The Patient-Centered Outcomes Research Institute (PCORI) has awarded Duke University School of Medicine researchers more than $22 million to conduct a trial to develop a treatment protocol for children who have not responded to initial medication for Juvenile Idiopathic Arthritis, one of the most common childhood rheumatic diseases in the world.
The open label, randomized trial, called Sequential Medications after TNFi failure in Juvenile Idiopathic Arthritis (SMART-JIA), is co-led by Laura Schanberg, MD, professor in the Duke Department of Pediatrics, and Huiman Barnhart, PhD, professor and associate chair of faculty mentorship and development in the Department of Biostatistics & Bioinformatics. Schanberg leads the Clinical Coordinating Center, and Barnhart leads the Data Coordinating Center.
This groundbreaking longitudinal study is the first international collaboration between the Childhood Arthritis and Rheumatology Alliance, the Pediatric Rheumatology European Society, and the Pediatric Rheumatology International Trials Organization. In total, 70 pediatric rheumatology centers from all over the world, with 35 based in the US and Canada, are expected to be sites for patient enrollment in this trial.
Children with juvenile idiopathic arthritis often face a lower quality of life and endure severe joint swelling, which can lead to debilitating pain, fatigue, and growth challenges. There is no cure, although several injectable drugs have been approved to treat it, like tumor necrosis factor alpha inhibitors (TNFi).
But for 25% of children with pcJIA, the first TNFi doesn’t improve their health, and they face an increased risk of complications. These children are prescribed a second TNFi, but if that drug doesn’t work, there is no other formal course of action, so providers begin trial and error with several other medications. This leads to additional health care costs for families. “From that, it’s hard to learn what the best order is to administer the drugs to patients,” Barnhart said. “But this trial will address that issue. It’s not about figuring out whether the drug works, it’s figuring out what sequence of drugs works for patients with failed initial TNFi.”
The SMART-JIA trial will compare the effectiveness of three different types of non-TNFi drugs that work differently from each other to a second new TNFi medication. Eligible children aged 2-17 who have consented to be in the study will be randomly assigned to one of these four medications and monitored closely by their doctor. Researchers will compare effectiveness of each of the three non-TNFi drugs to the second TNFi medication. If a child doesn’t respond the assigned medication after six months, they will be randomly assigned to another non-TNFi drug. Each child in the study will be followed for 12 months.
Patients are typically randomized once in a clinical trial. To investigate which sequence of medications works best for patients, researchers are using a new design called ‘Sequential Multiple Assignment Randomization Trial (SMART)’ for the study by randomizing patients twice. “Methodically, it’s a really interesting to be a part of this innovative trial design. Executing a new design that hasn’t been used as much, and how it will be implemented, is exciting to me,” Barnhart said. “It’s one thing to read papers about this type of design, but it’s a totally different thing when you're actually doing it to carry out realistic power calculations,” she continued.
As director of the Data Coordinating Center, Barnhart is responsible for statistical services, safety surveillance, and data management. “That center is required to make sure that the data is properly collected and entered into our database,” Barnhart said. “You want to make sure the trial's conducted in a manner that's trustful, and that the trial data is reliable. For meaningful interpretation of the trial data, we need a proper design and analyses.” Barnhart and Marie Davidian, Ph.D., a well-known professor in the Department of Statistics at North Carolina State University, will lead the trial design and analytical approaches.
Funding will be distributed in stages over six and a half years. The first is the feasibility stage, and the data coordinating center plays a major role in its success. Biostatisticians will be assisting with the development of trial protocol, creating a manual of operation, and building a database that clinical sites in the US, Canada, and Europe can use to enroll patients and store data. “Statisticians need to be part of studies to make sure there’s a sufficient number of patients to test the hypothesis in the study successfully with sufficient power,” Barnhart said.
The feasibility stage will likely begin in November 2023 and will last a year and a half. “That’s when you get all the logistics together, try it out on a few patients, and if you make progress the next round of funding will come through,” Barnhart said.
While there is still plenty of work to do, Barnhart says they were especially proud when they learned they earned grant funding. “It was a joyful moment,” Barnhart said. "Finally, they funded us. We put in a lot of work to prepare for this grant." They applied twice, faced several rounds of questions, and made several revisions before their funding application was accepted.
As a biostatistician with more than 30 years of experience, 20 of which spent at Duke, Barnhart is excited to face a series of ‘firsts’ with this trial. “I'm looking forward to gaining more experience with international trials. This is my first one. They have different regulations, it's a huge number of sites, and there's a lot of management involved. Working with people outside the US is on another level, another ball game, and that’s exciting,” Barnhart said.