NCT04473053

DEFINE - Evaluating Therapies for COVID-19

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 71 (actual)
• Sponsor: University of Edinburgh · Academic / Other
• Sex: All
• Age: 16 Years
• Healthy volunteers: Not accepted

Summary

COVID-19 is a community acquired pneumonia caused by infection with a novel coronavirus, SARS CoV2 and is a serious condition with high mortality in hospitalised patients, for which there is no currently approved treatment other than supportive care. Urgent investigation of potential treatments for this condition is required. This protocol describes an overarching and adaptive trial designed to provide safety, pharmacokinetic (PK)/ pharmacodynamic (PD) information and exploratory biological surrogates of efficacy which may support further development and deployment of candidate therapies in larger scale trials of COVID-19 positive patients receiving normal standard of care. Given the spectrum of clinical disease, community based infected patients or hospitalised patients can be included. Products requiring parenteral administration will only be investigated in hospitalised patients. Patients will be divided into cohorts, a) community b) hospitalised patients with new changes on a chest x-ray (CXR) or a computed tomography (CT) scan or requiring supplemental oxygen and c) hospitalised requiring assisted ventilation. Participants may be recruited from all three of these cohorts, depending on the experimental therapy, its route of administration and mechanism of action. The relevant cohort(s) for any given therapy will be detailed in the therapy-specific appendix. Candidate therapies can be added to the protocol and previous candidates removed from further investigation as evidence emerges. The trial will be monitored by an independent Data Monitoring Committee (DMC) to ensure patient safety. Each candidate cohort will include a small cohort of patients randomised to candidate therapy or existing standard of care management dependent on disease stage at entry. Cohort numbers will be defined in the protocol appendices. This is a Phase IIa experimental medicine trial and as such formal sample size calculations are not appropriate.

Detailed description

This trial platform aims to support the repurposing of promising therapeutic assets with prior use in humans but without prior information on use in COVID-19, to determine the PK-PD profile of the agent, compared to standard of care supportive therapy, in small cohorts of COVID-19 patients. The results of these studies are intended to provide initial safety, pharmacokinetic and pharmacodynamic data and experimental medicine data to support further evaluation in existing national and international trial networks for candidates demonstrating appropriate impact on the dynamic marker of interest. The key interception is to mitigate the lung damage in patients with COVID-19 that leads to respiratory failure. As such, the assets in this programme will focus on abrogating putative mechanisms implicated in COVID-19 respiratory disease. Existing approaches in clinical trials involve novel or repurposed antivirals or immunomodulatory approaches involving agents such as corticosteroids, interferon-β or hydroxychloroquine. A major limitation in the design of many early clinical trials is the limited amount of mechanistic data from patients with COVID-19. Mechanisms have been inferred from animal models, related infections or clinical syndromes. These approaches have infrequently translated to human disease. For example, remdesivir efficacy in animal models of Ebola Virus Disease (EVD) did not translate to human disease and hydroxychloroquine antiviral affects in vitro have not translated to humans against other viruses. Some drugs, such as repurposing of the anti-retroviral protease Kaletra, are still being pursued despite uncertain mechanism and despite evidence that this aspartyl protease cannot bind to the cysteine chymotrypsin-like protease that is Kaletra's putative target in COVID-19. There is a clear and urgent need to pursue experimental medicine studies in humans to establish a solid mechanistic basis for rapid evaluation, including in existing clinical trial platforms against COVID-19 (e.g DoH RECOVERY and NIHR-CLRN industry adopted studies). The trial will be as flexible as possible to ensure a broad range of patients can be recruited and candidate therapies can be added or removed as evidence emerges. The interim trial results will be monitored by an independent DMC to evaluate any patient safety signals. As COVID-19 follows a variable clinical path in individual patients, the protocol is designed to enable inclusion of patients across the disease stages. The trial is intended to provide mechanistic data from patients receiving standard of care therapy and from patients treated with the therapy candidates. The study will enable delivery of pharmacokinetic information and effects of standard of care and candidate agents on surrogate biomarkers of the disease process and the specific drug target.

Conditions

• COVID-19

Interventions

Type	Name	Description
DRUG	Nafamostat Mesilate	Nafamostat has been shown to have potential antiviral effects against MERS CoV and is thought to possibly inhibit SARS CoV2 infection via inhibition of viral entry due to inhibition of TMPRSS2. In addition, nafamostat has potent anticoagulant properties which may provide benefit in patients with DIC, a common finding in serious cases of COVID-19. Nafamostat has been broadly well tolerated in clinical trials in patients with DIC and acute pancreatitis.
DRUG	TD139	TD139 is a specific inhibitor of galectin-3 which has been investigated in healthy volunteers and patients with IPF. No serious drug related serious adverse events have been reported to date. TD139 had no impact on cardiac, haematological or biochemical measures of safety during trials in humans to date. Beneficial effects on biomarker measures of lung inflammation were observed in patients with IPF. It is the purpose of this investigation to examine the potential for delivery of this inhibitor in pre-ventilator patients hospitalised with COVID-19 to examine whether this may lead to detectable changes in blood biomarkers, reduce viral load and also reduce disease severity such as time to ventilation.
OTHER	Standard care	Patients will receive standard care.
BIOLOGICAL	Allogeneic SARS-CoV-2 VSTs	The allogeneic SARS-CoV-2 VSTs are manufactured in a single stage process directly from the starting material procured from suitable post COVID-19 recovered individuals. This is an early dose escalation safety trial phase Ib/IIa interventional clinical trial with SARS-CoV-2 VSTs.

Timeline

• Start date: 2020-07-03
• Primary completion: 2025-04-30
• Completion: 2025-04-30
• First posted: 2020-07-16
• Last updated: 2025-08-07

Locations

1 site across 1 country: United Kingdom