Crohn Disease
Conditions
Keywords
Crohn's Disease,, moderate to severe, remission, Mycobacterium avium paratuberculosis, antibiotic
Brief summary
An open label extension to the RHB-104-01 Study.
Detailed description
An Open Label Phase III Study to Assess the Efficacy and Safety of Fixed-Dose Combination RHB-104 in Subjects with Active Crohn's Disease Despite 26 Weeks of Participation in the MAP US RHB-104-01 Study.
Interventions
DRUGRHB-104 (fixed-dose combination: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine)
For patients on ACTIVE or PLACEBO in the parent study (RHB-104-01), who were not in remission after 26 weeks
Sponsors
RedHill Biopharma Limited
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Active
Eligibility
Sex/Gender
ALL
Age
18 Years to 76 Years
Healthy volunteers
No
Inclusion criteria
* Signed fully informed consent (ICF) provided as per this protocol. * Participation in RHB-104-01 for 26 weeks, and a Crohn's Disease Activity Index (CDAI) score of ≥ 150 at Visit Week 26. OR * More than 26 weeks, with a CDAI ≥150 at Visit Week 26 and all subsequent visits, and subject is between Week 26 and 52 within 4 weeks (28 days) of site activation (e.g. Subject with CDAI = 249 at week 26 and who is at week 38 at the time of site's activation for RHB-104-04 has a 4-week window to be enrolled in the open label study via the Optional Screening Visit) * Current treatment with at least one of the following therapies which may be discontinued by the investigator as clinically indicated after 8 weeks of open label RHB-104 treatment: * Oral 5-acetyl salicylic acid (5-ASA) compounds * Azathioprine or 6-mercaptopurine (6-MP) or methotrexate * Infliximab or adalimumab OR Current treatment with corticosteroid therapy which must begin tapering after 4 weeks of treatment with open label RHB-104 (Refer to Appendix 13) * White blood cell count ≥ 3.5x109 at screening (RHB-104-01 Visit Week 26 visit or Optional Screening visit) * Subject agrees to use the following effective contraceptive methods * diaphragm, cervical cap, contraceptive sponge or condom) with spermicidal foam/gel/cream/suppository * IUD (intrauterine device) /IUS (intrauterine system) * progestogen injection (Depo-Provera®) throughout the study and for at least 6 weeks after last study drug administration, unless subject or partner of subject is post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation, or has had a vasectomy. Post-menopausal is defined as having experienced 12 consecutive months without menstruation. In regions where local regulatory contraceptive requirements differ, the ICF (Informed Consent Form) will reflect local policies.
Exclusion criteria
1. Positive stool results for C. difficile. 2. Currently diagnosed or history of uveitis confirmed by either an ophthalmologist or optometrist. 3. Treatment with any medication that causes QT prolongation or Torsades de Pointes, including but not limited to: amiodarone, amitriptyline, astemizole, cisapride, citalopram dose greater than 20 mg/day, dihydroergotamine, disopyramide, dofetilide, dronedarone, ergotamine, ibutilide, ondansetron or other 5-HT3 (5-hydroxytryptamine three) receptor antagonists, pimozide, procainamide, quinidine, quinine, quinolones, ranolazine, risperidone, sotalol, terfenadine and tolterodine. QT prolonging drugs may be referenced at the CredibleMeds® web site: https://crediblemeds.org/index.php/drugsearch/ 4. Treatment with the following CYP3A4 interactive medications: alfentanyl, alprazolam, amlodipine, anti-retroviral agents, apixaban, aprepitant, aripiprazole, atorvastatin, boceprevir, buspirone, carbamazepine, carvedilol, colchicine, cyclosporine, digoxin, diltiazem, estrogens, felodipine, fluconazole, fluvoxamine, grapefruit juice, haloperidol, ketoconazole, lovastatin, lurasidone, metoprolol, nefazodone, nifedipine, nisoldipine, nitrendipine, propranol, roflumilast, simvastatin, St. John's wort, and voriconazole. 5. Any evidence of any newly diagnosed significant hematological, hepatic, renal, cardiac, pulmonary, metabolic, neurological, psychiatric or other disease (e.g. porphyria) that might interfere with subject's ability to safely enter and or complete the study requirements. 6. Females who have a positive pregnancy test or are lactating. 7. Refusal to sign the study informed consent form. 8. Inability to be able to adequately communicate with the investigator or their respective designee and/or comply with the requirements of the entire study. 9. Clinically significant abnormalities of hematology or biochemistry as confirmed by repeat testing based on investigator's discretion, including but not limited to, elevations greater than 2 times the upper limit of normal of Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) or creatinine clearance less than 60 ml/min at screening via estimated Cockcroft-Gault formula: Creatinine Clearance = \[140 - age in years\] \* weight (kg) / 72 \* Serum Creatinine (mg/dl) \[multiply estimated rate by 0.85 for women\], using actual body weight. 10. QTcF (shortening of the QT interval in the heart rate) \>450ms in males and QTcF\>460ms in females, bundle branch block, or major ST or T wave abnormalities that make the assessment of the QT impossible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients in Remission at Week 16 | Week 16 | The number of patients who achieved a reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150 points. Lower CDAI scores indicate a better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response at Week 16 | Week 16 | Reduction of the total Crohn's Disease Activity Index (CDAI) score by a minimum of 100 points Lower CDAI scores indicate a better outcome. |
| The Number of Weeks for Patients to Achieve Remission | Baseline through week 52 | \[Date of first observed remission (CDAI less than 150) - date of first dose, or date of randomization if not dosed, plus 1\] / 7 days. Subject who never experience remission during the study are censored at the time of their last CDAI assessment. |
| Number of Weeks the Patients Are in Remission | Baseline through week 52 | Duration of remission is defined as the number of weeks the subject is in remission (CDAI score \< 150). It is calculated as the first date following remission at which CDAI is ≥150 minus the date of first remission, plus 1 day, divided by 7. 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. |
| Number of Weeks the Patients Are in Response. | Baseline through week 52 | Duration of response is defined as the number of weeks the subject is in a state of response (a reduction from baseline of ≥ 100 in CDAI score). It is calculated as the first date following response at which the reduction from baseline in CDAI is \<100 minus the date of first response, plus 1 day, divided by 7. 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. |
| Durable Remission Week 16 Through Week 52 | Week 16 through week 52 | When a subject is in remission with a maximum CDAI score of 149 at every visit from week 16 through and including week 52. |
| Number of Weeks to Achieve 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Increase in Milliseconds (ms) QT Wave | week 52 | The increase in the number of milliseconds change-from-baseline to week 52 in QTcF (Fridericia's Correction Formula of QT wave interval) (based on cardiac safety report). |
Countries
Canada, Czechia, Israel, New Zealand, Poland, Serbia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RHB-104 RHB-104; a fixed-dose combination of 95 mg clarithromycin, 45 mg rifabutin, 10 mg clofazimine. | 54 |
| Total | 54 |
Baseline characteristics
| Characteristic | RHB-104 |
|---|---|
| Age, Continuous RHB-104 from placebo | 40.0 years STANDARD_DEVIATION 13.24 |
| Age, Continuous RHB-104 from RHB-104 | 48.6 years STANDARD_DEVIATION 9.92 |
| Baseline Crohn's Disease Activity Index (CDAI) score RHB-104 from placebo | 271.67 units on a scale STANDARD_DEVIATION 58.379 |
| Baseline Crohn's Disease Activity Index (CDAI) score RHB-104 from RHB-104 | 295.42 units on a scale STANDARD_DEVIATION 82.865 |
| Race (NIH/OMB) RHB-104 from placebo American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) RHB-104 from placebo Asian | 0 Participants |
| Race (NIH/OMB) RHB-104 from placebo Black or African American | 1 Participants |
| Race (NIH/OMB) RHB-104 from placebo More than one race | 0 Participants |
| Race (NIH/OMB) RHB-104 from placebo Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) RHB-104 from placebo Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) RHB-104 from placebo White | 36 Participants |
| Race (NIH/OMB) RHB-104 from RHB-104 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) RHB-104 from RHB-104 Asian | 0 Participants |
| Race (NIH/OMB) RHB-104 from RHB-104 Black or African American | 1 Participants |
| Race (NIH/OMB) RHB-104 from RHB-104 More than one race | 0 Participants |
| Race (NIH/OMB) RHB-104 from RHB-104 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) RHB-104 from RHB-104 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) RHB-104 from RHB-104 White | 15 Participants |
| Sex: Female, Male RHB-104 from placebo Female | 18 Participants |
| Sex: Female, Male RHB-104 from placebo Male | 20 Participants |
| Sex: Female, Male RHB-104 from RHB-104 Female | 6 Participants |
| Sex: Female, Male RHB-104 from RHB-104 Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 38 |
| other Total, other adverse events | 14 / 16 | 24 / 38 |
| serious Total, serious adverse events | 1 / 16 | 4 / 38 |
Outcome results
Primary
Number of Patients in Remission at Week 16
The number of patients who achieved a reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150 points. Lower CDAI scores indicate a better outcome.
Time frame: Week 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RHB-104 From ACTIVE Arm of RHB-104-01 | Number of Patients in Remission at Week 16 | 3 Participants |
| RHB-104 From PLACEBO Arm of RHB-104-01 | Number of Patients in Remission at Week 16 | 14 Participants |
Secondary
Durable Remission Week 16 Through Week 52
When a subject is in remission with a maximum CDAI score of 149 at every visit from week 16 through and including week 52.
Time frame: Week 16 through week 52
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RHB-104 From ACTIVE Arm of RHB-104-01 | Durable Remission Week 16 Through Week 52 | 1 Participants |
| RHB-104 From PLACEBO Arm of RHB-104-01 | Durable Remission Week 16 Through Week 52 | 7 Participants |
p-value: 0.4114Fisher Exact
Secondary
Number of Weeks the Patients Are in Remission
Duration of remission is defined as the number of weeks the subject is in remission (CDAI score \< 150). It is calculated as the first date following remission at which CDAI is ≥150 minus the date of first remission, plus 1 day, divided by 7. 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 from RHB-104 5 (83.3); RHB-104 from Placebo: 8 (40.0). Number of patients censored due to remaining in remission during the study, n (%): RHB-104 from RHB-104 1 (16.7); RHB-104 from Placebo: 12 (60.0)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RHB-104 From ACTIVE Arm of RHB-104-01 | Number of Weeks the Patients Are in Remission | 11.7 weeks |
| RHB-104 From PLACEBO Arm of RHB-104-01 | Number of Weeks the Patients Are in Remission | 45.0 weeks |
p-value: 0.0356Log Rank
Secondary
Number of Weeks the Patients Are in Response.
Duration of response is defined as the number of weeks the subject is in a state of response (a reduction from baseline of ≥ 100 in CDAI score). It is calculated as the first date following response at which the reduction from baseline in CDAI is \<100 minus the date of first response, plus 1 day, divided by 7. 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 from RHB-104 3 (60.0); RHB-104 from placebo 7 (33.3). Number of patients censored due to remaining in response during the study, n (%): RHB-104 from RHB-104 2 (40.0); RHB-104 from placebo 14 (66.7)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RHB-104 From ACTIVE Arm of RHB-104-01 | Number of Weeks the Patients Are in Response. | 29.4 Weeks |
| RHB-104 From PLACEBO Arm of RHB-104-01 | Number of Weeks the Patients Are in Response. | 45.0 Weeks |
p-value: 0.1259Log Rank
Secondary
Number of Weeks to Achieve 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 from RHB-104 5 (31.3); RHB-104 from Placebo 21 (55.3). Number of patients censored due to never achieving response, n (%): RHB-104 from RHB-104 11 (68.8); RHB-104 from Placebo 17 (44.7)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RHB-104 From ACTIVE Arm of RHB-104-01 | Number of Weeks to Achieve Response | NA Weeks |
| RHB-104 From PLACEBO Arm of RHB-104-01 | Number of Weeks to Achieve Response | 26.1 Weeks |
p-value: 0.0514Log Rank
Secondary
Response at Week 16
Reduction of the total Crohn's Disease Activity Index (CDAI) score by a minimum of 100 points Lower CDAI scores indicate a better outcome.
Time frame: Week 16
Population: Number of subjects achieved response
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RHB-104 From ACTIVE Arm of RHB-104-01 | Response at Week 16 | 4 Participants |
| RHB-104 From PLACEBO Arm of RHB-104-01 | Response at Week 16 | 14 Participants |
Secondary
The Number of Weeks for Patients to Achieve Remission
\[Date of first observed remission (CDAI less than 150) - date of first dose, or date of randomization if not dosed, plus 1\] / 7 days. Subject who never experience remission during the study are censored at the time of their last CDAI assessment.
Time frame: Baseline through week 52
Population: Number of subjects achieved remission, n (%) RHB-104 from RHB-104: 6 (37.5); RHB-104 from Placebo: 20 (52.6).~Number of patients censored due to never achieving remission, n (%) RHB-104 from RHB-104: 10 (62.5); RHB-104 from Placebo: 18 (47.4)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RHB-104 From ACTIVE Arm of RHB-104-01 | The Number of Weeks for Patients to Achieve Remission | NA weeks |
| RHB-104 From PLACEBO Arm of RHB-104-01 | The Number of Weeks for Patients to Achieve Remission | 25.1 weeks |
p-value: 0.2112Log Rank
Other Pre-specified
Increase in Milliseconds (ms) QT Wave
The increase in the number of milliseconds change-from-baseline to week 52 in QTcF (Fridericia's Correction Formula of QT wave interval) (based on cardiac safety report).
Time frame: week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| RHB-104 From ACTIVE Arm of RHB-104-01 | Increase in Milliseconds (ms) QT Wave | 23.9 ms |
| RHB-104 From PLACEBO Arm of RHB-104-01 | Increase in Milliseconds (ms) QT Wave | 27.6 ms |