Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C difficile infection: A Randomized clinical trial

Dale N. Gerding, Thomas Meyer, Christine Lee, Stuart H. Cohen, Uma K. Murthy, Andre Poirier, Trevor C VanSchooneveld, Darrell S. Pardi, Antonio Ramos, Michelle A. Barron, Hongzi Chen, Stephen Villano

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

IMPORTANCE: Clostridium difficile is the most common cause of health care-associated infection in US hospitals. Recurrence occurs in 25% to 30% of patients. OBJECTIVE: To determine the safety, fecal colonization, recurrence rate, and optimal dosing schedule of nontoxigenic C difficile strain M3 (VP20621; NTCD-M3) for prevention of recurrent C difficile infection (CDI). DESIGN, SETTING, AND PARTICIPANTS: Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from June 2011 to June 2013 among 173 patients aged 18 years or older who were diagnosed as having CDI (first episode or first recurrence) and had successfully completed treatment with metronidazole, oral vancomycin, or both at 44 study centers in the United States, Canada, and Europe. INTERVENTIONS: Patients were randomly assigned to receive 1 of 4 treatments: oral liquid formulation of NTCD-M3, 104 spores/d for 7 days (n = 43), 107 spores/d for 7 days (n = 44), or 107 spores/d for 14 days (n = 42), or placebo for 14 days (n = 44). MAIN OUTCOMES AND MEASURES: The primary outcome was safety and tolerability of NTCD-M3 within 7 days of treatment. Exploratory secondary outcomes included fecal colonization with NTCD-M3 from end of study drug through week 6 and CDI recurrence from day 1 through week 6. RESULTS: Among 168 patients who started treatment, 157 completed treatment. One or more treatment-emergent adverse events were reported in 78% of patients receiving NTCD-M3 and 86% of patients receiving placebo. Diarrhea and abdominal pain were reported in 46% and 17% of patients receiving NTCD-M3 and 60% and 33% of placebo patients, respectively. Serious treatment-emergent adverse events were reported in 7% of patients receiving placebo and 3% of all patients who received NTCD-M3. Headache was reported in 10% of patients receiving NTCD-M3 and 2% of placebo patients. Fecal colonization occurred in 69% of NTCD-M3 patients: 71% with 107 spores/d and 63% with 104 spores/d. Recurrence of CDI occurred in 13 (30%) of 43 placebo patients and 14 (11%) of 125 NTCD-M3 patients (odds ratio [OR], 0.28; 95% CI, 0.11-0.69; P = .006); the lowest recurrence was in 2 (5%) of 43 patients receiving 107 spores/d for 7 days (OR, 0.1; 95% CI, 0.0-0.6; P = .01 vs placebo]). Recurrence occurred in 2 (2%) of 86 patients who were colonized vs 12 (31%) of 39 patients who received NTCD-M3 and were not colonized (OR, 0.01; 95% CI, 0.00-0.05; P < .001). CONCLUSIONS AND RELEVANCE: Among patients with CDI who clinically recovered following treatment with metronidazole or vancomycin, oral administration of spores of NTCD-M3 was well tolerated and appeared to be safe. Nontoxigenic C difficile strain M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01259726.

Original languageEnglish (US)
Pages (from-to)1719-1727
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume313
Issue number17
DOIs
StatePublished - May 5 2015

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Clostridium difficile
Spores
Randomized Controlled Trials
Infection
Placebos
Recurrence
Odds Ratio
Metronidazole
Vancomycin
Therapeutics
Safety

ASJC Scopus subject areas

  • Medicine(all)

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Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C difficile infection : A Randomized clinical trial. / Gerding, Dale N.; Meyer, Thomas; Lee, Christine; Cohen, Stuart H.; Murthy, Uma K.; Poirier, Andre; VanSchooneveld, Trevor C; Pardi, Darrell S.; Ramos, Antonio; Barron, Michelle A.; Chen, Hongzi; Villano, Stephen.

In: JAMA - Journal of the American Medical Association, Vol. 313, No. 17, 05.05.2015, p. 1719-1727.

Research output: Contribution to journalArticle

Gerding, Dale N. ; Meyer, Thomas ; Lee, Christine ; Cohen, Stuart H. ; Murthy, Uma K. ; Poirier, Andre ; VanSchooneveld, Trevor C ; Pardi, Darrell S. ; Ramos, Antonio ; Barron, Michelle A. ; Chen, Hongzi ; Villano, Stephen. / Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C difficile infection : A Randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2015 ; Vol. 313, No. 17. pp. 1719-1727.
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TY - JOUR

T1 - Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C difficile infection

T2 - A Randomized clinical trial

AU - Gerding, Dale N.

AU - Meyer, Thomas

AU - Lee, Christine

AU - Cohen, Stuart H.

AU - Murthy, Uma K.

AU - Poirier, Andre

AU - VanSchooneveld, Trevor C

AU - Pardi, Darrell S.

AU - Ramos, Antonio

AU - Barron, Michelle A.

AU - Chen, Hongzi

AU - Villano, Stephen

PY - 2015/5/5

Y1 - 2015/5/5

N2 - IMPORTANCE: Clostridium difficile is the most common cause of health care-associated infection in US hospitals. Recurrence occurs in 25% to 30% of patients. OBJECTIVE: To determine the safety, fecal colonization, recurrence rate, and optimal dosing schedule of nontoxigenic C difficile strain M3 (VP20621; NTCD-M3) for prevention of recurrent C difficile infection (CDI). DESIGN, SETTING, AND PARTICIPANTS: Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from June 2011 to June 2013 among 173 patients aged 18 years or older who were diagnosed as having CDI (first episode or first recurrence) and had successfully completed treatment with metronidazole, oral vancomycin, or both at 44 study centers in the United States, Canada, and Europe. INTERVENTIONS: Patients were randomly assigned to receive 1 of 4 treatments: oral liquid formulation of NTCD-M3, 104 spores/d for 7 days (n = 43), 107 spores/d for 7 days (n = 44), or 107 spores/d for 14 days (n = 42), or placebo for 14 days (n = 44). MAIN OUTCOMES AND MEASURES: The primary outcome was safety and tolerability of NTCD-M3 within 7 days of treatment. Exploratory secondary outcomes included fecal colonization with NTCD-M3 from end of study drug through week 6 and CDI recurrence from day 1 through week 6. RESULTS: Among 168 patients who started treatment, 157 completed treatment. One or more treatment-emergent adverse events were reported in 78% of patients receiving NTCD-M3 and 86% of patients receiving placebo. Diarrhea and abdominal pain were reported in 46% and 17% of patients receiving NTCD-M3 and 60% and 33% of placebo patients, respectively. Serious treatment-emergent adverse events were reported in 7% of patients receiving placebo and 3% of all patients who received NTCD-M3. Headache was reported in 10% of patients receiving NTCD-M3 and 2% of placebo patients. Fecal colonization occurred in 69% of NTCD-M3 patients: 71% with 107 spores/d and 63% with 104 spores/d. Recurrence of CDI occurred in 13 (30%) of 43 placebo patients and 14 (11%) of 125 NTCD-M3 patients (odds ratio [OR], 0.28; 95% CI, 0.11-0.69; P = .006); the lowest recurrence was in 2 (5%) of 43 patients receiving 107 spores/d for 7 days (OR, 0.1; 95% CI, 0.0-0.6; P = .01 vs placebo]). Recurrence occurred in 2 (2%) of 86 patients who were colonized vs 12 (31%) of 39 patients who received NTCD-M3 and were not colonized (OR, 0.01; 95% CI, 0.00-0.05; P < .001). CONCLUSIONS AND RELEVANCE: Among patients with CDI who clinically recovered following treatment with metronidazole or vancomycin, oral administration of spores of NTCD-M3 was well tolerated and appeared to be safe. Nontoxigenic C difficile strain M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01259726.

AB - IMPORTANCE: Clostridium difficile is the most common cause of health care-associated infection in US hospitals. Recurrence occurs in 25% to 30% of patients. OBJECTIVE: To determine the safety, fecal colonization, recurrence rate, and optimal dosing schedule of nontoxigenic C difficile strain M3 (VP20621; NTCD-M3) for prevention of recurrent C difficile infection (CDI). DESIGN, SETTING, AND PARTICIPANTS: Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from June 2011 to June 2013 among 173 patients aged 18 years or older who were diagnosed as having CDI (first episode or first recurrence) and had successfully completed treatment with metronidazole, oral vancomycin, or both at 44 study centers in the United States, Canada, and Europe. INTERVENTIONS: Patients were randomly assigned to receive 1 of 4 treatments: oral liquid formulation of NTCD-M3, 104 spores/d for 7 days (n = 43), 107 spores/d for 7 days (n = 44), or 107 spores/d for 14 days (n = 42), or placebo for 14 days (n = 44). MAIN OUTCOMES AND MEASURES: The primary outcome was safety and tolerability of NTCD-M3 within 7 days of treatment. Exploratory secondary outcomes included fecal colonization with NTCD-M3 from end of study drug through week 6 and CDI recurrence from day 1 through week 6. RESULTS: Among 168 patients who started treatment, 157 completed treatment. One or more treatment-emergent adverse events were reported in 78% of patients receiving NTCD-M3 and 86% of patients receiving placebo. Diarrhea and abdominal pain were reported in 46% and 17% of patients receiving NTCD-M3 and 60% and 33% of placebo patients, respectively. Serious treatment-emergent adverse events were reported in 7% of patients receiving placebo and 3% of all patients who received NTCD-M3. Headache was reported in 10% of patients receiving NTCD-M3 and 2% of placebo patients. Fecal colonization occurred in 69% of NTCD-M3 patients: 71% with 107 spores/d and 63% with 104 spores/d. Recurrence of CDI occurred in 13 (30%) of 43 placebo patients and 14 (11%) of 125 NTCD-M3 patients (odds ratio [OR], 0.28; 95% CI, 0.11-0.69; P = .006); the lowest recurrence was in 2 (5%) of 43 patients receiving 107 spores/d for 7 days (OR, 0.1; 95% CI, 0.0-0.6; P = .01 vs placebo]). Recurrence occurred in 2 (2%) of 86 patients who were colonized vs 12 (31%) of 39 patients who received NTCD-M3 and were not colonized (OR, 0.01; 95% CI, 0.00-0.05; P < .001). CONCLUSIONS AND RELEVANCE: Among patients with CDI who clinically recovered following treatment with metronidazole or vancomycin, oral administration of spores of NTCD-M3 was well tolerated and appeared to be safe. Nontoxigenic C difficile strain M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01259726.

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