DESIGN ISSUES OF A NON-INFERIORITY TRIAL Prompt Panretinal Photocoagulation Versus Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy (A Tale of Two Diseases) Isoken Odia, O.D., MPH Michele Melia ScM   1

Diabetic Macular Edema (DME) A tale of two diseases Proliferative Diabetic Retinopathy (PDR) referred to as retinopathy Study disease Growth of new blood vessels in the retina caused by diabetes mellitus Advanced stage of diabetic retinopathy (DR) Currently treated with panretinal photocoagulation Diabetic Macular Edema (DME) referred to as macular edema Co-occurring disease Swelling of the macular (region of the retina used for central vision) Risk of macular edema increases with worsening of DR Currently treated with anti- vascular endothelial growth factor therapy e.g ranibizumab

Retinopathy (PDR) treatment Standard care Panretinal photocoagulation (referred to as laser) Use of lasers to stop vessels in the retina from leaking or growing Results in damage to the part of the retina responsible for peripheral vision Used for the treatment of retinopathy for over 30 years Study Drug 0.5 mg ranibizumab (referred to as study drug) Anti-vascular endothelial growth factor therapy Standard care for the treatment of macular edema Does not result in damage to the retina Prior trials of diabetic macular edema have suggested the efficacy of ranibizumab for the treatment of retinopathy

History of our study design Initially two trials Trial 1 Retinopathy with macular edema Trial 2 Retinopathy without macular edema Laser for retinopathy and Study drug for macular edema Laser for retinopathy and Study drug for macular edema (if it develops) Study drug for retinopathy and macular edema Study drug for retinopathy and macular edema (if it develops) Control group Study group Control group Study group

Trial 1 Baseline visual acuity will be worse in trial 1 than trial 2 Laser not expected to affect macular edema All eyes in both treatment groups will be treated for macular edema with the study drug using the same treatment regimen Effect of laser + drug on retinopathy is not believed to be synergistic The goal of our study is to test non-inferiority of the study drug

Trial 1:Treatment λ: Laser for the treatment of retinopathy Retinopathy with macular edema λ: Laser for the treatment of retinopathy µ: Amount of study drug needed for the treatment of macular edema ≥ 4 injections per protocol ρ: Additional study drug for the treatment of retinopathy If the same amount of study drug is needed for the treatment of macular edema and retinopathy, ρ will be 0 It will be difficult to tease out the treatment effects Laser for retinopathy and Study drug for macular edema Study drug for retinopathy and for macular edema Control group Study group λ + µ ρ + µ

Trial 2 Participants in this trial will have better visual acuity than participants in trial 1 We do not know the rate of macular edema development in each group, but if it develops it must be treated with the study drug (as it is the standard of care) In the laser group, the study drug is not given from baseline and this could result in larger treatment effect for retinopathy than trial 1, as there is greater separation between groups in amount of drug (but, ceiling effect limits improvement) Retinopathy without macular edema Laser for retinopathy and Study drug for macular edema (if it develops) Study drug for retinopathy and for macular edema (if it develops) Control group Study group

Final study design Retinopathy with or without macular edema Both trials were combined due to difficulty in recruiting the necessary sample size for two trials Primary outcome: Visual acuity (measure of vision) Non-Inferiority margin: -5 letters (equivalent to 1 line on the visual acuity chart) Some eyes in both groups may never need treatment for macular edema Laser for retinopathy and Study drug for macular edema (at baseline or if it develops) Study drug for retinopathy and macular edema (at baseline or if it develops) Control group Study group

How was macular edema handled? Presence/absence of macular edema was used as a stratification factor to ensure treatment group balance Treatment regimen for macular edema followed DRCR.net algorithm Algorithm is based on visual acuity and retinal thickness Initial treatment same for everyone Retreatment allows some investigator discretion At Baseline Ranibizumab Group (N = 191) PRP Group (N = 203) Presence of DME with vision impairment 22% 23% Presence of DME regardless of vision impairment 29% 31%

Interaction between treatment group and presence or absence of macular edema Possibility of interaction between the macular edema subgroups and treatment was big concern It was hypothesized that presence of macular edema with visual impairment will not influence the treatment effects Mechanism of action of laser and drug on retinopathy is different, so unlikely to interact Study not powered to test interaction Study drug in the laser group might severely and negatively impact sample size / power if testing superiority of drug However, still possible to test non-inferiority (even if interaction present)

Flexibility of the treatment regimen for macular edema We had an algorithm for the treatment of macular edema (DME) which was developed for DME studies, but it sometimes allowed administration of ranibizumab (study drug) at unmasked investigator’s discretion Frequency of drug injections was fewer in the laser group by protocol; can’t know if edema treated equally Macular edema could have been under-treated* in the laser group and this may have led to poorer visual acuity in this treatment group *Macular edema treatment in both groups did adhere to algorithm

Teasing out treatment effects It is difficult to know how much of the observed treatment effect was due to the different treatments for retinopathy vs differing amount of treatment for macular edema It might have been easier to tease out the treatment effects if a completely fixed regimen was established for the treatment of macular edema

Study results at 2 years (JAMA 2015;314(20):2137-46) 2-Year Adjusted Mean Difference: +2.2 letters 95% Confidence Interval: (-0.5, +5.0) (Meets pre-specified non-inferiority criterion of -5.0 letters)

Results stratified by baseline macular edema

Conclusions Need to treat concurrent disease with one of the study treatments did not preclude designing a trial Fixed regimen for treatment of macular edema might have made it easier to tease out retinopathy treatment effect This design would not have been suitable for testing the superiority of study drug Trial supports non-inferiority of drug treatment for retinopathy in context of necessity of concurrent management of edema

Thank You on Behalf of the Diabetic Retinopathy Clinical Research Network (DRCR.net) 16