Pathogenesis of BTK-mediated Hyper-Inflammatory Responses in COVID-19 (RESPOND)

Withdrawn

• Conditions: COVID-19

• Registration Number: NCT04394884
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary

Background:

Coronavirus disease 2019 (COVID-19) is an acute respiratory syndrome. It is caused by the SARS-CoV-2 virus. People with severe COVID-19 infection have a hyper-inflammatory response. Bruton tyrosine kinase (BTK) plays a role in the innate immune system. BTK inhibition can be used to target the innate immune system that appears to contribute to mortality. This could be an effective way to help the inflammatory responses in people with COVID-19.

Objective:

To learn more about the immunologic mechanisms by which BTK inhibition may decrease hyper-inflammatory responses in people with COVID-19.

Eligibility:

People ages 18 and older in one of the following groups:

* They are in the hospital with COVID-19. They will or will not be treated with a BTK inhibitor.

* They do not have COVID-19. They are or are not in the hospital. They will be treated with a BTK inhibitor for a reason other than COVID-19.

Design:

Participants will be screened with a review of their demographic and clinical information. Their medical history will be reviewed. If they have COVID-19, their symptoms will be assessed.

Participants will give 3-4 blood samples. These may be taken through a vein. They may also be taken through an existing central venous catheter.

Participants may give a stool sample. This will be collected by nursing staff. It will be collected using a stool collection vial. Stool collection is optional.

Participants samples will be collected over about 7 days. These will be used for research and genetic testing.

Detailed Description

Coronavirus disease 2019 (COVID-19) is an acute respiratory syndrome caused by the novel coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Severe COVID-19 infection is associated with a hyper-inflammatory response and evidence of innate immune cell activation. Bruton tyrosine kinase (BTK) plays a central role in innate immune cell signaling and activation and BTK inhibition represents a promising therapeutic strategy for ameliorating excessive inflammatory responses in patients with COVID-19. Understanding the mechanisms by which BTK inhibition modulates the host inflammatory response in patients with COVID-19 is critical in order to better understand COVID-19 pathogenesis.

In this multisite natural history laboratory study, hospitalized patients with COVID-19 (n=80) will be recruited at Walter Reed National Military Medical Center and The Johns Hopkins Hospital. Forty of these patients will be recipients of BTK inhibition, either as part of their standard clinical care or in another clinical trial. The other 40 will not be recipients of BTK inhibition and will serve as a control group. A third group of patients without COVID-19 (n=40) who will be recipients of BTK inhibition for other clinical indications will also be enrolled as a second control group.

Participants will have three or four longitudinal blood draws and may be asked to provide stool samples. All specimens and data will be coded and sent to the National Institutes of Health (NIH) for research analysis. Only site investigators will have access to the code s key for their respective sites; the NIH investigators will not have the keys. Coded blood samples will be used for genetic testing, transcriptional analyses, deep immunological phenotyping, soluble biomarker analysis, and other research tests. Coded clinical and laboratory data from routine care (e.g., basic demographic information, vital signs, medications, clinical labs, and radiologic imaging findings) will also be captured. Coded stool samples may be collected as part of this study to determine whether viable SARS-CoV-2 is present in stool, which will help advance our understanding of pathogenesis and enteric transmission.

Study Timeline

• Study First Submitted: 2020-05-19
• Study First Submitted QC: 2020-05-19
• Study First Posted: 2020-05-20
• Status Verified: 2022-02
• Study Start: 2022-02-17
• Primary Completion: 2022-02-17
• Study Completion: 2022-02-17
• Last Update Submitted: 2022-02-23
• Last Update Posted: 2022-02-24

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To characterize the immunologic mechanisms by which BTK inhibition may ameliorate hyper- inflammatory responses in patients with COVID-19.	day 0, 1,3,7	Inflammatory pathway analyses following BTK inhibition in COVID-19 patients.

Secondary Outcome Measures

Name	Time	Method
7. Evaluation of soluble biomarkers as surrogate markers of hyper- inflammation/prognosis and of response to BTK inhibition therapy in COVID-19 patients	day 0, 1,3,7	Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.
3. Transcriptional, chromatin, and epigenetic profiling of immune cells at the single cell level in COVID-19 patients before and after BTK inhibition.	day 0, 1,3,7	Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.
4. Longitudinal evaluation of TCR and BCR repertoire development in COVID-19 patients before and after BTK inhibition.	day 0, 1,3,7	Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.
5. Characterization of SARS- CoV-2 serological responses in COVID-19 patients with and without BTK inhibition.	day 0, 1,3,7	Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.
6. Characterization of genetic variants that correlate with disease severity and/or response to BTK inhibition treatment.	day 0, 1,3,7	Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.
1. Characterization of TLR3 and TLR7/8-dependent immunologic phenotypes in COVID-19 patients before and after BTK inhibition.	day 0, 1,3,7	Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.
2. Evaluation of mechanisms of immune cell-specific activation, cytokine production, exhaustion and apoptosis in COVID-19 patients before and after BTK inhibition.	day 0, 1,3,7	Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.

Trial Locations

Locations (3)

Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States

Walter Reed National Medical Center; 🇺🇸 Bethesda, Maryland, United States

National Institutes of Health Clinical Center; 🇺🇸 Bethesda, Maryland, United States