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    Clinical Trial Results:
    A phase II Clinical Trial on the use of ARA 290 for the treatment of diabetic macular oedema (ARA 290-DMO)

    Summary
    EudraCT number
    		 2015-001940-12
    Trial protocol
    		 GB  
    Global end of trial date
    29 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Aug 2019
    First version publication date
    17 Aug 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    14166NL-AS
    Additional study identifiers
    ISRCTN number
    		 ISRCTN16962255
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Belfast Health & Social Care Trust
    Sponsor organisation address
    Research & Development, 1st Floor, King Edward Buidling, Royal Hospitals, Grosvenor Road, Belfast, United Kingdom, BT12 6BA
    Public contact
    NICTU, Northern Ireland Clinical Trials Unit (NICTU), 028 90635794, info@nictu.hscni.net
    Scientific contact
    NICTU, Northern Ireland Clinical Trials Unit (NICTU), 028 90635794, info@nictu.hscni.net
    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
    30 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The aim or primary objective of the study is to determine whether ARA 290 administered at a daily dose of 4mg subcutaneously for 12 weeks to patients with diabetes mellitus (DM) and Diabetic Macular Oedema (DMO) will have a beneficial effect on mean change in best corrected visual acuity (BCVA) from baseline values to week 12.
    Protection of trial subjects
    Prior to commencement of recruitment to the study, the following safety measures were introduced: - On advice from MHRA the protocol was amended to exclude pregnant or breast feeding women. All female potential participants of child bearing age were given a pregnancy test before recruitment to the study. All females of child bearing age, and all male participants who had a female partner of child bearing age, were advised of the need to use effective contraception during and for at least 30 days post administration of the final dose of the study drug. Any participant who could not ensure this was not recruited to the study. - On advice from the Sponsor, the GP letter was amended to advise the patient GP that ARA 290 may have a possible improvement on the patient’s glucose levels which may lead to the necessity to amend the patient’s diabetes medicine accordingly. -Araim (study drug provider) advised that the first DSUR report for the APCP-112 study noted one patient who reported having suicidal thoughts. Although this patient had a history of depression and was receiving a higher dose of ARA 290 (8mg daily), on advice from the FDA it was agreed that all subsequent studies of ARA 290 should include a suicide screening tool. To comply with this, all participants to the ARA 290-DMO study completed the Columbia Suicide Severity Rating Scale (C-SSRS) at each study visit. The protocol mandated that participants whose sight was determined as deteriorating to the point of a 10 letter drop in sight would have ARA 290 stopped and would be offered the current standard care treatment. Likewise, patients who wished to withdraw from the study, or those who completed the duration of the study and in whom DMO persisted were offered standard care treatment. Study participants were assessed for adverse events at each study visit and assessed again by telephone 4 weeks after the final dose of study drug was taken.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    06 May 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 9
    Worldwide total number of subjects
    9
    EEA total number of subjects
    9
    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)
    6
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The ARA 290-DMO study recruited 9 out of the target of 10 patients before terminating early due to expiry of study drug (see Interruptions Globally section). The first patient was recruited on 06th May 2016. Recruitment was staggered in batches of 2 at the request of the study DMEC. The final patient 9 was recruited on 24th February 2017.

    Pre-assignment
    Screening details
    		 Patients attending ophthalmology clinics at Belfast Trust or referred to the CI by other BHSCT ophthalmology consultants. Patients ≥18 years old with DMO with central subfield thickness of ≥ 400 microns, determined by SD-OCT. Clear media and naïve to previous treatment for DMO. A total of 23 patients were screened.

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

    Arms
    Arm title
    		 Baseline - ARA290
    Arm description
    		 Subcutaneous daily administration of ARA 290 in a dose of 4mg for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARA 290-DMO
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    -ARA 290 used for subcutaneous injection is provided as aseptic vials containing 5.6mg ARA 290, which after reconstitution with 0.66ml sterile water for injection contains a solution of 8mg/ml ARA 290 in a 20mM sodium phosphate buffer, pH 6.5, containing 1% sucrose and 4% D-mannitol. A volume of 0.5mL contains 4mg ARA 290. -Participation in the study involves subcutaneous daily administration of ARA 290 at a dose of 4mg for 12 weeks duration. The first injection is self administered by the patient at the first clinic visit after receiving practical verbal and written instruction. The injection is given in the front or side of the thigh. In the unlikely event that the thigh cannot be used, the injection may be given in the abdomen. Each patient is given an initial pack of 30 vials to provide 28 day treatment and 2 extra to allow for spilling/spoilage. The pack is replaced at week 4, 8 and 12 study visit. Drug accountability of used/unused drug is maintained by BHSCT pharmacy.

    Number of subjects in period 1
    		Baseline - ARA290
    Started
    9
    Completed
    9
    Period 2
    Period 2 title
    12 Week
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 12 Week - ARA290
    Arm description
    		 Subcutaneous daily administration of ARA 290 in a dose of 4mg for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARA 290-DMO
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    -ARA 290 used for subcutaneous injection is provided as aseptic vials containing 5.6mg ARA 290, which after reconstitution with 0.66ml sterile water for injection contains a solution of 8mg/ml ARA 290 in a 20mM sodium phosphate buffer, pH 6.5, containing 1% sucrose and 4% D-mannitol. A volume of 0.5mL contains 4mg ARA 290. -Participation in the study involves subcutaneous daily administration of ARA 290 at a dose of 4mg for 12 weeks duration. The first injection is self administered by the patient at the first clinic visit after receiving practical verbal and written instruction. The injection is given in the front or side of the thigh. In the unlikely event that the thigh cannot be used, the injection may be given in the abdomen. Each patient is given an initial pack of 30 vials to provide 28 day treatment and 2 extra to allow for spilling/spoilage. The pack is replaced at week 4, 8 and 12 study visit. Drug accountability of used/unused drug is maintained by BHSCT pharmacy.

    Number of subjects in period 2 [1]
    		12 Week - ARA290
    Started
    8
    Completed
    8
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: One patient dropped out post baseline but prior to week 12 due to experiencing a 10 letter loss in vision. Total number of patients at baseline = 9. Total number of patients at week 12 = 8.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline Period
    Reporting group description
    		 Baseline Characteristics are calculated based on 9 patients at baseline. n=17 is presented above as per EudraCT advice on reporting single arm studies.

    Reporting group values
    		 Baseline Period Total
    Number of subjects
    		 9 9
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        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)
    		 6 6
        From 65-84 years
    		 3 3
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.6 ( 13.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 5 5
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 95.5 ( 20.5 ) -
    Height
    Units: metres
        arithmetic mean (standard deviation)
    		 1.6 ( 0.12 ) -
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 37.18 ( 12.1 ) -
    Systolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 145.2 ( 17.0 ) -
    Diastolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 74.9 ( 10.1 ) -
    Heart Rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 70.8 ( 14.1 ) -
    Temperature
    Units: degrees celsius
        arithmetic mean (standard deviation)
    		 36.3 ( 0.28 ) -
    Oxygen Saturation
    Units: Percentage
        arithmetic mean (standard deviation)
    		 98.0 ( 1.3 ) -
    C-peptide
    data available for n=6
    Units: ng/ml
        arithmetic mean (standard deviation)
    		 2.5 ( 3.2 ) -
    Glucose
    data available for n=8
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 9.7 ( 3.9 ) -
    HDL
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 1.2 ( 0.26 ) -
    LDL
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.1 ( 0.85 ) -
    Triglycerides
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.1 ( 1.0 ) -
    Albumin Creatinine Ratio
    Units: mmoL
        arithmetic mean (standard deviation)
    		 32.1 ( 72.2 ) -
    AST
    data available for n = 8
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 25.5 ( 9.5 ) -
    ALT
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 27.8 ( 16.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    Baseline - ARA290
    Reporting group description
    		 Subcutaneous daily administration of ARA 290 in a dose of 4mg for 12 weeks
    Reporting group title
    12 Week - ARA290
    Reporting group description
    		 Subcutaneous daily administration of ARA 290 in a dose of 4mg for 12 weeks

    Primary: Primary Outcome; best corrected distance visual acuity (study eye)

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    End point title
    		 Primary Outcome; best corrected distance visual acuity (study eye)
    End point description
    Changes from baseline to week 12 (+/– 7 days) in best corrected distance visual acuity (study eye)
    End point type
    Primary
    End point timeframe
    Change from baseline to week 12 in study eye
    End point values
    		 Baseline - ARA290 12 Week - ARA290
    Number of subjects analysed
    9
    8
    Units: logMAR
        arithmetic mean (standard deviation)
    68.1 ( 7.9 )
    66.3 ( 9.5 )
    Statistical analysis title
    		 Best corrected distance visual activity_Study Eye
    Statistical analysis description
    95% Confidence Interval for the primary outcome (study eye)
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.1
         upper limit
    		 1.3
    Variability estimate
    Standard deviation
    Dispersion value
    5
    Notes
    [1] - Mean Difference (95% CI) presented for change from Baseline to Week 12.

    Primary: Primary Outcome; best corrected distance visual acuity (non study eye)

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    End point title
    		 Primary Outcome; best corrected distance visual acuity (non study eye)
    End point description
    Changes from baseline to week 12 (+/– 7 days) in best corrected distance visual acuity (non study eye)
    End point type
    Primary
    End point timeframe
    Change from baseline to week 12 in non study eye
    End point values
    		 Baseline - ARA290 12 Week - ARA290
    Number of subjects analysed
    9
    8
    Units: logMAR
        arithmetic mean (standard deviation)
    69.0 ( 14.9 )
    75.9 ( 9.4 )
    Statistical analysis title
    		 Primary Outcome (Non study eye)
    Statistical analysis description
    95% Confidence Interval
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.88
         upper limit
    		 9.4
    Variability estimate
    Standard deviation
    Dispersion value
    6.1
    Notes
    [2] - Mean Difference (95% Confidence Interval) presented for change from Baseline to Week 12

    Secondary: Central Subfield Thickness (study eye)

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    End point title
    		 Central Subfield Thickness (study eye)
    End point description
    Central subfield retinal thickness (CST), as obtained in the central 1 mm area, will be determined by spectral domain optical coherence tomography (SD-OCT) and used for the analysis. In addition, presence or absence of intraretinal or subretinal fluid will be evaluated and recorded in the appropriate CRF. SD-OCT will be obtained in both eyes by an ophthalmic photographer at baseline and weeks 4, 8 and 12. If at week 12 the retina is dry, a further visit at week 16 will be undertaken and SD-OCT obtained at this visit.
    End point type
    Secondary
    End point timeframe
    Changes from baseline to week 12 (+/– 7 days)
    End point values
    		 Baseline - ARA290 12 Week - ARA290
    Number of subjects analysed
    9
    8
    Units: microns
        arithmetic mean (standard deviation)
    490.3 ( 61.9 )
    498.5 ( 127.1 )
    Statistical analysis title
    		 95% Confidence Interval
    Comparison groups
    12 Week - ARA290 v Baseline - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -69.1
         upper limit
    		 89.1
    Variability estimate
    Standard deviation
    Dispersion value
    94.6

    Secondary: Central subfield thickness (Non study eye)

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    End point title
    		 Central subfield thickness (Non study eye)
    End point description
    Central subfield retinal thickness (CST), as obtained in the central 1 mm area, will be determined by spectral domain optical coherence tomography (SD-OCT) and used for the analysis. In addition, presence or absence of intraretinal or subretinal fluid will be evaluated and recorded in the appropriate CRF. SD-OCT will be obtained in both eyes by an ophthalmic photographer at baseline and weeks 4, 8 and 12. If at week 12 the retina is dry, a further visit at week 16 will be undertaken and SD-OCT obtained at this visit.
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/– 7 days)
    End point values
    		 Baseline - ARA290 12 Week - ARA290
    Number of subjects analysed
    9
    8
    Units: Microns
        arithmetic mean (standard deviation)
    349.7 ( 72.5 )
    347.9 ( 78.1 )
    Statistical analysis title
    		 95% Confidence Interval
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.2
         upper limit
    		 23.2
    Variability estimate
    Standard deviation
    Dispersion value
    20

    Secondary: Central Retinal Sensistivity (Study Eye)

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    End point title
    		 Central Retinal Sensistivity (Study Eye)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290 12 Week - ARA290
    Number of subjects analysed
    9
    8
    Units: dB
        arithmetic mean (standard deviation)
    23.3 ( 2.2 )
    23.2 ( 2.3 )
    Statistical analysis title
    		 95% Confidence Interval
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 1.1
    Variability estimate
    Standard deviation
    Dispersion value
    1.9

    Secondary: Central Retinal Sensitivity (Non Study Eye)

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    End point title
    		 Central Retinal Sensitivity (Non Study Eye)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290 12 Week - ARA290
    Number of subjects analysed
    9
    8
    Units: dB
        arithmetic mean (standard deviation)
    23.3 ( 3.4 )
    24.2 ( 2.4 )
    Statistical analysis title
    		 95% Confidence Interval
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 1.7
    Variability estimate
    Standard deviation
    Dispersion value
    2

    Secondary: Retinal Perfusion_Macular Ischaemia (Study Eye)

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    End point title
    		 Retinal Perfusion_Macular Ischaemia (Study Eye)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290
    Number of subjects analysed
    8
    Units: N/A
        Extension
    0
        Reduction
    0
        No Change
    5
        N/A
    2
        UNOB
    1
    No statistical analyses for this end point

    Secondary: Retinal Perfusion_Foveal Ischaemia (Non Study Eye)

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    End point title
    		 Retinal Perfusion_Foveal Ischaemia (Non Study Eye)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290
    Number of subjects analysed
    8
    Units: N/A
        Extension
    0
        Reduction
    0
        No Change
    1
        N/A
    5
        UNOB
    2
    No statistical analyses for this end point

    Secondary: Retinal Perfusion_Foveal Ischaemia (Study Eye)

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    End point title
    		 Retinal Perfusion_Foveal Ischaemia (Study Eye)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290
    Number of subjects analysed
    8
    Units: N/A
        Extension
    0
        Reduction
    0
        No Change
    3
        N/A
    4
        UNOB
    1
    No statistical analyses for this end point

    Secondary: Retinal Perfusion_Macular Ischaemia (Non Study Eye)

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    End point title
    		 Retinal Perfusion_Macular Ischaemia (Non Study Eye)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290
    Number of subjects analysed
    8
    Units: N/A
        Extension
    0
        Reduction
    0
        No Change
    2
        N/A
    4
        UNOB
    2
    No statistical analyses for this end point

    Secondary: Retinal Perfusion_Peripheral Ischaemia (Study Eye)

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    End point title
    		 Retinal Perfusion_Peripheral Ischaemia (Study Eye)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290
    Number of subjects analysed
    8
    Units: N/A
        Extension
    0
        Reduction
    0
        No Change
    3
        N/A
    4
        UNOB
    1
    No statistical analyses for this end point

    Secondary: Retinal Perfusion_Peripheral Ischaemia (Non Study Eye)

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    End point title
    		 Retinal Perfusion_Peripheral Ischaemia (Non Study Eye)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290
    Number of subjects analysed
    8
    Units: N/A
        Extension
    0
        Reduction
    0
        No Change
    3
        N/A
    3
        UNOB
    2
    No statistical analyses for this end point

    Secondary: Tear Production (Study Eye)

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    End point title
    		 Tear Production (Study Eye)
    End point description
    The Schirmer test will be performed to measure tear production. The test will be undertaken by a Research Nurse at baseline and at week 12. If a further visit at week 16 is undertaken, this test will be also performed at this additional visit. This is a safe test which poses no risk to the patient. A negative test result is normal i.e. more than 10mm of moisture on the filter paper in 5 minutes. As both eyes normally secrete the same amount of tears, this test will be only done in the study eye (see Statistical Considerations section). This test will be done following completion of all functional tests (i.e. BCVA and microperimetry). This test is included as patients with DR often complain of dry eyes, most likely related to reduced corneal nerve fibre density.
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290 12 Week - ARA290
    Number of subjects analysed
    9
    8
    Units: mm
        arithmetic mean (standard deviation)
    13.4 ( 8.8 )
    13.8 ( 2.4 )
    Statistical analysis title
    		 95% Confidence Intervals
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 6.3
    Variability estimate
    Standard deviation
    Dispersion value
    7.7

    Secondary: Suicide Ideation

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    End point title
    		 Suicide Ideation
    End point description
    Suicidal ideation will be assessed using the Columbia Suicide Severity Rating Scale (C-SSRS) which will be administered to patients at baseline and weeks 4, 8 and 12. If at 12 weeks the retina is dry a further visit at week 16 will be arranged and questionnaires completed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Baseline - ARA290 12 Week - ARA290
    Number of subjects analysed
    9
    8
    Units: N/A
        Yes
    0
    0
        No
    9
    8
    No statistical analyses for this end point

    Secondary: NEI VFQ-25

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    End point title
    		 NEI VFQ-25
    End point description
    The NEI VFQ-25 is a vision specific patient reported quality of life tool. This validated questionnaire has been used widely to evaluate visual outcomes in patients with eye diseases including DR. In addition to eliciting information about general health and vision it specifically addresses difficulty with near vision, distance vision, driving and the effect of light conditions on vision. This provides a comprehensive evaluation of vision related quality of life.
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290 12 Week - ARA290
    Number of subjects analysed
    9
    8
    Units: N/A
    arithmetic mean (standard deviation)
        General Health
    47.2 ( 29.2 )
    46.9 ( 20.9 )
        General Vision
    64.4 ( 21.9 )
    70.0 ( 10.7 )
        Ocular Pain
    70.8 ( 22.5 )
    85.9 ( 10.4 )
        Near Activities
    69.9 ( 23.2 )
    80.2 ( 18.9 )
        Distance Activities
    80.1 ( 22.2 )
    85.4 ( 16.5 )
        Social Functioning
    91.7 ( 16.5 )
    98.4 ( 4.4 )
        Mental Health
    71.5 ( 27.6 )
    84.4 ( 12.9 )
        Role Difficulties
    79.2 ( 23.4 )
    92.2 ( 13.3 )
        Dependency
    84.3 ( 24.1 )
    92.7 ( 15.1 )
        Driving
    93.1 ( 8.2 )
    94.4 ( 6.8 )
        Colour Vision
    94.4 ( 16.7 )
    96.9 ( 8.8 )
        Peripheral Vision
    80.6 ( 24.3 )
    84.4 ( 12.9 )
        Composite Score
    79.0 ( 20.1 )
    87.5 ( 6.9 )
    Statistical analysis title
    		 95% Confidence Interval_General Health
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.8
         upper limit
    		 12.3
    Variability estimate
    Standard deviation
    Dispersion value
    22.2
    Statistical analysis title
    		 95% Confidence Interval_General Vision
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.9
         upper limit
    		 8.9
    Variability estimate
    Standard deviation
    Dispersion value
    10.7
    Statistical analysis title
    		 95% Confidence Interval_Ocular Pain
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 18.6
    Variability estimate
    Standard deviation
    Dispersion value
    11.1
    Statistical analysis title
    		 95% Confidence Interval_Near Activities
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.1
         upper limit
    		 26.6
    Variability estimate
    Standard deviation
    Dispersion value
    24.3
    Statistical analysis title
    		 95% Confidence Interval_Distance Activities
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.8
         upper limit
    		 11.8
    Variability estimate
    Standard deviation
    Dispersion value
    14.1
    Statistical analysis title
    		 95% Confidence Interval_Social Functioning
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 8.3
    Variability estimate
    Standard deviation
    Dispersion value
    8
    Statistical analysis title
    		 95% Confidence Interval_Mental Health
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 14.9
    Variability estimate
    Standard deviation
    Dispersion value
    11.3
    Statistical analysis title
    		 95% Confidence Interval_Role Difficulties
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 22.8
    Variability estimate
    Standard deviation
    Dispersion value
    16
    Statistical analysis title
    		 95% Confidence Interval_Dependency
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 10.5
    Variability estimate
    Standard deviation
    Dispersion value
    11.3
    Statistical analysis title
    		 95% Confidence Interval_Driving
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.8
         upper limit
    		 11.6
    Variability estimate
    Standard deviation
    Dispersion value
    9.7
    Statistical analysis title
    		 95% Confidence Interval_Colour Vision
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.5
         upper limit
    		 4.3
    Variability estimate
    Standard deviation
    Dispersion value
    8.8
    Statistical analysis title
    		 95% Confidence Interval_Peripheral Vision
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.5
         upper limit
    		 10.3
    Variability estimate
    Standard deviation
    Dispersion value
    16
    Statistical analysis title
    		 95% Confidence Interval_Composite Score
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 10
    Variability estimate
    Standard deviation
    Dispersion value
    3.1

    Secondary: EQ-5D-5L

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    End point title
    		 EQ-5D-5L
    End point description
    A generic health status measure EQ-5D-5L will be used to generate utility data. Total scores will be recorded and used for the analysis.
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290 12 Week - ARA290
    Number of subjects analysed
    9
    8
    Units: N/A
        arithmetic mean (standard deviation)
    0.7 ( 0.4 )
    0.8 ( 0.3 )
    Statistical analysis title
    		 95% Confidence Interval_Index
    Comparison groups
    Baseline - ARA290 v 12 Week - ARA290
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.1
    Variability estimate
    Standard deviation
    Dispersion value
    0.2

    Secondary: % of participants with >= 10 letter gain (Study Eye)

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    End point title
    		 % of participants with >= 10 letter gain (Study Eye)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290
    Number of subjects analysed
    8
    Units: N/A
        Yes
    0
        No
    8
    No statistical analyses for this end point

    Secondary: % of participants with >= 10 letter gain (Non Study Eye)

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    End point title
    		 % of participants with >= 10 letter gain (Non Study Eye)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290
    Number of subjects analysed
    8
    Units: N/A
        Yes
    1
        No
    7
    No statistical analyses for this end point

    Secondary: % of participants with >= 15 letter gain (Study Eye)

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    End point title
    		 % of participants with >= 15 letter gain (Study Eye)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290
    Number of subjects analysed
    8
    Units: N/A
        Yes
    0
        No
    8
    No statistical analyses for this end point

    Secondary: % of participants with >= 15 letter gain (Non Study Eye)

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    End point title
    		 % of participants with >= 15 letter gain (Non Study Eye)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 12 (+/- 7 days)
    End point values
    		 Baseline - ARA290
    Number of subjects analysed
    8
    Units: N/A
        Yes
    1
        No
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event reporting period began upon enrolment into the trial and ended 30 days following the last administration of the study drug. Each participant was assessed for AEs by telephone 4 weeks after they received the final dose of study drug.
    Adverse event reporting additional description
    Participants administered the first dose of ARA 290 at the first study visit. These participants were contacted by phone 2 weeks later to assess them for adverse events (AE). Participants were again assessed in person for AEs at each study visit and again by telephone 4 weeks after the last dose of ARA 290 was taken.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Subcutaneous daily administration of ARA 290 in a dose of 4mg for 12 weeks

    Serious adverse events
    		 Intervention
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intervention
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    Investigations
    GGT Increased
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Abnormal blood test results
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    General disorders and administration site conditions
    Head cold
         subjects affected / exposed
    4 / 9 (44.44%)
         occurrences all number
    5
    Headache
         subjects affected / exposed
    4 / 9 (44.44%)
         occurrences all number
    5
    Flu symptoms
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Raised Reticulocytes level
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Eye disorders
    Drop in visual acuity
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Flashing lights
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Facial Sunburn
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Infections and infestations
    Infections - other
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    5 / 9 (55.56%)
         occurrences all number
    5
    Hyperglycaemia
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    3
    Hypoglycaemia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Metabolism and nutrition disorders - other
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Nov 2015
    AMENDMENT 1: Sponsor requested changes: Protocol: -Amended from v1.0 to v2.0 to add advice re the process for recording and reporting of urgent safety measures. Protocol v2.0 to v3.0 to update study schematic to include pregnancy test and to update Recording and Reporting of Urgent Safety Measures to bring the wording in line with Sponsor SOPs. GP Letter: Amended from v1.0 to v2.0 to advise that ARA 290 may have a possible improvement on the patient’s glucose levels which may lead to the necessity to amend the patient’s diabetes medicine accordingly. Change of CI/PI address updated. Patient Information Sheet: Amended from v1.0 to v2.0 to explain to the participant why they are being asked to complete the C-SSRS questionnaire to ascertain their mental health status. Amended from v2.0 to v3.0 to advise the patient that ARA 290 may have a possible improvement on the patient’s glucose levels which may lead to the necessity to amend their diabetes medicine accordingly. ORECNI requested changes: Consent Form: Amended from v1.0 to v2.0 to remove the “witness” signature line. MHRA requested changes: Protocol: Amended from v1.0 to v2.0: •To add the exclusion: “Men who have a female partner and who are unwilling to undertake adequate precautions to prevent pregnancy for the duration of the trial” •A pregnancy test was added for females of child bearing age and advice on contraceptive use and pregnancy reporting added. •The change of address for the CI, Research Nurse and co-investigator was updated. •Advice added that Araim Pharmaceuticals, Inc. may also request consent to collect confidential information about the patient’s health and that of the baby in the event of pregnancy. -Study Drug Admin Guidelines: Amended from v1.0 to v2.0 to explain that the study drug should be injected immediately after reconstituting the study drug or discarded.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    06 May 2016
    As ARA 290 had not been trialled at a dose of 4mg for the study intervention period of 84 days, the study DMEC requested a staggered start to the study to minimise the risk to patient safety. To comply with this the first 2 patients were recruited and recruitment was put on hold until the DMEC had reviewed the data for these patients. Patients 3 and 4 were then recruited and recruitment was put on hold until the data for patients 1 to 4 was reviewed. Patients 5 and 6 were then recruited and recruitment was put on hold until the DMEC had reviewed the data for patients 1 - 6, at this point the DMEC advised that recruitment of patients 7 - 10 could progress. Patients 7 – 9 were recruited, however this delay in recruitment led to the expiry of the study drug. When 9 out of the target of 10 patients had been recruited it became apparent that it would not be possible to recruit patient 10 and have them complete the 84 day treatment period before the expiry of the stock of study drug. The study CI approached Araim Pharmaceuticals (study drug provider) to request an additional 84 day pack of the study drug to allow recruitment of patient 10 to continue. Araim Pharmaceuticals declined to provide this additional study drug, stating that all supplies of ARA 290 were committed to another study. After lengthy discussions between Araim and the study Sponsor it was reluctantly agreed to complete the trial with patient 9 and to report the study as an early termination on the basis that the 10th patient would not be recruited. The date of “end of complete trial” and “date of early termination” reflect the date of database closure as per end of trial definition in the study protocol. A sample size of 10 was considered sufficient to provide an indication of a potential beneficial effect of the drug on the outcomes investigated and further information on safety of ARA 290 in a diabetic population. Nine rather than ten subjects will still be sufficient to meet the objectives.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early termination of study - 9 out of the intended target of 10 patients recruited. As per protocol the study drug was stopped for patient 3 due to a 10 letter deterioration in sight. Data for this patient is only available up to week 4.
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