‘One of the few strategy trials in PsA’: CONTROL sheds light on escalation, biologic use
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Although there are plenty of drugs to treat psoriatic arthritis, and plenty of studies about those drugs individually, there are fewer trials examining strategies to treat patients who fail to respond to methotrexate in the first line.
Researchers aimed to fill that knowledge gap with the CONTROL trial.
In a paper published in The Lancet Rheumatology, Laura C. Coates, MBChB, associate professor in the Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences at the University of Oxford, in the United Kingdom, and colleagues tested a treatment strategy in patients with active PsA who responded inadequately to methotrexate: Comparing the addition of adalimumab (Humira, AbbVie) to methotrexate vs. increasing the methotrexate dose.
According to Coates and colleagues, a significantly higher proportion of patients reached minimal disease activity at 16 weeks in the adalimumab plus methotrexate group, compared with the escalated methotrexate group.
The phase 4, randomized, open-label CONTROL study was conducted at 46 sites in 14 countries. Eligible participants were biologic-naïve.
Part 1 of the study included the randomization of participants to receive methotrexate at 15 mg per week, orally or subcutaneously, plus adalimumab 40 mg subcutaneously every other week, or an escalating dose of methotrexate up to 25 mg per week. The primary endpoint of this part was minimal disease activity at 16 weeks.
In part 2, those who reached the part 1 endpoint had their treatment maintained or modified, while non-responders experienced escalation through 32 weeks.
The analysis included 287 patients enrolled between Aug. 5, 2016, and March 19, 2020. Ultimately, 245 patients completed the trial. The cohort was evenly split between men and women and 92% white.
Results demonstrated that, through the first 16 weeks, 41% of patients in the combination methotrexate-adalimumab group achieved minimal disease activity, while just 13% of those in the methotrexate group reached this endpoint (P < .0001).
Patients who responded initially generally continued to respond. Among 51 responders in the adalimumab group from part 1, 80% continued to respond through 32 weeks, while 67% of 15 methotrexate responders from part 1 also responded at 32 weeks.
In the adalimumab non-responder group, 30% of 57 patients ultimately reached minimal disease activity after adalimumab dose escalation through 32 weeks. In the methotrexate non-responder group, 55% of 91 patients reached minimal disease activity after adalimumab was added to their regimen.
Serious adverse events were rare, and no new safety signals emerged.
Healio sat down with Coates to discuss strategy in PsA treatment, combination therapies and the benefits of escalating both adalimumab and methotrexate.
Healio: What was the rationale behind this trial?
Coates: CONTROL is one of the few strategy trials in PsA. We have a number of drugs, but very little evidence of how we look at those drugs in terms of when and how to escalate conventional DMARDs, when to add a biologic or when to give up on methotrexate. There has been an explosion of drug vs. placebo studies but very little that actually guides clinicians in these important questions.
That becomes obvious when we write treatment recommendations. It has been difficult to create evidence-based protocols for how we treat PsA. CONTROL looked specifically at the question of what we do with patients who are not responding to methotrexate — whether to up the dose or move to a biologic.
Healio: Why did you choose adalimumab?
Coates: Two reasons. One, it was an Abbvie-funded study. But also, it is the market leader TNF inhibitor internationally and commonly used as a first-line biologic option.
Healio: Was it important that you chose biologic naïve patients?
Coates: Definitely. This study is looking at what to do for patients who are earlier in their disease course. We wanted to look at the threshold for moving on from conventional DMARDs.
Healio: Could you discuss the decision to choose minimal disease activity, rather than remission, as the key endpoint?
Coates: We wanted to pick an outcome that was more than just an improvement like ACR20 or ACR50, that showed a good measure of disease control. Also, we wanted to use something that would reflect improvements in the domains of both joints and skin. Minimal disease activity is becoming a more widely used outcome in clinical trials. Because this was not a registration trial — restricted by FDA/European Medicine Agency design — we could use a more comprehensive measure.
Healio: Could you talk about the responses you saw in the joints and the skin?
Coates: We saw benefit in both, in overall disease control and across specific domains, as well. This comprehensive response is important from the patient perspective. To get a good quality of life, patients want improvements in both the joints and the skin, because if one improves but not the other, they still feel like they are dealing with their disease. So when we are thinking about treatment strategies and designing clinical trials, it is important to think about different domains.
Healio: Could you talk about the open-label nature of the trial design?
Coates: That was more for the sake of practicality than anything else. In a perfect world, nobody knows what treatments the patients are receiving so we can assess their response blinded. For this study, because of the two-part design, and because patients were going to be switching or escalating therapies, it significantly increased the complexity for them.
They knew coming in the two groups they might end up in, that this was the design. It was part of the informed consent. They understood that they would be treated for 16 weeks and followed up for escalation or crossover. Also from their perspective, they understood that if they were struggling and were in the methotrexate-only group, they knew they could potentially benefit in part 2 with escalation or the addition of adalimumab.
Healio: Could you discuss the adverse event profiles?
Coates: This was an important balance between the two drug choices. We always need to balance adverse events with efficacy. However, we acknowledge that this was an unusual trial because we were studying both drugs, and that it would be difficult to separate which events were caused by which drugs.
We did ask, when people reported adverse events, whether they thought it was from the adalimumab or the methotrexate. So, in that regard, it required a bit of physician input. Our assessment is that we did see slightly more infection events in the adalimumab group, whereas in patients on the escalated methotrexate dose we saw increased problems with liver function tests and tolerability of the drug, such as nausea or fatigue.
Healio: Speaking of the two-drug nature of the trial, do you see these results as more of a comment on adalimumab or methotrexate?
Coates: I think the message here is that it is more of a strategy trial than a test of either individual drug. If you are treating a patient who has had an inadequate response, we wanted to think about how to maximize outcomes. We wanted to try to answer questions of how long you try with methotrexate, how long you wait to change or add therapies, how aggressive you can be with dosing and drugs. It also depends on the opinion of the patient, and what they may need, and how they may feel.
Reference:
Coates L, et al. Lancet Rhematol. 2022;doi:10.1016/S2665-9913(22)00008-X.
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