Primary: The primary objective of the Double-blind Acute Phase of the study is to assess clinical response to MMX mesalamine/mesalazine between a low and high dose in children and adolescents aged 5-17 years with mild to moderate UC.The primary…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoints
Double-blind Acute Phase:
The primary efficacy endpoint for the Double-blind Acute Phase is defined as
the proportion of subjects with a clinical response (defined as partial UC-DAI
<=1 with rectal bleeding=0, stool frequency <=1, and PGA=0) at Week 8. This
endpoint will be compared between treatment arms using a chi-squared test.
Double-blind Maintenance Phase:
The primary efficacy endpoint for the Double-blind Maintenance Phase is defined
as the proportion of subjects who have maintained a clinical response (defined
as partial UC-DAI <=1 with rectal bleeding=0, stool frequency <=1, and PGA=0) at
Week 26. This endpoint will be compared between treatment arms using a
Cochran-Mantel-Haenszel (CMH) test stratifying by Week 8 responder status.
Secondary outcome
Secondary Efficacy Endpoints
Double-blind Acute Phase:
• The proportion of subjects with a clinical and endoscopic response at Week 8,
defined as UC-DAI <=2 with rectal bleeding=0, stool frequency <=1, PGA=0, and
mucosal healing (endoscopy score <=1) based on central reading. In addition,
there must be at least a 1-point reduction in endoscopy score from baseline.
This endpoint will be compared between treatment arms using a chi-squared test.
• The proportion of subjects with a clinical and endoscopic response at Week 8,
defined as UC-DAI <=2 with rectal bleeding=0, stool frequency <=1, PGA=0, and
mucosal healing (endoscopy score <=1) based on local reading. In addition,
there must be at least a 1 point reduction in endoscopy score from baseline.
This endpoint will be compared between treatment arms using a chi-squared test.
• The change in the DUCS score from baseline to Week 8 of the Double-blind
Acute Phase. This endpoint will be compared between treatment arms using an
analysis of covariance, including the baseline DUCS score as a covariate in the
model.
• The percentage of subjects with an improvement (change of >=20 points) in
PUCAI score from baseline to Week 8 of the Double-blind Acute Phase. This
endpoint will be compared between treatment arms using a chi-squared test.
Double-blind Maintenance Phase:
• The proportion of subjects who have maintained a clinical and endoscopic
response at Week 26, defined as UC-DAI <=2 with rectal bleeding=0, stool
frequency <=1, PGA=0, and mucosal healing (endoscopy score <=1) based on central
reading. This endpoint will be compared between treatment arms using a CMH
test stratifying by Week 8 responder status.
• The proportion of subjects who have maintained a clinical and endoscopic
response at Week 26, defined as UC-DAI <=2 with rectal bleeding=0, stool
frequency <=1, PGA=0, and mucosal healing (endoscopy score <=1) based on local
reading. This endpoint will be compared between treatment arms using a CMH
test stratifying by Week 8 responder status.
• The change in the DUCS score from Double-blind Maintenance Phase Week 0 to
Week 26. This endpoint will be compared between treatment arms using an
analysis of covariance , including the DUCS score at Double-blind Maintenance
Phase Week 0 and Week 8 responder status as covariates in the model.
• The percentage of subjects in remission (PUCAI <10) at Double-blind
Maintenance Phase Week 26. This endpoint will be compared between treatment
arms using a CMH test stratifying by Week 8 responder status.
Safety Endpoints
Adverse Events (AEs) will be coded using MedDRA. Treatment-emergent AEs
(TEAEs) will be defined in the SAP. The number of events, incidence, and
percentage of TEAEs will be presented by treatment arm (ie, low or high dose),
and overall, by system organ class, and by preferred term. Treatment emergent
adverse events will be further summarized by treatment arm for severity and
relationship to investigational product. TEAEs related to investigational
product, TEAEs leading to withdrawal, serious adverse events, and deaths will
be summarized by treatment arm. Clinical laboratory tests and vital signs, and
their changes from baseline will be summarized by treatment arm and visit.
Exploratory Efficacy Endpoints:
· The change in fecal calprotectin from baseline to Week 8 in the Double-blind
Acute Phase.
· The change in fecal calprotectin from Double-blind Maintenance Phase Week 0
to Week 26 in the Double-blind Maintenance Phase.
Background summary
Ulcerative colitis is a serious chronic inflammatory disease of the colon and
rectum. The major clinical feature is bloody diarrhea. While an acute attack
can occasionally be fatal, the characteristic course for most patients is one
of remissions and exacerbations over a number of years. Life expectancy after
recovery from a first attack is unchanged; however, morbidity can be long
lasting and may be associated with various extra-intestinal and late
complications.
MMX mesalamine/mesalazine is approved for both the induction of remission in
adult patients with mild to moderate UC and for maintenance of remission of
UC. No data are available on the use of MMX mesalamine/mesalazine in children
and adolescents. Since most information pertaining to the use of 5-ASA is
based upon adult studies, Shire proposes to evaluate the effect of MMX
mesalamine/mesalazine in children and adolescents aged 5-17 years with mild to
moderate UC or who are in remission.
Commercially available MMX mesalamine/mesalazine is a novel, high-strength
formulation of 5-ASA (1.2g of mesalamine/mesalazine per tablet), which uses MMX
technology designed to release 5-ASA throughout the colon. For the purpose of
this study, 2 pediatric formulations (300mg and 600mg tablets) were developed,
which are smaller than the commercially available product.
This study is a PREA post-approval commitment with the US FDA.
Study objective
Primary:
The primary objective of the Double-blind Acute Phase of the study is to assess
clinical response to MMX mesalamine/mesalazine between a low and high dose in
children and adolescents aged 5-17 years with mild to moderate UC.
The primary objective of the Double-blind Maintenance Phase of the study is to
assess clinical response to MMX mesalamine/mesalazine between a low and high
dose in children and adolescents aged 5-17 years who are in remission.
Secondary:
Double-blind Acute Phase
• To assess clinical and endoscopic response to treatment with MMX
mesalamine/mesalazine between a low and high dose in children and adolescents
aged 5-17 years with mild to moderate UC in the Double blind Acute Phase
• To assess changes in the Daily Ulcerative Colitis Scale (DUCS) for children
and caregivers between a low and high dose of MMX mesalamine/mesalazine in
children and adolescents aged 5-17 years with mild to moderate UC in the
Double-blind Acute Phase
• To assess improvement in Pediatric Ulcerative Colitis Activity Index (PUCAI)
score between a low and high dose of MMX mesalamine/mesalazine in children and
adolescents aged 5-17 years with mild to moderate UC in the Double-blind Acute
Phase
Double-blind Maintenance Phase
• To assess clinical and endoscopic response to treatment with MMX
mesalamine/mesalazine between a low and high dose in children and adolescents
aged 5-17 years who are in remission in the Double blind Maintenance Phase
• To assess changes in the DUCS for children and caregivers between a low and
high dose of MMX mesalamine/mesalazine in children and adolescents aged 5-17
years who are in remission in the Double-blind Maintenance Phase
• To assess remission using the PUCAI score between a low and high dose of MMX
mesalamine/mesalazine in children and adolescents aged 5-17 years who are in
remission in the Double-blind Maintenance Phase
Safety
To evaluate the safety and tolerability of a low and high dose MMX
mesalamine/mesalazine in children and adolescents aged 5-17 years with mild to
moderate UC, in the Double blind Acute Phase, the Open label Acute Phase, and
the Double blind Maintenance Phase.
Exploratory Objectives:
To assess changes in fecal calprotectin in subjects between a low and high dose
of MMX mesalamine/mesalazine in both the Double-blind Acute and Double-blind
Maintenance Phases.
Study design
This is a prospective study with an 8-week Double-blind Acute Phase, and a
26-week Double-blind Maintenance Phase. Each phase includes 2 arms, and
subjects will be randomized to 1 of 2 doses (low or high) of MMX
mesalamine/mesalazine (900-4800mg/day, given once daily) at the beginning of
each phase. Randomization will be in a 1:1 ratio stratified by body weight
group. There is an additional 8-week, Open-label Acute Phase for subjects who
do not achieve a clinical response or who have withdrawn from the Double-blind
Acute Phase after a minimum of 2 weeks and, in the investigator*s opinion, have
not benefited from treatment in the Double-blind Acute Phase. Clinical
response is defined as partial UC DAI <=1 (rectal bleeding=0, stool frequency
<=1, and PGA=0) at the end of the Double-blind Acute Phase. In this Open-label
Acute Phase, subjects are treated with the high dose of MMX
mesalamine/mesalazine for their weight group.
At the Baseline Visit (Visit 2):
• Subjects with partial Ulcerative Colitis Disease Activity Index (UC-DAI) >=2
(a combined rectal bleeding and stool frequency score >=1 and PGA=1 or 2) will
be randomized into the Double-blind Acute Phase.
• Subjects with partial UC-DAI <=1 (rectal bleeding=0, stool frequency <=1, and
PGA=0) will be randomized into the Double-blind Maintenance Phase.
Subjects with a clinical response after completion of treatment in either the
Double-blind Acute Phase or the Open-label Acute Phase will be eligible to
enter the Double-blind Maintenance Phase.
Subjects without a clinical response after completion of acute treatment in the
Open-label Acute Phase must be withdrawn.
All subjects will have a Screening Visit (Visit 1), and screened subjects who
are eligible will proceed to the Baseline Visit (Visit 2). Study visits occur
at the following time points after the Baseline Visit (Visit 2), dependent on
the subject*s partial UC-DAI score:
Double-blind Acute Phase: Week 2, Week 4, Week 8 (Double-blind Acute Phase
Withdrawal)
Open-label Acute Phase: Week 2, Week 4, Week 8 (Open-label Acute Phase
Withdrawal)
Double-blind Maintenance Phase: Weeks 2-4 (investigational product
dispensation only), Week 13, Week 26 (Double-blind Maintenance Phase
Withdrawal)
Intervention
MMX mesalamine/mesalazine, administered orally, randomized in a 1:1 ratio
stratified by body weight group to the following doses:
900mg/day or 1800mg/day for subjects weighing 18 to <= 23kg
1200mg/day or 2400mg/day for subjects weighing >23 to <= 35kg
1800mg/day or 3600mg/day for subjects weighing >35 to <= 50kg
2400mg/day or 4800mg/day for subjects weighing >50 to <= 90kg
MMX mesalamine/mesalazine tablet strengths 300, 600, and 1200mg with matching
placebos to maintain the blind between low and high dose groups
Study burden and risks
See question E9.
It is possible that some of the topics in the questionnaires may be sensitive
or embarrassing. The investigators will ensure that the consultations take
place in a private environment and will make every effort to make the trial
subject/parent/caregiver as relaxed and comfortable as possible.
What is the potential for benefit to trial subjects?
There is no guaranteed benefit to the trial subjects from taking part in this
study. If treatment works it may help to control the disease. The investigator
will assess the balance of risks and benefits of continuing to participate in
the study. Even if the research participants do not benefit personally from the
study, the information gained may facilitate the development of better
treatment for other (pediatric) patients with Ulcerative Colitis.
At the end of the study, the lower doses (300 and 600mg) IMP will not be
available to patients. The 1200mg tablets are commercially available. The
investigator will discuss alternative treatment options with the
subject/parents/caregivers for subject's future care.
Shire Way 300
Lexington 02421
US
Shire Way 300
Lexington 02421
US
Listed location countries
Age
Inclusion criteria
General:
1. Ability to voluntarily provide written, signed, and dated (personally or via a legally authorized representative [LAR]) informed consent or assent as applicable to participate in the study.
2. Subject*s parent/LAR demonstrates an understanding, ability, and willingness to fully comply with study procedures and restrictions.
3. Male and female children and adolescents aged 5-17 years, inclusive, at the Baseline Visit (Visit 2).
4. Body weight 18-90 kg at the Screening Visit (Visit 1) and the Baseline Visit (Visit 2).
5. Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive requirements of the protocol or females of non-childbearing potential.
6. Diagnosed with mild to moderate UC, established by sigmoidoscopy or colonoscopy with compatible histology. Screened subjects may also have an unconfirmed diagnosis of mild to moderate UC* however the diagnosis of mild to moderate UC must have been established by sigmoidoscopy or colonoscopy with compatible histology prior to the Baseline Visit (Visit 2).
7. Subject is able to swallow the investigational product whole.
Doubleblind Acute Phase:
8. Partial UCDAI
score >=2 (a combined rectal bleeding and stool frequency score >=1 and PGA=1 or 2) at the Baseline Visit (Visit 2), for which 5ASA would be used as part of normal treatment.
9. If the subject is on 5ASA treatment prior to study entry, then the dose must be stable. Stable therapy is defined as no change in dose, or no initiation of 5ASA, from the onset of the current acute flare through discontinuation of therapy (required at the Baseline Visit [Visit 2]). Please see exclusion criterion 29 for an additional 5ASA dose related requirement.
Doubleblind Maintenance Phase:
10. Partial UCDAI <=1 (rectal bleeding=0, stool frequency <=1 and PGA=0) at the Baseline Visit (Visit 2).
Exclusion criteria
General:
1. Severe UC (defined by PGA=3) at the Baseline Visit (Visit 2).
2. Crohn*s disease, bleeding disorders, active peptic ulcer disease, or UC known to be confined to the rectum
(isolated rectal proctitis).
3. Asthma, only if known to be 5 ASA sensitive.
4. Positive stool culture for enteric pathogens (including Salmonella, Shigella, Yersina, Aeromonas, Plesiomonas, or
Campylobacter). Clostridium difficile toxin, ova, or parasites present.
5. Previous colonic surgery.
6. Any history of hepatic impairment, in the opinion of the investigator.
7. Moderate to severe renal impairment, in the opinion of the investigator
8. Immediate or significant risk of toxic megacolon, in the opinion of the investigator.
9. History of pancreatitis.
10. History of Reyes syndrome.
11. Systemic or rectal corticosteroid use within 4 weeks prior to the Screening Visit (Visit 1).
Topical, intranasal, or inhaled use is not exclusionary.
12. Immunomodulator (6mercaptopurine, azathioprine) use within 6 weeks prior to the Screening
Visit (Visit 1).
13. History of biologic (e.g., antitumor necrosis factor agents, integrin receptor antagonists) use at
any time.
14. Antibiotic use within 7 days prior to the Screening Visit (Visit 1).
15. Any anti-inflammatory drugs, not including 5ASA treatment but including non-steroidal
anti-inflammatory drugs such as aspirin, COX2 inhibitors or ibuprofen, within 7 days prior to
the Screening Visit (Visit 1) unless used at over-the-counter levels for <3 days. However,
prophylactic use of a stable dose of aspirin up to 325mg/day for cardiac
disease is permitted.
16. Prebiotic/probiotic use within 7 days prior to the Screening Visit (Visit 1). Yogurt products are
permitted.
17. Oral anticoagulant use (with the exception of subjects who have been on a stable dose of Vitamin K antagonists such as warfarin for at least 90 days prior to the Screening Visit [Visit 1] and who are medically stable).
18. Treatment with antidiarrheals and/or antispasmodics within 3 days prior to the Screening Visit (Visit 1).
19. Vaccination/immunization within 14 days prior to the Screening Visit (Visit 1).
20. Predisposed to the development of myo- or pericarditis.
21. Previously been screened or randomized into this study and withdrawn.
22. Current or recurrent disease that could affect the action, absorption, or disposition of the investigational product, or could effect clinical or laboratory assessments.
23. Current or relevant history of physical or psychiatric illness, any medical disorder that may require treatment, including surgery, or make the subject unlikely to fully complete the study, or any condition that presents undue risk from the investigational product or procedures.
24. Current use of any medication (including over-the-counter, herbal, or homeopathic preparations) that could affect (improve or worsen) the condition being studied, or could affect the action, absorption, or disposition of the investigational product(s), or clinical or laboratory assessment. (Current use is defined as use within 14 days of the Screening Visit [Visit 1].)
25. Known or suspected intolerance or hypersensitivity to the investigational product(s) (aminosalicylates [5 ASA]), closely related compounds (including but not limited to salicylates), or any of the stated ingredients.
26. Known history of alcohol or other substance abuse within the last year.
27. Within 30 days prior to the first dose of investigational product:
Have used an investigational product
Have been enrolled in a clinical study (including vaccine studies) that, in the investigator*s opinion, may impact this study.
Doubleblind Acute Phase:
28. Normal mucosal appearance (defined by endoscopic score=0) based on central reading or local reading (if central reading is not available) at the Screening Visit (Visit 1) or Baseline Visit (Visit 2).
29. Current relapse on a 5ASA dose higher than the low dose tested in the study (900mg for subjects weighing 18 to 23kg, 1200mg for subjects weighing >23 to 35kg, 1800mg for subjects weighing >35 to 50kg, and 2400mg for subjects weighing >50 to 90kg).
30. Acute flare with onset >6 weeks prior to the Baseline Visit (Visit 2) if being treated with 5ASA
for the flare. There is no limit to the onset of flare prior to the Baseline Visit (Visit 2) if the flare is untreated.
Doubleblind Maintenance Phase:
31. Mucosal appearance (endoscopic score)=2 or 3 based on central reading or local reading (if central reading is not available) at the Screening Visit (Visit 1) or Baseline Visit (Visit 2).;Re-randomization: Subjects with a clinical response i.e., partial UC-DAI <= 1 (rectal bleeding=0, stool frequency <=1, and PGA=0) after completion of treatment in either the Double-blind or the Open-label Acute Phases will be eligible for re-randomization into the Double-blind Maintenance
Phase provided they still meet all Baseline (Visit 2) inclusion and exclusion criteria (where re-assessed). Subjects may be re-randomized into the Double-blind Maintenance Phase if they turned 18 during participation in either Acute Phase of the study.
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 |
|---|---|
| Other | NCT02093663 |
| EudraCT | EUCTR2013-001744-65-NL |
| CCMO | NL48356.078.14 |