Dual studies will track long-term responses to aggressive and first-line treatments
BY MICHELE G. SULLIVAN
Sponsored by the Patient-Centered Outcomes Research Institute, TREAT-MS and DELIVER-MS will randomize patients to either early aggressive therapy or to the first-line drugs that are now the standard of care. Although the two trials vary slightly in their primary outcome measures, both will investigate how early intervention might reduce later disability in relapsing-remitting disease.
“The approved therapies for MS target the relapsing phase of the disease, but have minimal impact once the progressive phase has begun,” said Ellen Mowry, MD, MCR, one of the principal investigators for TREAT-MS. “It is unclear if, in the relapsing phase, there is an advantage of early treatment with the more aggressive medicines with respect to preventing long-term disability. The more aggressive medicines potentially have greater infection risks and other complications than the traditional therapies; therefore, it is of utmost importance to evaluate their effectiveness in preventing disability.
Dr. Ellen Mowry
TREAT-MS will help to determine whether patients most benefit from starting on an aggressive therapy or on a traditional therapy and switching to an aggressive therapy if relapses or new MRI lesions occur, said Dr. Mowry of Johns Hopkins University, Baltimore.
TREAT-MS aims to recruit 900 patients at 45 study sites in the U.S. Patients will be stratified into high- and low-risk groups based on their clinical characteristics, and then randomized 1:1 to the clinicians’ choice of early aggressive treatments (natalizumab, alemtuzumab, ocrelizumab, or rituximab) or first-line treatments (glatiramer acetate, subcutaneous or intramuscular interferon, pegylated interferon, teriflunomide, dimethyl fumarate, or fingolimod). The primary endpoint is time to sustained disability progression.
“The risk groups were created by using easily-assessed clinical and MRI data that a typical clinician has when evaluating a person newly diagnosed with MS. We categorize people’s risk in TREAT-MS based on how long it has been since their first MS attack. If the first attack was within the past 6 months, we consider the parts of the nervous system that were affected as well as how many MS lesions are seen on the MRI. For those who are seen more than 6 months after their first MS attack, we also consider whether their attack recovered completely or not, and whether they have had additional attacks or new changes on the MRI over time.”
The study will allow treatment changes within the initial randomization group if the first medication isn’t working well enough; for those who had low-risk MS features, this may involve a second randomization.
“This is a unique feature of the TREAT-MS trial, which also parallels a dilemma we face in real life: what to do when someone starts a medication, but it doesn’t really work. If someone seems to have low-risk MS features and starts on a traditional therapy, but the therapy isn’t working as well as hoped, it can be difficult to evaluate if they should switch to a different traditional therapy or switch to a more aggressive therapy. Thus, in the TREAT-MS trial, those considered to have low-risk features at onset who are initially randomized to a traditional medication but need to switch because it isn’t working will have one additional randomization to either another traditional therapy or to a more aggressive therapy to see if that decision influences long-term outcomes.”
Including low-risk patients in the study speaks to the unpredictability of the disease course, Dr. Mowry said.
“The data surrounding risk classification are not very precise. While we have some intuition that helps us classify patients as higher- or lower-risk when we see them, we really can’t say for sure that someone who doesn’t have some of the things we might consider high risk is not going to experience longer-term disability. Similarly, as clinicians, we often may think a person has features consistent with higher risk for disability down the road, only to see that person again 10 years later doing quite well and with no meaningful signs of disability. It’s really important for all people with MS to understand whether there is a relative benefit to their starting the more aggressive therapy up front, and the risk stratification will allow us to evaluate, if there is a benefit, whether it’s true in all patients or just in a subset.”
In addition to the primary endpoint of sustained disability, TREAT-MS will look at 25 secondary endpoints, including function, quality of life, cognitive measures, imaging endpoints, and social impact.
“We added a few unique endpoints that classical phase 3 trials don’t investigate, such as whether the treatment strategy selected leads to a difference in employment status or marital status at the end of the study, or whether it impacts the number of other medications a person has to take for MS-related symptoms, such as pain or depression. These endpoints are meaningful to people with MS and speak to the patient-centered approach.”
DELIVER-MS will randomize 800 MS patients in the U.S. and the U.K. This study asks a question similar to that of the TREAT-MS trial, but has a different primary endpoint: brain volume loss from baseline-36 months. Secondary endpoints include brain volume loss from months 6-36, the number of patients with clinical progression, and measures of neurological quality of life, including cognition, anxiety and depression, and social and physical function.
In this study, patients won’t be split by baseline risk assessment. And, in addition to the two randomized treatment arms of early highly-effective therapy and escalation therapy, there will be an observational arm for participants who will not be restricted to a group of MS therapies. Patients will enter this arm if they aren’t comfortable with randomization, not eligible to receive any of the treatments, or are not able to secure insurance coverage for any therapy in a randomized arm.
Right now, clinicians and patients face tough treatment decisions without much high-quality data to back them up. Dr. Mowry hopes that TREAT-MS and DELIVER-MS will change that.
“I can’t speak for all clinicians, but I and those I have worked with use the best information we have – observational studies, prior prognostic studies, etc. – as well as intuition and, importantly, the preferences of the patient and patient-specific factors to help guide people to select their therapies. It is hard, though, to tell people that we are taking an educated guess, and it was this agony of not having a strong evidence base to inform them that inspired the TREAT-MS trial.”
Dr. Mowry disclosed receiving research support from Teva Neuroscience.
|Research methods at a glance|
|Design||Randomized controlled trial|
|Population||Adults ages 18–60 years with relapsing-remitting MS who did not receive chemotherapy previously or take specific MS medicines for a long period of time|
|· Standard medicines (self-injected and oral therapies)
· Early aggressive medicines (infusible medicines)
|· Primary: long-term disability as assessed by neurologic examinations
· Secondary: patient-reported disability, fatigue, health-related quality of life
|Up to 4.5 years of follow-up for primary outcome|
Credit: Adapted from pcori.org