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Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN?-1b trial.

ABSTRACT: To examine the effects of interferon beta (IFN?)-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.For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFN?-1b 250 ?g 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.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 IFN?-1b 250 ?g 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 IFN?-1b 250 ?g-treated patients (46.0% among IFN?-1b 50 ?g-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect.There was a significant survival advantage in this cohort of patients receiving early IFN?-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 IFN?-1b benefit on all-cause mortality.This study provides Class III evidence that early treatment with IFN?-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.

SUBMITTER: Goodin DS

PROVIDER: S-EPMC3335454 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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

Goodin D S DS Reder A T AT Ebers G C GC Cutter G G Kremenchutzky M M Oger J J Langdon D D Rametta M M Beckmann K K DeSimone T M TM Knappertz V V

Neurology 20120411 17

<h4>Objective</h4>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.<h4>Methods</h4>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 random ...[more]

PMID: 22496198

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Project description:Compared with controls, multiple sclerosis (MS) patients die, on average, 7-14 years prematurely. Previously, we reported that, 21 years after their participation in the pivotal randomised, controlled trial (RCT) of interferon ?-1b, mortality was reduced by 46-47% in the two groups who received active therapy during the RCT. To determine whether the excessive deaths observed in placebo-treated patients was due to MS-related causes, we analysed the causes-of-death (CODs) in these three, randomised, patient cohorts.Long-term follow-up (LTF) of the pivotal RCT of interferon ?-1b.Eleven North American MS-centres participated.In the original RCT, 372 patients participated, of whom 366 (98.4%) were identified after a median of 21.1 years from RCT enrolment.Using multiple information sources, we attempted to establish COD and its relationship to MS in deceased patients.An independent adjudication committee, masked to treatment assignment and using prespecified criteria, determined the likely CODs and their MS relationships.Among the 366 MS patients included in this LTF study, 81 deaths were recorded. Mean age-at-death was 51.7 (±8.7) years. COD, MS relationship, or both were determined for 88% of deaths (71/81). Patients were assigned to one of nine COD categories: cardiovascular disease/stroke; cancer; pulmonary infections; sepsis; accidents; suicide; death due to MS; other known CODs; and unknown COD. Of the 69 patients for whom information on the relationship of death to MS was available, 78.3% (54/69) were adjudicated to be MS related. Patients randomised to receive placebo during the RCT (compared with patients receiving active treatment) experienced an excessive number of MS-related deaths.In this long-term, randomised, cohort study, MS patients receiving placebo during the RCT experienced greater all-cause mortality compared to those on active treatment. The excessive mortality in the original placebo group was largely from MS-related causes, especially, MS-related pulmonary infections.

Project description:Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment.

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Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN?-1b trial.

Publications

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

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