A Randomized Controlled Trial to Evaluate the Safety and Efficacy of a Novel Inhaled Biologic Therapeutic in Adults with Respiratory Distress Secondary to COVID-19 Infection.
COVID-19
Efficacy
Inhalation treatment
Safety
Journal
Infectious diseases and therapy
ISSN: 2193-8229
Titre abrégé: Infect Dis Ther
Pays: New Zealand
ID NLM: 101634499
Informations de publication
Date de publication:
Feb 2022
Feb 2022
Historique:
received:
06
10
2021
accepted:
29
10
2021
pubmed:
15
11
2021
medline:
15
11
2021
entrez:
14
11
2021
Statut:
ppublish
Résumé
Inhaled therapeutics may act to directly target and attenuate lung inflammation due to COVID-19. An inhalation form of a novel biologic drug, AMP5A, is being developed as an immunomodulatory agent to treat dysregulated immune responses and is being studied in hospitalized patients to treat respiratory complications due to COVID-19. A randomized, controlled, phase I trial was conducted to evaluate hospitalized adults with respiratory distress secondary to COVID-19. Patients received the standard care (SOC) for COVID-19, including respiratory therapy, corticosteroids, and antiviral therapies such as remdesivir. Patients were randomized 1:1 to inhalation treatment with AMP5A as an adjunct to SOC or to SOC alone (control). AMP5A was administered via inhalation daily for 5 days via hand-held nebulizer, non-invasive ventilator, or mechanical ventilation. Safety and clinical efficacy endpoints were evaluated. Forty subjects were enrolled and randomized (n = 19 AMP5A, n = 21 control). Remdesivir was used in fewer AMP5A subjects (26%) than control (52%), and dexamethasone was administered for most subjects (84% AMP5A, 71% control). The study met its primary endpoint with no AMP5A treatment-related adverse events (AEs), and the incidence and severity of AEs were comparable between groups: 18 AEs for control (8 mild, 1 moderate, 9 severe) and 19 AEs for AMP5A (7 mild, 7 moderate, 5 severe). Notably, subjects treated with AMP5A had fewer deaths (5% vs. 24%), shorter hospital stay (8 days vs. 12 days), fewer ICU admissions (21% vs. 33%), and a greater proportion with improved clinical outcomes than control. The phase I clinical results indicate inhaled AMP5A is safe, is well tolerated, and could lead to fewer patients experiencing deterioration or death. Based on the treatment effect (i.e., reduced mortality), a phase II trial has been initiated. Clinicaltrials.gov identifier: NCT04606784.
Identifiants
pubmed: 34775578
doi: 10.1007/s40121-021-00562-z
pii: 10.1007/s40121-021-00562-z
pmc: PMC8590808
doi:
Banques de données
ClinicalTrials.gov
['NCT04606784']
Types de publication
Journal Article
Langues
eng
Pagination
595-605Informations de copyright
© 2021. The Author(s).
Références
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese center for disease control and prevention. JAMA. 2020;323(13):1239–42.
doi: 10.1001/jama.2020.2648
Stringer S, Minica CC, Verweij KJ, Mbarek H, Bernard M, Derringer J, et al. Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium. Transl Psychiatry. 2016;6:e769.
doi: 10.1038/tp.2016.36
World Health Organization. (2020). https://apps.who.int/iris/handle/10665/331736 . License: CC BY-NC-SA 3.0 IGO Clinical care for severe acute respiratory infection: toolkit: COVID-19 adaptation. https://apps.who.int/iris/handle/10665/331736 . Accessed 27 Sep 2021.
Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405–7.
doi: 10.1016/j.healun.2020.03.012
Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK, et al. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe. 2016;19(2):181–93.
doi: 10.1016/j.chom.2016.01.007
Feldmann M, Maini RN, Woody JN, Holgate ST, Winter G, Rowland M, et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet. 2020;395(10234):1407–9.
doi: 10.1016/S0140-6736(20)30858-8
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.
doi: 10.1016/S0140-6736(20)30183-5
Food and Drug administration. https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs . Emergency Use Authorization. Accessed 27 Sep 2021.
Food and Drug administration. Know Your Treatment Options for COVID-19 https://www.fda.gov/consumers/consumer-updates/know-your-treatment-options-covid-19 . Accessed 27 Sep 2021.
Artigas A, Camprubi-Rimblas M, Tantinya N, Bringue J, Guillamat-Prats R, Matthay MA. Inhalation therapies in acute respiratory distress syndrome. Ann Transl Med. 2017;5(14):293.
doi: 10.21037/atm.2017.07.21
Thomas G, Frederick E, Thompson L, Bar-Or R, Mulugeta Y, Hausburg M, et al. LMWF5A suppresses cytokine release by modulating select inflammatory transcription factor activity in stimulated PBMC. J Transl Med. 2020;18(1):452.
doi: 10.1186/s12967-020-02626-z
Bar-Or D, Salottolo KM, Loose H, Phillips MJ, McGrath B, Wei N, et al. A randomized clinical trial to evaluate two doses of an intra-articular injection of LMWF-5A in adults with pain due to osteoarthritis of the knee. PLoS ONE. 2014;9(2):e87910.
doi: 10.1371/journal.pone.0087910
Cole B, McGrath B, Salottolo K, Bar-Or D. LMWF-5A for the treatment of severe osteoarthritis of the knee: integrated analysis of safety and efficacy. Orthopedics. 2018;41(1):e77–83.
doi: 10.3928/01477447-20171114-05
Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307(23):2526–33.
Siegel MH, RC. Ventilator management strategies for adults with acute respiratory distress syndrome. In: UpToDate, editor. https://www.uptodate.com/contents/ventilator-management-strategies-for-adults-with-acute-respiratory-distress-syndrome#H252021 . Accessed 27 Sep 2021.
World Health Organization. R&D blueprint novel coronavirus COVID-19 therapeutic trial synopsis. Geneva: WHO; 2020.
Recovery Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693–704.
doi: 10.1056/NEJMoa2021436
Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020;369:m1985.
doi: 10.1136/bmj.m1985
Angamo MT, Mohammed MA, Peterson GM. Efficacy and safety of remdesivir in hospitalised COVID-19 patients: a systematic review and meta-analysis. Infection. 2021. https://doi.org/10.1007/s15010-021-01671-0 .
doi: 10.1007/s15010-021-01671-0
pubmed: 34331674
pmcid: 8325414
Elsawah HK, Elsokary MA, Abdallah MS, ElShafie AH. Efficacy and safety of remdesivir in hospitalized Covid-19 patients: systematic review and meta-analysis including network meta-analysis. Rev Med Virol. 2021;31(4):e2187.
doi: 10.1002/rmv.2187
Singh S, Khera D, Chugh A, Khera PS, Chugh VK. Efficacy and safety of remdesivir in COVID-19 caused by SARS-CoV-2: a systematic review and meta-analysis. BMJ Open. 2021;11(6):e048416.
doi: 10.1136/bmjopen-2020-048416
Tasavon Gholamhoseini M, Yazdi-Feyzabadi V, Goudarzi R, Mehrolhassani MH. Safety and efficacy of remdesivir for the treatment of COVID-19: a systematic review and meta-analysis. J Pharm Pharm Sci. 2021;24:237–45.
doi: 10.18433/jpps31870
Salottolo K, Cole B, Bar-Or D. Intra-articular injection of the anti-inflammatory compound LMWF-5A in adults with severe osteoarthritis: a double-blind prospective randomized controlled multi-center safety and efficacy trial. Patient Saf Surg. 2018;12:11.
doi: 10.1186/s13037-018-0158-0
Bar-Or D, Thomas GW, Bar-Or R, Rael LT, Scarborough K, Rao N, et al. Commercial human albumin preparations for clinical use are immunosuppressive in vitro. Crit Care Med. 2006;34(6):1707–12.
doi: 10.1097/01.CCM.0000217923.53680.4C
Frederick ED, Hausburg MA, Thomas GW, Rael LT, Brody E, Bar-Or D. The low molecular weight fraction of human serum albumin upregulates COX2, prostaglandin E2, and prostaglandin D2 under inflammatory conditions in osteoarthritic knee synovial fibroblasts. Biochem Biophys Rep. 2016;8:68–74.
pubmed: 28955943
pmcid: 5613771
Thomas G, Frederick E, Hausburg M, Goldberg L, Hoke M, Roshon M, et al. The novel immunomodulatory biologic LMWF5A for pharmacological attenuation of the “cytokine storm” in COVID-19 patients: a hypothesis. Patient Saf Surg. 2020;14:21.
doi: 10.1186/s13037-020-00248-4
Thomas GW, Rael LT, Hausburg M, Frederick ED, Brody E, Bar-Or D. The low molecular weight fraction of commercial human serum albumin induces acetylation of alpha-tubulin and reduces transcytosis in retinal endothelial cells. Biochem Biophys Res Commun. 2016;478(4):1780–5.
doi: 10.1016/j.bbrc.2016.09.026
Thomas GW, Rael LT, Mains CW, Slone D, Carrick MM, Bar-Or R, et al. Anti-inflammatory activity in the low molecular weight fraction of commercial human serum albumin (LMWF5A). J Immunoassay Immunochem. 2016;37(1):55–67.
doi: 10.1080/15321819.2015.1047516
Del Valle DM, Kim-Schulze S, Huang HH, Beckmann ND, Nirenberg S, Wang B, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636–43.
doi: 10.1038/s41591-020-1051-9
Yang J. Serum levels of TNF-α, IL-1β, IL-9, and IL-15 in acute respiratory distress syndrome. Int J Clin Exp Pathol. 2017;10(1):781–8.
Shimonkevitz R, Thomas G, Slone DS, Craun M, Mains C, Bar-Or D. A diketopiperazine fragment of human serum albumin modulates T-lymphocyte cytokine production through rap1. J Trauma. 2008;64(1):35–41.
pubmed: 18188096
Thomas GW, Rael LT, Hausburg M, Frederick ED, Mains CW, Slone D, et al. The low molecular weight fraction of human serum albumin upregulates production of 15d-PGJ2 in peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2016;473(4):1328–33.
doi: 10.1016/j.bbrc.2016.04.072