Efficacy/Safety of Verteporfin Photodynamic Therapy and Ranibizumab Compared With Ranibizumab in Patients With Subfoveal Choroidal Neovascularization

A 24-month Randomized, Double-masked, Controlled, Multicenter, Phase IIIB Study Assessing Safety and Efficacy of Verteporfin Photodynamic Therapy Administered in Conjunction With Ranibizumab Versus Ranibizumab Monotherapy in Patients With Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration

This study evaluated the effect of combination therapy with verteporfin photodynamic therapy and ranibizumab on visual acuity and anatomic outcomes compared to ranibizumab monotherapy and the durability of response observed in patients with choroidal neovascularization secondary to age-related macular degeneration.

Study Overview

• Status: Completed
• Conditions: Macular Degeneration; Choroidal Neovascularization
• Intervention / Treatment: Drug: Verteporfin Photodynamic Therapy; Drug: Ranibizumab; Drug: Ranibizumab Placebo; Drug: Verteporfin Placebo

• Study Type: Interventional
• Enrollment (Actual): 321
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T5H OX5
      • Novartis Investigative Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 3N9
      • Novartis Investigative Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y6
      • Novartis Investigative Site
  • Ontario
    • London, Ontario, Canada, N6A 4G5
      • Novartis Investigative Site
    • London, Ontario, Canada, N6A 4G5
      • Ivey Eye Institute, Dr. Thomas Sheidow
    • Ottawa, Ontario, Canada, KIH 8L6
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H2L 4MI
      • Novartis Investigative Site
• United States
  • Arizona
    • Tucson, Arizona, United States, 85704
      • Novartis Investigative Site
  • California
    • Beverly Hills, California, United States, 90211
      • Novartis Investigative Site
    • Oakland, California, United States, 94609
      • Novartis Investigative Site
    • Pasadena, California, United States, 91105-3153
      • Novartis Investigative Site
    • Sacramento, California, United States, 95819
      • Novartis Investigative Site
    • San Francisco, California, United States, 94107
      • West Coast Retina Medical Group Inc. - 185 Berry St. Suite 130
    • Santa Ana, California, United States, 92705
      • Novartis Investigative Site
  • Colorado
    • Denver, Colorado, United States, 80210
      • Novartis Investigative Site
  • Hawaii
    • Aiea, Hawaii, United States, 96701
      • Novartis Investigative Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Novartis Investigative Site
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Novartis Investigative Site
  • Kentucky
    • Lexington, Kentucky, United States, 40509
      • Novartis Investigative Site
    • Paducah, Kentucky, United States, 42001
      • Novartis Investigative Site
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Novartis Investigative Site
  • Michigan
    • Grand Rapids, Michigan, United States, 49252
      • Novartis Investigative Site
    • Royal Oak, Michigan, United States, 48073
      • Novartis Investigative Site
    • Williamsburg, Michigan, United States, 49690
      • Novartis Investigative Site
  • Missouri
    • Independence, Missouri, United States, 64055
      • Novartis Investigative Site
    • St. Louis, Missouri, United States, 63110
      • Novartis Investigative Site
  • New Jersey
    • Toms River, New Jersey, United States, 08755
      • Novartis Investigative Site
  • New York
    • Lynbrook, New York, United States, 11563
      • Novartis Investigative Site
    • Rochester, New York, United States, 14620
      • Novartis Investigative Site
  • Ohio
    • Beachwood, Ohio, United States, 44122
      • Novartis Investigative Site
    • Cincinnati, Ohio, United States, 45242
      • Novartis Investigative Site
    • Cleveland, Ohio, United States, 44195
      • Novartis Investigative Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Novartis Investigative Site
    • West Mifflin, Pennsylvania, United States, 15122
      • Novartis Investigative Site
  • South Carolina
    • West Columbia, South Carolina, United States, 29169
      • Novartis Investigative Site
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Novartis Investigative Site
  • Tennessee
    • Kingsport, Tennessee, United States, 37660
      • Novartis Investigative Site
    • Knoxville, Tennessee, United States, 37909
      • Novartis Investigative Site
  • Texas
    • Austin, Texas, United States, 78705
      • Novartis Investigative Site
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Novartis Investigative Site
    • Richmond, Virginia, United States, 23226
      • Novartis Investigative Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects of either gender age 50 years or older
• Subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD)

Exclusion Criteria:

• Choroidal neovascularization due to causes other than AMD
• Prior treatment for neovascular AMD in the study eye

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Verteporfin With Standard Fluence Rate Plus Ranibizumab; Patients received three consecutive monthly ranibizumab injections on Day 1 and at Months 1 and 2, and thereafter as needed at intervals of at least 30 days based on retreatment criteria. These patients also received verteporfin photodynamic therapy (PDT) with standard fluence (SF) rate on Day 1 and then as needed from Month 3 at intervals of at least 90 days based on the retreatment criteria. From month 3 onward, retreatments were determined based on study-specific retreatment criteria that included retinal thickness by Optical Coherence Tomography (OCT), sub-retinal hemorrhage evaluated by ophthalmoscopic examination, visual acuity assessed using Early treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart and choroidal neovascularization (CNV) leakage assessed by fluorescein angiography (FA). Patients received sham intravitreal injections for the first 12 months if retreatment with ranibizumab was not warranted based on the retreatment criteria.	Drug: Verteporfin Photodynamic Therapy; After a 10-minute intravenous infusion of verteporfin at a dose of 6 mg/m^2 body surface area, verteporfin was activated by light application of 50 J/cm^2 (Standard Fluence rate) or 25 J/cm^2 (Reduced Fluence rate) to the study eye, begun 15 minutes after the start of the infusion.; Other Names: Visudyne; Drug: Ranibizumab; Ranibizumab 0.5 mg administered as an intravitreal injection.; Other Names: Lucentis; Drug: Ranibizumab Placebo; To maintain masking, patients in the combination groups received sham intravitreal injections whenever retreatment with active Ranibizumab was not warranted based on the retreatment algorithm.
ACTIVE_COMPARATOR: Ranibizumab Monotherapy; Patients received monthly ranibizumab injections for 12 months and thereafter as needed based on the retreatment criteria. These patients were also administered verteporfin placebo infusion with sham PDT on Day 1 and then as needed from Month 3 at intervals of at least 90 days based on the retreatment criteria. Retreatments were determined based on study specific retreatment criteria that included retinal thickness by Optical Coherence Tomography (OCT), sub-retinal hemorrhage evaluated by ophthalmoscopic examination, visual acuity assessed using Early treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart and choroidal neovascularization (CNV) leakage assessed by fluorescein angiography (FA).	Drug: Ranibizumab; Ranibizumab 0.5 mg administered as an intravitreal injection.; Other Names: Lucentis; Drug: Verteporfin Placebo; To maintain masking, as a placebo for verteporfin photodynamic therapy, patients were administered a 10-minute intravenous infusion of 5% dextrose solution, followed by light application of 50 J/cm^2 to the study eye, begun 15 minutes after the start of infusion.
EXPERIMENTAL: Verteporfin With Reduced Fluence Rate Plus Ranibizumab; Patients received three consecutive monthly ranibizumab injections on Day 1 and at Months 1 and 2, and thereafter as needed at intervals of at least 30 days based on retreatment criteria. These patients also received verteporfin PDT with reduced fluence (RF) rate on Day 1 and then as needed from Month 3 at intervals of at least 90 days based on the retreatment criteria. From month 3 onward, retreatments were determined based on study-specific retreatment criteria that included retinal thickness by Optical Coherence Tomography (OCT), sub-retinal hemorrhage evaluated by ophthalmoscopic examination, visual acuity assessed using Early treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart and choroidal neovascularization (CNV) leakage assessed by fluorescein angiography (FA). Patients received sham intravitreal injections for the first 12 months if retreatment with ranibizumab was not warranted based on the retreatment criteria.	Drug: Verteporfin Photodynamic Therapy; After a 10-minute intravenous infusion of verteporfin at a dose of 6 mg/m^2 body surface area, verteporfin was activated by light application of 50 J/cm^2 (Standard Fluence rate) or 25 J/cm^2 (Reduced Fluence rate) to the study eye, begun 15 minutes after the start of the infusion.; Other Names: Visudyne; Drug: Ranibizumab; Ranibizumab 0.5 mg administered as an intravitreal injection.; Other Names: Lucentis; Drug: Ranibizumab Placebo; To maintain masking, patients in the combination groups received sham intravitreal injections whenever retreatment with active Ranibizumab was not warranted based on the retreatment algorithm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) of the Study Eye at Month 12	BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An ETDRS visual acuity score of 85 is approximately 20/20. An increase in the VA score indicates improvement in visual acuity.	Baseline and Month 12
Percent of Patients With a Treatment-free Interval of at Least 3 Months Following the Month 2 Visit	The number of patients with a ranibizumab treatment-free interval, ie, no active ranibizumab treatments for at least 3 months duration (at least 2 consecutive monthly visits), anytime following the Month 2 ranibizumab treatment. Only active ranibizumab treatments were considered.	Month 2 up to Month 11

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Total Area of Leakage of the Study Eye at Month 12	Total area of leakage of the study eye was assessed at the Central Reading Center (CRC) using Fluorescein angiography (FA).	Baseline and Month 12
Percentage of Patients With Fluorescein Leakage in the Study Eye at Month 12	The percentage of patients with leakage of the study eye was assessed at the Central Reading Center (CRC) using Fluorescein angiography (FA).	Month 12
Change From Baseline in Central Retinal Thickness at Month 12	Optical coherence tomography was performed in the study eyes and the evaluations of the images were performed by the central reading center.	Baseline and Month 12

Collaborators and Investigators

• Sponsor: Novartis

Publications and helpful links

General Publications

• Kaiser PK, Boyer DS, Cruess AF, Slakter JS, Pilz S, Weisberger A; DENALI Study Group. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI study. Ophthalmology. 2012 May;119(5):1001-10. doi: 10.1016/j.ophtha.2012.02.003. Epub 2012 Mar 22.

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (ACTUAL): October 1, 2009
• Study Completion (ACTUAL): October 1, 2009

Study Registration Dates

• First Submitted: February 16, 2007
• First Submitted That Met QC Criteria: February 16, 2007
• First Posted (ESTIMATE): February 19, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): April 19, 2011
• Last Update Submitted That Met QC Criteria: March 23, 2011
• Last Verified: March 1, 2011

More Information

Terms related to this study

• Keywords: choroidal neovascularization; ranibizumab; verteporfin; Age-related macular degeneration; AMD
• Additional Relevant MeSH Terms: Pathologic Processes; Eye Diseases; Retinal Degeneration; Retinal Diseases; Uveal Diseases; Choroid Diseases; Metaplasia; Macular Degeneration; Choroidal Neovascularization; Neovascularization, Pathologic; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Photosensitizing Agents; Dermatologic Agents; Ranibizumab; Verteporfin
• Other Study ID Numbers: CBPD952A2308