Crohn's Disease
Conditions
Brief summary
The primary objective of this study was to demonstrate that tight control of disease activity, using stringent criteria based on Crohn's disease activity Index (CDAI), biomarkers (high sensitivity C-reactive protein \[hs-CRP\] and fecal calprotectin), and corticosteroid use, improves the rate of mucosal healing 48 weeks after randomization compared with management using less stringent criteria based only on CDAI and corticosteroid use.
Detailed description
The study included a 1- to 3-week screening period, up to 8 weeks of prednisone run-in treatment, a 48-week post-randomization treatment period, and a 70 day follow-up phone call or clinic visit, for a total duration of up to 69 weeks. Participants who met entry criteria were enrolled and initiated an oral prednisone regimen at Baseline (Week 0). At the first key visit, participants were randomized into 1 of 2 groups (Tight Control group or Clinically Driven group), with stratification according to screening smoking status, weight, and disease duration. The first key visit was the randomization visit; subsequent key visits occurred every 12 weeks following the first key visit. Randomization normally took place 9 weeks after Baseline. However, participants who fulfilled the early randomization criteria may have been randomized as early as the Baseline (Week 0) visit. Therapeutic option changes, if appropriate, occurred at key visits based on results from previous success criteria visits.
Interventions
BIOLOGICALAdalimumab
If adalimumab was initiated, it was administered subcutaneously as a 160 mg induction dose the first week, followed by 80 mg 2 weeks later, followed by 40 mg every other week as a maintenance dose. The dose of adalimumab was increased from 40 mg eow to 40 mg every week in participants with an inadequate response and de-escalated to 40 mg eow in participants who met success criteria.
DRUGPrednisone
The suggested regimen for participants initiating prednisone consisted of a maximum dose of prednisone 40 mg/day for 2 weeks, followed by a fixed taper for 6 weeks.
DRUGAzathioprine
Participants with normal thiopurine methyltransferase (TPMT) enzyme activity could receive oral azathioprine 2.5 mg/kg/day. In participants with intermediate TPMT enzyme activity azathioprine was initiated at a dose of 1.25 mg/kg/day. The dose of azathioprine was adjusted according to abnormalities of white blood cell (WBC) count, platelet count, liver function tests (LFTs; i.e. alanine transaminase \[ALT\], aspartate transaminase \[AST\], alkaline phosphatase), lipase, blood urea nitrogen (BUN), and serum creatinine.
Sponsors
AbbVie (prior sponsor, Abbott)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of ileal, colonic (including rectal), or ileocolonic Crohn's disease (CD) confirmed using imaging technology or endoscopy not more than 6 years prior to Baseline. * CDAI score of greater than or equal to 220 and less than or equal to 450 at the Baseline visit in participants not receiving prednisone or equivalent at Baseline. CDAI score of greater than or equal to 200 and less than or equal to 450 at the Baseline visit if the participant is receiving prednisone less than or equal to 20 mg or equivalent for at least 7 days before Baseline. CDAI score of greater than 150 and less than or equal to 450 at the Baseline visit if the participant is receiving prednisone higher than 20 mg or equivalent for greater than or equal to 7 days before Baseline * Participant or his/her legal representative have voluntarily signed and dated an informed consent approved by and compliant with the requirements of this study protocol which has been approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC). * Adequate cardiac, renal and hepatic function as determined by the Principal Investigator and demonstrated by Screening laboratory evaluations, questionnaires and physical examination results that do not indicate an abnormal clinical condition which would place the participant at undue risk and thus preclude participation in the study. * Participant must be able to self-inject and orally administer study medication or have a designee or Healthcare Professional who can assist
Exclusion criteria
* Previous or current biologic use for Crohn's disease or participation in a biologic study * Previous or current use of immunomodulators (e.g., methotrexate, azathioprine, 6-mercaptopurine, JAK inhibitor, alpha-integrin) for Crohn's disease or participation in a Crohn's disease study with immunomodulator(s). Current use of immunomodulators for non-Crohn's disease at Baseline. * Greater than two previous courses of corticosteroid (systemic corticosteroid) or budesonide) for Crohn's Disease. A course is defined as 1) total duration for burst and taper ≥ 4 weeks and 2) prednisone or equivalent ≥ 40 mg (or budesonide ≥ 9 mg) for at least 2 weeks. * Participants with a poorly controlled medical condition such as: uncontrolled diabetes with documented history of recurrent infections, unstable ischemic heart disease, moderate to severe congestive heart failure (New York Heart Association \[NYHA\] class III or IV), recent cerebrovascular accident and any other condition which, in the opinion of the Investigator or the sponsor, would put the participant at risk by participation in the protocol * Participants with positive C. difficile stool assay at Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Mucosal Healing and No Deep Ulcerations | 48 weeks after Randomization | Percentage of participants with mucosal healing (defined as Crohn's disease endoscopy Index of severity \[CDEIS\] \< 4) and no deep ulcerations on ileocolonoscopy (defined as the absence of all deep ulcerations in all segments explored in CDEIS) at 48 weeks after randomization (48 weeks after the 1st Key visit). The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The score ranges from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing data 48 weeks after Randomization were counted as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Biologic Remission 48 Weeks After Randomization | 48 weeks after Randomization | Biologic remission was defined as high sensitivity C-reactive protein (hs-CRP) \< 5 mg/L, fecal Calprotectin \< 250 μg/g, and CDEIS \< 4 at 48 weeks after randomization. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after Randomization were counted as non-responders. |
| Percentage of Participants With Mucosal Healing 48 Weeks After Randomization | 48 weeks after Randomization | Percentage of participants with mucosal healing (defined as a CDEIS \< 4) at 48 weeks after randomization (48 weeks after the 1st Key visit). The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after Randomization were counted as non-responders. |
| Percentage of Participants With Mucosal Healing and CDEIS < 4 in Every Segment 48 Weeks After Randomization | 48 weeks after Randomization | Percentage of participants with mucosal healing (defined as CDEIS \< 4) and CDEIS \< 4 in every segment on ileocolonoscopy at 48 weeks after randomization. The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after randomization were counted as non-responders. |
| Percentage of Participants With Complete Mucosal Healing 48 Weeks After Randomization | 48 weeks after Randomization | Complete mucosal healing was defined as CDEIS = 0. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after randomization were counted as non-responders. |
| Number of All-cause Hospitalizations After Randomization | From Randomization through 48 weeks after Randomization | Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. |
| Percentage of Participants With Endoscopic Response 48 Weeks After Randomization | 48 weeks after Randomization | Endoscopic response was defined as a decrease CDEIS \> 5 points. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after Randomization were counted as non-responders. |
| Change From Baseline in CDEIS at 48 Weeks After Randomization | Baseline and 48 weeks after Randomization | CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The score ranges from 0 to 44 where higher scores indicate more severe endoscopic activity. A negative change from Baseline indicates improvement. |
| Change From Baseline in CDAI Over Time | Baseline and 4 and 8 weeks during the prednisone run-in, and 2, 6, 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization. | The Crohn's Disease Activity Index (CDAI) is a research tool used to quantify the symptoms of patients with Crohn's disease. Participants were asked to record the frequency of stools, abdominal pain and general well-being on a daily basis. In addition to the diary data, the investigator assessed the following for the calculation of CDAI: presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. The CDAI is the sum of the products of each item multiplied by a weighting factor and generally ranges from 0 up to 600, where remission of Crohn's disease is defined as CDAI \< 150, and severe disease is defined as CDAI \> 450. A negative change from Baseline indicates improvement. |
| Time to Crohn's Disease Flare | From Randomization to 48 weeks after Randomization | Time to Crohn's disease flare, where flare is defined as an increase in CDAI ≥ 70 points compared to Week 8 or Early Randomization CDAI, and a CDAI \> 220. |
| Time to Clinical Remission | From Randomization through 48 weeks after Randomization | Clinical remission was defined as CDAI \< 150. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI scores generally range from 0 to 600 where higher scores indicate more severe disease. |
| Time to Steroid-free Remission | From Randomization through 48 weeks after Randomization | Steroid-free remission was defined as CDAI \< 150 and discontinuation from steroids for at least 8 weeks. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. |
| Percentage of Participants in Clinical Remission Over Time | Baseline and 4 and 8 weeks during the prednisone run-in, and 2, 6, 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization. | Clinical remission was defined as CDAI \< 150. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. Participants with missing data at each time point were counted as non-responders. |
| Percentage of Participants in Steroid-free Remission Over Time | 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization. | Steroid-free remission was defined as CDAI \< 150 and discontinuation from steroids for at least 8 weeks. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. Participants with missing data at each time point were counted as non-responders. |
| Time to All-cause Hospitalization | From Randomization through 48 weeks after Randomization | Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. |
| Time to Crohn's Disease-related Hospitalization or Hospitalization Due to Adverse Event Relating to Study Medication | From Randomization through 48 weeks after Randomization | Crohn's disease-related hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic for reasons related to Crohn's disease (CD). Hospitalization for adverse events relating to study medication, i.e., prednisone, azathioprine or adalimumab, were according to Investigator's clinical judgment. |
| Percentage of Participants in Deep Remission 48 Weeks After Randomization | 48 weeks after Randomization | Deep remission was defined as CDAI \< 150, discontinuation from steroids for at least 8 weeks, absence of draining fistula, CDEIS \< 4 and no deep ulcerations. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing data 48 weeks after randomization were counted as non-responders. |
| Number of Crohn's Disease-related Hospitalizations After Randomization | From Randomization through 48 weeks after Randomization | Any hospitalization with an overnight stay in hospital/clinic related to Crohn's disease. |
| Total Length of Stay in Hospital for All-cause Hospitalizations | From Randomization through 48 weeks after Randomization | — |
| Total Length of Stay in Hospital for Crohn's Disease-related Hospitalizations | From Randomization through 48 weeks after Randomization | — |
| Number of Crohn's Disease-related Surgical Procedures After Randomization | From Randomization through 48 weeks after Randomization | The total number of CD-related surgical procedures included major CD-related surgery, debridement, perineal related surgery - abscess drainage, seton placement, fistulotomy, and TPN. |
| Time to Crohn's Disease-related Hospitalization Due to Emergency | From Randomization through 48 weeks after Randomization | Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. Hospitalization due to emergency was defined as a hospitalization admitted through the emergency department. |
| Number of Crohn's Disease-related Hospitalizations Due to Emergency | From Randomization through 48 weeks after Randomization | Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. Hospitalization due to emergency was defined as a hospitalization admitted through the emergency department. |
| Change in Crohn's Disease Behavior According to Montreal Classification | From Baseline to 48 weeks after Randomization | Participants' Crohn's Disease was classified according to the Montreal Classification which classifies CD according to its predominant phenotypic elements (age at diagnosis, location, and disease behavior) based on the results of clinical examination and endoscopy. Disease behavior was classified according to the following: B1 = non-stricturing, non-penetrating; B2 = structuring; B3 = penetrating; P = perianal disease modifier. The change in Montreal Classification is presented in three categories: no change, deterioration, and improvement. Deterioration was defined as an increase in behavior index between 1 and 3, or development of perianal disease. Participants with missing data at Week 48 were classified as deterioration. |
| Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time | Baseline and 8 weeks during the prednisone run-in, and 11, 23, 35, and 48 weeks after Randomization. | High sensitivity C-reactive protein was analyzed by a central laboratory. |
| Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization | Baseline and 48 weeks after Randomization | Stool samples were analyzed by a central laboratory for fecal calprotectin qualitative measurement (\< 250 or ≥ 250 μg/g). Results are reported for participants in each category at Baseline and 48 weeks after Randomization. Participants with missing data 48 weeks after Randomization were counted as having fecal calprotectin ≥ 250µg/g. |
| Total Dose of Prednisone | From Baseline through 48 weeks after Randomization | The total dose of prednisone each participant received during both the run-in phase and post-randomization treatment phase. |
| Change From Baseline in Quality of Life in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score | Baseline and 48 weeks after Randomization | The IBDQ measures the effects of inflammatory bowel disease on daily function and quality of life. The IBDQ consists of 32 questions which address symptoms as a result of Crohn's disease, feeling in general, and mood. Each question is answered on a scale from 1 (all of the time) to 7 ( none of the time); the total score ranges from 7 (worst) to 224 (best). A positive change from baseline indicates improvement. |
| Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD) | Baseline and 48 weeks after Randomization | The WPAI:CD questionnaire was used to assess impairments in both paid work and unpaid work due to symptoms of Crohn's Disease. The self-administered questionnaire consisted of 6 questions. Work time missed was defined as the percentage of time absent from work due to Crohn's disease in the past week. Impairment while working is the participant's assessment of the degree to which Crohn's disease affected productivity while working in the past 7 days. Total work productivity impairment takes into account both hours missed due to Crohn's disease symptoms and the patient's assessment of the degree to which Crohn's disease affected their productivity while working. Total activity impairment is the percent impairment of non-work related activities due to Crohn's disease. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. A negative change from Baseline indicates improvement. |
| Change From Baseline in Patient Health Questionnaire - 9 (PHQ9) | Baseline and 48 weeks after Randomization | The PHQ-9 is a 9-item questionnaire for assessing the severity of depression. Each question is answered on a scale from 0 (not at all) to 3 (nearly every day). The total score ranges from 0 to 27, where higher scores indicate more severe depression. A negative change from Baseline score indicates improvement. |
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score | Baseline and 48 weeks after Randomization | The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, from 0 (not at all) to 4 (very much). The FACIT-Fatigue score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from Baseline score indicates an improvement. . |
| Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary and Mental Component Summary Scores | Baseline and 48 weeks after Randomization | The Medical Outcome Study Short Form 36-Item Health Survey (SF-36), Version 2 is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical component summary (PCS) score summarizes the subscales physical functioning, role-physical, bodily pain, and general health. The mental component summary (MCS) score summarizes the subscales vitality, social functioning, role-emotional, and mental health. Each score ranges from 0 to 100 where higher scores indicate a better quality of life. A positive change from Baseline score indicates an improvement. |
| Number of Major Crohn's Disease-related Surgeries After Randomization | From Randomization through 48 weeks after Randomization | Major Crohn's disease-related intra-abdominal surgery included: * bowel resection * ostomy * by-pass * strictureplasty * drainage of abdominal or pelvic abscess (surgical drainage or percutaneous drainage by interventional radiology). The following were excluded: * debridement * exploration laparotomy * abdominal surgery for other reason * perineal related surgery * abscess drainage * placement of setons * fistulotomy * Total parental nutrition (TPN) use |
Participant flow
Recruitment details
This study was conducted at 59 sites in Canada, European Union, Israel, Japan, Russia, South Africa, Switzerland, Turkey, and the Ukraine. The study included a screening period, up to 8 weeks of prednisone run-in treatment, a 48-week post-randomization treatment period, and a 70 day follow-up phone call or clinic visit.
Pre-assignment details
A total of 252 participants were enrolled and received study treatment, of whom * 165 entered the prednisone run-in * 157 randomized (45 prior to Week 9, 112 at Week 9) * 8 discontinued prior to randomization. * 87 randomized at Baseline. Randomization was stratified by smoking status, weight, and disease duration.
Participants by arm
| Arm | Count |
|---|---|
| Clinically Driven Management Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI) and corticosteroid use.
Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. | 122 |
| Tight Control Management Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI), high sensitivity C-reactive protein (hs-CRP), fecal calprotectin, and corticosteroid use.
Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. | 122 |
| Total | 244 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 16 |
| Overall Study | Lack of Efficacy | 12 | 5 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Miscellaneous | 1 | 5 |
| Overall Study | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Clinically Driven Management | Tight Control Management | Total |
|---|---|---|---|
| Age, Continuous | 31.10 years STANDARD_DEVIATION 11.4 | 32.10 years STANDARD_DEVIATION 11.97 | 31.60 years STANDARD_DEVIATION 11.67 |
| Age, Customized 40 to < 65 years | 23 Participants | 24 Participants | 47 Participants |
| Age, Customized < 40 years | 97 Participants | 96 Participants | 193 Participants |
| Age, Customized ≥ 65 years | 2 Participants | 2 Participants | 4 Participants |
| Crohn's Disease Activity Index (CDAI) | 267.7 units on a scale STANDARD_DEVIATION 58.35 | 273.3 units on a scale STANDARD_DEVIATION 59.48 | 270.5 units on a scale STANDARD_DEVIATION 58.86 |
| Crohn's Disease Endoscopy Index of Severity (CDEIS) | 14.26 units on a scale STANDARD_DEVIATION 6.925 | 13.38 units on a scale STANDARD_DEVIATION 6.049 | 13.82 units on a scale STANDARD_DEVIATION 6.503 |
| Current Tobacco Use No | 89 Participants | 91 Participants | 180 Participants |
| Current Tobacco Use Yes | 33 Participants | 31 Participants | 64 Participants |
| Disease Duration ≤ 2 years | 106 Participants | 106 Participants | 212 Participants |
| Disease Duration > 2 years | 16 Participants | 16 Participants | 32 Participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Multi-race | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 113 Participants | 113 Participants | 226 Participants |
| Sex: Female, Male Female | 69 Participants | 72 Participants | 141 Participants |
| Sex: Female, Male Male | 53 Participants | 50 Participants | 103 Participants |
| Weight < 70 kg | 79 Participants | 81 Participants | 160 Participants |
| Weight ≥ 70 kg | 43 Participants | 41 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 78 / 122 | 76 / 122 |
| serious Total, serious adverse events | 25 / 122 | 22 / 122 |
Outcome results
Primary
Percentage of Participants With Mucosal Healing and No Deep Ulcerations
Percentage of participants with mucosal healing (defined as Crohn's disease endoscopy Index of severity \[CDEIS\] \< 4) and no deep ulcerations on ileocolonoscopy (defined as the absence of all deep ulcerations in all segments explored in CDEIS) at 48 weeks after randomization (48 weeks after the 1st Key visit). The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The score ranges from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing data 48 weeks after Randomization were counted as non-responders.
Time frame: 48 weeks after Randomization
Population: All randomized participants; Participants with missing CDEIS values from endoscopies performed 48 weeks after randomization were imputed as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Management | Percentage of Participants With Mucosal Healing and No Deep Ulcerations | 30.3 percentage of participants |
| Tight Control Management | Percentage of Participants With Mucosal Healing and No Deep Ulcerations | 45.9 percentage of participants |
p-value: 0.01Cochran-Mantel-Haenszel
Secondary
Change From Baseline in CDAI Over Time
The Crohn's Disease Activity Index (CDAI) is a research tool used to quantify the symptoms of patients with Crohn's disease. Participants were asked to record the frequency of stools, abdominal pain and general well-being on a daily basis. In addition to the diary data, the investigator assessed the following for the calculation of CDAI: presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. The CDAI is the sum of the products of each item multiplied by a weighting factor and generally ranges from 0 up to 600, where remission of Crohn's disease is defined as CDAI \< 150, and severe disease is defined as CDAI \> 450. A negative change from Baseline indicates improvement.
Time frame: Baseline and 4 and 8 weeks during the prednisone run-in, and 2, 6, 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization.
Population: Randomized participants with non-missing data at each time point. CDAI was only measured at 14, 18, 26, 30, 38 and 42 weeks after randomization if a participant had initiated a change in treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clinically Driven Management | Change From Baseline in CDAI Over Time | Week 4 of Prednisone Run-in | -78.3 units on a scale | Standard Deviation 80.02 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | Week 8 of Prednisone Run-in | -64.2 units on a scale | Standard Deviation 90.48 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | 2 Weeks After Randomization | -80.2 units on a scale | Standard Deviation 82.27 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | 6 Weeks After Randomization | -93.1 units on a scale | Standard Deviation 100.81 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | 11 Weeks After Randomization | -103.5 units on a scale | Standard Deviation 98.65 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | 14 Weeks After Randomization | -71.1 units on a scale | Standard Deviation 89.18 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | 18 Weeks After Randomization | -69.9 units on a scale | Standard Deviation 78.95 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | 23 Weeks After Randomization | -143.3 units on a scale | Standard Deviation 97.83 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | 26 Weeks After Randomization | -71.8 units on a scale | Standard Deviation 129.09 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | 30 Weeks After Randomization | -47.9 units on a scale | Standard Deviation 143.75 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | 35 Weeks After Randomization | -140.4 units on a scale | Standard Deviation 104.83 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | 38 Weeks After Randomization | -60.8 units on a scale | Standard Deviation 83.51 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | 42 Weeks After Randomization | -76.8 units on a scale | Standard Deviation 78.53 |
| Clinically Driven Management | Change From Baseline in CDAI Over Time | 48 Weeks After Randomization | -146.2 units on a scale | Standard Deviation 102.87 |
| Tight Control Management | Change From Baseline in CDAI Over Time | 35 Weeks After Randomization | -166.4 units on a scale | Standard Deviation 93.12 |
| Tight Control Management | Change From Baseline in CDAI Over Time | Week 4 of Prednisone Run-in | -90.9 units on a scale | Standard Deviation 81.53 |
| Tight Control Management | Change From Baseline in CDAI Over Time | 23 Weeks After Randomization | -154.1 units on a scale | Standard Deviation 101.63 |
| Tight Control Management | Change From Baseline in CDAI Over Time | Week 8 of Prednisone Run-in | -105.5 units on a scale | Standard Deviation 88.4 |
| Tight Control Management | Change From Baseline in CDAI Over Time | 42 Weeks After Randomization | -107.4 units on a scale | Standard Deviation 99.19 |
| Tight Control Management | Change From Baseline in CDAI Over Time | 2 Weeks After Randomization | -110.1 units on a scale | Standard Deviation 85.06 |
| Tight Control Management | Change From Baseline in CDAI Over Time | 26 Weeks After Randomization | -135.7 units on a scale | Standard Deviation 112.43 |
| Tight Control Management | Change From Baseline in CDAI Over Time | 6 Weeks After Randomization | -130.8 units on a scale | Standard Deviation 89.4 |
| Tight Control Management | Change From Baseline in CDAI Over Time | 38 Weeks After Randomization | -132.8 units on a scale | Standard Deviation 103.15 |
| Tight Control Management | Change From Baseline in CDAI Over Time | 11 Weeks After Randomization | -141.0 units on a scale | Standard Deviation 97.82 |
| Tight Control Management | Change From Baseline in CDAI Over Time | 30 Weeks After Randomization | -143.8 units on a scale | Standard Deviation 103.54 |
| Tight Control Management | Change From Baseline in CDAI Over Time | 14 Weeks After Randomization | -101.2 units on a scale | Standard Deviation 115.9 |
| Tight Control Management | Change From Baseline in CDAI Over Time | 48 Weeks After Randomization | -175.8 units on a scale | Standard Deviation 97.69 |
| Tight Control Management | Change From Baseline in CDAI Over Time | 18 Weeks After Randomization | -112.0 units on a scale | Standard Deviation 115.01 |
Secondary
Change From Baseline in CDEIS at 48 Weeks After Randomization
CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The score ranges from 0 to 44 where higher scores indicate more severe endoscopic activity. A negative change from Baseline indicates improvement.
Time frame: Baseline and 48 weeks after Randomization
Population: Randomized participants with non-missing data at Baseline and 48 weeks after Randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Management | Change From Baseline in CDEIS at 48 Weeks After Randomization | -6.4 units on a scale | Standard Deviation 7.69 |
| Tight Control Management | Change From Baseline in CDEIS at 48 Weeks After Randomization | -7.7 units on a scale | Standard Deviation 7.25 |
p-value: 0.11695% CI: [-3.2, 0.4]ANCOVA
Secondary
Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score
The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, from 0 (not at all) to 4 (very much). The FACIT-Fatigue score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from Baseline score indicates an improvement. .
Time frame: Baseline and 48 weeks after Randomization
Population: Randomized participants with Baseline and at least 1 post-baseline value; last observation carried forward imputation was used
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Management | Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score | 7.6 units on a scale | Standard Deviation 10.85 |
| Tight Control Management | Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score | 13.0 units on a scale | Standard Deviation 13.19 |
Secondary
Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time
High sensitivity C-reactive protein was analyzed by a central laboratory.
Time frame: Baseline and 8 weeks during the prednisone run-in, and 11, 23, 35, and 48 weeks after Randomization.
Population: Randomized participants; last observation carried forward imputation was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clinically Driven Management | Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time | 11 Weeks After Randomization | -14.6 mg/L | Standard Deviation 31.87 |
| Clinically Driven Management | Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time | 35 Weeks After Randomization | -11.0 mg/L | Standard Deviation 31.22 |
| Clinically Driven Management | Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time | 23 Weeks After Randomization | -15.1 mg/L | Standard Deviation 31.59 |
| Clinically Driven Management | Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time | 48 Weeks After Randomization | -12.3 mg/L | Standard Deviation 28.97 |
| Clinically Driven Management | Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time | Week 8 of Prednisone Run-in | -10.3 mg/L | Standard Deviation 40.04 |
| Tight Control Management | Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time | 48 Weeks After Randomization | -13.2 mg/L | Standard Deviation 28.93 |
| Tight Control Management | Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time | Week 8 of Prednisone Run-in | -9.2 mg/L | Standard Deviation 33.67 |
| Tight Control Management | Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time | 11 Weeks After Randomization | -15.9 mg/L | Standard Deviation 26.38 |
| Tight Control Management | Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time | 23 Weeks After Randomization | -14.7 mg/L | Standard Deviation 28.94 |
| Tight Control Management | Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time | 35 Weeks After Randomization | -14.0 mg/L | Standard Deviation 28.85 |
Secondary
Change From Baseline in Patient Health Questionnaire - 9 (PHQ9)
The PHQ-9 is a 9-item questionnaire for assessing the severity of depression. Each question is answered on a scale from 0 (not at all) to 3 (nearly every day). The total score ranges from 0 to 27, where higher scores indicate more severe depression. A negative change from Baseline score indicates improvement.
Time frame: Baseline and 48 weeks after Randomization
Population: Randomized participants with Baseline and at least one post-baseline value; last observation carried forward imputation was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Management | Change From Baseline in Patient Health Questionnaire - 9 (PHQ9) | -3.6 units on a scale | Standard Deviation 5.65 |
| Tight Control Management | Change From Baseline in Patient Health Questionnaire - 9 (PHQ9) | -5.6 units on a scale | Standard Deviation 5.95 |
Secondary
Change From Baseline in Quality of Life in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score
The IBDQ measures the effects of inflammatory bowel disease on daily function and quality of life. The IBDQ consists of 32 questions which address symptoms as a result of Crohn's disease, feeling in general, and mood. Each question is answered on a scale from 1 (all of the time) to 7 ( none of the time); the total score ranges from 7 (worst) to 224 (best). A positive change from baseline indicates improvement.
Time frame: Baseline and 48 weeks after Randomization
Population: Randomized participants with baseline and at least one post-baseline value; last observation carried forward imputation was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Management | Change From Baseline in Quality of Life in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score | 31.2 units on a scale | Standard Deviation 39.33 |
| Tight Control Management | Change From Baseline in Quality of Life in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score | 41.9 units on a scale | Standard Deviation 36.9 |
Secondary
Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary and Mental Component Summary Scores
The Medical Outcome Study Short Form 36-Item Health Survey (SF-36), Version 2 is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical component summary (PCS) score summarizes the subscales physical functioning, role-physical, bodily pain, and general health. The mental component summary (MCS) score summarizes the subscales vitality, social functioning, role-emotional, and mental health. Each score ranges from 0 to 100 where higher scores indicate a better quality of life. A positive change from Baseline score indicates an improvement.
Time frame: Baseline and 48 weeks after Randomization
Population: Randomized participants with Baseline and at least one post-baseline value; last observation carried forward imputation was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clinically Driven Management | Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary and Mental Component Summary Scores | Physical Component Summary Score | 6.3 units on a scale | Standard Deviation 8.34 |
| Clinically Driven Management | Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary and Mental Component Summary Scores | Mental Component Summary Score | 5.8 units on a scale | Standard Deviation 12.24 |
| Tight Control Management | Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary and Mental Component Summary Scores | Physical Component Summary Score | 9.2 units on a scale | Standard Deviation 10.22 |
| Tight Control Management | Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary and Mental Component Summary Scores | Mental Component Summary Score | 9.3 units on a scale | Standard Deviation 12.4 |
Secondary
Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD)
The WPAI:CD questionnaire was used to assess impairments in both paid work and unpaid work due to symptoms of Crohn's Disease. The self-administered questionnaire consisted of 6 questions. Work time missed was defined as the percentage of time absent from work due to Crohn's disease in the past week. Impairment while working is the participant's assessment of the degree to which Crohn's disease affected productivity while working in the past 7 days. Total work productivity impairment takes into account both hours missed due to Crohn's disease symptoms and the patient's assessment of the degree to which Crohn's disease affected their productivity while working. Total activity impairment is the percent impairment of non-work related activities due to Crohn's disease. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. A negative change from Baseline indicates improvement.
Time frame: Baseline and 48 weeks after Randomization
Population: Randomized participants with baseline and at least one post-baseline value; last observation carried forward imputation was used. The first 3 scores were only calculated for participants who were employed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clinically Driven Management | Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD) | Work time missed | -12.8 percent impairment | Standard Deviation 30.17 |
| Clinically Driven Management | Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD) | Impairment while working | -17.5 percent impairment | Standard Deviation 23.37 |
| Clinically Driven Management | Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD) | Overall work impairment | -21.7 percent impairment | Standard Deviation 29.68 |
| Clinically Driven Management | Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD) | Activity impairment | -19.2 percent impairment | Standard Deviation 27.16 |
| Tight Control Management | Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD) | Activity impairment | -27.7 percent impairment | Standard Deviation 33.22 |
| Tight Control Management | Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD) | Work time missed | -17.6 percent impairment | Standard Deviation 41.33 |
| Tight Control Management | Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD) | Overall work impairment | -29.2 percent impairment | Standard Deviation 39.53 |
| Tight Control Management | Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD) | Impairment while working | -25.8 percent impairment | Standard Deviation 34.32 |
Secondary
Change in Crohn's Disease Behavior According to Montreal Classification
Participants' Crohn's Disease was classified according to the Montreal Classification which classifies CD according to its predominant phenotypic elements (age at diagnosis, location, and disease behavior) based on the results of clinical examination and endoscopy. Disease behavior was classified according to the following: B1 = non-stricturing, non-penetrating; B2 = structuring; B3 = penetrating; P = perianal disease modifier. The change in Montreal Classification is presented in three categories: no change, deterioration, and improvement. Deterioration was defined as an increase in behavior index between 1 and 3, or development of perianal disease. Participants with missing data at Week 48 were classified as deterioration.
Time frame: From Baseline to 48 weeks after Randomization
Population: All randomized participants; non-responder imputation was used.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Clinically Driven Management | Change in Crohn's Disease Behavior According to Montreal Classification | Deterioration | 54 Participants |
| Clinically Driven Management | Change in Crohn's Disease Behavior According to Montreal Classification | No Change | 64 Participants |
| Clinically Driven Management | Change in Crohn's Disease Behavior According to Montreal Classification | Improvement | 4 Participants |
| Tight Control Management | Change in Crohn's Disease Behavior According to Montreal Classification | Deterioration | 35 Participants |
| Tight Control Management | Change in Crohn's Disease Behavior According to Montreal Classification | No Change | 79 Participants |
| Tight Control Management | Change in Crohn's Disease Behavior According to Montreal Classification | Improvement | 8 Participants |
Secondary
Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization
Stool samples were analyzed by a central laboratory for fecal calprotectin qualitative measurement (\< 250 or ≥ 250 μg/g). Results are reported for participants in each category at Baseline and 48 weeks after Randomization. Participants with missing data 48 weeks after Randomization were counted as having fecal calprotectin ≥ 250µg/g.
Time frame: Baseline and 48 weeks after Randomization
Population: Randomized participants with Baseline data; non-responder imputation was used.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Clinically Driven Management | Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization | Baseline < 250µg/g and Week 48 < 250µg/g | 8 Participants |
| Clinically Driven Management | Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization | Baseline < 250µg/g and Week 48 ≥ 250µg/g | 9 Participants |
| Clinically Driven Management | Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization | Baseline ≥ 250µg/g and Week 48 < 250µg/g | 37 Participants |
| Clinically Driven Management | Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization | Baseline ≥ 250µg/g and Week 48 ≥ 250µg/g | 68 Participants |
| Tight Control Management | Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization | Baseline ≥ 250µg/g and Week 48 ≥ 250µg/g | 52 Participants |
| Tight Control Management | Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization | Baseline < 250µg/g and Week 48 < 250µg/g | 14 Participants |
| Tight Control Management | Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization | Baseline ≥ 250µg/g and Week 48 < 250µg/g | 44 Participants |
| Tight Control Management | Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization | Baseline < 250µg/g and Week 48 ≥ 250µg/g | 10 Participants |
Secondary
Number of All-cause Hospitalizations After Randomization
Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic.
Time frame: From Randomization through 48 weeks after Randomization
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Management | Number of All-cause Hospitalizations After Randomization | 37 hospitalizations |
| Tight Control Management | Number of All-cause Hospitalizations After Randomization | 25 hospitalizations |
Secondary
Number of Crohn's Disease-related Hospitalizations After Randomization
Any hospitalization with an overnight stay in hospital/clinic related to Crohn's disease.
Time frame: From Randomization through 48 weeks after Randomization
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Management | Number of Crohn's Disease-related Hospitalizations After Randomization | 29 hospitalizations |
| Tight Control Management | Number of Crohn's Disease-related Hospitalizations After Randomization | 14 hospitalizations |
Secondary
Number of Crohn's Disease-related Hospitalizations Due to Emergency
Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. Hospitalization due to emergency was defined as a hospitalization admitted through the emergency department.
Time frame: From Randomization through 48 weeks after Randomization
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Management | Number of Crohn's Disease-related Hospitalizations Due to Emergency | 11 emergency hospitalizations |
| Tight Control Management | Number of Crohn's Disease-related Hospitalizations Due to Emergency | 4 emergency hospitalizations |
Secondary
Number of Crohn's Disease-related Surgical Procedures After Randomization
The total number of CD-related surgical procedures included major CD-related surgery, debridement, perineal related surgery - abscess drainage, seton placement, fistulotomy, and TPN.
Time frame: From Randomization through 48 weeks after Randomization
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Management | Number of Crohn's Disease-related Surgical Procedures After Randomization | 9 surgical procedures |
| Tight Control Management | Number of Crohn's Disease-related Surgical Procedures After Randomization | 7 surgical procedures |
Secondary
Number of Major Crohn's Disease-related Surgeries After Randomization
Major Crohn's disease-related intra-abdominal surgery included: * bowel resection * ostomy * by-pass * strictureplasty * drainage of abdominal or pelvic abscess (surgical drainage or percutaneous drainage by interventional radiology). The following were excluded: * debridement * exploration laparotomy * abdominal surgery for other reason * perineal related surgery * abscess drainage * placement of setons * fistulotomy * Total parental nutrition (TPN) use
Time frame: From Randomization through 48 weeks after Randomization
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Management | Number of Major Crohn's Disease-related Surgeries After Randomization | 3 surgeries |
| Tight Control Management | Number of Major Crohn's Disease-related Surgeries After Randomization | 6 surgeries |
Secondary
Percentage of Participants in Biologic Remission 48 Weeks After Randomization
Biologic remission was defined as high sensitivity C-reactive protein (hs-CRP) \< 5 mg/L, fecal Calprotectin \< 250 μg/g, and CDEIS \< 4 at 48 weeks after randomization. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after Randomization were counted as non-responders.
Time frame: 48 weeks after Randomization
Population: All randomized participants; non-responder imputation was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Management | Percentage of Participants in Biologic Remission 48 Weeks After Randomization | 15.6 percentage of participants |
| Tight Control Management | Percentage of Participants in Biologic Remission 48 Weeks After Randomization | 29.5 percentage of participants |
p-value: 0.006Cochran-Mantel-Haenszel
Secondary
Percentage of Participants in Clinical Remission Over Time
Clinical remission was defined as CDAI \< 150. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. Participants with missing data at each time point were counted as non-responders.
Time frame: Baseline and 4 and 8 weeks during the prednisone run-in, and 2, 6, 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization.
Population: Randomized participants; non-responder imputation was used. CDAI was only measured at 14, 18, 26, 30, 38 and 42 weeks after randomization if a participant had initiated a change in treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | Week 8 of Prednisone Run-in | 14.8 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | 23 Weeks After Randomization | 50.8 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | 11 Weeks After Randomization | 41.8 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | 26 Weeks After Randomization | 4.1 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | 6 Weeks After Randomization | 32.8 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | 30 Weeks After Randomization | 3.3 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | 14 Weeks After Randomization | 8.2 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | 35 Weeks After Randomization | 45.1 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | 38 Weeks After Randomization | 4.1 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | 2 Weeks After Randomization | 23.8 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | 42 Weeks After Randomization | 4.1 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | 18 Weeks After Randomization | 9.0 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | 48 Weeks After Randomization | 43.4 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Clinical Remission Over Time | Week 4 of Prednisone Run-in | 24.6 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | 48 Weeks After Randomization | 59.8 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | Week 4 of Prednisone Run-in | 30.3 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | Week 8 of Prednisone Run-in | 22.1 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | 2 Weeks After Randomization | 41.0 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | 35 Weeks After Randomization | 59.8 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | 6 Weeks After Randomization | 47.5 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | 11 Weeks After Randomization | 62.3 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | 14 Weeks After Randomization | 6.6 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | 18 Weeks After Randomization | 8.2 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | 23 Weeks After Randomization | 65.6 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | 26 Weeks After Randomization | 20.5 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | 30 Weeks After Randomization | 23.0 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | 38 Weeks After Randomization | 9.0 percentage of participants |
| Tight Control Management | Percentage of Participants in Clinical Remission Over Time | 42 Weeks After Randomization | 7.4 percentage of participants |
Secondary
Percentage of Participants in Deep Remission 48 Weeks After Randomization
Deep remission was defined as CDAI \< 150, discontinuation from steroids for at least 8 weeks, absence of draining fistula, CDEIS \< 4 and no deep ulcerations. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing data 48 weeks after randomization were counted as non-responders.
Time frame: 48 weeks after Randomization
Population: All randomized participants; non-responder imputation was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Management | Percentage of Participants in Deep Remission 48 Weeks After Randomization | 23.0 percentage of participants |
| Tight Control Management | Percentage of Participants in Deep Remission 48 Weeks After Randomization | 36.9 percentage of participants |
p-value: 0.014Cochran-Mantel-Haenszel
Secondary
Percentage of Participants in Steroid-free Remission Over Time
Steroid-free remission was defined as CDAI \< 150 and discontinuation from steroids for at least 8 weeks. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. Participants with missing data at each time point were counted as non-responders.
Time frame: 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization.
Population: Randomized participants; non-responder imputation was used. CDAI was only measured at 14, 18, 26, 30, 38 and 42 weeks after randomization if a participant had initiated a change in treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clinically Driven Management | Percentage of Participants in Steroid-free Remission Over Time | 11 Weeks After Randomization | 23.8 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Steroid-free Remission Over Time | 14 Weeks After Randomization | 4.1 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Steroid-free Remission Over Time | 18 Weeks After Randomization | 3.3 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Steroid-free Remission Over Time | 23 Weeks After Randomization | 45.1 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Steroid-free Remission Over Time | 26 Weeks After Randomization | 2.5 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Steroid-free Remission Over Time | 30 Weeks After Randomization | 0.8 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Steroid-free Remission Over Time | 35 Weeks After Randomization | 42.6 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Steroid-free Remission Over Time | 38 Weeks After Randomization | 4.1 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Steroid-free Remission Over Time | 42 Weeks After Randomization | 4.1 percentage of participants |
| Clinically Driven Management | Percentage of Participants in Steroid-free Remission Over Time | 48 Weeks After Randomization | 39.3 percentage of participants |
| Tight Control Management | Percentage of Participants in Steroid-free Remission Over Time | 38 Weeks After Randomization | 9.0 percentage of participants |
| Tight Control Management | Percentage of Participants in Steroid-free Remission Over Time | 11 Weeks After Randomization | 39.3 percentage of participants |
| Tight Control Management | Percentage of Participants in Steroid-free Remission Over Time | 30 Weeks After Randomization | 21.3 percentage of participants |
| Tight Control Management | Percentage of Participants in Steroid-free Remission Over Time | 14 Weeks After Randomization | 4.9 percentage of participants |
| Tight Control Management | Percentage of Participants in Steroid-free Remission Over Time | 48 Weeks After Randomization | 59.8 percentage of participants |
| Tight Control Management | Percentage of Participants in Steroid-free Remission Over Time | 18 Weeks After Randomization | 7.4 percentage of participants |
| Tight Control Management | Percentage of Participants in Steroid-free Remission Over Time | 35 Weeks After Randomization | 59.0 percentage of participants |
| Tight Control Management | Percentage of Participants in Steroid-free Remission Over Time | 23 Weeks After Randomization | 63.1 percentage of participants |
| Tight Control Management | Percentage of Participants in Steroid-free Remission Over Time | 42 Weeks After Randomization | 7.4 percentage of participants |
| Tight Control Management | Percentage of Participants in Steroid-free Remission Over Time | 26 Weeks After Randomization | 18.9 percentage of participants |
Secondary
Percentage of Participants With Complete Mucosal Healing 48 Weeks After Randomization
Complete mucosal healing was defined as CDEIS = 0. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after randomization were counted as non-responders.
Time frame: 48 weeks after Randomization
Population: All randomized participants; non-responder imputation was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Management | Percentage of Participants With Complete Mucosal Healing 48 Weeks After Randomization | 16.4 percentage of participants |
| Tight Control Management | Percentage of Participants With Complete Mucosal Healing 48 Weeks After Randomization | 18.0 percentage of participants |
p-value: 0.728Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Endoscopic Response 48 Weeks After Randomization
Endoscopic response was defined as a decrease CDEIS \> 5 points. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after Randomization were counted as non-responders.
Time frame: 48 weeks after Randomization
Population: All randomized participants; non-responder imputation was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Management | Percentage of Participants With Endoscopic Response 48 Weeks After Randomization | 40.2 percentage of participants |
| Tight Control Management | Percentage of Participants With Endoscopic Response 48 Weeks After Randomization | 50.8 percentage of participants |
p-value: 0.067Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Mucosal Healing 48 Weeks After Randomization
Percentage of participants with mucosal healing (defined as a CDEIS \< 4) at 48 weeks after randomization (48 weeks after the 1st Key visit). The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after Randomization were counted as non-responders.
Time frame: 48 weeks after Randomization
Population: All randomized participants; non-responder imputation was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Management | Percentage of Participants With Mucosal Healing 48 Weeks After Randomization | 30.3 percentage of participants |
| Tight Control Management | Percentage of Participants With Mucosal Healing 48 Weeks After Randomization | 45.9 percentage of participants |
p-value: 0.01Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Mucosal Healing and CDEIS < 4 in Every Segment 48 Weeks After Randomization
Percentage of participants with mucosal healing (defined as CDEIS \< 4) and CDEIS \< 4 in every segment on ileocolonoscopy at 48 weeks after randomization. The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after randomization were counted as non-responders.
Time frame: 48 weeks after Randomization
Population: All randomized participants; non-responder imputation was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Management | Percentage of Participants With Mucosal Healing and CDEIS < 4 in Every Segment 48 Weeks After Randomization | 23.8 percentage of participants |
| Tight Control Management | Percentage of Participants With Mucosal Healing and CDEIS < 4 in Every Segment 48 Weeks After Randomization | 29.5 percentage of participants |
p-value: 0.299Cochran-Mantel-Haenszel
Secondary
Time to All-cause Hospitalization
Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic.
Time frame: From Randomization through 48 weeks after Randomization
Population: Randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clinically Driven Management | Time to All-cause Hospitalization | NA days |
| Tight Control Management | Time to All-cause Hospitalization | NA days |
p-value: 0.50195% CI: [0.5, 1.5]Regression, Cox
Secondary
Time to Clinical Remission
Clinical remission was defined as CDAI \< 150. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI scores generally range from 0 to 600 where higher scores indicate more severe disease.
Time frame: From Randomization through 48 weeks after Randomization
Population: Randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clinically Driven Management | Time to Clinical Remission | 78 days |
| Tight Control Management | Time to Clinical Remission | 43 days |
p-value: 0.00895% CI: [1.1, 1.9]Regression, Cox
Secondary
Time to Crohn's Disease Flare
Time to Crohn's disease flare, where flare is defined as an increase in CDAI ≥ 70 points compared to Week 8 or Early Randomization CDAI, and a CDAI \> 220.
Time frame: From Randomization to 48 weeks after Randomization
Population: Randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clinically Driven Management | Time to Crohn's Disease Flare | NA days |
| Tight Control Management | Time to Crohn's Disease Flare | NA days |
p-value: 0.01295% CI: [0.2, 0.8]Regression, Cox
Secondary
Time to Crohn's Disease-related Hospitalization Due to Emergency
Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. Hospitalization due to emergency was defined as a hospitalization admitted through the emergency department.
Time frame: From Randomization through 48 weeks after Randomization
Population: Randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clinically Driven Management | Time to Crohn's Disease-related Hospitalization Due to Emergency | NA days |
| Tight Control Management | Time to Crohn's Disease-related Hospitalization Due to Emergency | NA days |
p-value: 0.21295% CI: [0.1, 1.6]Regression, Cox
Secondary
Time to Crohn's Disease-related Hospitalization or Hospitalization Due to Adverse Event Relating to Study Medication
Crohn's disease-related hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic for reasons related to Crohn's disease (CD). Hospitalization for adverse events relating to study medication, i.e., prednisone, azathioprine or adalimumab, were according to Investigator's clinical judgment.
Time frame: From Randomization through 48 weeks after Randomization
Population: Randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clinically Driven Management | Time to Crohn's Disease-related Hospitalization or Hospitalization Due to Adverse Event Relating to Study Medication | NA days |
| Tight Control Management | Time to Crohn's Disease-related Hospitalization or Hospitalization Due to Adverse Event Relating to Study Medication | NA days |
p-value: 0.45995% CI: [0.4, 1.5]Regression, Cox
Secondary
Time to Steroid-free Remission
Steroid-free remission was defined as CDAI \< 150 and discontinuation from steroids for at least 8 weeks. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease.
Time frame: From Randomization through 48 weeks after Randomization
Population: Randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clinically Driven Management | Time to Steroid-free Remission | 162 days |
| Tight Control Management | Time to Steroid-free Remission | 159 days |
p-value: 0.05295% CI: [1, 1.8]Regression, Cox
Secondary
Total Dose of Prednisone
The total dose of prednisone each participant received during both the run-in phase and post-randomization treatment phase.
Time frame: From Baseline through 48 weeks after Randomization
Population: Participants who received prednisone
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Management | Total Dose of Prednisone | 1505.7 mg | Standard Deviation 1029.83 |
| Tight Control Management | Total Dose of Prednisone | 1369.8 mg | Standard Deviation 1137.65 |
Secondary
Total Length of Stay in Hospital for All-cause Hospitalizations
Time frame: From Randomization through 48 weeks after Randomization
Population: Randomized participants with all-cause hospitalizations
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Management | Total Length of Stay in Hospital for All-cause Hospitalizations | 40.2 days | Standard Deviation 45.72 |
| Tight Control Management | Total Length of Stay in Hospital for All-cause Hospitalizations | 50.1 days | Standard Deviation 85.69 |
Secondary
Total Length of Stay in Hospital for Crohn's Disease-related Hospitalizations
Time frame: From Randomization through 48 weeks after Randomization
Population: Randomized participants with Crohn's disease-related hospitalizations
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Management | Total Length of Stay in Hospital for Crohn's Disease-related Hospitalizations | 9.8 days | Standard Deviation 7.21 |
| Tight Control Management | Total Length of Stay in Hospital for Crohn's Disease-related Hospitalizations | 15.8 days | Standard Deviation 20.39 |