Diabetic macular edema (DME)
🌍Outline:
Ranibizumab: Resolve, RISE+RIDE, Protocol I, RETAIN
Afliercept: VIVID>ENDURANCE+VISTA, Protocol V
Protocol T
Steroids: (CHAMPLAIN), MEAD, FAME, Bevordex
Ranibizumab: Resolve, RISE+RIDE, Protocol I, RETAIN
Afliercept: VIVID>ENDURANCE+VISTA, Protocol V
Protocol T
Steroids: (CHAMPLAIN), MEAD, FAME, Bevordex
Faricimab: YOSEMITE and RHINE
Early Treatment Diabetic Retinopathy Study (ETDRS), 1991 ⏩
Safety and Efficacy of Ranibizumab in Diabetic Macular Edema (RESOLVE), 2010 ⏩
n=151, 12m
Study question: Ranibizumab (0.3 or 0.5 mg; n = 51 each) or sham for DME. Study results: mean BCVA improved by 10.3 ± 9.1 letters with ranibizumab (pooled data) and declined by 1.4 ± 14.2 letters with sham. More rescue laser photocoagulation in sham (34.7% vs 4.9%).
Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema (DRCR net Protocol I), 2010 ⏩
n=854, 12m
Study Question: Compare: Laser + Sham injections (n=293) VS Ranibizumab + Prompt Laser (n=187), Triamcinolone + Prompt Laser (n=186), Ranibizumab + Deferred laser by 24 weeks (n=188). Study Results: Ranibizumab groups better than either laser alone or triamcinolone w\ laser. VA letters gained: Ranibizumab + prompt laser group (+9±11), Ranibizumab + deferred laser group (+9±12), Triamcinolone + prompt laser (+4±13), sham + prompt laser (+3±13). Pseudophakic eyes (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups.
Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema (RESTORE), 2011 ⏩
n=345, 12m
Study question: Ranibizumab 0.5mg + sham laser VS ranibizumab + laser VS sham injections + laser. 3 mandatory injections then PRN. Study Results: Ranibizumab alone and combined with laser were superior to laser monotherapy in BCVA: +6.1 and +5.9 vs +0.8 ETDRS letters. 1st year mean 7 injections/year. 2nd year 3.9, third 2.9. At 1 year, no differences between the ranibizumab and ranibizumab + laser arms.
Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients (CHAMPLAIN), 2011 ⏩
N=55, 26 weeks
Study question: Use of Ozurdex for ME s/p PPV.
Results: Mean increase BCVA (54.5 letters) was 6.0 letters at Week 8. And 3.0 letters at Week 26 (P = 0.046).
Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema (FAME study), 2011 ⏩ and ⏩
n =768, 3y
Study Question: Iluvien low-dose insert (0.2 μg/d n = 375) vs high-dose insert (0.5 μg/d n = 393) vs sham (n=185) for DME. Two parallel RCT. Sutdy Results: 15 letter gain: 28.7% low dose, 27.8% in high-dose insert and 18.9% in the sham group. Mean BCVA improvement at 24m: 4.4 letters and 5.4 in the low- and high-dose groups vs 1.7 in the sham group. Glaucoma requiring incisional surgery occurred in 4.8% of the low-dose, 8.1% the high dose and 0.5% of the sham group. An improvement ≥2 steps in the Early Treatment Diabetic Retinopathy Study retinopathy scale occurred in 13.7% (low dose) and 10.1% (high dose) and 8.9% in the sham group.
A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema: 24-month data: report 3 (BOLT), 2012 ⏩
n=80, 2y
Study question: Bevacizumab VS Macular laser treatment (MLT) for DME. Study Results: Median gain in ETDRS letters in the bevacizumab arm was 9 letters vs 2.5 letters for MLT. Mean reduction in central macular thickness was 146 μm in the bevacizumab arm vs 118 μm in the MLT arm. The median number of treatments over 24 months was 13 for bevacizumab and 4 for MLT.
Early Treatment Diabetic Retinopathy Study (ETDRS), 1991 ⏩
N=3711, 5y
In light of the DRS results: laser photocoagulation reduced SVL in advanced stage of DR. Study Question: NPDR\DME early vs deferred laser. Early: full scatter\mild\focal. Aspirin vs placebo. Results: Defined ETDRS VA and "clinically significant macular edema". Scatter worsened VA in DME. Focal for DME imrpoved *2 visual angle. NPDR Early scatter – small reduction in severe VA loss. Mild/Mod NPDR-not for scatter. Aspirin-only reduction of CV morbidity.Safety and Efficacy of Ranibizumab in Diabetic Macular Edema (RESOLVE), 2010 ⏩
n=151, 12m
Study question: Ranibizumab (0.3 or 0.5 mg; n = 51 each) or sham for DME. Study results: mean BCVA improved by 10.3 ± 9.1 letters with ranibizumab (pooled data) and declined by 1.4 ± 14.2 letters with sham. More rescue laser photocoagulation in sham (34.7% vs 4.9%).
Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema (DRCR net Protocol I), 2010 ⏩
n=854, 12m
Study Question: Compare: Laser + Sham injections (n=293) VS Ranibizumab + Prompt Laser (n=187), Triamcinolone + Prompt Laser (n=186), Ranibizumab + Deferred laser by 24 weeks (n=188). Study Results: Ranibizumab groups better than either laser alone or triamcinolone w\ laser. VA letters gained: Ranibizumab + prompt laser group (+9±11), Ranibizumab + deferred laser group (+9±12), Triamcinolone + prompt laser (+4±13), sham + prompt laser (+3±13). Pseudophakic eyes (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups.
Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema (RESTORE), 2011 ⏩
n=345, 12m
Study question: Ranibizumab 0.5mg + sham laser VS ranibizumab + laser VS sham injections + laser. 3 mandatory injections then PRN. Study Results: Ranibizumab alone and combined with laser were superior to laser monotherapy in BCVA: +6.1 and +5.9 vs +0.8 ETDRS letters. 1st year mean 7 injections/year. 2nd year 3.9, third 2.9. At 1 year, no differences between the ranibizumab and ranibizumab + laser arms.
Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients (CHAMPLAIN), 2011 ⏩
N=55, 26 weeks
Study question: Use of Ozurdex for ME s/p PPV.
Results: Mean increase BCVA (54.5 letters) was 6.0 letters at Week 8. And 3.0 letters at Week 26 (P = 0.046).
Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema (FAME study), 2011 ⏩ and ⏩
n =768, 3y
Study Question: Iluvien low-dose insert (0.2 μg/d n = 375) vs high-dose insert (0.5 μg/d n = 393) vs sham (n=185) for DME. Two parallel RCT. Sutdy Results: 15 letter gain: 28.7% low dose, 27.8% in high-dose insert and 18.9% in the sham group. Mean BCVA improvement at 24m: 4.4 letters and 5.4 in the low- and high-dose groups vs 1.7 in the sham group. Glaucoma requiring incisional surgery occurred in 4.8% of the low-dose, 8.1% the high dose and 0.5% of the sham group. An improvement ≥2 steps in the Early Treatment Diabetic Retinopathy Study retinopathy scale occurred in 13.7% (low dose) and 10.1% (high dose) and 8.9% in the sham group.
A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema: 24-month data: report 3 (BOLT), 2012 ⏩
n=80, 2y
Study question: Bevacizumab VS Macular laser treatment (MLT) for DME. Study Results: Median gain in ETDRS letters in the bevacizumab arm was 9 letters vs 2.5 letters for MLT. Mean reduction in central macular thickness was 146 μm in the bevacizumab arm vs 118 μm in the MLT arm. The median number of treatments over 24 months was 13 for bevacizumab and 4 for MLT.
A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus (RIDE, RISE), 2012 ⏩
RISE n=377, RIDE n=382, 24m
Study question: 2 Parallel RCTs- Sham vs Q1M Ranibizumab 0.3 vs 0.5 for CME d/t BRVO. Study results: 15 letter gain in RISE: 18% of sham, 44% in 0.3mg and 39% in 0.5mg. RIDE 12%, 33%, 45% Ranibizumab tx required less grid laser tx. Delayed initiation of anti-VEGF treatment resulted in worse final VA.
Three-Year, Randomized, Sham-Controlled Trial of Dexamethasone Intravitreal Implant in Patients with Diabetic Macular Edema (MEAD Study), 2014 ⏩
n=1048, 3y
Study question: DEX implant 0.7 mg, vs 0.35 mg, vs sham for DME. Study results: Mean # of tx received over 3 years was 4.1, 4.4, and 3.3 with DEX implant 0.7 mg, DEX implant 0.35 mg, and sham, respectively. The percentage of patients with ≥15-letter improvement in BCVA was 22.2% for 0.7. 18.4% for 0.35 and 12.0% for sham. Mean reduction in CRT was greater with 0.7 DEX. Comparing 0.35 mg, and sham groups, respectively. IOP were usually controlled with medication or no therapy; only 2 patients (0.6%) in the DEX implant 0.7 mg group and 1 (0.3%) in the DEX implant 0.35 mg group required trabeculectomy.
Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies (VIVD, VISTA), 2016 ⏩
n=827, 3y
Study question: Aflibercept 2 mg q4w Vs 2 mg q8w after 5 monthly doses Vs laser. Study results: Mean BCVA gain 10.4, 10.5, and 1.4 letters (q4w, q8w, laser) in VISTA and 10.3, 11.7, and 1.6 letters in VIVID. Eyes that gained ≥15 letters was 42.9%, 35.8%, and 13.6% in VISTA and 41.2%, 42.2%, and 18.9% in VIVID. Aflibercept had more eyes w/ improvement of ≥2 steps in the Diabetic Retinopathy Severity Scale (VISTA 29.9%, 34.4% vs 20.1% ) and VIVID (44.3%, 47.8% vs. 17.4% in laser).
Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema (PROTOCOL I), 2016 ⏩ and ⏩
n=828, 5y
Study question: 4 arms: Ranibizumab 0.5 w\ prompt laser vs Ranibizumab 0.5 w\ deferred laser. 4 inj then PRN. vs Sham with prompt laser vsTriamcinolone (q4m) with prompt laser.
Study results: After 1 year protocol allowed all to get ranibizumab. At 5y Ranibizumab with deferred laser gained 9.8 letters vs prompt laser 7.2+. Concluded that prompt laser might be worse, especially for initial VA of 6/15 or less. Catch-up not complete for deferred ranibizumab. Post hoc analysis: improvement after 3 inj sustained throughout study, can predict response.
Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema (RETAIN) (2016) ⏩v
n=T&E 128, T&E and laser 128 , PRN-123, 2y
Study question: Ranibizumab T&E vs PRN. With or w/o laser. Study Results: Both T&E non-inferior to PRN but with 46% less visits. Mean # of injections: 12.4 and 12.8 in the T&E+laser and T&E groups and 10.7 in the PRN group. T&E Increase\decrease intervals of 1m.
Bevacizumab or Dexamethasone Implants for DME: 2-year Results (The BEVORDEX Study), 2016 ⏩
n=88,24m
Abbreviations used on this page:
$ - Financial funding disclosure, when relevant
# - number of
BCVA - Best corrected visual acuity
CV - Cardio-cascular
RISE n=377, RIDE n=382, 24m
Study question: 2 Parallel RCTs- Sham vs Q1M Ranibizumab 0.3 vs 0.5 for CME d/t BRVO. Study results: 15 letter gain in RISE: 18% of sham, 44% in 0.3mg and 39% in 0.5mg. RIDE 12%, 33%, 45% Ranibizumab tx required less grid laser tx. Delayed initiation of anti-VEGF treatment resulted in worse final VA.
Three-Year, Randomized, Sham-Controlled Trial of Dexamethasone Intravitreal Implant in Patients with Diabetic Macular Edema (MEAD Study), 2014 ⏩
n=1048, 3y
Study question: DEX implant 0.7 mg, vs 0.35 mg, vs sham for DME. Study results: Mean # of tx received over 3 years was 4.1, 4.4, and 3.3 with DEX implant 0.7 mg, DEX implant 0.35 mg, and sham, respectively. The percentage of patients with ≥15-letter improvement in BCVA was 22.2% for 0.7. 18.4% for 0.35 and 12.0% for sham. Mean reduction in CRT was greater with 0.7 DEX. Comparing 0.35 mg, and sham groups, respectively. IOP were usually controlled with medication or no therapy; only 2 patients (0.6%) in the DEX implant 0.7 mg group and 1 (0.3%) in the DEX implant 0.35 mg group required trabeculectomy.
Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies (VIVD, VISTA), 2016 ⏩
n=827, 3y
Study question: Aflibercept 2 mg q4w Vs 2 mg q8w after 5 monthly doses Vs laser. Study results: Mean BCVA gain 10.4, 10.5, and 1.4 letters (q4w, q8w, laser) in VISTA and 10.3, 11.7, and 1.6 letters in VIVID. Eyes that gained ≥15 letters was 42.9%, 35.8%, and 13.6% in VISTA and 41.2%, 42.2%, and 18.9% in VIVID. Aflibercept had more eyes w/ improvement of ≥2 steps in the Diabetic Retinopathy Severity Scale (VISTA 29.9%, 34.4% vs 20.1% ) and VIVID (44.3%, 47.8% vs. 17.4% in laser).
Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema (PROTOCOL I), 2016 ⏩ and ⏩
n=828, 5y
Study question: 4 arms: Ranibizumab 0.5 w\ prompt laser vs Ranibizumab 0.5 w\ deferred laser. 4 inj then PRN. vs Sham with prompt laser vsTriamcinolone (q4m) with prompt laser.
Study results: After 1 year protocol allowed all to get ranibizumab. At 5y Ranibizumab with deferred laser gained 9.8 letters vs prompt laser 7.2+. Concluded that prompt laser might be worse, especially for initial VA of 6/15 or less. Catch-up not complete for deferred ranibizumab. Post hoc analysis: improvement after 3 inj sustained throughout study, can predict response.
Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema (RETAIN) (2016) ⏩v
n=T&E 128, T&E and laser 128 , PRN-123, 2y
Study question: Ranibizumab T&E vs PRN. With or w/o laser. Study Results: Both T&E non-inferior to PRN but with 46% less visits. Mean # of injections: 12.4 and 12.8 in the T&E+laser and T&E groups and 10.7 in the PRN group. T&E Increase\decrease intervals of 1m.
Bevacizumab or Dexamethasone Implants for DME: 2-year Results (The BEVORDEX Study), 2016 ⏩
n=88,24m
Study question: bevacizumab PRN versus a slow-release intravitreal dexamethasone implant (Ozurdex) (as needed q4m) for DME. Study results: The VA improvement seen at 12 months in both groups was maintained at 24m. The mean improvement in VA was 6.9 letters in DEXimplante
treated eyes vs 9.6 letters in bevacizumab-treated eyes. Due to interval > 3 months in Ozurdex, VA sea-sawed. Bevacizumab received more inj (mean; 9.1; median, 9.0) vs DEX-implant (mean, 2.8; median 3). $ Allergan
Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema (Protocol T), 2016 ⏩ and ⏩
n=660, 2y
Study Question: 2.0-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab for central DME. Focal/Grid laser added after 6m if still DME. Study results: At 2y Mean VA improved similarly by 12.8, 10.0, and 12.3 letters (Aflibercept, Bevacizumab, Ranibizumab). Obliterating the advantage Aflibercept had At 1y in patients w\ initial VA of 6/15 or worse. Focal/grid laser was done to 41% of patients in the aflibercept group, 64% of the bevacizumab group and 52% of the ranibizumab group. Similar number of injections in all groups (~10 1st y, half in 2nd year). At 2y superiority of aflibercept over ranibizumab was equalized. Higher Anti-Platelet Trials Collaboration adverse events with ranibizumab (but more patients with coronary disease).
Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity (Protocol V), 2019 ⏩ and see ⏩
n=702, 2y
Study Question: DME involving the macular center and vision 20/25 or better: aflibercept vs laser photocoagulation vs observation. Aflibercept as rescue. Study results: 5-letter or more decrease in VA was not significantly different between groups initially managed with aflibercept (16%), laser photocoagulation (17%), and observation (19%). 2/3 of observation group did not require tx.
Randomized Trial of Treat and Extend Ranibizumab With and Without Navigated Laser Versus Monthly Dosing for Diabetic Macular Edema: TREX-DME 2-Year Outcomes, 2019 ⏩
n=150, 2y
Study question: Treat and extend (TREX) VS Trean and extend with laser (GILA) VS monthly ranibizumab 0.3mg for DME. Study results: BCVA improved by 7.5 in the monthly group, 9.6, T&E and 9.0 letters in GILA (P = .75). Central retinal thickness improved by 139, 140, and 175 μm (P = .09). Mean number of injections was 18.9 for TREX, 17.5 for GILA and 24.7 for monthly (P < .001). Laser did not affect T&E intervals.
treated eyes vs 9.6 letters in bevacizumab-treated eyes. Due to interval > 3 months in Ozurdex, VA sea-sawed. Bevacizumab received more inj (mean; 9.1; median, 9.0) vs DEX-implant (mean, 2.8; median 3). $ Allergan
Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema (Protocol T), 2016 ⏩ and ⏩
n=660, 2y
Study Question: 2.0-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab for central DME. Focal/Grid laser added after 6m if still DME. Study results: At 2y Mean VA improved similarly by 12.8, 10.0, and 12.3 letters (Aflibercept, Bevacizumab, Ranibizumab). Obliterating the advantage Aflibercept had At 1y in patients w\ initial VA of 6/15 or worse. Focal/grid laser was done to 41% of patients in the aflibercept group, 64% of the bevacizumab group and 52% of the ranibizumab group. Similar number of injections in all groups (~10 1st y, half in 2nd year). At 2y superiority of aflibercept over ranibizumab was equalized. Higher Anti-Platelet Trials Collaboration adverse events with ranibizumab (but more patients with coronary disease).
Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity (Protocol V), 2019 ⏩ and see ⏩
n=702, 2y
Study Question: DME involving the macular center and vision 20/25 or better: aflibercept vs laser photocoagulation vs observation. Aflibercept as rescue. Study results: 5-letter or more decrease in VA was not significantly different between groups initially managed with aflibercept (16%), laser photocoagulation (17%), and observation (19%). 2/3 of observation group did not require tx.
Randomized Trial of Treat and Extend Ranibizumab With and Without Navigated Laser Versus Monthly Dosing for Diabetic Macular Edema: TREX-DME 2-Year Outcomes, 2019 ⏩
n=150, 2y
Study question: Treat and extend (TREX) VS Trean and extend with laser (GILA) VS monthly ranibizumab 0.3mg for DME. Study results: BCVA improved by 7.5 in the monthly group, 9.6, T&E and 9.0 letters in GILA (P = .75). Central retinal thickness improved by 139, 140, and 175 μm (P = .09). Mean number of injections was 18.9 for TREX, 17.5 for GILA and 24.7 for monthly (P < .001). Laser did not affect T&E intervals.
Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema: two randomised, double-masked, phase 3 trials (YOSEMITE and RHINE), 2022 ⏩
RHINE n=951, YOSEMITE n=940. 100w with endpoint @ 52w.
Study question: Faricimab 6mg (6 monthly then q8w) VS Faricimab 6mg with 4 monthly then T&E (personalized treatment interval, PTI) VS to aflibercept 2mg- 5 monthly injections then q8w for DME with CST>325µm. Study results: ~51% of patients were able to maintain q16w tx interval with faricimab. ~70% receiving faricimab every 12 weeks or longer. Average VA gains after 1y was not inferior in Faricimab group (~10 letters) but YOSEMITE VA letter gain results favored aflibercept when both were q8w. CMT reduction was greater in the faricimab group and higher proportion of patients were dry (77-90% VS 64-77% with aflibercept) . See extension study RHONE X ($ Roche)
Abbreviations used on this page:
$ - Financial funding disclosure, when relevant
# - number of
BCVA - Best corrected visual acuity
CV - Cardio-cascular
CMT - central macular thickness
DME - Diabetic macular edema
ME - Macular edema
MLT - Macular laser treatment
NPDR - Non proliferative diabetic retinopathy
VA - Visual acuity
SVL - Severe vision loss
T&E - Treat and extend
PPV - Pars plana vitrectomy
PRN - Pro re nata, Monthly visits with injections as needed
T&E - Treat and extend
tx - treatment
w\o - without
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🚧 This page is still being constructed, please feel free to suggest any other trials we should add to this page using the contact us form at the bottom of this page
DME - Diabetic macular edema
ME - Macular edema
MLT - Macular laser treatment
NPDR - Non proliferative diabetic retinopathy
VA - Visual acuity
SVL - Severe vision loss
T&E - Treat and extend
PPV - Pars plana vitrectomy
PRN - Pro re nata, Monthly visits with injections as needed
T&E - Treat and extend
tx - treatment
w\o - without
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🚧 This page is still being constructed, please feel free to suggest any other trials we should add to this page using the contact us form at the bottom of this page
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