Clinical Trials Register

Summary
EudraCT Number:	2019-003426-24
Sponsor's Protocol Code Number:	GLC02-19
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:	2020-07-30
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2019-003426-24

A.3

Full title of the trial

24-hour efficacy and tolerability of the tafluprost-timolol fixed association without preservatives in glaucomatous or ocular hypertensive patients already treated with latanoprost preserved with BAK. A Prospective, open study of 3 months duration.

Efficacia nelle 24 ore e tollerabilità dell’associazione fissa tafluprost –timololo senza conservanti nei pazienti glaucomatosi o ipertesi oculari già in trattamento con latanoprost conservato con BAK. Studio prospettico in aperto della durata di 3 mesi.

A.3.1

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

3-months study to evaluate the efficacy and tolerability of the drug tafluprost –timolol without preservatives in people with glaucoma or high pressure in the eyes that have already taken latanoprost with preservative.

Studio della durata di 3 mesi per valutare l'efficacia e la tollerabilità del farmaco tafluprost –timololo senza conservanti in persone con glaucoma o pressione alta agli occhi che hanno già assunto latanoprost con conservante.

A.3.2

Name or abbreviated title of the trial where available

HERO

A.4.1

Sponsor's protocol code number

GLC02-19

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	IRCCS FONDAZIONE G.B. BIETTI PER LO STUDIO E LA RICERCA IN OFTALMOLOGIA ONLUS
B.1.3.4	Country	Italy
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	Santen d SA
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Link Neuroscience and Health Care srl - L.N.Age srl
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	Via Luigi Rizzo, 62
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00136
B.5.3.4	Country	Italy
B.5.6	E-mail	info@lnage.it

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	LOYADA - "15 MICROGRAMMI/ML + 5 MG/ML COLLIRIO, SOLUZIONE" 30 X 0,3ML CONTENITORI MONODOSE IN LDPE
D.2.1.1.2	Name of the Marketing Authorisation holder	Santen Italy srl
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Loyada
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	TAFLUPROST
D.3.9.2	Current sponsor code	N/A
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TIMOLOLO MALEATO
D.3.9.2	Current sponsor code	N/A
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	5
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

Glaucoma or ocular hypertension

Glaucoma o ipertensione oculare

E.1.1.1

Medical condition in easily understood language

Glaucoma or high pressure in the eyes

Glaucoma o pressione alta negli occhi

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	HLGT
E.1.2	Classification code	10018307
E.1.2	Term	Glaucoma and ocular hypertension
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

The primary objective is to evaluate the effectiveness in reducing the mean 24-hour IOP of the preservative-free fixed combination of Tafluprost 0.0015% and Timolol 0.5% administered once at night (8pm) in POAG or OHT patients suffering from mild OSD and requiring further IOP reduction while in topical treatment with BAK-preserved Latanoprost 0.05 mg/ml.

L'obiettivo primario è valutare l'efficacia nel ridurre la IOP media nelle 24 ore della combinazione fissa priva di conservanti di Tafluprost 0,0015% e Timololo 0,5% somministrata una volta di sera (8pm) in pazienti con POAG o OHT che soffrono di lieve OSD e che richiedono ulteriori riduzione della IOP durante il trattamento topico con Latanoprost conservato con BAK 0,05 mg / ml.

E.2.2

Secondary objectives of the trial

1) The reduction of IOP at each time of the 24-hour curve;
2) The value of the reduction of the IOP of the 24 hours and at each time point;
3) Daytime reduction and night of the IOP;
4) Patients achieving IOP reductions in average IOP of 24h;
5) Changes in the damage to the cornea and of the dry eye disease;
6) Changes of the dry eye disease;
7) Change in number and activation of corneal and conjunctival dendritic involved in the production of
the lachrymal film;
8) Change in the number of conjunctival goblet cells involved in the production of the lachrymal film
9) Changes in quality of life.

1. La riduzione di IOP in ogni momento della curva delle 24 ore;
2. Il valore della riduzione dell'IOP delle 24 ore e in ogni momento
punta;
3. Riduzione diurna e notturna dell'IOP;
4. Pazienti che hanno ottenuto riduzioni della IOP media nelle 24 ore;
5. Variazioni del danno alla cornea e della malattia dell’occhio secco;
6. Variazioni della malattia dell’occhio secco;
7. Variazioni del numero e nell’attivazione delle cellule dendritiche
corneali e congiuntivali coinvolte nella produzione del film
lacrimale;
8. Variazioni del numero delle “goblet cells” congiuntivali coinvolte
nella produzione del film lacrimale;
9. Cambiamenti della qualità della vita.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Ocular hypertension or primary open-angle glaucoma or secondary to dispersion of pigment or pseudoesfoliatio;
2. IOP <22 mmHg in latanoprost therapy in both eyes and> 17 mmHg in at least one eye;
3. OSD at least mild as defined by DEQ-5 (score> 6);
4. Examination of the visual field during the three months prior to enrollment (if not present, the patient must be subjected to a visual field at the screening visit);
5. Treatment with latanoprost BAK-preserved from at least 6 weeks;
6. Subject agrees to follow the study procedures and signs the EC-approved ICF;
7. For women of child-bearing potential, blood screening for beta-HCG before randomization and use of one effective method of birth control during the conduct of the study

1. Ipertensione oculare o glaucoma primario ad angolo aperto o secondario alla dispersione di pigmento o pseudoesfoliatio;
2. IOP <22 mmHg nella terapia con latanoprost in entrambi gli occhi e> 17 mmHg in almeno un occhio;
3. OSD almeno lieve come definito da DEQ-5 (punteggio> 6);
4. Esame del campo visivo durante i tre mesi precedenti l'arruolamento (se non presente, il paziente deve essere sottoposto a un campo visivo durante la visita di screening);
5. Trattamento con latanoprost BAK conservato da almeno 6 settimane;
6. Il soggetto accetta di seguire le procedure di studio e firma l'ICF approvato dal CE;
7. Per le donne in età fertile, screening del sangue per beta-HCG prima della randomizzazione e utilizzo di un metodo efficace di controllo delle nascite durante lo svolgimento dello studio

E.4

Principal exclusion criteria

1. Inability to understand and sign informed consent;
2. Age under 18 years;
3. Other forms of secondary glaucoma (besides pigmentary and pseudoesfoliatius);
4. Narrow angle or history of acute glaucoma attacks;
5. Previous history of trabeculoplasty in the previous 6 months;
6. History of glaucoma surgery or refractive surgery;
7. Cataract surgery in the 6 months prior to enrollment;
8. Contraindications to the use of beta-blockers (reactive airway disease, including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease; sinus bradycardia, sick sinus syndrome, including sinoatrial block, second or third degree atrioventricular block not controlled by pacemaker; full-blown heart failure, cardiogenic shock);
9. Damage to the visual field with a mean deviation (MD) <-20 dB;
10. BCVA <2/10;
11. Topical ocular drugs performed within 3 months prior to enrollment that may interfere with the study results (eg steroids, non-steroidal anti-inflammatory drugs, immunosuppressants, etc.);
12. Use of tear substitutes containing preservatives within 30 days prior to enrollment;
13. Any other condition that, in the opinion of the investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful completion of the study or would impair interpretation of results;
14. Corneal anomalies that preclude an accurate measurement of IOP (eg astigmatism> 3 D, keratoconus, opacity or corneal ulcers);
15. Any type of previous corneal or conjunctival surgery including pterygium removal or refractive surgery;
16. Unstable systemic disorders that may require the initiation or variation of therapies that may influence intraocular pressure during the study;
17. Woman of childbearing potential, or who is currently pregnant or breastfeeding;
18. Inability to adhere to the procedures required by the protocol or to the studio treatment;
19. Participation in another experimental therapeutic protocol within one month prior to baseline and during the study period (participation in natural history study is allowed);
20. Hypersensitivity to the active substances or to any of the excipients.

1. Incapacità di comprendere e firmare il consenso informato;
2. Età inferiore a 18 anni;
3. Altre forme di glaucoma secondario (oltre a pigmentario e pseudoesfoliatius);
4. Angolo stretto o storia di attacchi di glaucoma acuto;
5. Storia precedente di trabeculoplastica negli ultimi 6 mesi;
6. Storia di chirurgia del glaucoma o chirurgia refrattiva;
7. Chirurgia della cataratta nei 6 mesi precedenti l'arruolamento;
8. Controindicazioni all'uso dei beta-bloccanti (malattia reattiva delle vie aeree, incluse asma bronchjale o anamnesi di asma bronchiale, grave pneumopatia cronica ostruttiva; bradicardia sinusale, sindrome del seno malato, inclusi blocco senoatriale, blocco atrioventricolare, blocco atrioventricolare di secondo o terzo grado non controllato con pacemaker; insufficienza cardiaca conclamata, shock cardiogeno);
9. Danno al campo visivo con una deviazione media (MD) < -20 dB;
10. BCVA < 2/10;
11. Farmaci oculari topici eseguiti entro 3 mesi prima dell'arruolamento che potrebbero interferire con i risultati dello studio (ad esempio steroidi, farmaci antinfiammatori non steroidei, immunosoppressori, ecc.);
12. Uso di sostituti lacrimali contenenti conservanti entro 30 giorni prima dell'iscrizione;
13. Qualsiasi altra condizione che, a giudizio dello sperimentatore, possa compromettere la sicurezza o la conformità del paziente o impedirebbe al paziente di completare con successo lo studio o comprometterebbe l'interpretazione dei risultati;
14. Anomalie corneali che impediscono una misurazione accurata della IOP (ad es. Astigmatismo > 3 D, cheratocono, opacità o ulcere corneali);
15. Qualsiasi tipo di precedente intervento chirurgico corneale o congiuntivale inclusa la rimozione del pterigio o la chirurgia refrattiva;
16. Disturbi sistemici instabili che possono richiedere l'inizio o la variazione di terapie che possono influenzare la pressione intraoculare durante lo studio;
17. Donna in età fertile o che è attualmente in gravidanza o in allattamento;
18. Incapacità di aderire alle procedure richieste dal protocollo o al trattamento in studio;
19. Partecipazione a un altro protocollo terapeutico sperimentale entro un mese prima del basale e durante il periodo di studio (è consentita la partecipazione allo studio di storia naturale);
20. Ipersensibilità ai principi attivi o ad uno qualsiasi degli eccipienti.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint will be the evaluation of the mean 24-h absolute IOP reduction measured in mmHg (millimeters of mercury) from baseline to V3B.

L’outcome primario sarà la valutazione della riduzione assoluta media di IOP delle 24 ore misurata in mmHg (millimetri di mercurio) dal basale alla V3B.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline and V3B

Visita basale e V3B

E.5.2

Secondary end point(s)

1) Evaluation of the average reduction of IOP at each time of the 24-hour curve measured in mmHg (millimeters of mercury) at V3B compared with the 24-hour curve at baseline.
2) Evaluation of the percentage reduction of the average IOP of the 24 hours and at each time point to the V3B compared to the baseline.
3) Evaluation of the average daytime reduction (8:00, 11:00, 14:00, 17:00, 20:00) and night (23:00, 02:00, 05:00) of the IOP measured in mmHg (millimeters of mercury) to V3B compared to baseline.
4) Evaluation of the percentage of patients achieving IOP reductions in average IOP of 24h> 20%,> 25%,> 30% to V3B compared to baseline.
5) Evaluation of the changes in the CFS and tBUT parameters to V3A from baseline, respectively measured by extension of the area of the cornea colored by fluorescein and density of the staining, and the breaking time of the lachrymal film after staining with fluorescein
6) Evaluation of the changes in the Five-item dry eye (DEQ-5) questionnaire to V3A from baseline measured by the score assigned to the questions.
7) Evaluation of the changes of the number and activation of corneal and conjunctival dendritic cells to confocal microscopy to V3A from baseline
8) Evaluation of the changes of the number of conjunctival goblet cells to confocal microscopy compared to V3A from baseline.

1) Valutazione della riduzione media di IOP ad ogni momento della curva delle 24 ore misurata in mmHg (millimetri di mercurio) alla V3B rispetto alla curva delle 24 ore al basale;
2) Valutazione della riduzione percentuale media di IOP delle 24 ore e ad ogni momento alla V3B rispetto al basale;
3) Valutazione della riduzione media diurna (8:00, 11:00, 14:00, 17:00, 20:00) e notturna (23:00, 02:00, 05:00) di IOP misurata in mmHg (millimetri di mercurio) alla V3B rispetto al basale;
4) Valutazione della percentuale di pazienti che ottengono riduzioni di IOP nella IOP media delle 24 ore > 20%,> 25%,> 30% alla V3B rispetto al basale;
5) Valutazione delle variazioni dei parametri CFS e tBUT alla V3A rispetto al basale, misurate rispettivamente come estensione dell'area della cornea colorata dalla fluoresceina e dalla densità della colorazione e dal tempo di rottura del film lacrimale dopo colorazione con fluoresceina;
6) Valutazione delle variazioni nel questionario dei cinque punti dell'occhio secco (DEQ-5) alla V3A rispetto al basale misurata tramite il punteggio assegnato alle domande;
7) Valutazione delle variazioni del numero e dell’attivazione delle cellule dendritiche corneali e congiuntivali al microscopio confocale alla V3A rispetto al basale;
8) Valutazione delle variazioni del numero delle “globet cells” congiuntivali al microscopio confocale alla V3A rispetto al basale.

E.5.2.1

Timepoint(s) of evaluation of this end point

1), 2), 3), 4): baseline and V3B
5), 6), 7), 8): baseline and V3A

1), 2), 3), 4): visita basale e V3B
5), 6), 7), 8): visita basale e V3A

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

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

In aperto

Open study

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

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

Information not present in EudraCT

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:

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

F.3.3.1

Women of childbearing potential not using contraception

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

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)

At the discretion of the physician

A discrezione del medico curante

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

2020-02-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-12-17

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

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