The overall objective of the study is to evaluate the effect of treatment with filgotinib on the induction and maintenance of remission in subjects with moderately to severely active Ulcerative Colitis (UC). Subjects who are biologic-naïve and…
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Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy will be assessed by EBS remission, defined as an endoscopic
subscore (based on central reading) of 0 or 1 (referencing the Mayo Score),
rectal bleeding subscore of 0, and at least a 1 point decrease in stool
frequency from baseline to achieve a subscore of 0 or 1.
Secondary outcome
Efficacy will also be assessed using the full MCS composed of 4 subscores
(stool frequency, rectal bleeding, endoscopic findings, and PGA), ranging from
0 to 12. Assessments during non-endoscopic visits may use the partial MCS,
which includes all components except flexible sigmoidoscopy/colonoscopy.
Geboes histologic remission will be assessed using the Geboes histologic scores
composed of 6 different grades for evaluation of disease severity in UC.
Background summary
Ulcerative colitis (UC) is a chronic, intermittent, relapsing disease
characterized by inflammation
of the colonic mucosa, which is limited to the colon and rectum. The disease
characteristically
commences in the rectum and may extend proximally in an uninterrupted pattern
into the colon.
It can involve the entire colon (pan-colitis), the left colon, or isolated
recto-sigmoid disease with
patients being equally distributed in those 3 phenotypes. In the United States
(US), the
prevalence of UC has been estimated to be 238 per 100,000 adults {Kappelman et
al 2007}.
Europe has the highest reported prevalence values for inflammatory bowel disease
(IBD; 505 per 100,000 persons for UC and 322 for Crohn*s Disease [CD]). The
incidence and prevalence of inflammatory bowel disease (IBD) appear to be
increasing over time globally. The hallmark symptoms of the disease are bloody
diarrhea, rectal urgency, and tenesmus. The clinical coursetends to wax and
wane with periods of remission interspersed with periods of active disease.
Ulcerative colitis may also be associated with extra-intestinal manifestations
including ocular
lesions, skin lesions, arthritis, and primary sclerosing cholangitis. The exact
pathophysiology is
not known, but a combination of genetic predisposition and environmental
factors appear to
contribute to a disordered immune response in these patients {Rutgeerts et al
2005}.
In addition to the abdominal pain and frequent passage of bloody stools that
impact activities of
daily living and quality of life for patients with UC, the disease also carries
with it an increased
risk of colorectal cancer due to the chronic inflammation associated with the
disease {Velayos et
al 2006}. With poorly controlled
disease, the rate of developing colorectal cancer increases with time. Ten
years after diagnosis,
the cumulative probability of developing colorectal cancer is 2% and increases
to 18% after
30 years. Overall, the risk of a UC patient developing colorectal cancer may be
as high as
23-fold compared to the general population {Triantafillidis et al 2009}. Thus,
UC represents a
serious, life-threatening disease for which new therapies are needed to
interrupt the inflammatory
process to prevent disease progression and risk of colorectal cancer.
Treatment of UC is dependent on the severity and the location of disease. Goals
of treatment
include improved quality of life, reduction in long-term corticosteroid use,
and minimization of
cancer risk. Mild to moderate distal colitis may be treated with oral
aminosalicylates, topical
mesalamine, or topical steroids {Kornbluth et al 2010}. For moderate disease,
oral
corticosteroids, and immunomodulators such as azathioprine and 6-mercaptopurine
(6-MP) may
be utilized {Danese et al 2011}. For more moderate to severe disease, patients
are commonly
treated with a tumor necrosis factor-alpha (TNF*) antagonist infusion or
injection such as
infliximab (Remicade®), adalimumab (Humira®), and golimumab (Simponi®).
Vedolizumab
(Entyvio®), an injectable integrin *4*7 monoclonal antibody, is also approved
for moderately to
severely active disease. Ustekinumab (Stelara®, CNTO 1275; an IL-12 and IL-23
monoclonal.
antibody), tofacitinb (CP-690,550; JAK1 and JAK3 inhibitor), etrolizumab
(PRO145223;
monoclonal antibody targeting the *7 subunit of the heterodimeric integrins
*4*7 and *E*7), and
ozanimod (RPC1063; selective S1P1 and S1P5 receptor agonist) are currently
being tested in
Phase 3 clinical trials. Despite several classes of treatment options for
patients with UC, there remains an unmet
medical need, particularly in the treatment of moderately to severely active
disease. Agents with
novel mechanisms of action that target the inflammatory cascade, with oral
dosing and
acceptable immunomodulatory and hematologic effects, remain the most promising
option to
address these unmet needs.
Study objective
The overall objective of the study is to evaluate the effect of treatment with
filgotinib on the induction and maintenance of remission in subjects with
moderately to severely active Ulcerative Colitis (UC). Subjects who are
biologic-naïve and biologic-experienced will be enrolled in Cohorts A and B
respectively. Treatment assignments will be randomized within each Cohort.
Study design
These are combined Phase 2b/3, double-blind, randomized, placebo-controlled
studies evaluating the efficacy and safety of filgotinib in the induction and
maintenance of remission in subjects with moderately to severely active
ulcerative colitis.
These studies include:
Screening (Days -30 to -1)
Randomization (Day 1)
Blinded Induction Studies (Day 1 to Week 11)
- Cohorts A and B Week 10 efficacy assessments:
- At Week 10, MCS to assess MCS response or EBS remission
- Blinded Bridge Phase (Week 10 to 11): Dosing will continue in a blinded
fashion through the end of Week 10 until re-randomization at Week 11
Re-randomization (Week 11)
- Subjects in Cohorts A and B who complete the Induction Study and achieve
either EBS remission or MCS response at Week 10 will be re-randomized into the
Maintenance Study at Week 11
- Subjects who achieve neither EBS remission nor MCS response at Week 10 will
have the option to enter a separate, Long-Term Extension (LTE) study
(GS-US-418-3899)
Blinded Maintenance Study (Weeks 11 to 58)
Post-Treatment (PTx) safety assessments:* Subjects who opt out of the LTE study
(GS-US-418-3899) will
return 30 days after the last dose of study drug for PTx safety assessments
- Subjects who complete all procedures per protocol, including the endoscopy,
of the 58-week study will be offered the option to continue into the LTE study
(GS-US-418-3899)
- Subjects who are eligible and opt to participate in the LTE study
(GS-US-418-3899) can continue into the study without PTx safety assessments
Intervention
Treatment Regimen (Cohorts A and B Induction Studies)
Based on protocol eligibility criteria, subjects will be screened for
enrollment in either Cohort A or Cohort B.
Subjects who meet protocol eligibility criteria will be assigned to the
respective Cohort and subsequently randomized in a blinded fashion in a
2:2:1 ratio to 1 of 3 treatments as follows:
- Treatment Group 1 (n = 260): filgotinib 200 mg and placebo-to-match (PTM)
filgotinib 100 mg, once daily
- Treatment Group 2 (n = 260): filgotinib 100 mg and PTM filgotinib 200 mg,
once daily
- Treatment Group 3 (n = 130): PTM filgotinib 200 mg and PTM filgotinib 100 mg,
once daily
Note: United States (US) males who have not failed at least two biologic
therapies (any tumor necrosis factor-alpha [TNF*] antagonist and vedolizumab)
will be randomized in a 2:1 ratio to either filgotinib 100 mg or matching
placebo.
Study burden and risks
Please refer to the Risks section in the ICF for a full overview of the risks
associated with Filgotinib.
Lakeside Drive 333
Foster City CA 94404
US
Lakeside Drive 333
Foster City CA 94404
US
Listed location countries
Age
Inclusion criteria
Main inclusion criteria (cohorts A and B):
Subjects must meet all of the following inclusion criteria to be eligible for participation in either
the Cohort A or B Induction Study.
* Males or non-pregnant, non-lactating females, ages 18 to 75 years, inclusive based on the
date of the screening visit
* Documented diagnosis of UC of at least 6 months AND with a minimum disease extent of 15 cm from the anal verge. Documentation should include endoscopic and histopathologic evidence of UC as follows:
a) The criteria for documentation of UC based on endoscopy will be medical record
documentation of, or an ileocolonoscopy (full colonoscopy with the intubation of the
terminal ileum) report dated * 6 months before enrollment, which shows features
consistent with UC, determined by the procedure performing physician
b) The criteria for documentation of UC based on histopathology will be medical record
documentation of or a histopathology report indicating features consistent with UC as
determined by the pathologist
* A surveillance colonoscopy is required at screening in subjects with a history of UC for 8 or more years, if one was not performed in the prior 24 months
* 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 as determined by the Mayo clinic scoring system with endoscopy occurring during screening; total score must be between 6 and 12, inclusive
* May be receiving the following drugs (subjects on these therapies must be willing to remain on stable doses for the noted times):
a) Oral 5-aminosalicylate (5-ASA) compounds provided the dose prescribed has been stable for at least 4 weeks prior to randomization; dose must be stable for first 10 weeks after randomization
b) Azathioprine, 6-MP or MTX provided the dose prescribed has been stable for 4 weeks
prior to randomization; dose must be stable for first 10 weeks after randomization
c) Oral corticosteroid therapy (prednisone prescribed at a stable dose * 30 mg/day or
budesonide prescribed at a stable dose of * 9 mg/day) provided the dose prescribed has
been stable for 2 weeks prior to randomization; dose must be stable for first 14 weeks
after randomization;Cohort A (Biologic-naïve) Induction Study
Inclusion Criteria, Cohort A ONLY
Subjects must meet all of the additional following inclusion criteria to be eligible for
participation in Cohort A Induction Study.
1) Previously demonstrated an inadequate clinical response, loss of response to, or intolerance
of at least 1 of the following agents (depending on current country treatment
recommendations/guidelines):
a) Corticosteroids
i. Active disease despite a history of at least an induction regimen of a dose equivalent
to oral prednisone 30 mg daily for 2 weeks or intravenously (IV) for 1 week, OR
ii. Two failed attempts to taper steroids below a dose equivalent of 10 mg daily
prednisone, OR
iii. History of steroid intolerance including, but not limited to, Cushing*s syndrome,
osteopenia/osteoporosis, hyperglycemia, insomnia, serious infections, depression,
allergic reactions, mood disturbances, or any other condition that contributed to
discontinuation of the agent;b) Immunomodulators
i. Active disease despite a history of at least a 12-week regimen of oral azathioprine
(* 2 mg/kg/day) or 6-MP (* 1 mg/kg/day), or MTX (25 mg subcutaneously [SC] or
intramuscularly [IM] per week for induction and * 15mg IM per week for
maintenance) OR
ii. History of intolerance to at least 1 immunomodulator including, but not limited to,
serious infections, hepatotoxicity, cytopenia, pancreatitis, thiopurine
methyltransferase (TPMT) genetic mutation, allergic reactions, or any other condition
that contributed to discontinuation of the agent;Cohort B (Biologic-experienced) Induction Study
Inclusion Criteria, Cohort B ONLY
Previously demonstrated an inadequate clinical response, loss of response to, or intolerance
of at least one of the following agents (depending on current country treatment
recommendations/guidelines):
a) TNF* Antagonists
i. Infliximab: Minimum induction regimen of 5 mg/kg at 0, 2, and 6 weeks
(in the EU, duration of treatment of 14 weeks)
ii. Adalimumab: An 8-week induction regimen consisting of 160 mg
(four 40-mg injections in 1 day or two 40-mg injections per day for
2 consecutive days) on Day 1, followed by a second dose 2 weeks later
(Day 15) of 80 mg and a 40 mg dose 2 weeks later (Day 29), followed by a
40 mg dose every other week until Week 8 (Day 57).
iii. Golimumab: Minimum induction duration of 6 weeks (12 weeks in EU) is
required for golimumab, which includes 200 mg SC injection at Week 0,
followed by 100 mg at Week 2 and then 100 mg every 4 weeks. OR
iv. Recurrence of symptoms during maintenance therapy with the above agents, OR
v. History of intolerance to any TNF* antagonists including, but not limited to, serious
infections, hepatotoxicity, heart failure, allergic reactions, or any other condition that
contributed to discontinuation of the agent
b) Vedolizumab
i. Active disease despite a history of at least a 14 week (10 weeks in EU) induction
regimen of vedolizumab consisting of 300 mg IV at weeks 0, two, and six OR
ii. History of intolerance to vedolizumab including, but not limited to, serious infections,
hepatotoxicity, cytopenia, allergic reactions, or any other condition that contributed to
discontinuation of the agent
2) Must not have used any TNF* antagonist or vedolizumab * 8 weeks prior to screening or
any other biologic agent * 8 weeks prior to screening or within 5 times the half-life of the
biologic agent prior to screening, whichever is longer;Maintenance Study
Main Inclusion Criteria
* Completion of Cohort A or B induction study with MCS response or EBS remission based on week 10 assessments
Exclusion criteria
Main exclusion criteria (Cohorts A and B):
* Should not have Crohn*s disease, undetermined colitis, Ischemic colitis, Fulminant colitis, ulcerative proctitis or toxic megacolon
* Should not have active tuberculosis (tb) or a history of latent tb that is untreated
* Should not use any prohibited co-medications such as described in the protocol
Cohort A (Biologic naïve) induction research
Main Exclusion criteria, ONLY for cohort A:
* No previous or current treatment with TNF-*-antagonists inclusive (but not limited to) infliximab, adalimumab, golimumab, certolizumab or biosimilar agents, at any moment
* No previous or current treatment with vedolizumab, at any moment;Cohort B (biologic previously treated) induction research
Main exclusion criteria, ONLY cohort B
* May not have been treated with TNF-*-antagonist or vedolizumab * 8 weeks before screening, or another biological * 8 weeks before screening or within 5 times the half-life of the biological before screening, whichever is the longest.
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 | EUCTR2016-001392-78-NL |
| ClinicalTrials.gov | NCT02914522 |
| CCMO | NL58867.041.16 |