Subcutaneous Interferon-?1a Does Not Increase the Risk of Stroke in Patients with Multiple Sclerosis: Analysis of Pooled Clinical Trials and Post-Marketing Surveillance.
ABSTRACT: INTRODUCTION:Previous studies suggest that multiple sclerosis (MS) patients have a greater stroke risk than the general population but there is limited evidence of stroke risk in patients receiving disease-modifying treatment. We assessed stroke risk in MS patients treated with subcutaneous interferon-?1a (sc IFN-?1a) using pooled data from clinical trials and post-marketing surveillance. METHODS:Seventeen phase II-IV Merck KGaA-sponsored trials of sc IFN-?1a were assessed to estimate the stroke incidence rate (IR) and IR ratio (IRR) per 100 patient-years (PY), and associated 95% confidence intervals (CI). The association of treatment duration with stroke was assessed through a Cox model. IR, IRR, and hazard ratio (HR) were adjusted by age, sex, presence of any comorbidity, and MS duration. Individual case safety reports were retrieved from the Global Patient Safety Database. The reporting rates of stroke were calculated and classified as medically confirmed or non-medically confirmed according to the source of each report. RESULTS:In 17 clinical trials, 4412 patients were treated with sc IFN-?1a for a total of 10,622 PY and 1055 patients with placebo for 2005 PY. The IR/100 PY (95% CI) of stroke was 0.025 (0.004, 0.150) in sc IFN-?1a patients and 0.051 (0.008, 0.349) in placebo patients. The IRR for sc IFN-?1a vs placebo was 0.486 (0.238, 0.995) and the HR was 0.496 (0.235, 1.043) for time to stroke-related event for sc IFN-?1a treatment at any dose compared with placebo. Among sc IFN-?1a patients, the IRR in those treated for
Project description:In the PRISMS study, interferon beta-1a subcutaneously (IFN ?-1a SC) reduced clinical and radiological disease burden at 2 years in patients with relapsing-remitting multiple sclerosis. The study aimed to characterize efficacy of IFN ?-1a SC 44 ?g and 22 ?g three times weekly (tiw) at Year 1.Exploratory endpoints included annualized relapse rate (ARR), 3-month confirmed disability progression (1-point Expanded Disability Status Scale increase if baseline was <?6.0 [0.5-point if baseline was ?6.0]), active T2 lesions, and no evidence of disease activity (NEDA; defined as no relapses [subanalyzed by relapse severity], 3-month confirmed progression, or active T2 lesions). Effect of IFN ?-1a SC in prespecified patient subgroups was also assessed.Patients were randomized to IFN ?-1a 22 ?g (n?=?189), 44 ?g (n?=?184), or placebo (n?=?187). At 1 year, IFN ?-1a SC tiw reduced ARR (p?<?0.001), risk of disability progression (p???0.029), and mean number of active T2 lesions per patients per scan (p?<?0.001) versus placebo. Clinical and radiological benefits were seen as early as Month 2 and 3. Outcomes in subgroups were consistent with those in the overall population. More patients treated with IFN ?-1a SC tiw achieved NEDA status, versus placebo, regardless of relapse severity (p???0.006).Clinical, radiological, and NEDA outcomes at Year 1 were consistent with Year 2 results. Treatment efficacy was consistent in pre-specified patient subgroups.
Project description:On-treatment magnetic resonance imaging lesions may predict long-term clinical outcomes in patients receiving interferon ?-1a. This study aimed to assess the effect of active T2 and T1 gadolinium-enhancing (Gd+) lesions on relapses and 3-month confirmed Expanded Disability Status Scale (EDSS) progression in the PRISMS clinical trial.Exploratory analyses assessed whether active T2 and T1 Gd?+?lesions at Month 6, or active T2 lesions at Month 12, predicted clinical outcomes over 4 years in PRISMS.Mean active T2 lesion number at Month 6 was significantly lower with interferon beta-1a given subcutaneously (IFN ?-1a SC) 44 ?g and 22 ?g 3×/week (tiw) than with placebo (p <?0.0001). The presence of ?4 versus 0 active T2 lesions predicted disability progression at Years 3-4 in the IFN ?-1a SC 22 ?g group only (p <?0.05), whereas the presence of ?2 versus 0-1 active T2 lesions predicted disability progression in the placebo/delayed treatment (DTx) (Years 2-4; p <?0.05) and IFN ?-1a SC 22 ?g groups (Years 3-4; p <?0.05). Greater active T2 lesion number at 6 months predicted relapses in the placebo/DTx group only (?4 vs. 0, Years 1-4; ?2 vs. 0-1, Years 2-4; p <?0.05), and the presence of T1 Gd?+?lesions at 6 months predicted disability progression in the IFN ?-1a SC 44 ?g group only (Year 1; p <?0.05). The presence of ?2 versus 0-1 active T2 lesions at 12 months predicted disability progression over 3 and 4 years in the IFN ?-1a SC 44 ?g group.Active T2 lesions at 6 months predicted clinical outcomes in patients receiving placebo or IFN ?-1a SC 22 ?g, but not in those receiving IFN ?-1a SC 44 ?g. Active T2 lesions at 12 months may predict outcomes in those receiving IFN ?-1a SC 44 ?g and are possibly more suggestive of poor response to therapy than T2 results at 6 months.
Project description:The REFLEX study (NCT00404352) established that subcutaneous (sc) interferon (IFN) ?-1a reduced the risks of McDonald MS (2005 criteria) and clinically definite multiple sclerosis (CDMS) in patients with a first clinical demyelinating event suggestive of MS. The aim of this subgroup analysis was to assess the treatment effect of sc IFN ?-1a in patient subgroups defined by baseline disease and demographic characteristics (age, sex, use of steroids at the first event, classification of first event as mono- or multifocal, presence/absence of gadolinium-enhancing lesions, count of <9 or ?9 T2 lesions), and by diagnosis of MS using the revised McDonald 2010 MS criteria. Patients were randomized to the serum-free formulation of IFN ?-1a, 44 ?g sc three times weekly or once weekly, or placebo, for 24 months or until diagnosis of CDMS. Treatment effects of sc IFN ?-1a on McDonald 2005 MS and CDMS in the predefined subgroups were similar to effects found in the intent-to-treat population. McDonald 2010 MS was retrospectively diagnosed in 37.7 % of patients at baseline. Both regimens of sc IFN ?-1a significantly reduced the risk versus placebo of McDonald 2005 MS and CDMS, irrespective of McDonald 2010 status at baseline (risk reductions between 29 and 51 %). The effect of sc IFN ?-1a was not substantially influenced by baseline patient demographic and disease characteristics, or baseline presence/absence of McDonald 2010 MS.
Project description:OBJECTIVE:In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D3 in patients with RRMS. METHODS:Eligible patients with RRMS treated with SC interferon-?-1a (IFN-?-1a) 44 ?g 3 times weekly and serum 25(OH)D levels <150 nmol/L were included. From February 15, 2011, to May 11, 2015, 229 patients were included and randomized 1:1 to receive SC IFN-?-1a plus placebo (n = 116) or SC IFN-?-1a plus oral high-dose vitamin D3 14,007 IU/d (n = 113). The revised primary outcome was the proportion of patients with no evidence of disease activity (NEDA-3) at week 48. RESULTS:At 48 weeks, 36.3% of patients who received high-dose vitamin D3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53-1.63; p = 0.80). Compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52-0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: -0.074; p = 0.035). CONCLUSIONS:SOLAR did not establish a benefit for high-dose vitamin D3 as add-on to IFN-?-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS. CLINICALTRIALSGOV IDENTIFIER:NCT01285401. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that for patients with RRMS treated with SC IFN-?-1a, 48 weeks of cholecalciferol supplementation did not promote NEDA-3 status.
Project description:This study evaluated efficacy of subcutaneous (sc) interferon beta-1a (IFN ?-1a) 44 µg 3?×?weekly (tiw) in patients appearing to transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS). The PRISMS study included 560 patients with RRMS (EDSS 0-5.0;???2 relapses in previous 2 years), and the SPECTRIMS study included 618 patients with SPMS (EDSS 3.0-6.5 and???1-point increase in previous 2 years [??0.5 point if 6.0-6.5]) randomly assigned to sc IFN ?-1a 44 or 22 µg or placebo for 2-3 years, respectively. These post hoc analyses examined five subgroups of MS patients with EDSS 4.0-6.0: PRISMS (n?=?59), PRISMS/SPECTRIMS (n?=?335), PRISMS/SPECTRIMS with baseline disease activity (n?=?195; patients with either???1 relapse within 2 years before baseline or???1 gadolinium-enhancing lesion at baseline), PRISMS/SPECTRIMS without baseline disease activity (n?=?140), and PRISMS/SPECTRIMS with disease activity during the study (n?=?202). In the PRISMS and PRISMS/SPECTRIMS subgroups, sc IFN ?-1a delayed disability progression, although no significant effect was observed in PRISMS/SPECTRIMS subgroups with activity at baseline or activity during the study (regardless of baseline activity). In the PRISMS/SPECTRIMS subgroup, over year 1 (0-1) and 2 (0-2), sc IFN ?-1a 44 µg tiw significantly reduced annualized relapse rate (p???0.001), and relapse risk (p?<?0.05) versus placebo. Similar results were seen for the PRISMS/SPECTRIMS with baseline disease activity subgroup. Subcutaneous IFN ?-1a reduced T2 burden of disease and active T2 lesions in the PRISMS/SPECTRIMS subgroups overall, with and without baseline activity. In conclusion, these post hoc analyses indicate that effects of sc IFN ?-1a 44 µg tiw on clinical/MRI endpoints are preserved in a patient subgroup appearing to transition between RRMS and SPMS.
Project description:AIM:To determine whether regional variation in stroke incidence exists among individuals with AF. METHODS:Using healthcare utilization claims from 2 large US databases, MarketScan (2007-2014) and Optum Clinformatics (2009-2015), and the 2010 US population as the standard, we estimated age-, sex-, race- (only in Optum) standardized stroke incidence rates by the 9 US census divisions. We also used Poisson regression to examine incidence rate ratios (IRR) of stroke and the probability of anticoagulation prescription fills across divisions. RESULTS:Both databases combined included 970,683 patients with AF who experienced 15,543 strokes, with a mean follow-up of 23 months. In MarketScan, the age- and sex-standardized stroke incidence rate was highest in the Middle Atlantic and East South Central divisions at 3.8/1000 person-years (PY) and lowest in the West North Central at 3.2/1000 PY. The IRR of stroke and the probability of anticoagulation fills were similar across divisions. In Optum Clinformatics, the age-, sex-, and race-standardized stroke incidence rate was highest in the East North Central division at 5.0/1000 PY and lowest in the New England division at 3.3/1000 PY. IRR of stroke and the probability of anticoagulation fills differed across divisions when compared to New England. CONCLUSIONS:These findings suggest regional differences in stroke incidence among AF patients follow a pattern that differs from the hypothesized trend found in the general population and that other factors may be responsible for this new pattern. Cross-database differences provide a cautionary tale for the identification of regional variation using health claims data.
Project description:To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon ?-1a (SC IFN-?-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS).The impact of alemtuzumab 12 mg vs SC IFN-?-1a 44 ?g on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II).Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-?-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-?-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-?-1a.Alemtuzumab demonstrated greater efficacy than SC IFN-?-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-?-1a in RRMS.NCT00530348 and NCT00548405.The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-?-1a on multiple MRI endpoints.
Project description:To characterize effects of alemtuzumab treatment on measures of disability improvement in patients with relapsing-remitting multiple sclerosis (RRMS) with inadequate response (≥1 relapse) to prior therapy.Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II, a 2-year randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial, compared efficacy and safety of alemtuzumab 12 mg with subcutaneous interferon-β-1a (SC IFN-β-1a) 44 μg in patients with RRMS. Prespecified and post hoc disability outcomes based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Sloan low-contrast letter acuity (SLCLA) are reported, focusing on improvement of preexisting disability in addition to slowing of disability accumulation.Alemtuzumab-treated patients were more likely than SC IFN-β-1a-treated patients to show improvement in EDSS scores (p < 0.0001) on all 7 functional systems. Significantly more alemtuzumab patients demonstrated 6-month confirmed disability improvement. The likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than SC IFN-β-1a (p = 0.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores (p = 0.0014) and MSFC + SLCLA composite scores (p = 0.0097) than SC IFN-β-1a-treated patients.In patients with RRMS and inadequate response to prior disease-modifying therapies, alemtuzumab provides greater benefits than SC IFN-β-1a across several disability outcomes, reflecting improvement of preexisting disabilities.This study provides Class I evidence (based on rater blinding and a balance in baseline characteristics between arms) that alemtuzumab modifies disability measures favorably compared with SC IFN-β-1a.
Project description:<h4>Objective</h4>To report the long-term safety data of certolizumab pegol (CZP) in rheumatoid arthritis (RA) accumulated as of 30 November 2011.<h4>Design</h4>Data from 10 completed randomised controlled trials (RCT) of CZP in RA and several open-label extensions (OLE) were pooled across all doses. Reported adverse events (AE) occurred between the first dose and 84?days after the last dose. All deaths, serious infectious events (SIE) and malignancies were reviewed by external experts, classified according to predefined rules, and validated by an external steering committee. Incidence rates (IR) and event rates (ER) per 100 patient-years (PY) are presented.<h4>Results</h4>4049 RA patients who received CZP were included in the safety pooling; total exposure 9277 PY, mean exposure 2.1?years (range 0.04-7.6). SIE, most frequently pneumonia (IR 0.73/100 PY), were the most common serious AE, occurring more frequently in CZP compared to placebo-treated patients in RCT (IR 5.61/100 PY vs 1.35/100 PY, odds ratio (OR) 4.35, 95% CI 0.65 to 29.30). SIE rates were lower in the CZP-treated population including OLE (ER 4.33/100 PY). 44 patients developed tuberculosis (IR 0.47/100 PY), 39 from high endemic regions. 58 deaths occurred in CZP-exposed patients (IR 0.63/100 PY) and 70 developed malignancies excluding non-melanoma skin cancer (IR 0.76/100 PY), including five lymphomas (IR 0.05/100 PY).<h4>Conclusions</h4>No new or unexpected safety signals associated with CZP emerged in this updated long-term safety analysis. While SIE rates were higher for CZP than for placebo in RCT, the rate decreased with continued exposure to CZP. These rates are consistent with data previously reported for CZP and other tumour necrosis factor inhibitors.
Project description:IntroductionGuidelines for pre-exposure prophylaxis (PrEP) provide criteria to identify individuals at higher risk of HIV infection. We compared the ability to predict HIV seroconversion of four guidelines: the World Health Organization (WHO), the United States Public Health Service and Centers for Disease Control and Prevention (US CDC), the European AIDS Clinical Society (EACS) and the Portuguese National Health Service (PNHS).AimWe aimed to measure the association between guideline-specific eligibility and HIV seroconversion.MethodsWe studied 1,254 participants from the Lisbon Cohort of men who have sex with men with at least two evaluations between March 2014 and March 2018, corresponding to 1,724.54 person-years (PY) of follow-up. We calculated incidence rates (IR) according to each guideline eligibility definition and incident rate ratios (IRR) to test the association between eligibility at baseline and HIV seroconversion.ResultsWe found 28 incident cases (IR: 1.62/100 PY; 95% confidence interval (CI) 1.12-2.35). Guidelines' sensitivity varied from 60.7% (EACS) to 85.7% (PNHS) and specificity varied from 31.8% (US CDC) to 51.5% (EACS). IR was highest among those defined as eligible by the PNHS guideline (2.46/100 PY; IRR?=?4.61; 95% CI: 1.60-13.27) and lowest for the WHO guideline (1.89/100 PY; IRR?=?1.52; 95% CI: 0.69-3.35).ConclusionsBeing identified as eligible for PrEP was associated with a higher risk of infection. The magnitude of risk varied according to the guideline used. However, the number of HIV infections identified among ineligible participants highlights the potential for missing people who need PrEP.