Description of Studies

No trials were identified that exclusively enrolled the patient population of interest for this review (adults with DME who are pseudophakic). Thus this review includes two phase III randomized controlled trials (RCTs) that were pivotal in the Health Canada submission (Table 4).

Studies 206207-010 and 206207-011, hereafter referred to as MEAD-010 (N = 494) and MEAD-011 (N = 554), respectively, were similarly designed masked, sham-controlled, phase III superiority RCTs. Both trials were multi-centre and multinational, and recruited patients from centres located in North America (including Canada).

Populations

Baseline Characteristics

Details of patients’ baseline characteristics are presented in Table 5. Generally, the distributions of patient characteristics for the pseudophakic subpopulation were imbalanced across treatment groups and across trials.

Table 5

Summary of Baseline Characteristics (Pseudophakic Subgroup).

Patients in the pseudophakic subgroup enrolled in the MEAD trials had a mean age that ranged between ▬ and ▬ years (SD ranged between ▬ and ▬) of whom the majority (▬ to ▬) was older than 65 years of age. In the MEAD-010 trial, there were differences in the distribution of ages between groups. More than half of the patients enrolled in the MEAD trials were male ranging between ▬ and ▬ in both MEAD trials; however, MEAD-010 enrolled more male patients than MEAD-011. The majority of patients in both trials were Caucasian (50.0% to 90.0%); however, MEAD-011 had a greater representation of patients from different races/ethnicities (up to ▬ Asian and ▬ Hispanic). Overall, patients had mean IOP that ranged between ▬ and ▬ (SD ranged between ▬ and ▬), mean systolic blood pressure that ranged between ▬ and ▬ (SD ranged between ▬ and ▬), mean diastolic blood pressure that ranged between ▬ and ▬ (SD ranged between ▬ and ▬).

Most patients received prior therapy in both MEAD trials, the most common being laser therapy (▬ to ▬). Only a minority of patients had prior anti-VEGF therapy (▬ to ▬), and a greater percentage of patients (approximately 7% difference) in the sham group had prior anti-VEGF therapy compared with the dexamethasone group in MEAD-010.

The majority of patients in both MEAD trials had type 2 diabetes (88.0% to 100%) with differences between treatment groups in MEAD-010 with respect to the percentage of patients with type 1 versus type 2 diabetes. Patients had a mean A1C that ranged between ▬ and ▬ (SD ranged between ▬ and ▬), with most patients having an A1C ≤ 8.0% ranging between 69.0% and 79.5%. ▬▬▬▬▬

Generally, most patients had moderately severe DR or better (▬ to ▬). However, MEAD-010 and MEAD-011 had differences up to approximately ▬ and ▬ between treatment groups in severity of DR, respectively. ▬▬▬▬▬

Patients in the pseudophakic subgroup of the MEAD trials had mean BCVA that ranged between ▬ and ▬ letters (SD ranged between ▬ and ▬). Most patients had BCVA ▬ letters in both MEAD trials; ▬▬▬▬▬. Although the inclusion criteria of the MEAD trials are restricted BCVA scores between 34 letters and 68 letters in the study eye as measured by the ETDRS method at qualification/baseline, patients with BCVA scores greater than the inclusion thresholds were enrolled. Overall, the ≥ 36 to ≤ 45 and ≥ 46 to ≤ 55 BCVA categories had differences of approximately ▬ and ▬ in between treatment groups in MEAD-011, respectively. ▬▬▬▬▬

Interventions

Patients were randomized (1:1:1) to dexamethasone 700 mcg intravitreal injection, dexamethasone 350 mcg intravitreal injection or sham. Randomization was conducted using the Interactive Voice Response System (IVRS) or the Interactive Web Response System (IWRS). The intervention of interest for this CDR review is the dexamethasone 700 mcg administered by intravitreal injection; therefore, the dexamethasone 350 mcg intravitreal injection will not be discussed.

The treatment procedures in both MEAD trials were performed by treating investigators in a controlled and sterile setting according to a standardized protocol. Patients randomized to dexamethasone had the study drug (Ozurdex; dexamethasone 700 mcg) or dexamethasone 350 mcg placed into the vitreous (posterior segment of the eye) through the pars plana using the Dexamethasone Posterior Segment Drug Delivery System (DEX PS DDS). Patients randomized to sham treatment had the needleless applicator pressed against the conjunctiva to preserve masking. Ozurdex was embedded into an inactive biodegradable polymer matrix that slowly releases dexamethasone while gradually degrading over time. Treatments occurred at randomization (day 0) followed by assessments for retreatment eligibility every 3 months. Patients were eligible for retreatment if retinal thickness in the 1 mm central macular subfield as measured by optical coherence tomography (OCT) was > 225 µm, or upon investigator interpretation of the OCT for any evidence of residual retinal edema consisting of intraretinal cysts or any regions of increased retinal thickening (within or outside of the center subfield). The original retreatment retinal thickness threshold as measured by OCT was amended during the trial, reducing the required thickness from 225 µm to 175 µm.

Follow-up was conducted at one, seven and 21 days post injection, and regular treatment visits occurred every 1.5 months in the first year and every three months thereafter. Starting from the six-month visit and every three months thereafter, patients were evaluated for retreatment eligibility. Retreatment could occur no sooner than at six months, and patients could receive up to seven treatments during the three-year duration of the studies. Patients could have been treated with escape therapy and withdrawn from the studies or withdrawn due to visual acuity at the investigator’s discretion at any time during the studies.

IOP treatments, panretinal photocoagulation, cataracts surgeries, topical steroids or nonsteroidal anti-inflammatory drugs were permitted in the study eye during the trials.

Macular edema in the non-study eye could be treated with laser and/or local therapies (e.g., topical, periocular, intravitreal). Systemic therapies (e.g., oral or parenteral steroids, systemic anti-VEGFs) and doses of intravitreal anti-VEGFs higher than the doses detailed in the exclusion criteria were not to be used. Additionally, systemic steroids, additional non-study procedures or surgeries in the study eye with the exception of those related to cataracts were not permitted. Escape therapy for macular edema including intravitreal steroids other than the study medication, periocular steroids, laser or surgical treatments for macular edema, anti-VEGF therapy, systemic anti-VEGF therapy, and other pharmacologic therapies for macular edema in the study were also prohibited.

The use of escape therapy was permitted anytime during the trial; however, patients who received escape therapy in the study eye were considered study treatment failures and were no longer be eligible to receive study medication, and were withdrawn from the study. Reasons for use of escape therapy resulting in study withdrawal could have included:

• intravitreal steroids other than the study medication in the study eye
• periocular steroids in the study eye
• Laser and/or surgical treatments for macular edema in the study eye
• intravitreal anti-VEGF therapy in the study eye
• systemic anti-VEGF therapy
• other pharmacologic therapies for macular edema in the study eye.

Outcomes

Statistical Analysis

Originally, the study was designed to assess the effect of dexamethasone using the proportion of patients with ≥ 15 letter improvement as the primary end point and required a sample size of ▬ in total. The protocol was subsequently amended and the primary end point changed to the average BCVA mean change (AUC approach) from baseline during the study. Therefore a new sample size of 170 patients per treatment arm (510 patients in total) would have provided a power of 86% to detect a 4-letter mean difference in average BCVA mean change from baseline between dexamethasone 700 mcg and sham based on a 2-sided test at the 5% significance level in the primary efficacy end point assuming a standard deviation of 12 letters (standard deviation was based on two single-dose 6-month retinal vein occlusion studies reporting an observed standard deviation of 10 letters). No specific power calculation conducted for the pre-specified subgroup of interest for this CDR review and there was no specific power calculation for the subgroup of adult patients with DME who are pseudophakic.

The primary analysis of efficacy in the MEAD trials was performed based on measurements obtained during the masked treatment phase for the general DME population. Originally, the primary analysis of the MEAD trials was to be assessed after 12 months of follow-up. The trial duration was subsequently amended several times to include the possibility of a final assessment after 39 months of follow-up. The primary efficacy end point in both MEAD trials was the average BCVA mean change from baseline in the study eye based on the ETDRS method using an AUC approach. The primary efficacy end point was analyzed in the ITT population using an ANCOVA model stratified by treatment as fixed effects and baseline BCVA as the covariate. Although the manufacturer suggests that no imputation for missing data was performed for the primary analysis, the average BCVA mean change from baseline for patients with no post-baseline BCVA assessment was set to zero. To avoid confounding effects of other therapies, all patients in the MEAD study who required escape therapies were discontinued from the study and their values set to missing (not imputed); therefore, were not included in the final analyses. Data are presented as mean difference in the change from baseline compared with sham, with corresponding 95% CIs.

A gate-keeping procedure was used to control the overall type I error at the 5% level for between-group comparisons. The comparison of dexamethasone 700 mcg versus sham was considered significant if the P value was ≤ 0.05. Only if the comparison of dexamethasone 700 mcg versus sham was significant at the 0.05 level was the comparison of dexamethasone 350 mcg versus sham to be performed, at a significance level of 0.05. If the comparison of dexamethasone 700 mcg versus sham was not statistically significant, the comparison of dexamethasone 350 mcg versus sham was not to be considered statistically significant regardless of its P value.

Sensitivity analyses were also performed for the primary outcomes in the general DME population and included:

• Per-protocol (PP) population
• Multiple imputation for missing values (Markov chain Monte Carlo [MCMC] method)
• Using “as is” observed data.

Secondary efficacy analyses were also assessed in the general DME population using the ITT population; however, no adjustments were made to control for type I error. Contrary to the primary analysis, the secondary analyses used last observation carried forward (LOCF) methods to impute for missing data with the exception of the average change from baseline in retinal thickness of the central subfield during the study end point which did not impute for missing data (only based on observed data). Secondary efficacy outcomes included:

• BCVA change from baseline at every study visit (ANCOVA using baseline BCVA as a covariate)
• proportion of patients with Improvement/worsening of 10 or more letters from baseline at every study visit (Pearson’s chi-square test)
• proportion of patients with Improvement/worsening of 15 or more letters from baseline at every study visit (Pearson’s chi-square test)
• categorical change from baseline at every study visit (Wilcoxon Rank Sum Test)
• average change from baseline in retinal thickness of the central subfield during the study (AUC approach, observed cases [ANCOVA using baseline central subfield retinal thickness as a covariate])
• change from baseline in retinal thickness of the central subfield during the study at every study visit (ANCOVA baseline with central subfield retinal thickness as a covariate instead of BCVA).

Other efficacy analyses were also conducted in the general DME population based on patient reported outcomes using health-related quality of life measures (EQ-5D, SF-36v1, and NEI-VFQ-25) in the ITT population; however, no adjustments were made to control for type I error. For analyses of mean change from baseline at every study visit, missing values were imputed by LOCF methods, while the analyses of average change from baseline using AUC approaches were performed on observed data which did not impute for missing data. Post-baseline data for the EQ-5D and SF-36v1 were not provided for adult patients with DME who were pseudophakic, therefore no descriptions are provided in this CDR report. NEI-VFQ-25 was assessed using time-weighted average change from baseline derived from observed data using the AUC approach. Comparisons between treatment arms were performed using an ANCOVA model with treatment as a fixed effect and the baseline NEI-VFQ-25 score as a covariate. In addition, the proportions of patients with at least 5-point and at least 10-point improvement from baseline at each follow-up visit were analyzed using Pearson’s chi-square test or Fisher’s exact test.

Safety results were presented by treatment group (dexamethasone 700 mcg and sham) and summarized as a frequency distribution for all adverse events (regardless of causality) and treatment-related AEs, each broken down by ocular adverse events (study eye and non-study eye) and non-ocular adverse events analyzed using the safety population.

Pre-specified subgroups of patients defined by duration of diabetes, duration of DME, baseline A1C, prior laser treatment, treatment-naïve patients, lens status at baseline (phakic and pseudophakic), nonproliferative diabetic retinopathy severity at baseline, and country were also conducted. Only the duration of DME subgroup was analyzed in the pseudophakic subpopulation. The primary, secondary and other efficacy outcomes evaluated in subgroups were performed in a similar way as for the general DME population. Furthermore, only the PP sensitivity analysis was performed in the subgroup of adult patients with DME who were pseudophakic. Overall, subgroup analyses in both MEAD trials were not adjusted for multiple statistical tests and are therefore subject to inflated type I error. Randomization was not stratified for any of the pre-specified subgroups. No analyses were conducted for the subgroup of adult DME patients who are pseudophakic and either unsuitable for anti-VEGF therapy or have had inadequate response to prior anti-VEGF therapy.

Overall, no interim analyses were planned or conducted in any of the MEAD trials.

Patient Disposition

Of the 929 and 961 patients screened in MEAD-010 and MEAD0-011, 47% and 42% did not meet the criteria for enrolment, respectively. A total of 94 and 93 patients in the MEAD-010 and MEAD-011 trials satisfied the Health Canada indication (i.e., adults with DME who are pseudophakic). Generally, more patients discontinued the study in the sham groups compared with the dexamethasone groups (▬ and ▬ compared with ▬ and ▬ in MEAD-010 and MEAD-011, respectively). ▬▬▬▬▬ Data associated with treatment discontinuation were not provided in the subgroup of patients with DME who were pseudophakic. Details in regards to patient disposition in the MEAD trials are provided in Table 6.

Table 6

Patient Disposition.

Exposure to Study Treatments

The majority of patients in the MEAD in trials were treated with ▬ or more doses (ranging between ▬ and ▬), with the exception of the DEX 700 group in MEAD-011 wherein the majority of patients were treated with ▬ or more doses (▬). Overall, ▬ and ▬ were treated with ▬ or more doses of dexamethasone in both MEAD trials. Only between ▬ and ▬ of patients in the MEAD trial received a ▬ treatment. The mean number of treatments per patients ranged between ▬ and ▬ doses (SD ranged between ▬ and ▬) and the median number of treatments ranged between ▬ and ▬ doses (range 1 to 7). Overall, the majority of patients achieved ▬ months or more of follow-up during the MEAD trials (▬ to ▬) with the exception of the sham group in MEAD-011 (▬). Details in regards to exposure in the MEAD trials are provided in Table 7, Table 8 and Table 12.

Table 7

Number of Patients Categorized by the Total Number of Injections Received During the Study (Pseudophakic subgroup).

Table 8

Cumulative and Average Study Follow-up (Pseudophakic subgroup).

Internal Validity

The MEAD trials were similarly designed masked, sham-controlled RCTs that used appropriate methods to randomize patients (Interactive Voice/Web Response System). The MEAD trials were not initially designed to assess the average BCVA mean change from baseline as the primary end point. Rather, the original end point was the proportion of patients who achieved at least a 15-letter improvement by end of study, which the FDA still considered as the primary end point. Only subsequent to a protocol amendment was the primary end point changed to be the average BCVA mean change from baseline. The manufacturer provided adjustments to the sample size to accommodate the new end point. Based on the sample size calculations, the MEAD studies were designed as a superiority trial with the expectation to show a between-treatment difference of at least four letters. The primary end point used in the MEAD trials (average BCVA mean change from baseline) used the AUC approach. Although this method was considered to be more reliable and was expected to result in a more appropriate control of type I error compared with analysis at every individual time point according to the Health Canada reviewer report, it can also mask the variability of treatment effects across all time points.⁵¹ The FDA also commented on the robustness of the AUC approach, noting that the average mean change in BCVA during the study does not differentiate the short-term treatment effect (which the FDA indicated was prior to 36 months) from the long-term treatment effect.⁵² The FDA refused to accept the amendment to the primary end point and considered the original primary end point (i.e., proportion of patients who achieved at least a 15-letter improvement by end of study) more appropriate.⁵²

The use of the ANCOVA method of analysis would have ensured that the results were adjusted for variables including baseline BCVA and CRT as measured by OCT. All efficacy analyses were conducted using ITT analysis defined as all randomized patients analyzed according to the treatment to which the patient was randomized. In the ANCOVA model, missing data were imputed using the LOCF approach for all end points with the exception of those based on the AUC approach. Excluding patients with missing data is inconsistent with the true definition of an ITT analysis, in which all randomized participants are included. The exclusion of these patients can potentially bias the results, given the pattern of missing data. Overall, more withdrawals occurred in the sham groups compared with the dexamethasone groups in both MEAD trials, especially due to lack of efficacy (more prominently in MEAD-011). Given that missing data were not imputed in the AUC approach used for the primary analysis, the treatment effect may have been biased in favour of dexamethasone 700 mcg given that patients that were doing well would be overrepresented in that group. Furthermore, patients were excluded from the primary analysis if they received escape treatment. Excluding these patients can bias the results if withdrawals due to escape therapy were imbalanced between treatment groups, although this was not the case given that the numbers were well balanced between treatment groups in both MEAD trials. In addition, a sensitivity analysis using a PP population was also conducted; however, this does not lessen the concerns related to exclusion of patients. Furthermore, given that more than 50% of patients discontinued the studies in the both MEAD trials, the LOCF method for imputing data may be biased given that it does not account for patients who had an initial response but could not tolerate treatment. Given that the reasons for withdrawal are related to the study drug and are not balanced between study groups, using the LOCF alone as an imputation method for certain end points may not be sufficient to address the missing data. Sensitivity analyses using multiple imputation methods were evaluated in the overall DME population; however, the results were not reported for the pre-specified subgroup of patients with DME who are pseudophakic. The Health Canada reviewers report states that the results were no longer statistically significant in the overall DME population when using the multiple imputation method to handle missing data.⁵¹ The lack of a statistically significant difference from the multiple imputation analysis is due to the larger variance produced by the analysis compared the LOCF method which artificially reduces variance by repeating the same data point when data are missing.⁵¹ Overall, per Health Canada, had the missing data actually been captured, they would have been expected to have had some variance — which indicates that the multiple imputation model may be more appropriate than the LOCF method.

Although, different investigators were used to perform the study treatment procedure, follow-up, data collection and data analysis throughout the trial to maintain masking, post-injection safety visits at day one, seven and 21 which were conducted by the treating investigator, resulting in unblinded safety evaluations. Furthermore, the adverse event profile associated with intravitreal steroids (i.e., IOP) is well known, therefore some accidental unblinding may have occurred.^12,19 Given that prior intravitreal steroid experience was not an exclusion criterion in any of the trials, some patients with prior experience may have surmised that the allocated treatment was dexamethasone. However, considering that the primary end point of the MEAD trials is relatively objective, the potential for bias is of lesser concern. Unblinding may, however, lead to biases such as under or over reporting of subjective outcomes (i.e., AEs or health-related quality of life measures) which can impact the overall impressions with dexamethasone treatment. Treatment discontinuations during the studies were not reported in any of the MEAD trials. Overall, there were numerically more study discontinuations in the sham groups compared with the dexamethasone groups in both MEAD trials. The European Medicines Agency’s guideline on missing data in confirmatory clinical trials suggests that patients who do not complete a clinical trial may be more likely to have extreme values than patients who complete a trial.⁵³ Therefore, excluding these patients could underestimate the variability and artificially narrow the confidence interval for the treatment effect, and neither the LOCF method nor sensitivity analysis using the PP population would have overcome this potential limitation.

Dexamethasone response at each study visit varied considerably across both MEAD trials. The reason for the relatively large difference in response rate between the two trials remains unclear; however, it may be due to underlying confounders due to the imbalance in baseline characteristics between treatment groups and across studies. In the MEAD trials, the ANCOVA model only adjusted for BCVA and retinal thickness as measure by OCT as covariates. Other baseline line factors which may confound the results were not adjusted, such as duration of diabetes, duration of DME, severity of DR, and type of DME among others. If not adjusted appropriately, such confounding factors may influence the comparative efficacy, though the direction of bias is unclear.

In the MEAD trials, only the primary analyses were controlled for multiple statistical testing using a gate-keeping procedure (i.e., average BCVA mean change from baseline in the general DME population). Adjustments for type I error were conducted using a hierarchical approach for the dexamethasone 700 mcg versus sham comparison at the 0.05 level of significance first, followed by the dexamethasone 350 mcg versus sham comparison (also at the 0.05 level of significance) if the prior analysis was statistically significant. As a result, all other outcomes were not appropriately adjusted for multiplicity, which increases the risk of making a type I error. Further, subgroups typically do not maintain randomization (unless used as stratification variables for randomization, which was not the case). Inadequate randomization introduces biases through the presence of confounders (known and unknown). The imbalances present in the baseline characteristics of the subgroup of adult patients who are pseudophakic may suggest that randomization may have been compromised. Given the distribution of known and unknown confounders, the direction of the bias remains unclear; however, these biases may explain the differing treatment affect between MEAD-010 and MEAD-011. Subgroups are also likely underpowered (small sample size) to detect a statistically significant difference.

The MEAD trials were originally designed to evaluate the effects of dexamethasone in the general DME population. This CDR report is based on the results of a subgroup (i.e., adults with DME who are pseudophakic) which only consisted of approximately 20% of overall enrolled patients. While the risks of type I error and bias remain, the validity of the results for the subgroup of adult patients with DME who are pseudophakic are strengthened by its pre-specified nature and the biological plausibility of the interaction effect. It is known that intravitreal steroid injections result in the development and progression of cataracts (clouding of the natural lens) in eyes that are phakic (natural lens).¹⁹ Furthermore, treatment with dexamethasone has been shown to be associated with increased frequency of cataracts, which is outlined in the warning and precautions section of the Health Canada–approved product monograph.¹² It is believed that the formation of cataracts can potentially confound the overall treatment effect on the BCVA in patients with DME who are phakic; therefore, patients who have had their natural lens surgically replaced with an artificial lens (pseudophakic) would be expected to further benefit from treatment with dexamethasone given that the formation and progression of cataracts is no longer possible.⁵¹

External Validity

In the MEAD trials, 42% to 47% of patients were screening failures when considering the overall DME population. Stringent inclusion and exclusion criteria can result in a highly enriched population, which may not be completely representative of the DME population in Canada and can potentially limit the generalizability of the trial results. Furthermore, the MEAD trials were initially designed to assess the effects of dexamethasone in the general DME population. Only after a notice of non-compliance was issued (due to lack of efficacy due to confounding associated with cataracts) was an analysis subsequently conducted in the pre-specified subgroup of adult patients with DME who are pseudophakic. The Health Canada–approved indication was consequently limited to the treatment of patients with DME who are pseudophakic. Therefore, the focus of this CDR review is based on a subset of the overall DME population. In addition, the protocol for the present review considered further subgroups, including patients who are either unsuitable for anti-VEGF therapy or have had inadequate response to prior anti-VEGF therapy. Between ▬ and ▬ of the pseudophakic patients included in the MEAD trials had prior experience with anti-VEGF therapy, and it remains unclear if these patients responded to these treatments and were truly anti-VEGF refractory. It is also unclear if there were any patients included in the MEAD trials that were considered unsuitable for anti-VEGF therapy. According to the clinical expert consulted for this review, the date of conduct of the trials (between February 2005 to June 2012) was prior to the adoption of anti-VEGF therapies and may therefore may have influenced the number of patients having access to anti-VEGF therapy. It is therefore unclear if the results of the MEAD trials can be generalized to patients who are unsuitable for anti-VEGF therapy or have had an inadequate response to anti-VEGF therapy.

Both MEAD trials were multinational and included sites from Canada. The clinical expert consulted by CDR for this review highlighted that the MEAD trials appear to have recruited patients with characteristics similar to those of the overall DME population in Canada with some exceptions, however, the expert noted that the majority of patients recruited in the MEAD trials were aged > 65 years (▬ to ▬), which may represent an older DME population than what would be observed in Canadian clinical practice.

With respect to the study duration, the FDA suggested that 36 months is considered short term. The FDA recommends that the treatment effect be demonstrated at a time point of at least 36 months or later for the indication of DME given that earlier treatment success is not necessarily a good indicator of a later success.⁵² Therefore, it is unclear if the results of the MEAD trials would be representative of the long-term treatment effect.

Overall, the relatively large and imbalanced number of discontinuations in the MEAD trials may have led to a DME population that was generally healthier than those initially randomized into the study given that mostly patients who were doing well remained in the trial. This effect is artificially high in the sham groups of the MEAD trials because only patients who did not develop substantial visual deterioration without any treatment were included in the final analyses. Therefore, it remains unclear if the dexamethasone treatment effect observed in the MEAD trials is truly representative of the effect potentially observed in clinical practice.

The dexamethasone retreatment regimen could not occur more frequently than every six months in both MEAD trials. However, the clinical expert consulted for this CDR review suggests that the effects of intravitreal dexamethasone injections wane over time and are rarely sustained at month six, therefore dexamethasone may be used more frequently than every six months in clinical practice. The same expert suggested a retreatment regimen closer to every four months rather than a similar regimen included in the trials. The effects of dexamethasone associated with a more frequent injection regimen were not evaluated in the MEAD trials and therefore remain unclear.

Best-Corrected Visual Acuity

Details pertaining to BCVA outcomes for the pseudophakic subpopulation in MEAD trials are provided in Table 9.

Table 9

Visual Acuity Efficacy Outcomes (Pseudophakic Subgroup; ITT analysis).

Compared with sham, the adjusted least squares mean differences in average BCVA mean change from baseline using the AUC approach (the primary outcome) were 5.9 letters (95% CI, ▬), P < 0.001 and 3.6 letters (95% CI, ▬), P = 0.018 in MEAD-010 and MEAD-011, respectively. The results of sensitivity analyses (using a PP population instead of the ITT population) were consistent with the primary analyses: the adjusted least squares mean difference, versus sham, were ▬▬▬▬▬, respectively (Table 16).

In both trials, the change from baseline in BCVA was also measured at different times during the study, including at months 3, 6 9, 12, 18, 24, 30, 36, and 39. Assessments of BCVA at these time points (95% CI) ranged between ▬▬▬▬▬ (Table 15).

Other BCVA outcomes included ≥ 15 letter improvement from baseline at the last study visit. Overall, 15 (34.1%) patients in the dexamethasone group and eight (16.0%) patients in the sham group achieved a ≥ 15 letter improvement in MEAD-010 (difference versus sham of 18.1% [95% CI, 0.8 to 35.4] P = 0.043). In MEAD-011, five (11.9%) patients in the dexamethasone group and three (5.9%) patients in the sham group achieved a ≥ 15 letter improvement (difference versus sham of 6.0% [95% CI, −5.7 to 17.8] P = 0.461). Patients achieving other categories of BCVA change at the last study visit including ≥ 5 and < 15 letter improvement, no change (includes 5 letter improvement or worsening), ≥ 5 and < 15 letter worsening and ≥ 15 worsening (additionally reported as ≥ 15 letter worsening from baseline any time during the trial) were also evaluated and detailed in Table 15. Similarly 10-letter change analyses were also reported and detailed in Table 15.

National Eye Institute Visual Functioning Questionnaire 25 (NEI-VFQ-25)

The MEAD trials also evaluated vision-related outcomes using the National Eye Institute Visual Functioning Questionnaire-25. In general, NEI-VFQ-25 overall composite scores at baseline were similar across both treatment groups across both trials and ranged between ▬ and ▬. The adjusted average least squares mean differences for the overall composite score were ▬▬▬▬▬ in MEAD-010 and MEAD-011, respectively. Details pertaining to BCVA outcomes in the MEAD trials are provided in Table 10. In addition, the percentage of patients achieving five-point or more and 10-point or more improvement in the NEI-VFQ-25 overall composite score and its subscales were reported and detailed in Table 10; Overall, number of patients achieving the 10 or 5 letter thresholds were similar between treatment groups with few exceptions. However, the anomalies were not consistent across the MEAD trials.

Table 10

National Eye Institute Visual Functioning Questionnaire-25 (Pseudophakic Subgroup).

Short Form 36 Health Survey Version 1(SF-36v1)

No health-related quality of life post-baseline data using the SF-36v1 was provided for the subgroup of adult patients with DME who are pseudophakic in the MEAD trials.

EuroQol 5 Dimensions Health Questionnaire (EQ-5D)

No health-related quality of life post-baseline data using the EQ-5D was provided for the subgroup of adult patients with DME who are pseudophakic in the MEAD trials.

Retinal Thickness As Measured by Optical Coherence Tomography (CRT As Measured by OCT)

Compared with sham, the adjusted least squares mean difference in average CRT as measured by OCT were ▬▬▬▬▬ in MEAD-010 and MEAD-011, respectively. The change from baseline in CRT as measured by OCT was also measured at the last study visit in both MEAD trials and was consistent with the AUC approach in MEAD-010, but not in MEAD-011(adjusted least squares mean differences were ▬▬▬▬▬). Sensitivity analyses were also performed for this outcome using a PP population instead of the ITT population in both MEAD-010 and MEAD-011 (adjusted least squares mean differences were ▬▬▬▬▬, respectively). For detailed outcome data in regards to CRT as measure by OCT and the PP sensitivity analyses refer to Table 15 and Table 16.

Adverse Events

A total of 74.1% and 61.0% of patients experienced AEs in the dexamethasone and sham groups, respectively. Overall, 29.4% and 9.0% of patients experienced elevated IOP, 5.9% and 2.0% experienced secondary cataracts and ▬ experienced blepharitis in the dexamethasone and sham groups, respectively. Overall, the frequencies of other AEs were relatively similar across treatment groups.

Serious Adverse Events

Similar frequencies of SAEs were reported in the dexamethasone groups compared with the sham groups (▬ respectively). No data were provided regarding the most common reasons for ocular SAEs for the subgroup of adult patients with DME who are pseudophakic.

Withdrawal Due to Adverse Events

The overall WDAEs were similar between treatment groups, however, no data regarding the withdrawals due to ocular AEs was provided for the subgroup of adult patients with DME who are pseudophakic in the MEAD trials.

Mortality

A total of three deaths occurred in the MEAD trials in the pseudophakic subgroup, however, none of the deaths were considered to be related to study treatment by the investigators. Two deaths occurred in MEAD-010 (one in the dexamethasone group and one in the sham group) and one death occurred in MEAD-011 (one death in the sham group). ▬▬▬▬▬

Notable Harms

The occurrence of the remaining notable harms (other than elevated IOP and secondary cataracts), specifically, eye inflammation, retinal detachment, ATE, dislocated implants, glaucoma, damage to optic nerve, conjunctival hemorrhage, and vitreous hemorrhage, was approximately equivalent in both treatment groups across the MEAD trials. Endophthalmitis, eye infection, defects in visual acuity and visual field, and necrotizing retinitis were not reported for the subgroup of adult patients with DME who are pseudophakic in the MEAD trials.

Table 11

Ocular Harms (Pseudophakic Subgroup).