Clinical Trials Register

Summary
EudraCT Number:	2014-004042-96
Sponsor's Protocol Code Number:	32-009
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-02-15
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

2014-004042-96

A.3

Full title of the trial

A Phase IIIb, Multinational, Multicenter, Open-Label Extension Study
Assessing the Long-Term Safety of PRN Intravitreal Injections of DE-109 in
Subjects with Non-Infectious Uveitis of the Posterior Segment of the Eye
Who Have Participated in the SAKURA Development Program

Studio di estensione, in aperto, multicentrico, multinazionale, di fase IIIb per valutare la sicurezza a lungo termine di iniezioni intravitreali di DE-109 pro re nata (PRN) in soggetti con uveite non infettiva del segmento posteriore dell'occhio che hanno partecipato al programma di sviluppo SAKURA

A.3.1

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

A Phase III extension study to evaluate the long-term safety of DE-109 in
subjects with non-infectious uveitis of the posterior segment of the eye
who have participated in a previous SAKURA study

Studio di estensione di fase 3 per valutare la sicurezza a lungo termine di DE-109 in soggetti con uveite non infettiva del segmento posteriore dell'occhio che hanno partecipato al precedente studio SAKURA

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

32-009

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN00000000

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02251938

A.5.3

WHO Universal Trial Reference Number (UTRN)

U0000-0000-0000

A.5.4

Other Identifiers

Name:

Number:

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 INCORPORATED
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	Santen Incorporated
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	Santen Incorporated
B.5.2	Functional name of contact point	Crystal Browning
B.5.3	Address:
B.5.3.1	Street Address	2100 Powell Street, 16th Floor
B.5.3.2	Town/ city	Emeryville, CA
B.5.3.3	Post code	94608
B.5.3.4	Country	United States
B.5.4	Telephone number	001 415 268 9010
B.5.5	Fax number	001 510 655 5687
B.5.6	E-mail	CBrowning@Santeninc.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	DE-109
D.3.2	Product code	DE-109
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Rapamycin
D.3.9.1	CAS number	53123-88-9
D.3.9.2	Current sponsor code	DE-109
D.3.9.3	Other descriptive name	RAPA
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.0
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

non -infectious Uveitis of the Posterior Segment of the Eye

uveite non infettiva del segmento posteriore dell'occhio

E.1.1.1

Medical condition in easily understood language

active, non -infectious Uveitis

uveite attiva non infettiva

E.1.1.2

Therapeutic area

Body processes [G] - Ocular Physiological Phenomena [G14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10036370
E.1.2	Term	Posterior uveitis
E.1.2	System Organ Class	100000004862

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 objective of this extension study is to evaluate the long-term safety
of treatment with DE-109 (440 μg) in subjects with non-infectious
uveitis of the posterior segment of the eye who have participated in the
SAKURA development program.

L'obiettivo di questo studio di estensione è valutare la sicurezza a lungo termine del trattamento con DE-109 (440 μg) in soggetti con uveite non infettiva del segmento posteriore dell'occhio che hanno partecipato al programma di sviluppo SAKURA.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

At Day 1, a subject from the SAKURA program must meet all of the
following inclusion criteria:
1. Have a subject number from participation in the SAKURA program
2. Exited the SAKURA program under Amendment 05
3. Have received at least two injections of DE-109 in the first five months
of the SAKURA program
4. Received clinical benefit from treatment with DE-109 as determined
by the Investigator
5. Female participants of childbearing potential must not be pregnant or
breast-feeding, have a negative pregnancy test at Day 1 and must be
willing to undergo pregnancy tests throughout the study
6. Both female participants of childbearing potential and male
participants able to father children must have (or have a partner who
has) had a hysterectomy or vasectomy, must abstain from
intercourse or must agree to practice acceptable methods of
contraception throughout the course of the study
7. Ability to give informed consent and attend all study visits

Il Giorno 1, un soggetto proveniente dal programma SAKURA deve soddisfare tutti i criteri di inclusione seguenti:
1. Possedere un numero di soggetto ottenuto con la partecipazione al programma SAKURA
2. Essere uscito dal programma SAKURA ai sensi dell'Emendamento 05
3. Aver ricevuto almeno due iniezioni di DE-109 nei primi cinque mesi del programma SAKURA
4. Aver ottenuto un beneficio clinico dal trattamento con DE-109 secondo quanto determinato dallo Sperimentatore
5. Le partecipanti di sesso femminile in età fertile non devono essere in stato di gravidanza o di allattamento, devono presentare un test di gravidanza negativo al Giorno 1 e acconsentire di sottoporsi a test di gravidanza durante l'intero studio
6. Sia le partecipanti di sesso femminile in età fertile, sia i partecipanti di sesso maschile in grado di generare figli devono sottoporsi a isterectomia o vasectomia (oppure avere un partner/una partner che si sia sottoposto/a a tali procedure), si devono astenere dai rapporti sessuali o devono accettare di usare metodi contraccettivi accettabili per tutta la durata dello studio
7. Capacità di fornire il consenso informato e di partecipare a tutte le visite dello studio

E.4

Principal exclusion criteria

A subject from the SAKURA program with any of the following conditions
is not eligible to participate in the study:
Ocular:
1. Active infectious uveitis. However, if the uveitis is the consequence of
a previous infectious disease, such as tuberculosis, the previous
infectious disease must be confirmed as no longer
active.
2. Any implantable corticosteroid-eluting device (e.g. Ozurdex, I-vation,
Iluvien, fluocinolone acetonide [FA] intravitreal implant) in the study
eye:
a. If the Investigator confirms the device has no demonstrable efficacy
as indicated in the package insert, the subject will be eligible
b. If a Medidur implant, Iluvien or Retisert has been implanted no less
than 3 years and 90 days prior to Day 1, the subject will be eligible
c. If a Ozurdex implant has been implanted no less than 180 days prior
to Day 1, the subject will be eligible
3. Clinically suspected or confirmed central nervous system or ocular
lymphoma
4. Progressive glaucoma which is unresponsive to treatment.
5. Intraocular pressure of > 21 mmHg while on medical therapy, or
chronic hypotony (< 6 mmHg)
6. Any significant ocular disease that could compromise vision in the
study eye. These include, but are not limited to:
a. Diabetic retinopathy: proliferative diabetic retinopathy (PDR) or nonproliferative
diabetic retinopathy (NPDR) that compromises vision.
Subjects with NPDR or PDR that does not compromise vision are not
excluded from the study;
b. Wet age-related macular degeneration;
c. Myopic degeneration with active subfoveal choroidal
neovascularization
7. Any of the following treatments to the study eye:
a. Intravitreal injections in the past 14 days
b. Intravitreal injections of DE-109 in the past 60 days
8. Ocular surgery within the past 30 days
9. Ocular or periocular infection in either eye
10. History of or active herpetic infection in the study eye or adnexa
11. Presence of known active, inactive toxoplasmosis or toxoplasmosis
scar in either eye
12. Presence of any form of ocular malignancy in the either eye including
choroidal melanoma
13. History of vitrectomy in the study eye
Non-Ocular:
14. Allergy or hypersensitivity to study drug product or other study
related procedures/medications
15. Participation in other investigational drug (SAKURA is an exception)
or device clinical trials within 30 days prior to Day 1, or planning to
participate in other investigational drug or device
clinical trials for the entire duration of the study. This includes both
ocular and non-ocular clinical trials.
16. Any recent systemic infection within 30 days of Day 1
17. Known to be immunocompromised
18. History of cytomegalovirus infection or clinical evidence of active
cytomegalovirus infection at Day 1
19. History of other disease, metabolic dysfunction, physical examination
finding, or clinical laboratory finding giving reasonable suspicion of a
disease condition that contraindicates the use of an investigational drug,
might affect the interpretation of the results of the study, or renders the
subject at high risk for treatment complications 20. Malignancy in remission for less than 5 years prior to study
participation (except basal cell or squamous cell skin cancer, or treated
melanoma of the skin less than 24 months since last
treatment)
21. Females who are pregnant or lactating and females of child-bearing
potential who are not using adequate contraceptive precautions (i.e.,
intrauterine device, oral contraceptives, barrier
method, or other contraception deemed adequate by the Investigator)
22. Use of medically prescribed marijuana or other illegal medication
23. Active systemic sarcoidosis within the last 30 months (i.e. subjects
with uveitis secondary to sarcoidosis will be eligible as long as systemic
sarcoidosis is not active and systemic
immunosuppressive therapy has not been given in the last 30 months)
24. Therapeutic radiation to the head or neck within 90 days prior to Day
1 and throughout the study.
In addition, the Investigator or Santen Medical Monitor may declare a
subject ineligible for any sound reason.

Un soggetto del programma SAKURA con una qualsiasi delle condizioni seguenti non è idoneo a partecipare allo studio:
Oculare:
1. Uveite infettiva attiva. Tuttavia, se l'uveite è la conseguenza di una malattia infettiva precedente, come la tubercolosi, tale malattia infettiva precedente deve essere dichiarata non più attiva.
2. Qualsiasi dispositivo impiantabile di eluizione di corticosteroidi (ad es. Ozurdex, I-vation, Iluvien, impianto intravitreale fluocinolone acetonide [FA]) nell'occhio oggetto di studio:
a. Se lo Sperimentatore conferma che il dispositivo è privo di efficacia dimostrabile, come indicato nel foglietto illustrativo, il soggetto sarà idoneo
b. Se un impianto Medidur, Iluvien o Retisert è stato impiantato non meno di 3 anni e 90 giorni prima del Giorno 1, il soggetto sarà idoneo
c. Se un impianto Ozurdex è stato impiantato non meno di 180 giorni prima del Giorno 1, il soggetto sarà idoneo
3. Sospetto o conferma a livello clinico di linfoma del sistema nervoso centrale o linfoma oculare
4. Glaucoma in progressione che non risponde al trattamento
5. Pressione intraoculare > 21 mmHg durante la terapia medica oppure ipotonia cronica (< 6 mmHg)
6. Qualsiasi malattia oculare significativa che potrebbe compromettere la vista nell'occhio oggetto di studio. Queste comprendono, a titolo esemplificativo ma non esaustivo:
a. Retinopatia diabetica: retinopatia diabetica proliferativa (PDR) o retinopatia diabetica non proliferativa (NPDR) che compromette la vista. I soggetti con NPDR o PDR che non compromette la vista non sono esclusi dallo studio;
b. Degenerazione maculare umida legata all'età;
c. Degenerazione miopica con neovascolarizzazione coroideale subfoveale attiva
7. Uno qualsiasi dei seguenti trattamenti per l'occhio oggetto di studio:
a. Iniezioni intravitreali nei 14 giorni precedenti
b. Iniezioni intravitreali di DE-109 nei 60 giorni precedenti
8. Intervento chirurgico all'occhio nei 30 giorni precedenti
9. Infezione oculare o perioculare in uno dei due occhi
10. Anamnesi di oppure infezione erpetica attiva nell'occhio oggetto di studio o annessi
11. Presenza di nota toxoplasmosi inattiva, attiva o cicatrice da toxoplasmosi in uno dei due occhi
12. Presenza di una forma qualsiasi di malignità oculare in uno degli occhi, incluso melanoma della coroide
13. Anamnesi di vitrectomia nell'occhio oggetto di studio
Non oculari:
14. Allergia o ipersensibilità al prodotto farmaceutico sperimentale oppure ad altri procedimenti/farmaci correlati allo studio
15. Partecipazione ad altre sperimentazioni cliniche su farmaci o dispositivi sperimentali (SAKURA costituisce un'eccezione) nei 30 giorni precedenti il Giorno 1, oppure previsione di partecipare ad altre sperimentazioni cliniche su farmaci o dispositivi sperimentali per l'intera durata dello studio. Sono comprese sperimentazioni cliniche sia oculari, che non oculari.
16. Qualsiasi infezione sistemica recente nei 30 giorni precedenti il Giorno 1
17. Immunocompromissione nota
18. Anamnesi di infezione da citomegalovirus o evidenza clinica di infezione da citomegalovirus attiva al Giorno 1
19. Anamnesi di altra malattia, disfunzione metabolica, risultato di esami obiettivi o risultato di analisi cliniche di laboratorio che fornisca un ragionevole sospetto di una malattia o condizione che costituirebbe una controindicazione all’uso di un farmaco sperimentale o che potrebbe influire sull’interpretazione dei risultati dello studio o mettere il paziente a rischio di gravi complicazioni legate al trattamento
20. Tumore maligno in remissione da meno di 5 anni dalla partecipazione allo studio (tranne carcinoma cutaneo a cellule basali o a cellule squamose, oppure melanoma cutaneo curato meno di 24 mesi prima dell'ultimo trattamento)
21. Le donne in stato di gravidanza o di allattamento e le donne in età fertile che non stanno impiegando contraccettivi adeguati (cioè dispositivo endouterino, contraccettivi orali, metodo barriera o altro contraccettivo giudicato adatto dallo Sperimentatore)
22. Uso di marijuana prescritta per ragioni mediche o di altri farmaci illegali
23. Sarcoidosi sistemica attiva negli ultimi 30 mesi (ovvero i soggetti con uveite secondaria alla sarcoidosi saranno idonei se la sarcoidosi sistemica non è attiva e la terapia immunosoppressiva sistemica non è stata somministrata negli ultimi 30 mesi)
24. Terapia con radiazioni alla testa o al collo nei 90 giorni precedenti il Giorno 1 e per l'intera durata dello studio
Inoltre lo Sperimentatore o il Responsabile medico di Santen possono dichiarare un soggetto non idoneo per una qualsiasi ragione valida.

E.5 End points

E.5.1

Primary end point(s)

Collection of long term safety data on DE-109 (440 μg) dose

Raccolta dei dati sulla sicurezza a lungo termine relativi al dosaggio di DE- 109 (440 μg)

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months or commercial availability of DE-109, whichever comes first

12 mesi oppure disponibilità in commercio di DE-109, a seconda dell'evento che si verifica per primo

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

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

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

Austria

France

Germany

Italy

Poland

Turkey

United States

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

All subjects will exit the study at Month 12, unless terminated early

Tutti i soggetti usciranno dallo studio al Mese 12, salvo in caso di conclusione anticipata

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

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

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

170

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

200

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)

standard of care

terapia standard

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

2015-06-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-05-07

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
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