A Study of Ranibizumab Administered Monthly or on an As-needed Basis in Patients With Subfoveal Neovascular Age-related Macular Degeneration (HARBOR)

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Age-related Macular Degeneration

Intervention / Treatment
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* Drug: Ranibizumab


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ranibizumab 0.5 mg monthly<br>Patients received ranibizumab 0.5 mg monthly administered intravitreally for 24 months. | Drug: Ranibizumab<br>* Sterile solution for intravitreal injection.<br>* Other names: Lucentis;|
| Experimental: Ranibizumab 2.0 mg monthly<br>Patients received ranibizumab 2.0 mg monthly administered intravitreally for 24 months. | Drug: Ranibizumab<br>* Sterile solution for intravitreal injection.<br>* Other names: Lucentis;|
| Experimental: Ranibizumab 0.5 mg as-needed (pro re nata [PRN])<br>Patients received ranibizumab 0.5 mg monthly administered intravitreally for 3 months. Thereafter, patients' visual acuity and eye disease activity were assessed monthly for an additional 21 months. If study defined criteria were met at a monthly assessment, patients received ranibizumab 0.5 mg administered intravitreally. | Drug: Ranibizumab<br>* Sterile solution for intravitreal injection.<br>* Other names: Lucentis;|
| Experimental: Ranibizumab 2.0 mg as-needed (pro re nata [PRN])<br>Patients received ranibizumab 2.0 mg monthly administered intravitreally for 3 months. Thereafter, patients' visual acuity and eye disease activity were assessed monthly for an additional 21 months. If study defined criteria were met at a monthly assessment, patients received ranibizumab 2.0 mg administered intravitreally. | Drug: Ranibizumab<br>* Sterile solution for intravitreal injection.<br>* Other names: Lucentis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Best Corrected Visual Acuity (BCVA) at Month 12 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. A decrease in the BCVA score indicates a worsening of vision. A positive change score indicates improvement. | Baseline to Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Ranibizumab Injections up to But Not Including Month 12 |  | Baseline to Month 12 | 
| Percentage of Patients Who Gained ≥ 15 Letters in Best Corrected Visual Acuity (BCVA) From Baseline at Month 12 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. | Baseline to Month 12 | 
| Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Month 12 | VA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart starting at a test distance of 4 meters. An increase in the number of lines read correctly by the patient in the ETDRS chart indicates an improvement of vision. The Snellen equivalent of 20/40 is 14 lines correctly read in the EDTRS chart. | Month 12 | 
| Percentage of Patients With no Evidence of Fluid From Choroidal Neovascularization (CNV) at Month 12 | The presence of fluid from choroidal neovascularization (CNV) was assessed by spectral domain optical coherence tomography (SD-OCT). No evidence of fluid was defined as no subretinal fluid thickness, no cystoid spaces, no intraretinal fluid, no pigment epithelial defect thickness, and average central subfield thickness < 270 µm. | Month 12 | 
| Change From Baseline in Central Foveal Thickness at Day 7 and Months 1, 2, 3, 4, 6, 9, and 12 | Central foveal thickness was assessed by spectral domain optical coherence tomography (SD-OCT). | Baseline to Day 7 and Months 1, 2, 3, 4, 6, 9, and 12 | 
| Change From Baseline in Macular Volume at Day 7 and Months 1, 2, 3, 4, 6, 9, and 12 | Macular volume was assessed by spectral domain optical coherence tomography (SD-OCT). | Baseline to Day 7 and Months 1, 2, 3, 4, 6, 9, and 12 | 
| Change From Baseline in the Total Area of Choroidal Neovascularization (CNV) and Choroidal Neovascular Leakage at Month 12 | The total area of choroidal neovascularization (CNV) and choroidal neovascular leakage was assessed with fluorescein angiography (FA). Area was measured in disc area units; 1 disc area unit = 2.54 mm^2. | Baseline to Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lucentis, AMD, Age-related macular degeneration, Subfoveal neovascular age-related macular degeneration, Wet AMD, Macular degeneration, Ranibizumab