A Randomized, Double-Blind, Placebo-Controlled Multicenter Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients With Uncontrolled Gout Receiving Pegloticase: 12-Month Findings

Abstract

Objective: To assess 12-month safety and efficacy of pegloticase + methotrexate (MTX) versus pegloticase + placebo (PBO) cotherapy in a PBO-controlled, double-blind trial (A randomized, double-blind, placebo-controlled, multicenter, efficacy and safety study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase [MIRROR RCT]).

Methods: Patients with uncontrolled gout (serum urate level [SU] ≥7 mg/dl, oral urate-lowering therapy failure or intolerance, and presence of one or more gout symptoms [one or more tophi, two or more flares in 12 months, gouty arthropathy]) were randomized 2:1 to receive pegloticase (8-mg infusion every 2 weeks) with blinded MTX (oral 15 mg/week) or PBO for 52 weeks. Efficacy end points included proportion of responders (SU level <6 mg/dl for ≥80% of examined month) in the intent-to-treat population (ITT) (all randomized patients) during month 6 (primary end point), month 9, and month 12; proportion with resolution of one or more tophi (ITT); mean SU reduction (ITT); and time to SU-monitoring pegloticase discontinuation. Safety was evaluated via adverse event reporting and laboratory values.

Results: Month 12 response rate was significantly higher in patients cotreated with MTX (60.0% [60 of 100] vs. 30.8% [16 of 52]; difference: 29.1% [95% confidence interval (CI): 13.2%-44.9%], P = 0.0003), with fewer SU discontinuations (22.9% [22 of 96] vs. 63.3% [31 of 49]). Complete resolution of one or more tophi occurred in 53.8% (28 of 52) versus 31.0% (9 of 29) of MTX versus PBO patients at week 52 (difference: 22.8% [95% CI: 1.2%-44.4%], P = 0.048), more than at week 24 (34.6% [18 of 52] vs. 13.8% [4 of 29]). Consistent with observations through month 6, pharmacokinetic and immunogenicity findings showed increased exposure and lower immunogenicity of pegloticase when administered with MTX, with an otherwise similar safety profile. No infusion reactions occurred after 24 weeks.

Conclusion: Twelve-month MIRROR RCT data further support MTX cotherapy with pegloticase. Tophi resolution continued to increase through week 52, suggesting continued therapeutic benefit beyond month 6 for a favorable treatment effect.

Figure 1

Study disposition. ^aDiscontinued because of COVID‐19 concerns, not infection. ^bOne patient in each group continued to receive pegloticase through week 52 but had discontinued MTX or PBO prior to week 24. ITT, intent‐to‐treat; mITT, modified intent‐to‐treat; MTX, methotrexate; PBO, placebo.

Figure 2

A, Proportion of patients with sustained urate‐lowering response in the intent‐to‐treat population (all randomized patients) during each examined treatment month. *Significant difference between treatment groups as determined via Cochran–Mantel–Haenszel weighting to estimate common risk difference (P ≤ 0.0003). B, Least squares mean change in SU over time in patients treated with pegloticase + MTX and patients treated with pegloticase + PBO. Mean change from baseline in SU is shown for weeks 24 and 52. Shaded regions represent 95% CI. C, Kaplan–Meier curve for time to two consecutive SU measurements >6 mg/dl through week 52 (mITT population; one or more pegloticase doses received). Median time was NE (95% CI: NE, NE) in the MTX group and 69 days (95% CI: 29, 401) in the PBO group (P < 0.0001). MTX, methotrexate; PBO, placebo.

Figure 3

A, Proportion of patients with tophi at baseline who had resolution of one or more tophi. *Statistically significant difference between treatment groups (chi‐square test, both P ≤ 0.048). B, Least‐square mean change from baseline in HAQ‐DI, Pain, and Health scores. Baseline was defined as the last observation prior to MTX exposure (week −6). Day 1 (dotted line) indicates day of first pegloticase infusion. *Statistically significant difference between groups (all P ≤ 0.043). Error bars represent 95% confidence intervals. CFB, change from baseline; DI, disability index; HAQ, Health Assessment Questionnaire; MTX, methotrexate; PBO, placebo.

Figure 4

Proportion of patients who developed anti‐PEG antibodies during the pegloticase + MTX/PBO treatment period. “New” antibodies indicates any postbaseline antibody positivity in patients who were antibody‐negative at baseline or any increase in antibody titer in patients who were antibody‐positive at baseline. Median time to first new antibody development was NE (95% CI: NE, NE) vs. 155 days (95% CI: 43, NE) in the MTX versus. PBO group, respectively. ADA, antidrug antibody; CI, confidence interval; MTX, methotrexate; NE, not estimable; PBO, placebo; PEG, polyethylene glycol.

Figure 5

A, Summary of treatment‐emergent AEs occurring in ≥5% of either treatment group during the pegloticase + MTX/PBO treatment period (safety population). Treatment‐emergent AEs occurred within 30 days of the last dose of pegloticase or MTX/PBO (whichever was later). All serious AEs and AEs of special interest are shown. B, The proportion of patients with one or more gout flares during each treatment month. ^aAE of special interest, adjudicated. ^bKnown MTX‐associated AE (16). ^cIncludes carpal tunnel syndrome (two MTX), dizziness (four MTX, one PBO), facial spasm (one MTX), headache (one MTX, one PBO), hypoesthesia (two MTX), nerve compression (one MTX), neuralgia (one MTX), neuropathy peripheral (one MTX), paresthesia (two MTX, one PBO), somnolence (one MTX), syncope (two MTX), tension headache (one MTX), and tremor (one MTX). ^dIncludes fatigue (five MTX, two PBO), chest discomfort (two PBO), feeling hot (one MTX), peripheral edema (two MTX, one PBO), peripheral swelling (two MTX, one PBO), pain (one MTX. one PBO), and foreign body sensation (one MTX). ^eIncludes angina pectoris (one MTX), cardiac arrest (one MTX; one death), mitral valve incompetence (one MTX), palpitations (one MTX), and tachycardia (one MTX). ^fOne additional patient had an AE of elevated transaminase but had discontinued pegloticase + PBO more than 6 months prior to AE reporting. ^gIncludes COVID‐19 (two MTX; one death), soft tissue abscess (one PBO), and osteomyelitis (one MTX). ADH, antidiuretic hormone; AE, adverse event; LFT, liver function test (elevated LFT measurements includes elevated aspartate aminotransferase, alanine aminotransferase, and hepatic enzyme levels); MTX, methotrexate; PBO, placebo.