Quantum Leap Stops Cyclosporine Arm of I-SPY COVID Trial

Quantum Leap Healthcare Collaborative (QLHC), sponsor of the I-SPY COVID Trial, has terminated the cyclosporine arm of the study because it didn’t study endpoints. Cyclosporine, a calcineurin inhibitor and a well-known and commonly prescribed immunosuppressant medication, is best known for its efficacy in the prevention of solid organ transplant rejection.

The I-SPY COVID Trial is designed to rapidly screen agents that show promise for two primary endpoints: reducing the time to recovery or risk of mortality in critically ill patients with COVID-19. The study uses QLHC’s adaptive platform trial design methodology.

Angela Haczku, M.D., Ph.D.

“Although cyclosporine at the selected low dose and duration of treatment did not accomplish the primary endpoints set originally in the study design, we are currently analyzing the effects of this drug on immune biomarkers and other disease outcomes,” Angela Haczku, M.D., Ph.D., and Ari Moskowitz, M.D., who led the study of this agent in the I-SPY COVID Trial, said in a press release. Haczku is associate dean for Translational Research for the School of Medicine at UC Davis. Moskowitz is a Pulmonary and Critical Care attending at Beth Israel Deaconess Medical Center and an instructor of Medicine in Harvard Medical School.

The testing of cyclosporine was discontinued at the recommendation of the trial data monitoring committee after 108 subjects were randomized to the cyclosporine arm and analyzed in the intent-to-treat (ITT) population compared with 127 subjects who were randomized to the control arm. The probability that cyclosporine could reduce time to recovery was estimated to be 15.4%; the probability that the cyclosporine arm was superior to the concurrent arm to reduce mortality was estimated to be 54.8%. As a result, neither the recovery nor mortality outcomes met the pre-defined criteria for cyclosporine's graduation from the trial.

Investigators also observed that a higher fraction of subjects in the cyclosporine arm reported adverse events possibly related to the study agent compared with that of the concurrent control group, but they said this would be difficult to interpret in an open label trial. Given these data, the cyclosporine arm was closed to further enrollment.

Haczku and Moskowitz said there are several questions that would be important to address in future research. For example: What are the factors that contributed to the change in patient enrollment into the cyclosporine arm during the second year of the pandemic? What is the relationship of blood cyclosporine concentrations to biomarkers of COVID-19? How did the well-established and extensively detailed list of adverse cyclosporine effects influence the frequency of reporting in this open-label trial?

The I-SPY COVID Trial is an adaptive platform trial designed to increase trial efficiency by minimizing the number of participants and time required to evaluate experimental and/or repurposed drugs. Investigation into additional agents via the I-SPY COVID Trial is ongoing and remains an urgent priority for QLHC and its partners. The I-SPY COVID Trial now includes 33 sites as well as leaders in pulmonary and critical care centers from around the country.

One of the future goals is to improve biomarker classification of COVID-19 severe illness, investigators said.