Dataset Information

Comparison of two doses of leucovorin in severe low-dose methotrexate toxicity - a randomized controlled trial.

ABSTRACT:

Background

Leucovorin (folinic acid) is a commonly used antidote for severe toxicity with low-dose methotrexate, but its optimum dose is unclear, varying from 15 to 25 mg every 6-h.

Methods

Open-label RCT included patients with severe low-dose (≤ 50 mg/week) methotrexate toxicity defined as WBC ≤ 2 × 10^9/L or platelet ≤ 50 × 10^9/L and randomized them to receive either usual (15 mg) or high-dose (25 mg) intravenous leucovorin given every 6-h. Primary outcome was mortality at 30-days and secondary outcomes were hematological recovery and mucositis recovery.

Trial registration number

CTRI/2019/09/021152.

Results

Thirty-eight patients were included, most with underlying RA who had inadvertently overdosed MTX (taken daily instead of weekly). At randomization, the median white blood and platelet count were 0.8 × 10^9/L and 23.5 × 10^9/L. 19 patients each were randomized to receive either usual or high-dose leucovorin. Number (%) of deaths over 30-days was 8 (42) and 9 (47) in usual and high-dose leucovorin groups (Odds ratio 1.2, 95% CI 0.3 to 4.5, p = 0.74). On Kaplan-Meier, there was no significant difference in survival between the groups (hazard ratio 1.1, 95% CI 0.4 to 2.9, p = 0.84). On multivariable cox-regression, serum albumin was the only predictor of survival (hazard ratio 0.3, 95% CI 0.1 to 0.9, p = 0.02). There was no significant difference in hematological or mucositis recovery between the two groups.

Conclusion

There was no significant difference in survival or time-to hematological recovery between the two doses of leucovorin. Severe low-dose methotrexate toxicity carried a significant mortality.

SUBMITTER: Bhargava M

PROVIDER: S-EPMC10197821 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

Comparison of two doses of leucovorin in severe low-dose methotrexate toxicity - a randomized controlled trial.

Bhargava Mudit M Kopp Chirag Rajkumar CR Naidu Shankar S Dhibar Deba Prasad DP Saroch Atul A Khadwal Alka A Narang Tarun T Jain Siddharth S Khullar Aastha A Leishangthem Bidya B Sharma Aman A Kumar Susheel S Sharma Shefali S Jain Sanjay S Dhir Varun V

Arthritis research & therapy 20230519 1

<h4>Background</h4>Leucovorin (folinic acid) is a commonly used antidote for severe toxicity with low-dose methotrexate, but its optimum dose is unclear, varying from 15 to 25 mg every 6-h.<h4>Methods</h4>Open-label RCT included patients with severe low-dose (≤ 50 mg/week) methotrexate toxicity defined as WBC ≤ 2 × 10^9/L or platelet ≤ 50 × 10^9/L and randomized them to receive either usual (15 mg) or high-dose (25 mg) intravenous leucovorin given every 6-h. Primary outcome was mortality at 30-d ...[more]

PMID: 37208770

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Project description:IntroductionThere is reasonable evidence that folic acid 5-10 mg per week leads to reduction in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). However, this is based on studies conducted with lower MTX dosage than used currently. It is unclear whether higher doses of folic acid may be better in reducing toxicity.MethodsThis was a double-blind randomized controlled trial of 24 weeks duration. To be eligible, patients should have rheumatoid arthritis (1987 American College of Rheumatology criteria), be 18-75 years of age, not be on MTX and have active disease as defined by 'Modified Disease Activity Score using three variables' (DAS28(3)) > 3.2. MTX was started at 10 mg/week and escalated to 25 mg/week by 12 weeks. Folic acid was given at a dose of 10 mg (FA10) or 30 mg per week (FA30). Co-primary endpoints were incidence of toxicity (undesirable symptoms and laboratory abnormalities) and change in disease activity by 24 weeks. Intention-to-treat and per-protocol analyses were performed.ResultsAmong 100 patients enrolled, 51 and 49 were randomized to FA10 and FA30 respectively. By 24 weeks, there were 6 patient withdrawals in either group and mean(±SD) dose of MTX was 22.8 ± 4.4 and 21.4 ± 4.6 mg per week (p = 0.1). Frequency of patients with undesirable symptoms was non-significantly lower by 7.4% (95% confidence interval -27.4 to 12.7%) in FA10 compared to FA30. There was also no difference in frequency of transaminitis (>Upper limit of normal (ULN)) (42.6, 45.7%, p = 0.7) or transminitis as per primary endpoint (>2xULN) (10.6, 8.7%, p = 1.0) or cytopenias (4.3, 4.3%, p = 0.9). There was no difference in the primary end-point of occurrence of any adverse effect (symptom or laboratory) in FA10 and FA30 (46.8, 54.3%, p = 0.5). At 24 weeks, DAS28(3) declined in both groups by a similar extent (-1.1 ± 1.0, -1.3 ± 1.0, p = 0.2) and 'European League Against Rheumatism' good or moderate response occurred in 56.9 and 67.4% (p = 0.3).ConclusionsEven with the high doses of MTX used in current practice, there was no additional benefit (or harm) of a higher dose of folic acid (30 mg/week) over a usual dose (10 mg/week).Trial registrationClinicaltrials.gov NCT01583959 Registered 15 March 2012.

Project description:BackgroundLow-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.ObjectiveTo investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo.DesignPrespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333).SettingNorth America.ParticipantsAdults with known cardiovascular disease and diabetes or metabolic syndrome.InterventionRandom allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week.MeasurementsRisks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication.ResultsAfter 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]).LimitationThe trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period.ConclusionUse 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 sourceNational Institutes of Health.

Dataset Information

Comparison of two doses of leucovorin in severe low-dose methotrexate toxicity - a randomized controlled trial.

Background

Methods

Trial registration number

Results

Conclusion

Publications

Comparison of two doses of leucovorin in severe low-dose methotrexate toxicity - a randomized controlled trial.

Similar Datasets

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