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N Engl J Med. 2017 Jan 26;376(4):305-317. doi: 10.1056/NEJMoa1602615.

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection.

Collaborators (326)

Playford G, McGechie D, Iredell J, Allworth A, Cheng A, Choi NJ, Thalhammer F, Maieron A, Wenisch C, Meyer B, Jacobs F, Delmee M, Peetermans W, Giot JB, Munhoz AL, Kallas EG, Ladeira JP, Bernstein CN, Grimard D, McGeer A, Poirier A, Valiquette L, Miller M, Oughton M, Trottier S, Dolce P, Smyth D, Gambra P, Palma S, Rojas L, Northland R, Arellano MC, Perez J, Barreto MF, Gomez JM, Ramirez I, Correa A, Onate J, Rohacova H, Stastnik M, Zjevikova A, Blazek J, Kumpel P, Petersen AM, Gluud LL, Staugaard HM, Tvede M, Glerup H, Madsen SM, Helms M, Naumann R, Karthaus M, Reinshagen M, Raz R, Giladi M, Chowers M, Bishara J, Quirino T, Castelli F, Bassetti M, Rizzardini G, Vismara E, Puoti M, Viale P, Menichetti F, Cauda R, Bonfanti P, Franzetti F, Gori A, Minoli L, Noriega ER, Mills GD, Ritchie S, Burns A, Pithie A, dos Santos RM, Aldomiro F, Fernando PB, Rola J, Reis E, Van Zyl JH, Aboo N, Richards G, Hernandez MJ, de Medrano VA, Prunonosa LM, Gonzalez JL, Reinoso JC, Martinez AR, Cisneros JD, Banos JR, Sheridan R, Minton J, Williams J, Stanley P, Guleri A, Llewelyn M, Todd N, Barlow G, Bacon AE, Baird IM, Baxter R, Zenilman JM, Beshay M, Betts RF, Brettholz EM, Buitrago MI, Carlson RW, Cook PP, Dupont HL, Foley C, Freilich B, Giron JA, Golan Y, Green S, Hall MC, Johnson DJ, Jones RK, Graham DR, Kazimir M, Keating M, Brumble LM, Kumar PN, Liappis AP, Libke R, Mehra PK, Overcash SJ, Mullane KM, Nguyen MH, Patel MC, Powers CK, Pullman J, Keegan J, Nepal S, English G, Ricci RL, Risi GF, Rodriguez M, Schmitt CM, Sims MD, Kamepalli R, Tural A, Vazquez JA, Alangaden GJ, Weavind LM, Young MA, Chen ST, Liu E, Nguyen HH, Alfonso TB, Muse DD, Orenstein R, Yacyshyn B, Gebhard RE, Dinges W, Bolton M, Rubin M, Kuemmerle JF, Limaye AP, Friedenberg KA, Hiemenz JW, Quadri A, Martinez JV, Barcan LA, Cordova E, Mykietiuk A, Losso M, Fedorak RN, Steiner T, Gerson M, Weiss K, Dlouhy P, Vitous A, Benes J, Husa P, Knizek P, Anttila VJ, Broas M, Camou F, Postil D, Launay O, Corroyer-Simovic B, Meynard JL, Schneider S, Molina JM, Neau D, Zalcman G, Boutoille D, Ostermann H, Heinz W, Reuter S, Oren I, Schiff E, Umemoto T, Masubuchi T, Mukawa K, Yasuda K, Imokawa S, Fukuda K, Ohta H, Harada N, Fujii S, Tamaki S, Yasui S, Furukawa K, Takahashi M, Uraoka T, Watanabe M, Ikehara Y, Kodaira M, Komatsu H, Higashi K, Taguchi F, Ura N, Serizawa Y, Fukuchi T, Ashikawa T, Shabana M, Okubo M, Matsumoto M, Kurihara A, Miyasaka E, Shimizu M, Tominaga H, Kubota T, Kashiwazaki M, Masuda Y, Terasaki S, Okafuji H, Mieno H, Urabe T, Okamoto E, Kajimura M, Yamagishi Y, Rydzewska G, Mach T, Ciechanowski K, Podlasin R, Tomasiewicz K, Janczewska-Kazek E, Czarnobilski K, Halota W, Gryglewska B, Plesniak R, Dabrowiecki P, Lipowski D, Simanenkov V, Shcheglova L, Uspenskiy Y, Cheganov A, Han DS, Kim JS, Hong SP, Kim TI, Jang BI, Byeon JS, Kim E, Kim MJ, Lee J, Pai H, Cheong HJ, Lee S, Loyarte JA, Gonzalez JC, Santiago EB, Lopez JR, Baranda JM, Viladomiu AS, Calbo E, Lannergard A, Falt J, Gardlund B, Andersson LM, Fraenkel CJ, Rombo L, Widmer A, Chen YC, Sheng WH, Wang FD, Wang NC, Lee CH, Chen YH, Chuang YC, Unal S, Ozaras R, Esen S, Ural O, Ayaz C, Sakarya S, Celebi A, Mistik R, Bedimo R, Bressler A, Mckinley MJ, Quirk D, Talansky AL, Agronin ME, Akhrass FA, Ali M, Alrabaa SF, Assi MA, Calfee DP, Carson P, Mariani PG, Guerrero D, Dubberke ER, Hardi R, Hazan-Steinberg S, Itani KM, Jauregui-Peredo EL, Kasabji A, Hameed M, Murillo A, Odio AJ, Shah P, Braun TI, Slim J, Sloan L, Srinivasan S, Tan MJ, Clough LA, Herr D, Miller LG, Dorfmeister J, Khan O, Melik-Abrahamian F.

Author information

1
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.).

Abstract

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 .).

PMID:
28121498
DOI:
10.1056/NEJMoa1602615
[Indexed for MEDLINE]
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