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Low Dose Oral Methotrexate in Pediatric Crohn's Disease Patients Initiating Anti-Tumor Necrosis Factor (Anti-TNF) Therapy (COMBINE)

Primary Purpose

Pediatric Crohn's Disease

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Methotrexate
Sugar pill (placebo)
Sponsored by
University of North Carolina, Chapel Hill
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pediatric Crohn's Disease

Eligibility Criteria

undefined - 20 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Pediatric Crohn's Disease (PCD) patients, < 21 years of age, ≥20 kg, initiating anti-TNF therapy with infliximab or adalimumab (including biosimilars).
  • Diagnosis of Crohn's Disease (CD) established confirmed by the treating clinician, and established by standard clinical criteria (radiography, endoscopy, histology).
  • Ability to provide parental permission and child assent (where applicable), or adult consent for patients ages 18-20.

Exclusion Criteria:

  • Prior use of anti-TNF or other biological therapy for CD
  • Lack of stable home address that study medications can be mailed to
  • Anticipated short length of follow up at study center (plans for family to move, transition to adult GI (gastrointestinal) provider, etc.). Patients expected to leave practice < 12 months from enrollment should not be enrolled.
  • Concurrent pelvic or abdominal abscess. A recent history of abdominal or pelvic abscess, which is controlled, does not exclude the subject.
  • Prior intra-abdominal surgery without a clinically significant relapse (i.e. patients starting on anti-TNF for post-op prophylaxis or for endoscopic recurrence only should not be included)
  • Receipt of a live virus vaccine within the last 30 days
  • Pregnancy, planning to become pregnant, or high risk of pregnancy as determined by the local investigator
  • Breastfeeding
  • Refusal to stay abstinent or utilize 2 forms of birth control while on study medication (for female patients)
  • BMI > 98% for gender and age
  • Known previous or concurrent malignancy (other than that considered surgically cured, with no evidence for recurrence for 5 years). A recent history of basal cell or squamous cell carcinoma, which is considered surgically cured, does not exclude the subject.Those with a recent history of colonic adenoma or dysplastic lesions should be excluded.
  • Known high alcohol consumption (more than seven drinks per week)
  • Patients with serum albumin < 2.5 g/dl
  • Patients with white blood cell count (WBC) < 3.0 x109th/L
  • Patients with platelet count < 100 x109th/L
  • Patients with initial elevation of liver enzymes (AST or ALT) > 1.5 times above normal limit
  • Patients with known active infection with Clostridium difficile (C. difficile) (untreated infection based on clinician assessment does not apply to colonization or infection controlled with current or prior treatment.)
  • Patients with pre-existing hepatic disease
  • Patients with pre-existing renal dysfunction (creatinine > 0.8 for children age<10, creatinine > 1.2 mg/dl for children age 10-18, and creatinine > 1.5 mg/dl for adults age 18 years and older).
  • Patients with a pre-existing chronic lung disease other than well controlled asthma
  • Current treatment with one of the following drugs: Probenecid (Probalan), Acitretin (Soriatane), Streptozocin (Zanosar), Azathioprine (Imuran, Azasan), 6-mercaptopurine (Purinethol, Purixan)
  • Other concerns about the patient/family's ability to participate in the study

Sites / Locations

  • Children's of Alabama
  • Stanford Children's Health
  • Yale-New Haven Children's Hospital
  • Nemours Children's Health System - Wilmington
  • Nemours Children's Health System - Jacksonville
  • Nicklaus Children's Hospital
  • Nemours Children's Health System - Orlando
  • Children's Healthcare of Atlanta at Egleston/Emory University
  • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Riley Hospital for Children
  • University of Iowa Children's Hospital
  • MassGeneral Hospital for Children
  • Boston Children's Hospital
  • University of Michigan | CS Mott Children's Hospital
  • Children's Mercy Hospital
  • Cardinal Glennon Children's Medical Center
  • St. Louis Children's Hospital | Washington University
  • Children's Hospital and Medical Center Omaha
  • Mount Sinai Kravis Children's Hospital
  • Upstate Golisano Children's Hospital
  • University of North Carolina at Chapel Hill
  • Levine Children's Hospital
  • Cincinnati Children's Hospital Medical Center
  • Rainbow Babies & Children's Hospital
  • Nationwide Children's Hospital
  • Dayton Children's Hospital
  • Oklahoma University Medical Center
  • Monroe Carell Jr. Children's Hospital at Vanderbilt
  • The University of Vermont Children's Hospital
  • Pediatric Specialists of Virginia
  • Children's Hospital of The King's Daughters
  • Children's Hospital of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Methotrexate

Sugar pill (placebo)

Arm Description

Methotrexate (10, 12.5, or 15 mg), once weekly. Weight-based dosing. Ondansetron (4 mg), twice weekly, 1 hour prior to methotrexate dose and the morning after methotrexate dose. Folic Acid (1 mg) daily

Placebo for methotrexate, once weekly. Placebo for ondansetron, twice weekly, 1 hour prior to methotrexate placebo dose and the morning after methotrexate placebo dose. Folic Acid (1 mg) daily

Outcomes

Primary Outcome Measures

Percent of Participants Experiencing Treatment Failure
Treatment failure is defined as follows: Failure to achieve remission (short pediatric Crohn's disease activity index [SPCDAI] < 15) by the week 26 visit; If study initiated on steroids, failure to complete steroid taper by week 16; Short pediatric Crohn's disease activity index (SPCDAI) ≥ 15 attributed to active Crohn's disease, at two or more consecutive visits beyond the week 26 visit. Elevated SPCDAI (≥ 15) due to a non-Inflammatory Bowel Disease (IBD) reason does not count toward this outcome; Hospitalization for active Inflammatory Bowel Disease or abdominal surgery after week 25; Use of oral prednisone or prednisolone, enteral release budesonide, or intravenous (IV) methylprednisolone for over 10 weeks cumulatively, beyond week 16; Discontinuation of anti-TNF agent and/or study drug for lack of effectiveness or toxicity.

Secondary Outcome Measures

Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-52 Weeks
T-scores are a continuous variable. The mean in the general population is 50 (SD=10). Scores above 50 represent higher than average pain interference and scores below 50 represent lower than average pain interference. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6. The investigators will compare the mean of PROMIS Pain Interference T-scores at week 52 between the treatment groups.
Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-week 104
T-scores are a continuous variable. The mean in the general population is 50 (SD=10). Scores above 50 represent higher than average pain interference and scores below 50 represent lower than average pain interference. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6. The investigators will compare the mean of PROMIS Pain Interference T-scores at week 104 between the treatment groups
Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 52
T-scores are a continuous variable. The mean in the general population is 50 (SD=10). Scores above 50 represent higher than average fatigue and scores below 50 represent lower than average fatigue. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6. The investigators will compare the mean of PROMIS Fatigue T-scores at week 52 between the treatment groups
Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 104
T-scores are a continuous variable. The mean in the general population is 50 (SD=10). Scores above 50 represent higher than average fatigue and scores below 50 represent lower than average fatigue. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6. The investigators will compare the mean of PROMIS Fatigue T-scores at week 104 between the treatment groups
Percent of Patients With Positive Anti-TNF Antibody
Percent of patients with positive anti-TNF antibody will be compared between the two treatment groups using the chi-squared test.

Full Information

First Posted
April 27, 2016
Last Updated
April 10, 2023
Sponsor
University of North Carolina, Chapel Hill
Collaborators
Patient-Centered Outcomes Research Institute, ImproveCareNow (ICN), The Leona M. and Harry B. Helmsley Charitable Trust, Children's Hospital Medical Center, Cincinnati, Grifols Diagnostics Solutions, Inc, National Institutes of Health (NIH), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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1. Study Identification

Unique Protocol Identification Number
NCT02772965
Brief Title
Low Dose Oral Methotrexate in Pediatric Crohn's Disease Patients Initiating Anti-Tumor Necrosis Factor (Anti-TNF) Therapy
Acronym
COMBINE
Official Title
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Pragmatic Clinical Trial To Evaluate The Effectiveness Of Low Dose Oral Methotrexate In Patients With Pediatric Crohn's Disease Initiating Anti-TNF Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
October 2016 (undefined)
Primary Completion Date
April 7, 2022 (Actual)
Study Completion Date
April 7, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of North Carolina, Chapel Hill
Collaborators
Patient-Centered Outcomes Research Institute, ImproveCareNow (ICN), The Leona M. and Harry B. Helmsley Charitable Trust, Children's Hospital Medical Center, Cincinnati, Grifols Diagnostics Solutions, Inc, National Institutes of Health (NIH), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to determine whether adding low dose methotrexate to anti -TNF therapy is more effective than treatment with anti-TNF therapy alone in inducing and maintaining steroid-free remission for children with Crohn's Disease.
Detailed Description
Overall study duration: 6 years Multi-center study: up to 42 centers Number of subjects: 425 Duration of treatment for each subject: up to 156 weeks (3 years) The primary endpoint is percent of patients who experienced treatment failure over time.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pediatric Crohn's Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
306 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Methotrexate
Arm Type
Experimental
Arm Description
Methotrexate (10, 12.5, or 15 mg), once weekly. Weight-based dosing. Ondansetron (4 mg), twice weekly, 1 hour prior to methotrexate dose and the morning after methotrexate dose. Folic Acid (1 mg) daily
Arm Title
Sugar pill (placebo)
Arm Type
Placebo Comparator
Arm Description
Placebo for methotrexate, once weekly. Placebo for ondansetron, twice weekly, 1 hour prior to methotrexate placebo dose and the morning after methotrexate placebo dose. Folic Acid (1 mg) daily
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
Methotrexate Sodium
Intervention Description
Oral methotrexate (MTX): The weekly dose will be 15 mg for children ≥ 40kg, 12.5 mg for children 30 to <40 kg, and 10 mg for children 20 to <30 kg. A twice per week, 4mg dose of ondansetron will be provided as pre-treatment to prevent nausea (study provider may opt-out of this component based on clinical judgement). A 1 mg dose of folic acid per day will be provided. This will help to reduce the risk of side effects in the MTX group. Drug kits will contain a 3 month supply of each medication. Refills will be provided every 3 months until week 156 unless there is a failure to induce and maintain remission, development of unacceptable toxicity, pregnancy in a female participant, or failure of the participant to attend scheduled study visits.
Intervention Type
Other
Intervention Name(s)
Sugar pill (placebo)
Intervention Description
Placebo for methotrexate: The weekly dose will mimic that of methotrexate. Placebo for ondansetron: The weekly dose will mimic that of ondansetron (study provider may opt-out of this component based on clinical judgement). A 1 mg dose of folic acid per day will be provided to maintain blinding. Drug kits will contain a 3 month supply of each medication. Refills will be provided every 3 months until week 156 unless there is a failure to induce and maintain remission, development of unacceptable toxicity, pregnancy in a female participant, or failure of the participant to attend scheduled study visits.
Primary Outcome Measure Information:
Title
Percent of Participants Experiencing Treatment Failure
Description
Treatment failure is defined as follows: Failure to achieve remission (short pediatric Crohn's disease activity index [SPCDAI] < 15) by the week 26 visit; If study initiated on steroids, failure to complete steroid taper by week 16; Short pediatric Crohn's disease activity index (SPCDAI) ≥ 15 attributed to active Crohn's disease, at two or more consecutive visits beyond the week 26 visit. Elevated SPCDAI (≥ 15) due to a non-Inflammatory Bowel Disease (IBD) reason does not count toward this outcome; Hospitalization for active Inflammatory Bowel Disease or abdominal surgery after week 25; Use of oral prednisone or prednisolone, enteral release budesonide, or intravenous (IV) methylprednisolone for over 10 weeks cumulatively, beyond week 16; Discontinuation of anti-TNF agent and/or study drug for lack of effectiveness or toxicity.
Time Frame
From randomization until treatment failure, assessed up to 3 years.
Secondary Outcome Measure Information:
Title
Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-52 Weeks
Description
T-scores are a continuous variable. The mean in the general population is 50 (SD=10). Scores above 50 represent higher than average pain interference and scores below 50 represent lower than average pain interference. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6. The investigators will compare the mean of PROMIS Pain Interference T-scores at week 52 between the treatment groups.
Time Frame
Weeks 52 from randomization
Title
Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-week 104
Description
T-scores are a continuous variable. The mean in the general population is 50 (SD=10). Scores above 50 represent higher than average pain interference and scores below 50 represent lower than average pain interference. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6. The investigators will compare the mean of PROMIS Pain Interference T-scores at week 104 between the treatment groups
Time Frame
104 weeks from randomization
Title
Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 52
Description
T-scores are a continuous variable. The mean in the general population is 50 (SD=10). Scores above 50 represent higher than average fatigue and scores below 50 represent lower than average fatigue. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6. The investigators will compare the mean of PROMIS Fatigue T-scores at week 52 between the treatment groups
Time Frame
Week 52 from randomization
Title
Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 104
Description
T-scores are a continuous variable. The mean in the general population is 50 (SD=10). Scores above 50 represent higher than average fatigue and scores below 50 represent lower than average fatigue. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6. The investigators will compare the mean of PROMIS Fatigue T-scores at week 104 between the treatment groups
Time Frame
104 weeks from randomization
Title
Percent of Patients With Positive Anti-TNF Antibody
Description
Percent of patients with positive anti-TNF antibody will be compared between the two treatment groups using the chi-squared test.
Time Frame
Between 6 months and 2 years from randomization

10. Eligibility

Sex
All
Maximum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Pediatric Crohn's Disease (PCD) patients, < 21 years of age, ≥20 kg, initiating anti-TNF therapy with infliximab or adalimumab (including biosimilars). Diagnosis of Crohn's Disease (CD) established confirmed by the treating clinician, and established by standard clinical criteria (radiography, endoscopy, histology). Ability to provide parental permission and child assent (where applicable), or adult consent for patients ages 18-20. Exclusion Criteria: Prior use of anti-TNF or other biological therapy for CD Lack of stable home address that study medications can be mailed to Anticipated short length of follow up at study center (plans for family to move, transition to adult GI (gastrointestinal) provider, etc.). Patients expected to leave practice < 12 months from enrollment should not be enrolled. Concurrent pelvic or abdominal abscess. A recent history of abdominal or pelvic abscess, which is controlled, does not exclude the subject. Prior intra-abdominal surgery without a clinically significant relapse (i.e. patients starting on anti-TNF for post-op prophylaxis or for endoscopic recurrence only should not be included) Receipt of a live virus vaccine within the last 30 days Pregnancy, planning to become pregnant, or high risk of pregnancy as determined by the local investigator Breastfeeding Refusal to stay abstinent or utilize 2 forms of birth control while on study medication (for female patients) BMI > 98% for gender and age Known previous or concurrent malignancy (other than that considered surgically cured, with no evidence for recurrence for 5 years). A recent history of basal cell or squamous cell carcinoma, which is considered surgically cured, does not exclude the subject.Those with a recent history of colonic adenoma or dysplastic lesions should be excluded. Known high alcohol consumption (more than seven drinks per week) Patients with serum albumin < 2.5 g/dl Patients with white blood cell count (WBC) < 3.0 x109th/L Patients with platelet count < 100 x109th/L Patients with initial elevation of liver enzymes (AST or ALT) > 1.5 times above normal limit Patients with known active infection with Clostridium difficile (C. difficile) (untreated infection based on clinician assessment does not apply to colonization or infection controlled with current or prior treatment.) Patients with pre-existing hepatic disease Patients with pre-existing renal dysfunction (creatinine > 0.8 for children age<10, creatinine > 1.2 mg/dl for children age 10-18, and creatinine > 1.5 mg/dl for adults age 18 years and older). Patients with a pre-existing chronic lung disease other than well controlled asthma Current treatment with one of the following drugs: Probenecid (Probalan), Acitretin (Soriatane), Streptozocin (Zanosar), Azathioprine (Imuran, Azasan), 6-mercaptopurine (Purinethol, Purixan) Other concerns about the patient/family's ability to participate in the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael D Kappelman, MD
Organizational Affiliation
University of North Carolina, Chapel Hill
Official's Role
Study Director
Facility Information:
Facility Name
Children's of Alabama
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
Stanford Children's Health
City
Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Yale-New Haven Children's Hospital
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Facility Name
Nemours Children's Health System - Wilmington
City
Wilmington
State/Province
Delaware
ZIP/Postal Code
19803
Country
United States
Facility Name
Nemours Children's Health System - Jacksonville
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32207
Country
United States
Facility Name
Nicklaus Children's Hospital
City
Miami
State/Province
Florida
ZIP/Postal Code
33155
Country
United States
Facility Name
Nemours Children's Health System - Orlando
City
Orlando
State/Province
Florida
ZIP/Postal Code
32827
Country
United States
Facility Name
Children's Healthcare of Atlanta at Egleston/Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30329
Country
United States
Facility Name
Ann & Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Riley Hospital for Children
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
University of Iowa Children's Hospital
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
MassGeneral Hospital for Children
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Boston Children's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
University of Michigan | CS Mott Children's Hospital
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Children's Mercy Hospital
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
Cardinal Glennon Children's Medical Center
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63104
Country
United States
Facility Name
St. Louis Children's Hospital | Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Children's Hospital and Medical Center Omaha
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68114
Country
United States
Facility Name
Mount Sinai Kravis Children's Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Upstate Golisano Children's Hospital
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
University of North Carolina at Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27514
Country
United States
Facility Name
Levine Children's Hospital
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28203
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Rainbow Babies & Children's Hospital
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
Dayton Children's Hospital
City
Dayton
State/Province
Ohio
ZIP/Postal Code
45404
Country
United States
Facility Name
Oklahoma University Medical Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Monroe Carell Jr. Children's Hospital at Vanderbilt
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
The University of Vermont Children's Hospital
City
Burlington
State/Province
Vermont
ZIP/Postal Code
05401
Country
United States
Facility Name
Pediatric Specialists of Virginia
City
Fairfax
State/Province
Virginia
ZIP/Postal Code
22031
Country
United States
Facility Name
Children's Hospital of The King's Daughters
City
Norfolk
State/Province
Virginia
ZIP/Postal Code
23507
Country
United States
Facility Name
Children's Hospital of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Low Dose Oral Methotrexate in Pediatric Crohn's Disease Patients Initiating Anti-Tumor Necrosis Factor (Anti-TNF) Therapy

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