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.Diabetes affects >220 million people worldwide (1). Diabetic macular edema (DME) is one of the major causes of visual impairment (VI) in patients with diabetic retinopathy (2,3). With diabetes prevalence estimated to double during the next 20 years (4), in the future it is likely that DME may be responsible for substantial vision loss unless treated adequately.Laser photocoagulation is the mainstay of DME treatment; it reduces the risk of moderate vision loss by ∼50%, with 3% of eyes showing vision improvement (≥3 lines), but a substantial proportion of treated eyes remain unresponsive (5). In a recent report of a 2-year study, focal/grid laser photocoagulation was more effective and had fewer side effects than intravitreal triamcinolone acetonide (6). Pars plana vitrectomy is another treatment modality investigated for DME; however, both intravitreal triamcinolone acetonide and pars plana vitrectomy have limited efficacy and/or significant side effects (7,8).There is currently a significant unmet medical need for an effective DME treatment that not only stabilizes but improves and maintains vision and has a better safety profile than the available DME treatment options. Several proinflammatory cytokines including vascular endothelial growth factor (VEGF) have been shown to be extensively involved in the development and progression of DME (9). VEGF promotes neovascularization and microvascular leakage (10). Thus, inhibiting VEGF may provide an alternative therapeutic approach in DME. Anti-VEGF agents have been extensively investigated in neovascular age-related macular degeneration (nAMD). Given that anti-VEGF drugs delivered within the vitreous could pass into the systemic circulation, VEGF inhibition could in turn produce systemic adverse effects, which may be potentially serious for diabetic patients (11). Therefore, randomized clinical trials are required to establish both the efficacy and systemic adverse effects in this population.Ranibizumab is a fully humanized monoclonal antibody fragment (Fab), which binds to multiple variants of VEGF-A (12), and is approved for the treatment of nAMD. In a pilot study (10 patients with DME), ranibizumab was effective and well tolerated in maintaining or improving best-corrected visual acuity (BCVA) and in reducing central retinal thickness (CRT) (13). The 6-month Ranibizumab for Edema of the Macula in Diabetes (READ-2) study (phase II) was the first to compare the efficacy of ranibizumab with laser photocoagulation or a combination of both in patients with VI due to DME; ranibizumab led to significant improvements in mean BCVA (7.2 letters) compared with laser photocoagulation (−0.4 letters) or the combination (3.8 letters) (14). Studies in DME have also been conducted with other anti-VEGF agents, pegaptanib and bevacizumab (15–19). Initial results from these studies are encouraging in some patients with DME; further prospective randomized clinical trials may confirm their effects in DME.We report the results of the phase II RESOLVE study in patients with VI due to DME. This study evaluated the efficacy and safety of ranibizumab compared with sham treatment over 12 months.     

Public health impact of neovascular age-related macular degeneration treatments extrapolated from visual acuity

PURPOSE: To estimate the potential public health impact of treatment with new medications intended to preserve vision in patients with neovascular age-related macular degeneration (AMD). METHODS: A Markov model was used to simulate the natural history of AMD over the lifetime of patients with diagnosed neovascular AMD from clinical trials and epidemiologic surveys. It applied to a cohort of patients aged 75 years, with newly diagnosed neovascular AMD in one eye, whose visual acuity was 0.7 logMAR. Probabilities were calculated for the risk of AMD in the remaining eye and for premature mortality. Results of the model were expressed as the duration of low vision (worse eye VA>1.0 and better eye VA>0.7 logMAR) and blindness (bilateral VA >1.0 logMAR). Health consequences of blindness and low vision were estimated for depression, hip fractures, institutionalization, and life expectancy. RESULTS: For AMD patients with a 50% probability of VA >1.0 logMAR at 1 year, in one eye, the probability of lifetime bilateral blindness was >47%. The patients would live approximately 7 years with monocular vision >1.0 logMAR and an additional 4 years with bilateral blindness and a >15% probability of depression due to AMD. Life expectancy was decreased by approximately 2 years, >90/1000 patients would sustain a new hip fracture, and 1.5% of the patients would require institutional care for visual impairment due to AMD. To achieve a defined public health outcome (visual impairment and consequent comorbidity), it was necessary for the VA effectiveness of new treatments to increase in parallel with disease severity. CONCLUSIONS: Comorbidity related to visual impairment contributes significantly to the public health impact of AMD. Aggressive lesions need highly effective treatments. Models may be used to compare the public health impact of placebo-controlled clinical trial results.     

Impact of Structural Changes on Multifocal Electroretinography in Patients With Use of Hydroxychloroquine

PurposeTo investigate the relationship between retinal structure and macular function in eyes screened for hydroxychloroquine (HCQ) toxicity.MethodsParticipants referred for hydroxychloroquine retinopathy screening with spectral domain optical coherence tomography (SD-OCT) and multifocal electroretinogram (mfERG) testing were included in the analysis. Amplitude and implicit time of mfERG N1 and P1 responses were included in the analysis. Ring ratios were computed for amplitude values as the ratio of rings 1–3:5 (R1–3:R5). A control group of healthy participants was included for comparison of SD-OCT metrics.ResultsSixty-three eyes screened for HCQ retinopathy and 30 control eyes were analyzed. The outer nuclear layer (ONL) was significantly thinner in HCQ patients in the foveal (P = 0.008), parafoveal (P < 0.0001), and perifoveal (P < 0.0001) regions. The HCQ cohort was further divided into two subgroups according to the presence of structural clinically detectable retinopathy (i.e., structural damage as detected by multimodal imaging). HCQ eyes without retinopathy had a thinner ONL thickness in the foveal (P = 0.032), parafoveal (P < 0.0001), and perifoveal (P < 0.0001) regions and a thinner inner nuclear layer (INL) in the parafoveal region (P = 0.045 versus controls). Structural changes in HCQ patients without retinopathy were significantly associated with macular function as R2:R5 ring ratio of mfERG P1 amplitude was associated with INL (P = 0.002) and ONL (P = 0.044) thicknesses, and R3:R5 ring ratio of P1 amplitude was associated with ONL thickness (P = 0.004).ConclusionsOur results suggest that structural alterations secondary to HCQ toxicity may occur in the absence of clinically detectable retinopathy, and this may reflect in an impaired macular function.     

Optical coherence tomography versus stereoscopic fundus photography or biomicroscopy for diagnosing diabetic macular edema: a systematic review

PURPOSE: To review systematically the sensitivity and specificity of optical coherence tomography (OCT) for diagnosing macular edema attributable to diabetic retinopathy compared with well-established gold standard tests such as fundus stereophotography or contact and noncontact fundus biomicroscopy. METHODS: Medline and Embase were searched electronically and six major ophthalmic journals from 1998 to 2006 were hand searched. Two reviewers independently assessed trial searches, studied quality with the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) checklist, and extracted data. The target disease was clinically significant macular edema (CSME) according to Early Treatment of Diabetic Retinopathy Study (ETDRS) criteria. A bivariate model was used to obtain summary estimates of sensitivity and specificity and fit a summary receiver operating characteristic (ROC) curve. RESULTS: Fifteen studies were considered eligible. These studies were of good quality for most items of the QUADAS checklist, but most studies did not report masking of examiners and did not describe how withdrawals and undetermined results were treated. Seven studies included healthy control subjects, which could have artificially enhanced OCT diagnostic performance. All but one study included both eyes of the patients without taking into account the within-subject correlation in statistical analyses. Sensitivity and specificity data could be extracted from only 6 of 15 studies, because appropriate cross tabulations of index and reference tests were not reported by the others. In five of these studies, central retinal thickness cutoffs between 230 and 300 microm were adopted to define abnormal OCT results and considered the central type of CSME only, whereas in one study a complex algorithm accounting for extrafoveal CSME was used. The design of one study was case-control and was excluded from the meta-analysis. The expected operating point on the summary ROC, a pooled estimate of all studies, corresponded to a sensitivity of 0.79 (95% CI: 0.71-0.86), a specificity of 0.88 (95% CI: 0.80-0.93), a positive likelihood ratio of 6.5 (95% CI: 4.0-10.7), and a negative likelihood ratio of 0.24 (95% CI: 0.17-0.32). These values suggest a good overall performance of OCT for diagnosing CSME. CONCLUSIONS: OCT performs well compared with fundus stereophotography or biomicroscopy to diagnose diabetic macular edema. The quality of reporting of such studies should be improved, and authors should present cross tabulations of index and reference test results. Data adjusted for within-subject correlation should also be provided, although this issue represents a challenge for systematic reviewers.     

Chondrosarcoma of the mobile spine: report on 22 cases

STUDY DESIGN: A retrospective review of 22 cases of chondrosarcoma arising from the mobile spine. OBJECTIVE: To evaluate the role of oncologic and surgical staging in correlating management and outcome of chondrosarcoma involving the spine. SUMMARY OF BACKGROUND DATA: Approximately 10% of chondrosarcomas arise from the mobile spine, occurring mainly in adults, particularly elderly men. The course of the disease depends on the aggressiveness of the tumor, but also is influenced by the management. Intralesional surgery is followed almost constantly by local recurrence even with adjuvant therapy. METHODS: All charts, radiographs, and images were reviewed. The composite information provided by this review allowed for oncologic and surgical staging of the reviewed cases. According to Enneking criteria, the surgical procedures were defined as curettage (piecemeal excision) or en blocexcision. The margins were submitted to histologic study and reported as intralesional, marginal, or wide. - As primary management, 10 intralesional curettages (follow-up period, 2-119 months; average, 61 months) and 12 en bloc excisions (follow-up period, 39-207 months; average, 97 months) were performed. A total of 33 procedures were performed, including the management of the recurrences (18 curettages and 15 en bloc excisions: one for soft tissue recurrence). A clinical and radiographic follow-up period of of 2 to 236 months (average, 81 months; minimal follow-up period for survivors, 30 months; average follow-up period for survivors, 115 months) was available for all the patients. RESULTS: Three recurrences occurred in 14 patients treated by en bloc excision at onset or for recurrence, two in cases of histologically proven contaminated or intralesional margins. All but one patient were alive at final follow-up evaluation. Conversely, all the patients treated by one or more curettages (with or without adjuvant radiation therapy) had at least one recurrence, and 8 of 10 of these patients died of the disease. At final follow-up evaluation, nine patients had died of the disease; nine were continuously disease free (but one had died of another unrelated malignancy); and four were symptom free after management for recurrences (one was found alive 155 months after a soft-tissue metastasis en-bloc excision). CONCLUSIONS: En bloc excision, with wide or marginal histologic margins, is the suggested management for chondrosarcomas of the spine. Early diagnosis and careful surgical staging and planning are necessary for conducting adequate management. However, tumor contamination of the specimen margins, even in a small area, or spreading of the tumor myxoid content can worsen the prognosis.     

Vitreous laser absorption following fluorescein angiography in diabetic patients

Background: Sodium fluorescein staining of the vitreous following fluorescein angiography may interact with laser photocoagulation. Methods: We evaluated the laser absorption by fluorescein in the vitreous when photocoagulation is performed following fluorescein angiography in 15 eyes of nine diabetic patients. Axial fluorescein concentration in the vitreous was measured by a scanning vitreal fluorophotometer. The amount of light absorbed by the fluorescein within the vitreous was calculated according to the Lambert-Beer law. Results: The mean fluorescein concentration ranged from 2.93 ng cm^–3 to 105.16 ng cm^–3 at 1 h after injection of fluorescein and from 8.03 to 188.56 ng cm^–3 after 4 h. Maximum laser absorption at 488 nm ranged from 6.79% (after 1 h) to 14.53% (after 4 h); at 514.5 nm it ranged from 0.96% to 2.14%; at 532 nm it ranged from 0.03% to 0.07%. At >550 nm, laser absorption was found to be negligible. Conclusions: In order to optimize the effect of photocoagulation, especially during long photocoagulation sessions, argon blue laser (488 nm) should be avoided following fluorescein angiography. Argon green laser (514.5 nm) should be used within 1 h after fluorescein injection. Frequency-doubled Nd:YAG laser (532 nm), krypton laser (647 nm) or semiconductor diode laser (810 nm) may be used at any time.Presented at the Association for REsearch in Vision and Ophthalmology Annual Meeting, Sarasota, Florida, 1–6 May 1994