Crohn Disease
Conditions
Keywords
ABBV-066, BI 655066, risankizumab
Brief summary
This study is a proof of concept, multi-center, randomized, double-blind, placebo-controlled, parallel-group phase 2 dose-ranging study of BI 655066/ABBV-066 (risankizumab), an IL-23 p19 antagonist monoclonal antibody, in patients with moderately to severely active Crohn's disease.
Interventions
DRUGrisankizumab IV
risankizumab administered by IV infusion
DRUGrisankizumab SC
risankizumab administered by SC injection
DRUGPlacebo
Placebo for risankizumab administered by IV infusion
Sponsors
Boehringer Ingelheim
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Period 1 was blinded intravenous (IV) therapy, period 2 was open label IV therapy and period 3 was open label subcutaneous (SC) therapy.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Men or women 18-75 years at the time of consent. 2. Diagnosis of Crohn's disease (CD) at least 3 months prior to screening. 3. Moderate to severe active CD, defined as Crohn's Disease Activity Index (CDAI) ≥ 220 and ≤ 450. 4. Presence of mucosal ulcers in at least one segment of the ileum or colon and a Crohn's Disease Endoscopic Index of Severity (CDEIS) score ≥ 7 (for patients with isolated ileitis, ≥4), as assessed by ileocolonoscopy and confirmed by central independent reviewer before randomization 5. Patients who are naive or experienced to 1 or more TNF antagonists (infliximab, adalimumab, or certolizumab pegol) at a dose approved for CD. TNF antagonist experienced patients may have stopped anti-TNF treatment due to primary or secondary non-responsiveness, intolerance or for other reasons. 6. Female patients: Women of childbearing potential (not surgically sterilized and between menarche and 1 year postmenopause), that, if sexually active agree to use one of the appropriate medically accepted methods of birth control in addition to the consistent and correct use of a condom from date of screening until 15 weeks after last administration of study medication. Medically accepted methods of contraception are: ethinyl estradiol containing contraceptives, diaphragm with spermicide substance, and intra-uterine-device, or 1. Surgically sterilized female patients with documentation of prior hysterectomy, tubal ligation or complete bilateral oophorectomy, or 2. Postmenopausal women with postmenopausal is defined as permanent cessation = 1 year of previously occurring menses, and 3. Negative serum ß-Human Chorionic Gonadotrophin (ß-HCG) test at screening and urine pregnancy test prior to randomization. Male patients: 1. Who are documented to be sterile, or 2. Who consistently and correctly use effective method of contraception (i.e. condoms) during the study and 15 weeks after last administration of study medication. 7. Have the capacity to understand and sign an informed consent form. 8. Be able to adhere to the study visit schedule and other protocol requirements.
Exclusion criteria
1. Have complications of CD such as strictures, stenoses, short gut syndrome, or any other manifestation that might require surgery, could preclude the use of the CDAI to assess response to therapy, or would possibly confound the evaluation of benefit from treatment with BI 655066. 2. Have any current or prior abscesses, unless they have been drained and treated at least 6 weeks prior to randomization and are not anticipated to require surgery. Patients with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses present. 3. Have had any kind of bowel resection or diversion within 6 months or any other intra-abdominal surgery within 3 months prior to screening. Patients with a current ileostomy or colostomy are excluded. 4. Have received treatment with: * Total parenteral nutrition (TPN) within 2 weeks of screening. * Any dose of ustekinumab (Stelara®). * Anti-TNF therapy ≤ 8 weeks prior to the first administration of study medication or any other biologic ≤ 8 weeks prior to the first administration of study drug or within 5 times the half-life of the biologic prior to the first administration of study agent, whichever is longer. * Natalizumab, efalizumab, or agents that deplete B or T cells (e.g., rituximab, alemtuzumab, or visilizumab) within 6 months of screening, or, if after receiving these agents, evidence is available at screening of persistent depletion of the targeted lymphocyte population. * Any investigational drug within the previous 4 weeks or 5 times the half-life of the investigational agent prior to the first administration of study agent, whichever is longer. * Regular daily use of opioids for medical reasons within previous 3 months prior to the first administration of study agent. * Rectal 5-aminosalicylic acid (5-ASA) compounds, parenteral or rectal corticosteroids must have been discontinued at least 4 weeks prior to visit 2. * Cannot adhere to the concomitant medication requirements specified in section 4.2.2. 5. Are pregnant, nursing, or planning pregnancy (both men and women) while enrolled in the study, or within 15 weeks after receiving the last dose of study medication. 6. Have used apheresis (e.g., Adacolumn apheresis) ≤ 2 weeks prior to screening. 7. Have received any live bacterial or viral vaccination ≤ 12 weeks prior to Day 1. Patients must agree not to receive a live virus or bacterial vaccination during the study or up to 12 months after the last administration of study drug. 8. Have had a Bacille Calmette-Guérin (BCG) vaccination within 12 months of screening. Patient must agree not to receive a BCG vaccination during the study or up to 12 months after the last study drug administration. 9. Have signs or symptoms of infection, history of chronic or recurrent infection, have evidence of active herpes zoster infection ≤ 8 weeks of screening, have a stool culture or other examination positive for an enteric pathogen, have a history of latent or active granulomatous infection, infected with human immunodeficiency virus (HIV), hepatitis B (HepB) or hepatitis C (HepC) virus, established nonserious infections 10. Are not eligible according to tuberculosis (TB) screening criteria 11. Have severe, progressive or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral or psychiatric disease or signs and symptoms. 12. Have a transplanted organ 13. Have known history of lymphoproliferative disease 14. Have any malignancy or history of malignancy 15. Have previously undergone allergy immunotherapy 16. Are unable or unwilling to undergo multiple venipunctures 17. Are known to have substance abuse 18. Are currently or intending to participate in any other study 19. Have screening laboratory test results within the protocol stated parameters 20. Have a known hypersensitivity to study drug 21. Have evidence of current or previous clinically significant disease, medical condition other than CD, finding of the medical examination or lab value.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Clinical Disease Activity Index (CDAI) Clinical Remission at Week 12 | Week 12 | The CDAI is a measure of clinical response and remission. The CDAI includes 8 variables encompassing both patient-reported (symptoms, general well-being) and objective (medication usage, laboratory variables, presence of abdominal mass or complications, and weight) variables. For symptoms scores, patients keep track of daily symptoms on a diary card and the daily symptom scores are summed for the week. Each item in the CDAI is assigned a specific weight, and the weighted values of the items are totaled to produce the CDAI. Higher CDAI scores indicate greater disease activity, with a lower limit of 0 and no set upper limit: \< 150 indicates remission, 150 - 219 indicates mildly active disease, 220 - 450 indicates moderately active disease, and \> 450 indicates severely active disease. CDAI clinical remission is defined as CDAI \< 150 at Week 12. Nonresponder imputation (NRI): missing values were counted as nonresponders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving CDAI Clinical Response at Week 12 | Week 12 | The CDAI is a measure of clinical response and remission. The CDAI includes 8 variables encompassing both patient-reported (symptoms, general well-being) and objective (medication usage, laboratory variables, presence of abdominal mass or complications, and weight) variables. For symptoms scores, patients keep track of daily symptoms on a diary card and the daily symptom scores are summed for the week. Each item in the CDAI is assigned a specific weight, and the weighted values of the items are totaled to produce the CDAI. Higher CDAI scores indicate greater disease activity, with a lower limit of 0 and no set upper limit: \< 150 indicates remission, 150 - 219 indicates mildly active disease, 220 - 450 indicates moderately active disease, and \> 450 indicates severely active disease. CDAI clinical response is defined as either a CDAI \< 150 or a CDAI reduction from Baseline of at least 100 points at Week 12. NRI: missing values were counted as nonresponders. |
| Percentage of Participants Achieving Crohn's Disease Endoscopic Index of Severity (CDEIS) Remission at Week 12 | Week 12 | CDEIS is an index for determining the severity of Crohn's disease with endoscopic localization to ileum and colon. CDEIS considers 4 parameters (deep ulcerations, superficial ulcerations, surface involved by disease, and surface involved by ulcerations), each one evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The results of the individual segments of the colon are divided by the number of segments investigated; the presence of stenosis increases the score at the end of the computation. CDEIS remission is defined as a CDEIS ≤ 4 (or, for patients with initial isolated ileitis, a CDEIS ≤ 2) at Week 12. NRI: missing values were counted as nonresponders. |
| Percentage of Participants Achieving CDEIS Response at Week 12 | Week 12 | CDEIS is an index for determining the severity of Crohn's disease with endoscopic localization to ileum and colon. CDEIS considers 4 parameters (deep ulcerations, superficial ulcerations, surface involved by disease, and surface involved by ulcerations), each one evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The results of the individual segments of the colon are divided by the number of segments investigated; the presence of stenosis increases the score at the end of the computation. CDEIS response is defined as defined as ≥ 50% reduction of CDEIS from Baseline to Week 12. NRI: missing values were counted as nonresponders. |
| Percentage of Participants Achieving Mucosal Healing at Week 12 | Week 12 | Mucosal healing was defined as the absence of mucosal ulceration, i.e., a CDEIS ulceration sub-score (deep ulceration, superficial ulceration, ulcerated stenosis) of 0 at Week 12. NRI: missing values were counted as nonresponders. |
| Percentage of Participants Achieving Deep Remission at Week 12 | Week 12 | Deep remission is defined as clinical remission (CDAI \< 150) AND CDEIS remission (CDEIS ≤ 4, or ≤ 2 in participants with initial isolated ileitis) at Week 12. NRI: missing values were counted as nonresponders. |
Participant flow
Pre-assignment details
Participants were randomized to 1 of 3 double-blind treatment arms in Period 1; those who achieved deep remission in Period 1 entered Period 2 washout; those who did not achieve deep remission in Period 1 entered Period 2 open-label (OL) treatment. Participants who were in clinical remission at the end of Period 2 continued to Period 3 OL treatment
Participants by arm
| Arm | Count |
|---|---|
| Double-blind Placebo IV Participants randomized in Period 1 to receive double-blind placebo for risankizumab by intravenous (IV) injection for 12 weeks in Period 1, followed by open-label risankizumab 600 mg IV in Period 2, then open-label risankizumab 180 mg by subcutaneous (SC) injection in Period 3. | 39 |
| Double-blind Risankizumab 200 mg IV Participants randomized in Period 1 to receive double-blind risankizumab 200 mg by intravenous (IV) injection for 12 weeks in Period 1, followed by open-label risankizumab 600 mg IV in Period 2, then open-label risankizumab 180 mg by subcutaneous (SC) injection in Period 3. | 41 |
| Double-blind Risankizumab 600 mg IV Participants randomized in Period 1 to receive double-blind risankizumab 600 mg by intravenous (IV) injection for 12 weeks in Period 1, followed by open-label risankizumab 600 mg IV in Period 2, then open-label risankizumab 180 mg by subcutaneous (SC) injection in Period 3. | 41 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period 1 Double-blind IV | Adverse Event | 6 | 5 | 1 |
| Period 1 Double-blind IV | Other | 0 | 1 | 0 |
| Period 2 Open-label Risankizumab IV | Adverse Event | 1 | 0 | 0 |
| Period 2 Open-label Risankizumab IV | Other | 0 | 2 | 1 |
| Period 2 Open-label Risankizumab IV | Withdrawal by Subject | 3 | 0 | 0 |
| Period 3 Open-label Risankizumab SC | Adverse Event | 0 | 2 | 0 |
| Period 3 Open-label Risankizumab SC | Other | 0 | 0 | 1 |
| Period 3 Open-label Risankizumab SC | Protocol Violation | 2 | 0 | 0 |
| Period 3 Open-label Risankizumab SC | Withdrawal by Subject | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Double-blind Placebo IV | Double-blind Risankizumab 200 mg IV | Double-blind Risankizumab 600 mg IV | Total |
|---|---|---|---|---|
| Age, Continuous | 35.5 years STANDARD_DEVIATION 13.86 | 38.8 years STANDARD_DEVIATION 13.27 | 39.9 years STANDARD_DEVIATION 13.26 | 38.1 years STANDARD_DEVIATION 13.48 |
| Sex: Female, Male Female | 16 Participants | 15 Participants | 16 Participants | 47 Participants |
| Sex: Female, Male Male | 23 Participants | 26 Participants | 25 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 39 | 25 / 41 | 21 / 41 | 48 / 101 | 31 / 62 | 80 / 115 |
| serious Total, serious adverse events | 13 / 39 | 10 / 41 | 4 / 41 | 11 / 101 | 7 / 62 | 31 / 115 |
Outcome results
Primary
Percentage of Participants Achieving Clinical Disease Activity Index (CDAI) Clinical Remission at Week 12
The CDAI is a measure of clinical response and remission. The CDAI includes 8 variables encompassing both patient-reported (symptoms, general well-being) and objective (medication usage, laboratory variables, presence of abdominal mass or complications, and weight) variables. For symptoms scores, patients keep track of daily symptoms on a diary card and the daily symptom scores are summed for the week. Each item in the CDAI is assigned a specific weight, and the weighted values of the items are totaled to produce the CDAI. Higher CDAI scores indicate greater disease activity, with a lower limit of 0 and no set upper limit: \< 150 indicates remission, 150 - 219 indicates mildly active disease, 220 - 450 indicates moderately active disease, and \> 450 indicates severely active disease. CDAI clinical remission is defined as CDAI \< 150 at Week 12. Nonresponder imputation (NRI): missing values were counted as nonresponders.
Time frame: Week 12
Population: Full Analysis Set-Period 1 (FAS-P1): All randomized subjects who received at least 1 dose of study drug in the double-blind IV period (Period 1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo IV (Period 1) | Percentage of Participants Achieving Clinical Disease Activity Index (CDAI) Clinical Remission at Week 12 | 15.4 percentage of participants |
| Double-blind Risankizumab 200 mg IV (Period 1) | Percentage of Participants Achieving Clinical Disease Activity Index (CDAI) Clinical Remission at Week 12 | 19.5 percentage of participants |
| Double-blind Risankizumab 600 mg IV (Period 1) | Percentage of Participants Achieving Clinical Disease Activity Index (CDAI) Clinical Remission at Week 12 | 36.6 percentage of participants |
| Double-blind Risankizumab 200 + 600 mg IV (Period 1) | Percentage of Participants Achieving Clinical Disease Activity Index (CDAI) Clinical Remission at Week 12 | 28.0 percentage of participants |
Comparison: Statistics for the difference are calculated using the Cochran-Mantel-Haenszel risk difference stratified by anti-tumor necrosis factor (anti-TNF) exposure.p-value: 0.095595% CI: [-2.2, 27.5]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving CDAI Clinical Response at Week 12
The CDAI is a measure of clinical response and remission. The CDAI includes 8 variables encompassing both patient-reported (symptoms, general well-being) and objective (medication usage, laboratory variables, presence of abdominal mass or complications, and weight) variables. For symptoms scores, patients keep track of daily symptoms on a diary card and the daily symptom scores are summed for the week. Each item in the CDAI is assigned a specific weight, and the weighted values of the items are totaled to produce the CDAI. Higher CDAI scores indicate greater disease activity, with a lower limit of 0 and no set upper limit: \< 150 indicates remission, 150 - 219 indicates mildly active disease, 220 - 450 indicates moderately active disease, and \> 450 indicates severely active disease. CDAI clinical response is defined as either a CDAI \< 150 or a CDAI reduction from Baseline of at least 100 points at Week 12. NRI: missing values were counted as nonresponders.
Time frame: Week 12
Population: FAS-P1: All randomized subjects who received at least 1 dose of study drug in the double-blind IV period (Period 1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo IV (Period 1) | Percentage of Participants Achieving CDAI Clinical Response at Week 12 | 23.1 percentage of participants |
| Double-blind Risankizumab 200 mg IV (Period 1) | Percentage of Participants Achieving CDAI Clinical Response at Week 12 | 31.7 percentage of participants |
| Double-blind Risankizumab 600 mg IV (Period 1) | Percentage of Participants Achieving CDAI Clinical Response at Week 12 | 41.5 percentage of participants |
| Double-blind Risankizumab 200 + 600 mg IV (Period 1) | Percentage of Participants Achieving CDAI Clinical Response at Week 12 | 36.6 percentage of participants |
Comparison: Statistics for the difference are calculated using the Cochran-Mantel-Haenszel risk difference stratified by anti-TNF exposure.p-value: 0.115195% CI: [-3.3, 30.1]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving CDEIS Response at Week 12
CDEIS is an index for determining the severity of Crohn's disease with endoscopic localization to ileum and colon. CDEIS considers 4 parameters (deep ulcerations, superficial ulcerations, surface involved by disease, and surface involved by ulcerations), each one evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The results of the individual segments of the colon are divided by the number of segments investigated; the presence of stenosis increases the score at the end of the computation. CDEIS response is defined as defined as ≥ 50% reduction of CDEIS from Baseline to Week 12. NRI: missing values were counted as nonresponders.
Time frame: Week 12
Population: FAS-P1: All randomized subjects who received at least 1 dose of study drug in the double-blind IV period (Period 1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo IV (Period 1) | Percentage of Participants Achieving CDEIS Response at Week 12 | 12.8 percentage of participants |
| Double-blind Risankizumab 200 mg IV (Period 1) | Percentage of Participants Achieving CDEIS Response at Week 12 | 26.8 percentage of participants |
| Double-blind Risankizumab 600 mg IV (Period 1) | Percentage of Participants Achieving CDEIS Response at Week 12 | 36.6 percentage of participants |
| Double-blind Risankizumab 200 + 600 mg IV (Period 1) | Percentage of Participants Achieving CDEIS Response at Week 12 | 31.7 percentage of participants |
Comparison: Statistics for the difference are calculated using the Cochran-Mantel-Haenszel risk difference stratified by anti-TNF exposure.p-value: 0.010495% CI: [4.4, 33]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving Crohn's Disease Endoscopic Index of Severity (CDEIS) Remission at Week 12
CDEIS is an index for determining the severity of Crohn's disease with endoscopic localization to ileum and colon. CDEIS considers 4 parameters (deep ulcerations, superficial ulcerations, surface involved by disease, and surface involved by ulcerations), each one evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The results of the individual segments of the colon are divided by the number of segments investigated; the presence of stenosis increases the score at the end of the computation. CDEIS remission is defined as a CDEIS ≤ 4 (or, for patients with initial isolated ileitis, a CDEIS ≤ 2) at Week 12. NRI: missing values were counted as nonresponders.
Time frame: Week 12
Population: FAS-P1: All randomized subjects who received at least 1 dose of study drug in the double-blind IV period (Period 1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo IV (Period 1) | Percentage of Participants Achieving Crohn's Disease Endoscopic Index of Severity (CDEIS) Remission at Week 12 | 2.6 percentage of participants |
| Double-blind Risankizumab 200 mg IV (Period 1) | Percentage of Participants Achieving Crohn's Disease Endoscopic Index of Severity (CDEIS) Remission at Week 12 | 9.8 percentage of participants |
| Double-blind Risankizumab 600 mg IV (Period 1) | Percentage of Participants Achieving Crohn's Disease Endoscopic Index of Severity (CDEIS) Remission at Week 12 | 19.5 percentage of participants |
| Double-blind Risankizumab 200 + 600 mg IV (Period 1) | Percentage of Participants Achieving Crohn's Disease Endoscopic Index of Severity (CDEIS) Remission at Week 12 | 14.6 percentage of participants |
Comparison: Statistics for the difference are calculated using the Cochran-Mantel-Haenszel risk difference stratified by anti-TNF exposure.p-value: 0.005795% CI: [3.5, 20.6]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving Deep Remission at Week 12
Deep remission is defined as clinical remission (CDAI \< 150) AND CDEIS remission (CDEIS ≤ 4, or ≤ 2 in participants with initial isolated ileitis) at Week 12. NRI: missing values were counted as nonresponders.
Time frame: Week 12
Population: FAS-P1: All randomized subjects who received at least 1 dose of study drug in the double-blind IV period (Period 1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo IV (Period 1) | Percentage of Participants Achieving Deep Remission at Week 12 | 0 percentage of participants |
| Double-blind Risankizumab 200 mg IV (Period 1) | Percentage of Participants Achieving Deep Remission at Week 12 | 2.4 percentage of participants |
| Double-blind Risankizumab 600 mg IV (Period 1) | Percentage of Participants Achieving Deep Remission at Week 12 | 12.2 percentage of participants |
| Double-blind Risankizumab 200 + 600 mg IV (Period 1) | Percentage of Participants Achieving Deep Remission at Week 12 | 7.3 percentage of participants |
Comparison: Statistics for the difference are calculated using the Cochran-Mantel-Haenszel risk difference stratified by anti-TNF exposure.p-value: 0.010795% CI: [1.7, 13]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving Mucosal Healing at Week 12
Mucosal healing was defined as the absence of mucosal ulceration, i.e., a CDEIS ulceration sub-score (deep ulceration, superficial ulceration, ulcerated stenosis) of 0 at Week 12. NRI: missing values were counted as nonresponders.
Time frame: Week 12
Population: FAS-P1: All randomized subjects who received at least 1 dose of study drug in the double-blind IV period (Period 1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo IV (Period 1) | Percentage of Participants Achieving Mucosal Healing at Week 12 | 2.6 percentage of participants |
| Double-blind Risankizumab 200 mg IV (Period 1) | Percentage of Participants Achieving Mucosal Healing at Week 12 | 2.4 percentage of participants |
| Double-blind Risankizumab 600 mg IV (Period 1) | Percentage of Participants Achieving Mucosal Healing at Week 12 | 7.3 percentage of participants |
| Double-blind Risankizumab 200 + 600 mg IV (Period 1) | Percentage of Participants Achieving Mucosal Healing at Week 12 | 4.9 percentage of participants |
Comparison: Statistics for the difference are calculated using the Cochran-Mantel-Haenszel risk difference stratified by anti-TNF exposure.p-value: 0.497795% CI: [-4.5, 9.2]Cochran-Mantel-Haenszel