To evaluate the safety and tolerability of long term treatment with ontamalimab in subjects with moderate to severe UC or CD.
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the safety and tolerability of long term treatment with
ontamalimabin subjects with moderate to severe UC or CD.
Secondary outcome
Secondary Objectives - Subjects with Ulcerative Colitis
• To evaluate the maintenance of response to long-term treatment with
ontamalimab as measured by clinical composite score and biomarkers, with or
without endoscopy.
Secondary Objective - Subjects with Crohn's Disease:
• To evaluate the maintenance of response to long-term treatment with
ontamalimab as measured by Crohn's Disease Activity Index (CDAI) score and
biomarkers, with or without endoscopy
Background summary
Ulcerative colitis (UC) is a chronic, relapsing disease marked by ulceration
and inflammation of the colonic mucosa and submucosa. Initially it usually
involves the rectum but may extend proximally to involve a portion of, or the
entirety of, the colon. In the early stages, hemorrhagic and erythematous
tissue is observed, progressing to mucosal ulceration with purulent exudates in
severe cases. The ulceration pattern is continuous and may extend the entire
length of the colon. Perforation of the bowel wall causing ileus and
peritonitis can occur with transmural extension of the ulceration. Bloody
diarrhea with or without mucus and lower abdominal pain with periods of
remission and exacerbation are the most common symptoms.
Although UC can occur at any age, peak incidence has been observed in the
second to fourth decades of life. Ulcerative colitis is a lifelong condition
with a serious effect on the quality of life. Current treatment primarily
consists of symptomatic management with dietary modifications and opiates, as
well as disease modifying agents, systemic glucocorticoids, immunosuppressive
agents, and biologic therapy. Despite recent advances, there is still an unmet
need for an effective pharmacological treatment that will induce and maintain
remission.
Crohn*s disease (CD) is a chronic, relapsing disease marked by granulomatous
inflammation of the gastrointestinal (GI) tract. Although the terminal ileum
and right colon are the most commonly involved sites, CD can affect any part of
the GI tract, from the mouth to the perianal
region. Inflammation is typically transmural (full-thickness), segmental, and
discontinuous, and symptoms are predominantly determined by the part of bowel
or organ involved. Patients typically present with symptoms including abdominal
pain, diarrhea, rectal bleeding, which may
be persistent and lead to anemia, and weight loss due to pain on eating and
malabsorption. As the disease progresses, extraintestinal manifestations and
associated conditions can develop, including bowel obstruction, fistulas, and
stenosis, as well as painful skin ulcerations, eye pain, and arthritis.
Crohn*s disease is a lifelong condition with a serious effect on quality of
life. The traditional approach to therapy of CD has been the step-up approach
usually represented as a pyramid where, progressing from mild to severe
disease, therapeutic choices proceed step by step from
less potent drugs at the base of the pyramid to more potent but also more toxic
drugs at the top. Despite recent advances, there is still an
unmet need for a safe, effective, and durable pharmacological treatment that
will induce and
maintain remission.
The selectivity of lymphocyte homing to specialized lymphoid tissue and mucosal
sites of the gastrointestinal (GI) tract is influenced by the endothelial
expression of mucosal addressin cell adhesion molecule (MAdCAM). MAdCAM plays a
role in gut immune surveillance, and also appears to facilitate excessive
lymphocyte infiltration under conditions of chronic GI inflammation.
Ontamalimab is a fully human immunoglobulin G2 kappa (IgG2k) monoclonal
antibody that binds to human MAdCAM to reduce lymphocyte homing to the gut and
GI inflammation.
Study objective
To evaluate the safety and tolerability of long term treatment with ontamalimab
in subjects with moderate to severe UC or CD.
Study design
This is a Phase 3, multicenter extension study designed to evaluate the
long-term safety and efficacy of ontamalimab in subjects with moderate to
severe UC or CD. The study will enroll subjects from 6 separate Phase 3
studies: 4 multicenter, randomized, double-blind, placebo-controlled, parallel
group study studies evaluating SHP647 as an induction therapy in subjects with
moderate to severe UC (SHP647-301 and SHP647-302) or CD (SHP647-305 and
SHP647-306); and 2 multicenter, double-blind, randomized, placebo-controlled,
parallel-group studies evaluating SHP647 as maintenance therapy in subjects
with moderate to severe UC (SHP647-303) or CD (SHP647-307).
Additionally, the study will directly enroll subjects with moderate to severe
UC who had not participated in any of the Phase 3 induction studies
(SHP647-301, SHP647-302) or the maintenance study (SHP647-303). Direct-entry
subjects include UC subjects who were ineligible for an induction study due to
previous treatment with ontamalimab during a Phase 1 or Phase 2 study or
previous treatment with vedolizumab, or subjects who had met the eligibility
criteria for induction study SHP647-301 or SHP647-302 but were unable to enroll
because of an enrollment cap in their particular country.
Eligible subjects entering study SHP647-304 will be assigned to receive either
25 mg or 75 mg of ontamalimab every 4 weeks. Allocation is dependent on how the
subject entered into this study:
• Subjects who completed maintenance study SHP647-303 or SHP647-307 without
treatment failure and received either 25 mg or 75 mg of ontamalimab every 4
weeks will continue to receive the same dose of SHP647 in this long term safety
extension study.
• All other subjects will be randomized using a 1:1 allocation. Randomization
will be stratified by whether the subjects are entering this study following
(1) non-response in induction study ; (2) treatment failure in maintenance
study; or (3) maintenance study completion for subjects receiving placebo, to
facilitate balance of treatment assignment within each stratum.
Intervention
The participants receive a subcutaneous injection every 4 weeks; 1 group with
25 mg ontamalimab, and 1 group with 75 mg ontamalimab.
Study burden and risks
Ontamalimab may cause side effects. The most frequently reported side effects
(in more than 1 out of every 10 subjects) are: joint pain, headache, pain in
the belly, nausea, fever and nasopharyngitis. If the patient receives placebo
there is a possibility that symptoms of the disease may return or get worse.
Also the study procedures may be accompanied by risks and discomforts. In
addition the study drug, the study procedures and the combination of these may
lead to risks that are as yet unknown.
Ulcerative colitis (UC) is a chronic, relapsing disease marked by ulceration
and inflammation of the colonic mucosa and submucosa. Ulcerative colitis is a
lifelong condition with a serious effect on the quality of life. Current
treatment primarily consists of symptomatic management. Despite recent
advances, there is still an unmet need for an effective pharmacological
treatment that will induce and maintain remission.
Crohn*s disease (CD) is a chronic, relapsing disease marked by granulomatous
inflammation of the gastrointestinal (GI) tract. Although the terminal ileum
and right colon are the most commonly involved sites, CD can affect any part of
the GI tract, from the mouth to the perianal region. Crohn*s disease is a
lifelong condition with a serious effect on quality of life. Despite recent
advances, there is still an unmet need for a safe, effective, and durable
pharmacological treatment that will induce and maintain remission.
Considering the chronic and relapsing characteristics of these lifelong
diseases, we feel these side effects and the burden associated with
participation, are in proportion considering the positive effects that
participation in the study might have on the patients disease.
Shire Way 300
Lexington MA 02421
US
Shire Way 300
Lexington MA 02421
US
Listed location countries
Age
Inclusion criteria
Subjects with Ulcerative Colitis:
1. Subjects and/or their parent or legally authorized representative must have
an understanding, ability, and willingness to fully comply with study
procedures and restrictions.
2. Subjects must be able to voluntarily provide written, signed, and dated
(personally or via a legally authorized representative) informed consent and/or
assent, as applicable, to participate in the study.
3. Subjects must have been enrolled previously in Study SHP647-301 and are in
the treatment period of Study SHP647-303, completed the ET or Week 52 visit in
maintenance study SHP647 303, had responded to ontamalimab treatment (in the
induction and/or maintenance studies), and meet one of the following criteria:
• Subjects are on placebo at the maintenance study ET or Week 52 visit: they
received ontamalimab in the induction studies and fulfilled the maintenance
study response criteria, OR
• Subjects have received ontamalimab at the maintenance study ET or Week 52
visit:
* Clinical composite score that has decreased by >=2 points and >=30%, with an
accompanying decrease in the subscore for RB >=1 point or a subscore for RB <=1,
compared to the baseline value for induction studies, and/or
* Composite score that has decreased by >=30% and >=3 points compared to the
baseline value for induction studies.
4. Subjects receiving any treatment(s) for UC described in Section 5.1.2.1 are
eligible provided they have been, and are anticipated to be, on a stable dose
for the designated period of time.
Subjects with Crohn*s Disease:
1. Subjects and/or their parent or legally authorized representative must have
an understanding, ability, and willingness to fully comply with study
procedures and restrictions.
2. Subjects must be able to voluntarily provide written, signed, and dated
(personally or via a legally authorized representative) informed consent and/or
assent, as applicable, to participate in the study.
3. Subjects must have been enrolled previously in Study SHP647-305 and are in
the treatment period of Study SHP647-307, completed the ET or Week 52 visit in
maintenance study SHP647 307, had responded to ontamalimab treatment (in the
induction and/or maintenance studies), and meet one of the following criteria:
• Subjects are on placebo at the maintenance study ET or Week 52 visit: they
received ontamalimab in the induction study and fulfilled the maintenance study
response criteria, OR
• Subjects have received ontamalimab at the maintenance study ET or Week 52
visit:
* CDAI score that has decreased by >=100 points at EOT visit compared to the
baseline value for induction studies, and/or
* SES-CD that has decreased by >=25% compared to the baseline value for
induction studies.
4. Subjects receiving any treatment(s) for CD described in Section 5.2.2.1 are
eligible provided they have been, and are anticipated to be, on a stable dose
for the designated period of time.
Exclusion criteria
Subjects with UC Entering from an Induction or Maintenance Study/Subjects with
CD
1. Subjects who had major protocol deviation(s) (as determined by the sponsor)
in previous studies.
2. Subjects who permanently discontinued investigational product because of an
AE, regardless of relatedness to investigational product, in previous studies.
3. Subjects who are likely to require major surgery for UC/CD.
4. Subjects are females who became pregnant during the previous UC/CD studies,
females who are lactating, females who are planning to become pregnant during
the study period, or males or females of childbearing potential not agreeing to
continue using appropriate contraception methods (ie, highly effective methods
for female and medically appropriate methods for male study subjects) through
the conclusion of study participation.
5. Subjects who do not agree to postpone donation of any organ or tissue,
including male subjects who are planning to bank or donate sperm and female
subjects who are planning to harvest or donate eggs, for the duration of the
study and through 16 weeks after last dose of investigational product.
6. Subjects who, in the opinion of the investigator or the sponsor, will be
uncooperative or unable to comply with study procedures.
7. Subjects who have a newly-diagnosed malignancy or recurrence of malignancy
8. Subjects who have developed any major illness/condition or evidence of an
unstable clinical condition (except disease under study) 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.
9. Subjects with any other severe acute or chronic medical or psychiatric
condition or laboratory or electrocardiogram (ECG) abnormality that may
increase the risk associated with study participation or investigational
product administration or may interfere with the interpretation of study
results and, in the judgment of the investigator, would make the subject
inappropriate for entry into this study.
10. Subjects with known exposure to *.tuberculosis (TB) since testing at
screening in previous UC/CD studies and who have been advised to require
treatment for latent or active disease, but who are without a generally
accepted course of treatment.
Subjects with UC Entering directly
1. Subjects with indeterminate colitis, microscopic colitis, nonsteroidal
anti-inflammatory drug-induced colitis, ischemic colitis, infectious colitis,
or clinical/histologic findings suggestive of CD.
2. Subjects with colonic dysplasia or neoplasia.
3. Subjects with past medical history or presence of toxic megacolon.
4. Subjects with colonic stricture, past medical history of colonic resection,
a history of bowel surgery within 6 months before screening, or who are likely
to require surgery for UC during the treatment period.
5. Subjects at risk for colorectal cancer must have a colonoscopy (Eaden and
Mayberry, 2002) performed during the screening period with results available
within 10 days before the baseline visit (Visit 1), unless the subject has had
a surveillance colonoscopy performed within 1 year prior to screening, and any
adenomatous polyps found at that examination have been excised.
6. Subjects with known or suspected intolerance or hypersensitivity to the
investigational product(s), closely related compounds, or any of the stated
ingredients.
7. Subjects have received anti-TNF treatment within 60 days or vedolizumab
within 120 days before baseline
8. Subjects have received any biologic with immunomodulatory properties (other
than anti-TNFs) within 90 days before baseline
9. Subjects have received any nonbiologic treatment with immunomodulatory
properties within 30 days before baseline.
10. Subjects have ever received anti-integrin/adhesion molecule treatment (eg,
natalizumab, efalizumab, etrolizumab, or any other investigational
anti-integrin/adhesion molecule) with the exception of vedolizumab.
11. Subjects have received parenteral or rectal glucocorticoids, or rectal
5-ASA, within 14 days before screening endoscopic procedure.
12. Subjects have received leukocyte apheresis or selective lymphocyte,
monocyte, or granulocyte apheresis or plasma exchange within 30 days before
baseline
13. Subjects have participated in other investigational studies within either
30 days or 5 half-lives of investigational product used in the study before
baseline
14. Subjects have received a live (attenuated) vaccine within 30 days before
the baseline
15. Subjects with active enteric infections, Clostridium difficile infectionor
pseudomembranous colitis, evidence of active cytomegalovirus infection or
Listeria monocytogenes, known active invasive fungal infections, clinically
significant underlying disease that could predispose the subjects to
infections, or a history of serious infection within 4 weeks before the
baseline
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 | EUCTR2017-000574-11-NL |
| ClinicalTrials.gov | NCT03283085 |
| CCMO | NL62887.028.17 |