Crohn's Disease
Conditions
Brief summary
This study will primarily evaluate the safety and efficacy of andecaliximab in adults with active Crohn's disease. The study will consist of a Double-Blind Phase of 8 weeks followed by an Open-Label Extension. Participants who complete the Double-Blind Phase will be eligible to enroll in the optional Open-Label Extension for an additional 44 weeks. Participants who complete Week 52 assessments will be eligible to enter the Extended Treatment Phase to continue treatment with andecaliximab for an additional 156 weeks.
Interventions
DRUGAndecaliximab
Andecaliximab administered via subcutaneous (SC) injection
DRUGPlacebo
Placebo to match andecaliximab administered via SC injection
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Ability to provide a written informed consent * Females of childbearing potential must have a negative pregnancy test at screening and baseline * Documented diagnosis of Crohn's disease with a minimum disease duration of 6 months with involvement of the ileum and/or colon at a minimum * Moderately to severely active Crohn's disease as defined by a Crohn's Disease Activity Index (CDAI) total score between 220-450 (inclusive) AND with evidence of active disease as measured by ileocolonoscopy * Within the previous 5 years, demonstrated an inadequate clinical response or intolerance of at least one of the following agents: * Corticosteroids * Immunomodulators * Tumor necrosis factor-alpha (TNFα) antagonists * Vedolizumab * May be receiving the following drugs: * Oral 5-aminosalicylate (5-ASA) * Oral corticosteroid therapy * Antidiarrheals for chronic diarrhea * Azathioprine or 6-mercaptopurine (6-MP) or methotrexate * Antibiotics for the treatment of Crohn's disease * Able to comply with the dosing instructions for study drug and able to comply with the study visits and requirements Key
Exclusion criteria
* Evidence of abscess at screening * Extensive colonic resection (subtotal or total colectomy) or history of \> 2 small bowel resections * Ileostomy, colostomy, or symptomatic stenosis of the intestine * Current use of oral corticosteroids at a dose equivalent to \> 30 mg/day of prednisone * Ulcerative colitis or indeterminate colitis * Short bowel syndrome * Stool sample positive for Clostridium difficile (C. difficile) toxin, E. coli, Salmonella, Shigella, Campylobacter or Yersinia * Treatment with any monoclonal antibody within 4 weeks of screening * History or evidence of colonic mucosal dysplasia * HIV, hepatitis B, hepatitis C, or tuberculosis (TB) infection * Participated in a clinical study with an investigational drug or biologic within the last 30 days * Any chronic medical condition (including, but not limited to, cardiac or pulmonary disease) that, in the opinion of the investigator, would make the individual unsuitable for the study or would prevent compliance with the study protocol Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Clinical Response (PRO2 Score ≤ 8) at Week 8 of the Double-Blind Phase | Week 8 | Clinical response was defined as patient-reported outcomes (PRO2) score ≤ 8 at Week 8. PRO2 is the weighted average of the 2 variables of frequency of liquid or very soft stool and abdominal pain, based on 7-day participant diary data. The PRO2 score has a minimum score of 0 and has no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with a missing PRO2 value at the Week 8 analysis visit were imputed as not achieving the Clinical Response. |
| Percentage of Participants Achieving Endoscopic Response (≥ 50% Reduction From Baseline SES-CD) at Week 8 of the Double-Blind Phase | Week 8 | Endoscopic response was defined as ≥ 50% reduction from baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD) at Week 8. The SES-CD evaluates 4 endoscopic variables: ulcer size, ulcerated surface, affected surface, and presence of narrowings. The total SES-CD is calculated as the sum of the 4 variables for the 5 bowel segments: rectum, left colon, transverse colon, right colon, and ileum. Scores range from 0 to 60, with higher scores indicating more severe disease. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with missing SES-CD value at Week 8 analysis visit were imputed as not achieving Endoscopic Response. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving CDAI Remission (CDAI ≤ 150) at Week 8 of the Double-Blind Phase | Week 8 | Clinical remission was defined as Crohn's Disease Activity Index (CDAI) ≤ 150 at Week 8. CDAI is used as a measure of clinical response and remission. It includes 8 variables of patient-reported symptoms and objective variables: stool count, abdominal pain, general well-being, complications, use of anti-diarrheal medications, presence of abdominal mass, hematocrit values, and weight. It has a minimum range of 0 and no upper bound, with higher scores indicating greater disease activity. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with missing CDAI score at Week 8 analysis visit were imputed as not achieving CDAI Remission. |
| Percentage of Participants Achieving Mucosal Healing (SES-CD Size-of-Ulcer Subscore = 0) at Week 8 of the Double-Blind Phase | Week 8 | The SES-CD evaluates 4 endoscopic variables: ulcer size, ulcerated surface, affected surface, and presence of narrowings. The SES-CD size-of-ulcer subscore ranges from 0 (none) to 3 (very large). Mucosal healing at Week 8 was defined as the size-of-ulcer subscore for segments with non-zero baseline value changes to zero at Week 8 AND the size-of-ulcer subscore for segments with zero value at baseline remain zero at Week 8. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with missing SES-CD size-of-ulcer subscore at Week 8 analysis visit were imputed as not achieving Mucosal Healing. |
Countries
Australia, Canada, Czechia, France, Germany, Hungary, Italy, New Zealand, Poland, South Africa, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in North America, Europe, South Africa, and Asia Pacific. The first participant was screened on 30 April 2015. The last study visit occurred on 22 December 2016.
Pre-assignment details
315 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Andecaliximab 150 mg Every 2 Weeks Double-Blind Phase: Participants received 1 single-use PFS of andecaliximab 150 mg and matching placebo coadministered at Weeks 0, 2, 4, and 6 and 2 single-use PFS of placebo coadministered at Weeks 1, 3, 5 and 7.
Open-Label Phase and Extended Treatment Phase: Participants received 1 single-use PFS of andecaliximab 150 mg administered weekly. | 53 |
| Andecaliximab 150 mg Weekly Double-Blind Phase: Participants received 1 single-use PFS of andecaliximab 150 mg and matching placebo coadministered weekly for 8 weeks.
Open-Label Phase and Extended Treatment Phase: Participants received 1 single-use PFS of andecaliximab 150 mg administered weekly. | 53 |
| Andecaliximab 300 mg Weekly Double-Blind Phase: Participants received 2 single-use PFS of andecaliximab 150 mg coadministered weekly for 8 weeks.
Open-Label Phase and Extended Treatment Phase: Participants received 1 single-use PFS of andecaliximab 150 mg administered weekly. | 53 |
| Placebo Double-Blind Phase: Participants received 2 single-use PFS of placebo coadministered weekly for 8 weeks.
Open-Label and Extended Treatment Phase: Participants received 1 single-use PFS of andecaliximab 150 mg administered weekly. | 28 |
| Total | 187 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-Blind Phase (up to Week 8) | Adverse Event | 0 | 2 | 4 | 1 |
| Double-Blind Phase (up to Week 8) | Investigator's Discretion | 0 | 1 | 0 | 0 |
| Double-Blind Phase (up to Week 8) | Study Disease-Related Symptoms | 1 | 1 | 0 | 0 |
| Double-Blind Phase (up to Week 8) | Withdrew Consent | 0 | 1 | 2 | 0 |
| Extended Treatment Phase(up to Week 208) | Investigator's Discretion | 0 | 1 | 0 | 0 |
| Extended Treatment Phase(up to Week 208) | Study Disease-Related Symptoms | 1 | 0 | 0 | 0 |
| Extended Treatment Phase(up to Week 208) | Study Terminated by Sponsor | 2 | 1 | 2 | 2 |
| Open-Label Phase (up to Week 52) | Adverse Event | 6 | 1 | 2 | 6 |
| Open-Label Phase (up to Week 52) | Investigator's Discretion | 14 | 11 | 11 | 2 |
| Open-Label Phase (up to Week 52) | Lack of Efficacy | 0 | 1 | 0 | 0 |
| Open-Label Phase (up to Week 52) | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Open-Label Phase (up to Week 52) | Study Disease-Related Symptoms | 0 | 1 | 3 | 2 |
| Open-Label Phase (up to Week 52) | Study Terminated by Sponsor | 27 | 28 | 28 | 13 |
| Open-Label Phase (up to Week 52) | Withdrew Consent | 1 | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | Andecaliximab 150 mg Every 2 Weeks | Total | Andecaliximab 150 mg Weekly | Andecaliximab 300 mg Weekly | Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 38 years STANDARD_DEVIATION 12.8 | 39 years STANDARD_DEVIATION 12.8 | 39 years STANDARD_DEVIATION 13.5 | 42 years STANDARD_DEVIATION 11.7 | 38 years STANDARD_DEVIATION 13.5 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 1 Participants | 8 Participants | 1 Participants | 5 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 52 Participants | 171 Participants | 46 Participants | 47 Participants | 26 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 0 Participants | 8 Participants | 6 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black or African American | 3 Participants | 11 Participants | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 0 Participants | 8 Participants | 6 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 5 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race White | 48 Participants | 160 Participants | 42 Participants | 48 Participants | 22 Participants |
| Region of Enrollment Australia | 3 Participants | 9 Participants | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment Canada | 3 Participants | 4 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Czechia | 1 Participants | 5 Participants | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment France | 0 Participants | 8 Participants | 6 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Germany | 3 Participants | 15 Participants | 5 Participants | 5 Participants | 2 Participants |
| Region of Enrollment Hungary | 2 Participants | 5 Participants | 1 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Italy | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment New Zealand | 4 Participants | 5 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Poland | 3 Participants | 16 Participants | 5 Participants | 6 Participants | 2 Participants |
| Region of Enrollment South Africa | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Spain | 3 Participants | 5 Participants | 0 Participants | 2 Participants | 0 Participants |
| Region of Enrollment United Kingdom | 2 Participants | 6 Participants | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment United States | 29 Participants | 104 Participants | 28 Participants | 30 Participants | 17 Participants |
| Sex: Female, Male Female | 25 Participants | 90 Participants | 28 Participants | 22 Participants | 15 Participants |
| Sex: Female, Male Male | 28 Participants | 97 Participants | 25 Participants | 31 Participants | 13 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 | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 0 / 53 | 0 / 53 | 0 / 28 | 0 / 52 | 0 / 48 | 0 / 47 | 0 / 26 |
| other Total, other adverse events | 15 / 53 | 25 / 53 | 25 / 53 | 13 / 28 | 22 / 52 | 21 / 48 | 17 / 47 | 16 / 26 |
| serious Total, serious adverse events | 1 / 53 | 6 / 53 | 8 / 53 | 3 / 28 | 9 / 52 | 10 / 48 | 7 / 47 | 6 / 26 |
Outcome results
Primary
Percentage of Participants Achieving Clinical Response (PRO2 Score ≤ 8) at Week 8 of the Double-Blind Phase
Clinical response was defined as patient-reported outcomes (PRO2) score ≤ 8 at Week 8. PRO2 is the weighted average of the 2 variables of frequency of liquid or very soft stool and abdominal pain, based on 7-day participant diary data. The PRO2 score has a minimum score of 0 and has no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with a missing PRO2 value at the Week 8 analysis visit were imputed as not achieving the Clinical Response.
Time frame: Week 8
Population: Full Analysis Set included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Andecaliximab 150 mg Every 2 Weeks | Percentage of Participants Achieving Clinical Response (PRO2 Score ≤ 8) at Week 8 of the Double-Blind Phase | 17.0 percentage of participants |
| Andecaliximab 150 mg Weekly | Percentage of Participants Achieving Clinical Response (PRO2 Score ≤ 8) at Week 8 of the Double-Blind Phase | 13.2 percentage of participants |
| Andecaliximab 300 mg Weekly | Percentage of Participants Achieving Clinical Response (PRO2 Score ≤ 8) at Week 8 of the Double-Blind Phase | 11.3 percentage of participants |
| Placebo | Percentage of Participants Achieving Clinical Response (PRO2 Score ≤ 8) at Week 8 of the Double-Blind Phase | 14.3 percentage of participants |
Primary
Percentage of Participants Achieving Endoscopic Response (≥ 50% Reduction From Baseline SES-CD) at Week 8 of the Double-Blind Phase
Endoscopic response was defined as ≥ 50% reduction from baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD) at Week 8. The SES-CD evaluates 4 endoscopic variables: ulcer size, ulcerated surface, affected surface, and presence of narrowings. The total SES-CD is calculated as the sum of the 4 variables for the 5 bowel segments: rectum, left colon, transverse colon, right colon, and ileum. Scores range from 0 to 60, with higher scores indicating more severe disease. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with missing SES-CD value at Week 8 analysis visit were imputed as not achieving Endoscopic Response.
Time frame: Week 8
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Andecaliximab 150 mg Every 2 Weeks | Percentage of Participants Achieving Endoscopic Response (≥ 50% Reduction From Baseline SES-CD) at Week 8 of the Double-Blind Phase | 11.3 percentage of participants |
| Andecaliximab 150 mg Weekly | Percentage of Participants Achieving Endoscopic Response (≥ 50% Reduction From Baseline SES-CD) at Week 8 of the Double-Blind Phase | 13.2 percentage of participants |
| Andecaliximab 300 mg Weekly | Percentage of Participants Achieving Endoscopic Response (≥ 50% Reduction From Baseline SES-CD) at Week 8 of the Double-Blind Phase | 7.5 percentage of participants |
| Placebo | Percentage of Participants Achieving Endoscopic Response (≥ 50% Reduction From Baseline SES-CD) at Week 8 of the Double-Blind Phase | 10.7 percentage of participants |
Secondary
Percentage of Participants Achieving CDAI Remission (CDAI ≤ 150) at Week 8 of the Double-Blind Phase
Clinical remission was defined as Crohn's Disease Activity Index (CDAI) ≤ 150 at Week 8. CDAI is used as a measure of clinical response and remission. It includes 8 variables of patient-reported symptoms and objective variables: stool count, abdominal pain, general well-being, complications, use of anti-diarrheal medications, presence of abdominal mass, hematocrit values, and weight. It has a minimum range of 0 and no upper bound, with higher scores indicating greater disease activity. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with missing CDAI score at Week 8 analysis visit were imputed as not achieving CDAI Remission.
Time frame: Week 8
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Andecaliximab 150 mg Every 2 Weeks | Percentage of Participants Achieving CDAI Remission (CDAI ≤ 150) at Week 8 of the Double-Blind Phase | 20.8 percentage of participants |
| Andecaliximab 150 mg Weekly | Percentage of Participants Achieving CDAI Remission (CDAI ≤ 150) at Week 8 of the Double-Blind Phase | 17.0 percentage of participants |
| Andecaliximab 300 mg Weekly | Percentage of Participants Achieving CDAI Remission (CDAI ≤ 150) at Week 8 of the Double-Blind Phase | 11.3 percentage of participants |
| Placebo | Percentage of Participants Achieving CDAI Remission (CDAI ≤ 150) at Week 8 of the Double-Blind Phase | 21.4 percentage of participants |
Secondary
Percentage of Participants Achieving Mucosal Healing (SES-CD Size-of-Ulcer Subscore = 0) at Week 8 of the Double-Blind Phase
The SES-CD evaluates 4 endoscopic variables: ulcer size, ulcerated surface, affected surface, and presence of narrowings. The SES-CD size-of-ulcer subscore ranges from 0 (none) to 3 (very large). Mucosal healing at Week 8 was defined as the size-of-ulcer subscore for segments with non-zero baseline value changes to zero at Week 8 AND the size-of-ulcer subscore for segments with zero value at baseline remain zero at Week 8. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with missing SES-CD size-of-ulcer subscore at Week 8 analysis visit were imputed as not achieving Mucosal Healing.
Time frame: Week 8
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Andecaliximab 150 mg Every 2 Weeks | Percentage of Participants Achieving Mucosal Healing (SES-CD Size-of-Ulcer Subscore = 0) at Week 8 of the Double-Blind Phase | 5.7 percentage of participants |
| Andecaliximab 150 mg Weekly | Percentage of Participants Achieving Mucosal Healing (SES-CD Size-of-Ulcer Subscore = 0) at Week 8 of the Double-Blind Phase | 1.9 percentage of participants |
| Andecaliximab 300 mg Weekly | Percentage of Participants Achieving Mucosal Healing (SES-CD Size-of-Ulcer Subscore = 0) at Week 8 of the Double-Blind Phase | 1.9 percentage of participants |
| Placebo | Percentage of Participants Achieving Mucosal Healing (SES-CD Size-of-Ulcer Subscore = 0) at Week 8 of the Double-Blind Phase | 7.1 percentage of participants |