Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial.
OBJECTIVE
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).


METHODS
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.


METHODS
Patients were randomly assigned to receive 1 of 4 treatments: oral liquid formulation of NTCD-M3, 10(4) spores/d for 7 days (n = 43), 10(7) spores/d for 7 days (n = 44), or 10(7) spores/d for 14 days (n = 42), or placebo for 14 days (n = 44).


METHODS
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 10(7) spores/d and 63% with 10(4) 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 10(7) 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
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT01259726.
Edward Hines Jr VA Hospital, Hines, Illinois2Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois.
Dale N
DN
Gerding
Indiana University Health Arnett Hospital, Lafayette.
Thomas
T
Meyer
St Joseph's Healthcare Hamilton, McMaster University, Hamilton, Ontario, Canada.
Christine
C
Lee
Division of Infectious Diseases, University of California at Davis Medical Center, Sacramento.
Stuart H
SH
Cohen
VA Medical Center and Upstate Medical University, Syracuse, New York.
Uma K
UK
Murthy
Centre de Santé et de Services Sociaux de Trois-Rivières, Trois-Rivières, Québec, Canada.
Andre
A
Poirier
Division of Infectious Disease, University of Nebraska Medical Center, Omaha.
Trevor C
TC
Van Schooneveld
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
Darrell S
DS
Pardi
Hospital Universitario Puerta de Hierro, Madrid, Spain.
Antonio
A
Ramos
Internal Medicine and Infectious Diseases, University of Colorado Denver, Aurora.
Michelle A
MA
Barron
Shire, Wayne, Pennsylvania.
Hongzi
H
Chen
Shire, Wayne, Pennsylvania.
Stephen
S
Villano
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D016360:Clostridioides difficile; D003967:Diarrhea / Q000209:etiology; D004311:Double-Blind Method; D004761:Enterocolitis, Pseudomembranous / Q000150:complications / Q000188:drug therapy / Q000517:prevention & control*; D005243:Feces / Q000382:microbiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D055502:Secondary Prevention / Q000379:methods*; D013171:Spores, Bacterial
D000900:Anti-Bacterial Agents