una sostanza sperimentale entro gli ultimi 30 giorni dalla Visita basale.
10)Partecipazione concomitante ad un’altra sperimentazione clinica durante il presente studio.

E.5 End points

E.5.1

Primary end point(s)

1) The correlation between mean change from baseline in CFS score and symptoms
2) Frequenza degli eventi e tempo di insorgenza delle complicanze a livello della superficie oculare

1) Correlazione tra la variazione media rispetto al basale del punteggio CFS e dei sintomi

E.5.1.1

Timepoint(s) of evaluation of this end point

Throughout the study

Nell’intero studio:

E.5.2

Secondary end point(s)

Efficacy:
• CFS score and change from baseline at each visit
• Conjunctival fluorescein staining score and change from baseline at
each visit
• symptoms score and change from baseline at each visit
• TBUT and change from baseline at each visit
• Schirmer test and change from baseline
• Use of Artificial Tears
• Incidence and severity of ocular and systemic adverse events (AEs)
over the three-year study period.

E.5.2.1

Timepoint(s) of evaluation of this end point

Period 1- Baseline to month 12
Period 2 - Month 12 to month 36

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

Yes

E.8.1.7.1

Other trial design description

Period 1 -Open; Period 2 - double-blind

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

Information not present in EudraCT

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

Russian Federation

Turkey

France

Italy

Poland

Spain

Czechia

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

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.1.1.1

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:

175

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

175

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

105

F.4.2

For a multinational trial

F.4.2.1

In the EEA

205

F.4.2.2

In the whole clinical trial

350

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

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

2019-02-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-19

P. End of Trial
P.	End of Trial Status	Ongoing

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