Clinical Trials Register

Summary
EudraCT Number:	2020-000079-18
Sponsor's Protocol Code Number:	PHN-BBFC-NI101
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-02-13
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

Greece - EOF

A.2

EudraCT number

2020-000079-18

A.3

Full title of the trial

A phase III, multicentre, prospective, randomized, assessor-blinded, two-arm, parallel group, therapeutic non-inferiority 3-month clinical trial to compare the efficacy and safety of a generic fixed combination of brinzolamide 10 mg/mL + brimonidine tartrate 2 mg/mL eye drops suspension (Pharmathen) versus SIMBRINZA®/Alcon 10 mg/mL + 2 mg/mL eye drops suspension in the treatment of elevated intraocular pressure in adult patients with open-angle glaucoma or ocular hypertension

Μια φάσης III, πολυκεντρική, προοπτική, τυχαιοποιημένη, με τυφλοποιημένη αξιολόγηση των τελικών σημείων, δύο σκελών, παράλληλων ομάδων κλινική δοκιμή θεραπευτικής ισοδυναμίας (μη κατωτερότητας) διάρκειας 3 μηνών για τη σύγκριση της αποτελεσματικότητας και της ασφάλειας ενός γενόσημου οφθαλμικού εναιωρήματος σταθερού συνδυασμού βρινζολαμίδης 10mg/mL και τρυγικής βριμονιδίνης 2mg/mL (Pharmathen) έναντι του οφθαλμικού εναιωρήματος SIMBRINZA®/Alcon 10 mg/ mL+ 2mg/mL στην αντιμετώπιση της αυξημένης ενδοφθάλμιας πίεσης σε ενήλικες ασθενείς με γλαύκωμα ανοικτής γωνίας ή οφθαλμική υπερτονία

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

Therapeutic equivalence trial between two fixed combination of eye drops suspension

Μελέτη θεραπευτικής ισοδυναμίας μεταξύ δύο οφθαλμικών εναιωρημάτων σταθερού συνδυασμού

A.4.1

Sponsor's protocol code number

PHN-BBFC-NI101

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	Pharmathen S.A.
B.1.3.4	Country	Greece
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	Pharmathen S.A.
B.4.2	Country	Greece
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pharmathen S.A.
B.5.2	Functional name of contact point	Clinical Affairs Specialist
B.5.3	Address:
B.5.3.1	Street Address	6 Dervenakion Str.
B.5.3.2	Town/ city	Pallini Attica
B.5.3.3	Post code	15351
B.5.3.4	Country	Greece
B.5.4	Telephone number	+302106604300
B.5.5	Fax number	+302106666749
B.5.6	E-mail	amargaritis@pharmathen.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role
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	brinzolamide 10 mg/mL + brimonidine tartrate 2 mg/mL
D.3.4	Pharmaceutical form	Eye drops, suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ophthalmic use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BRINZOLAMIDE
D.3.9.1	CAS number	138890-62-7
D.3.9.4	EV Substance Code	SUB05892MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.3	Concentration number	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Brimonidine tartrate
D.3.9.1	CAS number	79570-19-7
D.3.9.4	EV Substance Code	SUB13122MIG
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	2
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	Comparator
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	SIMBRINZA
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	SIMBRINZA
D.3.4	Pharmaceutical form	Eye drops, suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ophthalmic use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BRINZOLAMIDE
D.3.9.1	CAS number	138890-62-7
D.3.9.4	EV Substance Code	SUB05892MIG
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	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Brimonidine tartrate
D.3.9.1	CAS number	79570-19-7
D.3.9.4	EV Substance Code	SUB13122MIG
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	2
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Open-angle glaucoma (OAG) or ocular hypertension (OHT)

Γλαύκωμα ανοιχτής γωνίας ή ενδοφθάλμια υπερτονία

E.1.1.1

Medical condition in easily understood language

Glaucoma is a progressive multifactorial complex chronic optic neuropathy that constitutes a leading cause of irreversible blindness worldwide, with OAG being the most common form of the disease

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	SOC
E.1.2	Classification code	10015919
E.1.2	Term	Eye disorders
E.1.2	System Organ Class	10015919 - Eye disorders

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	10030348
E.1.2	Term	Open angle glaucoma
E.1.2	System Organ Class	10015919 - Eye disorders

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	10030043
E.1.2	Term	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

To demonstrate that the generic BBFC 1%/0.2% ophthalmic suspension BID/Pharmathen (test product) is non-inferior to SIMBRINZA® (BBFC 1%/0.2% ophthalmic suspension BID)/Alcon (reference product) with respect to IOP-lowering efficacy at Month 3, in adult patients with OAG or OHT.

E.2.2

Secondary objectives of the trial

To compare the safety and tolerability profile of the generic BBFC 1%/0.2% ophthalmic suspension BID/Pharmathen (test product) versus SIMBRINZA® (BBFC 1%/0.2% ophthalmic suspension BID)/Alcon (reference product) with respect to treatment-emergent ocular and systemic AE and adverse drug reaction (ADR) occurrence and treatment discontinuation due to ADR occurrence over the 3-month treatment period, in adult patients with OAG or OHT.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

For inclusion in the study subjects should fulfill ALL of the following criteria:
•Female or male outpatients, of any race or ethnicity, aged at least 18 years at the time of signing the ICF
•Patients diagnosed with bilateral or unilateral open-angle glaucoma (including open-angle glaucoma with pseudoexfoliation or pigment dispersion) and/or ocular hypertension for whom, as per the investigator’s clinical judgment, monotherapy provides insufficient IOP reduction
• Patients who are able to safely discontinue use of all ocular hypotensive medication(s) and undergo appropriate washout period
• Mean IOP measurements in at least one (1) eye (the same eye), must be:
≥24 mmHg and ≤36 mmHg at the 09:00 a.m. time point, and
≥21 and ≤36 mmHg at the 11:00 a.m. time point at both the Eligibility 1 and Eligibility 2 visits after the required washout of any IOP-lowering medication.
•Mean IOP must be ≤36 mmHg in both eyes at both time points (09:00 a.m. and 11:00 a.m.) of the two Eligibility visits
•If females of childbearing potential, willingness to use an acceptable form of birth control during the clinical trial
•Patients who are able to comprehend and willing to follow the requirements of the study (including availability on scheduled visit dates)
•Patients who are able to understand and willing to provide voluntary written informed consent before any clinical trial-related procedure is performed.

E.4

Principal exclusion criteria

Patients who meet ANY of the following criteria will be excluded from the study:
•Females who are pregnant, breast feeding, or planning to become pregnant
•Females of childbearing potential who do not agree to utilize an adequate form of contraception
•Schaffer angle grade <2 in either eye, as measured by gonioscopy (extreme narrow angle with complete or partial closure)
•Central corneal thickness (CCT) >620 μm as measured by pachymetry in either eye
•Cup-to-disk ratio (CDR) >0.80 (horizontal or vertical measurement) in either eye
•Severe central visual field loss (i.e., sensitivity ≤10 decibel [dB] in at least 2 of the 4 visual field test points closest to the point of fixation) in either eye
•Chronic, recurrent, or current severe inflammatory eye disease (e.g., scleritis, uveitis, herpes keratitis) in either eye
•Ocular infection or ocular inflammation within the past 3 months prior to the Screening visit
•Ocular trauma within the past 6 months prior to the Screening visit
•Clinically significant or progressive retinal disease (e.g., retinal degeneration, diabetic retinopathy, retinal detachment) in either eye
•Other ocular pathology (including severe dry eye) in either eye that may, in the opinion of the Investigator, preclude the safe administration of a topical ocular alpha-adrenergic agonist and/or a topical carbonic anhydrase inhibitor
•Intraocular surgery (e.g., cataract surgery) within the past 6 months prior to the Screening visit
•Refractive surgery, filtering surgery, or laser surgery for IOP reduction within the past 12 months prior to the Screening visit
•Planned ocular surgery of any kind during study participation
•Any abnormality that would prevent accurate IOP readings with the applanation tonometry
•Best corrected visual acuity (BCVA) score worse than 55 ETDRS (Early Treatment Diabetic Retinopathy Study) letters (equivalent to approximately 20/80 Snellen, 0.60 logMAR or 0.25 decimal) in either eye
•Severe illness or other condition that would make the patient, in the opinion of the Investigator, unsuitable for the study
•Patients with severe renal impairment (creatinine clearance [CrCl] <30 mL/min) or hyperchloraemic acidosis
•Current or past history of severe, unstable, or uncontrolled cardiovascular, cerebrovascular, hepatic, or renal disease that would preclude the safe administration of a topical ocular alpha-adrenergic agonist and/or a topical carbonic anhydrase inhibitor, as per the Investigator’s clinical judgment
•Use within 4 weeks prior to the Eligibility 1 visit of:
systemic corticosteroid
high-dose (>1 gram daily) salicylate therapy
monoamine oxidase (MAO) inhibitor therapy
any antidepressant which affects noradrenergic transmission (e.g., tricyclic antidepressants, mianserin)
adrenergic-augmenting psychotropic drug (e.g., desipramine, amitriptyline)
any other medication that augments adrenergic response or precludes use of an alpha-adrenergic agonist
•Use within 2 weeks prior to Eligibility 1 visit of topical ophthalmic corticosteroid or topical corticosteroid
•Use within 6 months prior to Eligibility 1 visit of intravitreal or subtenon injection of ophthalmic corticosteroid
•Use at any time prior to Eligibility 1 visit of intraocular corticosteroid implant
•Patients who currently receive treatment with any investigational drug/device/intervention or who have received any investigational product within 30 days or 5 half-lives of the investigational agent (whichever is longer) before the screening
•History of drug or alcohol abuse within the past 6 months prior to screening
•Any contraindication to brimonidine tartrate or brinzolamide or hypersensitivity to sulfonamides or to any component (active substances or excipients) of the study medications
•Patients with less than 30 days stable dosing regimen before the Screening visit of any medication (excluding the IOP-lowering treatment) or substances administered by any route and used on a chronic basis that may affect IOP (e.g., beta-blockers). The dosing regimen of these medications should not change during the study
•Concurrent use of a MAO inhibitor, any additional systemic or topical ocular hypotensive medications in either eye, or glucocorticoid medications administered by any route during the study
•Patients who have known evidence of lack of adherence to medications and/or lack of ability to follow physician’s recommendations
•Previous treatment with the reference product (SIMBRINZA®)
•Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the investigational site)

E.5 End points

E.5.1

Primary end point(s)

•Difference between the test and reference product in the mean change from baseline in diurnal IOP at Month 3 (patient IOP changes averaged over the 09:00 a.m. and 11:00 a.m. time points).

E.5.1.1

Timepoint(s) of evaluation of this end point

At Month 3

E.5.2

Secondary end point(s)

•Difference between the test and reference product in the mean change from baseline in IOP at 09:00 a.m. at Month 3
•Difference between the test and reference product in the mean change from baseline in IOP at 11:00 a.m. at Month 3
•Difference between the test and reference product in the mean change from baseline in diurnal IOP at Week 6
•Difference between the test and reference product in the mean change from baseline in IOP at 09:00 a.m. at Week 6
•Difference between the test and reference product in the mean change from baseline in IOP at 11:00 a.m. at Week 6
•Difference between the test and reference product in the mean change from baseline in diurnal IOP at Week 2
•Difference between the test and reference product in the mean change from baseline in IOP at 09:00 a.m. at Week 2
•Difference between the test and reference product in the mean change from baseline in IOP at 11:00 a.m. at Week 2.
•Incidence of serious and non-serious treatment-emergent ocular and systemic AEs and ADRs in the two treatment arms (patients administered the test product and the reference product)
•Proportions of patients with permanent treatment discontinuation due to ADRs during the study treatment period, in the two treatment arms.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 2 and Week 6 post-treatment onset

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

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Non-inferiority trial

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

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Investigator masked

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

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

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

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.1.3

Elderly (>=65 years)

Yes

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

The Legally Acceptable Representative will be giving consent on subjects behalf

F.3.3.7

Others

Information not present in EudraCT

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

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

2020-03-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-02-14

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

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