Coprimary: The coprimary objectives of the study are to evaluate the efficacy of ontamalimab as maintenance treatment in subjects with moderate to severe Crohn*s disease (CD) based on:* Clinical remission based on 2 item patient-reported outcome (…
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Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Coprimary: The coprimary objectives of the study are to evaluate the efficacy
of ontamalimab as maintenance treatment in subjects with moderate to severe
Crohn*s disease (CD) based on:
* Clinical remission based on 2 item patient-reported outcome (PRO) (abdominal
pain severity and very soft stool/liquid stool frequency)
* Enhanced endoscopic response based on centrally read colonoscopy.
Secondary outcome
Key secondary:
* To evaluate the efficacy of ontamalimab as maintenance treatment on clinical
remission as measured by Crohn's Disease Activity Index (CDAI)
* To evaluate the efficacy of ontamalimab as maintenance treatment on
glucocorticoid free clinical remission based on patient-reported clinical signs
and symptoms (as measured by 2-item PRO)
* To evaluate the efficacy of ontamalimab as maintenance treatment on clinical
remission based on abdominal pain severity and very soft stool/liquid stool
frequency (alternate thresholds)
* To evaluate the efficacy of ontamalimab on maintenance of clinical remission
among subjects in clinical remission at baseline of the SHP647-307 study based
on patient-reported clinical signs and symptoms (as measured by 2-item PRO)
* To evaluate the efficacy of ontamalimab on maintenance of enhanced endoscopic
response among subjects with enhanced endoscopic response at baseline of the
SHP647-307 study based on centrally read colonoscopy
* To evaluate the efficacy of ontamalimab as maintenance treatment based on
achieving clinical remission as well as achieving enhanced endoscopic response
in the same subject
* To evaluate the effect of ontamalimab as maintenance treatment on complete
endoscopic healing.
Other secondary:
* To evaluate the safety and tolerability of ontamalimab as maintenance
treatment
* To evaluate the effect of ontamalimab as maintenance treatment on other
clinical outcomes (2 item PRO based clinical response over time, 2-item PRO
based and CDAI based clinical remission over time, and 2 item PRO based and
CDAI based sustained clinical remission over time)
* To evaluate the effect of ontamalimab on abdominal pain, very soft
stool/liquid stool frequency (as shown by type 6/7 on Bristol Stool Form Scale
[BSFS]), total stool frequency, rectal urgency, rectal bleeding, nausea,
vomiting, and rectal incontinence
* To evaluate the efficacy of ontamalimab as maintenance treatment on different
grades of clinical responses to treatment as measured by CDAI
* To evaluate the effect of ontamalimab as maintenance treatment on endpoints
related to endoscopic healing and histological changes
* To evaluate the effect of ontamalimab as maintenance treatment on
health-related quality of life (HRQL) (as measured by the Inflammatory Bowel
Disease Questionnaire [IBDQ] and the Short Form 36 Health Survey [SF-36])
* To evaluate the impact of ontamalimab as maintenance treatment on incidence
of hospitalizations and total inpatient days
* To evaluate the impact of ontamalimab as maintenance treatment on incidence
of CD related and other surgeries.
Background summary
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.
No clear difference in incidence has been observed between men and women.
Although CD can occur at any age, peak incidence has been observed in the
second to fourth decades of life, with a second modest rise in incidence in the
latter decades of life (Molodecky et al., 2012).
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 clinical
remission.
The selectivity of lymphocyte homing to specialized lymphoid tissue and mucosal
sites of the 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
Coprimary: The coprimary objectives of the study are to evaluate the efficacy
of ontamalimab as maintenance treatment in subjects with moderate to severe
Crohn*s disease (CD) based on:
* Clinical remission based on 2 item patient-reported outcome (PRO) (abdominal
pain severity and very soft stool/liquid stool frequency)
* Enhanced endoscopic response based on centrally read colonoscopy.
Key secondary:
* To evaluate the efficacy of ontamalimab as maintenance treatment on clinical
remission as measured by Crohn's Disease Activity Index (CDAI)
* To evaluate the efficacy of ontamalimab as maintenance treatment on
glucocorticoid free clinical remission based on patient-reported clinical signs
and symptoms (as measured by 2-item PRO)
* To evaluate the efficacy of ontamalimab as maintenance treatment on clinical
remission based on abdominal pain severity and very soft stool/liquid stool
frequency (alternate thresholds)
* To evaluate the efficacy of ontamalimab on maintenance of clinical remission
among subjects in clinical remission at baseline of the SHP647-307 study based
on patient-reported clinical signs and symptoms (as measured by 2-item PRO)
* To evaluate the efficacy of ontamalimab on maintenance of enhanced endoscopic
response among subjects with enhanced endoscopic response at baseline of the
SHP647-307 study based on centrally read colonoscopy
* To evaluate the efficacy of ontamalimab as maintenance treatment based on
achieving clinical remission as well as achieving enhanced endoscopic response
in the same subject
* To evaluate the effect of ontamalimab as maintenance treatment on complete
endoscopic healing.
Other secondary:
* To evaluate the safety and tolerability of ontamalimab as maintenance
treatment
* To evaluate the effect of ontamalimab as maintenance treatment on other
clinical outcomes (2 item PRO based clinical response over time, 2-item PRO
based and CDAI based clinical remission over time, and 2 item PRO based and
CDAI based sustained clinical remission over time)
* To evaluate the effect of ontamalimab on abdominal pain, very soft
stool/liquid stool frequency (as shown by type 6/7 on Bristol Stool Form Scale
[BSFS]), total stool frequency, rectal urgency, rectal bleeding, nausea,
vomiting, and rectal incontinence
* To evaluate the efficacy of ontamalimab as maintenance treatment on different
grades of clinical responses to treatment as measured by CDAI
* To evaluate the effect of ontamalimab as maintenance treatment on endpoints
related to endoscopic healing and histological changes
* To evaluate the effect of ontamalimab as maintenance treatment on
health-related quality of life (HRQL) (as measured by the Inflammatory Bowel
Disease Questionnaire [IBDQ] and the Short Form 36 Health Survey [SF-36])
* To evaluate the impact of ontamalimab as maintenance treatment on incidence
of hospitalizations and total inpatient days
* To evaluate the impact of ontamalimab as maintenance treatment on incidence
of CD related and other surgeries.
Study design
This study consists of a 52 week, double-blind treatment period, followed by a
16 week safety follow-up period for subjects who either discontinue treatment
early or who complete the treatment period and do not enter the long-term
safety extension (LTS) study (SHP647-304).
Eligible subjects who received active treatment in one of the induction studies
and fulfilled the efficacy entry criteria of this study, including achieving
endoscopic and/or clinical response, will be randomized as follows: subjects
who received 25 mg ontamalimab in one of the induction studies will be
randomized (1:1) to receive either 25 mg ontamalimab or placebo, and subjects
who received 75 mg ontamalimab in one of the induction studies will be
randomized (1:1) to receive either 75 mg ontamalimab or placebo.
Eligible subjects who received placebo in one of the induction studies and
fulfilled the efficacy entry criteria of this study including achieving
endoscopic and/or clinical response will be randomized in a 2:2:1 ratio to
receive 1 of 3 treatments (25 mg ontamalimab, 75 mg ontamalimab, or placebo,
respectively) during this maintenance study.
Subjects will be stratified according to glucocorticoid use at Study SHP647-307
baseline, the subject*s status of prior anti tumor necrosis factor (TNF)
treatment (naïve or experienced), and whether or not the subject achieved
clinical remission by 2-item PRO or enhanced endoscopic response in the
induction study.
Subjects enrolled in this study (SHP647-307) will receive double-blind
maintenance treatment in the form of SC injections, using a PFS, every 4 weeks
for 52 weeks. Subjects will undergo efficacy, biomarker, pharmacokinetic (PK),
safety, and health outcome assessments.
Subjects who complete the double-blind treatment period in this maintenance
study may be eligible to enter the LTS study (SHP647-304). Subjects who are
withdrawn from the study prior to completing the double-blind treatment period
due to fulfilling the criteria for treatment failure also may be eligible to
enter the LTS study. The intent of providing rescue treatment in the LTS study
rather than in this maintenance study following *treatment failure* is to
maintain study integrity. Offering treatment in the LTS study after exiting
this maintenance study allows non-responder subjects on placebo, as well as
subjects on active study drug, to potentially benefit from a prolonged or
different dose of active treatment. Subjects will enter a 16 week safety follow
up period if they withdraw early from the treatment period, are treatment
failures and do not enter the LTS study (SHP647-304), or complete the study and
do not wish to enter the LTS study.
Intervention
The participants receive a subcutaneous injection every 4 weeks; 1 group with
25 mg ontamalimab, 1 group with 75 mg ontamalimab, and 1 group with placebo.
Study burden and risks
Ontamalimab may cause side effects. The most frequently reported side effects
(in more than 1 out of every 10 subjects who received ontamalimab) across all
studies and from any cause, including possibly ontamalimab, were joint pain,
headache, pain in the belly, nausea, fever and inflammation or infection of the
nasal passages and the throat. These side effects were generally mild to
moderate.
Side effects reported less frequently (in more than 1 out every 20 subjects but
less than 1 out of every 10 subjects who received ontamalimab) across all
studies and from any cause, including possibly ontamalimab, were vomiting,
fatigue, back pain, diarrhea, influenza (the flu), urinary tract infections,
gastroenteritis (inflammation or infection of the gastrointestinal tract),
upper respiratory infection (inflammation of the bronchial tubes that carry air
to the lungs), bodily rash, pharyngitis (inflammation or infection of the
throat), and anemia (reduced red blood cells). These side effects were also
generally mild to moderate. 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.
Crohn*s disease (CD) is a chronic, relapsing disease marked by granulomatous
inflammation of the gastrointestinal (GI) tract. CD 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. Considering the chronic and relapsing characteristics of
this lifelong disease, 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
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Lexington MA 02421
US
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Inclusion criteria
Subjects must meet all of the following inclusion criteria to be eligible for
enrollment into the study:
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 completed the 16 week induction treatment period from
study SHP647 305 or SHP647 306 and met the following criteria at baseline in
maintenance Study SHP647 307:
a) Meet endoscopic response criteria of a reduction in the Simple Endoscopic
Score for CD (SES-CD) from induction study (SHP647 305 or SHP647 306) baseline
by *25% at Week 16 of induction study (SHP647 305 or SHP647 306)
OR
b) Meet at least 1 of the following 4 criteria at baseline in maintenance Study
SHP647-307, in addition to no worsening of endoscopic score as measured by
SES-CD relative to induction study (SHP647 305 or SHP647 306) baseline:
i. Achieving clinical remission as determined by meeting the criteria for
clinical remission using the 2 item PRO, ie, 2-item PRO subscores of average
worst daily abdominal pain *3 (based on 11 point numerical rating scale [NRS])
over the 7 most recent days* and average daily stool type frequency *2 of type
6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most
recent days*.
ii. A decrease of at least 100 points in CDAI score (CDAI-100) from induction
study (SHP647 305 or SHP647 306) baseline.
iii. A decrease of *30% and at least 2 points from induction study (SHP647 305
or SHP647 306) baseline in the average daily worst abdominal pain over the 7
most recent days*, with the average daily stool frequency of type 6/7 (very
soft stools/liquid stools) either: (i) not worsening from induction study
(SHP647 305 or SHP647 306) baseline and/or (ii) meeting the criteria for
clinical remission, ie, 2 item PRO subscore of average daily stool frequency *2
of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7
most recent days*.
iv. A decrease of *30% from induction study (SHP647 305 or SHP647 306) baseline
in the average daily stool frequency of type 6/7 (very soft stools/liquid
stools) as shown in the BSFS over the 7 most recent days*, with the average
daily worst abdominal pain either: (i) not worsening from induction study
(SHP647 305 or SHP647 306) baseline and/or (ii) meeting the criteria for
clinical remission, ie, 2 item PRO subscore of average worst daily abdominal
pain *3 (based on 11 point NRS) over the 7 most recent days*.
*Note: The 7 days may or may not be contiguous during the 10 days of data
collection before colonoscopy preparation, depending on days to be excluded
because of missing data. If fewer than 7 days are available, the criterion will
be calculated on all available most recent 6 or 5 days. If fewer than 5 days
are available, the criterion will be treated as missing.
4. Subjects receiving any treatment(s) for CD described in Section 5.2.1 of the
protocol are eligible provided they have been, and are anticipated to be, on a
stable dose for the designated period of time.
Exclusion criteria
Subjects are excluded from the study if any of the following exclusion criteria
are met:
1. Subjects who had major protocol deviation(s) (as determined by the sponsor)
in induction study SHP647 305 or SHP647 306.
2. Subjects who permanently discontinued investigational product because of an
adverse event (AE), regardless of relatedness to investigational product, in
induction study SHP647 305 or SHP647 306.
3. Subjects who are likely to require surgery for CD during the study period,
except minor interventions (eg, seton placement for anal fistulas).
4. Subjects are females who became pregnant during induction study SHP647-305
or SHP647 306, females who are lactating, females who are planning to become
pregnant during the study period, and males or females of childbearing
potential not agreeing to continue using appropriate contraception methods (ie,
highly effective methods for female subjects and medically appropriate methods
for males, as described in Section 4.4 of the protocol) 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 developed obstructive colonic stricture, or enterovesical
or enterovaginal fistulae during the induction study (SHP647 305 or SHP647-306).
8. Subjects who have a newly diagnosed malignancy or recurrence of malignancy
(other than resected cutaneous basal cell carcinoma, squamous cell carcinoma,
or carcinoma in situ of the uterine cervix that has been treated with no
evidence of recurrence).
9. Subjects who have developed any major illness/condition or evidence of an
unstable clinical condition (eg, renal, hepatic, hematologic, gastrointestinal
[except disease under study], endocrine, cardiovascular, pulmonary, immunologic
[eg, Felty*s syndrome], 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.
10. 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.
11. Subjects with known exposure to Mycobacterium tuberculosis since testing at
screening in induction study SHP647-305 or SHP647-306 and who have been advised
to require treatment for latent or active disease, but who are without a
generally accepted course of treatment.
12. Subjects with any of the following abnormalities in hematology and/or serum
chemistry profiles during the evaluation of the last visit in the SHP647 305 or
SHP647 306 studies. If the results are considered by the investigator to be
transient and inconsistent with the subject*s clinical condition, may be
repeated once prior to enrolment in Study SHP647-307.
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels
*3.0 x the upper limit of normal (ULN)
* Total bilirubin level *1.5 times the ULN or >2.0 x ULN if the subject has a
known documented history of Gilbert's syndrome
* Hemoglobin level *80 g/L (8.0 g/dL)
* Platelet count *100 × 109/L (100,000 cells/mm3) or *1000 × 109/L (1,000,000
cells/mm3)*
* White blood cell count *3.5 × 109/L (3500 cells/mm3)
* Absolute neutrophil count <2 ×109/L (<2000 cells/mm3)
* Serum creatinine level >1.5 x the ULN or estimated glomerular filtration rate
<30 mL/min/1.73 m2 based on the abbreviated Modification of Diet in Renal
Disease Study Equation.
*Note: If platelet count is <150,000 cells/mm3, a further evaluation should be
performed to rule out cirrhosis, unless another etiology has already been
identified.
13. Subjects who are investigational site staff members or relatives of those
site staff members or subjects who are sponsor employees directly involved in
the conduct of the study.
14. Subjects who are participating in other investigational studies (other than
induction study SHP647 305 or SHP647 306) or plan to participate in other
investigational studies during Study SHP647 307.
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 | EUCTR2017-000617-23-NL |
| Other | in process |
| CCMO | NL65341.028.18 |