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1 Sponsor Full Novartis CTRD Template Novartis Generic Drug Name Ranibizumab/RFB002 Therapeutic Area of Trial Ophthalmology Approved Indication Indicated for the treatment of patients with wet age-related macular degeneration (AMD) approved in > 100 countries Indicated for the treatment of patients with visual impairment due to diabetic macular edema (DME) approved in > 90 countries Indicated for the treatment of patients with visual impairment due to macular edema (ME) secondary to retinal vein occlusion (RVO) approved in > 90 countries Indicated for the treatment of patients with visual impairment due to choroidal neovascularisation secondary to pathologic myopia (myopic CNV - mcnv) approved in > 40 countries Investigational: Choroidal neovascularization secondary to non AMD and mcnv Macular edema secondary to non-dme or non-rvo Protocol Number CRFB002D2304 (RETAIN) Title A 2-year randomized, single-masked, multicenter, controlled phase IIIb trial assessing the efficacy and safety of ranibizumab in two treat and extend treatment algorithms vs. ranibizumab as needed in patients with macular edema and visual impairment secondary to Diabetes mellitus

2 Study Phase Phase IIIb Study Start/End Dates 20-Sep-2010 (first patient first visit) to 17-Apr-2013 (last patient last visit) Study Design/Methodology This was a 24-month, single-masked, three-arm parallel group, randomized, multicenter, controlled study in patients with visual impairment due to DME. Treatments with ranibizumab applying a treat and extend (TE) dosing regimen with and without adjunctive laser therapy were compared with ranibizumab alone given pro re nata (PRN = as needed). The study comprised four periods: a 14-day screening period, a 12-month treatment period I, a subsequent 11-month treatment period II, and a final follow-up period of 1 month. Centers A total of 64 centers in Europe: Belgium (2), Czech Republic (5), France (8), Greece (3), Hungary (4), Ireland (2), Italy (6), The Netherlands (5), Poland (4), Portugal (3), Spain (8), Switzerland (4), and United Kingdom (10). Publication None Objectives The primary objective of this clinical study was to demonstrate that a ranibizumab Treat and Extend (TE) dosing regimen with adjunctive laser and/or a ranibizumab TE dosing regimen alone was non-inferior, as assessed by the mean average change from baseline in best corrected visual acuity (BCVA) over a 12-month treatment period, to ranibizumab alone given PRN, in patients with visual impairment due to DME. If noninferiority was established in the first step, then superiority was tested. The condition for the interpretation of these results was the assessment of the extent to which the TE dosing regimens were maintained during the study duration. The secondary objectives were: To evaluate whether the mean average change from baseline in BCVA over a 24- month period in patients with visual impairment due to DME obtained with either a ranibizumab TE dosing regimen with adjunctive laser, or with ranibizumab TE dosing regimen alone is non-inferior to ranibizumab alone given PRN.

3 To investigate within the TE dosing concepts the impact of laser treatment on the number of retreatments up to Month 12 and Month 24. Interpretation of the corresponding results needs to be done under consideration of possible differences related to efficacy. To investigate the efficacy of ranibizumab TE dosing regimen with adjunctive laser, ranibizumab TE dosing regimen alone and ranibizumab alone given PRN on vision-related functioning and well-being assessed at Month 12 and at Month 24, as measured by the overall score assessed by the National Eye Institute (NEI) Visual Function Questionnaire-25 (VFQ-25) and EuroQol EQ-5D. To evaluate the time course of mean BCVA change from baseline to Month 12, and up to Month 24 obtained with either a ranibizumab TE dosing regimen with adjunctive laser, or with ranibizumab TE dosing regimen alone and with 0.5 mg ranibizumab alone given PRN. To compare the changes in development of central subfield thickness (CSFT) of 0.5 mg ranibizumab TE dosing regimen with adjunctive laser, ranibizumab TE dosing regimen alone and ranibizumab alone given PRN over time. To evaluate the mean number and pattern of treatments in all three treatment arms. To evaluate ocular and systemic safety in patients treated with intravitreal injections of ranibizumab and to explore the safety in patients undergoing bilateral treatment with ranibizumab i.e. having received three or more treatments with ranibizumab within 30 days. Test Product (s), Dose(s), and Mode(s) of Administration Ranibizumab /ml for intravitreal injection, administered as a treat and extend regimen, and laser Ranibizumab /ml for intravitreal injection, administered as a treat and extend regimen Ranibizumab /ml for intravitreal injection, administered as a PRN regimen al Methods The statistical analysis was performed by PAREXEL International personnel according to the al Analysis Plan. Data were summarized with respect to demographic and baseline disease characteristics, efficacy, drug exposure, and safety observations and assessments. Descriptive statistics included n (number of observations), mean, standard deviation (standard error, as applicable), median, lower quartile (Q1), upper quartile (Q3) and ranges for continuous variables, and frequencies and percentages for categorical variables, and were provided by treatment group unless otherwise specified. Where appropriate, estimates of treatment group differences, confidence intervals and p-values were presented. Unless otherwise specified, the following conventions were utilized throughout the analysis: Confidence intervals were 2-sided and at a 95% level

4 Hypothesis tests were evaluated at a two-sided 0.05 / one-sided level of significance The last assessment collected just prior to start of treatment was considered to be the baseline value. All assessments that were performed after the first study treatment were considered to be post baseline. The efficacy analyses of this study were based on the study eye data only. The primary variable was the difference between the average level of BCVA (letters) over all monthly post-baseline assessments from Month 1 to Month 12 and the baseline level of BCVA. Hypotheses of non-inferiority and superiority were tested using a sequentially rejective multiple testing procedure which protects the multiple one-sided significance level. The null hypotheses for the primary variable were tested applying a stratified Cochran- Mantel-Haenszel test stratified by categorized baseline BCVA ( 60 letters, > 60 letters and 73 letters, and > 73 letters) with the observed values as scores. During testing for noninferiority margin of 4 letters was used. The two sided 97.5% confidence intervals were constructed using Analysis of covariance (ANOVA), stratified by categorized baseline BCVA. The primary analysis was conducted within the Full analysis set (LOCF). Study Population: Inclusion/Exclusion Criteria and Demographics Inclusion Criteria: Patient Patients with Type 1 or Type 2 diabetes mellitus (according to American Diabetes Association or World Health Organization [WHO] guidelines) with glycosylated hemoglobin (HbA1c) 12.0% at screening (Visit 1). Patients should have been on diet, exercise, and/or pharmacological treatment for diabetes. Treatment for diabetes must have been stable for at least 3 month. Ocular Patients with visual impairment due to DME in at least one eye who were eligible for laser treatment in the opinion of the investigator. If both eyes were eligible, the one with the worse visual acuity, as assessed at Visit 1, was selected by the investigator as the study eye. BCVA 39 and 78 letters in the study eye and, inclusively, using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters (approximate Snellen equivalent of 20/32 to 20/160) at screening.

5 Concomitant conditions in the study eye were only permitted if, in the opinion of the investigator, they did not prevent improvement of visual acuity on study treatment. Exclusion Criteria: Patient Compliance/ Administrative Pregnant or nursing (lactating) women. Ocular medical history Active intraocular inflammation (grade trace or above) in either eye at enrollment. Any active infection (e.g. conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis) in either eye at the time of enrollment. History of uveitis in either eye at any time. Structural damage within 0.5 disc diameter of the center of the macular in the study eye likely to preclude improvement in visual acuity following the resolution of macular edema. Uncontrolled glaucoma in either eye at screening. Prior Ocular treatments Panretinal laser photocoagulation in the study eye within 6 months prior to randomization. Focal/grid laser photocoagulation in the study eye within 3 months prior to randomization. Treatment with anti-angiogenic drugs in either eye. Systemic conditions or treatments History of stroke within 6 months prior to enrollment. Renal failure requiring dialysis. Untreated diabetes mellitus. Blood pressure systolic > 160 mmhg or diastolic > 100 mmhg. Other protocol-defined inclusion/exclusion criteria may apply

6 Participant Flow Patient disposition at Month 24 (Randomized set) + Laser N=121 alone N=128 N=123 Total N=372 Disposition / Reason Completed 107 (88.4) 117 (91.4) 108 (87.8) 332 (89.2) Discontinued 14 (11.6) 11 (8.6) 15 (12.2) 40 (10.8) Adverse Event(s) 6 (5.0) 2 (1.6) 5 (4.1) 13 (3.5) Abnormal laboratory value(s) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Abnormal test procedure result(s) 1 (0.8) 0 (0.0) 0 (0.0) 1 (0.3) Unsatisfactory therapeutic effect 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Subject's condition no longer 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) requires study drug Subject withdrew consent 1 (0.8) 5 (3.9) 6 (4.9) 12 (3.2) Lost to follow-up 4 (3.3) 0 (0.0) 2 (1.6) 6 (1.6) Administrative problems 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Death 2 (1.7) 4 (3.1) 1 (0.8) 7 (1.9) Protocol deviation 0 (0.0) 0 (0.0) 1 (0.8) 1 (0.3) - Percentages are based on the number of patients in the Randomized set in the specific treatment group. Baseline Characteristics Demographic summary by treatment group (Randomized set) + Laser N=121 alone N=128 N=123 Total N=372 Demographic variable Age (years) n Mean SD Median Min Max Age group (years), < (14.0) 23 (18.0) 18 (14.6) 58 (15.6) 55 - < (39.7) 48 (37.5) 42 (34.1) 138 (37.1) 65 - < (37.2) 43 (33.6) 44 (35.8) 132 (35.5) >= (9.1) 14 (10.9) 19 (15.4) 44 (11.8) Sex, Male 78 (64.5) 77 (60.2) 77 (62.6) 232 (62.4) Female 43 (35.5) 51 (39.8) 46 (37.4) 140 (37.6) Predominant race, Caucasian 114 (94.2) 126 (98.4) 117 (95.1) 357 (96.0) Black 3 (2.5) 1 (0.8) 3 (2.4) 7 (1.9) Asian 1 (0.8) 0 (0.0) 1 (0.8) 2 (0.5) Other 3 (2.5) 1 (0.8) 2 (1.6) 6 (1.6) - Percentages are based on the number of patients in the Randomized set in the specific treatment group.

7 Diabetes characteristics at baseline by treatment group (Randomized set) + Laser N=121 alone N=128 N=123 Total N=372 Characteristics Diabetes type, Type I 10 (8.3) 12 (9.4) 10 (8.1) 32 (8.6) Type II 111 (91.7) 116 (90.6) 113 (91.9) 340 (91.4) HbA1c (percent) n Mean SD Median Min Max HbA1c (percent) group, <= 7 41 (33.9) 36 (28.1) 32 (26.0) 109 (29.3) > 7 and < 8 32 (26.4) 39 (30.5) 29 (23.6) 100 (26.9) >= 8 and < 9 21 (17.4) 26 (20.3) 36 (29.3) 83 (22.3) >= 9 and <= (12.4) 19 (14.8) 19 (15.4) 53 (14.2) > (9.1) 7 (5.5) 7 (5.7) 25 (6.7) Missing 1 (0.8) 1 (0.8) 0 (0.0) 2 (0.5) - Percentages are based on the number of patients in the Randomized set in the specific treatment group. Ocular characteristics of the study eye at baseline (Randomized set) + Laser N=121 alone N=128 N=123 Total N=372 Characteristics DME present, Yes 121 (100) 127 (99.2) 123 (100) 371 (99.7) No 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Missing 0 (0.0) 1 (0.8) 0 (0.0) 1 (0.3) Time since first diagnosis of DME (years) n Mean SD Median Min Max Overall assessment of DME type, n (%) (1) Focal 36 (29.8) 28 (22.0) 32 (26.0) 96 (25.9) Diffuse 62 (51.2) 72 (56.7) 70 (56.9) 204 (55.0) Other (2) 23 (19.0) 27 (21.3) 21 (17.1) 71 (19.1) Visual acuity (letters) n Mean SD Median Min Max Visual acuity group (letters), <= (37.2) 49 (38.3) 44 (35.8) 138 (37.1) (46.3) 56 (43.8) 55 (44.7) 167 (44.9) > (15.7) 22 (17.2) 24 (19.5) 65 (17.5)

8 + Laser N=121 alone N=128 N=123 Total N=372 Characteristics Missing 1 (0.8) 1 (0.8) 0 (0.0) 2 (0.5) Central subfield thickness (microns) - Overall n Mean SD Median Min Max Intraocular pressure (mmhg) n Mean SD Median Min Max Intraocular pressure group (mmhg), n (%) (96.7) 122 (95.3) 120 (97.6) 359 (96.5) (1.7) 3 (2.3) 2 (1.6) 7 (1.9) >= 30 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Missing 2 (1.7) 3 (2.3) 1 (0.8) 6 (1.6) - Percentages are based on the number of patients in the Randomized set in the specific treatment group except for (1). (1) Percentages are based on the number of patients with DME present = YES. (2) Other includes "Questionable", "Can't grade", "Not done", "Not applicable", and missing values. Outcome Measures Summary of Efficacy Primary Outcome Result(s) Visual acuity of the study eye (letters): Average change from baseline to Month 1 through Month 12 (Full analysis set - MV/LOCF) + Laser alone Baseline n Mean (SD) 62.3 (11.50) 64.1 (10.52) 65.1 (10.08) Median Min, Max 37, 80 39, 83 39, 84 Average Month 1 to Month 12 Mean (SD) (11.057) (10.284) (9.984) Median Min, Max 35.2, , , 87.7 Average change from baseline Mean (SD) 5.91 (5.532) 6.14 (5.717) 6.20 (6.005) Median Min, Max -7.0, , , 20.2 mean (1) Assessment of non-inferiority to PRN (4.90, 6.92) (5.13, 7.16) (5.10, 7.30)

9 CMH (transformed) (2) ANOVA (untransformed) Assessment of superiority to PRN CMH (untransformed) (2) Comparison of both TE groups One-sided p-value Difference in LS means(3) difference 97.5% CI for difference One-sided p-value + Laser alone < < (-1.03, 1.81) (-1.21, 1.59) (-1.24, 2.02) (-1.41, 1.79) ANOVA Difference 0.20 in LS means(3) (-1.20, 1.60) difference CMH (stratified) Two-sided p-value Baseline is the last measurement before the first administration of study treatment in the study eye. - Stratified analysis includes baseline visual acuity (<=60 letters, >60 letters and <=73 letters, >73 letters) as factor. (1) Two-sided confidence intervals (CI) are based on t-distribution. (2) CMH test uses row mean scores statistic. (3) Average change from baseline to Month 1 through Month 12 in BCVA analyzed using ANOVA with baseline BCVA (stratified see above) and treatment as factors. Secondary Outcome Result(s) Visual acuity of the study eye (letters): Average change from baseline to Month 1 through Month 24 (Full analysis set - MV/LOCF) + Laser alone Baseline n Mean (SD) 62.3 (11.50) 64.1 (10.52) 65.1 (10.08) Median Min, Max 37, 80 39, 83 39, 84 Average Month 1 to Month 24 Mean (SD) (11.261) ( ) (10.141) Median Min, Max 35.4, , , 88.8 Average change from baseline Mean (SD) 6.78 (5.986) 6.58 (7.070) 6.97 (6.430) Median Min, Max -8.6, , , 25.0 PRN minus TE ANOVA (untransformed) mean (1) Difference in LS (5.68, 7.87) (5.33, 7.83) (5.79, 8.15)

10 TE alone minus TE + Laser ANOVA PRN vs. TE CMH (1) ANOVA (2) TE alone vs. TE + Laser CMH (1) ANOVA (2) means difference Difference in LS means difference Two-sided p-value Two-sided p-value Two-sided p-value Two-sided p-value + Laser alone (-1.32, 1.92) -1.06, 2.13) (-1.83, 1.36) Baseline is the last measurement before the first administration of study treatment in the study eye. - Two-sided 95% confidence intervals are based on t-distribution. (1) Analyzed using the Cochran-Mantel-Haenszel (CMH) test (row mean scores statistic) stratified by baseline BCVA (<=60 letters, >60 letters and <=73 letters, >73 letters) with the observed values as scores. (2) Analyzed using analysis of variance (ANOVA) with baseline BCVA (<=60 letters, >60 letters and <=73 letters, >73 letters) and treatment as factors. Visual acuity of the study eye (letters): Change from baseline at Month 12 (Full analysis set - MV/LOCF) + Laser alone Baseline n Mean (SD) 62.3 (11.50) 64.1 (10.52) 65.1 (10.08) Median Min, Max 37, 80 39, 83 39, 84 Month 12 Mean (SD) (11.945) (11.742) (11.592) Median Min, Max 34.0, , , 92.0 Change from baseline Mean (SD) 6.79 (6.999) 6.80 (8.726) 7.44 (8.457) ANOVA Comparison to PRN CMH Comparison to PRN Median Min, Max -9.0, , , 28.0 mean (1) Difference in LS means (2) difference (2) (5.50, 8.07) (5.25, 8.34) (5.89, 8.98) (-1.28, 2.81) (-1.22, 2.80) p-value (2) p-value (3)

11 ANOVA Comparison between TE Difference in LS means (2) + Laser alone (-2.03, 1.98) difference (2) p-value (2) CMH Comparison between TE p-value (3) Baseline is the last measurement before the first administration of study treatment in the study eye. - Stratified analysis includes baseline visual acuity (<=60 letters, >60 letters and <=73 letters, >73 letters) as factor. (1) Two-sided confidence intervals (CI) are based on t-distribution. (2) ANOVA with baseline BCVA (stratified see above) and treatment as factors. (3) CMH test (row mean scores statistic, stratified see above) with the observed values as scores. Visual acuity of the study eye (letters): Change from baseline at Month 24 (Full analysis set - MV/LOCF) + Laser alone Baseline n Mean (SD) 62.3 (11.50) 64.1 (10.52) 65.1 (10.08) Median Min, Max 37, 80 39, 83 39, 84 Month 24 Mean (SD) (12.315) (13.481) (11.872) Median Min, Max 30.0, , , 93.0 Change from baseline Mean (SD) 8.30 (8.129) 6.49 (10.854) 8.06 (8.462) Median Min, Max -19.0, , , 32.0 ANOVA Comparison to PRN CMH Comparison to PRN ANOVA Comparison between TE mean (1) (6.81, 9.79) (4.57, 8.41) (6.51, 9.61) Difference in LS means (2) (-2.45, 2.22) (-0.56, 4.03) difference (2) p-value (2) p-value (3) Difference in LS means (2) (-4.15, 0.44) difference (2) p-value (2) CMH Comparison p-value (3) between TE - Baseline is the last measurement before the first administration of study treatment in the study eye. - Stratified analysis includes baseline visual acuity (<=60 letters, >60 letters and <=73 letters, >73 letters) as factor. (1) Two-sided confidence intervals (CI) are based on t-distribution. (2) ANOVA with baseline BCVA (stratified see above) and treatment as factors. (3) CMH test (row mean scores statistic, stratified see above) with the observed values as scores.

12 Visual acuity of the study eye (letters): Categorized change from baseline at Month 12 (Full analysis set - MV/LOCF) Gain or loss in visual acuity as compared to baseline + Laser r/ alone r/ r/ Gain of >= 1 letter 97/117 (82.9) 106/125 (84.8) 98/117 (83.8) Gain of >= 5 letters 69/117 (59.0) 76/125 (60.8) 82/117 (70.1) Gain of >= 10 letters (1) 38/117 (32.5) 53/125 (42.4) 46/117 (39.3) Gain of >= 15 letters (1) 23/117 (19.7) 38/125 (30.4) 31/117 (26.5) Loss of >= 5 letters 4/117 (3.4) 5/125 (4.0) 4/117 (3.4) Loss of >= 10 letters 0/117 (0.0) 3/125 (2.4) 1/117 (0.9) Loss of >= 15 letters 0/117 (0.0) 2/125 (1.6) 1/117 (0.9) - Baseline is the last measurement before the first administration of study treatment in the study eye. - n = Number of patients with a value at both baseline and the Month 24 visit. Percentages are based on n. - r = Responder, i.e. patients who fulfill the criterion for gain or loss. (1) specified gain, or BCVA of 84 letters or more Visual acuity of the study eye (letters): Categorized change from baseline at Month 24 (Full analysis set - MV/LOCF) + Laser r/ alone r/ r/ Gain or loss in visual acuity as compared to baseline Gain of >= 1 letter 102/117 (87.2) 105/125 (84.0) 106/117 (90.6) Gain of >= 5 letters 81/117 (69.2) 78/125 (62.4) 89/117 (76.1) Gain of >= 10 letters (1) 51/117 (43.6) 51/125 (40.8) 53/117 (45.3) Gain of >= 15 letters (1) 30/117 (25.6) 35/125 (28.0) 36/117 (30.8) Loss of >= 5 letters 5/117 (4.3) 10/125 (8.0) 6/117 (5.1) Loss of >= 10 letters 3/117 (2.6) 9/125 (7.2) 4/117 (3.4) Loss of >= 15 letters 1/117 (0.9) 5/125 (4.0) 3/117 (2.6) - Baseline is the last measurement before the first administration of study treatment in the study eye. - n = Number of patients with a value at both baseline and the Month 24 visit. Percentages are based on n. - r = Responder, i.e. patients who fulfill the criterion for gain or loss. (1) specified gain, or BCVA of 84 letters or more Central subfield thickness of the study eye: Percent change from baseline at Month 12 (Full analysis set - MV/LOCF) + Laser alone Percent change from baseline Mean (SD) (22.992) (22.027) (22.362) Median Min, Max -82.7, , , 53.1 mean (1) (-31.32, ) (-28.27, ) (-27.27, ) ANCOVA (2) Comparison Difference in

13 + Laser alone to PRN LS means (-4.56, 6.20) (-5.25, 5.22) difference p-value CMH (3) Comparison to PRN p-value ANCOVA (2) Comparison Difference in 0.84 between TE LS means (-4.42, 6.10) difference p-value CMH (3) Comparison p-value between TE - Baseline is the last measurement before the first administration of study treatment in the study eye. - Stratified analysis includes baseline visual acuity (<=60 letters, >60 letters and <=73 letters, >73 letters) as factor. (1) Two-sided confidence intervals (CI) are based on t-distribution. (2) ANCOVA with machine type, baseline BCVA (stratified see above) and treatment as factors and baseline central subfield thickness as covariate. (3) CMH test (row mean scores statistic, stratified see above) with the observed values as scores. Central subfield thickness of the study eye: Percent change from baseline at Month 24 (Full analysis set - MV/LOCF) + Laser alone Percent change from baseline Mean (SD) (25.628) (26.414) (26.678) Median Min, Max -82.7, , , 74.0 mean (1) (-36.75, ) (-29.68, ) (-29.88, ) ANCOVA (2) Comparison Difference in to PRN LS means (-3.26, 9.29) (-7.34, 4.87) difference p-value CMH (3) Comparison to PRN p-value ANCOVA (2) Comparison Difference in 4.24 between TE LS means (-1.89, 10.38) difference p-value CMH (3) Comparison between TE p-value Baseline is the last measurement before the first administration of study treatment in the study eye. - Stratified analysis includes baseline visual acuity (<=60 letters, >60 letters and <=73 letters, >73 letters) as factor. (1) Two-sided confidence intervals (CI) are based on t-distribution. (2) ANCOVA with machine type, baseline BCVA (stratified see above) and treatment as factors and baseline central subfield thickness as covariate. (3) CMH test (row mean scores statistic, stratified see above) with the observed values as scores.

14 Visual Functioning Questionnaire (VFQ-25): Summary statistics of absolute value and change from baseline, by total score at Month 12 (Full analysis set - MV/LOCF) TE Ranibizumab + Laser alone Baseline n Mean (SD) (17.317) (17.105) (18.581) SE Median Min, Max 18.2, , , st, 3rd 64.82, , , quartile Absolute value at visit n Mean (SD) (17.374) (16.629) (18.100) SE Median Min, Max 28.7, , , st, 3rd 67.74, , , quartile Change from baseline n Mean (SD) 4.60 (10.905) 3.95 (10.941) 5.41 (12.063) SE Median Min, Max -28.6, , , st, 3rd -0.80, , , quartile mean (2.60, 6.61) (1.99, 5.92) (3.17, 7.64) - Baseline is the last measurement before the first administration of study treatment in the study eye. - n is the number of patients with a value for both baseline and the specific post-baseline visit. - Two-sided 95% confidence intervals are based on t-distribution. Visual Functioning Questionnaire (VFQ-25): Summary statistics of absolute value and change from baseline, by total score at Month 24 (Full analysis set - MV/LOCF) TE Ranibizumab + Laser alone Baseline n Mean (SD) (17.317) (17.105) (18.581) SE Median Min, Max 18.2, , , st, 3rd 64.82, , , quartile Absolute value at visit n Mean (SD) (18.822) (17.251) (16.539) SE Median Min, Max 28.7, , , st, 3rd 65.82, , , quartile Change from baseline n

15 TE Ranibizumab + Laser alone Mean (SD) 4.06 (11.859) 2.31 (13.270) 5.96 (12.389) SE Median Min, Max -29.3, , , st, 3rd -1.40, , , quartile mean (1.88, 6.24) (-0.07, 4.69) (3.66, 8.26) - Baseline is the last measurement before the first administration of study treatment in the study eye. - n is the number of patients with a value for both baseline and the specific post-baseline visit. - Two-sided 95% confidence intervals are based on t-distribution. EQ-5D thermometer score: Summary statistics of absolute values and change from baseline at Month 12 (Full analysis set - MV/LOCF) TE Ranibizumab + Laser alone Baseline n Mean (SD) 71.4 (17.36) 70.7 (16.10) 72.2 (13.24) SE Median Min, Max 25, , , 100 1st, 3rd 60.0, , , 80.0 quartile Absolute value at visit n Mean (SD) (16.682) (16.002) (13.650) SE Median Min, Max 10.0, , , st, 3rd 60.00, , , quartile Change from baseline n Mean (SD) 0.47 (16.487) 0.91 (13.422) 2.52 (14.431) SE Median Min, Max -45.0, , , st, 3rd , , , quartile mean (-2.58, 3.51) (-1.49, 3.31) (-0.17, 5.21) - Baseline is the last measurement before the first administration of study treatment in the study eye. - n is the number of patients with a value for both baseline and the specific post-baseline visit. - Two-sided 95% confidence intervals are based on t-distribution.

16 EQ-5D thermometer score: Summary statistics of absolute values and change from baseline at Month 24 (Full analysis set - MV/LOCF) TE Ranibizumab + Laser alone Baseline n Mean (SD) 71.4 (17.36) 70.7 (16.10) 72.2 (13.24) SE Median Min, Max 25, , , 100 1st, 3rd 60.0, , , 80.0 quartile Absolute value at visit n Mean (SD) (16.002) (15.813) (14.452) SE Median Min, Max 10.0, , , st, 3rd 60.00, , , quartile Change from baseline n Mean (SD) 1.35 (17.464) 0.11 (14.755) 1.98 (14.812) SE Median Min, Max -43.0, , , st, 3rd , , , quartile mean (-1.88, 4.57) (-2.53, 2.74) (-0.78, 4.74) - Baseline is the last measurement before the first administration of study treatment in the study eye. - n is the number of patients with a value for both baseline and the specific post-baseline visit. - Two-sided 95% confidence intervals are based on t-distribution.

17 Summary of Safety Safety Results Ocular adverse events Number (%) of patients with ocular adverse events of the study eye (at least 2% in any group), by primary system organ class and preferred term (Safety set) + Laser alone Primary system organ class Preferred term Any AE 58 (46.0) 63 (50.0) 46 (39.0) Eye disorders 55 (43.7) 57 (45.2) 44 (37.3) Cataract 5 (4.0) 7 (5.6) 7 (5.9) Conjunctival haemorrhage 5 (4.0) 11 (8.7) 6 (5.1) Dry eye 6 (4.8) 3 (2.4) 4 (3.4) Vitreous floaters 0 (0.0) 1 (0.8) 4 (3.4) Eye pain 8 (6.3) 7 (5.6) 3 (2.5) Ocular hypertension 7 (5.6) 2 (1.6) 3 (2.5) Eye irritation 2 (1.6) 4 (3.2) 2 (1.7) Macular oedema 2 (1.6) 3 (2.4) 2 (1.7) Diabetic retinal oedema 4 (3.2) 2 (1.6) 1 (0.8) Glaucoma 3 (2.4) 1 (0.8) 1 (0.8) Conjunctivitis 6 (4.8) 2 (1.6) 0 (0.0) Keratitis 1 (0.8) 3 (2.4) 0 (0.0) Lacrimation increased 1 (0.8) 4 (3.2) 0 (0.0) Macular fibrosis 3 (2.4) 0 (0.0) 0 (0.0) Retinal haemorrhage 2 (1.6) 3 (2.4) 0 (0.0) Vitreous haemorrhage 8 (6.3) 2 (1.6) 0 (0.0) Investigations 3 (2.4) 8 (6.3) 5 (4.2) Intraocular pressure increased 2 (1.6) 7 (5.6) 5 (4.2) - Adverse events with start date on or after the date of first administration of study treatment in the study eye. - Primary system organ classes are presented alphabetically; preferred terms are sorted within primary system organ class in descending order of frequency of the PRN group. - A patient with multiple occurrences of a preferred term is counted only once in the preferred term row. - A patient with multiple adverse events within a primary system organ class is counted only once in the total row. - Percentages are based on the number of patients in the Safety set in the specific treatment group. - Coded with MedDRA version Number (%) of patients with non-ocular adverse events (at least 2% in any group), by primary system organ class and preferred term (Safety set) + Laser alone Primary system organ class Preferred term Any AE 97 (77.0) 99 (78.6) 83 (70.3) Blood and lymphatic system disorders 5 (4.0) 6 (4.8) 7 (5.9) Anaemia 4 (3.2) 5 (4.0) 5 (4.2) Cardiac disorders 8 (6.3) 11 (8.7) 6 (5.1) Atrial fibrillation 0 (0.0) 3 (2.4) 1 (0.8)

18 + Laser alone Primary system organ class Preferred term Myocardial infarction 4 (3.2) 1 (0.8) 1 (0.8) Myocardial ischaemia 1 (0.8) 3 (2.4) 1 (0.8) Ear and labyrinth disorders 1 (0.8) 2 (1.6) 5 (4.2) Vertigo 1 (0.8) 1 (0.8) 4 (3.4) Gastrointestinal disorders 22 (17.5) 18 (14.3) 13 (11.0) Diarrhoea 4 (3.2) 4 (3.2) 7 (5.9) Nausea 1 (0.8) 2 (1.6) 3 (2.5) Vomiting 3 (2.4) 4 (3.2) 3 (2.5) Constipation 3 (2.4) 1 (0.8) 0 (0.0) General disorders and administration site 14 (11.1) 13 (10.3) 14 (11.9) conditions Oedema peripheral 7 (5.6) 5 (4.0) 3 (2.5) Pyrexia 0 (0.0) 3 (2.4) 3 (2.5) Influenza like illness 3 (2.4) 0 (0.0) 1 (0.8) Infections and infestations 56 (44.4) 54 (42.9) 42 (35.6) Influenza 9 (7.1) 10 (7.9) 8 (6.8) Nasopharyngitis 11 (8.7) 10 (7.9) 8 (6.8) Cystitis 2 (1.6) 2 (1.6) 6 (5.1) Bronchitis 11 (8.7) 1 (0.8) 5 (4.2) Urinary tract infection 9 (7.1) 11 (8.7) 5 (4.2) Lower respiratory tract infection 3 (2.4) 3 (2.4) 4 (3.4) Upper respiratory tract infection 3 (2.4) 5 (4.0) 4 (3.4) Ear infection 1 (0.8) 1 (0.8) 3 (2.5) Cellulitis 1 (0.8) 5 (4.0) 1 (0.8) Herpes zoster 0 (0.0) 3 (2.4) 1 (0.8) Sinusitis 0 (0.0) 3 (2.4) 1 (0.8) Gastroenteritis viral 2 (1.6) 3 (2.4) 0 (0.0) Pneumonia 5 (4.0) 1 (0.8) 0 (0.0) Skin infection 0 (0.0) 3 (2.4) 0 (0.0) Injury, poisoning and procedural complications 15 (11.9) 15 (11.9) 15 (12.7) Ligament sprain 0 (0.0) 3 (2.4) 0 (0.0) Investigations 11 (8.7) 21 (16.7) 14 (11.9) Blood urine present 2 (1.6) 3 (2.4) 5 (4.2) Blood alkaline phosphatase increased 1 (0.8) 0 (0.0) 4 (3.4) Gamma-glutamyltransferase increased 3 (2.4) 6 (4.8) 4 (3.4) Blood glucose increased 2 (1.6) 4 (3.2) 3 (2.5) Blood lactate dehydrogenase increased 1 (0.8) 4 (3.2) 3 (2.5) Platelet count decreased 1 (0.8) 1 (0.8) 3 (2.5) Blood potassium increased 3 (2.4) 4 (3.2) 2 (1.7) Blood urea increased 3 (2.4) 4 (3.2) 2 (1.7) Blood uric acid increased 3 (2.4) 2 (1.6) 1 (0.8) Haemoglobin decreased 1 (0.8) 4 (3.2) 1 (0.8) Blood creatinine increased 2 (1.6) 4 (3.2) 0 (0.0) Metabolism and nutrition disorders 28 (22.2) 19 (15.1) 18 (15.3) Diabetes mellitus 6 (4.8) 4 (3.2) 4 (3.4) Diabetes mellitus inadequate control 4 (3.2) 5 (4.0) 4 (3.4) Gout 1 (0.8) 1 (0.8) 3 (2.5) Hypercholesterolaemia 2 (1.6) 3 (2.4) 3 (2.5) Hyperglycaemia 6 (4.8) 2 (1.6) 2 (1.7) Hypoglycaemia 6 (4.8) 4 (3.2) 1 (0.8) Musculoskeletal and connective tissue disorders 21 (16.7) 23 (18.3) 13 (11.0) Osteoporosis 0 (0.0) 1 (0.8) 4 (3.4) Back pain 8 (6.3) 10 (7.9) 3 (2.5)

19 + Laser alone Primary system organ class Preferred term Pain in extremity 3 (2.4) 2 (1.6) 3 (2.5) Osteoarthritis 1 (0.8) 3 (2.4) 1 (0.8) Arthralgia 1 (0.8) 4 (3.2) 0 (0.0) Arthritis 4 (3.2) 4 (3.2) 0 (0.0) Neck pain 3 (2.4) 1 (0.8) 0 (0.0) Neoplasms benign, malignant and unspecified 4 (3.2) 5 (4.0) 7 (5.9) (incl cysts and polyps) Prostate cancer 0 (0.0) 0 (0.0) 4 (3.4) Nervous system disorders 21 (16.7) 14 (11.1) 20 (16.9) Headache 4 (3.2) 1 (0.8) 4 (3.4) Cerebrovascular accident 1 (0.8) 2 (1.6) 3 (2.5) Dizziness 4 (3.2) 2 (1.6) 2 (1.7) Psychiatric disorders 5 (4.0) 4 (3.2) 9 (7.6) Depression 1 (0.8) 2 (1.6) 3 (2.5) Insomnia 4 (3.2) 0 (0.0) 1 (0.8) Renal and urinary disorders 7 (5.6) 10 (7.9) 8 (6.8) Renal failure 3 (2.4) 2 (1.6) 1 (0.8) Respiratory, thoracic and mediastinal disorders 12 (9.5) 10 (7.9) 8 (6.8) Cough 5 (4.0) 4 (3.2) 4 (3.4) Dyspnoea 2 (1.6) 2 (1.6) 3 (2.5) Skin and subcutaneous tissue disorders 7 (5.6) 11 (8.7) 5 (4.2) Skin ulcer 1 (0.8) 3 (2.4) 1 (0.8) Diabetic foot 0 (0.0) 4 (3.2) 0 (0.0) Vascular disorders 28 (22.2) 23 (18.3) 18 (15.3) Hypertension 20 (15.9) 18 (14.3) 8 (6.8) - Adverse events with start date on or after the date of first administration of study treatment in the study eye. - Primary system organ classes are presented alphabetically; preferred terms are sorted within primary system organ class in descending order of frequency of the PRN group. - A patient with multiple occurrences of a preferred term is counted only once in the preferred term row. - A patient with multiple adverse events within a primary system organ class is counted only once in the total row. - Percentages are based on the number of patients in the Safety set in the specific treatment group. - Coded with MedDRA version Serious Adverse Events and Deaths Number of patients who died or experienced other serious or clinically significant adverse events (Safety set) + Laser x/ alone x/ x/ Category Death 2/126 (1.6) 4/126 (3.2) 1/118 (0.8) Any serious AE 34/126 (27.0) 29/126 (23.0) 26/118 (22.0) Ocular AE of the study eye 2/126 (1.6) 1/126 (0.8) 0/118 (0.0) Ocular AE of the treated non-study eye 2/ 57 (3.5) 0/ 55 (0.0) 2/ 54 (3.7) Ocular AE of the fellow eye 0/126 (0.0) 0/125 (0.0) 1/118 (0.8) Non-ocular AE 33/126 (26.2) 29/126 (23.0) 23/118 (19.5) Any AE leading to discontinuation from study 10/126 (7.9) 6/126 (4.8) 5/118 (4.2) treatment Ocular AE of the study eye 1/126 (0.8) 0/126 (0.0) 0/118 (0.0) Ocular AE of the treated non-study eye 0/ 57 (0.0) 0/ 55 (0.0) 0/ 54 (0.0) Ocular AE of the fellow eye 0/126 (0.0) 0/125 (0.0) 0/118 (0.0)

20 Category + Laser x/ alone x/ x/ Non-ocular AE 9/126 (7.1) 6/126 (4.8) 5/118 (4.2) Any serious AE leading to discontinuation from 6/126 (4.8) 6/126 (4.8) 4/118 (3.4) study treatment Ocular AE of the study eye 0/126 (0.0) 0/126 (0.0) 0/118 (0.0) Ocular AE of the treated non-study eye 0/ 57 (0.0) 0/ 55 (0.0) 0/ 54 (0.0) Ocular AE of the fellow eye 0/126 (0.0) 0/125 (0.0) 0/118 (0.0) Non-ocular AE 6/126 (4.8) 6/126 (4.8) 4/118 (3.4) - Adverse events in study, fellow eye, and non-ocular AEs with start date on or after the date of first administration of study treatment in the study eye. - Adverse events in the treated non-study eye with start date on or after the date of first administration of study treatment in the treated non-study eye - The categories are not mutually exclusive. E.g. death is included in serious AEs. - x/n: x is the number of the patients with at least one AE in the corresponding category; n is the number of patients in the safety set in the specific treatment group except that a) for ocular AE of the treated non-study eye, n is the number of patients whose non-study eye ever falls into the category of "treated non-study eye"; b) for ocular AE of the fellow eye, n is the number of a subset of patients whose non-study eye ever falls into the category of "fellow eye". Number (%) of patients with ocular serious adverse events in the study eye, by primary system organ class and preferred term (Safety set) + Laser alone Primary system organ class Preferred term Any AE 2 (1.6) 1 (0.8) 0 (0.0) Eye disorders 1 (0.8) 0 (0.0) 0 (0.0) Vitreous haemorrhage 1 (0.8) 0 (0.0) 0 (0.0) Infections and infestations 1 (0.8) 0 (0.0) 0 (0.0) Endophthalmitis 1 (0.8) 0 (0.0) 0 (0.0) Injury, poisoning and procedural complications 0 (0.0) 1 (0.8) 0 (0.0) Periorbital haematoma 0 (0.0) 1 (0.8) 0 (0.0) - Adverse events with start date on or after the date of first administration of study treatment in the study eye. - Primary system organ classes are presented alphabetically; preferred terms are sorted within primary system organ class in descending order of frequency of the PRN group. - A patient with multiple occurrences of a preferred term is counted only once in the preferred term row. - A patient with multiple adverse events within a primary system organ class is counted only once in the total row. - Percentages are based on the number of patients in the Safety set in the specific treatment group. - Coded with MedDRA version Ocular serious adverse events of the treated non-study eye, regardless of study treatment relationship, by primary system organ class and preferred term (Safety set) Primary system organ class Preferred term + Laser alone Number of patients with treated non-study eye

21 Primary system organ class Preferred term + Laser alone Any primary system organ class 2 (3.5) 0 (0.0) 2 (3.7) Eye disorders 1 (1.8) 0 (0.0) 2 (3.7) Macular fibrosis 1 (1.8) 0 (0.0) 1 (1.9) Vitreous adhesion 0 (0.0) 0 (0.0) 1 (1.9) Infections and infestations 1 (1.8) 0 (0.0) 0 (0.0) Endophthalmitis 1 (1.8) 0 (0.0) 0 (0.0) - Adverse events with start date on or after the date of first administration of study treatment in the treated nonstudy eye. - Primary system organ classes are presented alphabetically; preferred terms are sorted within primary system organ class in descending order of frequency of the PRN group. - A patient with multiple occurrences of a preferred term is counted only once in the preferred term row. - A patient with multiple adverse events within a primary system organ class is counted only once in the total row. - Percentages are based on the number of a subset of patients whose non-study eye ever falls into the category of "treated non-study eye" in the Safety set in the specific treatment group. - Coded with MedDRA version 16.0 Number (%) of patients with non-ocular serious adverse events, by primary system organ class and preferred term (Safety set) + Laser alone Primary system organ class Preferred term Any AE 33 (26.2) 29 (23.0) 23 (19.5) Blood and lymphatic system disorders 0 (0.0) 1 (0.8) 1 (0.8) Anaemia 0 (0.0) 0 (0.0) 1 (0.8) Hypocoagulable state 0 (0.0) 1 (0.8) 0 (0.0) Cardiac disorders 8 (6.3) 8 (6.3) 1 (0.8) Cardiac failure 1 (0.8) 0 (0.0) 1 (0.8) Myocardial infarction 4 (3.2) 1 (0.8) 1 (0.8) Myocardial ischaemia 0 (0.0) 2 (1.6) 1 (0.8) Acute myocardial infarction 0 (0.0) 2 (1.6) 0 (0.0) Angina pectoris 1 (0.8) 1 (0.8) 0 (0.0) Atrial fibrillation 0 (0.0) 2 (1.6) 0 (0.0) Atrioventricular block 0 (0.0) 1 (0.8) 0 (0.0) Bradycardia 1 (0.8) 0 (0.0) 0 (0.0) Cardiac failure acute 1 (0.8) 0 (0.0) 0 (0.0) Cardiac failure congestive 0 (0.0) 1 (0.8) 0 (0.0) Cardiovascular disorder 1 (0.8) 0 (0.0) 0 (0.0) Coronary artery disease 0 (0.0) 1 (0.8) 0 (0.0) Congenital, familial and genetic disorders 1 (0.8) 0 (0.0) 1 (0.8) Hypertrophic cardiomyopathy 0 (0.0) 0 (0.0) 1 (0.8) Hydrocele 1 (0.8) 0 (0.0) 0 (0.0) Ear and labyrinth disorders 0 (0.0) 0 (0.0) 1 (0.8) Meniere s disease 0 (0.0) 0 (0.0) 1 (0.8)

22 + Laser alone Primary system organ class Preferred term Gastrointestinal disorders 3 (2.4) 2 (1.6) 1 (0.8) Ascites 0 (0.0) 0 (0.0) 1 (0.8) Abdominal hernia 1 (0.8) 0 (0.0) 0 (0.0) Duodenitis 1 (0.8) 0 (0.0) 0 (0.0) Gastrointestinal haemorrhage 0 (0.0) 1 (0.8) 0 (0.0) Pancreatitis chronic 1 (0.8) 0 (0.0) 0 (0.0) Small intestine ulcer 1 (0.8) 0 (0.0) 0 (0.0) Tooth loss 0 (0.0) 1 (0.8) 0 (0.0) General disorders and administration site 0 (0.0) 1 (0.8) 1 (0.8) conditions Chest pain 0 (0.0) 0 (0.0) 1 (0.8) Oedema peripheral 0 (0.0) 0 (0.0) 1 (0.8) Malaise 0 (0.0) 1 (0.8) 0 (0.0) Hepatobiliary disorders 3 (2.4) 1 (0.8) 1 (0.8) Cholecystitis 0 (0.0) 0 (0.0) 1 (0.8) Bile duct stenosis 1 (0.8) 0 (0.0) 0 (0.0) Cholelithiasis 1 (0.8) 0 (0.0) 0 (0.0) Gallbladder perforation 0 (0.0) 1 (0.8) 0 (0.0) Hepatic cirrhosis 1 (0.8) 0 (0.0) 0 (0.0) Jaundice cholestatic 1 (0.8) 0 (0.0) 0 (0.0) Infections and infestations 6 (4.8) 4 (3.2) 2 (1.7) Cellulitis 1 (0.8) 0 (0.0) 1 (0.8) Infected skin ulcer 0 (0.0) 0 (0.0) 1 (0.8) Lower respiratory tract infection 0 (0.0) 0 (0.0) 1 (0.8) Acarodermatitis 0 (0.0) 1 (0.8) 0 (0.0) Bacterascites 1 (0.8) 0 (0.0) 0 (0.0) Diabetic gangrene 0 (0.0) 1 (0.8) 0 (0.0) Gastroenteritis viral 0 (0.0) 1 (0.8) 0 (0.0) Orchitis 1 (0.8) 0 (0.0) 0 (0.0) Pneumonia 3 (2.4) 1 (0.8) 0 (0.0) Renal abscess 0 (0.0) 1 (0.8) 0 (0.0) Urinary tract infection 0 (0.0) 1 (0.8) 0 (0.0) Wound infection 0 (0.0) 1 (0.8) 0 (0.0) Injury, poisoning and procedural complications 4 (3.2) 1 (0.8) 1 (0.8) Scapula fracture 0 (0.0) 0 (0.0) 1 (0.8) Contusion 1 (0.8) 0 (0.0) 0 (0.0) Craniocerebral injury 1 (0.8) 0 (0.0) 0 (0.0) Facial bones fracture 1 (0.8) 0 (0.0) 0 (0.0) Fibula fracture 1 (0.8) 0 (0.0) 0 (0.0) Foot fracture 1 (0.8) 0 (0.0) 0 (0.0) Joint dislocation 0 (0.0) 1 (0.8) 0 (0.0) Meniscus injury 1 (0.8) 0 (0.0) 0 (0.0) Patella fracture 1 (0.8) 0 (0.0) 0 (0.0) Rib fracture 0 (0.0) 1 (0.8) 0 (0.0) Investigations 1 (0.8) 1 (0.8) 1 (0.8) Blood urine present 0 (0.0) 0 (0.0) 1 (0.8) Blood glucose increased 0 (0.0) 1 (0.8) 0 (0.0) International normalised ratio increased 1 (0.8) 0 (0.0) 0 (0.0) Metabolism and nutrition disorders 3 (2.4) 4 (3.2) 1 (0.8) Diabetes mellitus inadequate control 1 (0.8) 1 (0.8) 1 (0.8) Diabetes mellitus 1 (0.8) 1 (0.8) 0 (0.0) Hyperglycaemia 0 (0.0) 1 (0.8) 0 (0.0) Hypoglycaemia 1 (0.8) 0 (0.0) 0 (0.0)

23 + Laser alone Primary system organ class Preferred term Ketoacidosis 0 (0.0) 1 (0.8) 0 (0.0) Musculoskeletal and connective tissue disorders 1 (0.8) 3 (2.4) 0 (0.0) Intervertebral disc protrusion 1 (0.8) 0 (0.0) 0 (0.0) Musculoskeletal chest pain 0 (0.0) 1 (0.8) 0 (0.0) Osteoarthritis 0 (0.0) 1 (0.8) 0 (0.0) Rhabdomyolysis 0 (0.0) 1 (0.8) 0 (0.0) Neoplasms benign, malignant and unspecified 4 (3.2) 3 (2.4) 4 (3.4) (incl cysts and polyps) Prostate cancer 0 (0.0) 0 (0.0) 2 (1.7) Colon cancer 0 (0.0) 0 (0.0) 1 (0.8) Hepatic cancer 0 (0.0) 0 (0.0) 1 (0.8) Pancreatic carcinoma 0 (0.0) 0 (0.0) 1 (0.8) Lung adenocarcinoma 1 (0.8) 0 (0.0) 0 (0.0) Lung neoplasm malignant 0 (0.0) 1 (0.8) 0 (0.0) Metastases to peritoneum 1 (0.8) 0 (0.0) 0 (0.0) Metastases to soft tissue 1 (0.8) 0 (0.0) 0 (0.0) Ovarian cancer 0 (0.0) 1 (0.8) 0 (0.0) Pancreatic carcinoma metastatic 1 (0.8) 0 (0.0) 0 (0.0) Squamous cell carcinoma 0 (0.0) 1 (0.8) 0 (0.0) Nervous system disorders 4 (3.2) 5 (4.0) 4 (3.4) Cerebrovascular accident 1 (0.8) 2 (1.6) 3 (2.5) Aphasia 0 (0.0) 0 (0.0) 1 (0.8) Hypertensive encephalopathy 0 (0.0) 0 (0.0) 1 (0.8) Hypoaesthesia 0 (0.0) 0 (0.0) 1 (0.8) Transient ischaemic attack 1 (0.8) 1 (0.8) 1 (0.8) Carotid artery stenosis 0 (0.0) 1 (0.8) 0 (0.0) Cerebral infarction 1 (0.8) 0 (0.0) 0 (0.0) Cerebrovascular disorder 0 (0.0) 1 (0.8) 0 (0.0) Hepatic encephalopathy 1 (0.8) 0 (0.0) 0 (0.0) Myelopathy 1 (0.8) 0 (0.0) 0 (0.0) Status epilepticus 0 (0.0) 1 (0.8) 0 (0.0) Psychiatric disorders 0 (0.0) 0 (0.0) 1 (0.8) Confusional state 0 (0.0) 0 (0.0) 1 (0.8) Renal and urinary disorders 2 (1.6) 2 (1.6) 2 (1.7) Haematuria 0 (0.0) 0 (0.0) 1 (0.8) Nephrotic syndrome 0 (0.0) 0 (0.0) 1 (0.8) Renal failure 1 (0.8) 0 (0.0) 0 (0.0) Renal impairment 0 (0.0) 1 (0.8) 0 (0.0) Renal mass 1 (0.8) 0 (0.0) 0 (0.0) Urinary retention 0 (0.0) 1 (0.8) 0 (0.0) Reproductive system and breast disorders 1 (0.8) 2 (1.6) 1 (0.8) Uterine prolapse 1 (0.8) 1 (0.8) 1 (0.8) Benign prostatic hyperplasia 0 (0.0) 1 (0.8) 0 (0.0) Respiratory, thoracic and mediastinal disorders 2 (1.6) 2 (1.6) 2 (1.7) Acute pulmonary oedema 0 (0.0) 0 (0.0) 1 (0.8) Dyspnoea 0 (0.0) 0 (0.0) 1 (0.8) Acute respiratory failure 0 (0.0) 2 (1.6) 0 (0.0) Asthma 1 (0.8) 0 (0.0) 0 (0.0) Pulmonary embolism 1 (0.8) 0 (0.0) 0 (0.0) Skin and subcutaneous tissue disorders 0 (0.0) 3 (2.4) 0 (0.0) Diabetic foot 0 (0.0) 1 (0.8) 0 (0.0) Skin ulcer 0 (0.0) 2 (1.6) 0 (0.0) Vascular disorders 4 (3.2) 2 (1.6) 4 (3.4)

24 + Laser alone Primary system organ class Preferred term Arterial occlusive disease 0 (0.0) 1 (0.8) 1 (0.8) Arteriosclerosis 1 (0.8) 0 (0.0) 1 (0.8) Hypotension 1 (0.8) 0 (0.0) 1 (0.8) Peripheral ischaemia 0 (0.0) 0 (0.0) 1 (0.8) Diabetic macroangiopathy 0 (0.0) 1 (0.8) 0 (0.0) Diabetic vascular disorder 1 (0.8) 0 (0.0) 0 (0.0) Haematoma 1 (0.8) 0 (0.0) 0 (0.0) Hypertension 1 (0.8) 1 (0.8) 0 (0.0) - Adverse events with start date on or after the date of first administration of study treatment in the study eye. - Primary system organ classes are presented alphabetically; preferred terms are sorted within primary system organ class in descending order of frequency of the PRN group. - A patient with multiple occurrences of a preferred term is counted only once in the preferred term row. - A patient with multiple adverse events within a primary system organ class is counted only once in the total row. - Percentages are based on the number of patients in the Safety set in the specific treatment group. - Coded with MedDRA version Other Relevant Findings Not applicable Date of Clinical Trial Report 22 February 2014 Date Inclusion on Novartis Clinical Trial Results Database 07 April 2014 Date of Latest Update