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    Clinical Trial Results:
    Prostaglandin F2-alpha eye drops (Bimatoprost) in thyroid eye disease: a randomised controlled double blind crossover trial

    Summary
    EudraCT number
    		 2014-000540-15
    Trial protocol
    		 GB  
    Global end of trial date
    25 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Apr 2019
    First version publication date
    17 Apr 2019
    Other versions
    Summary report(s)
    		 BIMA study abstract

    Trial information

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    Trial identification
    Sponsor protocol code
    SPON1266-14
    Additional study identifiers
    ISRCTN number
    		 ISRCTN46696624
    US NCT number
    		 NCT02059655
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 NISCHR RESEARCH FOR PATIENT AND PUBLIC BENEFIT WAL: RFPPB-2012-1015, Research Ethics Committee: 14/WA/0081
    Sponsors
    Sponsor organisation name
    Cardiff University
    Sponsor organisation address
    Newport Road, Cardiff, United Kingdom, CF24 0DE
    Public contact
    Dr Shazli Draman, Cardiff University, 44 (0)29 208 79130, Shaw.C3@cardiff.ac.uk
    Scientific contact
    Dr Shazli Draman, Cardiff University, 44 (0)29 208 79130, Shaw.C3@cardiff.ac.uk
    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 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall objective is to determine if PGF2α eye drops can reduce proptosis in inactive thyroid eye disease.
    Protection of trial subjects
    The safety of Bimatoprost is already established in its use in other indications. However, preliminary risk assessments were conducted and the Trial Management Group routinely reviewed blinded adverse events on a three monthly basis. Since significant new adverse event information was not anticipated, a formal data safety monitoring board (DSMB) was not established. However, it was planned that if an unexpected rate of adverse event is observed, this will be discussed with the Trial Steering Committee and an independent DSMB would be convened to review unmasked data if considered appropriate.
    Background therapy
    		 N/A
    Evidence for comparator
    		 The placebo was an artificial tear. To enhance masking the placebo contained artificial tears with similar preservative (Benzalkonium chloride – marketed preparation) which replicated any mild stinging sensation experienced with Bimatoprost. Both products were relabelled by the trial pharmacist in accordance with EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Annex 13.
    Actual start date of recruitment
    20 Nov 2014
    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
    United Kingdom: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    23
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period from 20 November 2016 to 27 February 2015 in the UK. Single site study. A cross over study with the intention that all 31 patients recruited would take part in the IMP and placebo arms of the study with a washout period in between. 2 periods: Overall trial: specify primary endpoint Baseline period: not duplicated in above

    Pre-assignment
    Screening details
    		 Trial participants were identified from the database of the multidisciplinary thyroid eye disease clinic. The key eligibility criteria was for patients with stable proptosis for at least 6 months duration. Potential participants meeting the inclusion criteria were sent a letter informing them of the study and inviting their participation.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Placebo contained similar preservative as Bimatoprost to replicate the stinging sensation. PI, ophthalmologists & assessors no access to eye drop bottles. Patients instructed not to bring their eye drop bottles to the eye clinic, but only to the hospital pharmacy at the end of each treatment phase for disposal. Objective findings were recorded by the assessor (e.g. proptosis measurements). Assessor had no access to prior assessment records/photos to compare with current measurements.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Bimatoprost
    Arm description
    		 Prostaglandin F2-alpha eye drops
    Arm type
    		 Experimental

    Investigational medicinal product name
    Prostaglandin F2-alpha
    Investigational medicinal product code
    Other name
    Bimatoprost
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    One drop per eye daily of Bimatoprost 0.03%

    Arm title
    		 Placebo
    Arm description
    		 The placebo was an artificial tear. To enhance masking the placebo contained artificial tears with similar preservative (Benzalkonium chloride – marketed preparation) to replicate any stinging sensation experienced with Bimatoprost.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Hypromellose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    1 drop per day

    Number of subjects in period 1
    		Bimatoprost Placebo
    Started
    31
    31
    Allocation to treatment/placebo
    31
    31
    Washout period (2 months)
    31
    31
    Allocation to placebo/treatment
    30
    30
    Completed
    30
    30
    Not completed
    1
    1
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bimatoprost
    Reporting group description
    		 Prostaglandin F2-alpha eye drops

    Reporting group title
    Placebo
    Reporting group description
    		 The placebo was an artificial tear. To enhance masking the placebo contained artificial tears with similar preservative (Benzalkonium chloride – marketed preparation) to replicate any stinging sensation experienced with Bimatoprost.

    Reporting group values
    		 Bimatoprost Placebo Total
    Number of subjects
    		 31 31 31
    Age categorical
    >18 years of age
    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)
    		 23 23 23
        From 65-84 years
    		 8 8 8
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 55.2 (28 to 74) 55.2 (28 to 74) -
    Gender categorical
    Both male & female
    Units: Subjects
        Female
    		 26 26 26
        Male
    		 5 5 5
    Smoking
    Smoking history at visit 1 and any changes in smoking habits documented throughout the trial.
    Units: Subjects
        Smoker
        Non / ex smoker
    Total diplopia
    Units: Subjects
        Intermittent
        Inconstant
        Constant
    Clinical activity score
    Units: Subjects
        CAS 0
        CAS 1
        CAS 2
        CAS 3
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 ± ± -
    GO duration
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 -
    Exophthalmometer
    Units: mm
        arithmetic mean (standard deviation)
    		 ± ± -
    Palpebral aperture
    Units: mm
        arithmetic mean (standard deviation)
    		 ± ± -
    FT4
    Units: pmol/L
        median (inter-quartile range (Q1-Q3))
    		 -
    TSH
    Units: mU/L
        median (inter-quartile range (Q1-Q3))
    		 -
    Subject analysis sets

    Subject analysis set title
    Baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This randomised controlled double blind crossover trial was conducted in a single tertiary care academic medical centre. Patients with longstanding, inactive GO but persistent proptosis (> 20 mm in at least one eye) were recruited. Allowing for a 15% dropout rate, 31 patients were randomized in order to identify a treatment effect of 2.0 mm (p=0.05, two-sided, power 0.88). Following informed consent, participants were randomized to receive Bimatoprost or placebo for three months after which they underwent a two-month washout, before switching to the opposite treatment. The primary outcome was to compare the change in exophthalmometry readings over the two 3-month treatment periods.

    Subject analysis sets values
    		 Baseline
    Number of subjects
    31
    Age categorical
    >18 years of age
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    23
        From 65-84 years
    8
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    55.2 (28 to 74)
    Gender categorical
    Both male & female
    Units: Subjects
        Female
    26
        Male
    5
    Smoking
    Smoking history at visit 1 and any changes in smoking habits documented throughout the trial.
    Units: Subjects
        Smoker
    23
        Non / ex smoker
    8
    Total diplopia
    Units: Subjects
        Intermittent
    8
        Inconstant
    5
        Constant
    6
    Clinical activity score
    Units: Subjects
        CAS 0
    21
        CAS 1
    6
        CAS 2
    4
        CAS 3
    0
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    29 ± 6.5
    GO duration
    Units: years
        median (inter-quartile range (Q1-Q3))
    7.6 (3.6 to 12.3)
    Exophthalmometer
    Units: mm
        arithmetic mean (standard deviation)
    23.6 ± 2.5
    Palpebral aperture
    Units: mm
        arithmetic mean (standard deviation)
    11.1 ± 2.0
    FT4
    Units: pmol/L
        median (inter-quartile range (Q1-Q3))
    15.9 (13.5 to 17.4)
    TSH
    Units: mU/L
        median (inter-quartile range (Q1-Q3))
    0.87 (0.12 to 2.6)

    End points

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    End points reporting groups
    Reporting group title
    Bimatoprost
    Reporting group description
    		 Prostaglandin F2-alpha eye drops

    Reporting group title
    Placebo
    Reporting group description
    		 The placebo was an artificial tear. To enhance masking the placebo contained artificial tears with similar preservative (Benzalkonium chloride – marketed preparation) to replicate any stinging sensation experienced with Bimatoprost.

    Subject analysis set title
    Baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This randomised controlled double blind crossover trial was conducted in a single tertiary care academic medical centre. Patients with longstanding, inactive GO but persistent proptosis (> 20 mm in at least one eye) were recruited. Allowing for a 15% dropout rate, 31 patients were randomized in order to identify a treatment effect of 2.0 mm (p=0.05, two-sided, power 0.88). Following informed consent, participants were randomized to receive Bimatoprost or placebo for three months after which they underwent a two-month washout, before switching to the opposite treatment. The primary outcome was to compare the change in exophthalmometry readings over the two 3-month treatment periods.

    Primary: change in value

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    End point title
    		 change in value
    End point description
    Data analysis will proceed according to CONSORT guidelines for randomised controlled trials. This will be conducted under guidance of senior statistician. The first stage of the analysis will be to use descriptive statistics to describe the group of individuals recruited to the trial in relation to those eligible, and to investigate comparability of the trial arms at baseline. A tabulation of demographic and clinical variables will be carried out to identify any chance imbalances at baseline between the two treatment groups The mean change in proptosis measurement in the treated phase and control phase will be compared with a paired t-test in the first instance. In order to protect the independence of the data points, this will be carried out using the mean improvement of the two eyes where both have been treated. In addition to this proptosis both eyes for patients with both eyes treated and the one eye for patients with only one treated eye will be analysed using a multilev
    End point type
    Primary
    End point timeframe
    3 months
    End point values
    		 Bimatoprost Placebo
    Number of subjects analysed
    29
    29
    Units: mm
        arithmetic mean (standard deviation)
    0.17 ± 1.5
    0.26 ± 2.0
    Attachments
    		 Mean change in proptosis measurement
    Statistical analysis title
    		 paired t-test
    Statistical analysis description
    The mean change in proptosis measurement in the placebo phase and Bimatoprost phase was compared with a paired t-test. This was carried out using the mean improvement of the two eyes where both have been treated or the change in one eye where only one was treated. Multilevel model in STATA version 12 using demographic and clinical variables (including baseline, the order of treatment and carryover effects) was also used to adjust for unexplained variance and obtain better estimates of effect s
    Comparison groups
    Placebo v Bimatoprost
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 paired t-test two-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.67
         upper limit
    		 0.32
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    November 2014 - March 2016
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Serious adverse events
    		 Overall trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 29 (0.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 29 (75.86%)
    Surgical and medical procedures
    surgery - middle ear
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness postural
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    General disorders and administration site conditions
    Nasal cavity/paranasal sinus reactions
         subjects affected / exposed
    7 / 29 (24.14%)
         occurrences all number
    9
    Pain - migraine / headache
         subjects affected / exposed
    6 / 29 (20.69%)
         occurrences all number
    11
    Polydypsia
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Ear and labyrinth disorders
    auditory ear
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Eye disorders
    Foreign body sensation
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Conjunctival hyperemia
         subjects affected / exposed
    10 / 29 (34.48%)
         occurrences all number
    16
    Eye dryness
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Burning sensation
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    3
    Eye pruritus
         subjects affected / exposed
    5 / 29 (17.24%)
         occurrences all number
    5
    Eyelid swelling
         subjects affected / exposed
    5 / 29 (17.24%)
         occurrences all number
    5
    Conjunctivitis
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Difficulty eye opening
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    2
    Eye pain
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Eyelid pigmentation
    Additional description: Dark skin patch right eye
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Ptosis
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Meibomian cyst
         subjects affected / exposed
    4 / 29 (13.79%)
         occurrences all number
    4
    Gastrointestinal disorders
    Diarrhoea and vomiting
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Heartburn/dyspepsia
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Flu-like syndrome
         subjects affected / exposed
    5 / 29 (17.24%)
         occurrences all number
    6
    Bronchospasm
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Urticaria
    Additional description: eczema rash Prickly Heat generalised itchy skin
         subjects affected / exposed
    4 / 29 (13.79%)
         occurrences all number
    4
    Renal and urinary disorders
    Urine colour change
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthritis non-spectic
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Frozen shoulder
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    2
    Plantar fasciitis
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Pain back
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    5
    pain - chest wall
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Pain joint
    Additional description: joint pain aching shoulders Sore shoulder muscle
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    3
    Pain muscle
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Infections and infestations
    Infection
    Additional description: throat infection chest infection Lt Ear infection Chesty cough chest infection Cold sore
         subjects affected / exposed
    4 / 29 (13.79%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 May 2014
    The original placebo (Hypromellose), detailed in the initial CT application, became unavailable. An alternative manufacturer of the same product, Hypromellose, was been found. The excipients in two manufacturer brands were exactly the same.

    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/30880626
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