Crohn's Disease
Conditions
Keywords
Crohn's Disease, Inflammatory Bowel Disease, infliximab, TNF-alpha
Brief summary
REMICADE (infliximab) is a drug used to treat active Crohn's disease and is being tested in an experiment to see if it may be useful in preventing relapse of Crohn's disease after surgical resection. This study will compare the effects (both good and bad) of REMICADE (infliximab) to those of placebo. Placebo looks like the drug being studied but has no active ingredients.
Detailed description
The purpose of this study is to assess the effects of REMICADE (infliximab) in preventing relapse of Crohn's disease after surgical resection. Patients will be assigned to a group that will initially receive either infliximab or placebo. Each patient who is allowed to join the study is put into a group by chance (randomly), like flipping a coin. There is a possibility that patients can receive both the study drug and placebo at different times in the study. If a patient is initially randomized to receive placebo, and their study doctor confirms that they have had a return of active Crohn's Disease symptoms, they can receive infliximab. If a patient is initially randomized to receive infliximab, and their study doctor confirms that they are experiencing symptoms of Crohn's Disease, they may receive an increase in their infliximab dose. Infusions will be administered at Week 0 and then every 8 weeks thereafter through Week 200. The study will use a measure of Crohn's Disease activity that will be evaluated at each visit and at any time the patient has symptoms suggestive of their disease getting worse in order to capture recurrence. During the study, patients who meet the study definition of clinical recurrence will be eligible to have a blinded infliximab dose increase of 5 mg/kg. In other words, patients receiving placebo would receive infliximab 5 mg/kg, and patients receiving infliximab 5 mg/kg would have a dose increase to 10 mg/kg. Approximately 175 sites will be utilized, and approximately 290 patients will be enrolled. The interval between the first and last dose of study agent is 200 weeks. The planned duration of study participation is a maximum of 209 weeks (with a 1-week screening period, a 200-week treatment period, and a final study visit at Week 208). Group I (infliximab infusions): infliximab (5 mg/kg) will be administered by intravenous (IV) infusion at Week 0 and every 8 weeks thereafter through Week 200. Group II (placebo infusions): placebo will be administered by IV infusion at Week 0 and every 8 weeks thereafter through Week 200
Interventions
DRUGPlacebo
Type=equal, unit=mg, number=5, form=intravenous infusion, route=intravenous use, once every 8 weeks
BIOLOGICALInfliximab
Type=equal, unit=mg, number=5, form=intravenous infusion, route=intravenous use, once every 8 weeks
Sponsors
Janssen Biotech, Inc.
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 99 Years
Healthy volunteers
No
Inclusion criteria
* Have a documented diagnosis of CD confirmed by endoscopic, histologic and/or radiologic studies prior to resection or by tissue obtained at resection * Have undergone an ileocolonic surgical resection * Patients must also be at an increased risk of recurrence of active CD * Patients must not have previously discontinued infliximab as a result of tolerability issues or they must be naive to treatment with infliximab. Provided patients meet the above criteria pertaining to infliximab, they are eligible to enroll if they received prior treatment with adalimumab and/or certolizumab * Patients must undergo screening for HBV * Baseline CDAI \< 200 * Have adequate blood and liver test values
Exclusion criteria
* Have a history of latent or active granulomatous infection, including histoplasmosis or coccidioidomycosis, prior to screening * Have a chest radiograph within 3 months prior to the first infusion of study agent that shows a clinically significant abnormality, such as a malignancy or infection, or any abnormalities suggestive of TB * Have macroscopically active CD which was not resected at the time of surgery * Do not meet the criteria for being at an increased risk of postoperative recurrence of active CD as outlined in the inclusion criteria * Have evidence of an active infection at the time of randomization or have had a serious infection not related to CD (e.g., hepatitis, pneumonia, or pyelonephritis), within 6 months prior to screening * Have or have had an opportunistic infection (e.g., herpes zoster \[shingles\], cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria other than TB) within 6 months prior to screening * Have any known malignancy or history of malignancy within the 5-year period prior to screening (with the exception of squamous or basal cell carcinoma of the skin that has been completely excised without evidence of recurrence) * Have any condition that, in the opinion of the investigator, would compromise the well-being of the patient or the study or prevent the patient from meeting or performing study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Recurrence (CR) of Crohn's Disease (CD) Prior to or at Week 76 | Baseline up to Week 76 | CR criteria:1) A \>=70-point increase from baseline in CDAI score \[in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities\];2)A CDAI score \>=200;3)Evidence of endoscopic recurrence \[ileal Rutgeerts score of \>=i2 at anastomotic site or its equivalent elsewhere in GI tract\] and 4)A negative stool test for C. difficile toxin (if, in the opinion of the investigator, the participant's symptoms are predominantly diarrheal); or at least 1 of followings:1) developing a new draining external fistula;2)re-opening and draining of a previously existing external fistula;3)developing a new internal fistula;4)developing a new perianal abscess or 5)developing a new intra-abdominal abscess more than 3 months after date of index surgery. In addition, participants who had a treatment failure \[initiated a prohibited CD medication, had prohibited use of CD medication, or had surgery for CD\] before or at Week 76 were considered to have clinical recurrence. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Endoscopic Recurrence of CD Prior to or at Week 76 | Baseline up to Week 76 | Endoscopic recurrence is defined as an ileal Rutgeert's score of \>= i2 either at the anastomotic site or elsewhere in the gastrointestinal tract. In addition, participants who had a treatment failure (initiated a prohibited CD medication, had a prohibited use of a CD medication, or had a surgery for CD) prior to Week 76, and who developed a new draining external fistula or re-opening and draining of a previously existing external fistula or developed a new internal fistula, new perianal abscess or new intra-abdominal abscess more than 3 months after the date of the index surgery were considered to have had endoscopic recurrence prior to or at Week 76. |
| Percentage of Participants With Clinical Recurrence (CR) of Crohn's Disease (CD) Prior to or at Week 104 | Baseline up to Week 104 | CR criteria:1) A \>=70-point increase from baseline in CDAI score \[in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities\];2)A CDAI score \>=200;3)Evidence of endoscopic recurrence \[ileal Rutgeerts score of \>=i2 at anastomotic site or its equivalent elsewhere in GI tract\] and 4)A negative stool test for C. difficile toxin (if, in the opinion of the investigator, the participant's symptoms are predominantly diarrheal); or at least 1 of followings:1) developing a new draining external fistula;2)re-opening and draining of a previously existing external fistula;3)developing a new internal fistula;4)developing a new perianal abscess or 5)developing a new intra-abdominal abscess more than 3 months after date of index surgery. In addition, participants who had a treatment failure \[initiated a prohibited CD medication, had prohibited use of CD medication, or had surgery for CD\]before or at Week 104 were considered to have clinical recurrence. |
Countries
Australia, Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Netherlands, New Zealand, Poland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants randomized to receive placebo at Week 0 and then every 8 weeks thereafter through Week 200. | 150 |
| Infliximab 5 mg/kg Participants randomized to receive Infliximab 5 milligram per kilogram (mg/kg) at Week 0 and then every 8 weeks thereafter through Week 200. | 147 |
| Total | 297 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 32 | 41 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 7 | 1 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Randomized but not treated | 2 | 4 |
| Overall Study | Trial stopped by Sponsor | 71 | 68 |
| Overall Study | Undefined | 35 | 31 |
Baseline characteristics
| Characteristic | Placebo | Infliximab 5 mg/kg | Total |
|---|---|---|---|
| Age, Continuous | 35.4 years STANDARD_DEVIATION 12.41 | 37.1 years STANDARD_DEVIATION 13.49 | 36.3 years STANDARD_DEVIATION 12.96 |
| Sex: Female, Male Female | 69 Participants | 70 Participants | 139 Participants |
| Sex: Female, Male Male | 81 Participants | 77 Participants | 158 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 | 122 / 146 | 121 / 145 | 18 / 27 | 8 / 9 |
| serious Total, serious adverse events | 36 / 146 | 32 / 145 | 5 / 27 | 2 / 9 |
Outcome results
Primary
Percentage of Participants With Clinical Recurrence (CR) of Crohn's Disease (CD) Prior to or at Week 76
CR criteria:1) A \>=70-point increase from baseline in CDAI score \[in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities\];2)A CDAI score \>=200;3)Evidence of endoscopic recurrence \[ileal Rutgeerts score of \>=i2 at anastomotic site or its equivalent elsewhere in GI tract\] and 4)A negative stool test for C. difficile toxin (if, in the opinion of the investigator, the participant's symptoms are predominantly diarrheal); or at least 1 of followings:1) developing a new draining external fistula;2)re-opening and draining of a previously existing external fistula;3)developing a new internal fistula;4)developing a new perianal abscess or 5)developing a new intra-abdominal abscess more than 3 months after date of index surgery. In addition, participants who had a treatment failure \[initiated a prohibited CD medication, had prohibited use of CD medication, or had surgery for CD\] before or at Week 76 were considered to have clinical recurrence.
Time frame: Baseline up to Week 76
Population: Analysis population included all the participants who were randomly assigned to receive 1 of the study treatments.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Clinical Recurrence (CR) of Crohn's Disease (CD) Prior to or at Week 76 | 20.0 percentage of participants |
| Infliximab 5 mg/kg | Percentage of Participants With Clinical Recurrence (CR) of Crohn's Disease (CD) Prior to or at Week 76 | 12.9 percentage of participants |
p-value: 0.097Cochran-Mantel-Haenszel chi-square test
Secondary
Percentage of Participants With Clinical Recurrence (CR) of Crohn's Disease (CD) Prior to or at Week 104
CR criteria:1) A \>=70-point increase from baseline in CDAI score \[in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities\];2)A CDAI score \>=200;3)Evidence of endoscopic recurrence \[ileal Rutgeerts score of \>=i2 at anastomotic site or its equivalent elsewhere in GI tract\] and 4)A negative stool test for C. difficile toxin (if, in the opinion of the investigator, the participant's symptoms are predominantly diarrheal); or at least 1 of followings:1) developing a new draining external fistula;2)re-opening and draining of a previously existing external fistula;3)developing a new internal fistula;4)developing a new perianal abscess or 5)developing a new intra-abdominal abscess more than 3 months after date of index surgery. In addition, participants who had a treatment failure \[initiated a prohibited CD medication, had prohibited use of CD medication, or had surgery for CD\]before or at Week 104 were considered to have clinical recurrence.
Time frame: Baseline up to Week 104
Population: Analysis population included all the participants who were randomly assigned to receive 1 of the study treatments.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Clinical Recurrence (CR) of Crohn's Disease (CD) Prior to or at Week 104 | 25.3 percentage of participants |
| Infliximab 5 mg/kg | Percentage of Participants With Clinical Recurrence (CR) of Crohn's Disease (CD) Prior to or at Week 104 | 17.7 percentage of participants |
p-value: 0.098Cochran-Mantel-Haenszel chi-square test
Secondary
Percentage of Participants With Endoscopic Recurrence of CD Prior to or at Week 76
Endoscopic recurrence is defined as an ileal Rutgeert's score of \>= i2 either at the anastomotic site or elsewhere in the gastrointestinal tract. In addition, participants who had a treatment failure (initiated a prohibited CD medication, had a prohibited use of a CD medication, or had a surgery for CD) prior to Week 76, and who developed a new draining external fistula or re-opening and draining of a previously existing external fistula or developed a new internal fistula, new perianal abscess or new intra-abdominal abscess more than 3 months after the date of the index surgery were considered to have had endoscopic recurrence prior to or at Week 76.
Time frame: Baseline up to Week 76
Population: Analysis population included all the participants who were randomly assigned one of the treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Endoscopic Recurrence of CD Prior to or at Week 76 | 60.0 percentage of participants |
| Infliximab 5 mg/kg | Percentage of Participants With Endoscopic Recurrence of CD Prior to or at Week 76 | 30.6 percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel chi-square test