Crohn's Disease
Conditions
Brief summary
A randomized, placebo-controlled pilot study to determine endoscopic recurrence of Crohn's disease 12 months after curative, resective ileal or ileocolonic surgery in patients receiving post-operative infliximab or placebo
Interventions
DRUGinfliximab
5 mg/kg IV at baseline, 2 weeks, 6 weeks and then every 8 weeks x 6
DRUGplacebo
placebo IV at baseline, 2 weeks, 6 weeks and then every 8 weeks x 6
Sponsors
Centocor, Inc.
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 72 Years
Healthy volunteers
No
Inclusion criteria
* men/women \> 18 years of age * curative resection/ileocolonic anastomosis for Crohn's disease * may have received previously received infliximab * if on oral aminosalicylates or corticosteroids, dose must be stable for 4 weeks prior to surgery * if on 6-mercaptopurine,azathioprine or methotrexate,individual must have been on it for minimum of 3 months prior to surgery with stable dose for 4 weeks * men and women must use adequate birth control for duration of study and for 6 months after receiving the last infusion * antibiotics for treatment of Crohn's disease must be discontinued within 12 weeks after surgery; antibiotics are allowable throughout study as long as primary purpose of antibiotic therapy is not for primary treatment of Crohn's disease * screening lab results must meet screening criteria (hemoglobin = or \> 8.5g/dL; Serum glutamic oxaloacetic transaminase ,3 times upper normal limit,platelets =or\> 100 x 10 9th/L; lymphocytes count =or\> 0.5 x 10 9th/L and neutrophils =or\> 1.0 x 10 9th/L * have a documented negative reaction to a purified protein derivative skin test performed within 3 months prior to baseline * have a normal chest radiograph results within 3 months prior to baseline * are capable of providing written informed consent and obtained prior to conducting any protocol-specified procedures * willing to adhere to the study visit schedule and other protocol requirements * are considered eligible according to the tuberculosis eligibility assessment, screening and early detection of reactivation rules * patients who undergo resective surgery and primary ileocolonic anastomosis with a temporary ileostomy upon takedown of the diverting ileostomy.
Exclusion criteria
* patients with greater than 10 years of Crohn's disease requiring first resection of a short (\<10cm) fibrostenotic stricture * macroscopically active disease at anastomosis at time of surgery * presence of stoma * prior severe infusion reaction to infliximab * history of anaphylaxis to murine products or other chimeric proteins * any of the following medications taken within 12 weeks of surgery: cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, investigational drugs, or medications targeted at reducing tumor necrosis factor * have a positive stool culture for enteric pathogens, pathogenic ova or parasites, or Clostridium difficile toxin and have clinically significant signs of an enteric infection at screening * women who are pregnant, nursing or planning pregnancy during the trial or within 6 months after the last infusion * patient with active tuberculosis, patient newly diagnosed with latent tuberculosis who's receiving tuberculosis prophylaxis, patient with recent close contact to individual with active tuberculosis * have or have had opportunistic infection within 6 months of screening * have chest radiograph within 3 months prior to screening that shows malignancy, infection, or abnormalities suggestive of tuberculosis * documentation of seropositive for HIV * documentation of a positive test for hepatitis B surface antigen or a history of documented hepatitis C * have current signs/symptoms of systemic lupus erythematosus, or severe progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic or cerebral diseases * presence of a transplanted solid organ (with exception of corneal transplant \> 3 months prior to randomization) * Have any current or known malignancy or have history of malignancy within 5 years of screening(except for squamous or basal cell carcinoma of the skin that has been fully excised with no evidence of recurrence) * have history of lymphoproliferative disease or splenomegaly * have known substance abuse(drug/alcohol)/dependency within the previous 3 years, history of noncompliance with medical regimens, or other condition that may interfere with adherence to protocol requirements * are unwilling/unable to undergo multiple venipunctures because of poor tolerability or lack of easy access * known history of demyelinating disease * a chronic or recurrent infectious disease * serious infection, hospitalization for infection, or treatment with IV antibiotics for infection within 2 months prior to randomization * a serious concomitant illness that may interfere with participation in trial * concomitant diagnosis/history of congestive heart failure * current use of prescription doses or chronic/frequent use of non-steroidal anti-inflammatory drugs * ulcerative colitis * concurrent participation in another investigative trial * use of any investigational drug within 30 days prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endoscopic Recurrence: the Proportion of Patients in Endoscopic Recurrence at One Year | one year | Endoscopic recurrence was defined as i2,i3,i4. We used the Rutgeerts' Endoscopic Scoring System. Scores as follows i0, no lesions; i1, 5 or fewer aphthous lesions; i2, more than 5 aphthous lesions with normal mucosa between the lesions or skip areas of larger lesions or lesions confined to the ileocolonic anastomosis; i3, diffuse, aphthous ileitis with diffusely inflamed mucosa; and i4, diffuse inflammation with large ulcers, nodules, and/or narrowing. Endoscopic recurrence was defined as i2,i3,i4 and endoscopic remission was defined as i0 or i1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Recurrence at One Year: Defined by Crohn's Disease Activity Index (CDAI) > 200 | One year | The Crohn's Disease Activity Index (CDAI) is calculated by a measurement of symptoms, signs, and lab tests over a time period of the previous 7 days. The CDAI includes: Number of very soft stools; sum of abdominal pain ratings: (0=none, 1= mild, 2=moderate, 3=severe); general well being (0=well, 1=slightly below par, 2=poor, 3=very poor, 4=terrible); Symptoms or findings presumed related to Crohn's disease (present): arthritis or arthralgia, iritis or uveitis, erythema nodosum, pyoderma gangrenosum, aphthous stomatitis, anal fissure, fistula or perirectal abscess, other bowel related fistula, febrile episode over 100 degrees during past week, taking lomotil or opiates for diarrhea, abnormal mass (0=none; 0.4=questionable; 1=present) hematocrit \[(typical-current) X 6\] Normal average male = 47, female =42, body weight |
| Histological Recurrence of Crohn's Disease as Determined From Biopsies of Neo-terminal Ileum Above the Ileocolonic Anastomosis | One year | Histologic recurrence based on a histologic activity score and the presence of polymononuclear cells. The maximum score is 14 per biopsy site. |
| C-reactive Protein Concentration as a Surrogate Marker of Inflammation | one year | The CRP was obtained at each study visit as a surrogate marker of inflammation. The CRP was recorded as milligram per deciliter (mg/dl). A normal CRP was 0-0.8 mg/dl; levels exceeding 0.8 mg/dl indicated inflammation. |
| Mean Erythrocyte Sedimentation Rate | one year | erythrocyte sedimentation rate value - blood test |
Countries
United States
Participant flow
Recruitment details
Between 2005 and 2007 there were 24 adult patients with ileal or ileocolonic Crohn's disease undergoing resection who participated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Infliximab infliximab: 5 mg/kg IV at baseline, 2 weeks, 6 weeks and then every 8 weeks for 54 weeks | 11 |
| Placebo placebo: placebo IV at baseline, 2 weeks, 6 weeks and then every 8 weeks for 54 weeks | 13 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
Baseline characteristics
| Characteristic | Infliximab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 43.0 years | 32.0 years | 38.0 years |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 11 | 11 / 13 |
| serious Total, serious adverse events | 1 / 11 | 0 / 13 |
Outcome results
Primary
Endoscopic Recurrence: the Proportion of Patients in Endoscopic Recurrence at One Year
Endoscopic recurrence was defined as i2,i3,i4. We used the Rutgeerts' Endoscopic Scoring System. Scores as follows i0, no lesions; i1, 5 or fewer aphthous lesions; i2, more than 5 aphthous lesions with normal mucosa between the lesions or skip areas of larger lesions or lesions confined to the ileocolonic anastomosis; i3, diffuse, aphthous ileitis with diffusely inflamed mucosa; and i4, diffuse inflammation with large ulcers, nodules, and/or narrowing. Endoscopic recurrence was defined as i2,i3,i4 and endoscopic remission was defined as i0 or i1.
Time frame: one year
Population: The proportion of patients with endoscopic recurrence (\> or = i2) at 1 year after surgery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infliximab | Endoscopic Recurrence: the Proportion of Patients in Endoscopic Recurrence at One Year | 1 participants |
| Placebo | Endoscopic Recurrence: the Proportion of Patients in Endoscopic Recurrence at One Year | 11 participants |
p-value: 0.0005Fisher Exact
Secondary
Clinical Recurrence at One Year: Defined by Crohn's Disease Activity Index (CDAI) > 200
The Crohn's Disease Activity Index (CDAI) is calculated by a measurement of symptoms, signs, and lab tests over a time period of the previous 7 days. The CDAI includes: Number of very soft stools; sum of abdominal pain ratings: (0=none, 1= mild, 2=moderate, 3=severe); general well being (0=well, 1=slightly below par, 2=poor, 3=very poor, 4=terrible); Symptoms or findings presumed related to Crohn's disease (present): arthritis or arthralgia, iritis or uveitis, erythema nodosum, pyoderma gangrenosum, aphthous stomatitis, anal fissure, fistula or perirectal abscess, other bowel related fistula, febrile episode over 100 degrees during past week, taking lomotil or opiates for diarrhea, abnormal mass (0=none; 0.4=questionable; 1=present) hematocrit \[(typical-current) X 6\] Normal average male = 47, female =42, body weight
Time frame: One year
Population: CDAI score \> 200
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infliximab | Clinical Recurrence at One Year: Defined by Crohn's Disease Activity Index (CDAI) > 200 | 0 participants |
| Placebo | Clinical Recurrence at One Year: Defined by Crohn's Disease Activity Index (CDAI) > 200 | 5 participants |
Secondary
C-reactive Protein Concentration as a Surrogate Marker of Inflammation
The CRP was obtained at each study visit as a surrogate marker of inflammation. The CRP was recorded as milligram per deciliter (mg/dl). A normal CRP was 0-0.8 mg/dl; levels exceeding 0.8 mg/dl indicated inflammation.
Time frame: one year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Infliximab | C-reactive Protein Concentration as a Surrogate Marker of Inflammation | 0.5 mg/dL |
| Placebo | C-reactive Protein Concentration as a Surrogate Marker of Inflammation | 0.6 mg/dL |
Secondary
Histological Recurrence of Crohn's Disease as Determined From Biopsies of Neo-terminal Ileum Above the Ileocolonic Anastomosis
Histologic recurrence based on a histologic activity score and the presence of polymononuclear cells. The maximum score is 14 per biopsy site.
Time frame: One year
Population: Histologic activity score
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infliximab | Histological Recurrence of Crohn's Disease as Determined From Biopsies of Neo-terminal Ileum Above the Ileocolonic Anastomosis | 3 participants |
| Placebo | Histological Recurrence of Crohn's Disease as Determined From Biopsies of Neo-terminal Ileum Above the Ileocolonic Anastomosis | 11 participants |
Secondary
Mean Erythrocyte Sedimentation Rate
erythrocyte sedimentation rate value - blood test
Time frame: one year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Infliximab | Mean Erythrocyte Sedimentation Rate | 30 mm/h |
| Placebo | Mean Erythrocyte Sedimentation Rate | 19 mm/h |