The scientific rationale for the study is summarized above and further detailed in Section 3 and the Investigator Brochure (IB). This Phase 2 randomized, double-blind clinical trial is designed to assess the safety and efficacy of BMS-986165 in…
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- Gastrointestinal infections
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Outcome measures
Primary outcome
Primary Efficacy Objectives and Endpoints:
• Objective: To assess the effect of BMS-986165 on clinical remission and
endoscopic response at the end of the Induction Period (Week 12 [Day 85])
• Co-primary endpoints:
o Proportion of subjects achieving clinical remission at Week 12, and
o Proportion of subjects achieving endoscopic response at Week 12, both at a
population level.
Secondary outcome
Secondary Efficacy Objectives and Endpoints:
• To assess the effect of BMS-986165 on clinical response at the end of the
Induction Period
o Endpoint: Proportion of subjects who achieve a clinical response at Week 12
• To assess the effect of BMS-986165 on PRO2 remission at the end of the
Induction Period
o Endpoint: Proportion of subjects who achieve PRO2 remission at Week 12
• To assess the effect of BMS-986165 on gut mucosal disease activity by
endoscopy at the end of the Induction Period
o Endpoint: Change from baseline in SES-CD at Week 12
The exploratory objectives and endpoints are summarized in Section 4.3.
Background summary
Tyrosine kinase 2 (TYK2) is a protein involved in interleukin (IL)-12, IL-23
and Type I interferon (IFN) signaling, and it is required for the activation of
downstream signaling pathways. TYK2 is a widely expressed, non-receptor
tyrosine kinase that catalyzes the phosphorylation of signal transducer and
activator of transcription (STAT) proteins downstream of the receptors for the
p40-containing cytokines IL-12 and IL-23, as well as the Type I interferon
receptor. This results in the activation of STAT-dependent transcription and
functional responses specific for these cytokines. TYK2 dependent cytokines
(eg, IL-12, IL-23 and Type I IFNs) are distinct from those dependent on closely
related Janus kinase (JAK) family members JAK1 and JAK3 (eg, IL 2, IL-6, IL-7,
IL-15) or JAK2 (eg, erythropoietin, thrombopoietin, and granulocyte monocyte
colony-stimulating factor). Consequently, a TYK2 inhibitor is expected to have
a highly differentiated profile from inhibitors of other JAK family kinases.
TYK2-dependent pathways and the cytokine networks they modulate (eg, IL-23,
IL-17, IFNα) have been implicated in the pathophysiology of multiple
immune-mediated diseases, including Crohn*s disease (CD), ulcerative colitis,
psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE) and
spondyloarthritides.
BMS-986165 is an orally administered selective TYK2 inhibitor. A comprehensive
in vitro and in vivo characterization of BMS-986165 has been established and
supports the development of this compound in humans. Inhibition of TYK2 is
expected to provide therapeutic benefit for patients with CD for multiple
reasons: 1) IL-12 and IL 23 have been implicated in pathogenesis of CD; 2)
Biologic agents targeting IL-23p19 and IL 12/23p40 cytokines have been shown to
be efficacious in CD, and ustekinumab targeting IL 12/23p40 has been approved
for the treatment of CD; and 3) BMS-986165 has been shown to be efficacious in
psoriasis, an IL-23-mediated disease, in a recent Phase 2 study.
Study objective
The scientific rationale for the study is summarized above and further detailed
in Section 3 and the Investigator Brochure (IB). This Phase 2 randomized,
double-blind clinical trial is designed to assess the safety and efficacy of
BMS-986165 in patients with moderately to severely active CD. BMS-986165 acts
by inhibiting TYK2, a protein involved in IL-12 and IL-23 signaling, in
addition to Type I IFN signaling. Briefly, basic and translational studies have
implicated IL-12 and IL-23 as potential pathogenic cytokines in intestinal
inflammation. Clinical trial programs of biologic medications that inhibit the
IL-12p40 or IL-23p19 cytokine subunits have provided evidence that IL-12p40
inhibition is safe and efficacious in CD, while IL-23p19 inhibition has shown
promise in Phase 2 clinical trials in CD.
IL-12 and IL-23 have also been implicated in the pathogenesis of psoriasis.
Study IM011011 was a Phase 2 randomized, double-blind clinical trial of
BMS-986165 in 267 subjects with moderate to severe psoriasis. In Study
IM011011, treatment with BMS-986165 at doses of > 3 mg once daily (QD) were
associated with significantly greater clinical responses compared with placebo
at Week 12, as measured by a >= 75% reduction in the Psoriasis Area and Severity
Index (PASI, PASI 75) score. At Week 12, the percentage of patients with a PASI
75 response was 7% (3 of 45 patients) with placebo, 39% (17 of 44 patients)
with 3 mg QD, 69% (31 of 45 patients) with 3 mg BID, 67% (30 of 45 patients)
with 6 mg BID, and 75% (33 of 44 patients) with 12 mg QD (P value < 0.001 for
each comparison). Treatment with BMS-986165 at doses > 3 mg BID was also
associated with a numerically greater proportion of patients achieving >= 90%
reduction in PASI score (PASI 90), compared with placebo at Week 12. This study
provides a proof of concept that BMS-986165 may be effective in the treatment
of an IL-23 mediated disease in humans. Taken together, these data provide a
scientific rationale for studying BMS-986165 in CD.
The eligibility criteria are designed to ensure that subjects have moderately
to severely active CD at baseline and to minimize the risk for serious
infections that may be associated with immune modulating therapies.
Clinical disease activity is assessed in this study using the CDAI. CDAI is a
composite instrument that includes patient-reported abdominal pain (AP), stool
frequency (SF), general well-being, presence of complications of CD,
hematocrit, weight, presence of a CD-related abdominal mass, and the use of
antidiarrheal medication. CDAI has been widely used in registrational clinical
trial programs, but does have certain limitations: eg, (i) the AP and SF
components are weighted, (ii) the CDAI incorporates items that are not
patient-reported outcomes (PROs), (iii) the CDAI does not include an assessment
of mucosal inflammation, and (iv) the CDAI does not correlate well with
endoscopic findings. In order to address these limitations, a PRO2 instrument
that includes unweighted AP and SF will be evaluated during the study, and
mucosal inflammation will also be assessed by endoscopy and histology.
Mucosal disease activity is assessed in this study using the Simple Endoscopic
Score for Crohn's Disease (SES-CD). Clinical symptoms assessed by CDAI only
have a modest correlation with objective evidence of mucosal inflammation,
assessed by SES-CD. Consequently, in order to evaluate if BMS-986165 is
effective at improving both the clinical symptoms of CD and objective evidence
of mucosal inflammation, clinical remission (based on CDAI) and endoscopic
response (based on SES-CD) will be used as co-primary endpoints at Week 12, on
a population basis. The SES-CD will be assessed by a blinded central reader.
Additional endpoints of interest include CDAI-based clinical response, PRO2
remission, endoscopic remission, endoscopic normalization, deep remission
(clinical plus endoscopic remissions), histological endpoints, patient reported
measures of disease control and quality of life improvement, and measurement of
pharmacodynamic (PD) responses. The ability to measure biomarkers in peripheral
blood and gut tissue specimens from patients with CD both before and after
treatment allows for evaluation of target-specific and disease-specific PD
measures in the relevant tissues over time.
IM011023 is the first clinical trial of BMS-986165 in patients with active CD.
In order to explore the dose-response relationship of BMS-986165 in this
patient population, 2 dose regimens of BMS 986165 are included in this study,
in addition to a placebo arm. As substantial placebo responses have been
observed in previous CD clinical trials, the placebo arm provides an important
control for potential confounding factors derived from natural variability in
the clinical course of CD, and from potentially confounding effects of standard
medical care, as well as to provide a benchmark for safety. The number of
subjects exposed to placebo has been minimized (3:1 ratio of BMS
986165:placebo, overall), with provision for treatment of placebo
non-responders at Week 12 with BMS-986165 at the higher dose of 6 mg BID.
Subjects will also be allowed to continue 5 aminosalicylates (5 ASAs),
probiotics, CD-targeted antibiotics, and/or corticosteroids (subject to dose
stabilization requirements) through Week 12 (Day 85). In addition, 5-ASAs,
probiotics, and CD-related antibiotics can continue throughout the duration of
the study (104 weeks in total).
Corticosteroids (prednisone up to 20 mg/day or equivalent) are allowed in the
Induction Period of the study, subject to dose stabilization requirements.
Subjects who achieve clinical response at Week 12 must taper corticosteroids in
the Maintenance Period according to the tapering schedule in Section 5.1.4.2,
unless they exhibit signs or symptoms of adrenal insufficiency. This approach
limits the total duration of corticosteroid exposure for study subjects and
facilitates an exploratory analysis of whether treatment with BMS-986165 is
associated with corticosteroid-free efficacy in the Maintenance Period.
Randomization stratified by concomitant corticosteroid use, region, and
prior/current exposure to TNFi (ie, TNFi exposed or TNFi naïve) is being
implemented to distribute subjects equally across treatment groups (except in
Japan) based on these characteristics (Section 5.1.2), which may indicate the
background severity of disease and/or background level of disease control, and
to balance for potential regional differences in CD background medication.
There will be separate strata for Japan; however, the other stratification
factors (TNFi and concomitant corticosteroid use) will not be applied.
A justification for dose and regimen and a benefit/risk assessment are provided
in Section 3.2.2 and Section 3.2.3, respectively.
Study design
IM011023 is a Phase 2 randomized, double-blind, placebo-controlled clinical
study designed to assess the safety and efficacy of BMS 986165 compared to
placebo in subjects with moderately to severely active CD.
Approximately 240 subjects will be randomized in this study. After a 28-day
Screening Period, eligible subjects will be randomized in a 3:3:2 ratio to one
of three study arms: (i) BMS 986165 6 mg twice daily (BID) by mouth (PO); n*90,
(ii) BMS-986165 3 mg BID PO; n*90, or (iii) matched placebo; n*60.
Randomization will be stratified according to geographic region (US, Japan,
Rest of World), prior exposure to tumor necrosis factor inhibitor (TNFi;
Exposed/Naïve), and concomitant corticosteroid use (yes/no). Since the number
of subjects from Japan is expected to be small, the stratification factors of
prior exposure to TNFi and concomitant corticosteroid use will not be applied
in Japan.
This study has a 12-week double-blind Induction Period, a 40-week double-blind
Maintenance Period, and a 52-week Open label Extension (OLE) Period, leading to
a total of up to 104 weeks of exposure to investigational product (IP). The
primary efficacy assessment occurs at Week 12. The co-primary endpoints are
defined as achieving clinical remission (defined as Crohn*s Disease Activity
Index [CDAI] of < 150) and achieving endoscopic response (>= 50% improvement
from baseline in the Simple Endoscopic Score for Crohn*s Disease [SES CD]), on
a population basis, at Week 12.
This study has a treat-through design in order to explore sustained clinical
benefit and safety in the Maintenance Period. Subjects who achieve clinical
response (a reduction from baseline in the CDAI score of >= 100 points or a
total CDAI score < 150) at Week 12 (Day 85), are eligible to enter the
Maintenance Period and to continue on the same double-blind treatment regimen
that they received in the Induction Period for up to an additional 40 weeks, up
to Week 52. Subjects with a loss of response (LOR; an increase in the CDAI
score of >= 100 points compared to Week 12 and a total CDAI score of >= 220
points) at any time from Week 13 through Week 52 are eligible to enter an
open-label BMS-986165 6 mg BID PO arm through Week 52.
Subjects who do not achieve clinical response at Week 12 are eligible to enter
an open-label BMS 986165 6 mg BID PO arm. In this study arm, clinical response
is assessed at Week 26. Subjects who achieve clinical response at Week 26 may
continue in this arm through Week 52. Subjects who do not achieve clinical
response at Week 26 must discontinue IP and enter the Post treatment Follow-up
Period. Throughout the study, subjects who permanently discontinue IP prior to
Week 52 must enter the Post-treatment Follow-up Period.
Subjects who continue to derive a clinical benefit from IP at Week 52, as
judged by the investigator, are eligible to enter the OLE Period. The OLE
Period lasts 52 weeks, to Week 104.
Intervention
Subjects will be assigned into a group to receive either BMS-986165 or placebo.
The chances of receiving BMS-986165 are 2 in 3 (67%). They will be assigned
randomly to receive BMS-986165 or placebo, as oral capsules, at one of the
following doses:
• 6 mg twice daily or
• 3 mg twice daily or
• placebo twice daily
The doses will be arranged into sets of 4 capsules and you will have to take
them in the morning and in the evening, approximately 12 hours apart.
Study burden and risks
See ICF section 7.0.
Chaussée de la Hulpe 185
Brussels 1170
BE
Chaussée de la Hulpe 185
Brussels 1170
BE
Listed location countries
Age
Inclusion criteria
1) Signed Written Informed Consent
a) Willing to participate in the study and sign the ICF.
b) Willing and able to complete all study-specific procedures and visits.
2) Type of Subject and Target Disease Characteristics
a) Not applicable per Global Revised Protocol v3.0
b) Not applicable per Global Revised Protocol v3.0
c) Not applicable per Global Revised Protocol v3.0
d) Not applicable per Global Revised Protocol v3.0
e) Documented diagnosis of CD for at least 3 months prior to screening,
including ileal, colonic, or ileo-colonic disease distribution, confirmed by:
• Source: Medical records with report of a colonoscopy with ileal intubation
(ileocolonoscopy), which shows features consistent with CD, as determined by
the procedure performing physician, AND
• Source: Medical record documentation of a histopathology report showing
features consistent with CD, as determined by the local pathologist.
Note: If a histopathology report is not available, histologic samples can be
obtained at the screening endoscopy and sent to a local laboratory to confirm
diagnosis of CD before proceeding to randomization. The screening endoscopy
must show features consistent with CD.
f) Must have active moderate to severe CD, as defined by:
• CDAI score of 220 to 450 AND
• PRO2: Average daily score for abdominal pain >= 2 OR average daily number of
very soft (loose) or liquid (watery) stools (BSS Type 6 or 7 only; see APPENDIX
18) >= 4, (see Section 9.1), AND
• Evidence of active inflammation in at least 1 of the 5 ileocolonic segments
(based on central reading) with total SES-CD >= 6 or SES-CD >= 4 if only isolated
ileitis is present on baseline endoscopy
g) Must have had an inadequate response, LOR, or intolerance to a standard
treatment course of 1 or more of the following medications as below:
• Oral 5-ASAs: (eg, mesalamine, sulfasalazine, olsalazine, balsalazine) at or
above the approved label dose (or per local standard of care) for induction
therapy for at least 6 weeks
• Oral corticosteroids: Prednisone >= 40 mg/day or equivalent for 2 weeks, or 2
failed attempts to taper oral corticosteroids below prednisone or equivalent 10
mg daily, or a relapse within 3 months of discontinuing corticosteroids
• Intravenous (IV) corticosteroids: hydrocortisone >= 400 mg/day or equivalent
for at least 1 week
• Immunomodulators: AZA >= 1.5 mg/kg/day, 6-MP >= 0.75 mg/kg/day, MTX >= 15
mg/week, or as per Institutional Practice/Country-approved label or guideline,
for at least 12 weeks. At institutions that utilize thiopurine levels in
clinical practice: AZA or 6-MP prescribed for at least 12 weeks with at least 1
demonstration of therapeutic thiopurine metabolite levels. Note: subjects with
defined NUDT15 or TPMT mutations who experience intolerance to thiopurines at
lower doses than those listed above may be eligible for this study. This should
be discussed with the medical monitor on a case-by-case basis.
• Biologics: (eg, infliximab, adalimumab, certolizumab pegol, vedolizumab,
natalizumab, ustekinumab) as defined in APPENDIX 4. Subjects can be included if
treatment with a biologic was stopped due to primary or secondary nonresponse,
or were intolerant to treatment, as defined in APPENDIX 4.
3) Age and Reproductive Status
a) Men and women aged 18 to 75 years inclusive at the time of screening
b) Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human
chorionic gonadotropin) within 24 hours prior to the start of study treatment.
c) Women must not be breastfeeding
d) Not applicable per Global Revised Protocol v3.0
e) Not applicable per Global Revised Protocol v3.0
f) Not applicable per Global Revised Protocol v3.0
g) Not applicable per Global Revised Protocol v3.0
h) Azoospermic males are exempt from contraceptive requirements. WOCBP who are
continuously not heterosexually active are also exempt from contraceptive
requirements, and still must undergo pregnancy testing as described in this
section.
i) Not applicable per Global Revised Protocol v3.0
j) Not applicable per Global Revised Protocol v5.0
k) Investigators shall counsel WOCBP and men who are sexually active with WOCBP
on the importance of pregnancy prevention and the implications of an unexpected
pregnancy. Investigators shall advise on the use of methods of contraception
(APPENDIX 5).
l) Male subjects should maintain their usual practice with regards to
contraception (if any). However, no specific additional contraceptive measures
are required.
m) WOCBP must agree to at least an acceptable, less than highly effective means
of contraception (see APPENDIX 5) for the duration of treatment with study
treatment(s) (BMS-986165 or placebo).
Exclusion criteria
1) Target Population
a) Severe or fulminant colitis that is likely to require surgery or
hospitalization
b) Presence of a diagnosis of alternative forms of colitis (infectious,
inflammatory including ulcerative colitis, malignant, toxic, indeterminate,
etc) other than CD
c) Not applicable per Global Revised Protocol v3.0
d) History of intra-abdominal abscess within the last 60 days
• Previous intra-abdominal abscess that has been drained and successfully
treated with a local standard course of antimicrobial therapy is permitted (the
course must be completed at least 60 days prior to Day 1)
e) History of diverticulitis within the last 60 days
• Previous diverticulitis that has been successfully treated with a local
standard course of antimicrobial therapy is permitted. (the course must be
completed at least 60 days prior to Day 1)
f) Receiving tube feeding, defined formula diets, or total parenteral
alimentation
g) Current colonic dysplasia or past colonic dysplasia that has not been
definitively treated
h) History of infectious (bacterial, viral, fungal, parasitic, etc.) colitis
within past 30 days; must be fully treated to rescreen
i) Use of therapeutic enema or suppository, other than required for
ileocolonoscopy, within 7 days prior to screening or during the Screening Period
j) Not applicable per Global Revised Protocol v3.0
k) Not applicable per Global Revised Protocol v3.0
l) Previous exposure to BMS-986165 in any study
m) Not applicable per Global Revised Protocol v.5.0
n) Not applicable per Global Revised Protocol v3.0
o) Not applicable per Global Revised Protocol v.5.0
p) Prior treatment with specific lymphocyte-depleting agents, such as
alemtuzumab and rituximab, are prohibited within 12 months prior to the first
dose of study treatment during the Induction Period.
q) Receipt of either lymphocyte apheresis or selective monocyte, granulocyte
apheresis (eg, Cellsorba*) is prohibited within 12 months prior to the first
dose of study treatment during the Induction Period.
r) Previous treatment with investigational agents within 4 weeks or 5
half-lives (whichever is longer) prior to the first dose of study treatment
during the Induction Period. Subjects treated with investigational agents 4 to
12 weeks prior to the first dose of study treatment must be discussed with the
medical monitor.
s) Previous stem cell transplantation, (except local stem cell therapy to treat
perianal fistulae (eg, Alofisel® [darvadstrocel]). Please discuss on a case by
case basis with the medical monitor.
t) Presence of a stoma, gastric or ileoanal pouch, previous proctocolectomy or
total colectomy, or symptomatic, stenosing disease that is likely to confound
efficacy assessment (eg, symptomatic CD-related stricture), abscess or
suspected abscess, pouchitis, short bowel syndrome, or history of bowel
perforation. In addition, subjects with colonic or ileal strictures that are
not passable via colonoscope that the endoscopist normally uses in clinical
practice, or strictures in the ileum or ileocecal valve that are fibrotic in
nature, will be excluded.
2) Other Medical Conditions and History
a) Women who are pregnant or breastfeeding
b) Any major illness/condition or evidence of an unstable clinical condition
(eg, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary,
immunologic, psychiatric, or local active infection/infectious illness) that,
in the investigator*s judgment, will substantially increase the risk to the
subject if he or she participates in the study
c) Any major surgery within the last 30 days before the first dose of study
treatment, or any surgery planned during the course of the study
d) Not applicable per Global Revised Protocol v3.0
e) Female subjects with a breast cancer screen suspicious for malignancy, and
in whom the possibility of malignancy cannot be reasonably excluded after
additional clinical, laboratory, or other diagnostic evaluations
f) Significant blood loss (> 500 mL) or blood transfusion within 4 weeks of
study treatment administration
g) Inability to tolerate oral medication
h) Inability to undergo venipuncture and/or tolerate venous access
i) Not applicable per Global Revised Protocol v3.0
j) Any other sound medical, psychiatric, and/or social reason as determined by
the investigator
k) Potential subjects with the following characteristics will be excluded from
the study:
• History of any kind of bowel resection within 6 months or any other
intra-abdominal surgery within 3 months prior to baseline
• History of any surgical procedure requiring general anesthesia, other than
required for ileocolonoscopy, within 30 days prior to the first dose of study
treatment, or is planning to undergo surgery during the study period
• History of bleeding disorders or recent use of anti-platelet or
anti-thrombotic agents that in the investigator*s judgment preclude safely
performing endoscopic procedures and biopsy within the timeframe outlined in
the study protocol
• Currently on any therapy for chronic infection (eg, pneumocystis,
cytomegalovirus, herpes simplex, herpes zoster, invasive bacterial or fungal
infections, or atypical mycobacteria)
• History of congenital or acquired immunodeficiency
• Known serious infection, defined as any infection requiring hospitalization
or treatment with parenteral (intramuscular [IM] or IV) antimicrobial agents
(eg, antibiotics, antiviral, antifungal, or antiparasitic agents) within 30
days of the first dose of study treatment, or completion of oral antimicrobial
agents within 2 weeks of the first dose of study treatment. Antibiotics used to
cover a procedure such as endoscopy would not exclude the subject.
o In the case of prior SARS-CoV-2 infection, symptoms must have completely
resolved 4 weeks prior to screening and based on investigator assessment in
consultation with the medical monitor, there are no sequelae that would place
the subject at a higher risk of receiving BMS-986165. See Section 9.10 for
additional information regarding retesting subjects who have had prior
SARS-CoV-2 infection.
• Previous history of herpes zoster, herpes simplex, or influenza infection
within 12 weeks before the first dose of study treatment or a history of
disseminated/complicated herpes zoster infection (multidermatomal involvement,
ophthalmic zoster, central nervous system involvement, or post-herpetic
neuralgia)
• Cancer or history of cancer or lymphoproliferative disease within the
previous 5 years (other than adequately treated cutaneous basal cell or
squamous cell carcinoma or resected cervix carcinoma in situ with no evidence
of recurrence)
• Class III or IV congestive heart failure, as classified by the New York Heart
Association (NYHA) Functional Classification or any recent onset of heart
failure resulting in NYHA Class III/IV symptoms
• Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris)
and/or any history of significant cerebrovascular disease (eg, stroke, cerebral
hemorrhage, transient ischemic attack) within 24 weeks before screening
• Administration of a live vaccine within 90 days before the first dose of
study treatment administration. Heat-killed, or otherwise inactivated, protein
or subunit vaccines (eg, influenza and pneumococcal vaccines), nucleic acid
vaccines that do not encode potentially infectious virus, and replication
incompetent recombinant vector vaccines may be received at any time on study.
Furthermore, live vaccines should not be used during the study and within the 2
months following last dose, and any other inactivated vaccines (eg, tetanus,
etc.) should be used according to local guidelines during the treatment period.
• Current or recent (within 3 months before the first dose) gastrointestinal
disease, including gastrointestinal surgery, that could impact the absorption
o
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 | EUCTR2017-001976-48-NL |
| ClinicalTrials.gov | NCT03599622 |
| CCMO | NL74546.018.20 |