Clinical Study Synopsis

Transcription

1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.

2 16 FEB 2016 BAY / Page: 1 of 11 Synopsis Date of report: 16 FEB 2016 Study title: Sponsor s study number: A randomized, double masked, active controlled, phase III study of the efficacy and safety of repeated doses of intravitreal VEGF Trap Eye in subjects with diabetic macular edema NCT number: NCT EudraCT number: Sponsor: Not applicable Bayer HealthCare Clinical phase: 3 Study objectives: Test drug: Primary objective To assess the efficacy of intravitreally (IVT) administered Vascular endothelial growth factor (VEGF) Trap-Eye in comparison to macular laser photocoagulation treatment in improving best corrected visual acuity (BCVA) in subjects with diabetic macular edema (DME) with central involvement. Secondary objectives To evaluate the safety of IVT administered VEGF Trap-Eye in subjects with DME Aflibercept/VEGF Trap-Eye/Intravitreal Aflibercept Injection (IAI) (Eylea, BAY ) Name of active ingredient: BAY Dose: Route of administration: Duration of treatment: 2 mg Intravitreal injection 52 weeks (The last week of treatment was Week 48, and the last efficacy / safety assessments were performed at Week 52.)

3 16 FEB 2016 BAY / Page: 2 of 11 Reference treatment: Name of active ingredient: Dose: Route of administration: Indication: Diagnosis and main criteria for inclusion: Study design: Macular laser photocoagulation. Subjects in the laser arm received standard of care active macular laser photocoagulation treatment using the modified Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at baseline, i.e., at the initial dosing visit. Sham injections were given at every visit. Beginning at Week 12, macular laser photocoagulation re-treatment was allowed based on the laser re-treatment guideline, not more frequently than once every 12 weeks. If laser re-treatment was indicated, macular laser photocoagulation treatment was performed on the same day, prior to the sham IVT injection. Not applicable Not applicable Laser photocoagulation of macula Diabetic macular edema 1. Adults 18 years with type 1 or 2 diabetes mellitus 2. Subjects with DME secondary to diabetes mellitus involving the center of the macula (defined as the area of the center subfield of optical coherence tomography [OCT]) in the study eye 3. Decrease in vision determined to be primarily the result of DME in the study eye 4. Retinal thickness as assessed by OCT of 300 µm in the study eye 5. BCVA ETDRS letter score of 73 to 24 (20/40 to 20/320) in the study eye. 6. Willing and able to comply with clinic visits and study-related procedures. 7. Provide a signed informed consent form (ICF). This was a phase 3, randomized, active controlled, double-masked, multi-center international clinical trial to assess the potential benefit of VEGF Trap-Eye treatment administered IVT at a dosage of 2 mg (2 different dosing regimens) compared to the standard of care, macular laser photocoagulation, following the modified ETDRS protocol. The primary endpoint assessment was planned after 1 year (52 weeks). Last treatment was planned for week 48.

4 16 FEB 2016 BAY / Page: 3 of 11 Methodology Only 1 eye per subject was considered to be the study eye. For subjects who met eligibility criteria in both eyes, the eye with the worst visual acuity (VA) was selected as the study eye. After enrolment (visit 2, day 1), subjects were randomized into 1 of 3 treatment groups in a 1:1:1 ratio as follows: 2Q4 group: VEGF Trap-Eye 2 mg every 4 weeks (2Q4) with sham laser at baseline. 2Q8 group: VEGF Trap-Eye 2 mg every 4 weeks until week 16, followed by every 8 weeks (2Q8) with sham laser at baseline. After week 16, a sham injection was given every other 4 weeks (every 8 weeks), at those visits where VEGF Trap-Eye was not administered, to maintain masking. Laser control group: Macular laser photocoagulation at baseline and from week 12 onwards if ETDRS laser-retreatment criteria were met, with sham injections. In all treatment groups subjects were also assessed for laser/sham laser re-treatment beginning at week 12. In addition, subjects were considered for additional treatment at each visit starting with week 24, if the additional treatment criteria were met as assessed by the masked personnel. Additional treatment included VEGF Trap-Eye for the laser subjects (5 monthly doses following by every 8 weeks dosing) and laser for the VEGF Trap-Eye subjects. Subjects receiving additional treatment were to continue with study visits up to the final visit and would also continue to receive their randomized treatment. All masking measures continued in such cases. The non-study eye was the fellow eye. If the fellow eye had DME involving or threatening the center of the macula, standard of care therapy was administered if assessed as necessary by the investigator. Any therapy of the fellow eye was considered as routine medical care rather than a study intervention. Study center(s): This study was conducted in 25 centers in 4 countries: China (18), Hong Kong (2), Korea (2) and Russia (3). Publication(s) based on the study (references): None at the time of report creation. Study period: First subject, first visit: 18 FEB 2013 Last subject, last visit: 09 MAR 2015 Early termination Not applicable

5 16 FEB 2016 BAY / Page: 4 of 11 Number of subjects: Planned: A total of 375 randomized subjects (125 subjects in each group) Analyzed: 378 subjects were analyzed for safety and efficacy (124, 127, and 127 subjects in the laser, 2Q4, and 2Q8 groups, respectively) Criteria for evaluation Efficacy: Safety: Other: The primary efficacy variable was the change from baseline in BCVA in ETDRS letter score at week 52. Secondary endpoints were: Proportion of subjects who gained 10 ETDRS letters from baseline to week 52 Proportion of subjects who gained 15 ETDRS letters from baseline to week 52 Proportion of subjects with a 2-step improvement from baseline in the ETDRS DRSS assessed by FP from baseline to week 52 Change in central retinal thickness (CRT) from baseline to week 52, as assessed on OCT NEI VFQ-25 near activities subscale change from baseline to week 52 NEI VFQ-25 distance activities subscale change from baseline to week 52. Ongoing safety assessments included ophthalmic examinations, the recording and evaluation of AEs and laboratory measurements. Serum samples were analyzed for potential development of anti-vegf Trap-Eye antibodies.

6 16 FEB 2016 BAY / Page: 5 of 11 Statistical methods: The primary efficacy variable was the change from baseline in BCVA as measured by ETDRS letters at Week 52. For the change from baseline to week 52 in BCVA, an ANCOVA model was used with baseline BCVA measurement as a covariate and treatment group and geographic region as fixed factors. In contrast to the classical ANCOVA model, separate variances were estimated for each of the 3 treatment groups. To control the nominal family-wise type I error rate of 5%, for each of the 2 VEGF Trap-Eye groups a two-sided hypothesis was tested at a significance level of 2.5% within the ANCOVA model using the respective contrast. Analysis was performed on the full analysis set (FAS, primary analysis set of all randomized subjects who received any study treatment, had a baseline measurement of BCVA, and had at least 1 post baseline assessment of BCVA) and on the per protocol set (PPS, all subjects in the FAS that did not have any major protocol violations). A hierarchical testing procedure was carried out that included the primary and all secondary efficacy variables. For all efficacy analyses, measurements obtained after the initiation of additional treatment were censored. Missing or censored values were imputed using the last non-censored value (LOCF). Baseline values were not carried forward. Descriptive statistics were provided for subgroups for primary and all secondary efficacy endpoints based on the FAS. For the primary endpoint the analysis was conducted using the LOCF, observed case (OC), alocf (LOCF including values observed after additional treatment) and aoc (OC including values observed after additional treatment) approach. Several sensitivity analyses were performed to address the impact of missing data due to drop-outs or receipt of additional treatment (see the SAP located in Appendix 1.9.1). Safety was evaluated descriptively; for the description of adverse events, the Medical Dictionary for Regulatory Activities (MedDRA) version 18.0 was used.

7 16 FEB 2016 BAY / Page: 6 of 11 Substantial protocol changes: The original protocol was dated 31 JUL 2012 and was amended twice. Protocol amendment 1, dated 6 MAY 2013, was a local amendment for Korea that specified the following substantial changes: The definition for adult according to current Civil law in Korea was different from the wording in the original protocol. Therefore the term Adult was changed to Subject. Protocol amendment 2, dated 26 AUG 2014, was a global amendment and specified the following substantial changes: The secondary and additional efficacy endpoints were revised. The statistical methodology section was modified to be consistent with the revisions in the SAP. Study subjects A total of 539 subjects were screened in the study, 381 of whom were randomized with 127 subjects in each of the treatment groups: laser group, 2Q4 group and 2Q8 group. A total of 378 subjects received treatment; 3 subjects in the laser group were not treated. For the 378 subjects who received treatment, age ranged from 21 to 87 years, with a mean of 58.5 years. Most subjects were Asian (349, 92.3%); 29 (7.7%) were white. The ratio of male and female subjects was balanced with 190 (50.3%) males and 188 (49.7%) females. The majority of 355 subjects (93.2%) completed week 52 of the study. Of the 26 (6.8%) subjects who prematurely discontinued from the study, the primary reason was AE for 13 (3.4%) subjects followed by withdrawal by the subject for 8 (2.1%) subjects. Three (0.8%) subjects were lost to follow-up and 2 (0.5%) subjects discontinued due to protocol deviations.

8 16 FEB 2016 BAY / Page: 7 of 11 Efficacy evaluation An overview of the primary and secondary efficacy endpoint results is presented in the following table. Adjusted Group Difference versus Laser a VTE 2Q4 VTE 2Q8 Endpoint Estimate (97.5% CI) p-value Estimate (97.5% CI) p-value Hierarchy of testing Primary endpoint: Change in BCVA in ETDRS letter score from baseline to week 52 Proportion of subjects (%) who gained 10 ETDRS letters from baseline to week 52 Proportion of subjects (%) who gained 15 ETDRS letters from baseline to week 52 Proportion of subjects (%) who achieved a 2-step improvement on the ETDRS DRSS from baseline to week 52 Change in CRT from baseline to week 52, as assessed by OCT NEI VFQ-25 near activities subscale change from baseline to week (10.9,17.2) < (10.2,16.9) < (35.0,59.9) < (26.3,52.1) < (19.2,43.0) < (12.6,35.9) < (26.0,52.2) < (27.6,53.7) < (-171.2,-89.9) < (-172.8,-89.9) < (-0.41,11.97) b 6.87 (0.80,12.94) NEI VFQ-25 distant activities 2.81 (-2.90,8.53) c 8.01 (2.64,13.37) subscale change from baseline to week 52 a adjusted by region and baseline BCVA in the statistical model. For continuous variables (BCVA, CRT and NEI VFQ-25), estimates are least squares mean differences. For binary variables ( 10 and 15 ETDRS letters, 2 step DRSS improvement), group differences were calculated using a Cochran-Mantel-Haenszel test adjusted by region. b not statistically significant since was higher than the threshold (0.025 for this testing procedure). Thus, hierarchical testing was interrupted at this point. c p-value provided for descriptive purposes only since hierarchical testing was interrupted at the near activities subscale for the 2Q4 group. Note: Endpoints presented in this table are limited to those identified as primary or secondary, and listed in the sequence of hierarchical testing. BCVA = best corrected visual acuity; CI = confidence interval; CRT = central retinal thickness; DRSS = Diabetic Retinopathy Severity Scale; ETDRS = Early Treatment Diabetic Retinopathy Study; Laser = laser therapy at baseline (Day 1) and then as needed (but no more often than every 12 weeks); LOCF = last observation carried forward, censoring measurements after additional treatment was given; NEI VFQ-25 = National Eye Institute Visual Functioning Questionnaire-25; OCT = optical coherence tomography; VTE 2Q4 = 2 mg VTE (vascular endothelial growth factor [VEGF] Trap-Eye) given every 4 weeks; VTE 2Q8 = 2 mg VTE given every 8 weeks after receiving 5 initial monthly doses.

9 16 FEB 2016 BAY / Page: 8 of 11 VEGF Trap-Eye, administered every 4 weeks or every 8 weeks after 5 initial monthly doses through week 52, with the last treatment given at week 48, is effective for the treatment of DME in patients from Asia (China, Hong Kong, Korea) and Russia. Both VEGF Trap-Eye groups demonstrated clinically meaningful and statistical significant improvements over laser photocoagulation in the mean change in BCVA at week 52. VEGF Trap-Eye was similarly effective in both the 2Q4 and 2Q8 treatment groups, and immediate improvements in BCVA were seen as early as week 4 (the first post-treatment time point). VEGF Trap-Eye, dosed every 4 weeks or every 8 weeks after 5 initial monthly doses, had a higher percentage of subjects gaining 10 letters and 15 letters at week 52 compared to laser photocoagulation. VEGF Trap-Eye, dosed every 4 weeks or every 8 weeks after 5 initial monthly doses, is effective in treating diabetic retinopathy in subjects with DME, based on a significantly higher proportion of subjects experiencing 2-step improvement in ETDRS DRSS as compared to the laser photocoagulation group, indicating efficacy not only for treatment of DME, but also for the underlying diabetic retinopathy. VEGF Trap-Eye, dosed every 4 weeks or every 8 weeks after 5 initial monthly doses, showed a significant improvement in mean CRT as compared to laser photocoagulation. Improvements in CRT were seen as early as week 4 (the first post-treatment time point). Results in the NEI VFQ-25 near and distance subscales for the 2Q4 and 2Q8 groups compared to laser photocoagulation were statistically significant only for the 2Q8 group. Both the 2Q4 and the 2Q8 groups experienced a clinically meaningful change in scores (approximately 5 or more points) at week 52 in the NEI VFQ-25 near subscale. For the distance subscale, only the 2Q8 group had a clinically meaningful change in score. VEGF Trap-Eye was similarly efficacious in all predefined subgroups, although the interpretation of results is limited in subgroups with low subject numbers. These conclusions are supported by extensive sensitivity analyses, confirming the robustness of the results. VEGF Trap-Eye was superior to laser even in analyses that included measurements taken after the initiation of additional treatment (alocf, aoc), despite the fact that subjects in the laser group improved substantially after initiating treatment with VEGF Trap-Eye. Safety evaluation Exposure to VTE The exposure analyses showed sufficient compliance in all treatment groups and did not point to systematic treatment errors that might have biased the observed treatment outcomes. A total of 45 subjects (36.3%) in the laser group received additional rescue treatment with VTE beyond week 24, whereas only one subject (0.8%) in the 2Q4 group and 4 subjects (3.1%) in the 2Q8 group underwent additional rescue treatment with active laser.

10 16 FEB 2016 BAY / Page: 9 of 11 Adverse events An overview of the TEAE frequency over the 52 weeks' study duration is provided in the following table. Laser VTE 2Q4 (N=127) VTE 2Q8 (N=127) VTE combined a (N=254) (N=124) Any AE 112 (90.3%) 110 (86.6%) 113 (89.0%) 223 (87.8%) Any TEAE 111 (89.5%) 108 (85.0%) 109 (85.8%) 217 (85.4%) Any drug-related TEAE 4 ( 3.2%) 4 ( 3.1%) 7 ( 5.5%) 11 ( 4.3%) Any serious TEAE (SAE) b 24 (19.4%) 19 (15.0%) 22 (17.3%) 41 (16.1%) Any drug-related SAE 1 ( 0.8%) 0 1 ( 0.8%) 1 ( 0.4%) Any injection-related TEAE 8 ( 6.5%) 19 (15.0%) 23 (18.1%) 42 (16.5%) Any injection-related SAE 1 ( 0.8%) Any laser-related TEAE 3 ( 2.4%) 3 ( 2.4%) 3 ( 2.4%) 6 ( 2.4%) Any laser-related SAE 1 ( 0.8%) Any AEs leading to discontinuation of study drug c 4 ( 3.2%) 4 ( 3.1%) 4 ( 3.1%) 8 ( 3.1%) Deaths Any APTC-classified events 2 ( 1.6%) 4 ( 3.1%) 3 ( 2.4%) 7 ( 2.8%) Any ocular TEAE 92 (74.2%) 86 (67.7%) 78 (61.4%) 164 (64.6%) Study eye 72 (58.1%) 65 (51.2%) 60 (47.2%) 125 (49.2%) Fellow eye 58 (46.8%) 64 (50.4%) 59 (46.5%) 123 (48.4%) Any ocular SAE 7 ( 5.6%) 4 ( 3.1%) 3 ( 2.4%) 7 ( 2.8%) Study eye 6 ( 4.8%) 2 ( 1.6%) 1 ( 0.8%) 3 ( 1.2%) Any drug-related ocular TEAE 2 ( 1.6%) 4 ( 3.1%) 5 ( 3.9%) 9 ( 3.5%) Study eye 2 ( 1.6%) 4 ( 3.1%) 4 ( 3.1%) 8 ( 3.1%) Any drug-related ocular SAE 1 ( 0.8%) Study eye 1 ( 0.8%) Any injection-related ocular TEAE 8 ( 6.5%) 19 (15.0%) 23 (18.1%) 42 (16.5%) Study eye 8 ( 6.5%) 19 (15.0%) 23 (18.1%) 42 (16.5%) Any injection-related ocular SAE 1 ( 0.8%) Study eye 1 ( 0.8%) Any laser-related ocular TEAE 3 ( 2.4%) 3 ( 2.4%) 3 ( 2.4%) 6 ( 2.4%) Study eye 3 ( 2.4%) 3 ( 2.4%) 3 ( 2.4%) 6 ( 2.4%) Any laser-related ocular SAE 1 ( 0.8%) Study eye 1 ( 0.8%) Any non-ocular TEAE d 77 (62.1%) 79 (62.2%) 81 (63.8%) 160 (63.0%) Any non-ocular SAE 17 (13.7%) 15 (11.8%) 20 (15.7%) 35 (13.8%) Any drug-related non-ocular TEAE 2 ( 1.6%) 1 ( 0.8%) 2 ( 1.6%) 3 ( 1.2%) Any drug-related non-ocular SAE ( 0.8%) 1 ( 0.4%) a Sum of the columns VTE 2Q4 and VTE 2Q8 through study end at week 52. b All SAEs reported in this study are treatment-emergent. c Including one subject in the 2Q4 group with a non-treatment-emergent AE. An additional subject in the 2Q8 group was reported on the study end page to have withdrawn study drug due to AEs, but no corresponding AEs were reported on the AE page. d No injection-related or laser-related non-ocular TEAEs were reported. AE = adverse event; APTC = Anti-Platelet Trialists Collaboration; N = total number of subjects; SAE = serious AE; TEAE = treatment-emergent AE; VEGF = vascular endothelial growth factor; VTE 2Q4 = VEGF Trap-Eye (VTE) administered as 2 mg every 4 weeks; VTE 2Q8 = 2 mg VTE every 4 weeks until week 16 and every 8 weeks, thereafter.

11 16 FEB 2016 BAY / Page: 10 of 11 Overall, there were no differences in the frequency of any of the non-ocular TEAEs across treatment groups that were regarded as clinically meaningful. One pregnancy was reported, which was terminated at an early stage of gestation because of the pregnant subject's deliberate decision. Most ocular TEAEs in the study eye, which occurred in 58.1% of laser subjects vs. 49.2% of subjects in the combined VTE group, had a maximum intensity of mild or moderate. The most common ocular TEAE in the study eye occurring in the VTE groups were consistent with the active injection procedure, whereas the most common ocular TEAEs in the study eye in the laser group were consistent with DME progression. Consistently, TEAEs in the study eye explicitly classified as injection-related by the reporting investigators occurred more frequently in the VTE groups (16.5% in the combined VTE group vs. 6.5% in the laser group), while the incidence of laser-related TEAEs was identical in the 3 treatment groups (2.4% of subjects in each group). No subjects died during the course of the study. The proportions of subjects with ocular SAEs in the study eye were slightly higher in the laser group than in the VTE combined group (4.8% vs. 1.2%), while the proportions of subjects experiencing any non-ocular SAEs were quite similar (13.7% in the laser group and 13.8% in the combined VTE group). Likewise, the proportions of subjects who discontinued the study drug due to AEs were small and almost identical in the 3 treatment groups. Adjudicated APTC events were infrequent in all 3 treatment groups (2 subjects [1.6%] in the laser group, 4 subjects [3.1%] in the 2Q4 group, and 3 subjects [2.4%] in the 2Q8 group) and the analysis thus not robust enough to derive reliable conclusions on potential treatment group differences. Evaluation of laboratory data, vital signs, and ECG data (including QTc interval) did not reveal remarkable changes within the treatment groups during the course of the study or differences between the treatment groups, suggesting there were no substantial systemic effects associated with the study treatment. There were no indications that the superior efficacy outcomes in the VTE arms might have been promoted by a potentially better glycemic control in these arms. In summary, VEGF Trap-Eye showed a favorable safety profile and was well tolerated over a treatment duration of 52 weeks in this VIVID EAST study population. Immunogenicity Two subjects in the laser group and one subject in the 2Q8 group were positive in the ADA assay at baseline prior to first study drug exposure. Maximum titers were 1:120, which was low and close to the minimum sample dilution of 1:30. These findings suggested a high serum background or pre-existing immunoreactivity. While the 2 subjects in the laser group remained positive in the ADA assay at week 52 with an unchanged titer level, the subject in the 2Q8 group was no longer positive at this time point. Thus, no treatment-emergent antibody formation was detected in any of the study subjects through week 52, indicating that the immunogenicity associated with intravitreally administered VTE is very low.

12 16 FEB 2016 BAY / Page: 11 of 11 Overall conclusions Both VEGF Trap-Eye treatment regimens (2Q4 and 2Q8) were shown to be superior to laser photocoagulation in the mean change from baseline in BCVA. This is consistently supported by all visual acuity and anatomic endpoints, as well as by all sensitivity analyses. The 2Q8 regimen, in which 2 mg VEGF Trap-Eye was administered every 8 weeks after 5 initial monthly doses, demonstrated superior efficacy to laser treatment and similar efficacy to 2Q4, while maintaining a similarly favorable safety profile. This every 8 week regimen, allowing for less frequent IVT injections than a monthly regimen, may provide benefits in terms of decreased injection-related burden on the subjects, their caregivers and physicians, as well as the overall healthcare system. Treatment with VTE over an observation period of 52 weeks was generally safe and well tolerated in subjects enrolled in either VTE treatment group in this VIVID EAST study. No new safety signals were identified in this study. The safety profile of VEGF Trap-Eye observed in this study was consistent with other studies with VEGF Trap-Eye conducted outside of these countries.

13 Appendix to Clinical Study Synopsis Product Identification Information Product Type US Brand/Trade Name(s) Brand/Trade Name(s) ex-us Generic Name Main Product Company Code Other Company Code(s) Chemical Description Other Product Aliases Biological Product EYLEA EYLEA, EYLIA Aflibercept BAY N/A VEGF Trap belongs to the pharmacological class of VEGF inhibitors: it is a recombinant protein created by fusing the second Ig domain of human VEGFR1 with the third Ig domain of human VEGFR2, which is in turn fused to the constant region of human IgG1. Aflibercept is a potent, specific inhibitor of VEGF that is active in animal models of ocular neovascularisation after systemic and IVT administration. Aflibercept interferes with the biological actions of VEGF-A by binding to VEGF-A, preventing it from interacting with its receptors. It also binds to other VEGFR1 ligands, notably PlGF. VEGF Trap-Eye Date of last Update/Change: 29 Jul 2015