Methods

PIER methodology, including study design, eligibility, masking, treatment, assessments, and analyses, has been published in detail. All patients provided informed written consent prior to participation. Briefly, eligible patients were at least 50 years of age with a diagnosis of primary or recurrent subfoveal CNV (predominantly classic, minimally classic, or occult with no classic) secondary to AMD and baseline best-corrected VA of 20/40 to 20/320 Snellen equivalent, measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a distance of 4 meters.

Classic and/or occult CNV comprised ≥50% of the total AMD lesion area, and the total lesion was ≤12 disc areas (DA). If a CNV lesion was minimally classic or occult with no classic component, the treated eye was required to meet protocol-defined criteria for disease progression (ie, a 10% increase in lesion size based on fluorescein angiography [FA] obtained 1 month prior to study initiation [ie, day 0] compared to FA obtained 6 months prior to day 0; ≥5 ETDRS letter [1 Snellen line] VA loss within 6 months prior to day 0; or CNV-associated subretinal hemorrhage 1 month prior to day 0). Patients who had fibrosis or atrophy involving the center of the fovea or subretinal hemorrhage ≥1 DA or ≥50% of total lesion area with foveal involvement were excluded. One eye per patient was studied.

Eligible patients were randomized 1:1:1 to sham injections, 0.3 mg intravitreal ranibizumab, or 0.5 mg intravitreal ranibizumab ( Figure 1 ). Patients were masked to treatment. Randomization was stratified by best-corrected VA (≤54 ETDRS letters, ∼20/80 or worse Snellen equivalent vs ≥55 ETDRS letters, ∼20/80 or better Snellen equivalent) at day 0, CNV type (minimally classic vs occult with no classic vs predominantly classic), and study center. The protocol mandated that patients receive sham injections or intravitreal injections of their assigned ranibizumab dose once a month for 3 months (day 0, month 1, month 2) and every 3 months thereafter (months 5, 8, 11, 14, 17, 20, and 23), for the duration of the 2-year study. Fluorescein angiography and fundus photography were performed at months 3, 5, 8, 12, and 24 and were evaluated by a central reading center (Fundus Photograph Reading Center, University of Wisconsin, Madison, Wisconsin, USA). Patients underwent complete ocular examination, including VA assessment at each study visit (ie, the first 3 months and then quarterly). The Vision Functioning Questionnaire-25 (VFQ-25) was administered at baseline and at months 3, 8, 12, and 24, prior to patients completing any other study-related procedures. In addition to injection visits, clinic visits were scheduled at months 3, 12, and 24. Subsequent protocol amendments (crossover and rollover amendments described below) increased subject assessments from quarterly to monthly. The monthly assessments were identical to the previous quarterly assessments.

Ranibizumab for neovascular age-related macular degeneration trial: PIER randomization, crossover, and rollover scheme. The PIER study was initiated in September 2004 and completed in March 2007. Patients were randomized 1:1:1 to sham injection, 0.3 mg intravitreal ranibizumab, or 0.5 mg intravitreal ranibizumab. A February 2006 protocol amendment allowed sham patients to cross over to receive 0.5 mg intravitreal ranibizumab after completing the month-12 visit. An August 2006 amendment allowed all patients to roll over to receive 0.5 mg intravitreal ranibizumab monthly.

The incidence and severity of ocular and nonocular adverse events (AEs) and changes in vital signs were assessed at all study visits. In accordance with the criteria established by the worldwide Antiplatelet Trialists’ Collaboration, arterial thromboembolic events (ATEs), such as vascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, and nonfatal hemorrhagic stroke, were documented.

After careful review of 12-month data from the pivotal MARINA and ANCHOR trials, the study sponsor believed it to be in the best interest of sham group patients to be treated with ranibizumab. Thus, the protocol was amended on February 27, 2006 to provide sham-injection patients the opportunity to cross over to receive 0.5 mg ranibizumab quarterly after completing the month-12 visit (ie, the assessment time point for the primary analysis). Subsequently, after careful review of the 12-month PIER data, the protocol was amended again, on August 21, 2006, to provide all patients remaining in the study the opportunity to roll over to receive 0.5 mg ranibizumab monthly for the remainder of the 2-year study. No patients were unmasked to their original treatment assignment as a result of the crossover and rollover amendments.

The primary endpoint of PIER was mean change in best-corrected VA at month 12. Key visual outcomes at month 24 were mean change from baseline VA, proportion of patients who lost <15 VA letters from baseline, proportion of patients who gained ≥15 VA letters from baseline, proportion of patients with Snellen equivalent VA of 20/200 or worse, mean change from baseline VFQ-25 near and distance activities and vision-specific dependency subscale scores, mean change from baseline total area of CNV, and total area of CNV leakage plus retinal pigment epithelium (RPE) staining. Safety endpoints were incidence and severity of ocular and nonocular AEs, incidence of positive serum antibodies to ranibizumab, and changes in vital signs.

The intent-to-treat approach was used for visual and anatomic analyses and included all patients as randomized. Missing values were imputed using the last-observation-carried-forward method. All pairwise comparisons between the ranibizumab groups and the sham group were based on statistical models with 2 groups (ranibizumab vs sham) at a time. A type I error management plan was used to adjust for multiplicity of treatment comparisons and visual and anatomic endpoints. Unless otherwise noted, analyses were stratified by CNV type at baseline (minimally classic vs occult with no classic vs predominantly classic), as determined by the central reading center, and by baseline VA (≤54 vs ≥55 letters). For binary endpoints, stratified Cochran χ ² tests were used for between-group comparisons of the proportion of patients meeting the endpoint. Analysis-of-variance and analysis-of-covariance models were used to analyze continuous endpoints.

The study sample size was based on the primary endpoint (ie, change from baseline best-corrected VA at month 12). The target sample size of 180 subjects (determined by clinical trial simulation) provided 90% power in the intent-to-treat analysis to detect a 9-letter difference between 1 or both ranibizumab dose groups and the sham-injection group in mean change from baseline VA at month 12, according to the Hochberg-Bonferroni criterion (assumptions based on results of the TAP and VIP trials and anticipated proportions of each CNV type). Safety analyses were performed using descriptive statistics and included all treated patients. All analyses were performed with SAS software (SAS Institute Inc, Cary, North Carolina, USA).

Results

Between September 7, 2004 and March 16, 2005, 184 patients were randomized 1:1:1 to receive sham injection (n = 63), 0.3 mg ranibizumab (n = 60), or 0.5 mg ranibizumab (n = 61) at 43 US investigative sites. Baseline demographic and ocular characteristics were similar across treatment groups ( Table 1 ). Groups were predominantly white and nearly two-thirds female, with a mean age of 78 years. Mean baseline VA was 53 to 56 letters (Snellen equivalent ∼20/63 to 20/80) across groups.

The first diagnosis of neovascular AMD was within the previous year for 87% of patients. Overall, 80% of patients had either occult with no classic or minimally classic CNV lesions, but occult with no classic CNV was more common in the ranibizumab groups than in the sham injection group (nearly 50% vs <33% of study eye lesions, respectively). Nearly 50% of the study eyes in each group had lesions ≥4 DA. The mean total area of CNV lesion and CNV leakage plus RPE staining at baseline was similar across groups.

Forty-six of 63 (73%), 53 of 60 (88.3%), and 54 of 61 (88.5%) patients randomized to the sham-injection, 0.3 mg, and 0.5 mg groups, respectively, completed the study through month 24 ( Table 2 ). By month 24, 48 of 184 (26.1%) patients had discontinued treatment (25 of 184 [13.6%] at month 12), usually because the patient’s condition mandated other therapeutic intervention.

At the time of the February 2006 crossover amendment, 40 of 63 (63.5%) patients in the sham-injection group who had not discontinued study treatment were eligible to cross over to receive 0.5 mg ranibizumab quarterly, and 39 (61.9%) of those received at least 1 intravitreal injection, beginning at month 14. At the time of the August 2006 rollover amendment 34 of 63 (54.0%), 43 of 60 (71.7%), and 44 of 61 (72.1%) patients in the sham-injection, 0.3 mg, and 0.5 mg groups, respectively, who had not discontinued study treatment or completed the month-24 visit, rolled over to receive 0.5 mg ranibizumab monthly, beginning month 19. Results are presented according to group assignment at randomization and include post-crossover (sham) and post-rollover (sham, 0.3 mg, 0.5 mg) data.

At month 24, VA had decreased from baseline an average of 21.4 letters in the sham group, 2.2 letters in the 0.3 mg group, and 2.3 letters in the 0.5 mg group ( P < .0001 each ranibizumab dose vs sham), with about a 19-letter difference between sham-group and treated patients. The group differences at month 24 were similar to those at month 12 ( Table 3 ). At month 24, 47 of 60 (78.2%) patients in the 0.3 mg group and 50 of 61 (82.0%) of patients in the 0.5 mg group had lost <15 letters from baseline VA compared with 26 of 63 (41.3%) sham-injection patients ( P < .0001 each ranibizumab dose vs sham) ( Figure 2 ); and 21 of 63 (33.3%) patients in the sham group had lost ≥30 VA letters from baseline. Such severe vision loss was uncommon (∼3.0%) in patients who were originally randomized to ranibizumab treatment groups. Ranibizumab groups did not differ significantly from the sham group in the proportion of patients who gained ≥15 VA letters: 3 of 63 (4.8%) in the sham-injection group, 9 of 60 (15.0%) in the 0.3 mg group, and 5 of 61 (8.2%) in the 0.5 mg group.

Ranibizumab for neovascular age-related macular degeneration trial: visual acuity outcomes at months 12 and 24 of the PIER study. Percentage of patients in each of the 3 treatment groups who (Top) lost <15 ETDRS letters, (Middle) gained ≥15 ETDRS letters, or (Bottom) had 20/200 or worse Snellen equivalent VA at months 12 and 24. Post-crossover and post-rollover data are included. Error bars are ±1 standard error of the mean. Numbers below the bars in each graph are the number of patients for whom visual acuity data were available in the corresponding group. ETDRS = Early Treatment Diabetic Retinopathy Study; * P ≤ .0002 vs sham.

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