Margarita Gekkieva

Safety and Efficacy of Ranibizumab in Diabetic Macular Edema (RESOLVE Study) A 12-month, randomized, controlled, double-masked, multicenter phase II study

OBJECTIVE The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center. RESEARCH DESIGN AND METHODS This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age >18 years, type 1 or 2 diabetes, central retinal thickness [CRT] ≥300 μm, and best corrected visual acuity [BCVA] of 73–39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n = 51 each) or sham (n = 49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n = 151, patients receiving ≥1 injection). RESULTS At month 12, mean ± SD BCVA improved from baseline by 10.3 ± 9.1 letters with ranibizumab and declined by 1.4 ± 14.2 letters with sham (P < 0.0001). Mean CRT reduction was 194.2 ± 135.1 μm with ranibizumab and 48.4 ± 153.4 μm with sham (P < 0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P < 0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab. CONCLUSIONS Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety.

Efficacy and Safety of Monthly versus Quarterly Ranibizumab Treatment in Neovascular Age-related Macular Degeneration: The EXCITE Study

OBJECTIVE To demonstrate noninferiority of a quarterly treatment regimen to a monthly regimen of ranibizumab in patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN A 12-month, multicenter, randomized, double-masked, active-controlled, phase IIIb study. PARTICIPANTS Patients with primary or recurrent subfoveal CNV secondary to AMD (353 patients), with predominantly classic, minimally classic, or occult (no classic component) lesions. INTERVENTION Patients were randomized (1:1:1) to 0.3 mg quarterly, 0.5 mg quarterly, or 0.3 mg monthly doses of ranibizumab. Treatment comprised of a loading phase (3 consecutive monthly injections) followed by a 9-month maintenance phase (either monthly or quarterly injection). MAIN OUTCOME MEASURES Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline to month 12 and the incidence of adverse events (AEs). RESULTS In the per-protocol population (293 patients), BCVA, measured by Early Treatment Diabetic Retinopathy Study-like charts, increased from baseline to month 12 by 4.9, 3.8, and 8.3 letters in the 0.3 mg quarterly (104 patients), 0.5 mg quarterly (88 patients), and 0.3 mg monthly (101 patients) dosing groups, respectively. Similar results were observed in the intent-to-treat (ITT) population (353 patients). The mean decrease in CRT from baseline to month 12 in the ITT population was -96.0 μm in 0.3 mg quarterly, -105.6 μm in 0.5 mg quarterly, and -105.3 μm in 0.3 mg monthly group. The most frequent ocular AEs were conjunctival hemorrhage (17.6%, pooled quarterly groups; 10.4%, monthly group) and eye pain (15.1%, pooled quarterly groups; 20.9%, monthly group). There were 9 ocular serious AEs and 3 deaths; 1 death was suspected to be study related (cerebral hemorrhage; 0.5 mg quarterly group). The incidences of key arteriothromboembolic events were low. CONCLUSIONS After 3 initial monthly ranibizumab injections, both monthly (0.3 mg) and quarterly (0.3 mg/0.5 mg) ranibizumab treatments maintained BCVA in patients with CNV secondary to AMD. At month 12, BCVA gain in the monthly regimen was higher than that of the quarterly regimens. The noninferiority of a quarterly regimen was not achieved with reference to 5.0 letters. The safety profile was similar to that reported in prior ranibizumab studies.

The SECURE study:long-term safety of Ranibizumab 0.5 mg in neovascular age-related macular degeneration

OBJECTIVE To evaluate long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular age-related macular degeneration (nAMD). DESIGN Twenty-four-month, open-label, multicenter, phase IV extension study. PARTICIPANTS Two hundred thirty-four patients previously treated with ranibizumab for 12 months in the EXCITE/SUSTAIN study. METHODS Ranibizumab 0.5 mg administered at the investigators discretion as per the European summary of product characteristics 2007 (SmPC, i.e., ranibizumab was administered if a patient experienced a best-corrected visual acuity [BCVA] loss of >5 Early Treatment Diabetic Retinopathy Study letters measured against the highest visual acuity [VA] value obtained in SECURE or previous studies [EXCITE and SUSTAIN], attributable to the presence or progression of active nAMD in the investigators opinion). MAIN OUTCOME MEASURES Incidence of ocular or nonocular adverse events (AEs) and serious AEs, mean change in BCVA from baseline over time, and the number of injections. RESULTS Of 234 enrolled patients, 210 (89.7%) completed the study. Patients received 6.1 (mean) ranibizumab injections over 24 months. Approximately 42% of patients had 7 or more visits at which ranibizumab was not administered, although they had experienced a VA loss of more than 5 letters, indicating either an undertreatment or that factors other than VA loss were considered for retreatment decision by the investigator. The most frequent ocular AEs (study eye) were retinal hemorrhage (12.8%; 1 event related to study drug), cataract (11.5%; 1 event related to treatment procedure), and increased intraocular pressure (6.4%; 1 event related to study drug). Cataract reported as serious due to hospitalization for cataract surgery occurred in 2.6% of patients; none was suspected to be related to study drug or procedure. Main nonocular AEs were hypertension and nasopharyngitis (9.0% each). Arterial thromboembolic events were reported in 5.6% of the patients. Five (2.1%) deaths occurred during the study, none related to the study drug or procedure. At month 24, mean BCVA declined by 4.3 letters from the SECURE baseline. CONCLUSIONS The SECURE study showed that ranibizumab administered as per a VA-guided flexible dosing regimen recommended in the European ranibizumab SmPC at the investigators discretion was well tolerated over 2 years. No new safety signals were identified in patients who received ranibizumab for a total of 3 years. On average, patients lost BCVA from the SECURE study baseline, which may be the result of disease progression or possible undertreatment. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

A 2-Year, Phase IV, Multicentre, Observational Study of Ranibizumab 0.5 mg in Patients with Neovascular Age-Related Macular Degeneration in Routine Clinical Practice: The EPICOHORT Study

Purpose. To assess the safety profile of ranibizumab 0.5 mg in patients with neovascular age-related macular degeneration (nAMD) in routine clinical practice. Methods. This 2-year, multicentre, observational study was conducted to capture real-world early practice and outcomes across Europe, shortly after European licensing of ranibizumab for nAMD. Being observational in nature, the study did not impose diagnostic/therapeutic interventions/visit schedule. Patients were to be treated as per the EU summary of product characteristics (SmPC) in effect during the study. Key outcome measures were incidence of selected adverse events (AEs), treatment exposure, bilateral treatment, compliance to the EU SmPC, and best-corrected visual acuity (BCVA) over 2 years. Results. 755 of 770 patients received treatment. Ranibizumab was generally well tolerated with low incidence of selected AEs (0%–1.9%). Patients received 6.2 (mean) injections and 133 patients received bilateral treatment over 2 years. Protocol deviation to treatment compliance was reported in majority of patients. The observed decline in mean BCVA (Month 12, +1.5; Month 24, –1.3 letters) may be associated with undertreatment as suggested by BCVA subgroup analysis. Conclusion. The EPICOHORT study conducted in routine clinical practice reinforces the well-established safety profile of ranibizumab in nAMD. In early European practice it appeared that the nAMD patients were undertreated.

VISUAL ACUITY OUTCOMES OF RANIBIZUMAB TREATMENT IN PATHOLOGIC MYOPIC EYES WITH MACULAR RETINOSCHISIS AND CHOROIDAL NEOVASCULARIZATION.

Purpose: To investigate visual and morphological outcome in eyes with MRS and choroidal neovascularization (CNV) secondary to pathologic myopia treated with intravitreal (IVT) ranibizumab. Methods: Post hoc analysis of the patients included in the RADIANCE trial (n = 277) was performed to evaluate the impact of MRS on the functional outcome in patients with myopic choroidal neovascularization (mCNV) undergoing intravitreal ranibizumab injections. Results: Prevalence of MRS in pathologic myopia population is 6%. Respective patients were generally older than patients without MRS. Study eyes with MRS at baseline (BL) showed an initially poor treatment response after 3 months (mean change in best corrected visual acuity (BCVA) was 2.8 ± 12.4 letters, P = 0.009). After 12 months of treatment however, the mean change in BCVA was 7.1 ± 14.5 early treatment diabetic retinopathy study (ETDRS) letters (P = 0.025). Patients with MRS at baseline received more intravitreal injections than the other RADIANCE patients without MRS (MRS, n = 15 eyes: 5.8 ± 2.1 vs. RADIANCE non-MRS [n = 207 eyes]: 4.0 ± 2.9; P = 0.0001). Conclusion: Improvement of visual acuity is delayed and reduced after 3 months intravitreal ranibizumab in eyes with MRS and myopic choroidal neovascularization compared to eyes without MRS. More ranibizumab injections are needed in eyes with MRS to gain comparable BCVA at Month 12.