The primary objective of this study is to evaluate the long-term efficacy, safety, and tolerability of repeated administration of adalimumab in subjects with Crohn's disease (CD) who participated in and successfully completed Study M14-115.The…
ID
Source
Brief title
Condition
- Gastrointestinal ulceration and perforation
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of subjects with endoscopic improvement, defined as an SES-CD <= 4
and at least 2 point reduction versus baseline and no subscore greater than 1
in any individual variable, at Week 40 among subjects with endoscopic
improvement at Week 0 of Study M14-347.
Secondary outcome
For additional efficacy endpoints, the baseline is defined as the Baseline in
Study M14 115.
* Proportion of subjects with CDAI remission (CDAI < 150) over time among
subjects with CDAI remission at Week 0 of Study M14 347.
* Proportion of subjects with endoscopic improvement, defined as an SES-CD <= 4
and at least 2 point reduction versus baseline and no subscore greater than 1
in any individual variable at Week 40.
* Proportion of subjects with CDAI remission (CDAI < 150) over time.
* Proportion of subjects with CDAI < 150 at Week 40 and SES-CD <= 4 and at least
a 2 point reduction versus baseline and no subscore greater than 1 in any
individual variable at Week 40 among subjects with CDAI < 150 at Week 0 and
SES-CD <= 4 and at least a 2 point reduction versus baseline and no subscore
greater than 1 in any individual variable at Week 0 of Study M14 347.
* Proportion of subjects with CDAI < 150 at Week 40 and SES-CD <= 4 and at least
a 2 point reduction versus baseline and no subscore greater than 1 in any
individual variable at Week 40
* Proportion of subjects with endoscopic response at Week 40 among subjects
with endoscopic response at Week 0 of Study M13-740.
* Proportion of subjects with endoscopic response at Week 40.
* Change from Baseline in fecal calprotectin level over time.
* Proportion of subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 µg/g
over time among subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 µg/g
at Week 0 of Study M14-347.
* Proportion of subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 µg/g
over time.
* Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, and fecal
calprotectin < 250 µg/g over time among subjects with CDAI < 150, hs-CRP < 5
mg/L, and fecal calprotectin < 250 µg/g at Week 0 of Study M14-347
* Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, and fecal
calprotectin < 250 µg/g over time.
* Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD <= 4 and at
least 2 point reduction versus baseline and no subscore greater than 1 in any
individual variable, and fecal calprotectin < 250 µg/g at Week 40 among
subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD <= 4 and at least 2 point
reduction versus baseline and no subscore greater than 1 in any individual
variable, and fecal calprotectin < 250 µg/g at Week 0 of Study M14-347.
* Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD <= 4 and at
least 2 point reduction versus baseline and no subscore greater than 1 in any
individual variable, and fecal calprotectin < 250 µg/g at Week 40.
* Proportion of subjects with SES-CD <= 2 at Week 40 among subjects with SES-CD
<= 2 at Week 0 of Study M14-347.
* Proportion of subjects with SES-CD <= 2 at Week 40.
* Proportion of subjects with CDAI response (decrease in CDAI >= 70 points from
Baseline) over time among subjects with CDAI response at Week 0 of Study
M14-347.
* Proportion of subjects with CDAI response (decrease in CDAI >= 70 points from
Baseline) over time.
* Proportion of subjects with enhanced CDAI response (decrease in CDAI >= 100
points from Baseline) over time among subjects with enhanced CDAI response at
Week 0 of Study M14-347.
* Proportion of subjects with enhanced CDAI response (decrease in CDAI >= 100
points from Baseline) over time.
* Change in IBDQ from Baseline over time.
* Proportion of subjects who discontinue corticosteroid use at each visit among
subjects who used corticosteroids at Week 0 of Study M14-347.
* Proportion of subjects who achieve CDAI reemission and discontinue
corticosteroid use at each visit among subjects who used corticosteroids at
Week 0 of Study M14-347.
* Proportion of subjects with a SFPS remission (SFPS < 50) over time among
subjects with SFPS remission at Week 0 of Study M14 347.
* Proportion of subjects with a SFPS remission (SFPS < 50) over time.
* Time inProportion of subjects with a SFPS remission (SFPS < 50) over time
among subjects with SFPS >= 100 at Week 0 of Study M14-347.
* Proportion of subjects with SES-CD <= 3 and at least 2 point reduction versus
baseline and no subscore greater than 1 in any individual variable at Week 40
among subjects with SES-CD <= 3 and at least 2 point reduction versus baseline
and no subscore greater than 1 in any individual variable at Week 0 of Study
M14-347.
* Proportion of subjects with SES-CD <= 3 and at least 2 point reduction versus
baseline and no subscore greater than 1 in any individual variable at Week 40
* Proportion of subjects with SES-CD = 0 at Week 40 among subjects with SES-CD
= 0 at Week 0 of Study M14-347.
* Proportion of subjects with SES-CD = 0 at Week 40.
* Proportion of subjects with a decrease of SES-CD >= 3 points from Baseline of
Study M14-115 at Week 40.
* Change from Baseline in hs-CRP level over time.
* Proportion of subjects with Inflammatory Bowel Disease Questionnaire (IBDQ)
response (decrease >= 16 points from Baseline) over time among subjects with
Inflammatory Bowel Disease Questionnaire (IBDQ) response (decrease >= 16 points
from Baseline) at Week 0 of Study M14-347.
* Proportion of subjects with Inflammatory Bowel Disease Questionnaire (IBDQ)
response (decrease >= 16 points from Baseline) over time.
* Proportion of subjects with IBDQ remission (IBDQ >= 170 points) over time
among subjects with IBDQ remission (IBDQ >= 170 points) at Week 0 of Study
M14-347.
* Proportion of subjects with IBDQ remission (IBDQ >= 170 points) over time.
* Change in WPAI from Baseline over time.
* Change in European Quality of Life 5 Dimensions (EQ-5D) from Baseline over
time.
* Change in CDAI from Baseline over time.
* Change in SFPS from Baseline over time.
* Change in Abdominal Pain Rating Scale score from Baseline over time.
* Change in Bristol Stool Scale score from Baseline over time.
* Change in each CDAI component subscore (number of liquid or very soft stools,
abdominal pain rating, general well-being, CD related complications,
anti-diarrhea use, abdominal mass, hematocrit, body weight) from Baseline over
time.
* Time to first dose escalation.
* Proportion of subjects who require weekly dosing at Week 1 of Study M14 347.
* Proportion of subjects with major CD related event (e.g., hospitalization,
bowel surgery, abscess drainage).
* Proportion of subjects requiring dose escalation to weekly dosing during this
study.
* Proportion of subjects with no draining fistulas over time among subjects
with draining fistula at Baseline of Study M14-115.
* Proportion of subjects in each treatment group with > 50% reduction from
Baseline of Study M14-115 in the number of draining fistulas over time among
subjects with draining fistula at Baseline of Study M14-115.
* Resolution of extraintestinal manifestations over time.
* Proportion of subjects who achieve symptomatic remission, defined as average
daily stool frequency <= 1.5 (and not worse than baseline) and average daily
abdominal pain <= 1.0 (and not worse than baseline) over time.
* Proportion of subjects who achieve symptomatic response, defined as average
daily stool frequency at least 30% reduction from baseline and average daily
abdominal pain not worse than baseline or average daily abdominal pain at least
30% reduction and average daily stool frequency not worse than baseline, over
time.
Pharmacokinetic:
Blood samples for measurement of adalimumab concentrations will be obtained at
Weeks 0 (from Week 12 of Study M14-115), 8, 16, 24, 32, 40/PD, and unscheduled
visits if dose escalating or de escalating. AAA concentrations will be
obtained at Weeks 0, 24, 40/PD, and unscheduled visits if dose escalating or
de-escalating.
Safety:
Safety analyses will be performed on all subjects who receive at least one dose
of study drug. Incidence of adverse events (AEs), changes in vital signs,
physical examination results, and clinical laboratory data will be assessed.
Background summary
Crohn's disease (CD) encompasses a spectrum of clinical and pathological
processes manifested by focal asymmetric, transmural, and occasionally
granulomatous inflammation that can affect any segment of the gastrointestinal
tract.
Traditionally, therapy for CD has been focused on symptomatic improvement and
achievement of clinical remission as measured using the Crohn's disease
activity index (CDAI). In addition to improving symptoms, an emerging goal of
therapy is to improve the condition of the intestinal mucosa. It has been
shown that patients with endoscopic evidence of ulceration of the
gastrointestinal mucosa are at increased risk of experiencing a complicated
disease course. Therefore, it is reasonable that another goal of therapy be
improvement of the intestinal mucosal as visualized on endoscopy; as this has
been found to be associated with positive clinical benefits, including higher
rates of clinical remission, fewer hospitalizations, and fewer abdominal
surgeries.
Study M14-115 assessed the efficacy and safety of two adalimumab induction
regimens in achieving endoscopic improvement, (SES-CD <= 4 with an Ulcerated
Surface sub-score no greater than 1 in any segment) at Week 12 and clinical
remission (CDAI < 150) at Week 4 as well as the pharmacokinetics (PK) and
immunogenicity of the two adalimumab induction regimens. This study is
designed to investigate the long-term efficacy, safety, and tolerability of
repeated administration of adalimumab in adult subjects with CD who
participated and successfully completed Study M14-115.
Study objective
The primary objective of this study is to evaluate the long-term efficacy,
safety, and tolerability of repeated administration of adalimumab in subjects
with Crohn's disease (CD) who participated in and successfully completed Study
M14-115.
The secondary objective is to assess pharmacokinetics (PK) and immunogenicity
of adalimumab following subcutaneous (SC) administration.
Study design
This is an open-label extension (OLE) study which comprises a 40-week
open-label period designed to evaluate the long-term efficacy, safety, and
tolerability of adalimumab. Approximately 300 subjects with CD who
participated in and successfully completed Study M14-115 will be enrolled.
Subjects will be evaluated for entry into Study M14-347 at the final study
visit (Week 12) of Study M14-115. Subjects must meet all of the inclusion
criteria and none of the exclusion criteria to be eligible to participate in
this study. The Week 12 visit of Study M14-115 will be considered Week 0
(Baseline) of Study M14-347.
There will be a 70-day follow-up Phone call for subjects who complete the study
or discontinue from the study prematurely.
Intervention
All subjects will receive open-label adalimumab 40 mg every other week (eow)
beginning at Week 0. Subjects may be escalated to adalimumab 40 mg every week
(ew) at or after Week 2 should the subject meet the criteria for inadequate
response:
Inadequate Response =
Crohn's disease activity index (CDAI) >= 200 for two consecutive visits that are
at least fourteen (14) days apart, and at least one of the following criteria
is met: an increase of at least 1 mg/L in level of high sensitivity C reactive
protein (hs-CRP) from Baseline or a hs-CRP >= 5 mg/L. Assessment of inadequate
response should include consideration by the Investigator to rule out symptoms
caused by reasons other than Crohn's disease related inflammation.
For subjects taking corticosteroids at Baseline of Study M14-115, adalimumab
dose escalation should be considered in lieu of increases in steroid dose.
Subjects who continue to experience inadequate response on 40 mg ew who were
taking corticosteroids at Baseline may have their steroid dose increased, per
the Investigator's discretion, in order to manage the subject's symptoms. Any
subject who continues to experience inadequate response on 40 mg ew may be
discontinued from the study at the investigator's discretion after discussion
with the Study designated physician (SDP). Subjects who dose escalated to
adalimumab 40 mg ew, have one opportunity to de-escalate adalimumab dose to 40
mg eow provided the following criteria have been met: CDAI < 200, and
high-sensitivity C reactive protein (hs CRP) value equal to or lower than that
observed at the time of dose escalation. Subjects who experience inadequate
response after dose de-escalation (using the same criteria outlined above) may
again be escalated to 40 mg ew. A subject has only one opportunity to
dose-de-escalate and one opportunity to re-escalate to ew adalimumab dosing.
Study burden and risks
Extensive clinical and post marketing experience exists with adalimumab in a
wide range of disease states including
Crohn's disease and ulceralive colitis (UC). The safety profile of adalimumab
in those indications is well-established
with more than 50,000 patient-years of adalimumab clinical trial experience.
The clinical studies in adult CD have not
altered this safety profile and demonstrated a positive benefit/risk balance.
Conditions which may present a risk
s pecificallyfor patients with CD are exclusion criteria in this study (e.g.,
evidence of colonic dysplasia or active
infections ).
Knollstrasse 50
Ludwigshafen 67061
DE
Knollstrasse 50
Ludwigshafen 67061
DE
Listed location countries
Age
Inclusion criteria
1. Subject must have successfully enrolled in and completed Study M14-115, including the Week 12 ileocolonoscopy.
2. If female, subject is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy and/or hysterectomy) or is of childbearing potential and is practicing an approved method of birth control throughout the study and for 150 days after last dose of study drug. Examples of approved methods of birth control which result in a low failure rate (i.e., less than 1% per year) when used consistently are (see local informed consent for more detail):
• Implants, injectables, some intrauterine devices (IUDs), intrauterine hormone-releasing system (IUS)
• Sexual abstinence (when in line with preferred and usual lifestyle of the subject)
• A vasectomized partner
• Hormonal contraceptives for at least 90 days prior to study drug administration
Note: low-dose progestin-only oral contraceptives such as norethindrone 0.35 mg and lynestenol 0.5 mg are not considered adequate
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
3. Subject must be able and willing to give written informed consent and to comply with the requirements of this study protocol.
4. Subject must be able and willing to self-administer SC injections or have a qualified person available to administer SC injections.
Exclusion criteria
1. For any reason subject is considered by the investigator to be an unsuitable candidate.
2. Known hypersensitivity to adalimumab or its excipients.
3. Subject with an active systemic viral infection, or any active viral infection, that based on the investigator's clinical assessment makes the subject an unsuitable candidate for the study.
4. Positive pregnancy test at Baseline (Week 12 of Study M14-115).
5. Female subject who is considering becoming pregnant during the study.
6. History of malignancy other than a successfully treated non-metastatic cutaneous squamous cell, basal cell carcinoma and/or localized carcinoma in situ of the cervix. If the Week 12 (Study M14 115) colonoscopy shows evidence of dysplasia or a malignancy, subject must not be enrolled in the study.
7. Subject with a poorly controlled medical condition, such as uncontrolled diabetes, unstable ischemic heart disease, moderate or severe congestive heart failure, recent cerebrovascular accidents and any other condition which, in the opinion of the investigator or sponsor, would put the subject at risk by participation in this study.
8. Subject is not in compliance with prior and concomitant medication requirements throughout Study M14-115.
9. History of demyelinating disease (including myelitis) or neurologic symptoms suggestive of demyelinating disease.
10. History of invasive infection (e.g., listeriosis and histoplasmosis) or human immunodeficiency syndrome (HIV).
11. Subject who developed active Tuberculosis (TB) during Study M14-115, or subject who is non compliant with prophylaxis for latent TB initiated per Study M14-115 procedures.
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 | EUCTR2013-004034-15-NL |
| ClinicalTrials.gov | NCT02185014 |
| CCMO | NL49541.018.14 |