From Leeds Teaching Hospitals and University of Leeds, Leeds (M.H.W.), and the University of Edinburgh, Edinburgh (I.R.P.) - both in the United Kingdom; Loyola University Chicago Stritch School of Medicine, Maywood, and Edward Hines Jr. VA Hospital, Hines - both in Illinois (D.N.G.); Beth Israel Deaconess Medical Center and Harvard Medical School, Boston (C.K.); Idaho Falls Infectious Disease, Idaho Falls, Idaho (R.N.); Holy Name Medical Center, Teaneck (T.B.), and Merck, Kenilworth (L.G., A.P., K.E., R.T., D.G., N.K., M.-B.D.) - both in New Jersey; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Department I of Internal Medicine, Clinical Trials Center Cologne (ZKS Köln), German Center for Infection Research (DZIF), University Hospital of Cologne, Cologne, Germany (O.A.C.); Sheba Medical Center, Tel Hashomer, Israel (G.R.); Hospital Gregorio Maranon, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES) (CB06/06/0058), Madrid (E.B.); St. Joseph's Healthcare, Hamilton, ON, Canada (C.L.); Monash Health, Clayton, VIC, Australia (G.J.); Gustavo Fricke Hospital, Viña del Mar, Chile (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
N Engl J Med. 2017 Jan 26;376(4):305-317. doi: 10.1056/NEJMoa1602615.
BACKGROUND: Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS: 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). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS: Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239 .).
背景：艰难梭菌是住院患者中感染性腹泻最常见的原因。抗生素治疗后复发很常见。Actoxumab 和 bezlotoxumab 分别是针对艰难梭菌毒素 A 和 B 的人源单克隆抗体。
方法：我们进行了两项双盲、随机、安慰剂对照的 3 期试验，MODIFY I 和 MODIFY II，涉及 2655 名接受口服标准护理抗生素治疗原发性或复发性艰难梭菌感染的成年人。参与者接受 bezlotoxumab（每公斤体重 10 毫克）、actoxumab 和 bezlotoxumab（每公斤 10 毫克）或安慰剂输注；在 MODIFY I 中给予单独的 actoxumab（每公斤 10 毫克），但在计划的中期分析后停止。主要终点是在改良意向治疗人群中输注后 12 周内复发感染（初次临床治愈后的新发作）。
结果：在两项试验中，与安慰剂相比，单独使用 bezlotoxumab 的复发性艰难梭菌感染率显著降低（MODIFY I：17%[386 例中的 67 例] vs. 28%[395 例中的 109 例]；调整差异，-10.1%；95%置信区间[CI]，-15.9 至-4.3；P<0.001；MODIFY II：16%[395 例中的 62 例] vs. 26%[378 例中的 97 例]；调整差异，-9.9%；95%CI，-15.5 至-4.3；P<0.001），与安慰剂相比，使用 actoxumab 和 bezlotoxumab 的复发性艰难梭菌感染率也显著降低（MODIFY I：16%[383 例中的 61 例] vs. 28%[395 例中的 109 例]；调整差异，-11.6%；95%CI，-17.4 至-5.9；P<0.001；MODIFY II：15%[390 例中的 58 例] vs. 26%[378 例中的 97 例]；调整差异，-10.7%；95%CI，-16.4 至-5.1；P<0.001）。在预先指定的亚组分析（合并数据集）中，在高复发感染风险或不良结局风险的亚组中，接受 bezlotoxumab 的两组的复发感染率均低于安慰剂组。初始临床治愈率为 bezlotoxumab 单独治疗组 80%，actoxumab 和 bezlotoxumab 联合治疗组 73%，安慰剂组 80%；持续治愈率（12 周内无初始临床治愈和复发）分别为 64%、58%和 54%。这些组的不良事件发生率相似；最常见的事件是腹泻和恶心。
结论：在接受抗生素治疗原发性或复发性艰难梭菌感染的参与者中，与安慰剂相比，bezlotoxumab 显著降低了复发性感染的发生率，且安全性与安慰剂相似。添加 actoxumab 并未提高疗效。（由默克公司资助；MODIFY I 和 MODIFY II 临床试验.gov 编号，NCT01241552 和 NCT01513239）。
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