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

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ClinicalTrials.gov Identifier: NCT04394884
Recruitment Status : Suspended (Administrative hold until a new trial begins that would allow co-enrollment of subjects into this study.)
First Posted : May 20, 2020
Last Update Posted : March 24, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( 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.


Condition or disease
COVID-19

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.

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Study Type : Observational
Estimated Enrollment : 120 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Pathogenesis of BTK-mediated Hyper-Inflammatory Responses in COVID-19
Estimated Study Start Date : September 9, 2021
Estimated Primary Completion Date : April 30, 2023
Estimated Study Completion Date : April 30, 2023

Group/Cohort
COVID-19 -
will receive BTK therapy for other reasons
COVID-19 + BTK
will receive BTK therapy
COVID-19 + No BTK
will not receive BTK therapy



Primary Outcome Measures :
  1. To characterize the immunologic mechanisms by which BTK inhibition may ameliorate hyper- inflammatory responses in patients with COVID-19. [ Time Frame: day 0, 1,3,7 ]
    Inflammatory pathway analyses following BTK inhibition in COVID-19 patients.


Secondary Outcome Measures :
  1. 1. Characterization of TLR3 and TLR7/8-dependent immunologic phenotypes in COVID-19 patients before and after BTK inhibition. [ Time Frame: day 0, 1,3,7 ]
    Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.

  2. 2. Evaluation of mechanisms of immune cell-specific activation, cytokine production, exhaustion and apoptosis in COVID-19 patients before and after BTK inhibition. [ Time Frame: day 0, 1,3,7 ]
    Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.

  3. 3. Transcriptional, chromatin, and epigenetic profiling of immune cells at the single cell level in COVID-19 patients before and after BTK inhibition. [ Time Frame: day 0, 1,3,7 ]
    Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.

  4. 4. Longitudinal evaluation of TCR and BCR repertoire development in COVID-19 patients before and after BTK inhibition. [ Time Frame: day 0, 1,3,7 ]
    Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.

  5. 5. Characterization of SARS- CoV-2 serological responses in COVID-19 patients with and without BTK inhibition. [ Time Frame: day 0, 1,3,7 ]
    Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.

  6. 6. Characterization of genetic variants that correlate with disease severity and/or response to BTK inhibition treatment. [ Time Frame: day 0, 1,3,7 ]
    Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.

  7. 7. Evaluation of soluble biomarkers as surrogate markers of hyper- inflammation/prognosis and of response to BTK inhibition therapy in COVID-19 patients [ Time Frame: day 0, 1,3,7 ]
    Transcriptomic, genomic, serological and immunologic analyses of response to BTK inhibition therapy in COVID- 19 patients.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
people admitted to the participating sites who have COVID-19 or some other disease were they are already receiving or will receive BTK therapy
Criteria
  • INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

  1. Ability to provide informed consent, and
  2. Men and women >=18 years of age at the time of signing the informed consent form, and
  3. Diagnosis of COVID-19 in hospitalized patients with hypoxemia (SpO2 less than or equal to 94% on room air), with plan to receive or not receive BTK inhibition for clinical or for external research study purposes, or
  4. Does not have COVID-19 and does have plan to receive BTK inhibition therapy for a clinical indication other than COVID-19 (either hospitalized or not).

EXCLUSION CRITERIA:

Individuals meeting any of the following criteria will be excluded from study participation:

  1. Documented history of hemoglobin from most recent blood draw <7g/dL if known.
  2. Pregnant or breastfeeding.
  3. Any condition that, in the opinion of the investigator, contraindicates participation in this study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04394884


Locations
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United States, Maryland
Johns Hopkins Hospital
Baltimore, Maryland, United States, 21205
Walter Reed National Medical Center
Bethesda, Maryland, United States, 20301
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Principal Investigator: Michail S Lionakis, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
Additional Information:
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT04394884    
Other Study ID Numbers: 200114
20-I-0114
First Posted: May 20, 2020    Key Record Dates
Last Update Posted: March 24, 2021
Last Verified: March 2021
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
Sample Collection
Immunological Mechanisms
SARS-CoV-2
Serelogic Response
Imflammatory Pathway