To apply and compare two different methodological approaches (one applying diagnostics steps and contingencies and the other not) to the illustrative example described below: Illustrative Example - Objective I aims to characterize the risk of inpatient mortality [Primary Outcome] and progression to invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) [Secondary Outcome] up to 28 days after interleukin-6 receptor inhibitors (IL6Ri) or janus kinase inhibitor (JAKi) initiation among patients hospitalized with COVID-19 who initiate a corticosteroid of interest and require supplemental oxygen / non-invasive ventilation / high flow oxygen (O2/NIV/HFO) (but not IMV/ECMO). Illustrative Example - Objective II aims to characterize the risk of inpatient mortality [Primary Outcome] up to 28 days after IL6Ri or JAKi initiation among patients admitted to the ICU at hospital admission with COVID-19 who initiate a CSI and require IMV/ECMO. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) will be estimated and reported for all outcome risks in Illustrative Example objectives.
In this study we seek to evaluate current methodologies for observational comparative studies
of inpatient COVID-19 treatments [Overall Study Objective]. To support this overall study
objective, we have defined additional supporting objectives related to the research process
[Process Objectives] as applied to an illustrative example of an observational study to
evaluate the comparative effectiveness of inpatient COVID-19 treatments [Illustrative
Example].
Process Objectives:
Characterize differences in study results when an intentional multiphase approach (IMA) to
diagnostics and contingencies is applied to RWD analysis compared to an approach that
pre-specifies all covariates and statistical approaches without consideration of whether key
statistical assumptions hold (Single-phase Prespecification Approach, SPA).
Illustrative Example:
Our illustrative example will use a large population-based US claims data source to emulate a
hypothetical target trial to assess the comparative effectiveness of IL6Ri (TCZ or SAR)
versus JAKi (BAR or TOF) added to systemic corticosteroids of interest (CSI). The underlying
hypothetical target trial of interest consists of patients hospitalized and requiring
respiratory support for COVID-19 and receiving a CSI who are assigned to receive either an
IL6Ri or JAKi in addition to CSI within 4 days after hospital/ICU admission. The patients are
followed for up to 28 days for the outcomes of inpatient mortality and progression to
IMV/ECMO. The Illustrative Example is separated into two sub-objectives based on the
different COVID-19 severity populations of interest.
Illustrative Example - Objective I aims to characterize the risk of inpatient mortality
[Primary Outcome] and progression to IMV or ECMO [Secondary Outcome] up to 28 days after
IL6Ri or JAKi initiation among patients hospitalized with COVID-19 who initiate a CSI and
require supplemental O2/NIV/HFO (but not IMV/ECMO).
Illustrative Example - Objective II aims to characterize the risk of inpatient mortality
[Primary Outcome] up to 28 days after IL6Ri or JAKi initiation among patients admitted to the
ICU at hospital admission with COVID-19 who initiate a CSI and require IMV/ECMO.
Hazard ratios (HR) and corresponding 95% confidence intervals (CI) will be estimated and
reported for all outcome risks in Illustrative Example objectives.
Drug: Initiation of IL6Ri (tocilizumab or sarilumab) versus JAKi (baricitinib or tofacitinib) added to systemic corticosteroids of interest (CSI)
Real world use of either IL6Ri (TCZ or SAR) or JAKi (BAR or TOF)
Inclusion Criteria:
- Hospitalized from June 16, 2020 to February 01, 2022 with an ICD-10 diagnosis code of
U07.1 in an any admitting diagnosis position (Day 0)
- Initiate either IL6Ri or JAKi within 4 days after hospital admission (Days 0 to 4)
- Receiving systemic CSI on day of IL6Ri/JAKi initiation (Day T)
- Receipt of at least one respiratory support procedure (oxygen supplementation at a
minimum) from admission to IL6Ri/JAKi initiation (Days 0 to T)
For Illustrative Example - Objective I only:
-maximum mWHO disease severity of O2/NIV/HFO from admission to IL6Ri/JAKi initiation (Days
0 to T)
For Illustrative Example - Objective II only:
- Admission to ICU at hospital admission (Day 0) and mWHO disease severity of IMV/ECMO
from hospital/ICU admission to IL6Ri/JAKi initiation (Days 0 to T)
- Continuous medical claims enrollment (60-day gaps permitted) during the 183 day
baseline period prior to and including hospital or ICU admission (Days -183 to 0) to
minimize the potential for misclassification of baseline covariates
Exclusion Criteria:
- Exclude patients without continuous medical claims enrollment (60-day gaps permitted)
during the 183-day baseline period prior to and including hospital/ICU admission (Days
-183 to 0) to minimize the potential for misclassification of baseline covariates.
- Exclude patients if COVID-19 hospitalization (Day 0) begins >14 days after initial
COVID-19 diagnosis. Patients will be excluded if any COVID-19 diagnosis is recorded
from 90 days to 15 days before admission (Days -90 to -15) to exclude patients with
possible long-term COVID or post-acute sequelae while still permitting prior
infections recorded more than 90 days pre-admission.
- No age, sex, or geographic region recorded on hospital admission (Day 0)
- Age less than 18 years at hospital admission (Day 0)
- Evidence of a prior COVID-related inpatient hospitalization in the previous 14 days
(Days -14 to -3), with a two-day buffer to permit brief inpatient utilization directly
proceeding transfer to a chargemaster hospital (i.e., inpatient utilization permitted
on Days -2 to -1)
- Systemic CSI use (dispensing or remaining supply) in the previous 14 days (Days -14 to
-3), with a two-day buffer to permit CSI use beginning in the emergency department or
other healthcare setting immediately prior to chargemaster hospital admission (CSI use
permitted Days -2 to -1)
- Any recorded use of IL6Ri or JAKi (dispensing or remaining supply) in the 90-day
washout period before IL6Ri or JAKi initiation (Days -90 to T-1), to satisfy new use
definition
- Baseline receipt of oxygen or ventilation support for non-COVID conditions (e.g.,
supplemental oxygen for COPD), defined as two or more respiratory support procedures
recorded on different days from Days -90 to -15 via procedure codes from medical
claims, chargemaster, and where available, oxygen supplies recorded in pharmacy
settings.
- Death or discharge occurs before or on the day of treatment initiation (Days 0 to T)
- Recorded use of both IL6Ri and JAKi on Day T
Aetion, Inc.
New York, New York, United States