Researchers from Vita-Salute San Raffaele University as well as collaborative colleagues recently concluded a small retrospective study based in Italy focusing on the most at risk of COVID-19 patients. The mortality rates for those SARS-CoV-2 patients afflicted with acute respiratory distress syndrome (ARDS) and systemic inflammation is high—the loss of life is tragic. When the pathogen flares in a pandemic situation the number of individuals experiencing severe conditions can push health systems beyond their capacity and a number of patients must receive non-invasive ventilation outside of the Intensive Care Unit (ICU) effectively placing more patients in dire risk. The Italian research team sought to look at treatments for this at-risk population—focusing in on Anakinra, a recombinant interleukin-1 receptor antagonist that could potentially help this population. Part of a biobank study, the team found that treatment with high-dose anakinra was safe and associated with clinical improvements in 72% of patients. Of course the investigators acknowledge that a confirmation of the efficacy necessitates randomized controlled trials but nonetheless this study establishes an important data point for forthcoming research.
As COVID-19 raged through nations, such as Italy and the United States, in some locals the pandemic completely overwhelmed health systems where the actual number of patients with COVID-19 and ARDS exceeded the maximum capacity of local ICUs. In such situations, the overall lethality of the pathogen heightens creating a more dire overall situation. In many cases, while awaiting ICU access and additional therapeutic care, patients received maximum supportive treatment including non-invasive ventilation in medical wards for example.
Anakinra (Kineret) was profiled by TrialSite News when the drug maker, Swedish biotech Sobi, announced the use of the drug for a short-term clinical trial evaluating the efficacy and safety of both anakinra and emapalumab to treat hyper-inflammatory syndrome, one of the most dangerous complications associated with severe COVID-19. TrialSite News noted that Sobi responded to a request by Italian physicians to supply drug for the study by that country’s National Institute for infectious Disease.
With a trade name Kineret®, it is a recombinant protein drug approved for the treatment of patients with CAPS (Cryopyrin Associated Periodic Syndrome), RA (Rheumatoid Arthritis) and Still’s disease. This approved drug therapy harnesses the biological activity of IL-1 by binding to the interleukin-1 type 1 receptor, expressed in a wide variety of tissues and organs.
This small observational study was sponsored by Vita-Salute San Raffaele University in Milan, Italy. Also known as UniSR, this private university was founded in 1996 and is organized around three departments including Medicine, Philosophy and Psychology. The overarching observational biobank study is led by Professors Giovanni Landoni and Alberto Zangrillo. This specific ARDS study’s corresponding author is Giulio Cavalli, MD.
The Overarching Biobank Study
Led by Vita-Salute San Raffaele University and professors Zangrillo and Landoni and titled, “Study to Characterize Patients With SARS-Cov-2 Infection and to Create a Biobank to Identify Predictors of Disease Severity, Mortality and Treatment Response“ the Italian researchers are collecting COVD-19 patient data from up to 1,000 participants across a range of research sites in that European nation. More specifically, they are leveraging electronic health records and associated patient information to collect and analyze demographic, clinical radiographic and laboratory characteristics of COVID-19 patients in a quest to identify predictors of disease severity, mortality and treatment response, and to identify subgroup of patients that might benefit from specific therapeutic interventions.
The study team identified groups based on inclusion criteria including aged 18 and up with COVID-19 and moderate-to-severe ARDS plus hyperinflammation (defined at serum C-reactive protein ≥1100 mg/L, ≥900 ferritin 900 ng/mL, or both) who were managed with non-invasive ventilation outside of the ICU and who also were treated with lopinavir with 100 mg ritonavir twice a day orally as reported in the Lancet Rheumatology. The team thereafter observed and compared the survival, mechanical ventilation-free survival changes in C-reactive protein, respiratory function, and clinical status in a cohort of patients receiving addition treatment of anakinra (either 5 mg/kg twice a day intravenously [high dose] or 100 mg twice a day subcutaneously [low dose] with an identified retrospective cohort of patients not receiving anakinra (the standard treatment group). They assessed all outcomes within a 21-day time frame.
Study Findings Summary
The team focused their efforts for this cohort study at Milan’s San Raffaele Hospital. They identified a cohort receiving anakinra and one receiving standard of care. Their analysis suggests that those receiving the treatment typically used to address auto-inflammatory disorders like rheumatoid arthritis turned out to be “safe and associated with clinical improvement in 72% of patients.” Moreover, they found improvements associated with respiratory function and reductions in an inflammatory marker known as C-reactive protein.
More specifically, the actual cumulative survival rate for those in the anakinra cohort was significantly higher at 21 days as compared to the control group that received the standard of care (90% vs. 56% respectively, P=0.009). They did observe however, a non-significant difference between observational study drug and standard of care groups when in regards to the delta in mechanical ventilation-free survival. (72% vs. 50%, P=0.15) noted Giulio Cavalli, MD—the corresponding author—in the Lancet Rheumatology. For this latter group, the study included only 29 patients receiving anakinra and 16 standard of care.
No Conclusion but Important Data Points
No conclusions can be made from this study as the authors themselves note in their published report. A retrospective study with a small sample can’t be used to draw any conclusions. An associated editorial that accompanied the findings from Dr. Scott Cana from the University of Pittsburgh Medical Center noted that “in view of the biological plausibility of anakinra, the pharmacokinetic and safety profile of the drug, and a growing body of positive experience in autoinflammation and cytokine storm, these data are promising and support this approach in the planning and [enrollment] of [randomized] controlled trials.”
The study was funded by university department funds only.
Lead Research/Investigator (Corresponding Author)
Giulio Cavalli, MD, Vita-Salute San Raffaele University
Note, Dr. Cavalli was part of a significant study group. All of the researcher’s names can be viewed at the source in the Lancet Rheumatology.
Call to Action: Perhaps the study drug could be utilized in forthcoming randomized controlled trials involving COVID-19 patients with ARDS and inflammation.