Karola Beckmann

The DA VINCI Study: Phase 2 Primary Results of VEGF Trap-Eye in Patients with Diabetic Macular Edema

PURPOSE To determine whether different doses and dosing regimens of intravitreal vascular endothelial growth factor (VEGF) Trap-Eye are superior to focal/grid photocoagulation in eyes with diabetic macular edema (DME). DESIGN Multicenter, randomized, double-masked, phase 2 clinical trial. PARTICIPANTS A total of 221 diabetic patients with clinically significant macular edema involving the central macula. METHODS Patients were assigned to 1 of 5 treatment regimens: 0.5 mg VEGF Trap-Eye every 4 weeks; 2 mg VEGF Trap-Eye every 4 weeks; 2 mg VEGF Trap-Eye for 3 initial monthly doses and then every 8 weeks; 2 mg VEGF Trap-Eye for 3 initial monthly doses and then on an as-needed (PRN) basis; or macular laser photocoagulation. Assessments were completed at baseline and every 4 weeks thereafter. MAIN OUTCOME MEASURES Mean change in visual acuity and central retinal thickness (CRT) at 24 weeks. RESULTS Patients in the 4 VEGF Trap-Eye groups experienced mean visual acuity benefits ranging from +8.5 to +11.4 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters versus only +2.5 letters in the laser group (P ≤ 0.0085 for each VEGF Trap-Eye group vs. laser). Gains from baseline of 0+, 10+, and 15+ letters were seen in up to 93%, 64%, and 34% of VEGF Trap-Eye groups versus up to 68%, 32%, and 21% in the laser group, respectively. Mean reductions in CRT in the 4 VEGF Trap-Eye groups ranged from -127.3 to -194.5 μm compared with only -67.9 μm in the laser group (P = 0.0066 for each VEGF Trap-Eye group vs. laser). VEGF Trap-Eye was generally well tolerated. Ocular adverse events in patients treated with VEGF Trap-Eye were generally consistent with those seen with other intravitreal anti-VEGF agents. CONCLUSIONS Intravitreal VEGF Trap-Eye produced a statistically significant and clinically relevant improvement in visual acuity when compared with macular laser photocoagulation in patients with DME.

Survival in MS A randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial

Objective: To examine the effects of interferon beta (IFNβ)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments. Methods: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNβ-1b 250 μg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary. Results: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNβ-1b 250 μg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314–0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNβ-1b 250 μg–treated patients (46.0% among IFNβ-1b 50 μg–treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect. Conclusions: There was a significant survival advantage in this cohort of patients receiving early IFNβ-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNβ-1b benefit on all-cause mortality. Classification of Evidence: This study provides Class III evidence that early treatment with IFNβ-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.

Vascular Endothelial Growth Factor Trap-Eye for Macular Edema Secondary to Central Retinal Vein Occlusion: Six-Month Results of the Phase 3 COPERNICUS Study

OBJECTIVE To assess the efficacy and safety of intravitreal vascular endothelial growth factor (VEGF) Trap-Eye in eyes with macular edema secondary to central retinal vein occlusion (CRVO). DESIGN Multicenter, randomized, prospective, controlled trial. PARTICIPANTS One hundred eighty-nine eyes with macular edema secondary to CRVO. METHODS Eyes were randomized 3:2 to receive VEGF Trap-Eye 2 mg or sham injection monthly for 6 months. MAIN OUTCOME MEASURES The proportion of eyes with a ≥15-letter gain or more in best-corrected visual acuity (BCVA) at week 24 (primary efficacy end point), mean changes in BCVA and central retinal thickness (CRT), and proportion of eyes progressing to neovascularization of the anterior segment, optic disc, or elsewhere in the retina. RESULTS At week 24, 56.1% of VEGF Trap-Eye treated eyes gained 15 letters or more from baseline versus 12.3% of sham-treated eyes (P<0.001). The VEGF Trap-Eye treated eyes gained a mean of 17.3 letters versus sham-treated eyes, which lost 4.0 letters (P<0.001). Central retinal thickness decreased by 457.2 μm in eyes treated with VEGF Trap-Eye versus 144.8 μm in sham-treated eyes (P<0.001), and progression to any neovascularization occurred in 0 and 5 (6.8%) of eyes treated with VEGF Trap-Eye and sham-treated eyes, respectively (P = 0.006). Conjunctival hemorrhage, reduced visual acuity, and eye pain were the most common adverse events (AEs). Serious ocular AEs were reported by 3.5% of VEGF Trap-Eye patients and 13.5% of sham patients. Incidences of nonocular serious AEs generally were well balanced between both groups. CONCLUSIONS At 24 weeks, monthly intravitreal injection of VEGF Trap-Eye 2 mg in eyes with macular edema resulting from CRVO improved visual acuity and CRT, eliminated progression resulting from neovascularization, and was associated with a low rate of ocular AEs related to treatment.

VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study

Aim To evaluate intravitreal VEGF Trap-Eye (VTE) in patients with macular oedema secondary to central retinal vein occlusion (CRVO). Methods In this double-masked study, 177 patients were randomised (3:2 ratio) to intravitreal injections of VTE 2 mg or sham procedure every 4 weeks for 24 weeks. Best-corrected visual acuity was evaluated using the Early Treatment Diabetic Retinopathy Study chart. Central retinal thickness (CRT) was measured with optical coherence tomography. Results From baseline until week 24, more patients receiving VTE (60.2%) gained ≥15 letters compared with those receiving sham injections (22.1%) (p<0.0001). VTE patients gained a mean of 18.0 letters compared with 3.3 letters with sham injections (p<0.0001). Mean CRT decreased by 448.6 and 169.3 µm in the VTE and sham groups (p<0.0001). The most frequent ocular adverse events in the VTE arm were typically associated with the injection procedure or the underlying disease, and included eye pain (11.5%), increased intraocular pressure (9.6%) and conjunctival haemorrhage (8.7%). Conclusions VTE 2 mg every 4 weeks was efficacious in CRVO with an acceptable safety profile. Vision gains with VTE were significantly higher than with observation/panretinal photocoagulation if needed. Based on these data, VTE may provide a new treatment option for CRVO.

Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon β-1b trial in multiple sclerosis

Background Evaluating the long term benefit of therapy in multiple sclerosis (MS) is challenging. Although randomised controlled trials (RCTs) demonstrate therapeutic benefits on short term outcomes, the relationship between these outcomes and late disability is not established. Methods In a patient cohort from the pivotal interferon β-1b trial, the value of clinical and MRI measures were analysed, both at baseline and during the RCT, for predicting long term physical and cognitive outcome. Results Baseline disability correlated with both physical (R2=0.22; p<0.0001) and cognitive (R2=0.12; p<0.0001) outcome after 16 years. Accrual of disability during the RCT (R2=0.12; p<0.0001) and annualised relapse rates during the trial correlated with physical outcome (R2=0.12; p<0.0001) but not with cognition. In contrast, baseline MRI measures of atrophy and lesion burden correlated with cognitive (R2=0.21; p<0.0001), but not with physical, outcome. Accumulation of plaque burden measured by MRI did not correlate with late physical disability or with cognitive outcome. Multivariate regression analysis using stepwise elimination demonstrated that baseline variables contributed independently to predicting long term outcomes while trial outcome variables contributed little. Overall, and considerably dependent on baseline measures, the models developed by this method accounted for approximately half of the variance in long term cognitive and disability outcome. Conclusions Although on-trial change in some short term clinical measures correlated with long term physical and disability outcomes, the proportion of the variance explained by single commonly employed on-study variables was often small or undetectable. Better correlations were observed for several baseline measures, suggesting that long term outcome in MS may be largely determined early in the disease course. Trial registration number http://Clinical Trials.gov, study registration NCT00206635.

Cross-sectional study assessing long-term safety of interferon-β-1b for relapsing-remitting MS

Objective: The 16-Year Long-Term Follow-Up (LTF) to the pivotal interferon-β-1b (IFNβ-1b) trial explored clinical, MRI, cognitive, and patient-reported outcomes. Here, we report the safety assessments. Methods: In the pivotal study, 372 patients were randomized to placebo (n = 123), IFNβ-1b 50 μg (n = 125), or IFNβ-1b 250 μg (n = 124) subcutaneously every other day for up to 5 years. Sixteen years later, patients were asked to participate in this cross-sectional follow-up study. No particular therapy was stipulated during follow-up. Adverse events experienced since the pivotal trial were recorded. Neutralizing antibodies (NAbs) to IFNβ-1b were measured using the myxovirus protein A induction assay. Statistical analyses were descriptive. Results: In total, 88.2% of patients (328/372) were identified. Some centers achieved 100% ascertainment, obviating selection bias. Treatment-related adverse events (e.g., leukopenia and liver and thyroid dysfunction) reported by LTF participants were in keeping with those previously established. Based on a follow-up period that includes 2,000 patient-years of IFNβ-1b treatment, no new adverse events were observed that were associated with long-term IFNβ-1b exposure. By LTF, NAbs to IFNβ-1b disappeared in the majority (76%) of NAb-positive patients. NAb status during the pivotal study appeared to have no impact on long-term clinical and MRI outcomes. There were more deaths among patients assigned to placebo in the pivotal study (20/109 [18.3%]) compared with patients who received IFNβ-1b 50 μg (9/108 [8.3%]) or IFNβ-1b 250 μg (6/111 [5.4%]). Conclusion: The results from the 16-Year Long-Term Follow-Up study support the long-term safety of interferon-β-1b therapy in multiple sclerosis. Classification of evidence: This study provides Class III evidence that patients with relapsing-remitting MS taking IFNβ-1b 50 μg or 250 μg subcutaneously every other day for up to 5 years, with subsequent unspecified treatment, have fewer deaths after 16 years of follow-up than similar patients on placebo for up to 5 years, with subsequent unspecified treatment (risk difference 11.5%, 95% confidence interval 4–19).

Interferon β-1b-neutralizing antibodies 5 years after clinically isolated syndrome.

Objective: To determine the frequency and consequences of neutralizing antibodies (NAbs) in patients with a first event suggestive of multiple sclerosis (MS) treated with interferon β-1b (IFNβ-1b). Methods: In the Betaseron/Betaferon in Newly Emerging MS For Initial Treatment (BENEFIT) study, patients were randomly assigned to 250 μg IFNβ-1b (Betaferon) or placebo subcutaneously every other day for 2 years or until diagnosis of clinically definite MS (CDMS). Patients were then offered open-label IFNβ-1b for up to 5 years. NAb status was assessed every 6 months by the myxovirus protein A induction assay. A titer >20 NU/mL was considered NAb-positive, with low (≥20–100 NU/mL), medium (≥100–400 NU/mL), and high (≥400 NU/mL) titer categories. Here we examine early-treated patients, who received IFNβ-1b for up to 5 years. Results: NAbs were measured in 277 of 292 early-treated patients and detected at least once in 88 (31.8%) patients, with 53 (60.2%) reverting to NAb negativity by year 5. Time to CDMS, time to confirmed disability progression, and annualized relapse rate did not differ between NAb-positive and NAb-negative patients or between periods of NAb positivity vs NAb negativity within patients. Increases in newly active lesion number and T2 lesion volume and conversion to McDonald MS were associated with NAb positivity and were more pronounced with higher titers. Conclusions: Although NAb positivity was associated with increased brain MRI activity, no discernible effects on clinical outcomes were found. This finding may reflect the greater power of MRI compared with clinical outcomes to detect the treatment effects of IFNβ-1b and may also result from temporal changes in NAb titers and biology.

Interferon β-1b and glatiramer acetate effects on permanent black hole evolution

Objective: To compare interferon β-1b (IFNβ-1b) and glatiramer acetate (GA) on new lesion (NL) (gadolinium-enhancing, new T2) evolution into permanent black holes (PBH)—a marker of irreversible tissue damage—in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: BEYOND was a large, phase III, clinical trial comparing IFNβ-1b 250 μg, IFNβ-1b 500 μg, and GA (2:2:1). Patient scans were reexamined post hoc for PBH in a rater-blinded manner. Two predefined coprimary endpoints compared IFNβ-1b 250 μg with GA: first, number of PBH per patient at year 2 evolving from year 1 NL, then proportion of year 1 NL evolving into PBH at year 2. IFNβ-1b 500 μg and GA were compared in an exploratory fashion. Results: Approximately 90% (1,957/2,244) of patients had NL at year 1 with follow-up at year 2. Mean numbers of PBH per patient at year 2 evolving from year 1 NL were lower for IFNβ-1b 250 μg than GA (0.30 vs 0.43; p = 0.0451). The proportion of NL evolving into PBH was similar (IFNβ-1b 250 μg vs GA: 21.6% vs 23.5%; p > 0.20). For IFNβ-1b 500 μg, both the mean PBH number per patient at year 2 evolving from year 1 NL (0.26 vs 0.43; p = 0.0037) and proportion of NL evolving into PBH (16.3% vs 23.5%; p = 0.0409) were lower relative to GA. Conclusion: IFNβ-1b affected PBH development to a similar or better extent than GA. IFNβ-1b favorably influences an MRI outcome indicative of permanent tissue destruction in the brains of patients with multiple sclerosis. Classification of evidence: This study provides Class III evidence that IFNβ-1b is associated with a reduction in MRI PBH formation and evolution compared with GA between years 1 and 2 of treatment.

Establishing Long-Term Efficacy in Chronic Disease: Use of Recursive Partitioning and Propensity Score Adjustment to Estimate Outcome in MS

Context Establishing the long-term benefit of therapy in chronic diseases has been challenging. Long-term studies require non-randomized designs and, thus, are often confounded by biases. For example, although disease-modifying therapy in MS has a convincing benefit on several short-term outcome-measures in randomized trials, its impact on long-term function remains uncertain. Objective Data from the 16-year Long-Term Follow-up study of interferon-beta-1b is used to assess the relationship between drug-exposure and long-term disability in MS patients. Design/Setting To mitigate the bias of outcome-dependent exposure variation in non-randomized long-term studies, drug-exposure was measured as the medication-possession-ratio, adjusted up or down according to multiple different weighting-schemes based on MS severity and MS duration at treatment initiation. A recursive-partitioning algorithm assessed whether exposure (using any weighing scheme) affected long-term outcome. The optimal cut-point that was used to define “high” or “low” exposure-groups was chosen by the algorithm. Subsequent to verification of an exposure-impact that included all predictor variables, the two groups were compared using a weighted propensity-stratified analysis in order to mitigate any treatment-selection bias that may have been present. Finally, multiple sensitivity-analyses were undertaken using different definitions of long-term outcome and different assumptions about the data. Main Outcome Measure Long-Term Disability. Results In these analyses, the same weighting-scheme was consistently selected by the recursive-partitioning algorithm. This scheme reduced (down-weighted) the effectiveness of drug exposure as either disease duration or disability at treatment-onset increased. Applying this scheme and using propensity-stratification to further mitigate bias, high-exposure had a consistently better clinical outcome compared to low-exposure (Cox proportional hazard ratio = 0.30–0.42; p<0.0001). Conclusions Early initiation and sustained use of interferon-beta-1b has a beneficial impact on long-term outcome in MS. Our analysis strategy provides a methodological framework for bias-mitigation in the analysis of non-randomized clinical data. Trial Registration Clinicaltrials.gov NCT00206635

Neutralizing antibodies to interferon beta-1b multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial

Background: The frequency and impact of neutralizing antibodies (NAbs) to interferon beta-1b (IFNβ-1b) on clinical and radiographic outcomes is controversial. Objective: To assess NAb impact in the BEYOND study. Methods: 2244 patients were randomized (2:2:1) to receive IFNβ-1b, either 250 or 500 µg, or glatiramer acetate, 20 mg, and observed for 2–3.5 years. NAb titers were determined every 6 months. A titer ≥20 NU/ml was considered NAb positive. Efficacy was compared between NAb-positive and NAb-negative patients, using comprehensive statistical analyses, taking into account the delayed appearance of NAbs, the time-dependent changes in the relapse rate, spontaneous reversions to NAb-negative status, NAb-titer level, and also adjusting for baseline factors. Results: In the IFNβ-1b 250 µg group, NAb-positive titers were detected (≥ once) in 319 patients (37.0%); of these, 112 (35.1%) reverted to NAb-negative status. In the IFNβ-1b 500 µg group, 340 patients (40.7%) became NAb-positive and 119 (35.0%) reverted to NAb-negative status. In both IFNβ groups, especially the 250 µg arm, NAb-positive status was not associated with a convincing impact on any clinical outcome measure by any statistical analysis. By contrast, in both IFNβ groups, NAbs were associated with a very consistent deleterious impact on most MRI outcomes. Conclusion: There was a notable dissociation between the impact of NAbs on MRI and clinical outcomes. On MRI measures, the impact was consistent and convincing, whereas on clinical measures a negative impact of NAbs was not found. The basis for this clinico-radiographic paradox is unknown but it suggests that the relationship between NAbs and the therapeutic effects of IFNβ-1b is complex.