Efficacy and Safety of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: A Randomized Clinical Trial

Abstract

Importance: Polypoidal choroidal vasculopathy (PCV) is a common subtype of exudative age-related macular degeneration among Asian individuals. To our knowledge, there are no large randomized clinical trials to evaluate intravitreal ranibizumab, with and without verteporfin photodynamic therapy (vPDT), for the treatment of PCV.

Objective: To compare the efficacy and safety of combination therapy of ranibizumab and vPDT with ranibizumab monotherapy in PCV.

Design, setting, and participants: A double-masked, multicenter randomized clinical trial of 322 Asian participants with symptomatic macular PCV confirmed by the Central Reading Center using indocyanine green angiography was conducted between August 7, 2013, and March 2, 2017.

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

Main outcomes and measures: Step 1 assessed whether combination therapy was noninferior (5-letter margin) to monotherapy for change in best-corrected visual acuity from baseline and superior in complete polyp regression. If noninferiority was established, step 2 assessed whether combination therapy was superior to monotherapy measured by best-corrected visual acuity change at month 12.

Results: Baseline demographics of the 322 participants were comparable between the treatment groups. Mean (SD) age of the patients was 68.1 (8.8) years, and overall, 69.9% of the patients were men. At baseline, the overall mean best-corrected visual acuity and mean central subfield thickness were 61.1 letters and 413.3 μm, respectively. At 12 months, mean improvement from baseline was 8.3 letters with combination therapy vs 5.1 letters with monotherapy (mean difference, 3.2 letters; 95% CI, 0.4-6.1), indicating that combination therapy met the predefined criterion for noninferiority as well as being superior to monotherapy (P = .01). Combination therapy was also superior to monotherapy in achieving complete polyp regression at month 12 (69.3% vs 34.7%; P < .001). Over 12 months, the combination therapy group received a median of 4.0 ranibizumab injections compared with 7.0 in the monotherapy group. Vitreous hemorrhage was the only ocular serious adverse event (combination therapy group, 1 [0.6%]; monotherapy group, 3 [2.0%]).

Conclusions and relevance: After 12 months, combination therapy of ranibizumab plus vPDT was not only noninferior but also superior to ranibizumab monotherapy in best-corrected visual acuity and superior in complete polyp regression while requiring fewer injections. Combination therapy should be considered for eyes with PCV.

Trial registration: clinicaltrials.gov Identifier: NCT01846273.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Koh is a consultant for Novartis, Allergan, Carl Zeiss, Meditec, and Heidelberg Engineering. Dr Lai is a consultant for Allergan, Bayer, Novartis, and Genentech. Dr Takahashi is a consultant for Bayer and Novartis. Dr Wong received travel grants, writing/reviewing fees, and consultancy fees from Novartis and Bayer during the conduct of the study and consultancy fees from Abbott, Allergan, Genentech, Roche, and Pfizer outside the submitted work. Dr Chen receives financial support from Novartis and Bayer and is a consultant for Bayer. Dr Ruamviboonsuk is a consultant for Allergan, Bayer, and Novartis. Dr Tan receives conference support from Bayer, Heidelberg Engineering, and Novartis. Ms Feller and Dr Margaron are employees of Novartis Pharma AG, Basel, Switzerland. Dr Lim receives travel support from Heidelberg Engineering and Novartis. Dr Lee is a consultant for Alcon, Allergan, Bayer, Novartis, and Santen and is a trustee/board member for Alcon, Allergan, Bayer, and Novartis. No other disclosures were reported

Figures

Figure 1.. Patient Disposition (Randomized Set)

Randomized set consisted of all randomized participants. Percentages are based on the total number of participants in the randomized set in the respective treatment groups. The 5 participants discontinued from the study owing to protocol deviation were enrolled before the Central Reading Center confirmed polypoidal choroidal vasculopathy (PCV) diagnosis. One of the 2 participants whom the physician decided to withdraw did not respond to treatment and the primary investigator decided to change the treatment. In the other case, there were no documented reasons but the participant did not experience any adverse events. Spectral-domain optical coherence tomography, color fundus photography, fluorescein angiography, and indocyanine green angiography were assessed by the Central Reading Center.

Figure 2.. Mean Change in Best-Corrected Visual Acuity (BCVA) From Baseline to Month 12 (Full Analysis Set)

The total counts presented are the counts of patients in the specific treatment group who attended the specific visit. These total counts are used as the denominator for the percentages. Error bars represent 95% CIs. vPDT indicates verteporfin photodynamic therapy.

Figure 3.. Proportion of Participants With Complete Polyp Regression by Study Visits up to Month 12 in Full Analysis Set (FAS)

Assessed by Central Reading Center using indocyanine green angiography. Number values indicate the total number of participants in the FAS in the respective treatment group. Percentages are computed by considering the total number of participants in the respective treatment group who attended the specific visit as a denominator. vPDT indicates verteporfin photodynamic therapy.

Figure 4.. Mean Central Subfield Thickness (CSFT) Change

Mean CSFT change from baseline to month 12, full analysis set (FAS) (A) and proportion of participants with disease activity by visit (FAS) (B) as assessed by the investigators. Number values indicate the total number of participants in the FAS in the respective treatment group. Percentages are computed by considering the total number of participants in the respective treatment group who attended the specific visit as a denominator. vPDT indicates verteporfin photodynamic therapy.