Clinical Trial Results:
Efficacy and safety assessment of T4032 (unpreserved bimatoprost 0.01%) versus Lumigan® 0.01% in ocular hypertensive or glaucomatous patients.
Summary
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EudraCT number |
2017-000846-23 |
Trial protocol |
FR GB DE LT GR BE PL ES SK CZ LV BG IT |
Global end of trial date |
24 Feb 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
16 Mar 2022
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First version publication date |
16 Mar 2022
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Other versions |
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Summary report(s) |
LT4032-301_CSR synopsis |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
LT4032-301
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03825380 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Laboratoires Théa
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Sponsor organisation address |
12 Rue Louis Blériot, Clermont-Ferrand, France, 63017
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Public contact |
Clinical department, Laboratoires THEA, 0033 473981436, Aude.BARDIOT@theapharma.com
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Scientific contact |
Clinical department, Laboratoires THEA, 0033 473981436, Aude.BARDIOT@theapharma.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
13 Jul 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 Feb 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Feb 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate the non-inferiority of T4032 unpreserved Bimatoprost 0.01% eye drops compared to Lumigan® 0.01% in terms of efficacy.
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Protection of trial subjects |
Different assessments were done during subject visits in order to ensure subject safety:
• Assessment of the conjunctival hyperaemia on McMonnies photographic scale in each eye.
• Score of each ocular symptom throughout the day (irritation/burning, stinging, itching, tearing, eye dryness feeling, foreign body sensation) using 0-3 scale.
• Score of each ocular symptom upon instillation (irritation/burning, stinging, itching, tearing, eye dryness feeling, foreign body sensation) using 0-3 scale.
• Score of each ocular sign (blepharitis, eyelid oedema, iris pigmentation modification, abnormal eyelashes aspect, folliculo-papillary conjunctivitis, other ocular abnormality) in each eye using 0-3 scale.
• Corneal fluorescein staining according to Oxford grading scheme in each eye.
• Far Best Corrected Visual Acuity in each eye.
• Ocular tolerance assessed by the investigator and by the patient.
• Ocular and systemic AE reporting.
All AEs experienced by a patient, irrespective of the suspected causality, was 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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Nov 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 7
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Country: Number of subjects enrolled |
Georgia: 12
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Country: Number of subjects enrolled |
Mauritius: 1
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Country: Number of subjects enrolled |
Russian Federation: 61
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Country: Number of subjects enrolled |
Tunisia: 36
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Country: Number of subjects enrolled |
Ukraine: 30
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Country: Number of subjects enrolled |
Poland: 47
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Country: Number of subjects enrolled |
Slovakia: 22
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Country: Number of subjects enrolled |
Spain: 28
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Belgium: 8
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Country: Number of subjects enrolled |
Bulgaria: 80
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Country: Number of subjects enrolled |
Czechia: 40
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Country: Number of subjects enrolled |
Estonia: 14
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Country: Number of subjects enrolled |
France: 23
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Country: Number of subjects enrolled |
Germany: 8
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Country: Number of subjects enrolled |
Greece: 13
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Country: Number of subjects enrolled |
Hungary: 2
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Country: Number of subjects enrolled |
Italy: 25
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Country: Number of subjects enrolled |
Latvia: 20
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Country: Number of subjects enrolled |
Lithuania: 7
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Worldwide total number of subjects |
485
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EEA total number of subjects |
337
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
251
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From 65 to 84 years |
226
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85 years and over |
8
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Recruitment
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Recruitment details |
485 patients (from 723 screened patients) were included and randomised in the study: 485 patients in the intent-to-treat (ITT) set and Safety set, 469 in the modified ITT (mITT) set. The recruitment started on 23-NOV-2018 and was completed on 28-AUG-2020 and the last patient completed the study on 24-FEB-2021. | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Incl/Excl criteria checked at screening visit, then patients discontinued their current treatment to start the run-in period with Azopt, for 5 weeks. The Azopt was stopped 1 or 2 weeks before the randomisation visit (Day 1). Incl/Excl criteria are confirmed at Day 1. 723 screened patients, 485 randomised patients, 238 screen failure patients. | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind [1] | |||||||||||||||||||||||||||
Roles blinded |
Investigator, Data analyst [2] | |||||||||||||||||||||||||||
Blinding implementation details |
blinded investigator and sponsor.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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T4032 arm | |||||||||||||||||||||||||||
Arm description |
The investigator-masked, 3-month T4032 treatment period lasted from the randomisation visit (Day 1; Visit #2) to the final Week 12 visit (Day 84±7 days; Visit #4). Test product: T4032 •Unpreserved bimatoprost 0.01% eye drops presented in unit dose (UD) | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
T4032
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Eye gel in single-dose container
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Routes of administration |
Ocular use
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Dosage and administration details |
1 eyedrop in each eye at 20:00 every day
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Arm title
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Lumigan arm | |||||||||||||||||||||||||||
Arm description |
The investigator-masked, 3-month Lumigan treatment period lasted from the randomisation visit (Day 1; Visit #2) to the final Week 12 visit (Day 84±7 days; Visit #4). Reference product: Lumigan •Preserved bimatoprost 0.01% eye drops presented in multidose (MD) container | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
Lumigan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Eye drops, solution
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Routes of administration |
Ocular use
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Dosage and administration details |
1 drop in each eye at 20:00 every day
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Notes [1] - 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: Subject is not blinded. The study is not considered as double blinded study. However investigator and data analyst are blinded. [2] - The roles blinded appear inconsistent with a simple blinded trial. Justification: Subject is not blinded. The study is not considered as double blinded study. However investigator and data analyst are blinded. |
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Baseline characteristics reporting groups
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Reporting group title |
T4032 arm
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Reporting group description |
The investigator-masked, 3-month T4032 treatment period lasted from the randomisation visit (Day 1; Visit #2) to the final Week 12 visit (Day 84±7 days; Visit #4). Test product: T4032 •Unpreserved bimatoprost 0.01% eye drops presented in unit dose (UD) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Lumigan arm
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Reporting group description |
The investigator-masked, 3-month Lumigan treatment period lasted from the randomisation visit (Day 1; Visit #2) to the final Week 12 visit (Day 84±7 days; Visit #4). Reference product: Lumigan •Preserved bimatoprost 0.01% eye drops presented in multidose (MD) container | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Modified intention-to-treat T4032
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Subject analysis set type |
Modified intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
T4032 arm - All randomised patients having received at least one dose of IMP (T4032 or Lumigan®), with at least one baseline and one post-randomisation efficacy assessment on treatment and considered as-randomised (i.e., according to the treatment unit assigned at Day 1). m-ITT set will be the primary population for efficacy analysis.
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Subject analysis set title |
Modified intention-to-treat Lumigan
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Subject analysis set type |
Modified intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Lumigan arm - All randomised patients having received at least one dose of IMP (T4032 or Lumigan®), with at least one baseline and one post-randomisation efficacy assessment on treatment and considered as-randomised (i.e., according to the treatment unit assigned at Day 1). m-ITT set will be the primary population for efficacy analysis.
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End points reporting groups
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Reporting group title |
T4032 arm
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Reporting group description |
The investigator-masked, 3-month T4032 treatment period lasted from the randomisation visit (Day 1; Visit #2) to the final Week 12 visit (Day 84±7 days; Visit #4). Test product: T4032 •Unpreserved bimatoprost 0.01% eye drops presented in unit dose (UD) | ||
Reporting group title |
Lumigan arm
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Reporting group description |
The investigator-masked, 3-month Lumigan treatment period lasted from the randomisation visit (Day 1; Visit #2) to the final Week 12 visit (Day 84±7 days; Visit #4). Reference product: Lumigan •Preserved bimatoprost 0.01% eye drops presented in multidose (MD) container | ||
Subject analysis set title |
Modified intention-to-treat T4032
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
T4032 arm - All randomised patients having received at least one dose of IMP (T4032 or Lumigan®), with at least one baseline and one post-randomisation efficacy assessment on treatment and considered as-randomised (i.e., according to the treatment unit assigned at Day 1). m-ITT set will be the primary population for efficacy analysis.
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Subject analysis set title |
Modified intention-to-treat Lumigan
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
Lumigan arm - All randomised patients having received at least one dose of IMP (T4032 or Lumigan®), with at least one baseline and one post-randomisation efficacy assessment on treatment and considered as-randomised (i.e., according to the treatment unit assigned at Day 1). m-ITT set will be the primary population for efficacy analysis.
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End point title |
Change in Intraocular Pressure (IOP) between Day 1 and Week 12 at 8:00 in the worse eye. | ||||||||||||
End point description |
The primary endpoint was defined as the change in IOP between Day 1 and Week 12 at 8:00, 10:00 and 16:00 in the worse eye, therefore 3 definitions needed for describing the primary endpoint.
Three independent mixed model with repeated measures (MMRM) were performed, one for each time point (8:00, 10:00 and 16:00).
Least Squares (LS) means were adjusted by baseline IOP, wash-out duration as continuous covariates and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group and visit interaction with baseline IOP group, using the restricted maximum likelihood (REML) and unstructured covariance matrix.
The worse eye was defined as the eligible eye with the highest IOP at Day 1 at 8:00. In case of no IOP difference between both eyes, the right eye was considered as the worse eye.
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End point type |
Primary
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End point timeframe |
Baseline, Week 12 at 8:00.
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Statistical analysis title |
Analysis of change from BSL in IOP at 8:00 at Wk12 | ||||||||||||
Statistical analysis description |
Primary analysis of the change from baseline in IOP (mmHg) at 8:00 at Week 12 - MMRM analysis – Worse eye - m-ITT set
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Comparison groups |
Modified intention-to-treat Lumigan v Modified intention-to-treat T4032
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Number of subjects included in analysis |
468
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
Method |
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Parameter type |
Adjusted mean difference | ||||||||||||
Point estimate |
-0.17
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.62 | ||||||||||||
upper limit |
0.28 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.23
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Notes [1] - Noninferiority was demonstrated if the upper bound of the two-sided 95% Confidence Interval (CI) for the difference in mean change in IOP between treatment groups (T4032 - Lumigan) was lower than the margin of +1.5 mmHg for each of the 3 time points 8:00, 10:00 and 16:00. |
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End point title |
Change in Intraocular Pressure (IOP) between Day 1 and Week 12 at 10:00 in the worse eye. | ||||||||||||
End point description |
The primary endpoint was defined as the change in IOP between Day 1 and Week 12 at 8:00, 10:00 and 16:00 in the worse eye, therefore 3 definitions needed for describing the primary endpoint.
Three independent mixed model with repeated measures (MMRM) were performed, one for each time point (8:00, 10:00 and 16:00).
Least Squares (LS) means were adjusted by baseline IOP, wash-out duration as continuous covariates and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group and visit interaction with baseline IOP group, using the restricted maximum likelihood (REML) and unstructured covariance matrix.
The worse eye was 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 was considered as the worse eye
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End point type |
Primary
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End point timeframe |
Baseline, Week 12 at 10:00
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Statistical analysis title |
Analysis change from BSL in IOP at 10:00 at Wk12 | ||||||||||||
Statistical analysis description |
Primary analysis of the change from baseline in IOP (mmHg) at 10:00 at Week 12 - MMRM analysis – Worse eye - m-ITT set
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Comparison groups |
Modified intention-to-treat Lumigan v Modified intention-to-treat T4032
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Number of subjects included in analysis |
469
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [2] | ||||||||||||
Method |
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Parameter type |
Adjusted mean difference | ||||||||||||
Point estimate |
-0.15
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.58 | ||||||||||||
upper limit |
0.27 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.22
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Notes [2] - Noninferiority was demonstrated if the upper bound of the two-sided 95% Confidence Interval (CI) for the difference in mean change in IOP between treatment groups (T4032 - Lumigan) was lower than the margin of +1.5 mmHg for each of the 3 time points 8:00, 10:00 and 16:00. |
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End point title |
Change in Intraocular Pressure (IOP) between Day 1 and Week 12 at 16:00 in the worse eye. | ||||||||||||
End point description |
The primary endpoint was defined as the change in IOP between Day 1 and Week 12 at 8:00, 10:00 and 16:00 in the worse eye, therefore 3 definitions needed for describing the primary endpoint.
Three independent mixed model with repeated measures (MMRM) were performed, one for each time point (8:00, 10:00 and 16:00).
Least Squares (LS) means were adjusted by baseline IOP, wash-out duration as continuous covariates and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group and visit interaction with baseline IOP group, using the restricted maximum likelihood (REML) and unstructured covariance matrix.
The worse eye was 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 was considered as the worse eye.
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End point type |
Primary
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End point timeframe |
Baseline (Day 1), Week 12 at 16:00
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Statistical analysis title |
Analysis change from BSL in IOP at 16:00 at Wk12 | ||||||||||||
Statistical analysis description |
Primary analysis of the change from baseline in IOP (mmHg) at 16:00 at Week 12 - MMRM analysis – Worse eye - m-ITT set
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Comparison groups |
Modified intention-to-treat T4032 v Modified intention-to-treat Lumigan
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Number of subjects included in analysis |
468
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [3] | ||||||||||||
Method |
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Parameter type |
Adjusted mean difference | ||||||||||||
Point estimate |
-0.19
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.61 | ||||||||||||
upper limit |
0.23 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.22
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Notes [3] - Noninferiority was demonstrated if the upper bound of the two-sided 95% Confidence Interval (CI) for the difference in mean change in IOP between treatment groups (T4032 - Lumigan) was lower than the margin of +1.5 mmHg for each of the 3 time points 8:00, 10:00 and 16:00. |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse event reporting extends from start of the treatment until Day 112 follow-up phone call.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.0
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Reporting groups
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Reporting group title |
T4032
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Reporting group description |
The investigator-masked, 3-month treatment period lasted from the randomisation visit (Day 1; Visit#2) to the final Week 12 visit (Day 84±7 days; Visit #4). Test product: T4032 •Unpreserved bimatoprost 0.01% eye drops presented in unit dose (UD) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Lumigan
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Reporting group description |
The investigator-masked, 3-month Lumigan treatment period lasted from the randomisation visit (Day 1; Visit #2) to the final Week 12 visit (Day 84±7 days; Visit #4). Reference product: Lumigan •Preserved bimatoprost 0.01% eye drops presented in multidose (MD) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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05 Jul 2019 |
On 05-JUL-2019 a new protocol version (Version 3.0) was created with the following updates:
-Increase the number of countries and sites involved in the study
-Extension of the study duration
-Increase of the planned number of screened patients: 668 instead of 434
-Prolongation of the run-in/wash-out period: 49 days instead of 42 days, including 2 weeks ofwash-out instead of 1 week
-Clarification regarding premature discontinuation visit
-Clarification regarding analysis (efficacy analysis – washout duration) |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
None reported |