Pathogenesis of BTK-mediated Hyper-Inflammatory Responses in COVID-19 (RESPOND)
Ključne riječi
Sažetak
Opis
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.
Datumi
| Posljednja provjera: | 05/17/2020 |
| Prvo podneseno: | 05/18/2020 |
| Predviđena prijava poslana: | 05/18/2020 |
| Prvo objavljeno: | 05/19/2020 |
| Posljednje ažuriranje poslano: | 07/27/2020 |
| Posljednje ažuriranje objavljeno: | 07/28/2020 |
| Stvarni datum početka studija: | 08/02/2020 |
| Procijenjeni datum primarnog završetka: | 04/29/2023 |
| Procijenjeni datum završetka studije: | 04/29/2023 |
Stanje ili bolest
Faza
Grupe ruku
| Ruka | Intervencija / liječenje |
|---|---|
| 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 |
Kriterij prihvatljivosti
| Dobni uvjeti za studiranje | 18 Years Do 18 Years |
| Spolovi koji ispunjavaju uvjete za studij | All |
| Metoda uzorkovanja | Non-Probability Sample |
| Prihvaća zdrave volontere | Da |
| Kriteriji | - 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. |
Ishod
Primarne mjere ishoda
1. To characterize the immunologic mechanisms by which BTK inhibition may ameliorate hyper- inflammatory responses in patients with COVID-19. [day 0, 1,3,7]
Sekundarne mjere ishoda
1. 1. Characterization of TLR3 and TLR7/8-dependent immunologic phenotypes in COVID-19 patients before and after BTK inhibition. [day 0, 1,3,7]
2. 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]
3. 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]
4. 4. Longitudinal evaluation of TCR and BCR repertoire development in COVID-19 patients before and after BTK inhibition. [day 0, 1,3,7]
5. 5. Characterization of SARS- CoV-2 serological responses in COVID-19 patients with and without BTK inhibition. [day 0, 1,3,7]
6. 6. Characterization of genetic variants that correlate with disease severity and/or response to BTK inhibition treatment. [day 0, 1,3,7]
7. 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]
