Cohort 1:A data monitoring committee (DMC) will evaluate all available safety data from the study. The first 2 meetings for safety surveillance will occur after 50 and 100 subjects complete or discontinue from the Blinded Induction Phase from Cohort…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Objectives:
* To evaluate the efficacy of GS-5745 to induce EBS clinical remission at Week
8 (Cohort 1)
* To evaluate the efficacy of GS-5745 to maintain EBS clinical remission at
Week 52 (Cohort 2)
* To evaluate the safety and tolerability of GS-5745 (Cohort 1 & 2)
Secondary outcome
Secondary Objectives:
* To evaluate the efficacy of GS-5745 induction treatment on achieving Mayo
Clinical Score (MCS) defined remission and response at Week 8 (Cohort 1)
* To evaluate the efficacy of GS-5745 induction and maintenance treatment on
sustained EBS clinical remission at Week 52, defined as achieving EBS clinical
remission at both Week 8 and Week 52 (Cohort 1)
* To evaluate the efficacy of GS-5745 induction and maintenance treatment on
sustained MCS clinical remission at Week 52, defined as achieving MCS clinical
remission at both Week 8 and Week 52 (Cohort 1)
* To evaluate the efficacy of GS-5745 induction treatment on endoscopic
response (endoscopic subscore 0 or 1) and remission (endoscopic subscore of 0)
at Week 8 (Cohort 1)
* To evaluate the efficacy of GS-5745 induction treatment on mucosal healing as
determined by the Geboes histologic scoring system at Week 8 (Cohort 1)
* To evaluate remission as defined by MCS remission (alternative definition) at
Week 8 (Cohort 1)
* To evaluate the efficacy of GS-5745 maintenance treatment on MCS remission at
Week 52 (Cohort 2)
* To evaluate the efficacy of GS-5745 maintenance treatment on achieving
corticosteroid-free EBS clinical remission at Week 52 (Cohort 2)
* To evaluate the efficacy of GS-5745 maintenance treatment on endoscopic
remission (endoscopic subscore of 0) at Week 52 (Cohort 2)
* To evaluate the efficacy of GS-5745 maintenance treatment on mucosal healing
as determined by the Geboes histologic scoring system at Week 52 (Cohort 2)
* To evaluate remission as defined by MCS remission (alternative definition) at
Week 52 (Cohort 2)
* To evaluate the efficacy of GS-5745 maintenance treatment on achieving
corticosteroid-free EBS clinical remission for at least 24 weeks prior to Week
52 (Cohort 2)
* To assess the PK characteristics of GS-5745 (Cohorts 1 and 2)
* To evaluate the immunogenicity of GS-5745 treatment as measured by the
emergence of anti-drug-antibodies (ADA) (Cohorts 1 and 2)
Background summary
This protocol encompasses an Induction Study (Cohort 1) and a Maintenance Study
(Cohort 2).
Cohort 1:
The Induction Study consists of two parts: Part A (the first 150 subjects) and
Part B (up to 510 additional subjects), and an Extended Treatment Phase.
Screening into Cohort 1 will be halted between Part A and Part B. Results of a
futility analysis of safety and endoscopic efficacy data from Part A will be
reviewed by the Data Monitoring Committee (DMC). Continuation to Part B is
contingent on the DMC*s recommendation on whether to resume enrollment, modify
the study, or discontinue the study.
Cohort 2:
Once the optimal induction treatment is determined from Cohort 1, enrollment
into the Maintenance Study (Cohort 2) will be initiated with up to 940 new
subjects.
All subjects that complete 52 weeks of treatment including flexible
sigmoidoscopy/colonoscopy will have the option to continue receiving open label
GS-5745 for an additional 3 years in the Extended Treatment Phase.
Cohort 1 & 2:
The primary endpoint for both studies is termed EBS clinical remission, and is
defined as an Endoscopic subscore of 0 or 1, rectal Bleeding subscore of 0, and
at least a one point decrease in Stool frequency from baseline to achieve a
subscore of 0 or 1.
Study objective
Cohort 1:
A data monitoring committee (DMC) will evaluate all available safety data from
the study. The first 2 meetings for safety surveillance will occur after 50 and
100 subjects complete or discontinue from the Blinded Induction Phase from
Cohort 1 Part A. The third meeting will occur after all 150 subjects from
Cohort 1 Part A complete or discontinue from the Blinded Induction Phase of the
study.
Cohort 1 & 2:
Safety: Assessment of AEs and concomitant medications will continue throughout
the duration of the study. Safety evaluations include documentation of adverse
events, physical examination (complete or symptom driven), vital signs, and
clinical laboratory evaluations (hematology, chemistry, urinalysis). ECGs will
be performed at Screening, Weeks 8 and 52 or ET.
After cohort 1A, the DMC will evaluate all available data (safety and
endoscopic efficacy) to make a recommendation based on the pre-defined futility
criteria. If the study resumes, meetings thereafter will be held up to three
times a year for the remainder of the study based on enrollment rate.
Efficacy: Efficacy will be assessed using the MCS composed of 4 sub-scores
(stool frequency, rectal bleeding, endoscopic findings and physician*s global
assessment), the total of the sub-scores range from 0-12. Assessments during
non-endoscopic visits will use the partial MCS, which includes all components
except flexible sigmoidoscopy/colonoscopy.
Pharmacokinetics: Plasma PK sampling for GS-5745 will be collected at pre-dose
at Weeks 1, 5, 8, 9, 16, 28, and 40 and then Week 52.
An optional PK substudy will be performed in a subset of subjects
(approximately 30 subjects from Cohort 1 and approximately 30 subjects from
Cohort 2). In the PK substudy, additional plasma PK samples will be collected
following the first dose on Week 0 + 3 (± 1) days and Week 0 + 5 (± 1) days.
There must be at least 1 day separating the 2 collection time points.
Immunogenicity: Serum sampling for anti-drug antibodies (ADA) will be collected
at pre-dose Weeks 0, 1, 5, 8, 16, 28, 40, 52, and Week 55 (for subjects not
entering the Extended Treatment Phase only). For subjects in the Extended
Treatment Phase, additional ADA samples should be collected every 24 weeks
starting at Week 76.
Study design
Background Cohort 1 & Cohort 2:
There are two components to the study being conducted under this protocol: An
Induction Study (Cohort 1) and a Maintenance Study (Cohort 2), both of which
have the Extended Treatment Phase. Subjects in Cohort 1 are not eligible to
participate in Cohort 2. All subjects that complete 52 weeks of treatment (in
either study) will have the option to enter the Extended Treatment Phase.
Cohort 1:
Induction Study (Cohort 1, up to 660 subjects):
* Screening (Days -30 to -1)
* Blinded Induction Phase (Week 0 * Week 7) consisting of Part A and Part B
* Week 8 assessments including flexible sigmoidoscopy/colonoscopy, followed by
an additional dose of blinded study drug
* Central review of Week 8 flexible sigmoidoscopy/colonoscopy
* Subjects achieving EBS clinical remission and/or MCS response based on the
Week 8 assessments will continue on the same dosing regimen into the Blinded
Maintenance Phase (Week 9 * Week 51)
* Post treatment assessment visit (Week 52)
* Extended Treatment Phase (Week 52 * Week 207)
* Follow-up visit at Week 55 for subjects not entering Extended Treatment Phase
(or 30 within days after last dose of study drug for early termination)
The induction component of this study is divided into two sequential parts
(Part A and Part B).
Cohort 1, Part A:
Part A includes the first 150 subjects randomized (approximately 50 per group).
After the 150th subject has been randomized, all screening will be halted. An
interim futility analysis will be performed and results will be reviewed by the
DMC using safety and endoscopic data from the first 150 subjects that have been
randomized into the Blinded Induction Phase of Cohort 1. The DMC will make a
recommendation to resume screening, modify the study, or discontinue the study
based on pre-specified criteria (Appendix 1).
Cohort 1, Part B:
If criteria for continuation of the study are met as outlined in Appendix 1,
screening and enrollment will restart with either one or both GS-5745 treatment
groups, and the placebo group.
Cohort 2:
Once all subjects complete the Blinded Induction Phase, an analysis will be
performed to determine the optimal regimen of GS-5745 for the Cohort 2 Optimal
Open-Label Induction Phase and enrollment into Cohort 2 will be initiated.
MaintenanceStudy(Cohort2,approximately940subjects):
* Screening (Days -30 to -1)
* Optimal Open-Label Induction Phase, as determined from Cohort 1 (Week 0 *
Week 7)
* Week 8 assessments including flexible sigmoidoscopy/colonoscopy, followed by
an additional open-label dose of GS-5745
* Central review of Week 8 flexible sigmoidoscopy/colonoscopy
* Subjects achieving EBS clinical remission and/or MCS response based on the
Week 8 assessments will be randomized to the Blinded Maintenance Phase (Week 9
* Week 51)
* Post treatment assessment visit (Week 52)
* Extended Treatment Phase (Week 52 * Week 207)
* Follow-up visit at Week 55 for subjects not entering Extended Treatment Phase
(or 30 within days after last dose of study drug for early termination)
Open-LabelMaintenancePhase:
* All subjects who do not achieve EBS clinical remission or MCS response after
the Week 8 assessments have been completed will be offered GS-5745 open-label
study drug
* Subjects who meet protocol specified disease worsening discontinuation
criteria (Section 6.9 Criteria for Discontinuation of Study Treatment) any time
after the Week 8 assessments have been completed will be offered GS-5745
open-label study drug
Extended Treatment Phase:
* All Subjects who complete all week 52 assessments including flexible
sigmoidoscopy/colonoscopy will be offered open-label 150 mg GS-5745
administered by subcutaneous injections via a single-use prefilled syringe
weekly for an additional 156 weeks
* Subjects will not complete a follow-up visit at Week 55
* Follow-up visit within 30 days after last dose of study drug
Intervention
150 mg GS-5745 at a concentration of 150 mg/mL to be administered
subcutaneously in a 1mL pre-filled syringe.
GS-5745 matching placebo to be administered as a 1 mL injection subcutaneously
in a 1 mL pre-filled syringe.
Study burden and risks
See section E9.
Lakeside Drive 333
Foster City CA 94404
US
Lakeside Drive 333
Foster City CA 94404
US
Listed location countries
Age
Inclusion criteria
InclusionCriteria:
Subjects will be eligible if they meet all of the following inclusion criteria:
1) Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
2) Males or females (non-pregnant, non-lactating), ages 18 to 75 years, inclusive based on the date of the screening visit
3) Documented diagnosis of UC of at least 6 months AND with a minimum disease extent of 15 cm from the anal verge
4) A surveillance colonoscopy is required at screening in subjects with a history of ulcerative colitis for 8 or more years, if one was not performed in the prior 24 months
5) Moderately to severely active UC as determined by a centrally read endoscopy score * 2, a rectal bleeding score * 1, a stool frequency score * 1 and PGA of 2 or 3 as determined by the Mayo clinical scoring system with endoscopy occurring within 14 days to first dose of study drug
6) Demonstrated at any time over the prior 5 years, an inadequate clinical response or loss of response to, or intolerance of atleastone of the following agents:
* Corticosteroids
* Immunomodulators
* TNF* Antagonists
* Vedolizumab
7) May be receiving the following drugs:
* Oral 5-ASA compounds provided the dose has been stable for at least 2 weeks prior to screening, and/or
* Oral corticosteroid therapy (prednisone at a stable dose of
* 30 mg/day or equivalent) provided the dose has been stable for 2 weeks prior to screening, and/or
* Azathioprine or 6-MP or methotrexate provided the dose has been stable for 8 weeks prior to screening
8) Females of childbearing potential (see definition in Appendix 7) must have a negative pregnancy test at screening and baseline.
9) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 7.
Exclusion criteria
ExclusionCriteria:;Subjects will be ineligible if they meet any of the following exclusion criteria:;1) Known hypersensitivity to the study investigational medicinal products
2) Exhibit severe UC as defined by the following criteria:
* * 6 bloody stools daily ANDoneormore of the following:
* Oral temperature > 100.3 °F ( or 38 °C)
* Pulse > 90 beats/minute
3) Laboratory parameters:
* Liver panel (AST, ALT, total bilirubin, alkaline phosphatase)
> 3 times the ULN
* Serum creatinine > 2 times the ULN
* Hemoglobin < 8 g/dL (both males and females)
* Absolute neutrophil count (ANC) < 1.5 × 109/L (1,500 mm3)
* Platelets < 100 × 109/L
4) Use of rectal formulations of 5-ASA compounds or corticosteroids 2 weeks prior to screening
5) Crohn*s disease or indeterminate colitis
6) History of colectomy, partial colectomy, or dysplasia on biopsy
7) History of colonic or small bowel stoma
8) Stool sample positive for clostridium difficile (C. difficile) toxin, Escherichia coli, Salmonella, Shigella, Campylobacter or Yersinia
9) Stool sample positive for ova and parasites test (O&P) unless approved by the medical monitor
10) Treatment with infliximab, adalimumab, natalizumab, golimumab, vedolizumab, certolizumab, or TNF* biosimilar agent 4 weeks prior to screening (and last dose must be at least 8 weeks prior to randomization)
11) Treatment with non-biologic therapies (eg, cyclosporine, thalidomide) other than those permitted in Section 5.4 at least 4 weeks prior to screening
12) Other clinically significant active infection
13) Chronic medical or psychiatric problem that may interfere with subject*s ability to comply with study procedures
14) Co-infection with chronic HIV, hepatitis B or hepatitis C
15) Active tuberculosis or history of latent tuberculosis that has not been treated
16) History of malignancy in the last 5 years except for subjects who have been successfully treated for non-melanoma skin cancer or cervical carcinoma in situ
17) Any other investigational medicinal therapy or investigational biologics use 4 weeks prior to screening (and at least 8 weeks prior to randomization)
18) Any chronic medical condition (including, but not limited to, cardiac or pulmonary disease, alcohol or drug abuse) that, in the opinion of the Investigator, would make the subject unsuitable for the study or would prevent compliance with the study protocol procedures
19) Females who may wish to become pregnant and/or plan to undergo egg donation or egg harvesting for the purpose of current or future fertilization during the course of the study and up to 30 days of the last dose of the study drug
20) Male subjects unwilling to refrain from sperm donation for at least 90 days after the last dose of study drug
21) Treatment with tacrolimus
22) Treatment with apheresis
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-005217-24-NL |
| CCMO | NL54857.028.15 |