Pediatric Crohn's Disease
Conditions
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.
Interventions
DRUGMethotrexate
1. 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. 2. 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). 3. 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.
OTHERSugar pill (placebo)
1. Placebo for methotrexate: The weekly dose will mimic that of methotrexate. 2. Placebo for ondansetron: The weekly dose will mimic that of ondansetron (study provider may opt-out of this component based on clinical judgement). 3. 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.
Sponsors
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)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 20 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants Experiencing Treatment Failure | From randomization until treatment failure, assessed up to 3 years. | Treatment failure is defined as follows: 1. Failure to achieve remission (short pediatric Crohn's disease activity index \[SPCDAI\] \< 15) by the week 26 visit; 2. If study initiated on steroids, failure to complete steroid taper by week 16; 3. 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; 4. Hospitalization for active Inflammatory Bowel Disease or abdominal surgery after week 25; 5. Use of oral prednisone or prednisolone, enteral release budesonide, or intravenous (IV) methylprednisolone for over 10 weeks cumulatively, beyond week 16; 6. Discontinuation of anti-TNF agent and/or study drug for lack of effectiveness or toxicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-52 Weeks | Weeks 52 from randomization | 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 | 104 weeks from randomization | 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 | Week 52 from randomization | 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 | 104 weeks from randomization | 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 | Between 6 months and 2 years from randomization | Percent of patients with positive anti-TNF antibody will be compared between the two treatment groups using the chi-squared test. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Methotrexate 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
Methotrexate: 1) 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. 2) 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). 3) 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. | 156 |
| Sugar Pill (Placebo) 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
Sugar pill (placebo): 1) Placebo for methotrexate: The weekly dose will mimic that of methotrexate. 2) Placebo for ondansetron: The weekly dose will mimic that of ondansetron (study provider may opt-out of this component based on clinical judgement). 3) 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. | 141 |
| Total | 297 |
Baseline characteristics
| Characteristic | Sugar Pill (Placebo) | Total | Methotrexate |
|---|---|---|---|
| Age, Continuous | 14.0 years STANDARD_DEVIATION 2.8 | 13.9 years STANDARD_DEVIATION 2.6 | 13.8 years STANDARD_DEVIATION 2.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 8 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 138 Participants | 288 Participants | 150 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 32 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 13 Participants | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 113 Participants | 244 Participants | 131 Participants |
| Region of Enrollment United States | 141 Participants | 297 Participants | 156 Participants |
| Sex: Female, Male Female | 51 Participants | 104 Participants | 53 Participants |
| Sex: Female, Male Male | 90 Participants | 193 Participants | 103 Participants |
| Tumor Necrosis Factor (TNF) Inhibitor at Baseline Adalimumab | 39 Participants | 85 Participants | 46 Participants |
| Tumor Necrosis Factor (TNF) Inhibitor at Baseline Infliximab | 102 Participants | 212 Participants | 110 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 156 | 0 / 141 |
| other Total, other adverse events | 156 / 156 | 129 / 141 |
| serious Total, serious adverse events | 23 / 156 | 28 / 141 |
Outcome results
Primary
Percent of Participants Experiencing Treatment Failure
Treatment failure is defined as follows: 1. Failure to achieve remission (short pediatric Crohn's disease activity index \[SPCDAI\] \< 15) by the week 26 visit; 2. If study initiated on steroids, failure to complete steroid taper by week 16; 3. 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; 4. Hospitalization for active Inflammatory Bowel Disease or abdominal surgery after week 25; 5. Use of oral prednisone or prednisolone, enteral release budesonide, or intravenous (IV) methylprednisolone for over 10 weeks cumulatively, beyond week 16; 6. 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percent of Participants Experiencing Treatment Failure | 25.64 percentage of participants |
| Sugar Pill (Placebo) | Percent of Participants Experiencing Treatment Failure | 34.04 percentage of participants |
p-value: 0.0895% CI: [0.45, 1.05]Log Rank
Secondary
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.
Time frame: Weeks 52 from randomization
Population: Population includes those who completed surveys.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methotrexate | Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-52 Weeks | 37.5 T-score | Standard Deviation 12 |
| Sugar Pill (Placebo) | Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-52 Weeks | 39.5 T-score | Standard Deviation 11.9 |
p-value: 0.32Mixed Models Analysis
Secondary
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
Time frame: 104 weeks from randomization
Population: Population includes those who completed surveys.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methotrexate | Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-week 104 | 38.1 T-score | Standard Deviation 12.4 |
| Sugar Pill (Placebo) | Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-week 104 | 39.9 T-score | Standard Deviation 13.5 |
p-value: 0.69Mixed Models Analysis
Secondary
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
Time frame: 104 weeks from randomization
Population: Population includes those who completed surveys.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methotrexate | Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 104 | 41.1 T-score | Standard Deviation 14.5 |
| Sugar Pill (Placebo) | Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 104 | 41.5 T-score | Standard Deviation 14.9 |
p-value: 0.64Mixed Models Analysis
Secondary
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
Time frame: Week 52 from randomization
Population: Population includes those who completed surveys.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methotrexate | Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 52 | 41.8 T-score | Standard Deviation 14.4 |
| Sugar Pill (Placebo) | Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 52 | 41.8 T-score | Standard Deviation 14 |
p-value: 0.72Mixed Models Analysis
Secondary
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.
Time frame: Between 6 months and 2 years from randomization
Population: Analysis includes participants who provided a blood sample.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percent of Patients With Positive Anti-TNF Antibody | 28.5 percentage of participants |
| Sugar Pill (Placebo) | Percent of Patients With Positive Anti-TNF Antibody | 40 percentage of participants |
p-value: 0.0895% CI: [0.49, 1.04]Chi-squared