akinohanayuki ブログ

学位を持っても、センスのない、感染制御専門薬剤師のブログ.  I have Ph.D. but less sense ID pharmacist.

Journal Club : MODIFY I and MODIFY II ; Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

Journal ClubBezlotoxumab for Prevention of Recurrent Clostridium difficile Infection.

MODIFY I and MODIFY II

 

今週のプレゼンターは、感染症看護専門看護師

 

2017年1月NEJMに報告された、日本を含む30カ国322施設におけるC. difficile の初感染または再発に対し標準治療である経口抗菌薬投与を受けている成人に対する二重盲検無作為化プラセボ対照第 3 相試験。

ベズロトクスマブ(10 mg/kg)、アクトクスマブ+ベズロトクスマブ(それぞれ 10 mg/kg)またはプラセボによる点滴静注後 12 週間以内に再発した感染を主アウトカムとした試験。

 ベズロトクスマブは、CDトキシンBに対するモノクローナル抗体

 

 

 

P : 2655 adults receiving oral standard-of-care antibiotics for primary or re- current C. difficile infection

E : 

bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each)

C : placebo

O : 

In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001).

The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. 

T : double-blind, randomized, placebo-controlled, phase 3 trials,

 

limitation

First, the selection of standard-of-care antibiotic was not standardized but rather was at the discretion of the investigator. To control for this, the study groups were stratified according to the standard- of-care antibiotic and therefore were balanced with regard to that variable. Moreover, the efficacy of bezlotoxumab with regard to the rate of recurrent infection was not affected by the choice of standard-of-care antibiotic.

Second, although the time of study infusion relative to the onset of symptoms was balanced across treatment groups, the time interval was broad; thus, an assessment of the effect of neutralization of toxin B or toxin A on the severity and duration of the baseline episode could not be performed.

Third, the proportion of participants with a severe baseline episode of C. difficile infection is probably an underestimate, since more than 90% of partici- pants were receiving standard-of-care antibiotics when the severity assessment was performed.

Fourth, other therapies that are currently used for the prevention of recurrent C. difficile infec- tion were not allowed; therefore, the combined effect of bezlotoxumab and other approaches (e.g., fecal microbiota transplantation) is not known.

Finally, safety assessments were limited because of the relatively small number of pa- tients who received bezlotoxumab, which makes it difficult to detect potentially serious but lowfrequency toxic effects.

 

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参加者ディスカッション

プラセボ比較であれば、再発に差がつくのは当然であろう。VCMや便移植との比較や死亡率を主評価とした検討も今後期待したい。

研究期間も長い(2011-2015)、医療進化バイアスと対象患者リクルート困難なアンメットニーズ。

限界の1は、重要な問題。

 

研究デザインの理解が難しく、インパクトは限定的。

 

薬価は、100万近く高額設定の可能性がある。

購入意義はDOAC中和薬のように、病院としてのお守りなのか? 

 

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