Crohn's Disease
Conditions
Keywords
Crohn's Disease, moderate to severe, remission, MAP, antibiotic
Brief summary
The investigators hypothesize that RHB-104 will have greater efficacy than placebo in Crohn's disease.
Detailed description
A Randomized, Double Blind, Placebo-controlled, Multicenter, Parallel Group Study to Assess the Efficacy and Safety of Fixed-dose Combination RHB-104 in Subjects with Moderately to Severely Active Crohn's Disease.
Interventions
DRUGRHB-104
95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine
DRUGPlacebo
5 placebo capsules administered orally BID
Sponsors
RedHill Biopharma Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Signed fully informed consent provided as per this protocol. 2. Diagnosis of Crohn's Disease confirmed by endoscopy or radiography and/or histology at least 6 months prior to randomization into the study. 3. CD involving the ileum and/or colon 4. Moderately to severely active CD (Crohn's Disease Activity Index (CDAI) score of greater than or equal to 220 and less than or equal to 450) at baseline. 5. Current treatment with at least one of the following therapies: A. Oral 5-acetyl salicylic acid (5-ASA) compounds. Dose must be stable for at least 4 weeks before baseline. B. Corticosteroid therapy. Dose must be stable for at least 2 weeks before baseline. C. Azathioprine or 6-mercaptopurine (6-MP) or methotrexate. Dose must be stable for at least 8 weeks before baseline. D. Infliximab or adalimumab. Dose must be stable for at least 14 weeks before baseline. 6. White blood cell count greater than or equal to 3.5 x 109 at screening. 7. Active Crohn's disease, defined by at least one of the following: C-reactive protein greater than Upper Limit of Normal (ULN) at screening, fecal calprotectin greater than Upper Limit of Normal (ULN) at screening, OR radiographic (MRE or CTE) or endoscopic confirmation of the presence of active CD within 5 weeks of screening visit. . 8. Subject agrees to use barrier contraceptive methods (i.e. diaphragm, cervical cap, contraceptive sponge or condom) with spermicidal foam/gel/cream/suppository, IUD/IUS or progestogen injection (Depo-Provera®) throughout the study and for at least 6 weeks after last study drug administration, unless subject is post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation, or has had a vasectomy. In regions where local regulatory contraceptive requirements differ, the ICF will reflect local policies.
Exclusion criteria
1. Crohn's Disease involvement isolated to the mouth, upper gastrointestinal tract, or anus. 2. History of total colectomy with ileorectal anastomosis or a proctocolectomy. 3. Presence of active fistulizing Crohn's Disease or healed fistula within 2 months prior to screening. 4. Subject has postoperative stoma, ostomy, or ileoanal pouch. 5. Subject has short bowel syndrome. 6. Subject is scheduled for surgical bowel resection. 7. Subject has known symptomatic obstructive strictures or bowel perforation in the 6 months prior to screening. 8. Change in dose or discontinuation of oral 5-acetyl salicylic acid (5-ASA) compounds less than 4 weeks prior to baseline. 9. Change in dose or discontinuation of corticosteroids less than 2 weeks prior to baseline. 10. Change in dose or discontinuation of azathioprine, 6-mercaptopurine (6-MP) or methotrexate less than 8 weeks prior to baseline. 11. Change in dose or discontinuation of infliximab or adalimumab less than 14 weeks prior to baseline. 12. Treatment with vedolizumab less than 120 days prior to baseline or biological therapies (apart from infliximab or adalimumab) less than 60 days prior to baseline. 13. Previous treatment with rifabutin and/or clofazimine. 14. Oral or parenteral antibiotics in the 4 weeks prior to baseline (topical antibiotics are permitted). 15. Treatment with probiotics (excluding yogurt and yogurt-derived products) in the 4 weeks prior to baseline. 16. Females who have a positive pregnancy test or are lactating.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Remission at Week 26 | Week 26 | Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150. Lower CDAI scores indicate a better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response at Week 26 | Week 26 | Reduction of Crohn's Disease Activity Index (CDAI) score by a minimum of 100 points. Lower CDAI scores indicate a better outcome. |
| Remission at Week 52 | Week 52 | Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150. Lower CDAI scores indicate a better outcome. |
| Durable Remission Week 26 Through Week 52 | Week 26 through week 52 | When a subject is in remission with a maximum CDAI score of 149 at every visit from Week 26 through and including Week 52 |
| Remission at Week 16 | Week 16 | Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150. Lower CDAI scores indicate a better outcome. |
| Steroid Free Remission at Week 52 | Week 52 | Subjects who are maintained off steroids for a minimum of 3 weeks |
Other
| Measure | Time frame | Description |
|---|---|---|
| Duration of Remission | Baseline through week 52 | Number of weeks that a subject is in a state of remission. Subjects who experienced remission and continued to be in remission at the time of their last CDAI assessment are censored at the date of their last CDAI assessment. |
| Cardiac Safety | Week 26 | Change-from-baseline to week 26 in QTcF (based on cardiac safety report) |
| Duration of Response | Baseline through week 52 | Number of weeks a subject is in a state of response. Subjects who experienced response and continued to be in response at the time of their last CDAI assessment are censored at the date of their last CDAI assessment. |
| Time to Remission | Baseline through week 52 | \[Date of first observed remission (CDAI score \< 150) - Date of first dose or date of randomization if not dosed + 1\] / 7 Days. Subjects who never experienced remission during the study are censored at the date of their last CDAI assessment. |
| Time to Response | Baseline through week 52 | \[Date of first observed response (a reduction from baseline of ≥ 100 in CDAI score) - Date of first dose or date of randomization if not dosed + 1\] / 7 Days. Subjects who never experienced response during the study are censored at the date of their last CDAI assessment. |
| Durable Remission Week 16 Through Week 52 | Week 16 through week 52 | Remission in a subject from week 16 through week 52. |
| Response at Week 16 | Week 16 | Reduction of Crohn's Disease Activity Index (CDAI) score by a minimum of 100 points. Lower CDAI scores indicate a better outcome. |
Countries
Australia, Bulgaria, Canada, Czechia, Israel, New Zealand, Poland, Serbia, Slovakia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RHB-104 5 RHB-104 capsules administered orally BID
RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine | 166 |
| Placebo 5 placebo capsules administered orally BID
Placebo: 5 placebo capsules administered orally BID | 165 |
| Total | 331 |
Baseline characteristics
| Characteristic | RHB-104 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 39.0 years STANDARD_DEVIATION 12.51 | 39.3 years STANDARD_DEVIATION 12.56 | 39.1 years STANDARD_DEVIATION 12.52 |
| Anti-TNF Use at Baseline | 37 Participants | 41 Participants | 78 Participants |
| Baseline Crohn's Disease Activity Index (CDAI) score | 297.77 units on a scale STANDARD_DEVIATION 57.023 | 293.44 units on a scale STANDARD_DEVIATION 53.184 | 295.61 units on a scale STANDARD_DEVIATION 55.102 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 12 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 156 Participants | 150 Participants | 306 Participants |
| Region of Enrollment Europe | 47 participants | 50 participants | 97 participants |
| Region of Enrollment Israel | 18 participants | 20 participants | 38 participants |
| Region of Enrollment North America | 92 participants | 83 participants | 175 participants |
| Region of Enrollment Southeast Asia | 9 participants | 12 participants | 21 participants |
| Sex: Female, Male Female | 75 Participants | 67 Participants | 142 Participants |
| Sex: Female, Male Male | 91 Participants | 98 Participants | 189 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 166 | 0 / 165 |
| other Total, other adverse events | 115 / 166 | 90 / 165 |
| serious Total, serious adverse events | 31 / 166 | 31 / 165 |
Outcome results
Primary
Remission at Week 26
Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150. Lower CDAI scores indicate a better outcome.
Time frame: Week 26
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RHB-104 | Remission at Week 26 | 61 Participants |
| Placebo | Remission at Week 26 | 37 Participants |
p-value: 0.0048Cochran-Mantel-Haenszel
Secondary
Durable Remission Week 26 Through Week 52
When a subject is in remission with a maximum CDAI score of 149 at every visit from Week 26 through and including Week 52
Time frame: Week 26 through week 52
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RHB-104 | Durable Remission Week 26 Through Week 52 | 33 Participants |
| Placebo | Durable Remission Week 26 Through Week 52 | 21 Participants |
p-value: 0.0851Cochran-Mantel-Haenszel
Secondary
Remission at Week 16
Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150. Lower CDAI scores indicate a better outcome.
Time frame: Week 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RHB-104 | Remission at Week 16 | 70 Participants |
| Placebo | Remission at Week 16 | 48 Participants |
p-value: 0.0147Cochran-Mantel-Haenszel
Secondary
Remission at Week 52
Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150. Lower CDAI scores indicate a better outcome.
Time frame: Week 52
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RHB-104 | Remission at Week 52 | 47 Participants |
| Placebo | Remission at Week 52 | 32 Participants |
p-value: 0.0616Cochran-Mantel-Haenszel
Secondary
Response at Week 26
Reduction of Crohn's Disease Activity Index (CDAI) score by a minimum of 100 points. Lower CDAI scores indicate a better outcome.
Time frame: Week 26
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RHB-104 | Response at Week 26 | 73 Participants |
| Placebo | Response at Week 26 | 50 Participants |
p-value: 0.0116Cochran-Mantel-Haenszel
Secondary
Steroid Free Remission at Week 52
Subjects who are maintained off steroids for a minimum of 3 weeks
Time frame: Week 52
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RHB-104 | Steroid Free Remission at Week 52 | 11 Participants |
| Placebo | Steroid Free Remission at Week 52 | 5 Participants |
p-value: 0.151Cochran-Mantel-Haenszel
Other Pre-specified
Cardiac Safety
Placebo-corrected change-from-baseline to week 52 in QTcF (based on cardiac safety report)
Time frame: Baseline through week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| RHB-104 | Cardiac Safety | 29.8 ms |
| Placebo | Cardiac Safety | -0.8 ms |
Other Pre-specified
Cardiac Safety
Change-from-baseline to week 26 in QTcF (based on cardiac safety report)
Time frame: Week 26
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| RHB-104 | Cardiac Safety | 27.8 ms |
| Placebo | Cardiac Safety | 0.2 ms |
Other Pre-specified
Durable Remission Week 16 Through Week 52
Remission in a subject from week 16 through week 52.
Time frame: Week 16 through week 52
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RHB-104 | Durable Remission Week 16 Through Week 52 | 31 Participants |
| Placebo | Durable Remission Week 16 Through Week 52 | 14 Participants |
p-value: 0.0077Cochran-Mantel-Haenszel
Other Pre-specified
Duration of Remission
Number of weeks that a subject is in a state of remission. Subjects who experienced remission and continued to be in remission at the time of their last CDAI assessment are censored at the date of their last CDAI assessment.
Time frame: Baseline through week 52
Population: Reached duration of remission (dropped out of remission during the study), n (%): RHB-104 54 (53.5); Placebo: 49 (62.8). Censored (remain in remission during the study), n (%): RHB-104: 47 (46.5); Placebo 29 (37.2)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RHB-104 | Duration of Remission | 27.1 weeks |
| Placebo | Duration of Remission | 16.7 weeks |
p-value: 0.2402Log Rank
Other Pre-specified
Duration of Response
Number of weeks a subject is in a state of response. Subjects who experienced response and continued to be in response at the time of their last CDAI assessment are censored at the date of their last CDAI assessment.
Time frame: Baseline through week 52
Population: Reached duration of response (dropped out of response during the study), n (%) RHB-104: 52 (45.2); Placebo: 55 (59.8). Censored (remain in response during the study), n (%): RHB-104: 63 (54.8); Placebo: 37 (40.2)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RHB-104 | Duration of Response | 40.1 weeks |
| Placebo | Duration of Response | 22.1 weeks |
p-value: 0.046Log Rank
Other Pre-specified
Response at Week 16
Reduction of Crohn's Disease Activity Index (CDAI) score by a minimum of 100 points. Lower CDAI scores indicate a better outcome.
Time frame: Week 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RHB-104 | Response at Week 16 | 79 Participants |
| Placebo | Response at Week 16 | 60 Participants |
p-value: 0.0422Cochran-Mantel-Haenszel
Other Pre-specified
Time to Remission
\[Date of first observed remission (CDAI score \< 150) - Date of first dose or date of randomization if not dosed + 1\] / 7 Days. Subjects who never experienced remission during the study are censored at the date of their last CDAI assessment.
Time frame: Baseline through week 52
Population: Number of subjects achieved remission, n (%) RHB-104: 101 (60.8); Placebo 78 (47.3). Censored, n (%): RHB-104: 65 (39.2); Placebo 87 (52.7)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RHB-104 | Time to Remission | 12.1 weeks |
| Placebo | Time to Remission | 19.9 weeks |
p-value: 0.0031Log Rank
Other Pre-specified
Time to Response
\[Date of first observed response (a reduction from baseline of ≥ 100 in CDAI score) - Date of first dose or date of randomization if not dosed + 1\] / 7 Days. Subjects who never experienced response during the study are censored at the date of their last CDAI assessment.
Time frame: Baseline through week 52
Population: Number of subjects achieved response, n (%): RHB-104: 115 (69.3); Placebo: 92 (55.8); Censored, n (%): RHB-104: 51 (30.7); Placebo: 73 (44.2)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RHB-104 | Time to Response | 8.3 weeks |
| Placebo | Time to Response | 12.1 weeks |
p-value: 0.01Log Rank