Primary objectiveThe primary objective of the study is to estimate the effects of tofacitinib in maintaining a clinical response or being in remission in subjects with moderate to severe Crohn*s disease previously achieving clinical response or…
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Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The proportion of subjects maintaining clinical response-100, as defined by a
decrease in CDAI score at least 100 points from A3921083 baseline, or being in
clinical remission, as defined by a CDAI score less than 150, at Week 26.
Secondary outcome
•The proportion of subjects maintaining clinical response-100 or being in
clinical remission at Weeks 4, 8, 12, 20 and 26 from the A3921083 Baseline.
•The proportion of subjects maintaining at least a clinical response-100 at
Weeks 4, 8, 12, 20 and 26.
•The proportion of subjects in clinical remission at Weeks 4, 8, 12, 20 and 26.
•The proportion of subjects in clinical remission at Weeks 4, 8, 12, 20, and 26
among subjects in clinical remission at baseline of maintenance study.
•The proportion of subjects in sustained clinical remission in the maintenance
phase. Sustained clinical remission is defined as being in clinical remission
at both Weeks 20 and 26.
•The proportion of subjects achieving sustained clinical response in the
maintenance phase. Sustained clinical response is defined as having at least a
clinical response-100 at both Weeks 20 and 26 from the A3921083 Baseline.
• CDAI scores over time and CDAI scores change from Baseline.
• The time to relapse. Relapse is defined as increase in CDAI of >100 points
from the maintenance phase baseline and a CDAI score of >220
points.
•The proportion of subjects achieving a steroid-free clinical remission at Week
26 of the maintenance phase among subjects on steroids at baseline.
• Serum CRP and fecal calprotectin over time and change from baseline in CRP
and fecal calprotectin.
• Plasma concentrations of tofacitinib .
Background summary
Tofacitinib is being developed for the treatment of adult patients with
moderate-to-severe Crohn*s disease. Crohn*s disease is a chronic relapsing,
transmural inflammatory disease that can affect the entire gastrointestinal
tract and is most commonly located in the ileum and colon (40%) or just
involves the small bowel (30%) or the colon (25%). Although the cause remains
unknown, the most likely pathogenesis of Crohn*s disease is defective
immunoregulation in genetically susceptible patients, leading to an
upregulation of macrophages and Th1 lymphocytes and the production of an excess
of cytokines, interleukins and chemokines, all of which can lead to enhanced
inflammation, impaired wound healing and tissue damage. Increasing evidence
suggests that upregulation of some cytokines that use the common gamma-chain in
their signal transduction pathways may play a role in the pathogenesis of
inflammatory bowel disease.
At present, no current pharmacological therapy provides a cure for Crohn*s
disease and the treatment goal is to induce and then maintain remission.
Despite available treatment options, there is still a large unmet medical need
with many patients failing to achieve clinical remission or experiencing
apparent loss of initial efficacy with continued use. Surgery also is not
curative and often followed by disease recurrence. Thus, there is need for a
novel therapy that will surpass the efficacy of currently used agents, but will
have less toxicity and a more convenient route of administration.
Tofacitinib is a potent, selective inhibitor of the JAK family of kinases,
thereby blocking signaling through the common gamma chain-containing receptors
for several cytokines that are integral to lymphocyte activation, proliferation
and function: inhibition of this signaling pathway by tofacitinib may thus
result in modulation of multiple aspects of the immune response and thereby
offers a novel therapeutic approach for the treatment of Crohn*s disease.
The primary objective of this study is to estimate the effects of tofacitinib
in maintaining a clinical response or being in remission in subjects with
moderate to severe Crohn*s disease previously achieving clinical response or
remission in induction Study A3921083. Please see chapter 1 of the protocol
(introduction) for more details.
Study objective
Primary objective
The primary objective of the study is to estimate the effects of tofacitinib in
maintaining a clinical response or being in remission in subjects with moderate
to severe Crohn*s disease previously achieving clinical response or remission
in induction Study A3921083.
Secondary objectives
- To evaluate the safety and tolerability of tofacitinib as a maintenance
therapy in subjects with active Crohn*s disease.
- To estimate the effect of tofacitinib as a maintenance therapy on clinical
remission, sustained remission and sustained response rates in subjects with
Crohn*s disease.
- To evaluate the pharmacokinetics of tofacitinib as a maintenance therapy in
subjects with moderate to severe Crohn*s disease.
- To evaluate the effect of tofacitinib as a maintenance therapy on quality of
life in subjects with moderate to severe Crohn*s disease.
- To evaluate the effect of tofacitinib as a maintenance therapy on CRP and
fecal calprotectin.
Study design
This is a Phase 2b, randomized, double-blind, placebocontrolled, parallel
group, dose-ranging, multi-centre study in subjects with Crohn*s disease who
completed the double-blind induction treatment in Study A3921083 and achieved
clinical response-100 and/or clinical remission (CDAI<150) at Week 8. This
trial will include a 26-week double-blind treatment period and a 4-week
follow-up period.
The subject eligibility for Study A3921084 will be assessed based on study data
collected at the Week 8 visit of Study A3921083. Subjects who achieve clinical
response-100 and/or clinical remission (CDAI<150) after completion of the
8-week induction therapy in Study A3921083 and who fulfill all other
inclusion/exclusion criteria will be randomly assigned to receive one of three
treatments, tofacitinib 10 mg BID, 5 mg BID, or placebo BID with an allocation
ratio of 1:1:1. Subjects will be stratified according to the treatment
assignments and the degree of clinical response (remission or not) during Study
A3921083.
Intervention
Subjects will be randomly assigned to receive one of three treatments,
tofacitinib 10 mg BID, 5 mg BID, or placebo BID with an allocation ratio of
1:1:1. Subjects will be stratified according to the treatment assignments and
the degree of clinical response (remission or not) during Study A3921083.
Subjects will receive double-blind treatment for 26 weeks. The study drug and
placebo are in the form of tablets and patients will be asked to orally take 2
tablets twice a day. Please see section E4 of this ABR form for the procedures
to which the subjects will be subjected.
Study burden and risks
The unmet medical need in patients with Crohn*s disease, expected efficacy of
tofacitinib in this indication and the safety profile of the compound which
has emerged from the phase 2/3 programs in RA and other indications, imply that
tofacitinib has a novel anti-inflammatory mechanism of action which is
anticipated to be possibly effective in treating Crohn*s disease. The benefits
to the subjects participating in this study will be a potential control of the
disease activity by improving symptoms (stool frequency, abdominal pain) and
general well-being. All subjects may also benefit from gaining knowledge about
their health status through study tests and physician assessments, as well as
having close monitoring of their inflammatory bowel disease.
The risks associated with tofacitinib are similar to the risks associated with
the use of other immunosuppressive agents, including a potential increased risk
for infections. Decreases in white blood cell counts, particularly neutrophils,
and decreases in haemoglobin have been observed. These effects were usually
mild to moderate and returned to normal after discontinuation of therapy. In
previous studies with tofacitinib , increases in levels of LDL and HDL
cholesterol were also reported, with the ratios of total / HDL cholesterol
unchanged. The long-term implications of these changes for cardiovascular risk
are currently unknown. Also seen in previous studies were slight increases in
measured serum creatinine and serum transaminases. This effect generally
returned to normal after discontinuation of therapy. Infections, anemia and
neutropenia are all consistent with the pharmacology of tofacitinib as a potent
inhibitor of JAK3 with cross-over to JAK1 and moderate selectivity for JAK2.
Hypothetical safety risks that may be associated with the use of tofacitinib
include an increased risk of lymphoma and lymphoproliferative disorders,
malignancy and teratogenicity.
The available data on the potential and identified risks of tofacitinib are
thus considered to not preclude clinical studies in Crohn*s disease patients
and the risks are minimized through appropriate pre-enrolment screening and
close safety monitoring. Therefore, the overall risk-benefit assessment for
this study is considered to be favourable.
Arcola Rd 500
Colegeville, PA 19426
US
Arcola Rd 500
Colegeville, PA 19426
US
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Age
Inclusion criteria
•Subjects who met study entry criteria, and who completed Week 8 visit of Induction Study A3921083.
•Subjects who achieve clinical response-100 (reduction in CDAI by 100 points) and/or clinical remission (CDAI<150) in Study A3921083.
•Women of childbearing potential must test negative for pregnancy prior to study enrolment.;Inclusion criteria of the A3921083 induction study:
•Male or female subjects between the ages of 18 and 65 years at screening.
•Subjects with clinical diagnosis of Crohn's disease for at least 6 months prior to screening.
•Subjects with active moderate to severe ileal, ileocolic, or colonic CD defined by a baseline score of Crohn's Disease Activity Index (CDAI) of 220 to 450 at baseline.
Exclusion criteria
•Subjects who had major protocol violation (as determined by the Sponsor) in the A3921083 study.
•Fecal culture/toxin assay indicating presence of pathogenic infection,
unless the subject has completed a full course of treatment or, if
treatment is ongoing, be clinically improved in the judgement of the
investigator.
•Presence of active (draining) fistulae, intrabdominal or perineal
collection or abscess (MRI imaging is not required for entry to this study
unless clinically indicated).
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 | EUCTR2011-001754-28-NL |
| ClinicalTrials.gov | NCT01393899 |
| CCMO | NL38428.091.11 |