Clostridioides Difficile Infection
Conditions
Keywords
Clostridioides difficile, Clostridium difficile, C. difficile, C. diff
Brief summary
Summit is developing ridinilazole as a novel antimicrobial for Clostridioides difficile Infection (CDI), formerly known as Clostridium difficile Infection, with the goal of demonstrating an improved Sustained Clinical Response rate in subjects treated with ridinilazole as compared to subjects treated with vancomycin. A phase 2 proof of concept study, with vancomycin as comparator, demonstrated these attributes with a comparable safety profile. A high fecal concentration of ridinilazole and little systemic exposure were noted. The rationale for this phase 3 study is to confirm the improvement in sustained clinical response of CDI over vancomycin and to compare the safety and tolerability of ridinilazole to that of vancomycin. Ridinilazole plasma concentration will be assessed in a subset of patients.
Interventions
DRUGRidinilazole
ridinilazole (200 mg bid)
DRUGVancomycin
vancomycin (125 mg qid)
Sponsors
Summit Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
In both arms patients receive the same number of doses per day. Placebo tablets are included to maintain same number and appearance of IP in both arms.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients are eligible to be included in the study only if all the following criteria apply: 1. Patient must be at least 18 years of age, at the time of signing the informed consent. 2. Have signs and symptoms of CDI including diarrhea such that in the Investigator's opinion, CDI antimicrobial therapy is required. Diarrhea is defined as a change in bowel habits, with ≥3 unformed bowel movements (UBMs) (5, 6 or 7 on the Bristol Stool Chart) in the 24 h prior to randomization. 3. Have the presence of either toxin A and/or B of C. difficile in the stool determined by a positive free toxin test (using a Sponsor agreed test). The stool sample must be current (produced within 72 hours prior to randomization). 4. Male or Female Male patients: • A male patient must agree to use contraception as detailed in Section 10.4 of this protocol during the treatment period and for at least 30 days after the last dose of study treatment and refrain from donating sperm during this period. Female patients: • A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: i. Not a woman of childbearing potential (WOCBP) OR ii. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 30 days after the last dose of study treatment. 5. Has provided documented signed informed consent and any authorizations required by local law (e.g. Protected Health Information \[PHI\]). If unable to read, understand and sign the informed consent form a legally authorized representative (LAR) may provide consent on the patient's behalf if permitted by the Institutional Review Board (IRB)/Ethics Committee (EC).
Exclusion criteria
Patients are excluded from the study if any of the following criteria apply: 1. Have had more than one prior episode of CDI in the previous 3 months or more than 3 episodes in the past 12 months prior to randomization. 2. Have a history of chronic diarrheal disease including inflammatory bowel disease (Crohn's disease or ulcerative colitis). 3. Have had a positive diagnostic test for other GI pathogens, considered to be clinically relevant, within 2 weeks of randomization. 4. Have had major gastrointestinal (GI) surgery (e.g. significant bowel resection) within 3 months of randomization (this does not include appendectomy). The presence of a colostomy or ileostomy or likely requirement of an ostomy during the study. 5. Have life threatening or fulminant CDI with evidence of hypotension, septic shock, peritoneal signs or absence of bowel sounds, or toxic megacolon. 6. History of bone marrow or hematopoietic stem cell transplant at any time or a known current history of a severely compromised/suppressed immune system that, in the opinion of the Investigator, would make the patient unsuitable for the study. 7. Have had more than the equivalent of 24 hours of dosing of antimicrobial treatment active against the current episode of CDI prior to randomization. (i.e. more than four doses of oral vancomycin, two doses of fidaxomicin or three doses of metronidazole). 8. Prior or current use of anti-toxin antibodies including bezlotoxumab within the past 6 months prior to randomization. 9. Are unable to discontinue products used affecting disease progression at randomization. 10. Has been involved in a clinical trial and received an investigational medicinal product for indications other than CDI within 1 month or five half-lives (whichever is longer) or within 3 months if the investigational medical product was for CDI. 11. Have received an investigational vaccine against C. difficile. 12. Patients that the Investigator feels are inappropriate for the study this would include those; 1. with any other condition that, in the Investigator's judgment, would make the patient unsuitable for inclusion in the study. 2. who, in the opinion of the Investigator, are not likely to complete the study for whatever reason, e.g. short life expectancy. 3. with known hypersensitivity or intolerance to ridinilazole, vancomycin, and/or their excipients 4. who are unwilling or unable to comply with protocol requirements, e.g. complete the full course of study treatment per schedule, attend study visits, report diarrhea/suspected recurrence, provide stool samples, ingest capsules/tablets or blood draws.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Sustained Clinical Response (SCR) Defined as Clinical Response and no Recurrence of CDI Through 30 Days Post End of Treatment (EOT). | Day 40 | This primary outcome measures the number of participants with Sustained Clinical Response (SCR). SCR is defined as Clinical Response and no recurrence of CDI through 30 days post End of Treatment (EOT). At D40, D70 and D100 the Investigator or medically qualified designee will determine if the patient has a sustained clinical response or experienced RECURRENCE since the previous assessment. The Investigator will assess cure/failure and recurrence based on available information which includes, but is not limited to, improvement from baseline in the number of UBMs, signs & symptoms of CDI, and the requirement for CDI medication. The Investigator should assess cure/failure in a way that best reflects the Investigator's standard clinical practice. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Cure | Day 12 | defined as the resolution of diarrhea (\<3 UBMs in the 1-day period immediately prior to EOT, that is maintained for 2 days after EOT). |
| Sustained Clinical Response Over 60 Days | Day 70 | defined as Clinical Response and no recurrence of CDI through 60 days post EOT |
| Sustained Clinical Response Over 90 Days | Day 100 | defined as Clinical Response and no recurrence of CDI through 90 days post EOT |
| Clinical Response | Day 12 | defined as * less than 3 unformed bowel movements (UBMs) for consecutive days and maintained through EOT without further CDI treatment at EOT + 2 days, or * the investigator's assessment that the subject no longer needs specific CDI antimicrobial treatment after completion of the course of study medication. |
| Percentage of Change of α-diversity (Shannon Index) of the Microbiota in Stool Samples From Baseline to EOT. | Day 10 | This secondary outcome measures the percentage of change of α-diversity (Shannon Index) of the microbiota in stool samples from baseline to EOT. Shannon index is a weighted statistic measuring both species richness and evenness. The Shannon Index is calculated by taking the relative abundance of each species and sums the relative abundance times the natural log of the relative abundance for each species. The value is converted into a positive value by times minus one. A higher Shannon Index means higher diversity |
| Measure of β-diversity of the Gut Microbiota Between Baseline and EOT Stool Samples (Bray-Curtis Index/Dissimilarity). | Day 10 | This secondary outcome measures the β-diversity of the gut microbiota in stool samples from baseline to EOT. Bray-Curtis index/dissimilarity measures how different two samples are in the microbiome composition. The Bray-Curtis dissimilarity is graded between 0 and 1, where 0 means the two samples have the same composition (that is they share all the species and every species has the same abundance), and 1 means the two samples do not share any species. |
| Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Day 10 | This secondary outcome measures the relative abundance of the 3 main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) from Baseline to EOT. |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, Greece, Hungary, New Zealand, Poland, Romania, Russia, South Korea, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ridinilazole ridinilazole: ridinilazole (200 mg bid) | 370 |
| Vancomycin vancomycin: vancomycin (125 mg qid) | 375 |
| Total | 745 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 5 |
| Overall Study | Death | 24 | 22 |
| Overall Study | Lost to Follow-up | 6 | 7 |
| Overall Study | Other as indicated in CSR | 3 | 3 |
| Overall Study | Physician Decision | 3 | 2 |
| Overall Study | Sponsor Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 20 | 8 |
Baseline characteristics
| Characteristic | Total | Ridinilazole | Vancomycin |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 323 Participants | 161 Participants | 162 Participants |
| Age, Categorical Between 18 and 65 years | 422 Participants | 209 Participants | 213 Participants |
| Age, Continuous | 59.4 years STANDARD_DEVIATION 17.64 | 59.1 years STANDARD_DEVIATION 17.89 | 59.6 years STANDARD_DEVIATION 17.42 |
| BMI | 26.54 kg/m^2 STANDARD_DEVIATION 5.748 | 26.64 kg/m^2 STANDARD_DEVIATION 5.729 | 26.36 kg/m^2 STANDARD_DEVIATION 5.732 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 100 Participants | 40 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 627 Participants | 322 Participants | 305 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 8 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 21 Participants | 11 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 26 Participants | 10 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 16 Participants | 8 Participants | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 17 Participants | 7 Participants | 10 Participants |
| Race (NIH/OMB) White | 664 Participants | 333 Participants | 331 Participants |
| Region of Enrollment Argentina | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Australia | 8 participants | 6 participants | 2 participants |
| Region of Enrollment Brazil | 13 participants | 3 participants | 10 participants |
| Region of Enrollment Canada | 29 participants | 12 participants | 17 participants |
| Region of Enrollment Chile | 5 participants | 2 participants | 3 participants |
| Region of Enrollment Europe | 449 participants | 229 participants | 220 participants |
| Region of Enrollment Israel | 32 participants | 17 participants | 15 participants |
| Region of Enrollment Mexico | 16 participants | 5 participants | 11 participants |
| Region of Enrollment New Zealand | 4 participants | 3 participants | 1 participants |
| Region of Enrollment Peru | 1 participants | 1 participants | 0 participants |
| Region of Enrollment South Korea | 19 participants | 10 participants | 9 participants |
| Region of Enrollment United States | 168 participants | 81 participants | 87 participants |
| Sex: Female, Male Female | 436 Participants | 209 Participants | 227 Participants |
| Sex: Female, Male Male | 309 Participants | 161 Participants | 148 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 26 / 374 | 24 / 377 |
| other Total, other adverse events | 124 / 374 | 117 / 377 |
| serious Total, serious adverse events | 32 / 374 | 30 / 377 |
Outcome results
Primary
Number of Participants With Sustained Clinical Response (SCR) Defined as Clinical Response and no Recurrence of CDI Through 30 Days Post End of Treatment (EOT).
This primary outcome measures the number of participants with Sustained Clinical Response (SCR). SCR is defined as Clinical Response and no recurrence of CDI through 30 days post End of Treatment (EOT). At D40, D70 and D100 the Investigator or medically qualified designee will determine if the patient has a sustained clinical response or experienced RECURRENCE since the previous assessment. The Investigator will assess cure/failure and recurrence based on available information which includes, but is not limited to, improvement from baseline in the number of UBMs, signs & symptoms of CDI, and the requirement for CDI medication. The Investigator should assess cure/failure in a way that best reflects the Investigator's standard clinical practice.
Time frame: Day 40
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ridinilazole | Number of Participants With Sustained Clinical Response (SCR) Defined as Clinical Response and no Recurrence of CDI Through 30 Days Post End of Treatment (EOT). | SCR based on Clinical Cure | 238 Participants |
| Ridinilazole | Number of Participants With Sustained Clinical Response (SCR) Defined as Clinical Response and no Recurrence of CDI Through 30 Days Post End of Treatment (EOT). | SCR based on Clinical Cure Failure | 132 Participants |
| Vancomycin | Number of Participants With Sustained Clinical Response (SCR) Defined as Clinical Response and no Recurrence of CDI Through 30 Days Post End of Treatment (EOT). | SCR based on Clinical Cure | 225 Participants |
| Vancomycin | Number of Participants With Sustained Clinical Response (SCR) Defined as Clinical Response and no Recurrence of CDI Through 30 Days Post End of Treatment (EOT). | SCR based on Clinical Cure Failure | 150 Participants |
Secondary
Clinical Cure
defined as the resolution of diarrhea (\<3 UBMs in the 1-day period immediately prior to EOT, that is maintained for 2 days after EOT).
Time frame: Day 12
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ridinilazole | Clinical Cure | Clinical Cure | 275 Participants |
| Ridinilazole | Clinical Cure | Clinical Cure Failure | 95 Participants |
| Vancomycin | Clinical Cure | Clinical Cure Failure | 83 Participants |
| Vancomycin | Clinical Cure | Clinical Cure | 292 Participants |
Secondary
Clinical Response
defined as * less than 3 unformed bowel movements (UBMs) for consecutive days and maintained through EOT without further CDI treatment at EOT + 2 days, or * the investigator's assessment that the subject no longer needs specific CDI antimicrobial treatment after completion of the course of study medication.
Time frame: Day 12
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ridinilazole | Clinical Response | Clinical Response | 320 Participants |
| Ridinilazole | Clinical Response | Clinical Response Failure | 50 Participants |
| Vancomycin | Clinical Response | Clinical Response | 346 Participants |
| Vancomycin | Clinical Response | Clinical Response Failure | 29 Participants |
Secondary
Measure of β-diversity of the Gut Microbiota Between Baseline and EOT Stool Samples (Bray-Curtis Index/Dissimilarity).
This secondary outcome measures the β-diversity of the gut microbiota in stool samples from baseline to EOT. Bray-Curtis index/dissimilarity measures how different two samples are in the microbiome composition. The Bray-Curtis dissimilarity is graded between 0 and 1, where 0 means the two samples have the same composition (that is they share all the species and every species has the same abundance), and 1 means the two samples do not share any species.
Time frame: Day 10
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ridinilazole | Measure of β-diversity of the Gut Microbiota Between Baseline and EOT Stool Samples (Bray-Curtis Index/Dissimilarity). | 0.7 Bray-Curtis Index |
| Vancomycin | Measure of β-diversity of the Gut Microbiota Between Baseline and EOT Stool Samples (Bray-Curtis Index/Dissimilarity). | 0.81 Bray-Curtis Index |
Secondary
Percentage of Change of α-diversity (Shannon Index) of the Microbiota in Stool Samples From Baseline to EOT.
This secondary outcome measures the percentage of change of α-diversity (Shannon Index) of the microbiota in stool samples from baseline to EOT. Shannon index is a weighted statistic measuring both species richness and evenness. The Shannon Index is calculated by taking the relative abundance of each species and sums the relative abundance times the natural log of the relative abundance for each species. The value is converted into a positive value by times minus one. A higher Shannon Index means higher diversity
Time frame: Day 10
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ridinilazole | Percentage of Change of α-diversity (Shannon Index) of the Microbiota in Stool Samples From Baseline to EOT. | 37.06 percent change in Shannon Index |
| Vancomycin | Percentage of Change of α-diversity (Shannon Index) of the Microbiota in Stool Samples From Baseline to EOT. | -7.32 percent change in Shannon Index |
Secondary
Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT.
This secondary outcome measures the relative abundance of the 3 main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) from Baseline to EOT.
Time frame: Day 10
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ridinilazole | Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Secondary Bile Acid Group at Baseline | 33.34 percentage of abundance | Standard Deviation 35.68 |
| Ridinilazole | Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Secondary Bile Acid Group at EOT | 38.13 percentage of abundance | Standard Deviation 39.63 |
| Ridinilazole | Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Primary Bile Acid Group at Baseline | 55.03 percentage of abundance | Standard Deviation 34.06 |
| Ridinilazole | Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Primary Bile Acid Group at EOT | 55.99 percentage of abundance | Standard Deviation 38.06 |
| Ridinilazole | Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Conjugated Primary Bile Acid Group at Baseline | 11.64 percentage of abundance | Standard Deviation 21.93 |
| Ridinilazole | Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Conjugated Primary Bile Acid Group at EOT | 5.88 percentage of abundance | Standard Deviation 15.5 |
| Vancomycin | Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Conjugated Primary Bile Acid Group at Baseline | 12.31 percentage of abundance | Standard Deviation 21.56 |
| Vancomycin | Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Secondary Bile Acid Group at Baseline | 30.25 percentage of abundance | Standard Deviation 34.13 |
| Vancomycin | Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Primary Bile Acid Group at EOT | 65.72 percentage of abundance | Standard Deviation 33.9 |
| Vancomycin | Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Secondary Bile Acid Group at EOT | 7.87 percentage of abundance | Standard Deviation 22.69 |
| Vancomycin | Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Conjugated Primary Bile Acid Group at EOT | 26.42 percentage of abundance | Standard Deviation 31.62 |
| Vancomycin | Relative Abundance of the 3 Main Bile Acid Groups (Conjugated Primary, Primary and Secondary Bile Acids) From Baseline to EOT. | Primary Bile Acid Group at Baseline | 57.44 percentage of abundance | Standard Deviation 33.08 |
Secondary
Sustained Clinical Response Over 60 Days
defined as Clinical Response and no recurrence of CDI through 60 days post EOT
Time frame: Day 70
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ridinilazole | Sustained Clinical Response Over 60 Days | Sustained Clinical Response 60 Days Post EOT | 262 Participants |
| Ridinilazole | Sustained Clinical Response Over 60 Days | Sustained Clinical Response 60 Days Post EOT Failure | 108 Participants |
| Vancomycin | Sustained Clinical Response Over 60 Days | Sustained Clinical Response 60 Days Post EOT | 258 Participants |
| Vancomycin | Sustained Clinical Response Over 60 Days | Sustained Clinical Response 60 Days Post EOT Failure | 117 Participants |
Secondary
Sustained Clinical Response Over 90 Days
defined as Clinical Response and no recurrence of CDI through 90 days post EOT
Time frame: Day 100
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ridinilazole | Sustained Clinical Response Over 90 Days | Sustained Clinical Response 90 Days Post EOT | 259 Participants |
| Ridinilazole | Sustained Clinical Response Over 90 Days | Sustained Clinical Response 90 Days Post EOT Failure | 111 Participants |
| Vancomycin | Sustained Clinical Response Over 90 Days | Sustained Clinical Response 90 Days Post EOT | 249 Participants |
| Vancomycin | Sustained Clinical Response Over 90 Days | Sustained Clinical Response 90 Days Post EOT Failure | 126 Participants |