Clostridium Difficile Infection
Conditions
Keywords
Diarrhea, Clostridium difficile, Clostridium infections, Signs and Symptoms Digestive, Bacterial Infections, Pharmacologic Actions
Brief summary
The objectives of this study are: (1) to evaluate the safety and tolerability of VP 20621 dosed orally for up to 14 days in adults previously treated for CDI; (2) to characterize the frequency and duration of stool colonization with the VP 20621 strain of C. difficile; (3) to evaluate the efficacy of VP 20621 for prevention of recurrence of CDI; and (4)to select a dose regimen of VP 20621 to be used in future studies.
Interventions
BIOLOGICALVP20621
VP20621 as oral liquid once daily for 7 days followed by placebo as oral liquid once daily for seven days
OTHERPlacebo
10 mL placebo once daily for 14 days
Sponsors
Shire
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
1. Adult subjects, 18 years of age and over, who understand the risks and benefits of participation and have provided written informed consent for the study. 2. Subjects who are experiencing a first event or first recurrence of clostridium difficile (CDI) within the last 28 days and have been successfully treated with an antibiotic for CDI. 3. Subjects who are medically stable. 4. Subjects who are willing and able to comply with the study procedures and visit schedules outlined. 5. If female be post-menopausal, surgically sterile or agree to follow an acceptable method of birth control.
Exclusion criteria
1. Subjects who have had more than 2 episodes of CDI within the last 6 months. 2. Subjects who have been diagnosed with Inflammatory Bowel Disease,active Irritable Bowel Syndrome, celiac disease, active gastroparesis, toxic megacolon. 3. GI surgery within 6 weeks before the day of randomization 4. Have known immunodeficiency disorder, such as HIV Infection 5. Pregnant or breast feeding females. 6. Concurrent acute life-threatening diseases. 7. Inability to tolerate oral liquids. 8. Have an absolute neutrophil count \< 1000/mm3 at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Baseline up to 7 days after the last dose of study drug (up to Week 3) | An adverse event (AE) is any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurring in a study participant, regardless of causal relationship. TEAEs were defined as all AEs that start during the study drug treatment period (and up to 7 days after the last dose of the study drug) and were not seen at baseline, or were seen at baseline but increased in frequency and/or severity during the study drug treatment period (and up to 7 days after the last dose of study drug). SAE was any AE that results in any of the following outcomes: death, a life-threatening event, inpatient hospitalization or prolongation of an existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, other medically important events based upon appropriate medical judgement. |
| Number of Participants With Positive Clostridium Difficile Stool Cultures Demonstrating Non-Toxigenic Clostridium Difficile-Strain M3 | After study drug administration period (14 days) through Week 6 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clostridium Difficile Infection (CDI) Recurrence | Baseline (Day 1) up to Week 6 | CDI recurrence was defined as at least 1 event characterized by ALL of the following: \>=3 unformed (loose or watery) stools within 24 hours (data derived from Diarrhea case report form (CRF) page which was to be completed for any clinical event of diarrhea or loose/watery stool occurring between Day 1 and Week 6); a positive C. difficile stool assay, or pseudomembranes on endoscopy/surgery; and no other likely cause of the diarrhea in the opinion of the investigator. |
| Number of Participants With Use of Antibacterial Treatment for CDI | Baseline (Day 1) up to Week 6 | Any antibacterial medication used after Day 1 for which the investigator selected the indication antibacterial for C. difficile infection. |
| Number of Participants With Clinical Events of Diarrhea or Loose/Watery Stools | Baseline (Day 1) up to Week 6 | Data were derived from all AEs starting on or after Day 1 for which a Diarrhea CRF page was completed. |
| Time to First CDI Recurrence | Baseline (Day 1) up to Week 6 | CDI recurrence was defined as at least 1 event characterized by ALL of the following: \>=3 unformed (loose or watery) stools within 24 hours (data derived from Diarrhea CRF page which was to be completed for any clinical event of diarrhea or loose/watery stool occurring between Day 1 and Week 6); a positive C. difficile stool assay, or pseudomembranes on endoscopy/surgery; and no other likely cause of the diarrhea in the opinion of the investigator. Time of onset is from date of randomization to date of first CDI recurrence. Time to first CDI recurrence was assessed using Kaplan-Meier curve. Due to small number of subjects (\<50%) with CDI recurrence, median time to event was not evaluable. |
Countries
Belgium, Canada, Germany, Spain, Switzerland, United States
Participant flow
Recruitment details
This study was conducted at a total of 44 investigative sites \[United states (US)=33, Canada=4, and Europe=7\], and 3 of the 33 US sites did not enroll any participants (each had 1 screen failure).
Pre-assignment details
Of the 213 participants formally screened to participate in this study, 168 participants were treated. Five participants were randomized but not treated and 40 participants were screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo matched to VP 20621 oral liquid once daily from Day 1 to 14. | 43 |
| VP 20621 Low Dose and Placebo VP 20621 oral liquid containing 10\^4 purified spores of non-toxigenic Clostridium difficile-strain M3 (NTCD-M3; the dormant form of a live organism) once daily from Day 1 to 7 followed by placebo matched to VP 20621 oral liquid once daily from Day 8 to 14. | 41 |
| VP 20621 High Dose and Placebo VP 20621 oral liquid containing 10\^7 purified spores of NTCD-M3 once daily from Day 1 to 7 followed by placebo matched to VP 20621 oral liquid once daily from Day 8 to 14. | 43 |
| VP 20621 High Dose VP 20621 oral liquid containing 10\^7 purified spores of NTCD-M3 once daily from Day 1 to 14. | 41 |
| Total | 168 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 | 3 |
| Overall Study | Physician Decision | 2 | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo | VP 20621 Low Dose and Placebo | VP 20621 High Dose and Placebo | VP 20621 High Dose | Total |
|---|---|---|---|---|---|
| Age, Continuous | 54.7 years STANDARD_DEVIATION 19.19 | 58.2 years STANDARD_DEVIATION 14.42 | 57.2 years STANDARD_DEVIATION 18.46 | 60.6 years STANDARD_DEVIATION 16.4 | 57.6 years STANDARD_DEVIATION 17.2 |
| Sex: Female, Male Female | 26 Participants | 26 Participants | 24 Participants | 28 Participants | 104 Participants |
| Sex: Female, Male Male | 17 Participants | 15 Participants | 19 Participants | 13 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 37 / 43 | 31 / 41 | 34 / 43 | 34 / 41 |
| serious Total, serious adverse events | 8 / 43 | 5 / 41 | 8 / 43 | 6 / 41 |
Outcome results
Primary
Number of Participants With Positive Clostridium Difficile Stool Cultures Demonstrating Non-Toxigenic Clostridium Difficile-Strain M3
Time frame: After study drug administration period (14 days) through Week 6
Population: ITT-S population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Positive Clostridium Difficile Stool Cultures Demonstrating Non-Toxigenic Clostridium Difficile-Strain M3 | 4 Participants |
| VP 20621 Low Dose and Placebo | Number of Participants With Positive Clostridium Difficile Stool Cultures Demonstrating Non-Toxigenic Clostridium Difficile-Strain M3 | 26 Participants |
| VP 20621 High Dose and Placebo | Number of Participants With Positive Clostridium Difficile Stool Cultures Demonstrating Non-Toxigenic Clostridium Difficile-Strain M3 | 31 Participants |
| VP 20621 High Dose | Number of Participants With Positive Clostridium Difficile Stool Cultures Demonstrating Non-Toxigenic Clostridium Difficile-Strain M3 | 29 Participants |
p-value: <=0.0001Chi-squared
p-value: <0.0001Chi-squared
p-value: <0.0001Chi-squared
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An adverse event (AE) is any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurring in a study participant, regardless of causal relationship. TEAEs were defined as all AEs that start during the study drug treatment period (and up to 7 days after the last dose of the study drug) and were not seen at baseline, or were seen at baseline but increased in frequency and/or severity during the study drug treatment period (and up to 7 days after the last dose of study drug). SAE was any AE that results in any of the following outcomes: death, a life-threatening event, inpatient hospitalization or prolongation of an existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, other medically important events based upon appropriate medical judgement.
Time frame: Baseline up to 7 days after the last dose of study drug (up to Week 3)
Population: Intent-to-Treat-Safety (ITT-S) population was defined as all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with TEAEs | 37 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with treatment-emergent SAEs | 3 Participants |
| VP 20621 Low Dose and Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with treatment-emergent SAEs | 1 Participants |
| VP 20621 Low Dose and Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with TEAEs | 33 Participants |
| VP 20621 High Dose and Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with TEAEs | 34 Participants |
| VP 20621 High Dose and Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with treatment-emergent SAEs | 1 Participants |
| VP 20621 High Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with TEAEs | 31 Participants |
| VP 20621 High Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with treatment-emergent SAEs | 2 Participants |
Secondary
Number of Participants With Clinical Events of Diarrhea or Loose/Watery Stools
Data were derived from all AEs starting on or after Day 1 for which a Diarrhea CRF page was completed.
Time frame: Baseline (Day 1) up to Week 6
Population: ITT-S population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Clinical Events of Diarrhea or Loose/Watery Stools | 33 Participants |
| VP 20621 Low Dose and Placebo | Number of Participants With Clinical Events of Diarrhea or Loose/Watery Stools | 23 Participants |
| VP 20621 High Dose and Placebo | Number of Participants With Clinical Events of Diarrhea or Loose/Watery Stools | 25 Participants |
| VP 20621 High Dose | Number of Participants With Clinical Events of Diarrhea or Loose/Watery Stools | 23 Participants |
p-value: =0.045Chi-squared
p-value: =0.066Chi-squared
p-value: =0.045Chi-squared
Secondary
Number of Participants With Clostridium Difficile Infection (CDI) Recurrence
CDI recurrence was defined as at least 1 event characterized by ALL of the following: \>=3 unformed (loose or watery) stools within 24 hours (data derived from Diarrhea case report form (CRF) page which was to be completed for any clinical event of diarrhea or loose/watery stool occurring between Day 1 and Week 6); a positive C. difficile stool assay, or pseudomembranes on endoscopy/surgery; and no other likely cause of the diarrhea in the opinion of the investigator.
Time frame: Baseline (Day 1) up to Week 6
Population: ITT-S population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Clostridium Difficile Infection (CDI) Recurrence | 13 Participants |
| VP 20621 Low Dose and Placebo | Number of Participants With Clostridium Difficile Infection (CDI) Recurrence | 6 Participants |
| VP 20621 High Dose and Placebo | Number of Participants With Clostridium Difficile Infection (CDI) Recurrence | 2 Participants |
| VP 20621 High Dose | Number of Participants With Clostridium Difficile Infection (CDI) Recurrence | 6 Participants |
p-value: =0.088Chi-squared
p-value: =0.002Chi-squared
p-value: =0.088Chi-squared
Secondary
Number of Participants With Use of Antibacterial Treatment for CDI
Any antibacterial medication used after Day 1 for which the investigator selected the indication antibacterial for C. difficile infection.
Time frame: Baseline (Day 1) up to Week 6
Population: ITT-S population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Use of Antibacterial Treatment for CDI | 14 Participants |
| VP 20621 Low Dose and Placebo | Number of Participants With Use of Antibacterial Treatment for CDI | 6 Participants |
| VP 20621 High Dose and Placebo | Number of Participants With Use of Antibacterial Treatment for CDI | 4 Participants |
| VP 20621 High Dose | Number of Participants With Use of Antibacterial Treatment for CDI | 7 Participants |
p-value: =0.054Chi-squared
p-value: =0.008Chi-squared
p-value: =0.101Chi-squared
Secondary
Time to First CDI Recurrence
CDI recurrence was defined as at least 1 event characterized by ALL of the following: \>=3 unformed (loose or watery) stools within 24 hours (data derived from Diarrhea CRF page which was to be completed for any clinical event of diarrhea or loose/watery stool occurring between Day 1 and Week 6); a positive C. difficile stool assay, or pseudomembranes on endoscopy/surgery; and no other likely cause of the diarrhea in the opinion of the investigator. Time of onset is from date of randomization to date of first CDI recurrence. Time to first CDI recurrence was assessed using Kaplan-Meier curve. Due to small number of subjects (\<50%) with CDI recurrence, median time to event was not evaluable.
Time frame: Baseline (Day 1) up to Week 6
Population: ITT-S population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First CDI Recurrence | NA days |
| VP 20621 Low Dose and Placebo | Time to First CDI Recurrence | NA days |
| VP 20621 High Dose and Placebo | Time to First CDI Recurrence | NA days |
| VP 20621 High Dose | Time to First CDI Recurrence | NA days |