Mixed Results for Fecal Transplant in First Randomized Trial
Mixed Results for Fecal Transplant in First Randomized Trial
HONOLULU — Fecal microbiota transplantation prevented further Clostridium difficile episodes in patients with recurrent infection in one of two treatment centers, but in another center, there was no difference between transplantation and placebo, according to the first randomized trial of its kind.
"The differences in efficacy by site we observed may be explained by the different characteristics of enrolled subjects at each site," said Colleen Kelly, from Brown University in Providence, Rhode Island.
Dr Kelly presented the study results here at the American College of Gastroenterology 2015 Annual Meeting.
C difficile is currently the leading cause of healthcare-associated infection in the United States. An estimated 20% of patients experience a recurrence after treatment for an initial infection, and approximately 40% to 60% of patients who have had at least one recurrent infection will have further recurrences.
Leading Cause of Healthcare-Associated Infection
Fecal microbiota transplantation was shown to effectively reduce recurrence in patients with refractory C difficile infection in several case series and in two open-label clinical trials. But this is the first randomized double-blind placebo controlled trial to assess the technique in the refractory population.
Dr Kelly and her colleagues evaluated 46 adults who had experienced at least three recurrent infections and who had failed standard vancomycin therapy.
Twenty-two patients were randomly assigned to undergo transplantation with donor stool delivered through colonoscopy after a 3-day vancomycin washout period and standard bowel prep. The other 24 patients, who underwent transplantation with their own stool, served as the control group.
The procedures were performed at two centers: 24 patients were treated in Providence and 22 were treated in the Bronx, New York.
When a clinical cure — defined as resolution of diarrhea with no further requirement for C difficile therapy during 8 weeks of follow-up — was not achieved, patients were eligible for open-label transplantation with donor stool.
Curiously, transplantation was significantly more effective in the intervention group than in the control group in Rhode Island, but not in the Bronx.
Table. Clinical Cures
The investigators do not have a solid explanation for this discrepancy. However, they note, the duration of C difficile infection was generally longer in the Bronx than in Providence, the recurrences were more frequent, and the duration of vancomycin therapy was longer.
This suggests that more aggressively treated patients might have actually achieved a clinical cure before being enrolled in the study, Dr Kelly said.
In an intention-to-treat analysis of all patients, a clinical cure was achieved by more patients in the intervention group than in the control group (20 of 22 vs 15 of 24 patients; P = .024). Clinical failure occurred a mean of 10 days after the procedure (range, 1 to 42 days).
Of the 11 patients who developed recurrent infection and went on to open-label transplantation with donor stool, 10 remained free from further recurrence and one was lost to follow-up.
From week 8 to week 24 of follow-up, there were no late recurrences, Dr Kelly reported.
There were no serious adverse events directly related to fecal microbiota transplantation, and the rate of other adverse events did not differ significantly between the intervention and control groups, she explained.
A "Celebrity" Effect?
The high cure rate in the Bronx control group could have been a type II statistical error, a false negative related to the small sample, or it might have been related to a so-called celebrity effect, said Lauren Gerson, MD, MSc, from the California Pacific Medical in San Francisco, who was not involved in the study.
Dr Kelly's coinvestigator — Lawrence Brandt, MD, from the Montefiore Medical Center in the Bronx — "is very famous, and people wait a long time to see him," she told Medscape Medical News. "It's possible that during the waiting time, they got a lot more treatment, and by the time they saw him, they may have been clinically cured."
It is also possible that some of the patients had postinfection irritable bowel syndrome, not recurrent C difficile infection, which could explain the high response rate in the control group in the Bronx.
This study was supported by the National Institutes of Health. Dr Kelly reports being a consultant for Seres Health and receiving research support from Assembly Biosciences. Dr Gerson reports serving as a consultant for Ironwood, CapsoVision, IntroMedic, Covidien, Given Imaging, and Fujinon.
American College of Gastroenterology (ACG) 2015 Annual Meeting: Abstract 6. Presented October 19, 2015.
HONOLULU — Fecal microbiota transplantation prevented further Clostridium difficile episodes in patients with recurrent infection in one of two treatment centers, but in another center, there was no difference between transplantation and placebo, according to the first randomized trial of its kind.
"The differences in efficacy by site we observed may be explained by the different characteristics of enrolled subjects at each site," said Colleen Kelly, from Brown University in Providence, Rhode Island.
Dr Kelly presented the study results here at the American College of Gastroenterology 2015 Annual Meeting.
C difficile is currently the leading cause of healthcare-associated infection in the United States. An estimated 20% of patients experience a recurrence after treatment for an initial infection, and approximately 40% to 60% of patients who have had at least one recurrent infection will have further recurrences.
Leading Cause of Healthcare-Associated Infection
Fecal microbiota transplantation was shown to effectively reduce recurrence in patients with refractory C difficile infection in several case series and in two open-label clinical trials. But this is the first randomized double-blind placebo controlled trial to assess the technique in the refractory population.
Dr Kelly and her colleagues evaluated 46 adults who had experienced at least three recurrent infections and who had failed standard vancomycin therapy.
Twenty-two patients were randomly assigned to undergo transplantation with donor stool delivered through colonoscopy after a 3-day vancomycin washout period and standard bowel prep. The other 24 patients, who underwent transplantation with their own stool, served as the control group.
The procedures were performed at two centers: 24 patients were treated in Providence and 22 were treated in the Bronx, New York.
When a clinical cure — defined as resolution of diarrhea with no further requirement for C difficile therapy during 8 weeks of follow-up — was not achieved, patients were eligible for open-label transplantation with donor stool.
Curiously, transplantation was significantly more effective in the intervention group than in the control group in Rhode Island, but not in the Bronx.
Table. Clinical Cures
| Treatment Center | Intervention Group (n = 22) | Control Group (n = 24) | P Value |
| Providence | 9 of 10 | 6 of 14 | .019 |
| Bronx | 11 of 12 | 9 of 10 | .89 |
The investigators do not have a solid explanation for this discrepancy. However, they note, the duration of C difficile infection was generally longer in the Bronx than in Providence, the recurrences were more frequent, and the duration of vancomycin therapy was longer.
This suggests that more aggressively treated patients might have actually achieved a clinical cure before being enrolled in the study, Dr Kelly said.
In an intention-to-treat analysis of all patients, a clinical cure was achieved by more patients in the intervention group than in the control group (20 of 22 vs 15 of 24 patients; P = .024). Clinical failure occurred a mean of 10 days after the procedure (range, 1 to 42 days).
Of the 11 patients who developed recurrent infection and went on to open-label transplantation with donor stool, 10 remained free from further recurrence and one was lost to follow-up.
From week 8 to week 24 of follow-up, there were no late recurrences, Dr Kelly reported.
There were no serious adverse events directly related to fecal microbiota transplantation, and the rate of other adverse events did not differ significantly between the intervention and control groups, she explained.
A "Celebrity" Effect?
The high cure rate in the Bronx control group could have been a type II statistical error, a false negative related to the small sample, or it might have been related to a so-called celebrity effect, said Lauren Gerson, MD, MSc, from the California Pacific Medical in San Francisco, who was not involved in the study.
Dr Kelly's coinvestigator — Lawrence Brandt, MD, from the Montefiore Medical Center in the Bronx — "is very famous, and people wait a long time to see him," she told Medscape Medical News. "It's possible that during the waiting time, they got a lot more treatment, and by the time they saw him, they may have been clinically cured."
It is also possible that some of the patients had postinfection irritable bowel syndrome, not recurrent C difficile infection, which could explain the high response rate in the control group in the Bronx.
This study was supported by the National Institutes of Health. Dr Kelly reports being a consultant for Seres Health and receiving research support from Assembly Biosciences. Dr Gerson reports serving as a consultant for Ironwood, CapsoVision, IntroMedic, Covidien, Given Imaging, and Fujinon.
American College of Gastroenterology (ACG) 2015 Annual Meeting: Abstract 6. Presented October 19, 2015.
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