Clinical Trials

CDR’s systematic review included two phase III, multi-centre, multi-national, sham-controlled pivotal RCTs in patients with DME designed to assess the benefits and harms of dexamethasone based on BCVA using the ETDRS method. MEAD-010 (N = 494) and MEAD-011 (N = 554) randomized patients with DME in a 1:1:1 ratio of dexamethasone 700 mcg, dexamethasone 350 mcg, or sham. Retreatment could occur no sooner than six months and patients could receive up to seven treatments over the three-year duration of the studies. Both trials enrolled adults with type 1 or type 2 diabetes mellitus with fovea-involved DME, BCVA scores between 34 letters (approximately 20/200 Snellen equivalent) and 68 letters (approximately 20/50 Snellen equivalent) in the study eye as measured by the ETDRS method, and retinal thickness ≥ 300 μm as measured by optical coherence tomography (OCT) in the 1 mm central macular subfield of the study eye.

The Health Canada-approved indication is limited to adult patients with DME who are pseudophakic. Therefore, CDR focused on the pre-specified subgroup of patients enrolled in the MEAD trials that had a pseudophakic lens status (MEAD-010, n = 141; MEAD-011, n = 134 across the dexamethasone 700 mcg, 350 mcg, and sham treatment groups) that were derived from the intent-to-treat population and the safety population of the overall DME population. Furthermore, the Health Canada–approved intervention of interest for CDR was the dexamethasone 700 mcg intravitreal injection treatment arm; therefore, the dexamethasone 350 mcg intravitreal injection treatment arm will not be discussed.

Key limitations associated with the interpretation of the data from the MEAD trials include randomization not being stratified based on pseudophakic lens status, a lack of adjustment for multiple statistical testing, and imbalances in attrition and patient characteristics between treatment groups.

No clinical trials of dexamethasone implant versus other active treatments for pseudophakic patients with DME met the criteria for inclusion in the CDR systematic review. Three phase II trials which evaluated the effects of dexamethasone implant compared to anti-VEGF therapies (ranibizumab, bevacizumab) were identified, however these trials enrolled the general DME population, of which approximately 24% to 50% were pseudophakic. Some pseudophakic subgroup results were reported, however the lack of stratification at randomization based on this factor, as well as the absence of reporting on baseline characteristics for the pseudophakic population make it difficult to assess the comparative efficacy and harms between dexamethasone and anti-VEGF agents (i.e., bevacizumab and ranibizumab). These trials were also likely underpowered to detect differences between treatments in the psuedophakic subgroup and there was no control for multiple statistical testing.

Outcomes

Outcomes were defined a priori in the CDR systematic review protocol. Of these, CDEC discussed:

• average BCVA mean change from baseline using the area-under-the-curve (AUC) approach, change from baseline in BCVA at different times during the study, and ≥ 15-letter improvement from baseline by end of study, all of which were assessed using the ETDRS 14-line/70-letter visual acuity chart
• health-related quality of life as assessed by the National Eye Institute Visual Functioning Questionnaire–25 (NEI VFQ-25)
• central retinal thickness (CRT) as measured by OCT
• adverse events (AEs), serious adverse events (SAEs), withdrawals due to adverse events (WDAEs), and notable harms (specifically, endophthalmitis, eye inflammation, eye infections, retinal detachment, increased intraocular pressure, arterial thrombotic event, dislocated implants, glaucoma, damage to optic nerve, defects in visual acuity and visual field, necrotizing retinitis, conjunctival hemorrhage, and vitreous hemorrhage).

Originally, the primary efficacy outcome in the MEAD trials was the proportion of patients with ≥ 15-letter improvement by the end of the study. The protocol was subsequently amended and the primary end point was changed to the average BCVA mean change (using the AUC approach) from baseline during the study.

Efficacy

The efficacy results presented are for the Health Canada-approved dose of dexamethasone (700 mcg intravitreal injection) for the subgroup of patients who are pseudophakic.

The adjusted least-square mean differences in average BCVA mean change from baseline between dexamethasone 700 mcg and sham treatment as measured by the ETDRS and using the AUC approach in the intention-to-treat population 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 minimal clinically important difference ranges were between 10 and 15 letters. Sensitivity analyses using a per-protocol population in both MEAD-010 and MEAD-011 were consistent with the primary analysis.

The difference in the proportion of patients achieving a ≥ 15-letter improvement by study end versus sham was 18.1% ([95% CI, 0.8 to 35.4], P = 0.043) and 6.0% ([95% CI, −5.7 to 17.8], P = 0.461) in MEAD-010 and MEAD-011, respectively. Based on pooled analysis of the two trials the difference in the proportion of patients achieving a ≥15 letter improvement at last visit was 12.4% (95% CI, 1.6 to 23.2) in favour of dexamethasone.

The adjusted least-square mean differences in average CRT as measured by OCT using the AUC approach were −117.9 µm ([95% CI, ▬], P < 0.001) and −61.5 µm ([95% CI, ▬], P = 0.007) in MEAD-010 and MEAD-011, respectively. The changes from baseline in CRT as measured by OCT were also evaluated at the last study visit and in a sensitivity analysis using the per-protocol population and were consistent with the AUC method.

The MEAD trials evaluated vision-related outcomes using the NEI VFQ-25. No statistically significant differences were observed between treatment groups with adjusted average least-square mean differences for the overall composite score of 2.4 ([95% CI, −2.0 to 6.8], P = 0.288) and −1.5 ([95% CI, −6.2 to 3.3], P = 0.542) in MEAD-010 and MEAD-011, respectively.

Harms (Safety and Tolerability)

Frequencies of AEs, SAEs, WDAEs, and notable harms were provided for the individual MEAD trials. However the most common AEs, SAEs, WDAEs, and notable harms were only reported based on a pooled analysis of adult patients with DME who were pseudophakic from the two MEAD trials.

A greater proportion of patients in the dexamethasone group experienced AEs compared with the sham group (74.1% and 61.0%, respectively). The AEs that occurred more frequently in the dexamethasone treatment groups compared with the sham groups were elevated intraocular pressure (29.4% and 9.0%, respectively) and secondary cataracts (5.9% and 2.0%, respectively), which is consistent with the AE profile of intravitreal steroid therapies. The frequency of blepharitis in the dexamethasone groups was lower than those observed in the sham groups (▬, respectively).

Similar frequencies of SAEs were reported in the dexamethasone groups compared with the sham groups. No data regarding the most common reasons for ocular SAEs were provided for the subgroup of patients who are pseudophakic. The overall WDAEs were similar between treatment groups; however, no data regarding the withdrawals due to ocular AEs were provided for the subgroup of adult patients with DME who are pseudophakic in the MEAD trials.

A total of three deaths occurred in the MEAD trials in the pseudophakic subgroup. However, investigators did not consider any of the deaths to be related to study treatment.

The occurrence of the remaining notable harms (specifically, eye inflammation, retinal detachment, arterial thrombotic event, dislocated implants, glaucoma, damage to the optic nerve, conjunctival hemorrhage, and vitreous hemorrhage) was similar in both treatment groups across the MEAD trials. Endophthalmitis, eye infection, defects in visual acuity and visual field, and necrotizing retinitis were not reported in the MEAD trials.

Indirect Treatment Comparison

The manufacturer submitted an unpublished IDC to assess the comparative efficacy and safety of dexamethasone implant for use in the treatment of DME. ▬ ▬ ▬ ▬ ▬

Cost and Cost-Effectiveness

Dexamethasone intravitreal implant is available as a 700 mcg single use implant for intravitreal injection, at a submitted price of $1,400 per implant. At the recommended dose of one implant per treatment as required, the annual cost per patient may range from $1,400 (one dose per year) to $5,600 (four doses per year).

The manufacturer submitted a cost-utility analysis comparing dexamethasone implant with a no-treatment ‘watch and wait’ strategy for the treatment of DME in adults who are pseudophakic. The analysis was conducted from the public payer perspective over a 15 year time horizon. The manufacturer incorporated health states based on best corrected visual acuity measured by ETDRS scores (35 letters or less, then for every 10 letters gained, up to 76 letters or more). Patients could transition between health states every 3 months, and were assumed to receive dexamethasone implant at month 0, month 6, and then at every 3 months for a maximum of three years. The manufacturer also undertook scenario analyses comparing dexamethasone implant with ranibizumab (an anti-VEGF), but did not regard ranibizumab as a relevant comparator. Clinical inputs were primarily sourced from the three-year MEAD trials which compared dexamethasone implant with a sham procedure (a proxy for ‘watch and wait’), and an IDC that incorporated one-year MEAD trials results along with other treatments including laser and anti-VEGFs.

The manufacturer highlighted a subgroup of patients: adults with DME who are pseudophakic and unsuitable for anti-VEGF therapy. They deemed this population to be clinically the same as the population assessed in the base case. The manufacturer presented a cost comparison analysis for the population of adults with DME who are pseudophakic and have had inadequate response to prior anti-VEGF therapy, based on a summary of post-hoc analysis, meta-analysis, and retrospective study data, to support a claim of superiority of dexamethasone implant compared to anti-VEGF therapy.

In their base case, the manufacturer reported that dexamethasone implant was associated with an incremental cost-utility ratio (ICUR) of $32,074 per quality-adjusted life-year (QALY) compared with the “watch and wait” strategy. The ICUR was less than $50,000 per QALY in 53% of probabilistic iterations. In the cost comparison, dexamethasone implant was cost-saving compared to anti-VEGF treatment.

CDR identified the following key limitations:

• Clinical data for the Health Canada-approved indication and key subgroup populations were limited and associated with uncertainty.
• The manufacturer did not consider all relevant comparators (e.g., laser therapy, intravitreal steroids).
• The comparative clinical effectiveness of dexamethasone implant with relevant comparators is uncertain. The primary outcome for the indicated population from MEAD trials lacked stratified randomization or adjustment for multiplicity and the submitted IDC (comparing dexamethasone implant with laser therapy and anti-VEGF treatments) was associated with substantial uncertainty given the clinical and methodological heterogeneity of the included trials.

CADTH considered an alternate measure of treatment effects using relative risks based on MEAD trial data provided by the manufacturer and revised cost information in re-analyses, resulting in an ICUR of $168,439 per QALY for dexamethasone implant compared with “watch and wait”. There remains notable uncertainty associated with the cost-effectiveness of dexamethasone implant as the magnitude of incremental clinical benefit is unclear and there were limitations which could not be addressed by CADTH.