Antibiotic-associated Diarrhea, Clostridium Difficile, Diarrhea
Conditions
Keywords
antibiotic, associated, diarrhoea, saccharomyces boulardii, Antibiotic-associated diarrhoea (AAD), Clostridium difficile-associated-diarrhoea (CDAD)
Brief summary
When patients in hospitals receive antibiotics they often develop diarrhoea. The consequences may be grave for the patient. Thus far, no preventive measure is available. The investigators hypothesize that the apathogenic yeast Saccharomyces boulardii, administered in addition to the antibiotic, may prevent episodes of diarrhoea or may lead to less pronounced diarrhoea. To test this hypothesis, the investigators are carrying out a clinical trial in 1520 adult patients in several hospitals.
Detailed description
Antibiotic-associated diarrhoea (AAD) is a frequent condition in hospitalised patients receiving antibiotic treatment. The same is true for Clostridium difficile-associated diarrhoea (CDAD) with even more grave consequences of increased morbidity and mortality. The development and evaluation of preventive strategies is one key public health challenge. In the absence of clinically evaluated alternatives, probiotics have been suggested to be beneficial for the prevention of AAD and CDAD. However, data have so far been inconclusive and recently published meta-analyses strongly recommended large state-of-the-art clinical trials on probiotic substances for the prevention of AAD and CDAD. Since the efficacy, side-effects and modes of action of different probiotic bacteria and yeast are strain specific, benefits and risks cannot be generalised. The non-pathogenic yeast Saccharomyces cerevisiae var. boulardii (Sac. boulardii) is considered the most promising probiotic substance for the prevention of AAD and CDAD. We carry out a randomised, placebo controlled, double blind multicentre clinical trial to evaluate Sac. boulardii for the indication of prevention of AAD and CDAD in 1520 adult, hospitalised patients.
Interventions
Units: 500 mg per day Route of administration : Oral Use Hard-Capsule
DRUGPlacebo
Placebo
Sponsors
German Federal Ministry of Education and Research
Bernhard Nocht Institute for Tropical Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* adult patient (≥ 18 years) * patient hospitalized * patient receives systemic antibiotic treatment * patient contractually capable * patient able to follow study procedures * informed consent of patient
Exclusion criteria
* allergy against yeast and/or Perenterol® forte und/oder placebos containing Saccharomyces cerevisiae HANSEN CBS 5926, lactose-monohydrate, magnesium stearate, gelatine, sodium dodecyl sulfate, titan dioxide, microcrystalline cellulose. * central venous catheter * immunosuppression * diarrhoea and/or chronic diarrhoea * regular intake of Perenterol®, Perenterol® forte oder Yomogi® in the last seven days before the start of the study * systemic antimycotic treatment * systemic antibiotic treatment within the last 6 weeks * no protection against conception, pregnancy, or lactation * simultaneous participation in other clinical trials
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Total Number of Antibiotic-associated Diarrhea Episodes | 29 months |
Secondary
| Measure | Time frame |
|---|---|
| Incidence Density of Antibiotic-associated Diarrhea | 29 months |
| Total Number of Clostridium Difficile-associated Diarrhea Episodes | 29 months |
| Total Number of Antibiotic-associated Diarrhea Episodes Without Evidence of Clostridium Difficile (Toxins) | 29 months |
| Average Number of Bowel Movements in Patients With Antibiotic-associated Diarrhoea and Clostridium Difficile-associated Diarrhea | 29 months |
| Total Number of Discontinuation or Change of Initially Prescribed Antibiotic | 29 months |
| Average Duration of Antibiotic-associated Diarrhoea and Clostridium Difficile-associated Diarrhea | 29 months |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Saccharomyces Boulardii Participants received Saccharomyces boulardii 250 mg capsules twice per day within 24 hours of initiating antibiotic treatment and continued treatment for 7 days after antibiotic discontinuation
Saccharomyces boulardii: Units: 500 mg per day Route of administration : Oral Use Hard-Capsule | 246 |
| Microcristallin Cellulose Participants received matching placebo twice per day within 24 hours of initiating antibiotic treatment and continued treatment for 7 days after antibiotic discontinuation
Placebo: Placebo | 231 |
| Total | 477 |
Baseline characteristics
| Characteristic | Saccharomyces Boulardii | Microcristallin Cellulose | Total |
|---|---|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 16.5 | 56.5 years STANDARD_DEVIATION 17.8 | 58.4 years STANDARD_DEVIATION 17.2 |
| Body height | 171.8 cm STANDARD_DEVIATION 9.4 | 171.7 cm STANDARD_DEVIATION 10 | 171.7 cm STANDARD_DEVIATION 9.7 |
| Body mass index | 28.1 kg/m^2 STANDARD_DEVIATION 5.2 | 28.1 kg/m^2 STANDARD_DEVIATION 5.6 | 28.1 kg/m^2 STANDARD_DEVIATION 5.4 |
| Body weight | 83.1 kg STANDARD_DEVIATION 17 | 83.0 kg STANDARD_DEVIATION 18.1 | 83.0 kg STANDARD_DEVIATION 17.5 |
| C-reactive protein (CRP) | 71.0 mg/L STANDARD_DEVIATION 89.3 | 72.2 mg/L STANDARD_DEVIATION 98.9 | 71.6 mg/L STANDARD_DEVIATION 93.9 |
| Leukocyte count | 10.3 10^9 cells/L STANDARD_DEVIATION 4.6 | 11.4 10^9 cells/L STANDARD_DEVIATION 6.7 | 10.8 10^9 cells/L STANDARD_DEVIATION 5.7 |
| Region of Enrollment Germany | 246 participants | 231 participants | 477 participants |
| Sex: Female, Male Female | 106 Participants | 102 Participants | 208 Participants |
| Sex: Female, Male Male | 140 Participants | 129 Participants | 269 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 245 | 9 / 222 |
| serious Total, serious adverse events | 9 / 245 | 3 / 222 |
Outcome results
Primary
Total Number of Antibiotic-associated Diarrhea Episodes
Time frame: 29 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saccharomyces Boulardii | Total Number of Antibiotic-associated Diarrhea Episodes | 21 Episodes |
| Microcristallin Cellulose | Total Number of Antibiotic-associated Diarrhea Episodes | 19 Episodes |
p-value: 0.9495% CI: [0.55, 1.9]Regression, Cox
p-value: 0.25Fisher Exact
p-value: 0.87Log Rank
Secondary
Average Duration of Antibiotic-associated Diarrhoea and Clostridium Difficile-associated Diarrhea
Time frame: 29 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saccharomyces Boulardii | Average Duration of Antibiotic-associated Diarrhoea and Clostridium Difficile-associated Diarrhea | 4.48 days | Standard Deviation 4.13 |
| Microcristallin Cellulose | Average Duration of Antibiotic-associated Diarrhoea and Clostridium Difficile-associated Diarrhea | 4.26 days | Standard Deviation 3.85 |
Secondary
Average Number of Bowel Movements in Patients With Antibiotic-associated Diarrhoea and Clostridium Difficile-associated Diarrhea
Time frame: 29 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saccharomyces Boulardii | Average Number of Bowel Movements in Patients With Antibiotic-associated Diarrhoea and Clostridium Difficile-associated Diarrhea | 4.48 bowel movements per day | Standard Deviation 3.82 |
| Microcristallin Cellulose | Average Number of Bowel Movements in Patients With Antibiotic-associated Diarrhoea and Clostridium Difficile-associated Diarrhea | 4.07 bowel movements per day | Standard Deviation 3.13 |
Secondary
Incidence Density of Antibiotic-associated Diarrhea
Time frame: 29 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saccharomyces Boulardii | Incidence Density of Antibiotic-associated Diarrhea | 0.78 cases per year |
| Microcristallin Cellulose | Incidence Density of Antibiotic-associated Diarrhea | 0.64 cases per year |
p-value: 0.695% CI: [0.96, 1.08]Regression, Logistic
p-value: 0.65395% CI: [1, 1.01]Regression, Logistic
Secondary
Total Number of Antibiotic-associated Diarrhea Episodes Without Evidence of Clostridium Difficile (Toxins)
Time frame: 29 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saccharomyces Boulardii | Total Number of Antibiotic-associated Diarrhea Episodes Without Evidence of Clostridium Difficile (Toxins) | 19 episodes |
| Microcristallin Cellulose | Total Number of Antibiotic-associated Diarrhea Episodes Without Evidence of Clostridium Difficile (Toxins) | 17 episodes |
p-value: 0.895% CI: [0.49, 1.73]Regression, Cox
p-value: 0.9395% CI: [0.53, 2.03]Regression, Cox
Secondary
Total Number of Clostridium Difficile-associated Diarrhea Episodes
Time frame: 29 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saccharomyces Boulardii | Total Number of Clostridium Difficile-associated Diarrhea Episodes | 2 episodes |
| Microcristallin Cellulose | Total Number of Clostridium Difficile-associated Diarrhea Episodes | 2 episodes |
Secondary
Total Number of Discontinuation or Change of Initially Prescribed Antibiotic
Time frame: 29 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saccharomyces Boulardii | Total Number of Discontinuation or Change of Initially Prescribed Antibiotic | 14 participants |
| Microcristallin Cellulose | Total Number of Discontinuation or Change of Initially Prescribed Antibiotic | 7 participants |