Crohn's Disease
Conditions
Brief summary
The goal of this study was to test whether adalimumab can induce mucosal healing in subjects with moderate to severe ileocolonic Crohn's Disease.
Interventions
BIOLOGICALadalimumab
At Baseline (Week 0), subjects received an OL dose of 160 mg adalimumab SC followed by an OL dose of 80 mg adalimumab SC at Week 2 (induction dose). At Week 4, subjects were randomized to either adalimumab 40 mg SC eow or placebo SC eow. Adalimumab 40 mg eow dosing through blinded portion of study, which continued through Week 52. While all subjects began blinded study drug (placebo or adalimumab), subjects could have switched to an OL dose of adalimumab upon disease flare or non-response at or after Week 8.
BIOLOGICALplacebo
At Baseline (Week 0), subjects received an OL dose of 160 mg adalimumab SC followed by an OL dose of 80 mg adalimumab SC at Week 2 (induction dose). At Week 4, subjects were randomized to either adalimumab 40 mg SC eow or placebo SC eow. Placebo SC eow dosing through blinded portion of study, which continued through Week 52. While all subjects began blinded study drug (placebo or adalimumab), subjects could have switched to an OL dose of adalimumab upon disease flare or non-response at or after Week 8.
Sponsors
Abbott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of Crohn's Disease for greater than 4 months. * A diagnosis of ileocolonic Crohn's Disease confirmed by endoscopy or radiologic evaluation within 3 years of Baseline. * For subjects who have had operations in the ileocolonic region of the intestine after documented diagnosis of ileocolonic disease, postoperative recurrence of the disease must be documented. * Endoscopic documentation of ulceration at Screening corresponding to a score of 2 or 3 in at least one of the five segments of the colon on the Ulcerated Surface subscore of the Simple Endoscopic Score for Crohn's Disease (SES-CD). * Crohn's Disease Activity Index (CDAI) score of \>= 220 and \<= 450. * Males and females \>= 18 and \<= 75 years of age at the Baseline visit. * 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 subject at undue risk and thus preclude subject participation in the study. * Subjects must be able to self-inject study medication or have a designee or healthcare professional who can inject the study medication. * Subjects must agree to undergo up to 4 endoscopies.
Exclusion criteria
* History of cancer or lymphoproliferative disease other than a successfully and completely treated cutaneous squamous cell or basal cell carcinoma or carcinoma - in-situ of the cervix. * History of listeria, human immunodeficiency virus (HIV), hepatitis B, an immunodeficiency syndrome, central nervous system (CNS) demyelinating disease, or untreated tuberculosis (TB). * Subject with a current diagnosis of ulcerative colitis or indeterminate colitis as determined by the Investigator and Abbott Medical Monitor. * Subject who has had surgical bowel resections within the past 6 months or is planning any resection at any time point while enrolled in the study. * Subject with an ostomy or ileoanal pouch. (Subjects with a previous ileo-rectal anastomosis are not excluded). * Subject who has received any investigational biological agent in the past 3 months or 5 half-lives prior to Baseline (whichever is longer). * Subjects with a poorly controlled medical condition and any other condition which, in the opinion of the Investigator or the sponsor, would put the subject at risk by participation in the protocol. * Subject who has previously used infliximab or any anti-TNF (anti tumor necrosis factor), even investigational, within 8 weeks of Baseline. * Subject who has previously used infliximab or any anti-TNF agent and has not clinically responded. * Previous treatment with adalimumab or previous participation in an adalimumab clinical study. * Subjects on prednisone \> 40 mg/day (or equivalent). * Subjects on budesonide \> 9 mg/day. * Subjects with any prior exposure to Tysabri® (natalizumab). * Subjects with a previous history of dysplasia of the gastrointestinal tract, or found to have dysplasia in any biopsy performed during the Screening endoscopy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Without Mucosal Ulceration at Week 12 | Week 12 | Subjects were to have undergone up to 4 endoscopies to evaluate the presence or absence of mucosal ulceration: at Screening, at Week 12 (subjects who moved to open label (OL) drug between Week 8 and Week 12 because of disease flare or non-response were evaluated by endoscopy prior to receiving OL dosing), at the time of switch from blinded study drug to OL adalimumab at any time after Week 12, and at Week 52 or Early Termination. Subjects who remained blinded for the entire 52-week trial or switched to OL adalimumab between Week 8 and Week 12 were to have undergone 3 endoscopies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Clinical Remission Crohn's Disease Activity Index (CDAI) < 150 at Week 12 | Week 12 | Clinical remission is defined as a CDAI less than 150. A lower score correlates with less severe Crohn's disease activity. The CDAI range for this study was 0 to 961. |
| Number of Subjects Without Mucosal Ulceration at Week 52 | Week 52 | The number of subjects receiving blinded study drug in each treatment group who were without mucosal ulceration at Week 52. |
| Number of Subjects With Clinical Remission (CDAI < 150) at Week 52 | Week 52 | Clinical remission is defined as a Crohn's Disease Activity Index (CDAI) less than 150. A lower score correlates with less severe Crohn's disease activity. The CDAI range for this study was 0 to 961. |
| Number of Subjects Without Mucosal Ulceration at Both Week 12 and Week 52 | Weeks 12 and 52 | The number of subjects receiving blinded study drug in each treatment group who were without mucosal ulceration at both Week 12 and Week 52. |
| Number of Subjects With Clinical Remission (CDAI < 150) at Both Week 12 and Week 52 | Weeks 12 and 52 | Clinical remission is defined as a Crohn's Disease Activity Index (CDAI) less than 150. A lower score correlates with less severe Crohn's disease activity. The CDAI range for this study was 0 to 961. |
Countries
Austria, Belgium, Canada, France, Germany, Italy, Netherlands, United States
Participant flow
Recruitment details
Subjects were to be enrolled in 9 countries. Subjects were enrolled at 19 sites in 8 countries. No subjects were enrolled in Sweden.
Pre-assignment details
All subjects (135 subjects) enrolled in the study received an open-label dose of 160 mg adalimumab subcutaneously (SC) at Baseline (Week 0) followed by 80 mg adalimumab SC at Week 2 (induction dose). At Week 4, subjects were randomized to either adalimumab 40 mg SC every other week (eow) or placebo SC eow(129 subjects).
Participants by arm
| Arm | Count |
|---|---|
| Placebo At Baseline (Week 0), subjects received an OL dose of 160 mg adalimumab SC followed by an OL dose of 80 mg adalimumab SC at Week 2 (induction dose). At Week 4, subjects were randomized to either adalimumab 40 mg SC eow or placebo SC eow. | 65 |
| Adalimumab 40 mg Every Other Week At Baseline (Week 0), subjects received an OL dose of 160 mg adalimumab SC followed by an OL dose of 80 mg adalimumab SC at Week 2 (induction dose). At Week 4, subjects were randomized to either adalimumab 40 mg SC eow or placebo SC eow. | 64 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind | Adverse Event | 2 | 5 |
| Double Blind | Lack of Efficacy | 2 | 2 |
| Double Blind | Pregnancy | 0 | 1 |
| Double Blind | Protocol Violation | 0 | 1 |
| Double Blind | Withdrawal by Subject | 1 | 1 |
| Induction | Adverse Event | 0 | 2 |
| Induction | Protocol Violation | 0 | 4 |
| Open Label | Administrative reasons | 0 | 5 |
| Open Label | Adverse Event | 0 | 8 |
| Open Label | Lack of Efficacy | 0 | 13 |
| Open Label | Lost to Follow-up | 0 | 1 |
| Open Label | Pregnancy | 0 | 1 |
| Open Label | Sponsor decision | 0 | 1 |
| Open Label | Subject moved to the United States | 0 | 1 |
| Open Label | Withdrawal by Subject | 0 | 4 |
Baseline characteristics
| Characteristic | Placebo | Adalimumab 40 mg Every Other Week | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 63 Participants | 62 Participants | 125 Participants |
| Age Continuous | 37.2 years STANDARD_DEVIATION 12.6 | 37.1 years STANDARD_DEVIATION 11.1 | 37.1 years STANDARD_DEVIATION 11.84 |
| Region of Enrollment Austria | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Belgium | 14 participants | 25 participants | 39 participants |
| Region of Enrollment Canada | 22 participants | 18 participants | 40 participants |
| Region of Enrollment France | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Germany | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Italy | 2 participants | 3 participants | 5 participants |
| Region of Enrollment Netherlands | 1 participants | 2 participants | 3 participants |
| Region of Enrollment United States | 20 participants | 12 participants | 32 participants |
| Sex: Female, Male Female | 41 Participants | 40 Participants | 81 Participants |
| Sex: Female, Male Male | 24 Participants | 24 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 43 / 65 | 49 / 64 |
| serious Total, serious adverse events | 0 / 0 | 20 / 135 |
Outcome results
Primary
Number of Subjects Without Mucosal Ulceration at Week 12
Subjects were to have undergone up to 4 endoscopies to evaluate the presence or absence of mucosal ulceration: at Screening, at Week 12 (subjects who moved to open label (OL) drug between Week 8 and Week 12 because of disease flare or non-response were evaluated by endoscopy prior to receiving OL dosing), at the time of switch from blinded study drug to OL adalimumab at any time after Week 12, and at Week 52 or Early Termination. Subjects who remained blinded for the entire 52-week trial or switched to OL adalimumab between Week 8 and Week 12 were to have undergone 3 endoscopies.
Time frame: Week 12
Population: Analysis was on ITT subjects with mucosal ulceration at Screening. Subjects who did not have endoscopy at Week 12 were considered to have mucosal ulceration at Week 12 (NRI). If subjects had endoscopy at Week 8, the endoscopy results from Week 8 were carried forward to Week 12 for the primary efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects Without Mucosal Ulceration at Week 12 | 8 Subjects |
| Adalimumab | Number of Subjects Without Mucosal Ulceration at Week 12 | 17 Subjects |
Comparison: ITT population: all subjects randomized at Week 4 who had at least 1 dose of blinded therapy. The sample-size (placebo = 65 subjects; adalimumab = 65 subjects) for the primary efficacy analysis was calculated using 88% power at 0.05 alpha level based on the assumption that 25% and 5% of subjects were without mucosal ulceration at Week 12 in adalimumab 40 mg eow and placebo groups, respectively. However, subjects without mucosal ulceration at Screening were excluded from the primary analysis.p-value: 0.056Cochran-Mantel-Haenszel
Secondary
Number of Subjects With Clinical Remission (CDAI < 150) at Both Week 12 and Week 52
Clinical remission is defined as a Crohn's Disease Activity Index (CDAI) less than 150. A lower score correlates with less severe Crohn's disease activity. The CDAI range for this study was 0 to 961.
Time frame: Weeks 12 and 52
Population: ITT set. NRI method was used to impute the missing values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects With Clinical Remission (CDAI < 150) at Both Week 12 and Week 52 | 3 Subjects |
| Adalimumab | Number of Subjects With Clinical Remission (CDAI < 150) at Both Week 12 and Week 52 | 19 Subjects |
Comparison: The null hypothesis was that there is no difference in proportion of subjects with clinical remission at Week 12 in the two treatment groups.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Number of Subjects With Clinical Remission (CDAI < 150) at Week 52
Clinical remission is defined as a Crohn's Disease Activity Index (CDAI) less than 150. A lower score correlates with less severe Crohn's disease activity. The CDAI range for this study was 0 to 961.
Time frame: Week 52
Population: ITT set. NRI method was used to impute the missing values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects With Clinical Remission (CDAI < 150) at Week 52 | 6 Subjects |
| Adalimumab | Number of Subjects With Clinical Remission (CDAI < 150) at Week 52 | 21 Subjects |
Comparison: The null hypothesis was that there is no difference in proportion of subjects with clinical remission at Week 52 in the two treatment groups.p-value: 0.001Cochran-Mantel-Haenszel
Secondary
Number of Subjects With Clinical Remission Crohn's Disease Activity Index (CDAI) < 150 at Week 12
Clinical remission is defined as a CDAI less than 150. A lower score correlates with less severe Crohn's disease activity. The CDAI range for this study was 0 to 961.
Time frame: Week 12
Population: ITT set. NRI method was used to impute the missing values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects With Clinical Remission Crohn's Disease Activity Index (CDAI) < 150 at Week 12 | 18 Subjects |
| Adalimumab | Number of Subjects With Clinical Remission Crohn's Disease Activity Index (CDAI) < 150 at Week 12 | 30 Subjects |
Comparison: The null hypothesis was that there is no difference in proportion of subjects with clinical remission at Week 12 in the two treatment groups.p-value: 0.021Cochran-Mantel-Haenszel
Secondary
Number of Subjects Without Mucosal Ulceration at Both Week 12 and Week 52
The number of subjects receiving blinded study drug in each treatment group who were without mucosal ulceration at both Week 12 and Week 52.
Time frame: Weeks 12 and 52
Population: Analysis was on ITT subjects who completed the Double Blind period and had Week 52 evaluations while in the Double Blind period. NRI method was used to impute the missing values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects Without Mucosal Ulceration at Both Week 12 and Week 52 | 0 Subjects |
| Adalimumab | Number of Subjects Without Mucosal Ulceration at Both Week 12 and Week 52 | 7 Subjects |
Comparison: The null hypothesis was that there is no difference between proportions of subjects without mucosal ulceration at both Week 12 and Week 52 in the two treatment groups.p-value: 0.15Cochran-Mantel-Haenszel
Secondary
Number of Subjects Without Mucosal Ulceration at Week 52
The number of subjects receiving blinded study drug in each treatment group who were without mucosal ulceration at Week 52.
Time frame: Week 52
Population: The secondary efficacy analysis included the ITT subjects who had mucosal ulceration at screening. NRI method was used to impute the missing values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects Without Mucosal Ulceration at Week 52 | 0 Subjects |
| Adalimumab | Number of Subjects Without Mucosal Ulceration at Week 52 | 15 Subjects |
Comparison: The null hypothesis was that there is no difference between proportions of subjects without mucosal ulceration at Week 52 in the two treatment groups.p-value: <0.001Cochran-Mantel-Haenszel