Clinical Trial Results:
Rectal Bacteriotherapy, Faecal microbiota transplantation or oral vancomycin for the treatment of recurrent Clostridium Difficile infection: A randomised controlled trial
Summary
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EudraCT number |
2015-003062-82 |
Trial protocol |
DK |
Global end of trial date |
18 Sep 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
01 May 2021
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First version publication date |
01 May 2021
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Other versions |
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Summary report(s) |
Table of all AEs and SAEs in the trial |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
RBI/FMT-CDI
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02774382 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Department of Medicine, Zealand University Hospital
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Sponsor organisation address |
Lykkebækvej 1, Køge, Denmark, 4600
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Public contact |
Clinical Trial Information, Department of Medicine, Zealand University Hospital, Køge, Denmark, +45 23345235, aala@regionsjaelland.dk
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Scientific contact |
Clinical Trial Information, Department of Medicine, Zealand University Hospital, Køge, Denmark, +45 47322405, aala@regionsjaelland.dk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Sep 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Sep 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Sep 2019
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To investigate the treatment effect of rectal bacteriotherapy instillation (RBI) and faecal microbiota transplantation /FMT) against the standard antibotic treatment with vancomycin for patients with recurrent Clostridium Difficile infection in a randomised controlled trial
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Protection of trial subjects |
All participants gave written informed consent. The Regional Committee of Health Research Ethics (SJ-478),
the Danish Medicines Agency (2015-003062-82) and The Danish Data Protection Agency (REG-103-2015) approved the study. We conducted the trial according to the Helsinki Declaration II and to the principles of Good Clinical Practice. An external party monitored the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 May 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Denmark: 98
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Worldwide total number of subjects |
98
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EEA total number of subjects |
98
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
27
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From 65 to 84 years |
55
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85 years and over |
16
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Recruitment
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Recruitment details |
We assessed the eligibility of all consecutive individuals with a positive test for C difficile from all clinical microbiological laboratories in eastern Denmark from May 2017 - December 2018 at Zealand University Hospital and from June 2017 - March 2019 at Hvidovre University hospital. Predefined inclusion- and exclusion criteria were used. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
We screened 1020 persons with a repeated positive CD test within 90 days, yet only included 98. Exclusion were primarily due to the person being asymptomatic at the time of testing or not being able to give informed consent. Furthermore, some were excluded due to having other GI-disease with diarrhoea or declined to participate | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Blinding implementation details |
Computer-generated stratified randomisation in blocks of six was used with allocation concealment in sealed opaque envelopes with sequential
numbers for each stratum. An independent party conducted the block size, randomisation code and packing of envelopes. The trial personnel were blinded to this process. After allocation, the trial was open-label.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Faecal microbiota transplantation (FMT) | ||||||||||||||||||||||||
Arm description |
Participants were pre-treated with oral vancomycin 125 mg four times a day for 7-14 days. This was discontinued 36 hours prior to FMT. Frozen donor stool from a donor stool bank was administered by rectal enema once, but with a possibility to repeat it up to two times within 14 days after the first infusion. The indication for repetition was ongoing or new-onset diarrhoea (≥3 loose or liquid stools per day), as judged by a trial physician, without new testing for C difficile. We used a different donor when repeating FMTs. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Donor stool (not considered a medicinal product)
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Investigational medicinal product code |
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Other name |
FMT
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Pharmaceutical forms |
Gastroenteral solution, Rectal suspension
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Routes of administration |
Gastroenteral use, Rectal use
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Dosage and administration details |
Frozen donor stool from a donor stool bank. One product consists of 50 g stool, 150 mL NaCl and 20 mL glycerol (85%). It was administered by rectal enema once, but with a possibility to repeat it up to two times within 14 days after the first infusion. The indication for repetition was ongoing or new-onset diarrhoea (≥3 loose or liquid stools per day), as judged by a trial physician, without new testing for C difficile. We used a different donor when repeating FMTs.
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Arm title
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Rectal bacteriotherapy (RBT) | ||||||||||||||||||||||||
Arm description |
The standardised laboratory-based bacterial mixture used for rectal bacteriotherapy consisted of 12 bacterial strains suspended in 200 ml isotonic saline with concentrations of 5 × 10-10 bacteria of each strain. Included strains: Escherichia coli MT-1108-1, Escherichia coli MT-1109, Enterococcus cassiliflavus, Enterococcus gallinarum, Bacteroides thetaiotaomicron, Bacteroides ovatus, Bacteroides vulgatus, Clostridium bifermentans, Clostridium innocuum, Coprobacillus cateniformis, LactobacilIus rhamnosus, LactobacilIus gasserii. Participants were pretreated with oral vancomycin 125 mg four times a day for 7-14 days. This was discontinued 12 hours prior to RBT. RBT was administered by rectal enema with three infusions on three consecutive days for all participants in this group. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Rectal bacteriotherapy
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Investigational medicinal product code |
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Other name |
RBT
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Pharmaceutical forms |
Rectal suspension
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Routes of administration |
Rectal use
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Dosage and administration details |
The bacterial mixture used for rectal bacteriotherapy consisted of 12 bacterial strains suspended in 200 ml isotonic saline with concentrations of 5 × 10-10 bacteria of each strain. Included strains: Escherichia coli MT-1108-1, Escherichia coli MT-1109, Enterococcus cassiliflavus, Enterococcus gallinarum, Bacteroides thetaiotaomicron, Bacteroides ovatus, Bacteroides vulgatus, Clostridium bifermentans, Clostridium innocuum, Coprobacillus cateniformis, LactobacilIus rhamnosus, LactobacilIus gasserii.
RBT was administered by rectal enema with three infusions on three consecutive days for all participants in this group.
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Arm title
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Oral vancomycin (control) | ||||||||||||||||||||||||
Arm description |
All participants in the vancomycin group received monotherapy with oral capsule vancomycin 125 mg four times daily for 14 days. Furthermore, participants with ≥2 recurrences of CDI were treated with additionally 5 weeks of tapering as recommended in guidelines. The tapering regimen included oral vancomycin 125 mg twice daily for 1 week, 125 mg once daily for 1 week, 125 mg every other day for 1 week and 125 mg every third day for 2 weeks. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Vancomcyin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
All participants in the vancomycin group received monotherapy with oral capsule vancomycin 125 mg four times daily for 14 days.
Furthermore, participants with ≥2 recurrences of CDI were treated with additionally 5 weeks of tapering as recommended in guidelines.
The tapering regimen included oral vancomycin 125 mg twice daily for 1 week, 125 mg once daily for 1 week, 125 mg every other day for 1 week and 125 mg every third day for 2 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Faecal microbiota transplantation (FMT)
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Reporting group description |
Participants were pre-treated with oral vancomycin 125 mg four times a day for 7-14 days. This was discontinued 36 hours prior to FMT. Frozen donor stool from a donor stool bank was administered by rectal enema once, but with a possibility to repeat it up to two times within 14 days after the first infusion. The indication for repetition was ongoing or new-onset diarrhoea (≥3 loose or liquid stools per day), as judged by a trial physician, without new testing for C difficile. We used a different donor when repeating FMTs. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Rectal bacteriotherapy (RBT)
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Reporting group description |
The standardised laboratory-based bacterial mixture used for rectal bacteriotherapy consisted of 12 bacterial strains suspended in 200 ml isotonic saline with concentrations of 5 × 10-10 bacteria of each strain. Included strains: Escherichia coli MT-1108-1, Escherichia coli MT-1109, Enterococcus cassiliflavus, Enterococcus gallinarum, Bacteroides thetaiotaomicron, Bacteroides ovatus, Bacteroides vulgatus, Clostridium bifermentans, Clostridium innocuum, Coprobacillus cateniformis, LactobacilIus rhamnosus, LactobacilIus gasserii. Participants were pretreated with oral vancomycin 125 mg four times a day for 7-14 days. This was discontinued 12 hours prior to RBT. RBT was administered by rectal enema with three infusions on three consecutive days for all participants in this group. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Oral vancomycin (control)
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Reporting group description |
All participants in the vancomycin group received monotherapy with oral capsule vancomycin 125 mg four times daily for 14 days. Furthermore, participants with ≥2 recurrences of CDI were treated with additionally 5 weeks of tapering as recommended in guidelines. The tapering regimen included oral vancomycin 125 mg twice daily for 1 week, 125 mg once daily for 1 week, 125 mg every other day for 1 week and 125 mg every third day for 2 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Faecal microbiota transplantation (FMT)
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Reporting group description |
Participants were pre-treated with oral vancomycin 125 mg four times a day for 7-14 days. This was discontinued 36 hours prior to FMT. Frozen donor stool from a donor stool bank was administered by rectal enema once, but with a possibility to repeat it up to two times within 14 days after the first infusion. The indication for repetition was ongoing or new-onset diarrhoea (≥3 loose or liquid stools per day), as judged by a trial physician, without new testing for C difficile. We used a different donor when repeating FMTs. | ||
Reporting group title |
Rectal bacteriotherapy (RBT)
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Reporting group description |
The standardised laboratory-based bacterial mixture used for rectal bacteriotherapy consisted of 12 bacterial strains suspended in 200 ml isotonic saline with concentrations of 5 × 10-10 bacteria of each strain. Included strains: Escherichia coli MT-1108-1, Escherichia coli MT-1109, Enterococcus cassiliflavus, Enterococcus gallinarum, Bacteroides thetaiotaomicron, Bacteroides ovatus, Bacteroides vulgatus, Clostridium bifermentans, Clostridium innocuum, Coprobacillus cateniformis, LactobacilIus rhamnosus, LactobacilIus gasserii. Participants were pretreated with oral vancomycin 125 mg four times a day for 7-14 days. This was discontinued 12 hours prior to RBT. RBT was administered by rectal enema with three infusions on three consecutive days for all participants in this group. | ||
Reporting group title |
Oral vancomycin (control)
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Reporting group description |
All participants in the vancomycin group received monotherapy with oral capsule vancomycin 125 mg four times daily for 14 days. Furthermore, participants with ≥2 recurrences of CDI were treated with additionally 5 weeks of tapering as recommended in guidelines. The tapering regimen included oral vancomycin 125 mg twice daily for 1 week, 125 mg once daily for 1 week, 125 mg every other day for 1 week and 125 mg every third day for 2 weeks. |
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End point title |
Clinical cure within 90 days | ||||||||||||||||
End point description |
Clinical cure was defined as absence of C. difficile infection (i.e. absence of diarrhoea or diarrhoea with a negative C difficile test), within 90 days after ended treatment.
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End point type |
Primary
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End point timeframe |
Within 90 days after ended treatment
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Attachments |
Clinical cure rate |
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Statistical analysis title |
Comparison of primary end point | ||||||||||||||||
Comparison groups |
Faecal microbiota transplantation (FMT) v Rectal bacteriotherapy (RBT) v Oral vancomycin (control)
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||
Method |
Chi-squared | ||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||
Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
25 | ||||||||||||||||
upper limit |
75 |
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End point title |
180-day mortality | ||||||||||||||||
End point description |
All-cause mortality
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End point type |
Secondary
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End point timeframe |
180 days after ended treatment
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Attachments |
All-cause mortality at 180-days follow-up |
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Statistical analysis title |
Odds ratio | ||||||||||||||||
Comparison groups |
Faecal microbiota transplantation (FMT) v Rectal bacteriotherapy (RBT) v Oral vancomycin (control)
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||
Method |
Fisher exact | ||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||
Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
25 | ||||||||||||||||
upper limit |
75 |
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Adverse events information
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Timeframe for reporting adverse events |
From inclusion to 14 days after ended treatment
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
NA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
NA
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Reporting groups
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Reporting group title |
Faecal microbiota transplantation (FMT)
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Reporting group description |
Participants were pre-treated with oral vancomycin 125 mg four times a day for 7-14 days. This was discontinued 36 hours prior to FMT. Frozen donor stool from a donor stool bank was administered by rectal enema once, but with a possibility to repeat it up to two times within 14 days after the first infusion. The indication for repetition was ongoing or new-onset diarrhoea (≥3 loose or liquid stools per day), as judged by a trial physician, without new testing for C difficile. We used a different donor when repeating FMTs. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Rectal bacteriotherapy (RBT)
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Reporting group description |
The standardised laboratory-based bacterial mixture used for rectal bacteriotherapy consisted of 12 bacterial strains suspended in 200 ml isotonic saline with concentrations of 5 × 10-10 bacteria of each strain. Included strains: Escherichia coli MT-1108-1, Escherichia coli MT-1109, Enterococcus cassiliflavus, Enterococcus gallinarum, Bacteroides thetaiotaomicron, Bacteroides ovatus, Bacteroides vulgatus, Clostridium bifermentans, Clostridium innocuum, Coprobacillus cateniformis, LactobacilIus rhamnosus, LactobacilIus gasserii. Participants were pretreated with oral vancomycin 125 mg four times a day for 7-14 days. This was discontinued 12 hours prior to RBT. RBT was administered by rectal enema with three infusions on three consecutive days for all participants in this group. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Oral vancomycin (control)
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Reporting group description |
All participants in the vancomycin group received monotherapy with oral capsule vancomycin 125 mg four times daily for 14 days. Furthermore, participants with ≥2 recurrences of CDI were treated with additionally 5 weeks of tapering as recommended in guidelines. The tapering regimen included oral vancomycin 125 mg twice daily for 1 week, 125 mg once daily for 1 week, 125 mg every other day for 1 week and 125 mg every third day for 2 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
A interim analysis was performed for the first 90 participants. When the reported results were apparent, including the mortality data, the study was terminated due to futility and ethical concerns—even though the Haybittle-Peto boundary was not met | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/33694229 http://www.ncbi.nlm.nih.gov/pubmed/31273647 |