Medline ® Abstract for Reference 102
of 'Clostridium difficile in adults: Treatment'
Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection.
Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, Cornely OA, Rahav G, Bouza E, Lee C, Jenkin G, Jensen W, Kim YS, Yoshida J, Gabryelski L, Pedley A, Eves K, Tipping R, Guris D, Kartsonis N, Dorr MB, MODIFY I and MODIFY II Investigators
N Engl J Med. 2017;376(4):305.
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 .).
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