medwireNews: Findings from the phase 2 ARCADIA trial suggest that treatment with a glucokinase activator may aid the recovery of people with diabetes who are hospitalized with severe COVID-19.
The trial did not actually achieve its primary endpoint, which was clinical improvement at day 14 according to the World Health Organization 8-point Ordinal Scale for Clinical Improvement (WHO OSCI).
However, John Martin (University College London, UK) and study co-authors note that both the primary endpoint measure and the power calculation were determined according to data available before any therapies were approved for COVID-19.
Dexamethasone was approved after the trial design period and was used in 71.3% of the 80 trial participants given the glucokinase activator twice daily and 75.3% of the 73 given placebo. The glucokinase activator used was AZD1656, which underwent clinical trials in people with type 2 diabetes but proved to have only a transient (3–4 month) effect on glucose levels.
At day 14, 76.3% of the AZD1656 group and 69.9% of the placebo group had achieved a clinical response, defined as a score of 1, 2, or 3 on the WHO OSCI. The difference between the groups was not statistically significant.
But there was a strong trend toward reduced mortality for study participants given AZD1656 rather than placebo, with rates of 0.0% versus 8.2% at day 7, 1.3% versus 8.2% at day 21 (the time of study medication discontinuation), and 5.0% versus 12.3% at day 28.
Also, people taking AZD1656 were more likely to be discharged within 7 days of hospitalization than those taking placebo, at rates of 37.5% versus 24.7%. In addition, people with low vitamin D levels (<25 nmol/L) and high interleukin-6 levels (≥13 pg/mL) had shorter hospital stays if treated with AZD1656 rather than placebo.
These are “clinically meaningful findings which need to be tested in a larger trial,” write Martin and team in eClinicalMedicine.
They add: “It is of pharmacological interest and potential clinical significance that the apparent therapeutic effect was achieved early in dosing, given that the mean duration of treatment was just over 7 days for all patients.”
Almost all the study participants had type 2 diabetes, with just three having type 1 diabetes. Their average age was approximately 64 years and about two-thirds were men. The most common comorbidity considered to be a COVID-19 risk factor was obesity, in about 30%, followed by asthma, in about 12%, and chronic obstructive pulmonary disease, in about 8%.
A number of studies have pinpointed hyperglycemia as a risk factor for poor COVID-19 outcomes, but glucose levels were not significantly different between the AZD1656 and placebo groups.
Instead, the researchers found differences in various immune system variables, pointing to “an active rebalancing of the immune response,” including a smaller increase in circulating inflammatory monocytes in the AZD1656 versus the placebo group and differential changes in activated T cells, including T-helper 1, T-helper 2, and T regulatory cells.
Martin and colleagues stress that the clinical and immune response differences associated with AZD1656 treatment were in addition to the benefits of dexamethasone.
“Whilst the risk of false positives in a phase II trial exists, the ARCADIA trial data suggest that specific metabolic activation of [regulatory T cells] brings about changes in the immune system which are associated with early clinical improvement in patients suffering inflammatory disease caused by a virus,” they conclude.
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group
22 August 2022: The coronavirus pandemic is affecting all healthcare professionals across the globe. Medicine Matters’ focus, in this difficult time, is the dissemination of the latest data to support you in your research and clinical practice, based on the scientific literature. We will update the information we provide on the site, as the data are published. However, please refer to your own professional and governmental guidelines for the latest guidance in your own country.