| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mild to Moderate Ulcerative Colitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Inflammatory Disease of the colon and rectrum. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 Duoble-blind Maintenance Phase of the study is to assess clinical response to MMX between a low and high dose in cihldren and adolescents aged 5-17 years who are in remission. |
|
| E.2.2 | Secondary objectives of the trial |
| Double-blind Acute Phase:Assess clinical&endoscopic response to treatment with MMX between low&high dose in children&adolescents 5-17yrs with mild-moderateUC,changes in DUCS for children&caregivers between low&high dose of MMX in children&adolescents 5-17yrs with mild-moderateUC,improvement in PUCAI score between low&high dose of MMX in children&adolescents 5-17yrs with mild-moderate UC.Double-blind Maintenance Phase:Assess clinical&endoscopic response to treatment with MMX between low&high dose in children&adolescents 5-17yrs who arein remission,changes in DUCS for children&caregivers between low&high dose of MMX in children&adolescents 5-17yrs who are in remission,remission using the PUCAI score between low&high dose of MMX in children&adolescents 5-17yrs who are in remission.Safety: Evaluate the safety&tolerability of low&high dose of MMX in children&adolescents 5-17yrs with mild-moderateUC, in the Doubleblind Acute Phase, the Open-label Acute Phase&the Doubleblind Maintenance Phase |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Ability to voluntarily provide written, signed, and dated (personally or via a 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 18-90kg 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.
Double-blind Acute Phase:
8. Partial UC-DAI score ≥2 (a combined rectal bleeding and stool frequency score ≥1 and
PGA=1 or 2) at the Baseline Visit (Visit 2), for which 5-ASA would be used as part of
normal treatment.
9. If the subject is on 5-ASA treatment prior to study entry, then the dose must be stable.
Stable therapy is defined as no change in dose, or no initiation of 5-ASA, from the onset
of the current acute flare through discontinuation of therapy (required at the Baseline
Visit; Visit 2). See exclusion criterion 29 for an additional 5-ASA dose-related
requirement.
Double-blind Maintenance Phase:
10. Partial UC-DAI ≤1 (rectal bleeding=0, stool frequency ≤1, and PGA=0) at the Baseline
Visit (Visit 2). |
|
| E.4 | Principal exclusion criteria |
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.
Immunomodulator (eg, 6-mercaptopurine, azathioprine) use within 6 weeks prior to the
Screening Visit (Visit 1).
13. History of biologic (eg, anti-tumor 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 5-ASA treatment but including
non-steroidal anti-inflammatory drugs such as aspirin, COX-2 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 anti-diarrheals and/or anti-spasmodics 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 affect 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].) See Section 5 (Prior and Concomitant Treatment) for a list of
prohibited and restricted medications.
25. Known or suspected intolerance or hypersensitivity to the investigational product(s)
(aminosalicylates eg, 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.
Double-blind 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 5-ASA 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 5-ASA for the flare. There is no limit to the onset of flare prior to the Baseline
Visit (Visit 2) if the flare is untreated.
Double-blind 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). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints for this study are defined separately for both the Double-blind Acute
Phase and Double-blind Maintenance Phases and will be conducted using the appropriate
Safety Analysis Set for the Phase:
9.8.1.1 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.
Subjects with missing data at Week 8 will be assumed not to have had a clinical response.
The primary efficacy endpoint will be compared between treatment arms using a continuity
corrected chi-squared test on the Double-blind Acute Phase Safety Analysis Set. The null hypothesis to be tested is that there is no difference in the proportion of subjects with a
clinical response at Week 8 between low and high doses of MMX mesalamine/mesalazine.
9.8.1.2 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.
Subjects with missing data at Week 26 will be assumed not to have had a clinical response.
The primary efficacy endpoint will be compared between treatment arms using a CMH test
stratifying for 3 levels of responder status at Week 26 of the Double-blind Maintenance Phase
(entered Maintenance Phase directly, responder at Week 8 of the Double-blind Acute Phase,
or responder at Week 8 of the Open-label Acute Phase) on the Double-blind Maintenance
Phase Safety Analysis Set. The null hypothesis to be tested is that there is no difference in the
proportion of subjects with a clinical response at Week 26 between low and high doses of
MMX mesalamine/mesalazine. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Double blind Acute Phase week 8
Double Blind miantenance Phase week 26 |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints for this study are defined separately for both the Double-blind Acute
and Double-blind Maintenance Phases and will be conducted using the appropriate Safety
Analysis Set for the Phase. These endpoints will be described using appropriate summary
statistics (n [%]) for categorical variables, n, mean, standard deviation, median, minimum and
maximum for continuous variables).
9.8.3.1 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Double blind Acute Phase week 8
Double Blind miantenance Phase week 26 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Hungary |
| Israel |
| Netherlands |
| Poland |
| Slovakia |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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