Supplementary Appendix
`
`This appendix has been provided by the authors to give readers additional information about their work.
`
`Supplement to: Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related
`macular degeneration. N Engl J Med 2006;355:1419-31.
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`This appendix has been provided by the authors to give readers additional information about their work.
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`Supplement to: Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related
`macular degeneration. N Engl J Med 2006;355:1419-31.
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`Table 1. Eligibility Criteria for MARINA Study
`
`Inclusion Criteria
`
`(cid:120) Age 50 years or older.
`
`(cid:120) Active primary or recurrent subfoveal lesions with choroidal neovascularization (CNV)
`
`secondary to age-related macular degeneration (AMD) in the study eye. “Active” was
`defined as meeting any of the following criteria: (1) exhibiting a (cid:149)10% increase in lesion
`
`size, as determined by comparing a fluorescein angiogram performed within 1 month
`
`preceding Day 0, inclusive, with a fluorescein angiogram performed within 6 months
`
`preceding Day 0, inclusive; or (2) resulting in a visual acuity loss of >1 Snellen line (or
`
`equivalent) and occurring at any time within the prior 6 months; or (3) subretinal
`
`hemorrhage associated with CNV within 1 month preceding Day 0.
`
`(cid:120) Lesions with occult CNV component are permissible. However, if classic CNV (well-
`
`demarcated hyperfluorescence boundaries in the early phase of the fluorescein
`
`angiogram) is present, the area of classic CNV must be less than 50% of the total lesion
`
`size.
`
`(cid:120) The total area of CNV (including both classic and occult components) encompassed
`
`within the lesion must be 50% or more of the total lesion area.
`
`(cid:120) The total lesion area must be 12 disc areas or less in size.
`
`(cid:120) Best corrected visual acuity, using Early Treatment of Diabetic Retinopathy Study
`
`(ETDRS) charts, of 20/40 to 20/320 (Snellen equivalent) in the study eye.
`
`Exclusion Criteria
`
`(cid:120) Prior treatment with verteporfin photodynamic therapy, external-beam radiation therapy,
`
`or transpupillary thermotherapy in the study eye.
`
`(cid:120) Treatment with verteporfin photodynamic therapy in the nonstudy eye less than 7 days
`
`preceding day 0.
`
`(cid:120) Previous participation in a clinical trial (for either eye) involving antiangiogenic drugs
`
`(pegaptanib, ranibizumab, anecortave acetate, protein kinase C inhibitors, etc.)
`
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`Table 1. Eligibility Criteria for MARINA Study (cont’d)
`
`Exclusion Criteria (cont’d)
`
`(cid:120) Previous intravitreal drug delivery (e.g., intravitreal corticosteroid injection or device
`
`implantation) in the study eye.
`
`(cid:120) Previous subfoveal focal laser photocoagulation in the study eye.
`
`(cid:120) Laser photocoagulation (juxtafoveal or extrafoveal) in the study eye within 1 month
`
`preceding day 0.
`
`(cid:120) History of vitrectomy surgery in the study eye.
`
`(cid:120) History of submacular surgery or other surgical intervention for AMD in the study eye.
`
`(cid:120) Previous participation in any studies of investigational drugs within 1 month preceding
`
`day 0 (excluding vitamins and minerals).
`
`(cid:120) Subretinal hemorrhage in the study eye that involves the fovea, if the size of the
`
`hemorrhage is either 50% or more of the total lesion area or 1 or more disc areas in size.
`
`(cid:120) Subfoveal fibrosis or atrophy in the study eye.
`
`(cid:120) CNV in either eye due to other causes, such as ocular histoplasmosis, trauma, or
`
`pathologic myopia.
`
`(cid:120) Retinal pigment epithelial tear involving the macula in the study eye.
`
`(cid:120) Any concurrent intraocular condition in the study eye (e.g., cataract or diabetic
`
`retinopathy) that, in the opinion of the investigator, could either (a) require medical or
`
`surgical intervention during the 24-month study period to prevent or treat visual loss that
`
`might result from that condition, or (b) if allowed to progress untreated, could likely
`
`contribute to loss of at least 2 Snellen equivalent lines of best corrected visual acuity over
`
`the 24-month study period.
`
`(cid:120) Active intraocular inflammation (grade trace or above) in the study eye.
`
`(cid:120) Current vitreous hemorrhage in the study eye.
`
`(cid:120) History of rhegmatogenous retinal detachment or macular hole (Stage 3 or 4) in the study
`
`eye.
`
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`Table 1. Eligibility Criteria for MARINA Study (cont’d)
`
`Exclusion Criteria (cont’d)
`
`(cid:120) History of idiopathic or autoimmune-associated uveitis in either eye.
`
`(cid:120)
`
`Infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye.
`
`(cid:120) Aphakia or absence of the posterior capsule in the study eye.
`
`(cid:120) Spherical equivalent of the refractive error in the study eye demonstrating more than (cid:16)8
`
`diopters of myopia.
`
`(cid:120)
`
`Intraocular surgery (including cataract surgery) in the study eye within 2 months
`
`preceding day 0.
`
`(cid:120) Uncontrolled glaucoma in the study eye (defined as intraocular pressure of 30 mmHg or
`
`more despite treatment with antiglaucoma medications.
`
`(cid:120) History of glaucoma filtering surgery in the study eye.
`
`(cid:120) History of corneal transplant in the study eye.
`
`(cid:120) Premenopausal women not using adequate contraception.
`
`(cid:120) 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 of an investigational drug or that might affect interpretation of the
`
`results of the study or render the subject at high risk for treatment complications.
`
`(cid:120) Current treatment for active systemic infection.
`
`(cid:120) History of allergy to fluorescein, not amenable to treatment with diphenhydramine.
`
`Inability to obtain fundus photographs or fluorescein angiogram of sufficient quality to be
`
`analyzed and graded by the central reading center.
`
`Inability to comply with study or follow-up procedures.
`
`(cid:120)
`
`(cid:120)
`
`
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`Table 2. Patient Disposition in MARINA Trial
`
`
`Ranibizumab
`
`Ranibizumab
`
`
`
`Enrolled
`
`Sham
`
`(cid:16)(cid:16)(cid:16)(cid:3)
`
`0.3 mg
`
`(cid:16)(cid:16)(cid:16)(cid:3)
`
`0.5 mg
`
`(cid:16)(cid:16)(cid:16)(cid:3)
`
`Total
`
`716 (100)
`
`Randomly assigned to treatment
`
`238 (100)
`
`238 (100)
`
`240 (100)
`
`716 (100)
`
`Received randomized treatment*
`
`236 (99.2)
`
`238 (100)
`
`239 (99.6)
`
`713 (99.6)
`
`Intent-to-treat patients for efficacy
`
`analyses
`
`238 (100)
`
`238 (100)
`
`240 (100)
`
`716 (100)
`
`Included in safety evaluation
`
`236 (99.2)
`
`238 (100)
`
`239 (99.6)
`
`713 (99.6)
`
`Completed Month 12†
`
`Crossed over from Sham to
`
`0.5 mg ranibizumab
`
`At Month 22
`
`212 (89.1)
`
`226 (95.0)
`
`226 (94.2)
`
`664 (92.7)
`
`12 (5.0)
`
`5 (2.1)
`
`----
`
`----
`
`----
`
`----
`
`----
`
`----
`
`----
`
`----
`
`At Month 23
`
`Completed Study
`
`7 (2.9)
`
`----
`
`190 (79.8)
`
`210 (88.2)
`
`215 (89.6)
`
`615 (85.9)
`
`Discontinued from study
`
`48 (20.2)
`
`28 (11.8)
`
`25 (10.4)
`
`101 (14.1)
`
`5 (2.1)
`
`6 (2.5)‡
`
`16 (2.2)
`
`5 (2.1)
`
`3 (1.3)
`
`10 (4.2)
`
`1 (0.4)
`
`0
`
`0
`
` 16 (2.2)
`
`8 (1.1)
`
`45 (6.3)
`
`2 (0.3)
`
`2 (0.3)
`
`12 (1.7)
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`Death
`
`Adverse event
`
`Lost to follow-up
`
`Patient’s decision
`
`Physician’s decision
`
`Noncompliance
`
`Patient’s condition mandated
`
`other therapeutic intervention(cid:120)
`
`5 (2.1)
`
`8 (3.4)(cid:105)
`
`2 (0.8)
`
`20 (8.4)
`
`1 (0.4)
`
`1 (0.4)
`
`3 (1.3)
`
`3 (1.3)
`
`15 (6.3)
`
`0
`
`1 (0.4)
`
`11 (4.6)
`
`1 (0.4)
`
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`
`Table 2. Patient Disposition in MARINA Trial (cont’d)
`
`
`Ranibizumab
`
`Ranibizumab
`
`
`
`Sham
`
`0.3 mg
`
`0.5 mg
`
`Total
`
`Discontinued treatment#
`
`68 (28.6)
`
`30 (12.6)
`
`33 (13.8)
`
`131 (18.3)
`
`Death
`
`Adverse event
`
`Lost to follow-up
`
`Patient’s decision
`
`Physician’s decision
`
`Noncompliance
`
`Patient’s condition mandated
`
`other therapeutic intervention(cid:120)
`
`5 (2.1)
`
`13 (5.5)
`
`2 (0.8)
`
`25 (10.5)
`
`2 (0.8)
`
`1 (0.4)
`
`5 (2.1)
`
`8 (3.4)
`
`2 (0.8)
`
`17 (7.1)
`
`1 (0.4)
`
`0
`
`23 (9.7)
`
`1 (0.4)
`
`3 (1.3)‡
`
`15 (6.3)‡
`
`3 (1.3)
`
`13 (5.4)
`
`2 (0.8)
`
`0
`
`0
`
`13 (1.8)
`
`36 (5.0)
`
`7 (1.0)
`
`55 (7.7)
`
`5 (0.7)
`
`1 (0.1)
`
`24 (3.4)
`
`*Reasons for not receiving randomized treatment included patient became apprehensive about
`
`intravitreal injections (1 Sham), and patient was randomized ahead of the schedule before the safety
`eligibility confirmation for an intravitreal injection (1 each for Sham and Ranibizumab 0.5 mg).
`†Defined as having the visual acuity assessment at Month 12. Data from patients who missed the Month
`
`12 visit but stayed in the study for the second year were not counted. The visual acuity score at Month 12
`
`for one patient in the 0.5-mg ranibizumab group was obtained at 4 meters only.
`
`‡Three patients discontinued from treatment because of an adverse event that resulted in death (the
`
`primary reason for study discontinuation).
`
`(cid:105)One patient discontinued from study because of congestive heart failure and died on the same date of
`
`the event.
`
`(cid:120)The mandated therapeutic interventions included verteporfin photodynamic therapy with or without
`
`triamcinolone acetonide injection and intravitreal injection of pegaptanib sodium.
`
`#Some patients remained in the study after treatment discontinuation.
`
`
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`Table 3. Criteria for Serious (Sight-Threatening) Ocular Adverse Events*
`
`(cid:120) Adverse event causes a decrease in visual acuity of (cid:116)30 letters (compared with the last
`assessment of visual acuity prior to the most recent treatment) >1 hour.
`
`
`
`(cid:120) Adverse event causes a decrease in visual acuity to the level of Light Perception or worse
`lasting (cid:33) 1 hour post-injection/sham procedure.
`
`
`
`(cid:120) Adverse event requires surgical intervention (e.g., conventional surgery, vitreous tap or
`biopsy with intravitreal injection of anti-infectives, or laser or retinal cryopexy with gas) to
`prevent permanent loss of sight.
`
`
`
`(cid:120) Adverse event is associated with severe intraocular inflammation (i.e., 4 (cid:14) anterior chamber
`cell/flare or 4 (cid:14) vitritis).
`
`
`
`(cid:120)
`
`In the opinion of the investigator, adverse event may require medical intervention to prevent
`permanent loss of sight.
`
`
`*An adverse event meeting any one of these five criteria was considered serious.
`
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`Table 4. Grading Scales for Flare/Cells*
`
`Flare
`
`
`
`0
`
`No protein is visible in the anterior chamber when viewed by an experienced observer
`
`using slit lamp biomicroscopy; a small, bright, focal slit-beam of white light; and high
`
`magnification.
`
`Trace Trace amount of protein detectable in the anterior chamber. This protein is visible only
`
`with careful scrutiny by an experienced observer using slit lamp biomicroscopy; a small,
`
`bright, focal slit-beam of white light; and high magnification.
`
`1+
`
`Mild amount of protein detectable in the anterior chamber. The presence of protein in
`
`the anterior chamber is immediately apparent to an experienced observer using slit
`
`lamp biomicroscopy and high magnification, but such protein is detected only with
`
`careful observation with the naked eye and a small, bright, focal slit-beam of white light.
`
`2–3+ Moderate amount of protein detectable in the anterior chamber. These grades are
`
`similar to 1+ but the opacity would be readily visible to the naked eye of an observer
`
`using any source of a focused beam of white light. This is a continuum of moderate
`
`opacification, with 2+ being less apparent than 3+.
`
`4+
`
`A large (severe) amount of protein is detectable in the anterior chamber. Similar to 3+,
`
`but the density of the protein approaches that of the lens. Additionally, frank fibrin
`
`deposition is frequently seen in acute circumstances. It needs to be noted that because
`
`fibrin may persist for a period of time after partial or complete restoration of the
`
`blood–aqueous barrier, it is possible to have resorbing fibrin present with lower numeric
`
`assignations for flare (e.g., 1+ flare with fibrin).
`
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`Table 4. Grading Scales for Flare/Cells* (cont’d)
`
`Cells
`
`
`
`0
`
`No cells are seen in any optical section when a large slit lamp beam is swept across the
`
`anterior chamber.
`
`Trace Rare (1–3) cells are observed when the slit lamp beam is swept across the anterior
`
`chamber. When the instrument is held stationary, not every optical section contains
`
`circulating cells.
`
`1+
`
`3–10 cells/optical section are seen when the slit-beam of light sweeps across the
`
`anterior chamber. When the instrument is held stationary, every optical section contains
`
`circulating cells.
`
`2+
`
`10–25 cells are seen when the slit-beam of light sweeps across the anterior chamber.
`
`When the instrument is held stationary, every optical section contains circulating cells.
`
`3+
`
`25–50 cells are seen when the slit-beam of light sweeps across the anterior chamber.
`
`When the instrument is held stationary, every optical section contains circulating cells.
`
`Keratic precipitates or cellular deposits on the anterior lens capsule may be present.
`
`4+
`
`More than 50 cells are seen when the slit-beam of light sweeps across the anterior
`
`chamber. When the instrument is held stationary, every optical section contains cells,
`
`or hypopyon is noted. As for fibrin deposition, hypopyon may persist for some period of
`
`time after the active exudation of cells into the anterior chamber has diminished or
`
`ceased entirely, making it possible to have 1+ circulating cells in the anterior chamber
`
`with a resolving hypopyon.
`
`*Modified from Hogan MH, Kimura SJ, Thygeson P. Signs and symptoms of uveitis. I. Anterior uveitis. Am
`
`J Ophthalmol 1959;47:155.22
`
`
`
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`Table 5. Grading Scale for Vitreous Cells*†
`
`Cells in
`
`Retroilluminated Field
`
`Description
`
`0–1
`
`2–20
`
`21–50
`
`51–100
`
`101–250
`
`>251
`
`Clear
`
`Few opacities
`
`Scattered opacities
`
`Moderate opacities
`
`Many opacities
`
`Dense opacities
`
`Grade
`
`0
`
`Trace
`
`1
`
`2
`
`3
`
`4
`
`*Using a Hruby lens.
`
`†Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis: fundamentals and
`
`clinical practice. 2nd rev. ed. New York:Mosby, 1996, p. 64.23
`
`
`
`
`
`
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`Table 6. Nonocular Hemorrhagic Adverse Events
`
`Ranibizumab
`
`Ranibizumab
`
`MedDRA* Preferred
`
`Sham
`
`0.3 mg
`
`Term
`
`(n = 236)
`
`(n = 238)
`
`Total† — no. (%)
`
`13 (5.5)
`
`22 (9.2)
`
`3 (1.3)
`
`3 (1.3)
`
`0
`
`2 (0.8)
`
`2 (0.8)
`
`0
`
`5 (2.1)
`
`4 (1.7)
`
`3 (1.3)
`
`2 (0.8)
`
`3 (1.3)
`
`0
`
`Epistaxis
`
`Hematoma
`
`Ecchymosis
`
`Rectal hemorrhage
`
`Hematuria
`
`Vaginal hemorrhage
`
`Gastrointestinal
`
`hemorrhage
`
`Lower gastrointestinal
`
`0.5 mg
`
`(n = 239)
`
`21 (8.8)
`
`4 (1.7)
`
`3 (1.3)
`
`3 (1.3)
`
`2 (0.8)
`
`1 (0.4)
`
`3 (1.3)
`
`1 (0.4)
`
`1 (0.4)
`
`1 (0.4)
`
`hemorrhage
`
`1 (0.4)
`
`1 (0.4)
`
`Cerebral hemorrhage
`
`Diarrhea hemorrhagic
`
`Gastritis hemorrhagic
`
`Hematochezia
`
`Hemorrhagic stroke
`
`Mallory-Weiss
`
`syndrome
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.4)
`
`1 (0.4)
`
`1 (0.4)
`
`1 (0.4)
`
`1 (0.4)
`
`1 (0.4)
`
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`Table 6. Nonocular Hemorrhagic Adverse Events (cont’d)
`
`Ranibizumab
`
`Ranibizumab
`
`MedDRA* Preferred
`
`Sham
`
`0.3 mg
`
`Term
`
`(cont’d) — n (%)
`
`Upper gastrointestinal
`
`hemorrhage
`
`Hemoptysis
`
`Hemorrhage
`
`Lip hemorrhage
`
`Melena
`
`Periorbital hematoma
`
`Subarachnoid
`
`hemorrhage
`
`Subdural hemorrhage
`
`Gastric ulcer
`
`hemorrhage
`
`Hematotympanum
`
`Hemorrhage urinary
`
`tract
`
`(n = 236)
`
`(n = 238)
`
`
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.4)
`
`1 (0.4)
`
`1 (0.4)
`
`
`
`0
`
`1 (0.4)
`
`1 (0.4)
`
`1 (0.4)
`
`1 (0.4)
`
`1 (0.4)
`
`1 (0.4)
`
`1 (0.4)
`
`0
`
`0
`
`0
`
`*Medical Dictionary for Regulatory Avtivities.
`† The number of patients with any nonocular hemorrhagic adverse event.
`
`0.5 mg
`
`(n = 239)
`
`
`
`1 (0.4)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
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`METHODS (online)
`
`Study Design
`
`MARINA was a 2-year, prospective, multicenter, randomized, double-masked, sham
`
`injection–controlled study of the safety, tolerability, and efficacy of repeated intravitreal
`
`injections of ranibizumab in patients with choroidal neovascularization due to
`
`neovascular AMD. The prespecified primary efficacy analysis was at 12 months.
`
`Institutional Review Board approval was obtained prior to patient enrollment, and
`
`HIPAA-compliance was achieved at each of the 96 study sites throughout the United
`
`States. Patients provided written, informed consent before determination of their full
`
`eligibility. The screening period could last up to 28 days.
`
`
`
`Full patient eligibility criteria are available online (Table 1). The following are the
`
`major inclusion criteria: age at least 50 years old; best corrected visual acuity of 20/40
`
`to 20/320 (Snellen equivalent) determined using a standardized refraction protocol with
`
`the Early Treatment Diabetic Retinopathy Study (ETDRS) charts; diagnosis of primary
`
`or recurrent choroidal neovascularization, secondary to AMD, involving the foveal
`
`center; lesion assessed by the investigator, using fluorescein angiography and fundus
`
`photography, as minimally classic (less than 50 percent of the lesion consisted of
`
`classic choroidal neovascularization) or occult with no classic choroidal
`
`neovascularization; maximum lesion size of 12 disc areas (DA), with the neovascular
`
`component comprising at least 50 percent of the entire lesion; and presumed recent
`
`disease progression evidenced by the presence of blood, recent vision loss, or a recent
`
`increase in a lesion’s greatest linear diameter by 10 percent or more. The definition of a
`
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`lesion included the choroidal neovascularization and also blockage from hemorrhage,
`
`blocked fluorescence not from hemorrhage, pigment epithelial detachment, and fibrosis.
`
`Before enrollment, lesion eligibility was confirmed by an independent central reading
`
`center using trained masked graders and standardized criteria.
`
`
`
`Major patient exclusion criteria were any prior treatment of the neovascular lesion
`
`(other than thermal laser sparing the foveal center), and treatment of the nonstudy eye
`
`with verteporfin photodynamic therapy less than 7 days before the first study treatment
`
`(day 0). There were no exclusion criteria regarding preexisting cardiovascular,
`
`cerebrovascular, or peripheral vascular conditions.
`
`Study Treatment
`
`Eligible patients were randomly assigned in a 1:1:1 ratio, using a dynamic
`
`randomization algorithm, to receive ranibizumab (LUCENTIS™, Genentech, Inc., South
`
`San Francisco, CA) 0.3 or 0.5 mg or a sham injection monthly (30 (cid:114) 7 days) for 2 years
`
`(24 injections). Randomization was stratified by baseline visual acuity score (< 55 letters
`
`[approximately worse than 20/80] vs. (cid:116) 55 letters) at day 0, by choroidal
`
`neovascularization subtype (minimally classic or occult with no classic), and by study
`
`center. Only one eye per patient received the study treatment. If both eyes were eligible,
`
`the eye with the better visual acuity was treated unless, for medical reasons, the
`
`investigator considered the other eye more appropriate.
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`Page 13
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`Apotex Exhibit 1026
`Page 14 of 18
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`Masking of treatment assignment required at least two investigators per study
`
`site: an evaluating physician (masked to treatment assignment), and an injecting
`
`physician (unmasked regarding ranibizumab or sham treatment but masked to
`
`ranibizumab dose). All other study site personnel (except those assisting with
`
`injections), patients, and central reading center personnel were masked to treatment
`
`assignment.
`
`
`
`Following unmasking of first-year results and discussion with the Data Safety
`
`Monitoring Committee, the study protocol was amended in October 2005 to offer access
`
`to ranibizumab (0.5 mg) to patients in the sham group who had not completed the
`
`treatment period. Patients in the ranibizumab arms remained in their originally
`
`assigned treatment group. The study drug kits continued to be dispensed via the
`
`Interactive Voice Response System to maintain the masking of patients and all site
`
`personnel other than the injecting physician and those assisting in the injecting
`
`procedure.
`
`
`
`Verteporfin photodynamic therapy for the study eye was allowed if the choroidal
`
`neovascularization in the study eye converted to a predominantly classic pattern.
`
`Following a national policy decision by the Centers for Medicare and Medicaid Services
`
`on April 1, 2004, to reimburse photodynamic therapy for small, minimally classic, and
`
`occult lesions, the study protocol was amended to allow photodynamic therapy for
`
`active minimally classic or occult with no classic lesions that were no larger than 4 DA in
`
`size and accompanied by a 20-letter or greater loss from baseline visual acuity
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`Page 14
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`Apotex Exhibit 1026
`Page 15 of 18
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`confirmed at consecutive study visits. When photodynamic therapy was used, the
`
`scheduled study treatment was held until the next scheduled monthly study visit.
`
`
`
`For 3 days before and after each injection, patients self-administered prescribed
`
`topical antimicrobial drops to the study eye. On injection days, after antiseptic
`
`preparation of the eye and pretreatment with local anesthesia and antimicrobials,
`
`patients in the ranibizumab groups received their assigned dose in a 50-(cid:80)L solution
`
`administered as an intravitreal injection. Sham-treated patients underwent the same
`
`pre- and postinjection procedures, but ethical considerations precluded actual
`
`intravitreal injections. Instead, a sham injection was performed whereby pressure was
`
`applied to the eye at the site of a typical injection but using a syringe without a needle.
`
`
`
`After injection, patients remained in the clinic at least 60 (±10) minutes for
`
`additional safety monitoring and measurement of intraocular pressure. Site personnel
`
`contacted patients 2 ( (cid:114) 1) days postinjection to elicit reports of any new ocular
`
`symptoms in the study eye, and to inquire whether patients self-administered the
`
`prescribed antimicrobials. Patients were evaluated 7 days after their first ranibizumab or
`
`sham injection, but they did not return 7 days after subsequent injections.
`
`Study Assessments
`
`For the prespecified primary analysis of treatment efficacy, best corrected visual acuity
`
`and lesion characteristics at 12 months were compared with baseline. The primary
`
`efficacy end point was the proportion of patients losing fewer than 15 letters
`
`(approximately 3 lines) from baseline visual acuity, assessed with the ETDRS chart
`
`using a standardized refraction and testing protocol at a starting test distance of 2
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`Page 15
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`Apotex Exhibit 1026
`Page 16 of 18
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`
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`meters. Other prespecified visual acuity efficacy end points included mean change over
`
`time, proportion of patients gaining 15 or more letters, and proportion of patients with a
`
`Snellen equivalent of 20/200 or worse. Exploratory visual acuity end points included the
`
`proportion of patients with a Snellen equivalent of 20/40 or better, the proportion of
`
`patients with a Snellen equivalent of 20/20 or better, and the proportion of patients
`
`losing 30 letters (approximately 6 lines) or more. Prespecified secondary end points
`
`involving lesion characteristics included mean change in the area of choroidal
`
`neovascularization and the area of leakage (including intense, progressive retinal
`
`pigment epithelium staining). To assess the long-term maintenance of treatment
`
`efficacy, the above end points were also evaluated at 24 months. Indirect
`
`ophthalmoscopy, intraocular pressure measurement, visual acuity testing, and slit lamp
`
`examination were performed by the evaluating physician before every monthly study
`
`treatment. Intraocular pressure was also measured at 60 minutes postinjection. Safety
`
`outcomes included incidence and severity of ocular and nonocular adverse events (see
`
`Tables 3-5 online for criteria and grading of ocular serious adverse events), changes
`
`and abnormalities in clinical laboratory parameters and vital signs, and assessment of
`
`immunoreactivity to ranibizumab. During the study, an independent data monitoring
`
`committee met twice per year to review unmasked safety summaries prepared by an
`
`external statistical coordinating center.
`
`Analysis Methods
`
`
`
`Efficacy analyses were performed on an intent-to-treat basis (all randomized
`
`patients) using a last observation carried forward method to handle missing data. For
`
`all pairwise comparisons, the statistical model stratified by baseline visual acuity score
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`Page 16
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`Apotex Exhibit 1026
`Page 17 of 18
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`
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`(< 55 letters versus (cid:149) 55 letters) and choroidal neovascularization subtype at baseline
`
`(minimally classic versus occult with no classic). Cochran (cid:70)2 tests21 were used for
`
`between-group comparisons for dichotomous end points. Analysis of variance models
`
`were used to analyze change from baseline visual acuity. For lesion characteristic end
`
`points, analysis of covariance models that adjusted for baseline value were used. The
`
`Hochberg-Bonferroni multiple comparison procedure22 was used to adjust for the two
`
`pairwise treatment comparisons for the primary end point. Safety analyses included all
`
`patients who received at least one study treatment. All adverse event reports and
`
`safety assessments made after sham-treated patients crossed over to ranibizumab
`
`were excluded from the main analyses and evaluated separately.
`
`Sample Size and Power Calculation
`
`The sample size was determined based on the primary efficacy end point. Calculations
`
`were based on a 1:1:1 randomization ratio, the Pearson’s (cid:70)2 test for comparison of two
`
`proportions, and the Hochberg-Bonferroni multiple comparison procedure at an overall
`
`Type I error of 0.0497 (after adjusting for the three planned safety interim analyses prior
`
`to the primary efficacy analysis). Monte Carlo simulations were used to evaluate the
`
`power of the study. The planned sample size of 720 would have provided 95 percent
`
`power to detect a statistically significant difference between one or both ranibizumab
`
`groups and the sham control group in the proportion of patients losing fewer than 15
`
`letters at 12 months, assuming a proportion of 65 percent in each ranibizumab group
`
`and 50 percent in the sham control group.
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`
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`
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`Page 17
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`Apotex Exhibit 1026
`Page 18 of 18
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