title: Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI study.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  Prospective, multicenter, double-masked, randomized, phase IIIb clinical trial.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Cleveland Clinic Foundation, Cleveland, OH, USA. pkkaiser@aol.com
authors.forename: Peter K
authors.initials: PK
authors.lastname: Kaiser
authors.forename: David S
authors.initials: DS
authors.lastname: Boyer
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cruess
authors.forename: Jason S
authors.initials: JS
authors.lastname: Slakter
authors.forename: Stefan
authors.initials: S
authors.lastname: Pilz
authors.forename: Annemarie
authors.initials: A
authors.lastname: Weisberger
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000503:physiopathology; D003131:Combined Modality Therapy; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D015994:Incidence; D008268:Macular Degeneration / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000009:adverse effects / Q000627:therapeutic use*; D011166:Porphyrins / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D000069579:Ranibizumab; D016896:Treatment Outcome; D000077362:Verteporfin; D014792:Visual Acuity / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D017319:Photosensitizing Agents; D011166:Porphyrins; D000077362:Verteporfin; D000069579:Ranibizumab