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Clinical Trial Results:
Efficacy and safety assessment of T4030 eye drops (unpreserved fixed combination of bimatoprost 0.01% and timolol 0.1% or 0.5%) versus Ganfort® UD (Unit Dose) in ocular hypertensive or glaucomatous patients.

Summary
EudraCT number	2017-002823-46
Trial protocol	AT PL HU BE
Global end of trial date	12 Feb 2020

Results information
Results version number	v1(current)
This version publication date	24 Feb 2021
First version publication date	24 Feb 2021
Other versions
Summary report(s)	LT4030-201 study result summary

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

LT4030-201

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Laboratoires Thea

Sponsor organisation address

12 rue Blériot, Z.I. du Brézet, Clermont-Ferrand, France, 63100

Public contact

Research and Development Department, Laboratoires THÉA, 33 473981436, lydia.bresson@theapharma.com

Scientific contact

Research and Development Department, Laboratoires THÉA, 33 473981436, lydia.bresson@theapharma.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

19 Mar 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Feb 2020

Global end of trial reached?

Yes

Global end of trial date

12 Feb 2020

Was the trial ended prematurely?

Main objective of the trial

To compare each combination of T4030 eye drops (unpreserved fixed combination of bimatoprost 0.01% and timolol 0.1% or 0.5%) with Ganfort® UD in terms of efficacy.

Protection of trial subjects

Different assessments were done during subject visits in order to ensure subject safety: - Score of each ocular symptom throughout the day (irritation/burning, stinging, itching, tearing, eye dryness feeling, foreign body sensation), - Score of each ocular symptom upon instillation (irritation/burning, stinging, itching,tearing, eye dryness feeling, foreign body sensation), - Score of each ocular sign (blepharitis, eyelid oedema, iris hyperpigmentation, abnormal eyelashes aspect, folliculo-papillary conjunctivitis) in each eye, - Corneal fluorescein staining according to Oxford grading scheme in each eye, - Far Best Corrected Visual Acuity in each eye, - ECG, - Clinical systemic examination (heart rate, blood pressure), - Ocular tolerance assessed by the investigator, - Ocular tolerance assessed by the patient, - Ocular and systemic AE reporting. All AEs experienced by a patient, irrespective of the suspected causality, monitored until the event has resolved, any abnormal laboratory values have returned to baseline or stabilised at a level acceptable to the investigator and Medical expert, until there is a satisfactory explanation for the changes observed, or until the patient is lost to follow-up.

Background therapy

Patients must follow a run-in period with only brinzolamide eye drops 1% (Azopt®), one drop in each eye twice a day (morning and evening) for 5 weeks. The Azopt® treatment must be stopped 7 days before the Randomisation Visit (Day 1).

Evidence for comparator

This study compare the efficacy, safety and pharmacokinetics of the two different formulations of unpreserved fixed combination of bimatoprost 0.01%/timolol 0.1% or 0.5% (T4030a or T4030c) to the reference product Ganfort® UD (Allergan), in OAG or OHT patients initially treated either by a combination therapy of prostaglandin and timolol (fixed or not) and controlled for at least 6 months or by a first line monotherapy for at least 6 months and insufficiently controlled. Like for most glaucoma medications (including PGAs and -blockers eye drops),the BAK contained in the BTFC formulation has been proved to cause dose- and timedependent toxic effects to the eye structures of the anterior segment including the tear film,cornea, conjunctiva, and even trabecular meshwork cells (Baudouin et al. 2010). Thus, the European Medicines Agency (EMA) recommended to avoid the use of preservatives “forthose patients who do not tolerate eye drops with preservatives” and “for long-term treatment”, or to use, when preservatives are required, “concentration at the minimum levelconsistent with satisfactory antimicrobial function in each individual preparation” (EMEA 2009). Consequently, a preservative-free BTFC was developed and shown to be non-inferior in terms of efficacy compared to the preserved formulation (Goldberg et al. 2014). This preservative-free BTFC formulation is marketed since 2013 in unit dose (Ganfort® UD, Allergan)

Actual start date of recruitment

28 Sep 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 43

Country: Number of subjects enrolled

Austria: 6

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Hungary: 36

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

130 patients signed informed consent. 86 subjects were randomised (+ 1 randomised by mistake)in the study in one period of 1 year. 24 participating centres in 4 countries: Austria (1), Belgium (1), Hungary (10) and Poland (12). Recruitment started on 28SEP2018 and over on 03OCT2019.

Screening details

Incl/excl criteria are checked at screening visit (Day -42 ±3).Then there is period a run-in period (D-42 to D-7) where patient instilled Azopt wash-out period of 7 days. This period is followed by a wash-out period of 7 days. Incl/Excl criteria are confirmed at randomization visit (D1) there is a treatment period of 12 weeks.

Number of subjects started

130 ^[1]

Number of subjects completed

Reason: Number of subjects

screen failure: 44

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The reported worldwide number enrolled in the trial correspond to the the number of subjects randomized. However, 130 subjects were screened and start pre-assignement period.

Period 1 title

treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind ^[2]

Roles blinded

Investigator, Data analyst, Assessor ^[3]

Blinding implementation details

Subject is not blind. It is not consider as double blind study. However assesor and data analyst are blinded.

Are arms mutually exclusive

Yes

T4030a

Arm description

Arm type

Experimental

Investigational medicinal product name

T4030a

Investigational medicinal product code

Other name

Pharmaceutical forms

Eye gel in single-dose container

Routes of administration

Ocular use, Ophthalmic use

Dosage and administration details

patient administer the assigned treatment T4030a once daily at 20h00 (± 1 hour) in the conjunctival cul-de-sac of each eye.

T4030c

Arm description

Arm type

Experimental

Investigational medicinal product name

T4030c

Investigational medicinal product code

Other name

Pharmaceutical forms

Eye gel in single-dose container

Routes of administration

Ocular use, Ophthalmic use

Dosage and administration details

Patient administer the assigned treatment T4030c once daily at 20h00 (± 1 hour) in the conjunctival cul-de-sac of each eye.

Ganfort

Arm description

Arm type

Active comparator

Investigational medicinal product name

Ganfort®

Investigational medicinal product code

Other name

Pharmaceutical forms

Eye drops, solution in single-dose container

Routes of administration

Ocular use, Ophthalmic use

Dosage and administration details

patient administer the assigned treatment Ganfort® UD once daily at 20h00 (± 1 hour) in the conjunctival cul-de-sac of each eye.

Notes
[2] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
Justification: During treatement period data analyst and assessor were also blinded in this study.
[3] - The roles blinded appear inconsistent with a simple blinded trial.
Justification: Subject is not blind. It is not consider as double blind study. However assesor and data analyst are blinded.

Number of subjects in period 1	T4030a	T4030c	Ganfort
Started	29	29	28
Completed	27	27	26
Not completed	2	2	2
Adverse event, non-fatal	2	2	2

Baseline characteristics

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Reporting group title

T4030a

Reporting group description

Reporting group title

T4030c

Reporting group description

Reporting group title

Ganfort

Reporting group description

Reporting group values	T4030a	T4030c	Ganfort	Total
Number of subjects	29	29	28	86
Age categorical
The mean age is 61.6±10.9 years (range 27 to 80 years)
Units: Subjects
Adults (18-64 years)	14	14	16	44
From 65-84 years	15	15	12	42
Gender categorical
Units: Subjects
Female	20	22	17	59
Male	9	7	11	27

Subject analysis set title

modified intent-to-treat

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All randomised patients who received at least one dose of IMP, with at least one baseline and one post-randomisation efficacy assessment on treatment and considered as-treated (i.e., according to the treatment unit assigned at Day 1)

Subject analysis sets values	modified intent-to-treat
Number of subjects	86
Age categorical
The mean age is 61.6±10.9 years (range 27 to 80 years)
Units: Subjects
Adults (18-64 years)	44
From 65-84 years	42
Age continuous
Units:
	( )
Gender categorical
Units: Subjects
Female	59
Male	27

End points

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Reporting group title

T4030a

Reporting group description

Reporting group title

T4030c

Reporting group description

Reporting group title

Ganfort

Reporting group description

Subject analysis set title

modified intent-to-treat

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Primary: Change in IOP between Day1 and Week 12 at 8h00 in the worse eye.

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End point title

Change in IOP between Day1 and Week 12 at 8h00 in the worse eye.

End point description

End point type

Primary

End point timeframe

The Change in IOP between Day1 and Week 12 at 8h00 in the worse eye. The worse eye is defined as the eligible eye with the highest IOP at Day 1 at 8h00. In case of no IOP difference between both eyes, the right eye will be considered.

End point values	T4030a	T4030c	Ganfort	modified intent-to-treat
Number of subjects analysed	29	29	28	86
Units: mmHg
arithmetic mean (confidence interval 95%)	-9.83 (-10.66 to -9.01)	-10.14 (-11.12 to -9.15)	-9.98 (-11.12 to -8.84)	-9.98 (-11.12 to -8.84)

Primary analysis MMRM

Comparison groups

T4030a v Ganfort

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

adjusted mean difference

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

-1.04

upper limit

1.36

Primary analysis MMRM

Comparison groups

T4030c v Ganfort

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

adjusted mean difference

Point estimate

1.39

Confidence interval

level

95%

sides

2-sided

lower limit

-1.03

upper limit

1.39

Primary analysis MMRM

Comparison groups

T4030a v T4030c

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

adjusted mean difference

Point estimate

1.17

Confidence interval

level

95%

sides

2-sided

lower limit

-1.21

upper limit

1.17

Adverse events

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Timeframe for reporting adverse events

Adverse event reporting extend from start of th treatment until the final study visit.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

T4030a

Reporting group description

Reporting group title

T4030c

Reporting group description

Reporting group title

Ganfort

Reporting group description

Serious adverse events	T4030a	T4030c	Ganfort
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	0 / 28 (0.00%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	T4030a	T4030c	Ganfort
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 29 (34.48%)	10 / 29 (34.48%)	9 / 28 (32.14%)
Investigations
Abnormal sensation in eye
subjects affected / exposed	0 / 29 (0.00%)	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Vital dye staining cornea present
subjects affected / exposed	1 / 29 (3.45%)	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Blood pressure decreased
subjects affected / exposed	0 / 29 (0.00%)	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Breath sounds
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Injury, poisoning and procedural complications
Documented hypersensitivity to administered product
subjects affected / exposed	0 / 29 (0.00%)	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Ankle fracture
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Wound
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)	2 / 28 (7.14%)
occurrences all number	0	1	2
Vascular pain
subjects affected / exposed	0 / 29 (0.00%)	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Nervous system disorders
Headache
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	1
General disorders and administration site conditions
Influenza like illness
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Pyrexia
subjects affected / exposed	1 / 29 (3.45%)	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Eye disorders
Blepharitis
subjects affected / exposed	2 / 29 (6.90%)	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	2	0	1
Eye irritation
subjects affected / exposed	1 / 29 (3.45%)	2 / 29 (6.90%)	0 / 28 (0.00%)
occurrences all number	1	2	0
Vision blurred
subjects affected / exposed	0 / 29 (0.00%)	2 / 29 (6.90%)	1 / 28 (3.57%)
occurrences all number	0	2	1
Conjunctival hyperaemia
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Erythema of eyelid
subjects affected / exposed	1 / 29 (3.45%)	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	1	1	0
Eye allergy
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Eye pruritus
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	1
Eye symptom
subjects affected / exposed	0 / 29 (0.00%)	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Eyelids pruritus
subjects affected / exposed	0 / 29 (0.00%)	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Musculoskeletal and connective tissue disorders
Athralgia
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Arthrisis
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 29 (0.00%)	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1
Osteoarthritis
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Infections and infestations
Conjunctivitis
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Bronchitis
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Cystitis
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Nasopharyngitis
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	1
Pneumonia
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Pharyngitis
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)	1 / 28 (3.57%)
occurrences all number	0	1	1
Rhinitis
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 29 (0.00%)	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	0	1	0
Viral infection
subjects affected / exposed	1 / 29 (3.45%)	0 / 29 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0

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Were there any global substantial amendments to the protocol? Yes

01 Jun 2019

- Adjustment of the number of patients to be screened in the study, due to higher screen failure rate than expected - Adjustment of the expected number of sites participating in the study (three additional sites in Poland and one additional site in Belgium) - Clarification of the exclusion criteria - More flexibility given to sites for the collection of the ICF - More flexibility given to sites for organising and performing the ECG - More flexibility given to site personal for management of pregnancy tests, vital signs and blood samplings - Allowing a time-window at the timepoints for blood sampling for pharmacokinetic analysis - Inclusion and specification of the risk-based monitoring approach - Minor clarification and administrative changes

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
Efficacy and safety assessment of T4030 eye drops (unpreserved fixed combination of bimatoprost 0.01% and timolol 0.1% or 0.5%) versus Ganfort® UD (Unit Dose) in ocular hypertensive or glaucomatous patients.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in IOP between Day1 and Week 12 at 8h00 in the worse eye.

Primary: Change in IOP between Day1 and Week 12 at 8h00 in the worse eye.

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: Efficacy and safety assessment of T4030 eye drops (unpreserved fixed combination of bimatoprost 0.01% and timolol 0.1% or 0.5%) versus Ganfort® UD (Unit Dose) in ocular hypertensive or glaucomatous patients.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in IOP between Day1 and Week 12 at 8h00 in the worse eye.

Primary: Change in IOP between Day1 and Week 12 at 8h00 in the worse eye.

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Efficacy and safety assessment of T4030 eye drops (unpreserved fixed combination of bimatoprost 0.01% and timolol 0.1% or 0.5%) versus Ganfort® UD (Unit Dose) in ocular hypertensive or glaucomatous patients.