Цель:
Оценить эффективность и переносимость тоцилизумаба в многоцентровом рандомизированном двойном слепом плацебо-контролируемом исследовании у рефрактерных взрослых пациентов с дерматомиозитом (ДМ) и полимиозитом (ПМ).
Методы:
Тридцать шесть пациентов с вероятным или определенным ДМ/ПМ были включены в 6-месячное клиническое исследование фазы 2B и рандомизированы 1:1 для получения тоцилизумаба (8 мг/кг внутривенно) или плацебо каждые 4 недели в течение 24 недель. Подходящие субъекты с ДМ имели сыпь, либо аутоантитела, ассоциированные с миозитом, либо подтвержденный диагноз ПМ.
Активное заболевание определялось по крайней мере тремя из шести показателей аномального набора основных показателей (CSMs), включая ручное мышечное тестирование (MMT)-8 баллов менее 136/150. Если оценка MMT-8 была больше 136, то требовался кожный балл 3 или более (визуальная аналоговая шкала 10 см) наряду с тремя дополнительными аномальными CSMs, указывающими на активность заболевания.
Первичная конечная точка сравнивала общий балл улучшения (TIS) между обеими группами с 4 по 24 неделю. Вторичные результаты включали время до достижения общего минимального балла улучшения (TIS), изменения в основных показателях (CSMs), время до ухудшения, стероид-ассоциированные эффекты, долю субъектов, отвечающих более строгим критериям улучшения, и результаты безопасности.
Результаты:
Не было никакой существенной разницы (Р= 0,86) в TIS в течение 24 недель между группами тоцилизумаба и плацебо. Вторичные конечные точки времени до улучшения (минимальное, умеренное или значительное), времени до ухудшения, изменений CSMs, результаты безопасности и стероид-ассоциированные эффекты также существенно не различались между группами.
Заключение:
Тоцилизумаб был безопасен и хорошо переносился, но не соответствовал результатам первичной или вторичной эффективности при рефрактерном ДМ и ПМ в этом 24-недельном исследовании фазы 2B.
Chester V. Oddis, Howard E. Rockette, Lei Zhu and others
https://doi.org/10.1002/acr2.11 493
DOI 10.1002/acr2.11 493
Figure 1. Participant flow diagram. Participant flow diagram of subjects enrolled in tocilizumab in myositis trial. AE, adverse event.
| Characteristic | Tocilizumab | Placebo | P value |
| (n = 18) | (n = 18) | ||
| Caucasian, n (%) | 12 (67) | 14 (78) | 0.71a |
| Age (y), mean (range) | 54.3 (31.3−83.4) | 50.4 (21.5−70.7) | 0.41b |
| Female, n (%) | 15 (83) | 13 (72) | 0.69a |
| IIM subset, n (%) | 0.30 | ||
| PM | 8 (44) | 5 (28) | |
| DM | 10 (56) | 13 (72) | |
| Prednisone dose (mg/dayc), mean (SD) | 8.3 (7.5) | 17.8 (20.5) | 0.07b |
| Patients on prednisone, n (%) | 12 (67) | 15 (83) | 0.44a |
| Patients taking nonglucocorticoid IS and/or immunomodulatory agents, n (%) | 15 (83) | 15 (83) | 1.00a |
| Mtx | 4 (22) | 6 (33) | |
| Mtx + Aza | 1 (6) | 1 (6) | |
| Mtx + IVIg | 1 (6) | 1 (6) | |
| Mtx + MMF | 0 (0) | 1 (6) | |
| MMF | 6 (33) | 0 (0) | |
| Aza | 1 (6) | 0 (0) | |
| Aza + IVIg | 0 (0) | 1 (6) | |
| Tacrolimus | 1 (6) | 2 (11) | |
| IVIg | 1 (6) | 3 (17) | |
| Patients with positive myositis autoantibodies, n (%) | 8 (44) | 10 (56) | 0.51 |
| Antisynthetase | 0 (0) | 4 (22) | |
| Anti-TIF1-γ | 2 (11) | 1 (6) | |
| Anti-Mi-2 | 2 (11) | 2 (11) | |
| SRPd | 2 (11) | 0 (0) | |
| HMGCRe | 0 (0) | 1 (6) | |
| MJ/NXP-2 | 1 (6) | 1 (6) | |
| MDA-5 | 1 (6) | 0 (0) | |
| Ro60 | 0 (0) | 1 (6) | |
| MMT-8 score, mean (SD) | 126.7 (15.3) | 132.8 (11.5) | 0.19b |
| Global assessment by VAS (0−10 cm scale), mean (SD) | |||
| Physician | 5.1 (1.7) | 4.7 (1.4) | 0.47b |
| Patient | 6.1 (2.1) | 5.4 (2.4) | 0.37b |
| HAQ disability index (range 0−3), mean (SD) | 1.3 (0.7) | 1.3 (0.6) | 0.94b |
| Muscle enzyme (xULN)f, median (IQR) | 9.1 (1.0−9.8) | 1.5 (1.0−2.4) | 0.41g |
| Extramuscular score by VAS (0−10 cm scale), mean (SD) | 3.3 (2.5) | 3.3 (1.6) | 0.95b |
Abbreviations: Aza, azathioprine; DM, dermatomyositis; HAQ, health assessment questionnaire; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; IIM, idiopathic inflammatory myopathy; IQR, interquartile range; IS, immunosuppressive; IVIg, intravenous immunoglobulin; MDA, melanoma differentiation-associated protein 5; MMF, mycophenolate mofetil; MMT, manual muscle testing; Mtx, methotrexate; NXP-2, anti-nuclear matrix protein-2; PM, polymyositis; SRP, signal recognition particle; VAS, visual analog scale; xULN, times the upper limit of normal.
a Fisher’s exact test P value (χ2 tests were performed for all other categorical variables listed in the above table to generate the P values). b Two sample t test P value. c Prednisone dose (mg/day) in subjects taking any dose of prednisone. d Signal recognition particle. e 3-hydroxy-3-methyl glutaryl-CoA reductase. f Upper limit normal. g Wilcoxon test P valu
Figure 2. The average total improvement scores of the placebo and treatment groups at each of the six follow-up visits. Figure 2. The average total improvement scores of the placebo and treatment groups at each of the six follow-up visits.
| Core set measures | Tocilizumab | Placebo | |||
| Baseline | Week 24 | Baseline | Week 24 | ||
| (average) | (average) | (average) | (average) | P valuea | |
| Extramuscular global assessment (MDAAT) | 3.3 | 3.0 | 3.3 | 1.9 | 0.49 |
| Physician global disease activity | 5.1 | 3.9 | 4.7 | 2.3 | 0.19 |
| Muscle enzyme (xULNb) | 9.1 | 3.5 | 2.5 | 2.8 | 0.22 |
| Patient global disease activity | 6.1 | 4.2 | 5.4 | 4.1 | 0.07 |
| MMT-8 | 126.7 | 135.1 | 132.8 | 139.7 | 0.82 |
| HAQ DI | 1.3 | 1.0 | 1.3 | 1.0 | 0.60 |
Abbreviations: HAQ DI, Health Assessment Questionnaire Disability Index; MDAAT, Myositis Disease Activity Assessment Tool; MMT-8, manual muscle testing. a GEE model P values, for comparing the overtime changes (4−24 weeks) in each core set measure between the two treatment groups. b Times upper limit normal.
Figure 3. Change in glucocorticoid dose between baseline and completion of the 24-week treatment phase. TCZ, tocilizumab.
Randomized Trial of Tocilizumab in the Treatment of Refractory Adult Polymyositis and Dermatomyositis
Objective:
To assess the efficacy and tolerability of tocilizumab in a multicenter, randomized, double-blind, placebo-controlled trial in refractory adult patients with dermatomyositis (DM) and polymyositis (PM).
Methods:
Thirty-six subjects with probable or definite DM/PM were enrolled in a 6-month phase 2B clinical trial and randomized 1:1 to receive tocilizumab (8 mg/kg intravenously) or placebo every 4 weeks for 24 weeks. Eligible subjects had either a DM rash, a myositis-associated autoantibody or an adjudicated PM diagnosis. Active disease was defined by at least three of six abnormal core set measures (CSMs), including a manual muscle testing (MMT)-8 score of less than 136/150.
If the MMT-8 score was greater than 136, then a cutaneous score of 3 or more (10 cm visual analogue scale) was required along with three additional abnormal CSMs indicating disease activity. The primary endpoint com-pared the Total Improvement Score (TIS) between both arms from week 4 to 24. Secondary outcomes included time to meeting minimal TIS improvement, changes in CSMs, time to worsening, steroid-sparing effect, proportion of subjects meeting more stringent improvement criteria, and safety outcomes.
Results:
There was no significant difference (P= 0.86) in the TIS over 24 weeks between tocilizumab and placebo arms. The secondary endpoints of time to improvement (minimal, moderate, or major), time to worsening, CSM changes, safety outcomes, and steroid-sparing effect were also not significantly different between arms.
Conclusion:
Tocilizumab was safe and well tolerated but did not meet the primary or secondary efficacy outcomes in refractory DM and PM in this 24-week phase 2B study.
