Should rheumatoid arthritis trials exclude patients based on their Covid-19 vaccine status? – Clinical Trials Arena

Covid-19 continues to make an impact on clinical trial design, and rheumatoid arthritis (RA) is no exception. While more evidence is needed, there is a hypothesis that a Covid-19 infection can worsen RA complications.

Theoretically, RA patients may have a disease flare alongside a Covid-19 infection because the SARS-CoV-2 virus triggers an overreaction of the immune system and RA is an autoimmune disease, explains University Medical Center Utrecht professor of rheumatology Dr Hans Bijlsma. In fact, RA therapies have been repurposed to investigate its effect on Covid-19’s inflammatory stage, he adds.

What does this mean for clinical trials? “I would insist on [trial participant] vaccination unless there is a contraindication,” says Dr Leonard Calabrese, director of the RJ Fasenmyer Center for Clinical Immunology at the Cleveland Clinic. Trials that study an immunomodulator or immunosuppressor warrant maximum protection for participants from a virus that can induce an immune response, he adds.

But, Bijlsma says: “My first question would be ‘is this ethical?’ Smoking can exaggerate RA. Obesity can lead to more severe RA. But these patients are not excluded in trials, so why should we exclude nonvaccinated people?” 

Further, there is a need to recruit diverse patients to represent the broader population, he adds. Perhaps one solution is to collect vaccination data – much like smoking and obesity data – and see if there are trends, he says.

Reassuringly, by and large, a Covid-19 infection does not appear to have a dramatic effect on RA and most rheumatic diseases, Calabrese says. There is only a small number of cases where Covid-19 exaggerates RA symptoms, Bijlsma adds. Also, there is very little evidence that Covid-19 triggers a new RA diagnosis, he notes.

Clear side effect profile ideal

According to GlobalData’s Clinical Trials Database, there are 521 ongoing and planned Phase I-III rheumatoid arthritis clinical trials. Of these, 166 are still in the planning stage. GlobalData is the parent company of Clinical Trials Arena.

There are 18 ongoing or planned clinical trials that refer to Covid-19 vaccines in their inclusion and exclusion criteria. While 14 of these trials are investigating the impact of a Covid-19 infection or vaccine in RA patients, the other four studies are investigating RA therapies. Of these, one is ongoing and three are being planned.  

Kiniksa Pharmaceuticals’s ongoing Phase II trial (NCT05198310) studying KPL-404 in moderate-to-severe RA has an inclusion criterion that notes the participant should be vaccinated at least three weeks ahead of the first dose. KPL-404 is a monoclonal antibody that inhibits the interaction of CD40 with CD154 to regulate B cell proliferation and T cell activation.  

One concern with recruiting unvaccinated patients is that an investigational therapy’s safety profile may be blurred. If a trial participant is infected and progresses to severe Covid-19, it may be hard to know if the experimental therapy helped exaggerate it, Calabrese says. This is a burning issue in all patients with an immune-mediated inflammatory disease, he adds.

But the need to exclude nonvaccinated participants can come down to the investigational asset’s mechanism. If the drug’s mechanism is related to the immune system, a uniform trial population of vaccinated individuals would be ideal, Calabrese notes.

Nevertheless, more data is needed to solidify the connection between Covid-19 and rheumatoid arthritis. The severity of RA symptoms in the same patient can vary, Bijlsma says. Some patients with RA and Covid-19 may have worse symptoms while others may not, he adds. “We don’t know for sure if Covid-19 exaggerates [RA].”

Also, the connection between RA and Covid-19 is blurred by the fact that in the past two years, RA patients may have altered their therapies on account of not having to visit clinicians or forestalling medications, Calabrese says. Many patients may not have had disease control in the past two years compared to years before the pandemic, he explains.

While the jury is still out, Calabrese says RA patients should be fully vaccinated anyway considering unvaccinated patients are most vulnerable to severe Covid-19 outcomes. There is no palpable signal that there is an increase of a major disease flare after being vaccinated for Covid-19, he adds.

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