Primary objective: To test the hypothesis that treatment with LY3074828 is superior to placebo in the proportion of subjects with endoscopic response at Week 12, defined as 50% reduction from baseline in SES-CD ScoreSecondary objective: • To…
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of subjects achieving endoscopic response at Week 12
Secondary outcome
• AEs and discontinuation rates; mean change vital signs; laboratory values
• Proportion of subjects achieving endoscopic response at Week 52
• Proportion of subjects achieving endoscopic remission at Week 12
• Proportion of subjects achieving endoscopic remission at Week 52
• Proportion of subjects achieving PRO remission at Week 12
• Proportion of subjects achieving PRO remission at Week 52
• The mean change from baseline for PGRS score, PGRC score, IBDQ score,
FACIT-Fatigue, and SF-36 at Weeks 12 and 52
• Clearance and volume of distribution
Background summary
LY3074828 is being developed for the treatment of autoimmune diseases where the
IL-23 pathway is thought to have a significant pathogenic role. LY3074828
neutralizes IL-23 activity by binding the p19 subunit.
Treatment of autoimmune/inflammatory diseases with IL-23 targeted therapy is
being pursued by several companies. The first such biologic to demonstrate
clinical benefit in autoimmune disease was ustekinumab, which is a Food and
Drug Administration (FDA)-approved monoclonal antibody for the treatment of
psoriasis and psoriatic arthritis (Stelara® prescribing information 2014).
Ustekinumab has recently demonstrated clinical activity in Phase 3 trials for
the treatment of Crohn*s disease (Toussirot et al. 2013; Sanborn et al. 2008;
Sandborn et al 2012; Simon et al. 2016). Ustekinumab binds the common p40
subunit of IL-12 and IL-23; therefore, it targets both cytokines, rather than
IL-23 specifically. Blockade of the IL-12 pathway may prevent Th1 cell-induced
interferon blockade of Th17 cell development, thus potentially limiting the
clinical activity of p40 targeting antibodies. Experimental studies suggest
that blocking the IL-23/Th17/IL-17 immune axis alone is sufficient to treat
autoimmune inflammation (Monteleone et al. 2009). Agents specifically targeting
the IL-23 p19 subunit have demonstrated clinical activity in psoriasis
(including LY3074828 in Study AMAA) and Crohn*s disease (Sofen et al. 2014;
Kopp et al. 2015; Krueger et al. 2015 ). IL-23 p19-specific antibodies have
also demonstrated clinical activity in Crohn*s disease (Sands et al. 2015;
Feagan et al. 2016 ). The IL-23/Th17 pathway is believed to have a significant
role in this disease (Gheita et al. 2014; Globig et al. 2014; El-Bassat et al.
2015).
Eli Lilly and Company (hereafter Lilly) has one completed study (AMAA) and 2
ongoing studies (AMAD and AMAC). The most updated information about these
studies can be found in the Investigator*s Brochure (IB).
Study objective
Primary objective: To test the hypothesis that treatment with LY3074828 is
superior to placebo in the proportion of subjects with endoscopic response at
Week 12, defined as 50% reduction from baseline in SES-CD Score
Secondary objective:
• To evaluate the safety and tolerability of treatment with LY3074828
• To evaluate the effect of LY3074828 on the proportion of subjects with
endoscopic response at Week 52, defined as 50% reduction from baseline in
SES-CD score
• To evaluate the efficacy of treatment with LY3074828 as superior to placebo
in endoscopic
remission (defined as an SES-CD score of <4 ilealcolonic or <2 for isolated
ileal disease, and no subscore >1) at Week 12
• To evaluate the effect of LY3074828 on the proportion of subjects with
endoscopic remission (defined as an SES-CD score of <4 ileal-colonic or <2 for
isolated ileal disease, and no subscore >1) at Week 52
• To evaluate the efficacy of treatment with LY3074828 as superior to placebo
in PRO remission (defined as SF <=2.5 and AP <=1) at Week 12
• To evaluate the effect of LY3074828 on the proportion of subjects with PRO
remission (defined as SF <=2.5 and AP <=1) at Week 52
• To evaluate the effect of LY3074828 on health outcomes/quality of life
measures (including: PGRS score, PGRC score, IBDQ score, SF-36 score, and
FACIT-Fatigue) at Weeks 12 and 52
• To characterize the PK of LY3074828
Study design
Study AMAG is a multicenter, randomized, parallel-arm, placebo-controlled trial
in which approximately 180 subjects will be randomized.
Intervention
Period 1 (Weeks 0 to 12): A 12-week dosing period is designed to evaluate the
efficacy and safety of LY3074828 administered intravenously (IV) at Weeks 0, 4,
8. At baseline, subjects will be randomized with a 2:1:1:2 allocation across
the 4 treatment arms (LY3074828, and placebo) and stratified on the basis of
previous
exposure to biologic therapy for treatment of Crohn*s disease.
Period 2 (Weeks 12 to 52): In Period 2, all subjects will continue dosing and
be randomized evenly to continue baseline treatment assignment or subcutaneous
(SC) LY3074828 every 4 weeks (Q4W)*except for all subjects in the placebo
group, and subjects in the LY3074828 treatment groups who have not had any
improvement in SES-CD score from baseline at Week 12 (determined by the central
reader), who will receive intravenous (IV) LY3074828 Q4W.
Period 3 (Weeks 52 to 104): All subjects having clinical benefit will continue
on study in Period 3 and receive SC LY3074828 Q4W open-label. Clinical benefit
is defined as having an endoscopic response (50% reduction from baseline in
SES-CD score), or a 25% reduction from baseline in SES-CD score, combined with
a 40% reduction from baseline in stool frequency (SF) or abdominal pain (AP)
score.
Follow-Up: At Week 104, subjects will stop treatment and be followed for safety
for an additional 16 weeks.
Study burden and risks
The study medicine may have side effects and other undesirable effects.
Very common effects (happening in more than 1 in 10 patients) reported after
giving LY3074828 that could have been related to the patient*s disease(s),
other medications taken by the patient, LY3074828, or a combination of some or
all of these factors are summarized below:
• common cold
• headache
You can find more details about possible side effects in Appendix D of the
subject information form.
Lilly Corporate Center DC1526
Indianapolis, Indiana 46285
US
Lilly Corporate Center DC1526
Indianapolis, Indiana 46285
US
Listed location countries
Age
Inclusion criteria
Subjects will be eligible for the study only if they meet all of the following criteria within the screening period, which is <=28 days prior to the start of study treatment, unless specifically defined:
Type of Subject and Disease Characteristics
• have had a diagnosis of Crohn*s disease for >=3 months before baseline
• have active Crohn*s disease as defined absolute SF >=4 (loose and waterystools defined as Bristol Stool Scale Category 6 or 7) and/or AP >=2 at baseline
• have a SES-CD score >=7 (centrally read) for subjects with ileal-colonic or >=4 for subjects with isolated ileal disease within 14 days before the first dose ofstudy treatment
Prior IBD Treatment
• must have received prior treatment for Crohn*s disease (according to the criteria below):
have received treatment with >=1 biologic agents (such as TNF antagonists, vedolizumab, experimental biologic Crohn*s disease therapeutics) with or without documented history of failure to respond to or tolerate suchtreatment:
o The treatment must have been discontinued according to the followingtimeline:
* anti-TNF therapy at least 8 weeks before baseline
* vedolizumab treatment at least 12 weeks before baseline
* experimental biologic Crohn*s disease therapy at least 8 weeks beforebaseline.
• may be receiving a therapeutic dosage of the following drugs:
• Oral 5-aminosalicylic (ASA) compounds: if the prescribed dose has been stablefor at least 3 weeks before screening colonoscopy or stopped treatment at least 3 weeks prior to screening colonoscopy.
• Oral corticosteroids must be at a prednisone-equivalent dose of <=20 mg/day, or <=9 mg/day of budesonide, and have been at a stable dose for at least 3 weeks prior to the screening colonoscopy. If stopping oral corticosteroid treatment prior to baseline, they must be stopped at least 3 weeks prior to screening colonoscopy.
• AZA, 6-MP, or methotrexate (MTX): if the prescribed dose has been stable for at least 4 weeks before screening endoscopy. Subjects who have discontinued therapy with AZA, 6-MP, or MTX must have stopped the medication at least 4 weeks prior to screening endoscopy to be considered eligible for enrollment.
• Crohn*s disease-specific antibiotics: if the prescribed dose has been stable 4 weeks prior to baseline or stopped treatment at least 3 weeks prior to screening endoscopy.;A complete list of inclusion criteria can be found in the protocol (section 6.1)
Exclusion criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria within the screening period, which is <=28 days prior to the start of study treatment, unless specifically defined:
Study Disease Conditions or Treatments
• have complications of Crohn*s disease such as strictures, stenoses, or any other manifestation for which surgery might be indicated or could confoundthe evaluation of efficacy
• diagnosis of conditions affecting the digestive tract, such as UC, indeterminate colitis, fistulizing disease, abdominal or perianal abscess, adenomatous colonic polyps not excised, colonic mucosal dysplasia, and short bowelsyndrome
• have had any kind of bowel resection, diversion, or placement of a stoma within 6 months or any other intra-abdominal surgery within 3 months prior toscreening
• have received any of the following for treatment of Crohn*s disease:
• 6-thioguanine (6-TG), cyclosporine, tacrolimus, sirolimus, pentoxifylline, or mycophenolate mofetil within 8 weeks prior to baseline
• corticosteroid enemas, IV corticosteroids, corticosteroid suppositories, or topical treatment within 3 weeks prior to screening colonoscopy
• rectal 5-ASA within 3 weeks prior to screening colonoscopy
• have used apheresis (for example, Adacolumn apheresis) <=2 weeks prior to screening.
• have previous exposure to any biologic therapy targeting IL-23 p19 eitherlicensed or investigational, or prior exposure to ustekinumab
• have received natalizumab or agents that deplete B or T cells (for example, rituximab, alemtuzumab, or visilizumab) within 12 months of screening, or, if after receiving these agents, evidence is available at screening of persistentdepletion of the targeted lymphocyte population
• have been treated with any investigational drug for Crohn*s disease within8 weeks prior to baseline or 5 half-lives of the drug (whichever is longer), OR
with interferon therapy within 8 weeks before baseline;A complete list of exclusion criteria can be found in the protocol (section 6.2)
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 | EUCTR2016-002204-84-NL |
ClinicalTrials.gov | NCT02891226 |
CCMO | NL59632.018.16 |