Safety and Efficacy of MMX Mesalamine/Mesalazine in Pediatric Subjects With Mild to Moderate Ulcerative Colitis (PACE)

A Phase 3, Multicenter, Randomized, Double-blind Study to Determine the Safety and Efficacy of MMX Mesalamine/Mesalazine in Pediatric Subjects With Mild to Moderate Ulcerative Colitis, in Both Acute and Maintenance Phases

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 Ulcerative Colitis (UC) or who are in remission.

Study Overview

• Status: Completed
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Drug: MMX Mesalamine/Mesalazine (Low Dose); Drug: MMX Mesalamine/Mesalazine (High Dose)

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1C9
      • University of Alberta Pediatric Gastroenterology & Nutrition
• Hungary
  • Budapest, Hungary, H-1023
    • Szent Janos Korhaz És Észak-budai Egyesitett Korha
  • Gyula, Hungary, H-5700
    • Békés Megyei Pándy Kálmán Kórház
  • Miskolc, Hungary, 3526
    • BAZ Megyei Korhaz es Egyetemi Oktatokorhaz
  • Nyiregyhaza, Hungary, 4400
    • Szabolcs-Szatmar-Bereg Megyei Korhazak es Egyetemi Oktato Korhaz
  • Szeged, Hungary, H-6720
    • Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont
• Israel
  • Be'er Sheva, Israel, 85025
    • Soroka Medical Center
  • Haifa, Israel, 31096
    • Rambam Health Corporation
  • Jerusalem, Israel, 91031
    • Shaare Zedek Medical Center
  • Petach Tikva, Israel, 49202
    • Schneider Medical Centre
• Poland
  • Bialystok, Poland, 15-247
    • Uniwersytecki Dzieciecy Szpital Kliniczny im. Ludwika Zamenhofa
  • Krakow, Poland, 30-663
    • Klinika Pediatrii Gastroenterologii I Zywienia
  • Lodz, Poland, 93-338
    • Klinika Gastroenterologii I Pediatrii
  • Olsztyn, Poland, 10-561
    • Wojewodzki Specjalistyczny Szpital Dzieciecy
  • Rzeszow, Poland, 35-302
    • Gabinet Lekarski-Bartosz Korczowski
  • Warszawa, Poland, 04-730
    • Oddzial Gastroenterologii I Hepatologii
  • Wrocław, Poland, 50-369
    • Uniwersytecki Szpital Kliniczny we Wrocławiu
• Slovakia
  • Banska Bystrica, Slovakia, 974 09
    • Detská fakultná nemocnica s poliklinikou
  • Bratislava, Slovakia, 833 40
    • University Children's Hospital
  • Martin, Slovakia, 03659
    • Univerzitná nemocnica Martin
• United Kingdom
  • Liverpool, United Kingdom, LI2 2AP
    • Alder Hey Children's Hospital
  • London, United Kingdom, SE5 9RS
    • King's College Hospital
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital
  • London, United Kingdom, E1 1BB
    • Barts Health NHS Trust, Royal London Hospital
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Children's Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Newton, Massachusetts, United States, 02462
      • Newton Wellesley Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • University of Minnesota Children's Hospital
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Gastroenterology
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
  • Texas
    • Southlake, Texas, United States, 76092
      • Texas Digestive Disease Consultants
  • Virginia
    • Roanoke, Virginia, United States, 24013
      • Carilion Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

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.
4. Body weight 18-90kg.
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 baseline visit.

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, 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).

   Double-blind Maintenance Phase:

10. Partial UC-DAI ≤1 (rectal bleeding=0, stool frequency ≤1, and PGA=0) at the Baseline Visit.

Exclusion Criteria:

1. Severe UC (defined by PGA=3).
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, Yersinia, Aeromonas, Plesiomonas, or Campylobacter). Clostridium difficile toxin, ova, or parasites present.
5. Systemic or rectal corticosteroid use within 4 weeks prior to the Screening Visit. Topical, intranasal, or inhaled use is not exclusionary.
6. Immunomodulator (6-mercaptopurine, azathioprine) use within 6 weeks prior to the Screening Visit.
7. History of biologic (eg, anti-tumor necrosis factor agents, integrin receptor antagonists) use at any time.
8. Antibiotic use within 7 days prior to the Screening Visit.
9. 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 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.
10. Prebiotic/probiotic use within 7 days prior to the Screening Visit. Yogurt products are permitted.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MMX Mesalamine/Mesalazine (Low Dose); Once daily, tablets - the amount depends on the participants weight; 900 milligram per day (mg/day) for participants weighing 18 kg to less than or equal to (<=) 23 kilograms (kg); 1200 mg/day for participants weighing greater than (>) 23 kg to <= 35 kg; 1800 mg/day for participants weighing > 35 kg to <= 50 kg; 2400 mg/day for participants weighing > 50 kg to <= 90 kg.	Drug: MMX Mesalamine/Mesalazine (Low Dose); Once daily, tablets - the amount depends on the participants weight; 900 milligram per day (mg/day) for participants weighing 18 kg to less than or equal to (<=) 23 kilograms (kg); 1200 mg/day for participants weighing greater than (>) 23 kg to <= 35 kg; 1800 mg/day for participants weighing > 35 kg to <= 50 kg; 2400 mg/day for participants weighing > 50 kg to <= 90 kg.; Other Names: Lialda; Mezavant
Experimental: MMX Mesalamine/Mesalazine (High Dose); Once daily, tablets - the amount depends on the participants weight;1800 mg/day for participants weighing 18 kg to <= 23 kg; 2400 mg/day for participants weighing > 23 kg to <= 35 kg; 3600 mg/day for participants weighing > 35 kg to <= 50 kg; 4800 mg/day for participants weighing > 50 kg to <= 90 kg.	Drug: MMX Mesalamine/Mesalazine (High Dose); Once daily, tablets - the amount depends on the participants weight;1800 mg/day for participants weighing 18 kg to <= 23 kg; 2400 mg/day for participants weighing > 23 kg to <= 35 kg; 3600 mg/day for participants weighing > 35 kg to <= 50 kg; 4800 mg/day for participants weighing > 50 kg to <= 90 kg.; Other Names: Lialda; Mezavant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Clinical Response During Double-Blind Acute Phase at Week 8	Clinical response was defined as partial ulcerative colitis disease activity index (UC-DAI) score < or =1 with rectal bleeding = 0, stool frequency < or =1, and physician's global assessment (PGA = 0). Number of participants with clinical response were reported.	Week 8
Number of Participants With Clinical Response During Double-blind Maintenance Phase at Week 26	Clinical response was defined as partial UC-DAI <=1 with (rectal bleeding = 0, stool frequency < or =1, and PGA = 0). Number of participants who had maintained clinical response were reported.	Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Clinical and Endoscopic Response During Double Blind Acute Phase at Week 8 Using Central Reading	Clinical and endoscopic response was defined as UC-DAI <=2 with rectal bleeding = 0 and stool frequency <=1, and PGA = 0, and with mucosal healing (endoscopy score <=1) at least a 1 point reduction in endoscopy score from baseline based on central reading. Participants with missing data at week 8 were assumed not to had a clinical response. Participants who completed week 8 but did not have central reading endoscopies at both baseline and week 8 were excluded. Number of participants with clinical and endoscopic response were reported.	Week 8
Number of Participants With Clinical and Endoscopic Response During Double Blind Acute Phase at Week 8 Using Local Reading	Clinical and endoscopic response was defined as UC-DAI < or =2 with rectal bleeding = 0 and stool frequency < or =1, and PGA = 0, and with mucosal healing (endoscopy score < or =1) at least a 1 point reduction in endoscopy score from baseline based on local reading. Participants with missing data at week 8 were assumed not to had a clinical response. Participants who completed week 8 but did not have local reading endoscopies at both baseline and week 8 were excluded. Number of participants with clinical and endoscopic response were reported.	Week 8
Change From Baseline in Daily Ulcerative Colitis Scale (DUCS) Score During Double-Blind Acute Phase	DUCS score was to measure 7 specific signs or symptom and one impact (abdominal pain, nocturnal stool, daytime stool, blood in stool, diarrhea, urgency, tiredness) of UC with each item score ranged from 0 (worst) to 10 (best) with the overall score ranged from 0 (worst) to 70 (best) based on the responses. Change in the DUCS score from baseline to Week 8 during DBA phase were reported.	Baseline to Week 8
Number of Participants With Improvement in Pediatric Ulcerative Colitis Activity Index (PUCAI) Score During Double-blind Acute Phase at Week 8	PUCAI was a physician-administered measure that focuses on 6 key signs and symptoms of UC and activity limitations producing a total score ranging from 0-85 with higher scores being worse. Recommended cut-off scores to differentiate disease activity are < 10 (remission); 11-30 (mild); 31-64 (moderate) and > 65 (severe). Participants with an improvement (change of greater than or equal to [> or =] 20 points) in PUCAI score. Number of participants with improvement in PUCAI score during Double-blind Acute Phase at Week 8 were reported.	Week 8
Number of Participants With Clinical and Endoscopic Response During Double-Blind Maintenance Phase at Week 26 Using Central Reading	Clinical and endoscopic response was defined as UC-DAI < or =2 with rectal bleeding=0, stool frequency < or =1, PGA=0, and with mucosal healing (endoscopy score < or =1) based on central reading at Week 26. Number of participants with clinical and endoscopic response during double-blind maintenance phase at Week 26 using central reading were reported.	Week 26
Number of Participants With Clinical and Endoscopic Response During Double-Blind Maintenance Phase at Week 26 Using Local Reading	Clinical and endoscopic response was defined as UC-DAI < or = 2 with rectal bleeding=0, stool frequency < or = 1, PGA=0, and with mucosal healing (endoscopy score < or = 1) based on local reading. Number of participants who had maintained clinical and endoscopic response during double-blind maintenance phase at week 26 using local reading were reported.	Week 26
Change From Baseline in Daily Ulcerative Colitis Scale (DUCS) Score During Double-Blind Maintenance Phase	DUCS score was to measure 7 specific signs or symptom and one impact (abdominal pain, nocturnal stool, daytime stool, blood in stool, diarrhea, urgency, tiredness) of UC with each score range from 0 (worst) to 10 (best) with the overall score ranging from 0 (worst) to 70 (best) based on the responses. Change from Baseline in DUCS score during double-blind maintenance phase at week 13 and Week 26 wwere reported.	Baseline, Week 13, and Week 26
Number of Participants With Remission at Pediatric Ulcerative Colitis Activity Index (PUCAI) Score During Double-Blind Maintenance Phase at Week 26	PUCAI was a physician-administered measure that focuses on 6 key signs and symptoms of UC and activity limitations producing a total score ranging from 0-85 with higher scores being worse. Recommended cut-off scores to differentiate disease activity are < 10 (remission); 11-30 (mild); 31-64 (moderate) and > 65 (severe). Number of participants with remission at PUCAI score during double-blind maintenance phase at week 26 were reported.	Week 26

Collaborators and Investigators

• Sponsor: Shire
• Investigators: Study Director: Shire Director, Takeda

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2014
• Primary Completion (Actual): November 28, 2018
• Study Completion (Actual): November 28, 2018

Study Registration Dates

• First Submitted: March 17, 2014
• First Submitted That Met QC Criteria: March 19, 2014
• First Posted (Estimate): March 21, 2014

Study Record Updates

• Last Update Posted (Actual): June 9, 2021
• Last Update Submitted That Met QC Criteria: May 25, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Moderate; Mild
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Mesalamine
• Other Study ID Numbers: SPD476-319; 2013-001744-65 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)