Lead Investigator: Dennis McGonagle, University of Leeds
Title of Proposal Research: The effect of Body Mass Index (BMI) and Age on Baricitinib efficacy in Covid-19 patients
Vivli Data Request: 8450
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Since the beginning of the pandemics, the Covid-19 infection has killed millions of people worldwide. The mortality in Covid-19 patients has been linked to both alveolar damage and immunothrombosis in the pulmonary capillary network. Alveolar damage is described as specific changes that occur to the structure of the lungs during injury or disease, while immunothrombosis refers to the formation of blood coagulation and platelet aggregation which may result in lack of blood flow through the circulatory system, resulting in depletion of oxygen that may cause irreversible damage. The Sars-Cov-2 virus leads to virally mediated inflammation in the alveolus which can lead to destruction of type 2 pneumocytes with subsequent fibrosis causing alveolar damage. The pulmonary arterial three ultimately divides into a network of billions of capillaries that ensheath the alveoli and mediates gas exchange. Immunothrombosis in these sites prevents this happening. It has been widely described in severe covid-19 patients.
Baricitinib is a reversible Janus-Kinase (JAK) inhibitor drug with selectivity for JAK1 and JAK2. JAK proteins are associated to receptors for many inflammatory molecules and essential for their action. Baricitinib was licensed initially for the treatment of Rheumatoid Arthritis and works by the combinatorial inhibition of key cytokines, including interleukin-6 (IL-6), and also the modulation of lymphocyte function.
Most recently, Baricitinib was proven to reduce mortality and need for mechanical ventilation among hospitalized Covid-19 patients, being effective especially in subjects with severe Covid-19 that require supplemental oxygen. Other immunomodulatory agents including corticosteroids and il-6 blockers have also been proven to be effective for severe Covid-19.
We believe that the benefit of JAK inhibition in Covid-19 relates to the ability of these drugs to mitigate against immunothrombosis in COVID-19 pneumonia. We also think that poorer clinical outcomes in COVID-19 in obese subjects, older subjects with ischemic heart disease, i.e, atherosclerotic coronary artery disease, that typically manifests as myocardial infarction, angina pectoris or heart failure, and other cardiovascular risk factors relate to the immunothrombosis.
We want to analyze closer the COV BARRIER data (a Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Study of Baricitinib in Patients With COVID-19 Infection) and evaluate possible links between survival and Body Mass Index (BMI)—a surrogate marker for the determination of the degree of obesity – and age across the BMI and age spectrum.
We expect that younger subjects with normal BMI and COVID-19 pneumonia may benefit less from the Baricitinib treatment as the immunothrombosis, which we believe is beneficially modulated, is more severe in older subjects that have higher BMI. Thrombosis is general commoner with older age. This is multifaceted and linked to factors such as “immunesenescence”, where there is generally a greater reliance on innate immune cells for immune responses and we theorize this may be a factor in Covid-19 severity.
Statistical Analysis Plan:
The study population comprises the cohort originally enrolled for the COV-BARRIER trial, without further exclusion. Exposure is considered blinded treatment with baricitinib according to the COV-BARRIER trial protocol. Exposure will be regarded in an intention-to-treat manner. The index date will be considered the date of randomization.
Comparing the baricitinib group with the placebo group, the primary outcome will be considered all-cause mortality by day 28, and by day 60. The secondary outcome will be a composite of several features reflecting disease severity according to the National Institute of Allergy and Infectious Disease Ordinal Scale (NIAID-OS) including the proportion of participants who progressed to high-flow oxygen or non-invasive ventilation (NIAID-OS score 6), invasive mechanical ventilation or extracorporeal membrane oxygenation (NIAID-OS score 7), or death (NIAID-OS score 8) by day 28.
Logistic regression will be used for dichotomous endpoints, proportional odds models will be used for ordinal endpoints, Linear regression will be used for continuous endpoints. Log-rank tests and hazard ratios (HRs) from Cox proportional hazard models were used for time-to-event analyses.
Prespecified subgroup analyses for the primary and secondary endpoints will evaluate treatment effect across different sections of the following subgroups: BMI (<25; 31-35; >35 kg/m2 ), Age (20-60; 61-80; >81 years).
We firstly intended to categorize the age in four subgroups (20-40, 41-60, 61-80, > 81 years old)
However, we understand that there are few patients in the lower age group. As indicated, age will be treated both as a continuous variable, to investigate a linear trend, as well as a categorized variable, to investigate possible differential efficacy of baricitinib. For example, perhaps younger patients with very high BMI could have additional benefit from the treatment with baricitinib. These types of associations could not be discovered without appropriate categorization and cross analyses. Nonetheless the concern raised regarding lower rates of outcomes is appropriate therefore we decided to unite the age categories of 20-40 years old and 40-60 years old together into a single age group of 20-60 years old which will ensure a higher number of events.
Statistical tests of treatment effects were done at a two-sided significance level of 0·05, unless otherwise stated. All statistical analysis was done using SPSS software, version 26 (SPSS, Armonk, NY: IBM Corp).
Requested Studies:
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Study of Baricitinib in Patients With COVID-19 Infection
Data Contributor: Lilly
Study ID: NCT04421027
Sponsor ID: 17830
Public Disclosures:
David, P., Hen, O., Ben-Shabbat, N., Macleod, T., Amital, H., Watad, A. and McGonagle, D.G., 2024. Pronounced benefits of JAK inhibition with baricitinib in COVID-19 pneumonia in obese but not lean subjects. RMD open, 10(2), p.e004045. Doi : 10.1136/rmdopen-2023-004045