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Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection.

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
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Authors

Mayor MeshTerms

Clostridium difficile

Keywords
Journal Title the new england journal of medicine
Publication Year Start




PMID- 28121498
OWN - NLM
STAT- MEDLINE
DA  - 20170125
DCOM- 20170207
LR  - 20170207
IS  - 1533-4406 (Electronic)
IS  - 0028-4793 (Linking)
VI  - 376
IP  - 4
DP  - 2017 Jan 26
TI  - Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection.
PG  - 305-317
LID - 10.1056/NEJMoa1602615 [doi]
AB  - 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&lt;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&lt;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&lt;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&lt;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
      .).
FAU - Wilcox, Mark H
AU  - Wilcox MH
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Gerding, Dale N
AU  - Gerding DN
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Poxton, Ian R
AU  - Poxton IR
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Kelly, Ciaran
AU  - Kelly C
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Nathan, Richard
AU  - Nathan R
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Birch, Thomas
AU  - Birch T
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Cornely, Oliver A
AU  - Cornely OA
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Rahav, Galia
AU  - Rahav G
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Bouza, Emilio
AU  - Bouza E
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Lee, Christine
AU  - Lee C
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Jenkin, Grant
AU  - Jenkin G
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Jensen, Werner
AU  - Jensen W
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Kim, You-Sun
AU  - Kim YS
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Yoshida, Junichi
AU  - Yoshida J
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Gabryelski, Lori
AU  - Gabryelski L
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Pedley, Alison
AU  - Pedley A
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Eves, Karen
AU  - Eves K
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Tipping, Robert
AU  - Tipping R
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Guris, Dalya
AU  - Guris D
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Kartsonis, Nicholas
AU  - Kartsonis N
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
FAU - Dorr, Mary-Beth
AU  - Dorr MB
AD  - 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 Koln), 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 Investigacion
      Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion
      Biomedica 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, Vina del Mar, Chile
      (W.J.); Inje University Seoul Paik Hospital, Seoul, South Korea (Y.-S.K.); and
      Shimonoseki City Hospital, Shimonoseki, Japan (J.Y.).
CN  - MODIFY I and MODIFY II Investigators
LA  - eng
SI  - ClinicalTrials.gov/NCT01241552
SI  - ClinicalTrials.gov/NCT01513239
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - N Engl J Med
JT  - The New England journal of medicine
JID - 0255562
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (actoxumab)
RN  - 0 (bezlotoxumab)
SB  - AIM
SB  - IM
CIN - N Engl J Med. 2017 Jan 26;376(4):381-382. PMID: 28121509
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Anti-Bacterial Agents/therapeutic use
MH  - Antibodies, Monoclonal/adverse effects/*therapeutic use
MH  - Antibodies, Neutralizing/adverse effects/*therapeutic use
MH  - Clostridium Infections/*prevention &amp; control
MH  - *Clostridium difficile
MH  - Double-Blind Method
MH  - Drug Therapy, Combination
MH  - Female
MH  - Humans
MH  - Infusions, Intravenous
MH  - Intention to Treat Analysis
MH  - Kaplan-Meier Estimate
MH  - Male
MH  - Middle Aged
MH  - Secondary Prevention
MH  - Young Adult
EDAT- 2017/01/26 06:00
MHDA- 2017/02/09 06:00
CRDT- 2017/01/26 06:00
AID - 10.1056/NEJMoa1602615 [doi]
PST - ppublish
SO  - N Engl J Med. 2017 Jan 26;376(4):305-317. doi: 10.1056/NEJMoa1602615.

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