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    Clinical Trial Results:
    Correlation of functional and structural outcomes with serum antibody profiles in patients with neovascular age-related macular degeneration treated with ranibizumab and healthy subjects: a prospective, controlled monocenter trial

    Summary
    EudraCT number
    		 2013-003352-20
    Trial protocol
    		 DE  
    Global end of trial date
    09 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jun 2021
    First version publication date
    02 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    469055
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Medical Center of the Johannes Gutenberg - University Mainz
    Sponsor organisation address
    Langenbeckstraße 2, Mainz, Germany, 55131
    Public contact
    Clinical Trial Center, University Medical Center of Johannes-Gutenberg University Mainz, +49 6131175741, christina.korb@unimedizin-mainz.de
    Scientific contact
    Clinical Trial Center, University Medical Center of Johannes-Gutenberg University Mainz, +49 6131175741, christina.korb@unimedizin-mainz.de
    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
    09 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy (change in BCVA) of IVT administered ranibizumab in subjects with all subtypes of neovascular AMD.
    Protection of trial subjects
    The procedures set out in the trial protocol, pertaining to the conduct, evaluation, and documenta-tion of this trial, were designed to ensure that all persons involved in the trial abide by GCP and the ethical principles described in the Declaration of Helsinki. The trial was carried out in keeping with local legal and regulatory requirements. The requirements of the AMG, the GCP regulation, and the Federal Data Protection Law (BDSG) were adhered to.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jul 2016
    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
    Germany: 71
    Worldwide total number of subjects
    71
    EEA total number of subjects
    71
    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
    49
    85 years and over
    16

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment and treatment of subjects was performed in one trial center. Eligible trial participants for the AMD group were ≥ 50 years of age, showed subfoveal, juxtafoveal and/or extrafoveal choroidal neovascularisation due to neovascular age-related macular degeneration and had a visual acuity of 20/400 or better in the study eye.

    Pre-assignment
    Screening details
    		 71 subjects were enrolled in this study. This comprises 50 patients with neovascular AMD and 20 control subjects. One subject was screened incorrectly and was excluded from the study. 65 subjects completed the trial.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AMD Group (neovascular age-related macular degeneration)
    Arm description
    		 Patients in the AMD group received three IVT Lucentis injections (0.5mg) within the first three months, followed by an individual therapy based on clinical progress (pro re nata, PRN). Patients had a total of six visits.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lucentis (Ranibizumab, Novartis Pharma GmbH)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Three monthly IVT injections of 0.5mg Lucentis (Ranibizumab), followed by PRN therapy.

    Arm title
    		 Control group
    Arm description
    		 Control group of 20 healthy volunteers. Subject received no treatment. Subjects had one visit.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		AMD Group (neovascular age-related macular degeneration) Control group
    Started
    50
    20
    Completed
    45
    20
    Not completed
    5
    0
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    2
    -
         Physician decision
    2
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: This Period consist of one visit only and subjects either still participated in the study at this timepoint of not. Therefore, subjects starting and ending the period are equal, whereas subject number in subsequent periods can vary.
    Period 2
    Period 2 title
    Visit 4
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 AMD Group - Visit 4
    Arm description
    		 Patients in the AMD group received three IVT Lucentis injections (0.5mg) within the first three months, followed by an individual therapy based on clinical progress (pro re nata, PRN). Patients had a total of six visits.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lucentis (Ranibizumab, Novartis Pharma GmbH)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Three monthly IVT injections of 0.5mg Lucentis (Ranibizumab), followed by PRN therapy.

    Number of subjects in period 2 [2]
    		AMD Group - Visit 4
    Started
    49
    Completed
    49
    Notes
    [2] - 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: This Period consist of one visit only and subjects either still participated in the study at this timepoint of not. Therefore, subjects starting and ending the period are equal, whereas subject number in subsequent periods can vary.
    Period 3
    Period 3 title
    Visit 7
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 AMD Group - Visit 7
    Arm description
    		 Patients in the AMD group received three IVT Lucentis injections (0.5mg) within the first three months, followed by an individual therapy based on clinical progress (pro re nata, PRN). Patients had a total of six visits.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lucentis (Ranibizumab, Novartis Pharma GmbH)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Three monthly IVT injections of 0.5mg Lucentis (Ranibizumab), followed by PRN therapy.

    Number of subjects in period 3 [3]
    		AMD Group - Visit 7
    Started
    45
    Completed
    45
    Notes
    [3] - 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: This Period consist of one visit only and subjects either still participated in the study at this timepoint of not. Therefore, subjects starting and ending the period are equal, whereas subject number in subsequent periods can vary.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AMD Group (neovascular age-related macular degeneration)
    Reporting group description
    		 Patients in the AMD group received three IVT Lucentis injections (0.5mg) within the first three months, followed by an individual therapy based on clinical progress (pro re nata, PRN). Patients had a total of six visits.

    Reporting group title
    Control group
    Reporting group description
    		 Control group of 20 healthy volunteers. Subject received no treatment. Subjects had one visit.

    Reporting group values
    		 AMD Group (neovascular age-related macular degeneration) Control group Total
    Number of subjects
    		 50 20 70
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 3 3 6
        From 65-84 years
    		 33 16 49
        85 years and over
    		 14 1 15
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 78.48 (58 to 92) 71.05 (50 to 89) -
    Gender categorical
    Units: Subjects
        Female
    		 26 15 41
        Male
    		 24 5 29
    BCVA - ETDRS letters (study eye)
    Visual acuity (VA) was assessed at every study visit. VA measurements were done using the 4 meter Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Best-corrected visual acuity (BCVA) examiners followed the operations manual and training materials by EMMES Corporation. ETDRS letter scores have been measured to monitor the BCVA in patients receiving ranibizumab injections during the study. Reported are the mean values of the ETDRS letter score for each group. VA was not assesed in the control group. The values for the control group were set to 0.
    Units: ETDRS letter score
        arithmetic mean (standard deviation)
    		 59.56 ( 18.69 ) 0 ( 0 ) -
    Central retinal thickness (CRT)
    Central retinal thickness (CRT) in µm, measured by OCT. CRT was not evalued in the control group. Values for the control group are entered as 0.
    Units: micrometer
        arithmetic mean (standard deviation)
    		 414.400 ( 109.943 ) 0 ( 0 ) -
    Number of IVT Lucentis injections
    Mean number of IVT ranibizumab injections needed up to Week 24 (Visit 7) in the study eye
    Units: Number
        arithmetic mean (full range (min-max))
    		 0 (0 to 0) 0 (0 to 0) -
    Anti TTR antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Transthyretin.
    Units: NFI
        arithmetic mean (standard deviation)
    		 329.293044 ( 431.943317 ) 1566.17808 ( 6469.5959 ) -
    Anti CA2 antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Carbonic anhydrase 2.
    Units: NFI
        arithmetic mean (standard deviation)
    		 78920.0649 ( 83062.665 ) 82277.5998 ( 137369.877 ) -
    Anti ACO2 antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Aconitate hydratase, mitochondrial.
    Units: NFI
        arithmetic mean (standard deviation)
    		 421.379196 ( 527.218781 ) 415.459782 ( 939.568278 ) -
    Anti HSPD1 antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against 60 kDa heat shock protein, mitochondrial.
    Units: NFI
        arithmetic mean (standard deviation)
    		 51105.2926 ( 82597.9777 ) 28166.4324 ( 28429.8058 ) -
    Anti MBP antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Myelin basic protein.
    Units: NFI
        arithmetic mean (standard deviation)
    		 4327.52687 ( 5323.6392 ) 5302.23291 ( 15823.628 ) -
    Anti SOD antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Superoxid dismutase.
    Units: NFI
        arithmetic mean (standard deviation)
    		 1339.36517 ( 2675.99626 ) 775.195033 ( 1965.63135 ) -
    Anti SNCG antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Gamma-synuclein.
    Units: NFI
        arithmetic mean (standard deviation)
    		 11879.0444 ( 21368.6767 ) 6843.90305 ( 8509.90635 ) -
    Anti ALB antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Albumin.
    Units: NFI
        arithmetic mean (standard deviation)
    		 11626.4445 ( 20103.2013 ) 6169.12712 ( 12009.731 ) -
    Anti Mucin antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Mucin.
    Units: NFI
        arithmetic mean (standard deviation)
    		 2384.57079 ( 2463.19117 ) 4437.92132 ( 11389.5247 ) -
    Anti BDNF antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Brain-derived neurotrophic factor.
    Units: NFI
        arithmetic mean (standard deviation)
    		 20712.2938 ( 35670.3539 ) 27359.6591 ( 36640.9169 ) -
    Anti CALR antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Calretuculin.
    Units: NFI
        arithmetic mean (standard deviation)
    		 41323.5932 ( 46052.176 ) 65456.0954 ( 127619.468 ) -
    Anti NTF3 antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Neutrophin-3.
    Units: NFI
        arithmetic mean (standard deviation)
    		 23553.6116 ( 27445.1585 ) 56117.993 ( 148412.373 ) -
    Anti TF antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Serotransferrin.
    Units: NFI
        arithmetic mean (standard deviation)
    		 12805.6082 ( 23422.2683 ) 16308.7444 ( 29590.8418 ) -
    Anti OGFR antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Opioid growth factor receptor.
    Units: NFI
        arithmetic mean (standard deviation)
    		 4710.51796 ( 6215.37289 ) 6354.39204 ( 11293.1811 ) -
    Anti groEL2 antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against 60kDa chaperonin 2.
    Units: NFI
        arithmetic mean (standard deviation)
    		 45606.0488 ( 75093.5616 ) 25624.7987 ( 28341.476 ) -
    Anti NTF4 antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Neurotrophin-4.
    Units: NFI
        arithmetic mean (standard deviation)
    		 2229.58324 ( 3200.51454 ) 3070.13054 ( 6567.93249 ) -
    Anti Dermcidin antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Dermcidin.
    Units: NFI
        arithmetic mean (standard deviation)
    		 13639.2395 ( 34467.3342 ) 10111.0475 ( 14190.151 ) -
    Anti CLUS antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Clusterin.
    Units: NFI
        arithmetic mean (standard deviation)
    		 3613.51411 ( 4544.54803 ) 4695.5411 ( 10040.046 ) -
    Anti VEGF antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Vascular endothelial growth factor.
    Units: NFI
        arithmetic mean (standard deviation)
    		 5270.56345 ( 10764.55 ) 7918.14187 ( 22694.7257 ) -
    Anti EIF4A1 antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Eukaryotic initiation factor 4A-I.
    Units: NFI
        arithmetic mean (standard deviation)
    		 1384.61068 ( 2451.61235 ) 1828.40721 ( 3855.40767 ) -
    Anti PRKCSH antibody
    Normalized fluorescence intensity obtained by protein microarray measurements of autoantibody reactivity against Glucosidase 2 subunit beta.
    Units: NFI
        arithmetic mean (standard deviation)
    		 4092.94729 ( 4680.60189 ) 4280.82021 ( 5309.7701 ) -

    End points

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    End points reporting groups
    Reporting group title
    AMD Group (neovascular age-related macular degeneration)
    Reporting group description
    		 Patients in the AMD group received three IVT Lucentis injections (0.5mg) within the first three months, followed by an individual therapy based on clinical progress (pro re nata, PRN). Patients had a total of six visits.

    Reporting group title
    Control group
    Reporting group description
    		 Control group of 20 healthy volunteers. Subject received no treatment. Subjects had one visit.
    Reporting group title
    AMD Group - Visit 4
    Reporting group description
    		 Patients in the AMD group received three IVT Lucentis injections (0.5mg) within the first three months, followed by an individual therapy based on clinical progress (pro re nata, PRN). Patients had a total of six visits.
    Reporting group title
    AMD Group - Visit 7
    Reporting group description
    		 Patients in the AMD group received three IVT Lucentis injections (0.5mg) within the first three months, followed by an individual therapy based on clinical progress (pro re nata, PRN). Patients had a total of six visits.

    Primary: Change from Baseline (visit 1) in BCVA (ETDRS letter score) at Week 12 (visit 4) in the study eye

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    End point title
    		 Change from Baseline (visit 1) in BCVA (ETDRS letter score) at Week 12 (visit 4) in the study eye [1]
    End point description
    The study was designed to assess the efficacy of IVT administered ranibizumab in subjects with all subtypes of neovascular AMD. The primary endpoint is the analysis of changes in BCVA, evaluated by ETDRS scores, from baseline (visit 1) to week 12 (visit 4). Regarding the ETDRS scores of all AMD patients, a significant increase in the BCVA can be observed in week 12 after study begin. At the start point of the study, the mean ETDRS letter score of the study population was at 59.347. After 12 weeks of Lucentis treatment, the score increased to 62.939. Treated patients gained 3.6 letters on average.
    End point type
    Primary
    End point timeframe
    Baseline (visit 1) to week 12 (visit 4)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: BCVA was not assessed in the control group.
    End point values
    		 AMD Group (neovascular age-related macular degeneration) AMD Group - Visit 4
    Number of subjects analysed
    49
    49
    Units: ETDRS letter score
        arithmetic mean (standard deviation)
    59.347 ( 18.820 )
    62.939 ( 18.431 )
    Statistical analysis title
    		 AMD group V1 vs V4
    Comparison groups
    AMD Group (neovascular age-related macular degeneration) v AMD Group - Visit 4
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.005
    Method
    		 Paired two-sided t test
    Confidence interval

    Secondary: Change from Baseline (visit 1) in BCVA (ETDRS letter score) at Week 24 (visit 7) in the study eye

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    End point title
    		 Change from Baseline (visit 1) in BCVA (ETDRS letter score) at Week 24 (visit 7) in the study eye [2]
    End point description
    The secondary endpoints included the analysis of changes in BCVA from baseline (visit 1) to week 24 (visit 7). The mean ETDRS letter score of all AMD patients treated with ranibizumab increased from 59.444 to 62.911, but this ef-fect could not reach the .05 level for significance.
    End point type
    Secondary
    End point timeframe
    Baseline (visit 1) to week 24 (visit 7).
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: BCVA was not assessed in the control group.
    End point values
    		 AMD Group (neovascular age-related macular degeneration) AMD Group - Visit 7
    Number of subjects analysed
    45
    45
    Units: ETDRS letter score
        arithmetic mean (standard deviation)
    59.444 ( 18.555 )
    62.911 ( 20.020 )
    Statistical analysis title
    		 paired t test
    Comparison groups
    AMD Group (neovascular age-related macular degeneration) v AMD Group - Visit 7
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.11
    Method
    		 Paired two sided t test
    Confidence interval

    Secondary: Absolute change from baseline (visit 1) in central retinal thickness at week 24 (visit 7)

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    End point title
    		 Absolute change from baseline (visit 1) in central retinal thickness at week 24 (visit 7) [3]
    End point description
    The absolute change from baseline (visit 1) in central retinal thickness at week 24 (visit 7) in the study eye was assesed. Changes in central retinal thickness (CRT) in the study population were analysed by OCT. CRT values of V1 and V7 were compared by two-sided paired t test. CRT measured in the complete AMD study population was significantly (p<0.001) decreased at week 24 compared to the baseline measurement. The mean CRT dropped from 393.4μm to 296.8μm.
    End point type
    Secondary
    End point timeframe
    Baseline (visit 1) to week 24 (visit 7).
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Central retinal thickness was not assessed in the control group.
    End point values
    		 AMD Group (neovascular age-related macular degeneration) AMD Group - Visit 7
    Number of subjects analysed
    45
    45
    Units: micrometer
        arithmetic mean (standard deviation)
    393.400 ( 109.170 )
    296.822 ( 75.659 )
    Statistical analysis title
    		 paired t test
    Comparison groups
    AMD Group (neovascular age-related macular degeneration) v AMD Group - Visit 7
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001
    Method
    		 Paired two sided t test
    Confidence interval

    Secondary: Mean number of IVT ranibizumab injections

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    End point title
    		 Mean number of IVT ranibizumab injections
    End point description
    The mean number of IVT ranibizumab injections in the AMD group is 4.956
    End point type
    Secondary
    End point timeframe
    Baseline (visit 1) to week 24 (visit 7)
    End point values
    		 AMD Group - Visit 7
    Number of subjects analysed
    45
    Units: Count
        number (not applicable)
    4.956
    No statistical analyses for this end point

    Secondary: Change in anti TTR levels

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    End point title
    		 Change in anti TTR levels
    End point description
    Relative changes in serological autoantibody levels to TTR.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    329.293044 ( 431.943317 )
    1566.17808 ( 6469.5959 )
    589.946731 ( 841.376927 )
    No statistical analyses for this end point

    Secondary: Change in anti CA2 levels

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    End point title
    		 Change in anti CA2 levels
    End point description
    Relative changes in serological autoantibody levels to TTR.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    78920.0649 ( 83062.665 )
    82277.5998 ( 137369.877 )
    131123.099 ( 137131.564 )
    No statistical analyses for this end point

    Secondary: Change in ACO2 antibodies

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    End point title
    		 Change in ACO2 antibodies
    End point description
    Relative changes in serological autoantibody levels to ACO2.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    421.379196 ( 527.218781 )
    415.459782 ( 939.568278 )
    705.688399 ( 975.255285 )
    No statistical analyses for this end point

    Secondary: Change in HSPD1 antibodies

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    End point title
    		 Change in HSPD1 antibodies
    End point description
    Relative changes in serological autoantibody levels to HSPD1.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    51105.2926 ( 82597.9777 )
    28166.4324 ( 28429.8058 )
    90819.3211 ( 144238.578 )
    No statistical analyses for this end point

    Secondary: Change in MBP antibodies

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    End point title
    		 Change in MBP antibodies
    End point description
    Relative changes in serological autoantibody levels to MBP.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    4327.52687 ( 5323.6392 )
    5302.23291 ( 15823.628 )
    11874.9915 ( 28818.5154 )
    No statistical analyses for this end point

    Secondary: Change in SOD antibodies

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    End point title
    		 Change in SOD antibodies
    End point description
    Relative changes in serological autoantibody levels to SOD.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    1339.36517 ( 2675.99626 )
    775.195033 ( 1965.63135 )
    1950.46017 ( 4314.98206 )
    No statistical analyses for this end point

    Secondary: Change in SNCG antibodies

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    End point title
    		 Change in SNCG antibodies
    End point description
    Relative changes in serological autoantibody levels to SNCG.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    11879.0444 ( 21368.6767 )
    6843.90305 ( 8509.90635 )
    15918.4531 ( 30303.8745 )
    No statistical analyses for this end point

    Secondary: Change in ALB antibodies

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    End point title
    		 Change in ALB antibodies
    End point description
    Relative changes in serological autoantibody levels to ALB.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    11626.4445 ( 20103.2013 )
    6169.12712 ( 12009.731 )
    21660.8042 ( 55524.1703 )
    No statistical analyses for this end point

    Secondary: Change in Mucin antibodies

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    End point title
    		 Change in Mucin antibodies
    End point description
    Relative changes in serological autoantibody levels to Mucin 5B.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    2384.57079 ( 2463.19117 )
    4437.92132 ( 11389.5247 )
    5710.1092 ( 7395.27252 )
    No statistical analyses for this end point

    Secondary: Change in BDNF antibodies

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    End point title
    		 Change in BDNF antibodies
    End point description
    Relative changes in serological autoantibody levels to BDNF.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    20712.2938 ( 35670.3539 )
    27359.6591 ( 36640.9169 )
    38896.7629 ( 86988.8332 )
    No statistical analyses for this end point

    Secondary: Change in CALR antibodies

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    End point title
    		 Change in CALR antibodies
    End point description
    Relative changes in serological autoantibody levels to CALR.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    41323.5932 ( 46052.176 )
    65456.0954 ( 127619.468 )
    88559.5047 ( 128164.807 )
    No statistical analyses for this end point

    Secondary: Change in NTF3 antibodies

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    End point title
    		 Change in NTF3 antibodies
    End point description
    Relative changes in serological autoantibody levels to NTF3.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    23553.6116 ( 27445.1585 )
    56117.993 ( 148412.373 )
    60781.7721 ( 81896.6784 )
    No statistical analyses for this end point

    Secondary: Change in TF antibodies

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    End point title
    		 Change in TF antibodies
    End point description
    Relative changes in serological autoantibody levels to TF.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    12805.6082 ( 23422.2683 )
    16308.7444 ( 29590.8418 )
    32491.9646 ( 55884.5263 )
    No statistical analyses for this end point

    Secondary: Change in OGFR antibodies

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    End point title
    		 Change in OGFR antibodies
    End point description
    Relative changes in serological autoantibody levels to OGFR.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    4710.51796 ( 6215.37289 )
    6354.39204 ( 11293.1811 )
    13931.4798 ( 38234.8327 )
    No statistical analyses for this end point

    Secondary: Change in groEL2 antibodies

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    End point title
    		 Change in groEL2 antibodies
    End point description
    Relative changes in serological autoantibody levels to groEL2.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    45606.0488 ( 75093.5616 )
    25624.7987 ( 28341.476 )
    78762.2063 ( 117962.448 )
    No statistical analyses for this end point

    Secondary: Change in NTF4 antibodies

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    End point title
    		 Change in NTF4 antibodies
    End point description
    Relative changes in serological autoantibody levels to NTF4.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    2229.58324 ( 3200.51454 )
    3070.13054 ( 6567.93249 )
    4857.94573 ( 6272.06139 )
    No statistical analyses for this end point

    Secondary: Change in Dermcidin antibodies

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    End point title
    		 Change in Dermcidin antibodies
    End point description
    Relative changes in serological autoantibody levels to Dermcidin.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    13639.2395 ( 34467.3342 )
    10111.0475 ( 14190.151 )
    19040.8268 ( 20508.2208 )
    No statistical analyses for this end point

    Secondary: Change in CLUS antibodies

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    End point title
    		 Change in CLUS antibodies
    End point description
    Relative changes in serological autoantibody levels to CLUS.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    3613.51411 ( 4544.54803 )
    4695.5411 ( 10040.046 )
    9231.28756 ( 11712.3194 )
    No statistical analyses for this end point

    Secondary: Change in VEGF antibodies

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    End point title
    		 Change in VEGF antibodies
    End point description
    Relative changes in serological autoantibody levels to VEGF.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    5270.56345 ( 10764.55 )
    7918.14187 ( 22694.7257 )
    13302.2931 ( 17108.5068 )
    No statistical analyses for this end point

    Secondary: Change in EIF4A1 antibodies

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    End point title
    		 Change in EIF4A1 antibodies
    End point description
    Relative changes in serological autoantibody levels to EIF4A1.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    1384.61068 ( 2451.61235 )
    1828.40721 ( 3855.40767 )
    3028.33669 ( 6104.8793 )
    No statistical analyses for this end point

    Secondary: Change in PRKCSH antibodies

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    End point title
    		 Change in PRKCSH antibodies
    End point description
    Relative changes in serological autoantibody levels to PRKCSH.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 AMD Group (neovascular age-related macular degeneration) Control group AMD Group - Visit 7
    Number of subjects analysed
    50
    20
    45
    Units: NFI
        arithmetic mean (standard deviation)
    4092.94729 ( 4680.60189 )
    4280.82021 ( 5309.7701 )
    8881.44175 ( 20014.9407 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 weeks
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    AMD Group
    Reporting group description
    		 AMD Group receiving three Lucentis injections (0.5mg) within the first three months, followed by individual therapy interval based on the clinical progress (pro re nata, PRN).

    Serious adverse events
    		 AMD Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 50 (8.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Injury, poisoning and procedural complications
    Traumatic arthrosis
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal disorders
    Inguinal hernia
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial haemorrhage
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Device related infection
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Osteomyelitis
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary sepsis
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Product issues
    Device loosening
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 AMD Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 50 (74.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Eye naevus
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Skin papilloma
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Vascular disorders
    Blood pressure fluctuation
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Flushing
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Haematoma
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    General disorders and administration site conditions
    Application site pain
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Fibrosis
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Sensation of foreign body
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Prostatitis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    Oropharyngeal pain
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Serum ferritin decreased
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Ligament sprain
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Patella fracture
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Skin laceration
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    Neuritis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Eye disorders
    Blepharitis
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    Cataract
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Chalazion
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Conjunctival haemorrhage
         subjects affected / exposed
    7 / 50 (14.00%)
         occurrences all number
    7
    Corneal erosion
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Detachment of retinal pigment epithelium
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Dry eye
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Exfoliation syndrome
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Eye haematoma
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Eye pain
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    Macular cyst
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Macular oedema
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Neovascular age-related macular degeneration
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Ocular hyperaemia
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Retinal pigment epithelial tear
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Retinal pigment epitheliopathy
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Subretinal fluid
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    1
    Trichiasis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Visual acuity reduced
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    Vitreous detachment
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    Vitreous disorder
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Gastritis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Gastrointestinal infection
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Myalgia
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Cystitis
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    Gingivitis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Laryngitis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    6
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3

    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
    For support, Contact us.
    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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