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    Clinical Trial Results:
    Safety and efficay of 0.2% propranolol eye drops in newborns with retinopathy of prematurity: a pilot study

    Summary
    EudraCT number
    		 2014-005472-29
    Trial protocol
    		 IT  
    Global end of trial date
    20 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Nov 2021
    First version publication date
    21 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DROP-ROP-0.2%
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02504944
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 na: na
    Sponsors
    Sponsor organisation name
    AZIENDA OSPEDALIERO UNIVERSITARIA MEYER
    Sponsor organisation address
    VIALE PIERACCINI 24, FIRENZE, Italy, 50139
    Public contact
    CLINICAL TRIAL OFFICE, AZIENDA OSPEDALIERO UNIVERSITARIA MEYER, 0039 0555662425, clinicaltrialoffice@meyer.it
    Scientific contact
    CLINICAL TRIAL OFFICE, AZIENDA OSPEDALIERO UNIVERSITARIA MEYER, 0039 0555662425, clinicaltrialoffice@meyer.it
    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
    07 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the safety and efficacy of 0.2% propranolol eye drops to stop the progression of classic retinopathy of prematury (ROP) stage 1 towards stage 2 plus or stage 3 plus, therefore avoiding interventions such as laser therapy or anti-VEGF therapy.
    Protection of trial subjects
    No specific risks were expected for trial subjects, therefore no specific protection measures were put in place for trial subjects.
    Background therapy
    		 No background treatments are used in the trial for the specific condition (retinopathy of prematury, ROP). Otherwise, patients will be treated according to clinical practice for other clinical conditions, if any.
    Evidence for comparator
    		 No active comparator or placebo were used in the trial.
    Actual start date of recruitment
    15 Aug 2015
    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
    Italy: 98
    Worldwide total number of subjects
    98
    EEA total number of subjects
    98
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    98
    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)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Preterm newborns delivered at gestational age ranging from 23 to 32 weeks and admitted to Italian neonatal intensive care units (NICU) participating to the study were considered for recruitment. Recruitment period began in August 2015 and lasted two years.

    Pre-assignment
    Screening details
    		 According to clinical practice and international guideline, preterm newborns delivered at gestational age ranging from 23 to 32 weeks undergone to ophtalmological screening for ROP evaluation. During this screening patients were evaluated for enrollment.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Single arm
    Arm description
    		 This is a single arm study. This study was planned according to the Simon optimal two-stage design for phase II clinical trials. Therefore, the study analysis plan required 37 participants to be enrolled in Stage 1, with <6 participants meeting failure criteria in Stage 1 before Stage 2 was conducted. If Stage 1 criteria was not met, the study would be terminated for lack of efficacy. If <6 participants met Stage 1 failure criteria, additional participants would be enrolled in Stage 2. A total of <13 failures of the 96 total participants (in both Stages) would indicate sufficient promise to warrant further investigation. 96 patients was the initial calculated sample size.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Propranolol 0.2% eye-drops
    Investigational medicinal product code
    Propranolol
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Newborns received three micro-drops of 6 μL (12 μg propranolol per micro-drop) in each eye, applied with a micropipette, every 6h. After each administration, the nasolacrimal duct was carefully compressed for 30 sec to decrease the drug absorption through the conjunctival and nasal vessels. Treatment was continued until retinal vascularization was complete, but for no longer than 90 days.

    Number of subjects in period 1
    		Single arm
    Started
    98
    Completed
    97
    Not completed
    1
         Adverse event, serious fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period
    Reporting group description
    		 Number of overall enrolled patients

    Reporting group values
    		 Overall period Total
    Number of subjects
    		 98 98
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 98 98
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Gestational age, weeks, mean ± SD
    Units: weeks
        arithmetic mean (standard deviation)
    		 26.7 ± 2.0 -
    Gender categorical
    Units: Subjects
        Female
    		 50 50
        Male
    		 48 48
    Cesarean delivery
    Units: Subjects
        Cesarean delivery
    		 72 72
        Other
    		 26 26
    Stained amniotic fluid
    Units: Subjects
        Stained amniotic fluid
    		 7 7
        Other
    		 91 91
    Apgar Score, 1 min
    Units: minute
        median (full range (min-max))
    		 5 (1 to 9) -
    Apgar Score, 5 min
    Units: minute
        median (full range (min-max))
    		 8 (4 to 10) -
    Post menstrual age
    Units: week
        arithmetic mean (standard deviation)
    		 34.2 ± 2.3 -

    End points

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    End points reporting groups
    Reporting group title
    Single arm
    Reporting group description
    		 This is a single arm study. This study was planned according to the Simon optimal two-stage design for phase II clinical trials. Therefore, the study analysis plan required 37 participants to be enrolled in Stage 1, with <6 participants meeting failure criteria in Stage 1 before Stage 2 was conducted. If Stage 1 criteria was not met, the study would be terminated for lack of efficacy. If <6 participants met Stage 1 failure criteria, additional participants would be enrolled in Stage 2. A total of <13 failures of the 96 total participants (in both Stages) would indicate sufficient promise to warrant further investigation. 96 patients was the initial calculated sample size.

    Primary: Number of infants who progress from ROP Stage 1 to Stage 2 or 3

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    End point title
    		 Number of infants who progress from ROP Stage 1 to Stage 2 or 3 [1]
    End point description
    Number of infants who progress from ROP Stage 1 in zone II or III, without plus, to Stage 2 with plus or Stage 3 with plus.
    End point type
    Primary
    End point timeframe
    From the begin to the end of treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was planned according to the Simon optimal two stage design for phase II clinical trials. The study analysis plan required 37 participants to be enrolled in Stage 1. If <6 participants met Stage 1 failure criteria, 59 additional participants would be enrolled in Stage 2. A total of <13 failures of the 96 total participants (in both Stages) would indicate sufficient promise to warrant further investigation. No further statistical analysis were expected.
    End point values
    		 Single arm
    Number of subjects analysed
    97
    Units: Number of patients
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Study period
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Single arm
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse event related to propranolol were reported.
    Serious adverse events
    		 Single arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 98 (4.08%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    3
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
    Additional description: Not related to study drug
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Eye disorders
    Retinal haemorrhage
    Additional description: Not related to study drug
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bilateral papillary pallor
    Additional description: Not related to study drug
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lens opacities
    Additional description: Not related to study drug
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
    Additional description: Not related to study drug
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Infections and infestations
    Viral sepsis
    Additional description: Not related to study drug
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Single arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 98 (0.00%)

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28709412
    http://www.ncbi.nlm.nih.gov/pubmed/31134171
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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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