ACCORD: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients: A structured summary of a study protocol for a randomised controlled trial

Wilkinson, Tom; Dixon, Rupert; Page, Clive; Carroll, Miles W.; Griffiths, Gareth; Ho, Ling-Pei; Soyza, Anthony De; Felton, Timothy; Lewis, Keir; Phekoo, Karen; Chalmers, James D.; Gordon, Anthony; McGarvey, Lorcan; Doherty, J C; Read, Robert C.; Shankar-Hari, Manu; Martinez-Alier, Nuria; O’Kelly, Michael; Duncan, Graeme; Walles, Roelize; Sykes, J.M.; Summers, Charlotte; Singh, Dave

doi:10.1186/s13063-020-04584-9

Cited by 64 publications

(74 citation statements)

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“…It is anticipated that a MASP inhibitor such as Narsoplimab will not exert a massive therapeutic effect on the EM pathogenesis since no evidence is available so far that is suggestive of a key involvement of the complement lectin pathway in the EM lesion formation. Various prospective anti-complement inhibitors studied so far are listed in Table 1 and Figure 4 ( 128 , 141 – 176 ).…”

Section: Possibility Of Anti-complement Immunotherapy In Endometriosimentioning

confidence: 99%

Immunological Basis of the Endometriosis: The Complement System as a Potential Therapeutic Target

et al. 2021

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Endometriosis (EM) is a chronic disease characterized by the presence and proliferation of functional endometrial glands and stroma outside the uterine cavity. Ovaries and pelvic peritoneum are the most common locations for endometrial ectopic tissue, followed by deep infiltrating EM sites. The cyclic and recurrent bleeding, the progressive fibrosis and the peritoneal adhesions of ectopic endometrial glands, may cause different symptoms depending on the origin involved. EM is a frequent clinical condition affecting around 10% of women of mainly reproductive age, as well as in post-menopausal women and adolescents, especially with uterine anomalies. The risk of developing EM depends on a complex interaction between genetic, immunological, hormonal, and environmental factors. It is largely considered to arise due to a dysfunction of immunological surveillance. In fact, women with EM exhibit altered functions of peritoneal macrophages, lymphocytes and natural killer cells, as well as levels of inflammatory mediators and growth factors in the peritoneal fluid. In EM patients, peritoneal macrophages are preponderant and highly active compared to healthy women. Peritoneal macrophages are able to regulate the events that determine the production of cytokines, prostaglandins, growth factors and complement components. Several studies have shown alteration in the regulation of the complement activation, leading to chronic inflammation characteristic of EM. Aberrant regulation/activation of the complement system has been observed in the peritoneal cavity of women affected by EM. Thus, complement inhibition may represent a new approach for the treatment of EM, given that a number of complement inhibitors are under pre-clinical and clinical development. Such an intervention may provide a broader therapeutic control of complement-mediated inflammatory damage in EM patients. This review will focus on our current understanding of the role of complement activation in EM and possible modalities available for complement-based therapy.

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Section: Possibility Of Anti-complement Immunotherapy In Endometriosimentioning

confidence: 99%

Immunological Basis of the Endometriosis: The Complement System as a Potential Therapeutic Target

et al. 2021

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“…Positive results in Phase 1b studies in renal indications are announced on their webpage, however, no further details are provided ( 216 ). On 11 May 2020, a prospective clinical study of zilucoplan in COVID-19 was initiated ( 217 ).…”

Section: Terminal Complement Pathway Inhibitors In Other Indicationsmentioning

confidence: 99%

“…A similar effect has been suggested in SARS-CoV ( 228 , 234 ) and increased C5a levels have been found in COVID-19 patients ( 18 ). Consequently, several C5, C5a, and C5aR1 inhibitors are currently undergoing clinical studies in COVID-19, such as eculizumab, which has already showed preliminary efficacy ( 236 ), ravulizumab ( 237 ), zilucoplan ( 217 ), IFX-1 ( 203 ), and avdoralimab ( 224 ).…”

Section: Terminal Complement Pathway Inhibitors In Other Indicationsmentioning

confidence: 99%

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

et al. 2020

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The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.

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“…Aiming at reducing the hyper inflammation found in the lungs of SARS-CoV-2-infected patients, different clinical studies are currently investigating the activities of mAbs anti-JAK, anti-GM-CSF, anti-GM-CSF receptor, anti-M-CSF receptor, anti-CD14, anti-IFNg, anti-VEGF, anti-BKT, anti-CCR5, anti-IL-6, anti-IL-6 receptor, anti-TNFa, anti-IL1b, anti-IL1b receptor, and complement C5 inhibitor (220,251,252). Similarly, ongoing clinical trials have sought to reverse the hyper-thrombotic state found in critically ill patients by using anti-P-selectin, anti-CTGF, and factor XIIa antagonist mAbs (253,254).…”

Section: Antibody-based Therapymentioning

confidence: 99%

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

et al. 2020

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Coronavirus Disease 2019 (COVID-19) has been classified as a global threat, affecting millions of people and killing thousands. It is caused by the SARS-CoV-2 virus, which emerged at the end of 2019 in Wuhan, China, quickly spreading worldwide. COVID-19 is a disease with symptoms that range from fever and breathing difficulty to acute respiratory distress and death, critically affecting older patients and people with previous comorbidities. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and mainly spreads through the respiratory tract, which it then uses to reach several organs. The immune system of infected patients has been demonstrated to suffer important alterations, such as lymphopenia, exhausted lymphocytes, excessive amounts of inflammatory monocytes and macrophages, especially in the lungs, and cytokine storms, which may contribute to its severity and difficulty of establishing an effective treatment. Even though no specific treatment is currently available, several studies have been investigating potential therapeutic strategies, including the use of previously approved drugs and immunotherapy. In this context, this review addresses the interaction between SARS-CoV-2 and the patient's host immune system during infection, in addition to discussing the main immunopathological mechanisms involved in the development of the disease and potential new therapeutic approaches.

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ACCORD: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients: A structured summary of a study protocol for a randomised controlled trial

Cited by 64 publications

References 0 publications

Immunological Basis of the Endometriosis: The Complement System as a Potential Therapeutic Target

Immunological Basis of the Endometriosis: The Complement System as a Potential Therapeutic Target

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

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