Results Summary
What was the research about?
Crohn’s disease causes inflammation in the intestines and stomach, leading to long-term diarrhea and stomach pain. It can also lead to growth problems and lower quality of life. For children, the illness can get worse over time.
Doctors treat Crohn’s disease with antibiotics, steroids, or anti-TNF medicines. Anti-TNF medicines help reduce inflammation. Along with anti-TNF medicines, doctors may also prescribe another type of medicine called methotrexate. This medicine lowers inflammation. But it may cause problems like infections.
In this study, the research team wanted to learn whether anti-TNF medicines and methotrexate work better together than anti-TNF medicines alone. The team compared:
- Anti-TNF medicine plus methotrexate. Patients received an anti-TNF medicine that their doctors prescribed, plus methotrexate. The anti-TNF medicines were adalimumab or infliximab.
- Anti-TNF medicine alone. Patients received adalimumab or infliximab, which their doctors prescribed.
The research team looked at time to treatment failure. They defined treatment failure as having uncontrolled symptoms, having a hospital stay, having to use a steroid, or stopping the medicine because it wasn’t working or due to side effects.
What were the results?
After one year, patients who received an anti-TNF medicine plus methotrexate and patients who received an anti-TNF medicine alone didn’t differ in the time to treatment failure, pain, or fatigue.
Compared with patients who received adalimumab plus methotrexate, patients who received adalimumab alone had a shorter time until treatment failure. Time to treatment failure didn’t differ between patients who received infliximab plus methotrexate or infliximab alone.
Who was in the study?
The study included 297 children and adolescents under 21 years of age with Crohn’s disease who were starting anti-TNF medicines. Of these patients, 82 percent were White, 11 percent were Black, 1 percent were Asian, and 4 percent identified as multiple or other races. The average age was 14, and 65 percent were male. All were receiving care from one of 35 clinics across the United States.
What did the research team do?
The research team assigned patients by chance to one of the two groups. The team looked at health records up to one year after patients started anti-TNF medicines. The team also called patients one and two years after they started anti-TNF medicines to ask about their pain and fatigue.
Parents of children with Crohn’s disease and doctors helped design the study.
What were the limits of the study?
Fewer children enrolled in the study than planned, making it hard to find differences in study outcomes. Also, the study didn’t look at other health outcomes that show how well medicines work, like healing of the stomach and intestines.
Future research could compare how well medicines treat other health outcomes from Crohn’s disease.
How can people use the results?
Parents and doctors can use the results when considering treatments for children who have Crohn’s disease.
Professional Abstract
Objective
To compare the effectiveness of anti-tumor necrosis factor (TNF) medication plus methotrexate versus anti-TNF medication alone in reducing time to treatment failure and improving patient-reported outcomes in children and adolescents with Crohn’s disease
Study Design
| Design Element | Description |
|---|---|
| Design | Randomized controlled trial |
| Population | 297 children and adolescents under age 21 with Crohn’s disease starting anti-TNF medication |
| Interventions/ Comparators |
|
| Outcomes | Primary: time to treatment failure (defined by failure to achieve remission, hospitalization for inflammatory bowel disease, use of steroids, or discontinuation of anti-TNF medication for lack of effectiveness or toxicity) Secondary: patient-reported pain and fatigue |
| Timeframe | 1-year follow-up for primary outcome |
This randomized controlled trial compared the effectiveness of anti-TNF medication plus methotrexate, versus anti-TNF medication alone, in reducing time to treatment failure and improving patient-reported outcomes in children and adolescents with Crohn’s disease.
Researchers randomly assigned patients to one of two groups. In the first group, patients received one of the anti-TNF medications, adalimumab or infliximab, plus methotrexate. Their doctors determined which of the two anti-TNF medications patients received. In the second group, patients received adalimumab or infliximab alone. Doctors asked patients to remain on their medications for the duration of the study.
The study included 297 children and adolescents who were younger than age 21, diagnosed with Crohn’s disease, and were starting anti-TNF medication. Of these patients, 82% were White, 11% were Black, 1% were Asian, and 4% identified as multiple or other races. The average age was 14, and 65% were male. All received care at one of 35 clinics across the United States.
Researchers defined treatment failure as failure to achieve remission, hospitalization for inflammatory bowel disease, use of steroids, or discontinuation of anti-TNF medication for lack of effectiveness or toxicity. To assess time to treatment failure, researchers reviewed patient medical records one year after patients started treatment. Researchers also contacted patients one and two years after they started treatment to assess their pain and fatigue.
Parents of children with Crohn’s disease and clinicians helped design the study.
Results
After one year, patients who received either anti-TNF medication plus methotrexate and patients who received one of the anti-TNF medications alone did not differ significantly in time to treatment failure or patient-reported pain or fatigue.
Compared with patients who received adalimumab plus methotrexate, patients who received adalimumab alone had a shorter time to treatment failure (p=0.03). Patients who received infliximab plus methotrexate did not differ significantly in time to treatment failure from patients who received infliximab alone.
Limitations
Because study enrollment was lower than expected, the study may have been underpowered to detect meaningful differences in outcomes between the groups. Also, the study only considered outcomes that were routinely assessed in clinical care and did not look at other outcomes that measure treatment effectiveness, like mucosal healing.
Conclusions and Relevance
In this study, patients who received adalimumab plus methotrexate had a longer time to treatment failure than patients who received adalimumab alone. The addition of methotrexate for patients who received infliximab did not show a benefit compared with patients who received infliximab alone.
Future Research Needs
Future research could compare the use of anti-TNF medications plus methotrexate versus anti-TNF medications alone to determine their effectiveness in treating other outcomes, such as mucosal healing.
Final Research Report
This project's final research report is expected to be available by June 2024.
Journal Citations
Results of This Project
Related Journal Citations
Peer-Review Summary
Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.
The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments.
Peer reviewers commented and the researchers made changes or provided responses. Those comments and responses included the following:
- The reviewers urged the researchers to structure their report to present primary and secondary outcome results before subgroup analyses even though the primary and secondary outcomes showed no additive value of methotrexate to antitumor necrosis factor (TNF) therapy. The reviewers questioned the report’s focus on significant results for a subgroup analysis showing beneficial effects of methotrexate augmentation to adalimumab for the treatment of pediatric Crohn’s disease. While this is an important finding, the study was underpowered to make definitive statements about subgroup effects. The researchers restructured the report as requested so that the results and discussion clearly describe the lack of significant differences between the combination treatment and monotherapy with an anti-TNF agent.
- The reviewers noted that the two anti-TNF drugs, adalimumab and infliximab, have important differences in dosing and therefore therapeutic drug levels in the body, and these differences may be factors in whether or not methotrexate augmentation provides a benefit. The researchers acknowledged this issue and referred to it in the report’s discussion, stating that infliximab had easier dose adjustments than adalimumab, which could mean less treatment failure and therefore less need for augmentation with methotrexate. In addition, the study clinics practiced proactive drug monitoring so they kept closer watch on therapeutic medication levels and adjusted anti-TNF treatment accordingly.
- The reviewers asked for more evidence that the researchers worked with patients and caregivers in identifying key patient-reported outcome measures for this study as well as laying out the study design. The researchers expanded their discussion of patient and stakeholder engagement to describe how they engaged members of the ImproveCareNow community in determining the study question and used qualitative methods with patients and caregivers to identify the best measures to use for the study.