Comparison of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: The EVEREST II Randomized Clinical Trial

Abstract

Importance: The 2-year efficacy and safety of combination therapy of ranibizumab administered together with verteporfin photodynamic therapy (vPDT) compared with ranibizumab monotherapy in participants with polypoidal choroidal vasculopathy (PCV) are unclear.

Objective: To compare treatment outcomes of ranibizumab, 0.5 mg, plus prompt vPDT combination therapy with ranibizumab, 0.5 mg, monotherapy in participants with PCV for 24 months.

Design, setting, and participants: This 24-month, phase IV, double-masked, multicenter, randomized clinical trial (EVEREST II) was conducted among Asian participants from August 7, 2013, to March 2, 2017, with symptomatic macular PCV confirmed using indocyanine green angiography.

Interventions: Participants (N = 322) were randomized 1:1 to ranibizumab, 0.5 mg, plus vPDT (combination therapy group; n = 168) or ranibizumab, 0.5 mg, plus sham PDT (monotherapy group; n = 154). All participants received 3 consecutive monthly ranibizumab injections, followed by a pro re nata regimen. Participants also received vPDT (combination group) or sham PDT (monotherapy group) on day 1, followed by a pro re nata regimen based on the presence of active polypoidal lesions.

Main outcomes and measures: Evaluation of combination therapy vs monotherapy at 24 months in key clinical outcomes, treatment exposure, and safety. Polypoidal lesion regression was defined as the absence of indocyanine green hyperfluorescence of polypoidal lesions.

Results: Among 322 participants (mean [SD] age, 68.1 [8.8] years; 225 [69.9%] male), the adjusted mean best-corrected visual acuity (BCVA) gains at month 24 were 9.6 letters in the combination therapy group and 5.5 letters in the monotherapy group (mean difference, 4.1 letters; 95% CI, 1.0-7.2 letters; P = .005), demonstrating that combination therapy was superior to monotherapy by the BCVA change from baseline to month 24. Combination therapy was superior to monotherapy in terms of complete polypoidal lesion regression at month 24 (81 of 143 [56.6%] vs 23 of 86 [26.7%] participants; P < .001). Participants in the combination group received fewer ranibizumab injections (median, 6.0 [interquartile range (IQR), 4.0-11.0]) than the monotherapy group (median, 12.0 [IQR, 7.0-17.0]) up to month 24. The combination group required a median of 2.0 (IQR, 1.0-3.0) vPDT treatments for 24 months, with 75 of 168 participants (44.6%) requiring only 1 vPDT treatment.

Conclusions and relevance: The 24-month data findings confirm that ranibizumab therapy, given as monotherapy or in combination with vPDT, is efficacious and safe for treatment of PCV. Combination therapy with vPDT added to ranibizumab achieved superior BCVA gain, increased odds of complete polypoidal lesion regression, and fewer treatment episodes compared with ranibizumab monotherapy.

Trial registration: ClinicalTrials.gov Identifier: NCT01846273.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lim reported receiving grants from Tan Tock Seng Hospital during the conduct of the study; receiving travel reimbursement from Heidelberg Engineering, and being an advisory board member of Novartis, with honorarium and travel reimbursement being paid to his institution. Dr Lai reported receiving grants and personal fees from Bayer Healthcare, Chengdu KangHong Biotech, Novartis Pharma AG, and Roche during the conduct of the study; receiving grants from Bayer Healthcare, Novartis Pharma AG, Roche, and Santen; receiving lecture fees from Allergan, Bausch & Lomb, Bayer Healthcare, and Novartis Pharma AG; and being a consultant for Allergan, Bayer Healthcare, Boehringer Ingelheim, Genentech, Novartis Pharma AG, Oculis, and Roche outside the submitted work. Dr Takahashi reported receiving financial support from Alcon (Japan), Allergan (Japan), Bayer Healthcare, HOYA, KOWA, Kyowa Kirin, Novartis Pharma AG, Nitto Medic, Ohtsuka, Ono, Santen, and Senjyu. Dr Wong reported receiving grants and personal fees from Novartis Pharma AG during the conduct of the study; receiving grants and personal fees from Bayer Healthcare and Genentech; receiving personal fees from Roche and Samsung outside the submitted work; being a co-inventor and cofounder of Plano and EyRiS; and being a consultant for Allergan, Bayer Healthcare, Boehringer-Ingelheim, Genentech, Merck, Novartis Pharma AG, Oxurion (formerly ThromboGenics), Roche, and Samsung. Dr Chen reported receiving lecture fees from Bayer Healthcare and personal fees from Novartis Pharmaceuticals outside the submitted work. Dr Ruamviboonsuk reported receiving grants and consulting fees from Bayer Healthcare, Novartis Pharma AG, and Roche. Dr Tan reported receiving personal fees from Novartis Pharma AG during the conduct of the study; receiving nonfinancial support from Heidelberg Engineering; receiving personal fees and nonfinancial support from Bayer Healthcare and Novartis Pharma AG outside the submitted work; and receiving conference support from Allergan, Bayer, and Novartis Pharma AG. Dr Lee reported receiving consulting fees from Allergan, Bayer Healthcare, Boehringer Ingelheim, Novartis Pharma AG, Roche, and Santen outside the submitted work. Dr Cheung reported receiving grants, personal fees, and nonfinancial support from Novartis Pharma AG during the conduct of the study; receiving grants, personal fees, and nonfinancial support from Bayer Healthcare, Boehringer Ingelheim, Topcon, and Carl Zeiss; and receiving personal fees and nonfinancial support from Allergan and Roche during the conduct of the study. Dr Ngah reported receiving lecture fees from Allergan, Bayer Healthcare, and Novartis Pharma AG and receiving research grants from Novartis for the study. Dr Patalauskaite reported being an employee of Novartis Ireland Ltd during the conduct of the study. Dr Margaron reported being an employee of Novartis Pharma AG, Basel, Switzerland, during the conduct of the study. Dr Koh reported receiving consulting fees and honoraria from Alcon, Allergan, Apellis, Bayer, Boehringer Mannheim, Carl Zeiss Meditec, Heidelberg, Novartis Pharma AG, and Topcon.

Figures

Figure 1.. CONSORT Diagram of Study Participants

vPDT indicates verteporfin photodynamic therapy. aPrimary end point at month 12. bPatients were at different levels of progression in the study at the therapy switch time point, which occurred after month 21 for half of the patients from the switched group.

Figure 2.. Mean Best-Corrected Visual Acuity (BCVA) Gain Up to Month 24 in the Combination and Monotherapy Groups

Data on the full analysis set are shown. Change from baseline was calculated as the number of participants with a value for both baseline and specific postbaseline visits. During year 2, 41 participants randomized to ranibizumab, 0.5 mg, were switched to ranibizumab, 0.5 mg, plus vPDT, but only 14 from the switched group had at least 1 treatment after the switch. ETDRS indicates Early Treatment Diabetic Retinopathy Study; vPDT, verteporfin photodynamic therapy.

Figure 3.. Treatments Received Up to Month 24 in the Combination and Monotherapy Groups

Data on the full analysis set are shown. A, Percentages are based on the total number of participants in the respective treatment group, with 168 in the combination treatment group and 154 in the monotherapy group. B, Percentages are based on the total number of participants in the combination treatment group (n = 168). vPDT indicates verteporfin photodynamic therapy.