DEFINE - Evaluating Therapies for COVID-19

Study Overview
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Brief Summary
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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
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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.

Official Title
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DEFINE - Evaluating Therapies for COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Nafamostat Mesilate
* Drug: TD139
* Other: Standard care
* Biological: Allogeneic SARS-CoV-2 VSTs


Participation Criteria
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Eligibility Criteria
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Eligibility criteria for each arm is specified in the appendix and may vary depending on the intervention. As an example, eligibility criteria from the Nafamostat and TD139 arms has been provided: Inclusion Criteria: Provision of informed consent from the patient or representative Aged at least 16 years If the patient is of child bearing potential, the patient, and their partner(s), agree to use medically-accepted double-barrier methods of contraception (eg, barrier methods, including male condom, female condom or diaphragm with spermicidal gel) during the study (if randomised to a treatment arm) and for at least 90 days after termination of study therapy. A vasectomised partner would be considered an appropriate birth control method provided that the partner is the sole male sexual partner and the absence of sperm has been confirmed. COVID-19 positive Exclusion Criteria: Current or recent history, as determined by the Investigator, of severe, progressive, and/or uncontrolled cardiac disease (NYHA class IV), uncontrolled renal disease (eGFR <30 mL/min/1.73 m2), severe liver dysfunction (ALT/AST >5x ULN) or bone marrow failure (Hb <80 g/L AND ANC<0.5 mm3 AND platelet count <50,000 uL) Women who are pregnant or breastfeeding. Participation in another clinical trial of an investigational medicinal product (CTIMP) Known hypersensitivity to the IMP or excipients (e.g. lactose) Pre-existing or Cconcomittant use of off-label treatments for COVID-19 that are not recognised as locally approved standard care. Significant electrolyte disturbance (hyperkalaemia potassium >5.0 mmol/L or hyponatraemia sodium < 120mmol/L) Patient currently receiving potassium sparing diuretics that cannot be reasonably withheld Patient currently receiving prophylactic or therapeutic anticoagulantsanticoagulation or antiplatelet agents that cannot be reasonably withheld if randomised to Nafamostat Patients (or their partners) planning on donating sperm/eggs during the trial period Ongoing dialysis History of serious liver disease (Child Pugh score > 10) Hemoglobin < 80 g/L Any known allergy to the IMP/excipients Severe uncontrolled diabetes mellitus In the Investigator's opinion, patient is unwilling or unable to comply with drug administration plan, laboratory tests or other study procedures.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised clinical trial - currently two treatment arms and one standard of care arm. More assets will be added to the protocol as evidence emerges.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nafamostat<br>It is intended that the licensed dose (0.2mg/kg/hr) in Japan will be used. Patients randomised to Nafamostat will receive a continuous intravenous infusion at 0.2 mg/kg/hr for 7 days. If a participant is discharged from hospital or can no longer receive this treatment, the treatment will be stopped. | Drug: Nafamostat Mesilate<br>* 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.<br>|
| Experimental: TD139<br>Patients will inhale 5mg x 2 (10 mg) twice daily for the first 48 hrs and then subsequently 5mg x 2 (10 mg) once daily for the remaining 12 days. Unless a participant is discharged from hospital or can no longer use an inhaler - in which case treatment will be stopped at such time. CE marked inhalers will be provided by the Manufacturer. All patients will receive guidance on how to use the inhaler by an appropriately trained member of the research team. Two individual inhalers will be used by each patient over the course of the 14 day study period (each inhaler will be used by one patient for 7 days) and will be thoroughly cleaned with an antiseptic wipe before and after each use. | Drug: TD139<br>* 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.<br>|
| Active Comparator: Standard of Care<br>Nafamostat and TD139 will be compared to the Standard of Care arm. | Other: Standard care<br>* Patients will receive standard care.<br>|
| Experimental: Allogeneic SARS-CoV-2 VSTs<br>This is an early dose escalation safety trial phase Ib/IIa interventional clinical trial with SARS-CoV-2 VSTs. This is a standalone arm of the Define study and will not be compared to any other trial appendices. A dose escalation strategy from 2x104 cells/kg to 2x106 cells/kg (based on standard 75kg weight) will be administered to patients with COVID-19 infection, and patients will be followed up to ensure their safety. | Biological: Allogeneic SARS-CoV-2 VSTs<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety of the candidate therapies in COVID-19 patients by measuring physiological changes in the circulatory and respiratory system. | Measure vital signs (blood pressure/heart rate/temperature and respiratory rate) | Up to 16 days post treatment | 
| The safety of the candidate therapies in COVID-19 patients by recording the number of treatment related adverse events. | Record number of participants With treatment-related adverse events | Up to 90 days post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measuring the PK of the proposed trial treatments in COVID-19 patients. | Measure maximum plasma concentration [Cmax] in blood samples. | 6 months | 
| Measure a change in the expression of key coagulation biomarkers in the blood of COVID-19 patients during and after treatment period. | Change in expression or activity of coagulation markers in serial blood samples taken before, during and after treatment. | 6 months | 
| Measure a change in the expression of key cytokines in the blood of COVID-19 patients during and after treatment period. | Change in expression or activity of inflammatory cytokines in serial blood samples taken before, during and after treatment. | 6 months | 
| To evaluate the improvement or deteroriation of patients in each treatment arm. | Record changes in National Early Warning Score (NEWS) 2 score. Scale is from 0-20, with a higher number indicating a higher risk of morbidity. | 16 days | 
| To evaluate the number of oxygen-free days. | Duration (days) of oxygen use | 16 days | 
| To evaluate incidence of any form of new ventilation use. | Duration (days) of ventilation | 16 days | 
| To evaluate ventilator-free days | Duration of ventilation-free days. • Incidence of any form of new ventilation use and duration (days) of new ventilation use. | 16 days | 
| Change in the ratio of the oxygen saturation to fraction of inspired oxygen concentration (SpO2/FiO2) | SpO2/FiO2, measured daily from randomisation to Day 15, hospital discharge, or death | 16 days | 
| To evaluate SARS-CoV-2 viral load. | Qualitative and quantitative polymerase chain reaction (PCR) determination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in oropharyngeal/nasal/saliva swab while hospitalised on Days 1, 3, 5, 8, 11, 15. | 15 days | 
| To evaluate time to discharge | Duration of total hospital stay • Duration to discharge following treatment | 16 days | 
| To evaluate the use of renal dialysis or haemofiltration for each treatment arm. | Record requirement for renal dialysis or haemofiltration | 16 days |