Safety and Efficacy of Andecaliximab (GS-5745) in Adults With Moderately to Severely Active Ulcerative Colitis

A Combined Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Induction and Maintenance Study Evaluating the Safety and Efficacy of GS-5745 in Subjects With Moderately to Severely Active Ulcerative Colitis

Status

Terminated

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02520284

Enrollment

165

Registered

2015-08-11

Start date

2015-09-30

Completion date

2016-11-30

Last updated

2019-04-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Ulcerative Colitis

Brief summary

The primary objectives of this study are as follows: 1) To evaluate the efficacy of andecaliximab to induce endoscopy, rectal bleeding, and stool frequency (EBS) clinical remission at Week 8 (Cohort 1); 2) To evaluate the efficacy of andecaliximab to maintain EBS clinical remission at Week 52 (Cohort 2); and 3) To evaluate the safety and tolerability of andecaliximab. The study will consist of 3 parts: Induction Phase (Cohort 1), Maintenance Phase (Cohort 2), and an optional Extended Treatment Phase.

Interventions

BIOLOGICALAndecaliximab

Andecaliximab 150 mg administered via SC injection

BIOLOGICALPlacebo

Placebo matched to andecaliximab administered via SC injection

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

Inclusion criteria

Key Inclusion Criteria: * Ulcerative Colitis (UC) confirmed on endoscopy * Moderately to severely active UC (Mayo Score 6-12) * May be receiving oral 5-aminosalicylate (ASA), oral corticosteroid, azathioprine, 6-mercaptopurine (MP), or methotrexate * Treatment failure with at least one of the following agents received: corticosteroids, immunomodulators, tumor necrosis factor-alpha (TNFα) antagonists, vedolizumab Key

Exclusion criteria

* Diagnose of Crohn's disease or indeterminate colitis * Pregnant or lactating females * Any chronic medical condition (including, but not limited to cardiac or pulmonary disease, alcohol or drug abuse) * Exhibit severe UC / clinically significant active infection * History of malignancy in the last 5 years Note: Other protocol defined Inclusion/

Design outcomes

Primary

Measure	Time frame	Description
For Cohort 1, Percentage of Participants With EBS Clinical Remission at Week 8	Week 8	EBS clinical remission was defined as an endoscopic subscore of 0 or 1 (endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease \[spontaneous bleeding, ulceration\]); rectal bleeding subscore of 0 (rectal bleeding subscore range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes); and at least a 1-point decrease in stool frequency from baseline to achieve a subscore of 0 or 1 (stool frequency subscore range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal).

Secondary

Measure	Time frame	Description
For Cohort 1, Percentage of Participants With MCS Response at Week 8	Week 8	The MCS was composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal), and PGA. The PGA acknowledged the participant's daily recollection of abdominal discomfort and general sense of wellbeing, and other observations, such as physical findings and the participant's performance status. The PGA score ranged from 0 to 3 with higher score indicating the severe disease. Total score for MCS ranged from 0 to 12 (sum of all subscores), with higher scores indicating disease worsening. The MCS response was defined as a MCS reduction of ≥ 3 points and at least 30% from baseline, with an accompanying decrease in rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0 or 1.
For Cohort 1, Percentage of Participants With Endoscopic Remission at Week 8	Week 8	Endoscopic remission was defined as endoscopic subscore of 0. Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease (spontaneous bleeding, ulceration).
For Cohort 1, Percentage of Participants With MCS Remission at Week 8	Week 8	The MCS was composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal), and physician's global assessment (PGA). The PGA acknowledged the participant's daily recollection of abdominal discomfort and general sense of wellbeing, and other observations, such as physical findings and the participant's performance status. The PGA score ranged from 0 to 3 with higher score indicating the severe disease. The MCS remission was defined as a MCS of ≤ 2 points and no individual subscore \> 1 point. Total score for MCS ranged from 0 to 12 (sum of all subscores), with higher scores indicating disease worsening.
For Cohort 1, Percentage of Participants With Mucosal Healing as Determined by the Geboes Histologic Scoring System at Week 8	Week 8	Mucosal healing was defined as elimination of ulcers/erosion, elimination of crypt destruction, elimination of intraepithelial neutrophils, elimination of lamina propria neutrophils, and reduction in lamina propria chronic inflammatory cells to at most a mild increase. When measured by the Geboes histologic scoring system, it was the selection of the following combined scores of ≤ 3 for Grade 0 (Structural Architectural Change), ≤ 1 for Grade 1 (Chronic Inflammatory Infiltrate), ≤ 3 for Grade 2A (Lamina Propria Eosinophils), and 0 for Grade 2B (Lamina Propria Neutrophils), Grade 3 (Neutrophils in Epithelium), Grade 4 (Crypt Destruction), and Grade 5 (Erosion or Ulceration). Total Geboes histologic score ranged from 0 to 22, with higher scores indicating greater disease severity.
For Cohort 1, Percentage of Participants With MCS Remission (Alternative Definition) at Week 8	Week 8	The MCS remission (alternative definition) was defined as a rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal), and PGA subscore (range: 0 to 3 with higher score indicating the severe disease) of 0, and an endoscopic subscore (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease \[spontaneous bleeding, ulceration\]) of 0 or 1 for an overall MCS of ≤ 1. Total score for MCS ranged from 0 to 12 (sum of all subscores), with higher scores indicating disease worsening.
For Cohort 1, Percentage of Participants With Endoscopic Response at Week 8	Week 8	Endoscopic response was defined as endoscopic subscore of 0 or 1. Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease (spontaneous bleeding, ulceration).

Countries

Australia, Belgium, Bulgaria, Canada, Czechia, France, Hungary, Ireland, Italy, Latvia, Netherlands, New Zealand, Poland, Romania, Russia, Slovakia, South Africa, South Korea, Switzerland, Taiwan, Ukraine, United Kingdom, United States

Participant flow

Recruitment details

Participants were enrolled at study sites in South Africa, Europe, North America, and Asia Pacific. The first participant was screened on 15 September 2015. The last study visit occurred on 22 November 2016.

Pre-assignment details

241 participants were screened.

Participants by arm

Arm	Count
Andecaliximab Every 2 Weeks Blinded Induction Phase: Participants received andecaliximab 150 mg administered via SC injection alternating with matching placebo weekly for a total of 4 doses of andecaliximab. Blinded Maintenance Phase: Participants who achieved EBS clinical remission and/or MCS response, based on Week 8 assessments, continued to receive andecaliximab 150 mg administered via SC injection alternating with matching placebo weekly for up to approximately 40 weeks. Open-Label Maintenance Phase: Participants who achieved neither EBS clinical remission nor MCS response, based on Week 8 assessments, were offered open-label andecaliximab 150 mg administered via SC injection once weekly for up to approximately 41 weeks.	54
Andecaliximab Weekly Blinded Induction Phase: Participants received andecaliximab 150 mg administered via SC injection once weekly for a total of 8 doses. Blinded Maintenance Phase: Participants who achieved EBS clinical remission and/or MCS response, based on Week 8 assessments, continued to receive andecaliximab 150 mg administered via SC injection once weekly for up to approximately 33 weeks. Open-Label Maintenance Phase: Participants who achieved neither EBS clinical remission nor MCS response, based on Week 8 assessments, were offered open-label andecaliximab 150 mg administered via SC injection once weekly for up to approximately 34 weeks.	56
Placebo Blinded Induction Phase: Participants received placebo matched to andecaliximab administered via SC injection once weekly for a total of 8 doses. Blinded Maintenance Phase: Participants who achieved EBS clinical remission and/or MCS response, based on Week 8 assessments, continued to receive placebo matched to andecaliximab administered via SC injection once weekly for up to approximately 39 weeks. Open-Label Maintenance Phase: Participants who achieved neither EBS clinical remission nor MCS response, based on Week 8 assessments, were offered open-label andecaliximab 150 mg administered via SC injection once weekly for up to approximately 38 weeks.	55
Total	165

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Blinded Induction Phase: Up to Week 8	Adverse Event	1	3	0
Blinded Induction Phase: Up to Week 8	Study Terminated by Sponsor	0	0	1
Blinded Induction Phase: Up to Week 8	Withdrew Consent	1	1	1
Blinded Maintenance Phase: Up to Week 51	Adverse Event	1	1	0
Blinded Maintenance Phase: Up to Week 51	Disease Worsening	2	2	3
Blinded Maintenance Phase: Up to Week 51	Disposition Error	0	2	0
Blinded Maintenance Phase: Up to Week 51	Study Terminated by Sponsor	17	11	15
Open-Label MaintenancePhase: Upto Week51	Adverse Event	2	1	3
Open-Label MaintenancePhase: Upto Week51	Investigator's Discretion	2	1	1
Open-Label MaintenancePhase: Upto Week51	Study Terminated by Sponsor	25	29	28
Open-Label MaintenancePhase: Upto Week51	Withdrew Consent	3	4	2

Baseline characteristics

Characteristic	Andecaliximab Weekly	Total	Placebo	Andecaliximab Every 2 Weeks
Age, Continuous	43 years STANDARD_DEVIATION 13.2	43 years STANDARD_DEVIATION 13.3	43 years STANDARD_DEVIATION 12.8	44 years STANDARD_DEVIATION 14.1
Race/Ethnicity, Customized Ethnicity Hispanic or Latino	0 Participants	2 Participants	2 Participants	0 Participants
Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino	56 Participants	161 Participants	51 Participants	54 Participants
Race/Ethnicity, Customized Ethnicity Not Permitted	0 Participants	2 Participants	2 Participants	0 Participants
Race/Ethnicity, Customized Race Asian	4 Participants	10 Participants	4 Participants	2 Participants
Race/Ethnicity, Customized Race Black	3 Participants	10 Participants	3 Participants	4 Participants
Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander	0 Participants	1 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized Race Not Permitted	0 Participants	1 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized Race Other	1 Participants	2 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized Race White	48 Participants	141 Participants	45 Participants	48 Participants
Region of Enrollment Australia	0 Participants	5 Participants	2 Participants	3 Participants
Region of Enrollment Belgium	3 Participants	6 Participants	2 Participants	1 Participants
Region of Enrollment Bulgaria	0 Participants	1 Participants	0 Participants	1 Participants
Region of Enrollment Canada	2 Participants	5 Participants	3 Participants	0 Participants
Region of Enrollment Czechia	0 Participants	2 Participants	1 Participants	1 Participants
Region of Enrollment France	0 Participants	1 Participants	1 Participants	0 Participants
Region of Enrollment Hungary	2 Participants	5 Participants	2 Participants	1 Participants
Region of Enrollment Ireland	1 Participants	1 Participants	0 Participants	0 Participants
Region of Enrollment Italy	2 Participants	4 Participants	2 Participants	0 Participants
Region of Enrollment Latvia	0 Participants	1 Participants	0 Participants	1 Participants
Region of Enrollment Netherlands	1 Participants	1 Participants	0 Participants	0 Participants
Region of Enrollment New Zealand	3 Participants	4 Participants	1 Participants	0 Participants
Region of Enrollment Poland	4 Participants	23 Participants	8 Participants	11 Participants
Region of Enrollment Romania	2 Participants	7 Participants	1 Participants	4 Participants
Region of Enrollment Russia	4 Participants	10 Participants	4 Participants	2 Participants
Region of Enrollment Slovakia	0 Participants	1 Participants	0 Participants	1 Participants
Region of Enrollment South Africa	1 Participants	2 Participants	0 Participants	1 Participants
Region of Enrollment South Korea	3 Participants	7 Participants	2 Participants	2 Participants
Region of Enrollment Switzerland	2 Participants	2 Participants	0 Participants	0 Participants
Region of Enrollment Taiwan	1 Participants	1 Participants	0 Participants	0 Participants
Region of Enrollment Ukraine	3 Participants	9 Participants	3 Participants	3 Participants
Region of Enrollment United Kingdom	2 Participants	6 Participants	2 Participants	2 Participants
Region of Enrollment United States	20 Participants	61 Participants	21 Participants	20 Participants
Sex: Female, Male Female	18 Participants	61 Participants	24 Participants	19 Participants
Sex: Female, Male Male	38 Participants	104 Participants	31 Participants	35 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	EG008 affected / at risk
deaths Total, all-cause mortality	0 / 54	0 / 56	0 / 55	0 / 20	0 / 16	0 / 18	0 / 32	0 / 35	0 / 34
other Total, other adverse events	24 / 54	31 / 56	26 / 55	12 / 20	12 / 16	13 / 18	9 / 32	6 / 35	12 / 34
serious Total, serious adverse events	0 / 54	2 / 56	1 / 55	1 / 20	2 / 16	1 / 18	1 / 32	3 / 35	2 / 34

Outcome results

Primary

For Cohort 1, Percentage of Participants With EBS Clinical Remission at Week 8

EBS clinical remission was defined as an endoscopic subscore of 0 or 1 (endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease \[spontaneous bleeding, ulceration\]); rectal bleeding subscore of 0 (rectal bleeding subscore range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes); and at least a 1-point decrease in stool frequency from baseline to achieve a subscore of 0 or 1 (stool frequency subscore range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal).

Time frame: Week 8

Population: Full Analysis Set included all randomized participants who received at least 1 dose of study drug in the Blinded Induction Phase (Cohort 1).

Arm	Measure	Value (NUMBER)
Andecaliximab Every 2 Weeks	For Cohort 1, Percentage of Participants With EBS Clinical Remission at Week 8	7.4 percentage of participants
Andecaliximab Weekly	For Cohort 1, Percentage of Participants With EBS Clinical Remission at Week 8	1.8 percentage of participants
Placebo	For Cohort 1, Percentage of Participants With EBS Clinical Remission at Week 8	7.3 percentage of participants

Secondary

For Cohort 1, Percentage of Participants With Endoscopic Remission at Week 8

Endoscopic remission was defined as endoscopic subscore of 0. Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease (spontaneous bleeding, ulceration).

Time frame: Week 8