Baseline visual acuity strongly predicts visual acuity gain in patients with diabetic macular edema following anti-vascular endothelial growth factor treatment across trials.

OBJECTIVE: This study was designed to evaluate the correlation of baseline visual acuity (VA) with VA outcome in response to anti-vascular endothelial growth factor (VEGF) in diabetic macular edema using a retrospective analysis of nine clinical trials. The result will help assess the relevance of VA gain comparisons across trials. METHODS: A correlation analysis was performed between mean baseline VA and VA gain at month 12 for 1,616 diabetic macular edema patients across nine randomized clinical trials (RESOLVE, RISE, RIDE, RESTORE, RETAIN, DRCR.net Protocol I, DA VINCI, VIVID, VISTA) with anti-VEGF treatment regimens ranibizumab 0.5 mg and aflibercept 2 mg. RESULTS: The mean baseline VA ranged from 56.9 to 64.8 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. The mean VA gain at month 12 ranged from 6.8 to 13.1 ETDRS letters across trials. There was a strong inverse correlation between mean baseline VA and VA gain at month 12 (r=-0.85). The mean VA at 12 months plateaued at ~70 (68.5-73.0) ETDRS letters (20/40 Snellen VA equivalent) for the anti-VEGF treatment groups from all trials, regardless of dosing regimens and agents. CONCLUSION: Cross-trial comparisons based on changes in best-corrected visual acuity should be done cautiously and only after adjusting for best-corrected visual acuity at baseline. Furthermore, the total VA afforded by treatment appears to be subject to a plateau effect, which warrants further exploration.

Severe Ocular Inflammation Following Ranibizumab or Aflibercept Injections for Age-Related Macular Degeneration: A Retrospective Claims Database Analysis.

PURPOSE: Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents including ranibizumab and aflibercept are used to treat patients with ocular disorders such as neovascular age-related macular degeneration (nAMD); however, the injections are associated with rare instances of severe ocular inflammation. This study compared severe ocular inflammation rates in patients treated with ranibizumab versus aflibercept. METHODS: United States physician-level claims data covering an 18-month period for each therapy were analyzed. The primary analysis compared severe ocular inflammation event rates per 1000 injections. Sensitivity and subgroup analyses evaluated the impact of factors including intraocular surgery, intravitreal antibiotic administration, and previous intravitreal injections. RESULTS: The analysis included 432,794 injection claims (ranibizumab n = 253,647, aflibercept n = 179,147); significantly, more unique severe ocular inflammation events occurred in patients receiving aflibercept than ranibizumab (1.06/1000 injections, 95% confidence interval [CI], 0.91-1.21, vs. 0.64/1000 injections, 95% CI 0.54-0.74; p < 0.0001). Comparable results were observed for analyses of patients who had undergone glaucoma or cataract surgeries, had antibiotic-associated endophthalmitis, had non-antibiotic-associated endophthalmitis, and were non-treatment-naive. In contrast, no significant differences in severe ocular inflammation claims were recorded in treatment-naive patients who had no record of anti-VEGF treatment in the 6 months preceding the index claim. No significant change occurred in the rate of severe ocular inflammation claims over time following ranibizumab treatment. CONCLUSIONS: Severe ocular inflammation was more frequent following intravitreal injection with aflibercept than with ranibizumab during routine clinical use in patients with nAMD. This highlights the importance of real-world, post-approval, observational monitoring of novel medicines, and may aid clinical decision-making, including choice of anti-VEGF agent.

Effect of switching from intramuscular interferon ß-1a to oral fingolimod on time to relapse in patients with relapsing-remitting multiple sclerosis enrolled in a 1-year extension of TRANSFORMS.

BACKGROUND: In the absence of controlled, parallel-group studies, statistical methods developed to estimate treatment effects in patients receiving alternative/rescue treatment in clinical trials may be used to estimate the effects of multiple sclerosis (MS) therapy switch using available clinical trial data. OBJECTIVE: To use TRANSFORMS data and parametric models to assess the time to first confirmed relapse in MS patients who switched from intramuscular interferon ß-1a (IFNß-1a IM) 30 µg/mL once weekly to oral fingolimod 0.5 or 1.25mg once daily vs. remaining on IFNß-1a IM. METHODS: Post hoc analyses were conducted using data from the intent-to-treat population. The Branson and Whitehead switch model with iterative parameter estimation was used to estimate the ratio of the observed time to first confirmed relapse over the estimated time. RESULTS: Log-linear regression model results showed that fingolimod 0.5 and 1.25mg prolonged time to relapse, with an estimated median time to first relapse of 5.07 years (P=0.0026 vs. IFNß-1a IM) and 4.11 years (P=0.0113), respectively, versus 2.26 years with IFNß-1a IM. The estimated ratio of observed time to first confirmed relapse to the estimated time had the patient remained on IFNß-1a IM was 2.09 (95% CI, 1.45-3.04) for switching to fingolimod 0.5mg and 1.84 (95% CI, 1.30-2.65) for switching to fingolimod 1.25mg. CONCLUSION: During the extension, time to first confirmed relapse was approximately doubled in patients switching from IFNß-1a IM to fingolimod. These analytic methods may be useful in evaluating treatment switch effects in clinical trials with extension data.

Impact of a switch to fingolimod versus staying on glatiramer acetate or beta interferons on patient- and physician-reported outcomes in relapsing multiple sclerosis: post hoc analyses of the EPOC trial.

BACKGROUND: The Evaluate Patient OutComes (EPOC) study assessed physician- and patient-reported outcomes in individuals with relapsing multiple sclerosis who switched directly from injectable disease-modifying therapy (iDMT; glatiramer acetate, intramuscular or subcutaneous interferon beta-1a, or interferon beta-1b) to once-daily, oral fingolimod. Post hoc analyses evaluated the impact of a switch to fingolimod versus staying on each of the four individual iDMTs. METHODS: Overall, 1053 patients were randomized 3:1 to switch to fingolimod or remain on iDMT. The primary endpoint was the change in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction score. Secondary endpoints included changes in scores for TSQM Effectiveness, Side Effects and Convenience subscales, Beck Depression Inventory-II (BDI-II), Fatigue Severity Scale (FSS), Patient-Reported Outcome Indices for Multiple Sclerosis (PRIMUS) Activities, 36-item Short-Form Health Survey (SF-36) Mental Component Summary (MCS) and Physical Component Summary (PCS) and mean investigator-reported Clinical Global Impressions of Improvement (CGI-I). All outcomes were evaluated after 6 months of treatment. RESULTS: Changes in TSQM Global Satisfaction scores were superior after a switch to fingolimod when compared with scores in patients remaining on any of the iDMTs (all p <0.001). Likewise, all TSQM subscale scores improved following a switch to fingolimod (all p <0.001), except when compared with glatiramer acetate for the TSQM Side Effects subscale (p = 0.111). FSS scores were found to be superior for fingolimod versus remaining on subcutaneous interferon beta-1a and interferon beta-1b, BDI-II scores were significantly improved for fingolimod except for the comparison with intramuscular interferon beta-1a, and SF-36 scores were superior with fingolimod compared with remaining on interferon beta-1b (MCS and PCS; p = 0.030 and p = 0.022, respectively) and subcutaneous interferon beta-1a (PCS only; p = 0.024). Mean CGI-I scores were superior with fingolimod when compared with continuing treatment with any of the iDMTs (all p <0.001). CONCLUSIONS: After 6 months, a switch to fingolimod showed superiority compared with remaining on each iDMT for a range of patient- and physician-reported outcomes, including global satisfaction with treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01216072 .

Characteristics influencing therapy switch behavior after suboptimal response to first-line treatment in patients with multiple sclerosis.

BACKGROUND: Factors driving disease-modifying therapy (DMT) switch behavior are not well understood. OBJECTIVE: The objective of this paper is to identify patient characteristics and clinical events predictive of therapy switching in patients with suboptimal response to DMT. METHODS: This retrospective study analyzed patients with relapsing-remitting multiple sclerosis (MS) and a suboptimal response to initial therapy with either interferon ß or glatiramer acetate. Suboptimal responders were defined as patients with ≥1 MS event (clinical relapse, worsening disability, or MRI worsening) while on DMT. Switchers were defined as those who changed DMT within six to 12 months after the MS event. RESULTS: Of 606 suboptimal responders, 214 (35.3%) switched therapy. Switchers were younger at symptom onset (p = 0.012), MS diagnosis (p = 0.004), DMT initiation (p < 0.001), and first MS event (p = 0.011) compared with nonswitchers. Compared with one relapse alone, MRI worsening alone most strongly predicted switch behavior (odds ratio 6.3; 95% CI, 3.1-12.9; p < 0.001), followed by ≥2 relapses (2.8; 95% CI, 1.1-7.3; p = 0.040), EDSS plus MRI worsening (2.5; 95% CI, 1.1-5.9; p = 0.031) and EDSS worsening alone (2.2; 95% CI, 1.2-4.1; p = 0.009). CONCLUSIONS: Younger patients with disease activity, especially MRI changes, are more likely to have their therapy switched sooner than patients who are older at the time of MS diagnosis and DMT initiation.

First-dose effects of fingolimod after switching from injectable therapies in the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis.

BACKGROUND: In pivotal phase 3 studies, fingolimod treatment initiation was associated with a transient reduction in heart rate (HR). Atrioventricular (AV) conduction delays, which were typically asymptomatic, were detected in a small minority of patients. OBJECTIVE: We report the first-dose effects of fingolimod in patients who switched from injectable therapies during the Evaluate Patient OutComes (EPOC) study (ClinicalTrials.gov Identifier: NCT01216072). METHODS: This was a phase 4, 6-month, randomized, active-comparator, open-label, multicenter study. It included over 900 fingolimod-treated patients with relapsing multiple sclerosis, with subgroups of individuals who were receiving common concomitant HR-lowering medications or had pre-existing cardiac conditions (PCCs). Vital signs were recorded hourly for 6h post-dose. A 12-lead electrocardiogram was obtained at baseline and at 6h post-dose. RESULTS: A transient decrease in mean HR and blood pressure occurred within 6h of the first fingolimod dose. The incidence of symptomatic bradycardia was low (1%); eight patients reported dizziness and there was one case each of fatigue, palpitations, dyspnea, cardiac discomfort, and gait disturbance. These symptomatic events were typically mild or moderate in severity and all resolved spontaneously, without intervention or fingolimod discontinuation. CONCLUSION: First-dose effects in patients with PCCs and in those receiving concomitant HR-lowering medications were consistent with effects observed in the overall study population and with results from previous clinical trials. The EPOC study provides additional data demonstrating the transient and generally benign nature of fingolimod first-dose effects on HR and AV conduction in a large population that is more representative of patients encountered in routine clinical practice than in the pivotal trials.

Impact of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod: Subgroup analyses of the Fingolimod Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study.

BACKGROUND: Fingolimod is a once-daily, oral sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing multiple sclerosis. OBJECTIVE: This post-hoc analysis of phase 3 FREEDOMS data assessed whether the effects of fingolimod are consistent among subgroups of patients defined by prior treatment history. METHODS: Annualized relapse rate and safety profile of treatment with fingolimod 0.5mg, 1.25mg, or placebo once-daily for 24 months were analyzed in 1272 relapsing multiple sclerosis patients, by subgroups based on disease-modifying therapy history (treatment-naive; prior interferon-ß or glatiramer acetate), reason for discontinuation of prior disease-modifying therapy (unsatisfactory therapeutic response or adverse events), and prior disease-modifying therapy duration. RESULTS: Both fingolimod doses significantly reduced annualized relapse rate in patients that received prior interferon-ß or glatiramer acetate, discontinued prior disease-modifying therapy owing to unsatisfactory therapeutic effect, were treatment-naive, or had prior disease-modifying therapy duration of >1-3 years (P≤0.0301 for all comparisons vs placebo). Fingolimod 1.25mg resulted in greater reductions in annualized relapse rate in patients that discontinued prior disease-modifying therapy for adverse events or had prior disease-modifying therapy duration of ≤1 year or >3 years (P≤0.0194 vs placebo). CONCLUSIONS: Fingolimod demonstrated similar efficacy in relapsing multiple sclerosis patients regardless of prior treatment history. Clinicaltrials.gov identifier: NCT00289978.

Treatment benefit of dapoxetine for premature ejaculation: results from a placebo-controlled phase III trial.

OBJECTIVE: To evaluate the overall treatment benefit of dapoxetine for premature ejaculation (PE), with specific emphasis on improvements in personal distress and interpersonal difficulty related to ejaculation. Although these factors are key elements of numerous sets of diagnostic criteria for PE, they have rarely been evaluated as outcome measures in clinical trials. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled, phase III trial we enrolled men aged > or =18 years, from the USA and Canada, who had a Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision, diagnosis of PE (1238 men). Men were randomized to receive placebo or dapoxetine 60 mg as needed or once daily for 9 weeks. The once-daily treatment arm was included for analysis of withdrawal symptoms (primary endpoint; presented elsewhere). Patients completed the Premature Ejaculation Profile (PEP) on day 1 (before dosing), and on days 28 and 63 (or study endpoint), which comprised the outcome measures for perceived control over ejaculation, satisfaction with sexual intercourse, and personal distress and interpersonal difficulty related to ejaculation. The patient-reported global impression of change in PE was reported on day 63 (or study endpoint). Treatment benefit measures included the composite criteria of at least a two-category increase in perceived control over ejaculation and at least a one-category decrease in personal distress related to ejaculation from baseline at study endpoint. RESULTS: At baseline, approximately 5% of patients in any treatment group reported 'not at all' or 'a little bit' of personal distress related to ejaculation, which increased to 54.3% of those receiving dapoxetine (vs 35.3% with placebo; P < 0.001). Similarly, 43.0% and 40.9% of men in the placebo and dapoxetine groups, respectively, reported 'not at all' or 'a little bit' of interpersonal difficulty related to ejaculation at baseline, which increased to 76.8% and 64.2% of those with dapoxetine and placebo, respectively (P < 0.001). The percentage of men who achieved the composite criteria with dapoxetine 'as needed' was 47.6%, vs 21.7% with placebo (difference from placebo, 25.9%; P < 0.001). The distribution of responses for the PEP among men who achieved the composite criteria was similar to that reported for men without PE in a previous observational study in the USA. The most common adverse events were nausea, dizziness, headache, diarrhoea and insomnia, which were more common with dapoxetine than with placebo. CONCLUSION: Dapoxetine reduced the personal distress and interpersonal difficulty associated with PE, and was associated with patient-reported improvements in their condition. The percentage of patients who achieved a composite of a two-category or greater increase in perceived control over ejaculation and a one-category or greater decrease in personal distress related to ejaculation was substantially greater than with placebo, as were all outcome measures.