Methodologies for Observational Studies Comparing Inpatient COVID-19 Treatments

Methodologies for Observational Studies Comparing Inpatient COVID-19 Treatments: IL-6 Receptor Inhibitors and JAK Inhibitors for Hospitalized COVID-19 Patients Receiving Corticosteroid Therapy

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 Coronavirus Disease 2019 (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.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Initiation of IL6Ri (tocilizumab or sarilumab) versus JAKi (baricitinib or tofacitinib) added to systemic corticosteroids of interest (CSI)

Detailed Description

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 real world data (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.

• Study Type: Observational
• Enrollment (Actual): 1442

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10001
      • Aetion, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The overall cohort for our Illustrative Example will consist of insured adults hospitalized with COVID-19 between June 16, 2020 to February 01, 2022 who require supplemental oxygen or ventilation support and initiate either IL6Ri (TCZ or SAR) or JAKi (BAR or TOF) in addition to systemic CSIs within 4 days after hospital admission. All patients will be required to have at least one procedure for oxygen supplementation and at least one recorded CSI administration from admission to treatment initiation, since during the study period IL6Ri and JAKi were only indicated for patients receiving CSIs and some level of oxygen or ventilation support.

Description

Inclusion Criteria:

• Hospitalized from June 16, 2020 to February 01, 2022 with an international classification of diseases (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 modified World Health Organization (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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Interleukin-6 receptor inhibitor (IL6Ri) initiators vs Janus kinase inhibitor (JAKi) initiators; Hospitalized patients who initiate an IL6Ri versus JAKi in addition to a corticosteroid of interest	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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inpatient mortality	Inpatient mortality up to 28 days after IL6Ri or JAKi initiation	up to 28 days after IL6Ri or JAKi initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression to IMV or ECMO	Progression to IMV or ECMO up to 28 days after IL6Ri or JAKi initiation (Illustrative Example - Objective I only)	up to 28 days after IL6Ri or JAKi initiation

Collaborators and Investigators

• Sponsor: Aetion, Inc.
• Investigators: Principal Investigator: Vera Frajzyngier, PhD, Aetion, Inc.; Principal Investigator: Liz M Garry, PhD, Aetion, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 16, 2020
• Primary Completion (Actual): September 25, 2023
• Study Completion (Actual): September 25, 2023

Study Registration Dates

• First Submitted: December 2, 2022
• First Submitted That Met QC Criteria: December 2, 2022
• First Posted (Actual): December 6, 2022

Study Record Updates

• Last Update Posted (Actual): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 16, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Janus Kinase Inhibitors; Tofacitinib
• Other Study ID Numbers: BAA1-RO3-20221202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Study results will report aggregated findings

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No