The COVID-19 pandemic interrupted clinical trials worldwide, including type 1 diabetes immune intervention trials. Some type 1 diabetes trials have resumed, but the debate over the resumption of immune intervention trials remains unsettled.
That debate continued Friday afternoon at the Scientific Sessions during the mini-symposium Debate—Should Immune Intervention Trials Occur during the COVID-19 Pandemic? The session can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.
“We now have information and mitigation strategies to maximize benefits and minimize risks,” said Carla Greenbaum, MD, Diabetes Program Director, Benaroya Research Institute Center for Interventional Immunology & Diabetes, Virginia Mason University. “Potential risk-benefit analysis supports clinical trial mitigation strategies, including requirements for COVID vaccination. We owe these trials to our participants and to future generations of individuals with type 1 diabetes.”
Not so fast, countered Adriana Weinberg, MD, Professor of Infectious Diseases and Medical Director, Clinical Molecular and Virology Laboratory, University of Colorado Hospital. Immunosuppressed individuals are at increased risk for infection and contribute to the development of more severe COVID-19 variants, she said.
“A few known risks and many unknowns justify pausing trials of immunosuppressants with unproven benefits for participants until study candidates acquire protection against SARS-CoV-2 through vaccination and/or the circulation of SARS-CoV-2 falls below epidemic levels. And at this point, we do not know what that level is,” Dr. Weinberg said.
Four immunotherapy agents—hydroxychloroquine, abatacept, anti-thymocyte globulin, and rituximab—were under study for type 1 diabetes when the pandemic began. Researchers paused those trials in March 2020 due to the potential risks of COVID-19.
“We were surprised by the speed of the [SARS-CoV-2] infection spread,” Dr. Weinberg said. “The R0 early in the U.S. was 5.7, with every infected individual infecting 5.7 others. That compares with an R0 of only 1.4 to 1.6 with H1N1 influenza in 2009. The disease spread so rapidly because we did not have effective mitigation strategies available.”
Age has emerged as the strongest determinant of severe COVID infection and mortality. The current evidence suggests that death is rare in children and individuals under the age of 50.
“Our population demographic puts them at extremely low risk from COVID,” Dr. Greenbaum said.
Treatment with most biologics or JAK (Janus kinase) inhibitors is associated with lower odds of hospitalization from COVID, although any treatment leading to prolonged B-cell depletion may be cause for concern. Ocrelizumab has been associated with mild COVID-19 disease while rituximab has been linked with mild, severe, and fatal COVID-19. Both are anti-CD20 antibody agents.
And while there are few data from patients with both COVID-19 and type 1 diabetes, multiple literature reviews of immunosuppressed populations with cancer, solid organ transplants, HIV, and other conditions suggest that not all immune suppression is the same.
For Dr. Greenbaum, the availability of safe and effective COVID-19 vaccines shifted the risk-benefit analysis. The TrialNet network strongly advises all individuals to receive COVID vaccination, she noted.
COVID-19 vaccination is a solid beginning, Dr. Weinberg said, but vaccination is not sufficient to safely restart clinical trials of immunosuppressive agents. There are no good COVID therapeutic interventions, she noted, and immune suppression in renal transplant patients has already been observed to favor the selection of SARS-CoV-2 variants. There are also emerging data showing that immunosuppression can reduce the effectiveness of COVID-19 vaccines.
“Immune suppression allows the virus to develop resistance to neutralizing antibodies produced by the host,” Dr. Weinberg said. “Immune-compromised individuals contribute significantly to the emergence of severe variants.”
Both Dr. Greenbaum and Dr. Weinberg noted the ethical principles that guide all clinical research: Respect for participants and their families, doing no harm by maximizing benefits and minimizing risks, and judging who should receive the benefits of research against who should bear the burdens of research.
Despite that common ground, no consensus was reached on whether type 1 diabetes immune intervention trials should resume before the end of the pandemic.