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    Clinical Trial Results:
    Non-inferiority, Randomized, Observer-blind, two Parallel Group, Clinical Trial for Comparing the Efficacy and Tolerability of a new Generic BAC-free Formulation of Latanoprost 0.05 mg/mL eye drops, solution in single-dose container vs Xalatan® eye drops in Patients with Open Angle Glaucoma or Ocular Hypertension

    Summary
    EudraCT number
    		 2020-004307-14
    Trial protocol
    		 GR  
    Global end of trial date
    30 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Aug 2023
    First version publication date
    24 Aug 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BECRO/ACT/LATANOS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    actrevo GmbH
    Sponsor organisation address
    Großer Burstah 25, Hamburg, Germany, 20457
    Public contact
    actrevo GmbH, actrevo GmbH, +49 4022864810, info@actrevo.com
    Scientific contact
    actrevo GmbH, actrevo GmbH, +49 4022864810, info@actrevo.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Feb 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm the clinical non-inferiority of a generic BAC-free formulation of Latanoprost 0.05 mg/mL eye drops, solution in single-dose container with the marketed preservative-containing Xalatan® eye drops in patients with open angle glaucoma or ocular hypertension (IOP ≥22 mmHg) by examining the change of IOP at 08:00 am from end of study to baseline.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the declaration of Helsinki, the International Conference on Harmonisation (ICH) and the further guidelines in place on Good Clinical Practice (GCP). All the local regulatory requirements pertinent to the safety of trial subjects were followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jun 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Greece: 170
    Worldwide total number of subjects
    170
    EEA total number of subjects
    170
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    60
    From 65 to 84 years
    103
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was an observer-blind, two parallel group, randomized, multi-centre clinical phase III trial planned to enrol 170 patients. Patients diagnosed with open-angle glaucoma or ocular hypertension and IOP ≥22 mmHg were selected to participate in the study.

    Pre-assignment
    Screening details
    		 A total of 170 patients who met the inclusion and exclusion criteria signed the ICF and were initially selected to participate in the study. No screening period with induction therapy was foreseen.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    The study was performed as observer-blind because of the differences in the packaging of IMPs. The test product was a preservative-free preparation in single-dose container whereas the reference product was supplied as multi-dose bottle. In the clinical trial site, there were "blind" and "non-blind" clinical trial staff. The "blind" staff contacted the patients and perform all trial-related examinations while the "non-blind" staff was responsible for distributing the drugs (IMPs).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Latanoprost
    Arm description
    		 A new preservative-free formulation of Latanoprost 0.05 mg/mL eye drops, solution in single-dose container in the treatment of open-angle glaucoma or ocular hypertension.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Preservative-free Latanoprost 0.05 mg/mL eye drops, solution
    Investigational medicinal product code
    Other name
    BAC-free Latanoprost 0.05 mg/mL eye drops, solution
    Pharmaceutical forms
    Eye drops, solution in single-dose container
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Product was self-administered by the patient as indicated: One drop in the affected eye(s) once daily in the evening.

    Arm title
    		 Xalatan®
    Arm description
    		 The preserved medicinal product Xalatan® in the treatment of open-angle glaucoma or ocular hypertension. The reference product is marketed in a multi-dose bottle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Xalatan® eye drops, solution
    Investigational medicinal product code
    Other name
    BAC-preserved Latanoprost 0.05 mg/mL eye drops, solution
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Product was self-administered by the patient as indicated: One drop in the affected eye(s) once daily in the evening.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The study design was "observer-blind".
    Number of subjects in period 1
    		Latanoprost Xalatan®
    Started
    86
    84
    Completed
    84
    82
    Not completed
    2
    2
         Physician decision
    1
    -
         ICF withdrawal
    1
    -
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Latanoprost
    Reporting group description
    		 A new preservative-free formulation of Latanoprost 0.05 mg/mL eye drops, solution in single-dose container in the treatment of open-angle glaucoma or ocular hypertension.

    Reporting group title
    Xalatan®
    Reporting group description
    		 The preserved medicinal product Xalatan® in the treatment of open-angle glaucoma or ocular hypertension. The reference product is marketed in a multi-dose bottle.

    Reporting group values
    		 Latanoprost Xalatan® Total
    Number of subjects
    		 86 84 170
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 29 31 60
        From 65-84 years
    		 53 50 103
        85 years and over
    		 4 3 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.02 ( 10.70 ) 67.17 ( 11.67 ) -
    Gender categorical
    Units: Subjects
        Female
    		 44 36 80
        Male
    		 42 48 90
    Subject analysis sets

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) analysis includes all randomized patients who had at least one post-baseline IOP measurement.

    Subject analysis set title
    Per protocol (PP) population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) analysis includes all those of the ITT population who had no major protocol violations, who completed IOP measurements, who completed at least 12 weeks of treatment with the last dose administered before the 12-week visit, and who did not take prohibited concurrent medication.

    Subject analysis set title
    Safety population (SP)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population (SP) comprises all patients who have received at least 1 eye drop of the test or the reference medication.

    Subject analysis sets values
    		 Intent-to-treat (ITT) population Per protocol (PP) population Safety population (SP)
    Number of subjects
    169
    151
    170
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    60
    54
    60
        From 65-84 years
    102
    90
    103
        85 years and over
    7
    7
    7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    67.52 ( 11.15 )
    67.68 ( 11.04 )
    67.60 ( 11.16 )
    Gender categorical
    Units: Subjects
        Female
    79
    69
    80
        Male
    90
    82
    90

    End points

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    End points reporting groups
    Reporting group title
    Latanoprost
    Reporting group description
    		 A new preservative-free formulation of Latanoprost 0.05 mg/mL eye drops, solution in single-dose container in the treatment of open-angle glaucoma or ocular hypertension.

    Reporting group title
    Xalatan®
    Reporting group description
    		 The preserved medicinal product Xalatan® in the treatment of open-angle glaucoma or ocular hypertension. The reference product is marketed in a multi-dose bottle.

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) analysis includes all randomized patients who had at least one post-baseline IOP measurement.

    Subject analysis set title
    Per protocol (PP) population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) analysis includes all those of the ITT population who had no major protocol violations, who completed IOP measurements, who completed at least 12 weeks of treatment with the last dose administered before the 12-week visit, and who did not take prohibited concurrent medication.

    Subject analysis set title
    Safety population (SP)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population (SP) comprises all patients who have received at least 1 eye drop of the test or the reference medication.

    Primary: Change in IOP in study eye from baseline to last visit

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    End point title
    		 Change in IOP in study eye from baseline to last visit
    End point description
    The primary endpoint for evaluating the efficacy was the change in IOP at 08:00 am in study eye from end of treatment (week 12) to baseline (week 0) in subjects treated with the test product as compared to subjects treated with the reference product. According to the clinical protocol, the non-inferiority of the test product was evaluated based on the intent-to-treat (ITT) population.
    End point type
    Primary
    End point timeframe
    Between baseline (week 0) to last visit (week 12)
    End point values
    		 Latanoprost Xalatan®
    Number of subjects analysed
    86
    83
    Units: mmHg
    arithmetic mean (standard deviation)
        IOP 08:00 am (baseline)
    24.94 ( 1.80 )
    24.63 ( 2.15 )
        IOP 08:00 am (week 2)
    18.12 ( 2.77 )
    17.83 ( 3.39 )
        IOP 08:00 am (week 6)
    17.65 ( 2.77 )
    17.22 ( 3.17 )
        IOP 08:00 am (last visit)
    16.57 ( 2.91 )
    16.70 ( 3.25 )
    Statistical analysis title
    		 Change in IOP in study eye
    Statistical analysis description
    The primary endpoint is the change in IOP at 08:00 am in study eye from end of treatment (week 12) to baseline (week 0) in subjects treated with the test product as compared to subjects treated with the reference product. The analysis of covariance (ANCOVA) model was used to analyse the change in IOP with baseline IOP as the covariate, and treatment as a factor. The treatment difference and a two-sided 95 % confidence interval (CI) for the difference have been calculated.
    Comparison groups
    Latanoprost v Xalatan®
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.05 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.547
         upper limit
    		 0.994
    Variability estimate
    Standard deviation
    Notes
    [1] - The generic preservative-free test product Latanoprost 0.05 mg/mL eye drops, solution in single-dose container is considered to be non-inferior to the marketed reference Xalatan® (preserved with BAC) if the upper limit of the 95 % CI of the difference is <1.5 mmHg. The primary analysis is based on the ITT analysis; the per protocol (PP) analysis is used to validate the results of the ITT analysis.
    [2] - A statistical result is considered significant at P <0.05.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events occurring during the clinical study were documented.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Latanoprost
    Reporting group description
    		 Test product

    Reporting group title
    Xalatan®
    Reporting group description
    		 Reference product

    Serious adverse events
    		 Latanoprost Xalatan®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 84 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Latanoprost Xalatan®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 86 (46.51%)
    50 / 84 (59.52%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 84 (1.19%)
         occurrences all number
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Instillation site foreign body sensation
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Instillation site pain
         subjects affected / exposed
    6 / 86 (6.98%)
    7 / 84 (8.33%)
         occurrences all number
    6
    7
    Eye disorders
    Abnormal sensation in eye
         subjects affected / exposed
    5 / 86 (5.81%)
    1 / 84 (1.19%)
         occurrences all number
    5
    1
    Blepharitis
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 84 (1.19%)
         occurrences all number
    2
    1
    Conjunctival hyperaemia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Dry eye
         subjects affected / exposed
    5 / 86 (5.81%)
    6 / 84 (7.14%)
         occurrences all number
    5
    6
    Erythema of eyelid
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 84 (2.38%)
         occurrences all number
    2
    2
    Eye irritation
         subjects affected / exposed
    4 / 86 (4.65%)
    5 / 84 (5.95%)
         occurrences all number
    4
    5
    Eye pain
         subjects affected / exposed
    1 / 86 (1.16%)
    13 / 84 (15.48%)
         occurrences all number
    1
    13
    Eye pruritus
         subjects affected / exposed
    4 / 86 (4.65%)
    4 / 84 (4.76%)
         occurrences all number
    4
    4
    Foreign body sensation in eyes
         subjects affected / exposed
    4 / 86 (4.65%)
    17 / 84 (20.24%)
         occurrences all number
    4
    17
    Lacrimation increased
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    9 / 86 (10.47%)
    6 / 84 (7.14%)
         occurrences all number
    9
    6
    Vision blurred
         subjects affected / exposed
    5 / 86 (5.81%)
    1 / 84 (1.19%)
         occurrences all number
    5
    1
    Visual impairment
         subjects affected / exposed
    2 / 86 (2.33%)
    3 / 84 (3.57%)
         occurrences all number
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Sinusitis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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