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Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: Rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study.

ABSTRACT: The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo-controlled trial of LDM in the secondary prevention of cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT.CIRT will randomize up to 7000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose: 15-20mg/week) or placebo for an average follow-up period of 3-5 years; subjects in both treatment arms receive folic acid 1mg daily for 6 days each week. The primary endpoints of CIRT include recurrent cardio vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events.CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice.

SUBMITTER: Sparks JA

PROVIDER: S-EPMC5765986 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: Rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study.

Sparks Jeffrey A JA Barbhaiya Medha M Karlson Elizabeth W EW Ritter Susan Y SY Raychaudhuri Soumya S Corrigan Cassandra C CC Lu Fengxin F Selhub Jacob J Chasman Daniel I DI Paynter Nina P NP Ridker Paul M PM Solomon Daniel H DH

Seminars in arthritis and rheumatism 20170210 1

<h4>Background</h4>The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo-controlled trial of LDM in the secondary ...[more]

PMID: 28284844

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Project description:Background:Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred. Objective:To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo. Design:Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333). Setting:North America. Participants:Adults with known cardiovascular disease and diabetes or metabolic syndrome. Intervention:Random allocation to LD-MTX (?20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week. Measurements:Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication. Results:After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]). Limitation:The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period. Conclusion:Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased. Primary Funding Source:National Institutes of Health.

Project description:IntroductionReflux symptoms are frequently associated with esophageal acid exposure. However, other potential causes unrelated to acid secretion are possible, and the relationship between acid control and symptomatic improvement remains unclear. This study investigated the correlation between individual intragastric pH control and heartburn relief among subjects with frequent heartburn who are likely to self-treat with over-the-counter (OTC) medications. We hypothesized that improved acid control would provide greater symptomatic improvement among individuals representative of an OTC population.MethodsThis phase 4, single-center, randomized, double-blind, placebo-controlled study was conducted in subjects without diagnosed gastroesophageal reflux disease or other gastrointestinal conditions who were experiencing frequent heartburn (≥ 3 episodes/week; ≥ 2 nighttime episodes/week over past 30 days) that was responsive to treatment. Subjects entered a 7-day run-in phase, received placebo BID (before breakfast and dinner), and completed symptom diaries. During the treatment phase, subjects received esomeprazole 20 mg BID, esomeprazole 20 mg then placebo, or placebo BID. Subjects underwent 24-h intragastric pH monitoring at baseline and day 14 and completed daily symptom diaries.ResultsIn the per-protocol population (n = 39), mean (SD) change from baseline in percentage of time with intragastric pH > 4 was 58.7% (± 26.4%) versus 41.0% (± 30.4%) for those who did and did not achieve 24-h heartburn relief. Significant correlations were observed between change in percentage of time with intragastric pH > 4 and 24-h heartburn relief (OR 1.028; 95% CI 1.001, 1.055; P = 0.0442) and complete resolution (OR 1.034; 95% CI 1.003, 1.065; P = 0.0301).ConclusionsIndividuals with greater improvements in duration of intragastric acid suppression had an increased likelihood of achieving heartburn relief and resolution. These results indicate that individuals not adequately controlling their intragastric pH may require an escalation in dose of their acid-suppressive therapy, assessment with 24-h pH monitoring, or a change in treatment regimen to address non-reflux-related etiologies of their heartburn.Trial registrationClinicalTrials.gov identifier: NCT02708355.FundingPfizer Consumer Healthcare, Madison, NJ, USA. Plain language summary available for this article.

Dataset Information

Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: Rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study.

Publications

Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: Rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study.

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