Clinical trial NCT00891735: A Study of Ranibizumab Administered Monthly or on an As-needed Basis in Patients With Subfoveal Neovascular Age-related Macular Degeneration (HARBOR)
Official title: A Phase III, Double-masked, Multicenter, Randomized, Active Treatment-controlled Study of the Efficacy and Safety of 0.5 mg and 2.0 mg Ranibizumab Administered Monthly or on an As-needed Basis (PRN) in Patients With Subfoveal Neovascular Age-related Macular Degeneration
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Age-related Macular Degeneration
Keywords: Lucentis
AMD
Age-related macular degeneration
Subfoveal neovascular age-related macular degeneration
Wet AMD
Macular degeneration
Ranibizumab
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2009-05-01
Enrollment: 1097
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase III, multicenter, randomized, double-masked, dose-comparison study of the efficacy and safety of ranibizumab injection administered intravitreally to patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Results are presented for the first 12 months of the study.


Eligibility criteria: Inclusion Criteria:

* For sexually active women of childbearing potential, agreement to the use of an appropriate form of contraception (or abstinence) for the duration of the study.

Ocular Inclusion Criteria (Study Eye)

* Best corrected visual acuity (BCVA), using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, of 20/40-20/320 (Snellen equivalent).
* Choroidal neovascularization (CNV) lesions with classic CNV component, occult CNV, or with some classic CNV component were permissible.
* Total area of lesion \< 12 disc area or 30.48 mm\^2.

Exclusion Criteria:

* History of vitrectomy surgery, submacular surgery, or other surgical intervention for age-related macular degeneration (AMD) in the study eye.
* Prior treatment with Visudyne(R), external-beam radiation therapy, or transpupillary thermotherapy (TTT) in the study eye.
* Previous intravitreal drug delivery (eg, intravitreal corticosteroid injection, anti-angiogenic drugs, or device implantation) in the study eye.
* Previous treatment or participation in a clinical trial involving anti-angiogenic drugs (Avastin(R), anecortave acetate, protein kinase C inhibitors, etc), in the non-study eye within 3 months of Day 0 (first day of treatment). The patient may not have received Lucentis(R) or Macugen(R) in the non-study eye within 7 days of Day 0.
* Treatment with Visudyne(R) in the non-study eye \< 7 days preceding Day 0.
* Subretinal hemorrhage in the study eye that involves the center of the fovea, if the size of the hemorrhage is either \> 50% of the total area of the lesion or \> 1 disc area (2.54 mm\^2) in size.
* Subfoveal fibrosis or atrophy in the study eye.
* CNV in either eye due to other causes, such as ocular histoplasmosis, trauma, or pathologic myopia.
* Retinal pigment epithelial tear involving the macula in the study eye.
* Any concurrent intraocular condition in the study eye (eg, cataract or diabetic retinopathy) that, in the opinion of the investigator, could either: Require medical or surgical intervention during the 24-month study period to prevent or treat visual loss that might result from that condition; or if allowed to progress untreated, could likely contribute to loss of at least 2 Snellen equivalent lines of best corrected visual acuity (BCVA) over the 24-month study period.
* Uncontrolled blood pressure.
* Atrial fibrillation not managed by patient's primary care physician or cardiologist within 3 months of screening visit.
* History of stroke within the last 3 months of screening visit.
* History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use an investigational drug or that might affect interpretation of the results of the study or renders the patient at high risk for treatment complications.
* Current treatment for active systemic infection.
* Active malignancy.
* History of allergy to fluorescein, not amenable to treatment.
* Previous participation in any studies of investigational drugs within 1 month preceding Day 0 (excluding vitamins and minerals).

Primary outcomes:
measure: Change From Baseline in Best Corrected Visual Acuity (BCVA) at Month 12
timeFrame: Baseline to Month 12
Secondary outcomes:
measure: Number of Ranibizumab Injections up to But Not Including Month 12
timeFrame: Baseline to Month 12
measure: Percentage of Patients Who Gained ≥ 15 Letters in Best Corrected Visual Acuity (BCVA) From Baseline at Month 12
timeFrame: Baseline to Month 12
measure: Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Month 12
timeFrame: Month 12
measure: Percentage of Patients With no Evidence of Fluid From Choroidal Neovascularization (CNV) at Month 12
timeFrame: Month 12
measure: Change From Baseline in Central Foveal Thickness at Day 7 and Months 1, 2, 3, 4, 6, 9, and 12
timeFrame: Baseline to Day 7 and Months 1, 2, 3, 4, 6, 9, and 12
measure: Change From Baseline in Macular Volume at Day 7 and Months 1, 2, 3, 4, 6, 9, and 12
timeFrame: Baseline to Day 7 and Months 1, 2, 3, 4, 6, 9, and 12
measure: Change From Baseline in the Total Area of Choroidal Neovascularization (CNV) and Choroidal Neovascular Leakage at Month 12
timeFrame: Baseline to Month 12
Other outcomes:
Locations:
city: Phoenix
country: United States
state: Arizona
city: Tucson
country: United States
state: Arizona
city: Arcadia
country: United States
state: California
city: Beverly Hills
country: United States
state: California
city: Campbell
country: United States
state: California
city: Chico
country: United States
state: California
city: La Jolla
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Mountain View
country: United States
state: California
city: Oakland
country: United States
state: California
city: Palm Desert
country: United States
state: California
city: Poway
country: United States
state: California
city: Sacramento
country: United States
state: California
city: San Francisco
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Santa Ana
country: United States
state: California
city: Santa Barbara
country: United States
state: California
city: Torrance
country: United States
state: California
city: Ventura
country: United States
state: California
city: Westlake Village
country: United States
state: California
city: Aurora
country: United States
state: Colorado
city: Colorado Springs
country: United States
state: Colorado
city: Golden
country: United States
state: Colorado
city: Danbury
country: United States
state: Connecticut
city: Hamden
country: United States
state: Connecticut
city: New Haven
country: United States
state: Connecticut
city: New London
country: United States
state: Connecticut
city: Altamonte Springs
country: United States
state: Florida
city: Boynton Beach
country: United States
state: Florida
city: Fort Lauderdale
country: United States
state: Florida
city: Fort Myers
country: United States
state: Florida
city: Palm Beach Gardens
country: United States
state: Florida
city: Pensacola
country: United States
state: Florida
city: Stuart
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Winter Haven
country: United States
state: Florida
city: Augusta
country: United States
state: Georgia
city: Aiea
country: United States
state: Hawaii
city: Chicago
country: United States
state: Illinois
city: Oak Park
country: United States
state: Illinois
city: Indianapolis
country: United States
state: Indiana
city: Shawnee Mission
country: United States
state: Kansas
city: Wichita
country: United States
state: Kansas
city: Lexington
country: United States
state: Kentucky
city: Paducah
country: United States
state: Kentucky
city: Portland
country: United States
state: Maine
city: Baltimore
country: United States
state: Maryland
city: Hagerstown
country: United States
state: Maryland
city: Boston
country: United States
state: Massachusetts
city: Boston
country: United States
state: Massachusetts
city: Worcester
country: United States
state: Massachusetts
city: Jackson
country: United States
state: Michigan
city: Edina
country: United States
state: Minnesota
city: Saint Louis
country: United States
state: Missouri
city: Lincoln
country: United States
state: Nebraska
city: Las Vegas
country: United States
state: Nevada
city: Lawrenceville
country: United States
state: New Jersey
city: New Brunswick
country: United States
state: New Jersey
city: Northfield
country: United States
state: New Jersey
city: Teaneck
country: United States
state: New Jersey
city: Vauxhall
country: United States
state: New Jersey
city: Great Neck
country: United States
state: New York
city: Lynbrook
country: United States
state: New York
city: New York
country: United States
state: New York
city: Rochester
country: United States
state: New York
city: Shirley
country: United States
state: New York
city: Asheville
country: United States
state: North Carolina
city: Charlotte
country: United States
state: North Carolina
city: Beachwood
country: United States
state: Ohio
city: Cincinnati
country: United States
state: Ohio
city: Columbus
country: United States
state: Ohio
city: Portland
country: United States
state: Oregon
city: Camp Hill
country: United States
state: Pennsylvania
city: Huntingdon Valley
country: United States
state: Pennsylvania
city: Johnstown
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: West Mifflin
country: United States
state: Pennsylvania
city: Greenville
country: United States
state: South Carolina
city: Ladson
country: United States
state: South Carolina
city: West Columbia
country: United States
state: South Carolina
city: Rapid City
country: United States
state: South Dakota
city: Nashville
country: United States
state: Tennessee
city: Abilene
country: United States
state: Texas
city: Austin
country: United States
state: Texas
city: Desoto
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: McAllen
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Temple
country: United States
state: Texas
city: The Woodlands
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Richmond
country: United States
state: Virginia
city: Virginia Beach
country: United States
state: Virginia
city: Milwaukee
country: United States
state: Wisconsin
city: Casper
country: United States
state: Wyoming
Study officials:
affiliation: Genentech, Inc.
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Staurenghi G, Cozzi M, Sadda S, Hill L, Gune S. Characteristics that Correlate with Macular Atrophy in Ranibizumab-Treated Patients with Neovascular Age-Related Macular Degeneration. Ophthalmol Retina. 2023 Apr;7(4):300-306. doi: 10.1016/j.oret.2022.11.002. Epub 2022 Nov 11.
citation: Lally DR, Hill L, Amador-Patarroyo MJ. Subretinal Fluid Resolution and Visual Acuity in Patients with Neovascular Age-Related Macular Degeneration: A HARBOR Post Hoc Analysis. Ophthalmol Retina. 2022 Nov;6(11):1054-1060. doi: 10.1016/j.oret.2022.05.026. Epub 2022 May 30.
citation: Sheth V, D'Rozario M, Gune S, Blotner S. Fluctuations in central foveal thickness and association with vision outcomes with anti-VEGF therapy for nAMD: HARBOR post hoc analysis. BMJ Open Ophthalmol. 2022 Mar 9;7(1):e000957. doi: 10.1136/bmjophth-2021-000957. eCollection 2022.
citation: Freund KB, Staurenghi G, Jung JJ, Zweifel SA, Cozzi M, Hill L, Blotner S, Tsuboi M, Gune S. Macular neovascularization lesion type and vision outcomes in neovascular age-related macular degeneration: post hoc analysis of HARBOR. Graefes Arch Clin Exp Ophthalmol. 2022 Aug;260(8):2437-2447. doi: 10.1007/s00417-022-05586-w. Epub 2022 Mar 3.
citation: Pawloff M, Bogunovic H, Gruber A, Michl M, Riedl S, Schmidt-Erfurth U. SYSTEMATIC CORRELATION OF CENTRAL SUBFIELD THICKNESS WITH RETINAL FLUID VOLUMES QUANTIFIED BY DEEP LEARNING IN THE MAJOR EXUDATIVE MACULAR DISEASES. Retina. 2022 May 1;42(5):831-841. doi: 10.1097/IAE.0000000000003385.
citation: Holekamp NM, Sadda S, Sarraf D, Guymer R, Hill L, Blotner S, Spicer G, Gune S. Effect of Residual Retinal Fluid on Visual Function in Ranibizumab-Treated Neovascular Age-Related Macular Degeneration. Am J Ophthalmol. 2022 Jan;233:8-17. doi: 10.1016/j.ajo.2021.06.029. Epub 2021 Jul 18.
citation: Javaheri M, Hill L, Ghanekar A, Stoilov I. Changes in Treatment-Naive Pigment Epithelial Detachments Associated With the Initial Anti-Vascular Endothelial Growth Factor Injection: A Post Hoc Analysis From the HARBOR Trial. JAMA Ophthalmol. 2021 Feb 1;139(2):219-223. doi: 10.1001/jamaophthalmol.2020.5130.
citation: Sadda SR, Abdelfattah NS, Lei J, Shi Y, Marion KM, Morgenthien E, Gune S, Balasubramanian S. Spectral-Domain OCT Analysis of Risk Factors for Macular Atrophy Development in the HARBOR Study for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2020 Oct;127(10):1360-1370. doi: 10.1016/j.ophtha.2020.03.031. Epub 2020 Apr 2.
citation: Khurana RN, Chang L, Day BM, Ghanekar A, Stoilov I. Timing of Peak Vision Gains in Patients with Neovascular Age-Related Macular Degeneration Treated with Ranibizumab. Ophthalmol Retina. 2020 Aug;4(8):760-766. doi: 10.1016/j.oret.2020.02.011. Epub 2020 Feb 27.
citation: Li E, Donati S, Lindsley KB, Krzystolik MG, Virgili G. Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2020 May 5;5(5):CD012208. doi: 10.1002/14651858.CD012208.pub2.
citation: Khurana RN, Hill L, Ghanekar A, Gune S. Agreement of Spectral-Domain OCT with Fluorescein Leakage in Neovascular Age-Related Macular Degeneration: Post Hoc Analysis of the HARBOR Study. Ophthalmol Retina. 2020 Nov;4(11):1054-1058. doi: 10.1016/j.oret.2020.04.016. Epub 2020 Apr 28.
citation: Patel Y, Miller DM, Fung AE, Hill LF, Rosenfeld PJ. Are Dilated Fundus Examinations Needed for OCT-Guided Retreatment of Exudative Age-Related Macular Degeneration? Ophthalmol Retina. 2020 Feb;4(2):141-147. doi: 10.1016/j.oret.2019.09.006. Epub 2019 Sep 18.
citation: Khurana RN, Chang LK, Hill LF, Ghanekar A, Stoilov I. The Value of Prior Response to Anti-Vascular Endothelial Growth Factor for Age-Related Macular Degeneration: A HARBOR Subanalysis. Ophthalmol Retina. 2020 Jan;4(1):13-18. doi: 10.1016/j.oret.2019.06.008. Epub 2019 Jul 5.
citation: Nassisi M, Lei J, Abdelfattah NS, Karamat A, Balasubramanian S, Fan W, Uji A, Marion KM, Baker K, Huang X, Morgenthien E, Sadda SR. OCT Risk Factors for Development of Late Age-Related Macular Degeneration in the Fellow Eyes of Patients Enrolled in the HARBOR Study. Ophthalmology. 2019 Dec;126(12):1667-1674. doi: 10.1016/j.ophtha.2019.05.016. Epub 2019 May 29.
citation: Hallak JA, de Sisternes L, Osborne A, Yaspan B, Rubin DL, Leng T. Imaging, Genetic, and Demographic Factors Associated With Conversion to Neovascular Age-Related Macular Degeneration: Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol. 2019 Jul 1;137(7):738-744. doi: 10.1001/jamaophthalmol.2019.0868.
citation: Sarraf D, London NJ, Khurana RN, Dugel PU, Gune S, Hill L, Tuomi L. Ranibizumab Treatment for Pigment Epithelial Detachment Secondary to Neovascular Age-Related Macular Degeneration: Post Hoc Analysis of the HARBOR Study. Ophthalmology. 2016 Oct;123(10):2213-24. doi: 10.1016/j.ophtha.2016.07.007. Epub 2016 Aug 23.
citation: Frenkel RE, Shapiro H, Stoilov I. Predicting vision gains with anti-VEGF therapy in neovascular age-related macular degeneration patients by using low-luminance vision. Br J Ophthalmol. 2016 Aug;100(8):1052-7. doi: 10.1136/bjophthalmol-2015-307575. Epub 2015 Nov 5.
citation: Busbee BG, Ho AC, Brown DM, Heier JS, Suner IJ, Li Z, Rubio RG, Lai P; HARBOR Study Group. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2013 May;120(5):1046-56. doi: 10.1016/j.ophtha.2012.10.014. Epub 2013 Jan 23.