Verteporfin plus Ranibizumab for Choroidal Neovascularization in Age-Related Macular Degeneration: Twelve-Month Results of the DENALI Study

doi:10.1016/j.ophtha.2012.02.003

Ophthalmology

Volume 119, Issue 5, May 2012, Pages 1001-1010

https://doi.org/10.1016/j.ophtha.2012.02.003 Get rights and content

Purpose

To demonstrate noninferiority of ranibizumab in combination with verteporfin photodynamic therapy (PDT) versus ranibizumab monotherapy in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD).

Design

Prospective, multicenter, double-masked, randomized, phase IIIb clinical trial.

Participants

Three hundred twenty-one patients randomized to receive either ranibizumab 0.5 mg monotherapy (n = 112), standard fluence (SF) verteporfin PDT combination therapy (n = 104), or reduced fluence (RF) verteporfin PDT combination therapy (n = 105).

Methods

Ranibizumab was administered monthly in the monotherapy group. In both combination therapy groups, ranibizumab was initiated with 3 consecutive monthly injections, followed by retreatment as needed (pro re nata) with monthly monitoring. All patients were evaluated monthly for 12 months.

Main Outcome Measures

Mean change in best-corrected visual acuity (BCVA) from baseline at month 12 and proportion of patients randomized to either combination therapy with a ranibizumab treatment-free interval of 3 months or longer.

Results

Two hundred eighty-six patients (89.1%) completed the 12-month study. Mean BCVA change at month 12 was +5.3 and +4.4 letters with verteporfin SF (n = 103) or verteporfin RF (n = 105) plus ranibizumab, respectively, compared with +8.1 letters with ranibizumab monotherapy (n = 110; adjusted 97.5% confidence interval [CI], (−7.90 to infinity); P = 0.0666; and 97.5% CI, (−8.51 to infinity); P = 0.1178; for combination regimens vs. monotherapy, respectively). Noninferiority of either combination regimen to monthly ranibizumab monotherapy was not demonstrated (primary end point). A ranibizumab treatment-free interval of 3 months or longer was achieved in 92.6% and 83.5% of the patients randomized to verteporfin SF or verteporfin RF groups, respectively, with a mean of 5.1 and 5.7 ranibizumab injections, respectively, and patients in the ranibizumab monotherapy arm received 10.5 injections. At month 12, mean central retinal thickness decreased by 151.7 μm and 140.9 μm for the verteporfin SF and RF groups, respectively, and by 172.2 μm with ranibizumab monotherapy. Safety and tolerability of all 3 regimens were similar to and consistent with previous studies in neovascular AMD. The number of ocular serious adverse events was low and occurred largely as single cases.

Conclusions

Ranibizumab monotherapy or combined with verteporfin PDT improved BCVA at month 12; however, noninferiority (7-letter margin) of combination regimens to ranibizumab monotherapy was not demonstrated. Verteporfin RF did not confer clinical benefits over verteporfin SF. All treatments were well tolerated.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Section snippets

Study Design and Objectives

The DENALI study was a randomized, double-masked, active-controlled, multicenter, phase IIIb clinical trial assessing the efficacy and safety of verteporfin PDT administered in conjunction with ranibizumab versus ranibizumab monotherapy for the treatment of subfoveal CNV secondary to AMD. The study was conducted according to the ethical principles of the Declaration of Helsinki and was approved by the appropriate ethics committees. All study participants provided written informed consent.

The

Study Population

A total of 321 patients were randomized to receive verteporfin SF combination therapy (n = 104), verteporfin RF combination therapy (n = 105), or ranibizumab monotherapy (n = 112). Overall, the baseline demographics across the 3 groups were well balanced. Mean baseline BCVA scores were comparable (53.8, 54.6, and 54.5 letters in the verteporfin SF plus ranibizumab, verteporfin RF plus ranibizumab, and the ranibizumab monotherapy groups, respectively). Ocular characteristics were comparable

Discussion

Because of their different methods of action, the combination of ranibizumab with verteporfin PDT has a theoretical potential to reduce the frequency and cost of neovascular AMD treatment while maintaining the VA improvements observed with ranibizumab monotherapy. The SUMMIT clinical trials program is the first large-scale clinical investigation to address this combination.

In this trial, ranibizumab was administered initially as 3 consecutive monthly injections (and then PRN) in both the

Acknowledgments

The authors thank Ruthline Laylor, Chameleon Communications International, for providing medical writing services with funding from Novartis Pharma AG, and Ruchika Srinivasan, Medical Communications, Novartis Healthcare Pvt. Ltd., for the revisions (based on author input) and resubmission of this article.

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Citation Excerpt :
After an independent review, 52 articles were excluded for several reasons. Finally, 8 RCTs were included [25–32]. The reference search process and exclusion reasons are summarized in Fig. 1.
To evaluate the efficacy and safety between photodynamic therapy (PDT) combined with intravitreal ranibizumab (IVR) and ranibizumab monotherapy in treating wet age-related macular degeneration (AMD).
A systematic search was performed in the PubMed, Embase, Web of Science and the Cochrane Library databases through December 31, 2017. The methodological quality of the references was evaluated according to the Cochrane quality assessment. RevMan 5.3 software was used to perform the meta-analysis.
Eight RCTs involving 817 participants were included. Wet AMD eyes in the mono-group achieved better best-corrected vision acuity (BCVA) than the combination group in month 12 (WMD = -0.19, 95% CI = -0.32 to -0.06, P = 0.004, I² = 18%). The proportion of patients gaining more than 15 letters from baseline in the mono-group was larger than that in the combination group (RR = 0.70, 95% CI: 0.56 to 0.87, P = 0.001). However, the number of ranibizumab injections with combination therapy was smaller than that with mono-therapy (MD = -1.13, 95% CI: -2.11 to -0.15, P = 0.02, I² = 85%). No significant differences were observed in the proportions of patients losing more than 15 letters, central retinal thickness (CRT), lesion size of choroidal neovascularization (CNV) and adverse events.
Combination therapy decreased the number of injections of ranibizumab, although its BCVA improvement was inferior to that of monotherapy over 12 months of follow-up. Given the inherent limitations of the included trials, more studies are needed to further validate and update the findings in this area.
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: Manuscript no. 2011-638.

: Supported by Novartis Pharma AG, Basel, Switzerland. This study is registered with Clinicaltrials.gov (NCT00436553). The sponsor participated in the design of the study, data management, data analysis, and review of the manuscript.

Financial Disclosure(s): The author(s) have made the following disclosure(s):

Peter K. Kaiser - Consultant - Novartis Pharma AG, Genentech, Inc.

David S. Boyer - Consultant - Novartis Pharma AG, Genentech, Inc., Alcon

Alan F. Cruess - Consultant - Novartis Pharma AG; Lecturer - Novartis Pharma AG, Alcon

Jason S. Slakter - Consultant - Novartis Pharma AG, Genentech, Inc., Regeneron

Stefan Pilz - Employee - Novartis Pharma AG

Annemarie Weisberger - Employee - Novartis Pharmaceuticals Corporation

: At all stages the authors have had control over the content of this manuscript, for which they have given final approval and take full responsibility. Novartis Pharma AG enforces a no ghost-writing policy. As funding sponsors, they have had the opportunity to review the manuscript, but do not have authority to change any aspect of the manuscript.

^⁎: Appendix 1 (available at http://aaojournal.org) contains a list of the principal investigators who participated in this study.

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Original articleVerteporfin plus Ranibizumab for Choroidal Neovascularization in Age-Related Macular Degeneration: Twelve-Month Results of the DENALI Study

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Study Design and Objectives

Study Population

Discussion

Acknowledgments

J Biol Chem

Int J Biochem Cell Biol

Surv Ophthalmol

Exp Eye Res

Ophthalmology

Ophthalmology

Ophthalmology

Verteporfin photodynamic therapy and anti-angiogenic drugs: potential for combination therapy in exudative age-related macular degeneration

Curr Med Res Opin

Hypoxic regulation of vascular endothelial growth factor in retinal cells

Arch Ophthalmol

Cell biology of intraocular vascular diseases [in Japanese]

Nihon Ganka Gakkai Zasshi

Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—Verteporfin in Photodynamic Therapy report 2

Am J Ophthalmol

Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-year results of a randomized clinical trial—VIP report no. 3

Ophthalmology

Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: 5-year results of two randomized clinical trials with an open-label extension: TAP report no. 8

Graefes Arch Clin Exp Ophthalmol

Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium-derived factor

Invest Ophthalmol Vis Sci

Original article
Verteporfin plus Ranibizumab for Choroidal Neovascularization in Age-Related Macular Degeneration: Twelve-Month Results of the DENALI Study