DEFINE - Evaluating Therapies for COVID-19

University of Edinburgh

Status and phase: Completed; Phase 2; Phase 1

Conditions: COVID-19

Treatments: Drug: TD139; Other: Standard care; Drug: Nafamostat Mesilate; Biological: Allogeneic SARS-CoV-2 VSTs

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT04473053

AC20063

Details and patient eligibility

About

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.

Full 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.

Enrollment: 71 patients

Sex: All

Ages: 16+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

---

71 participants in 4 patient groups

Nafamostat

Experimental group

Description:

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.

Treatment:

Drug: Nafamostat Mesilate

TD139

Experimental group

Description:

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.

Treatment:

Drug: TD139

Standard of Care

Active Comparator group

Description:

Nafamostat and TD139 will be compared to the Standard of Care arm.

Treatment:

Other: Standard care

Allogeneic SARS-CoV-2 VSTs

Experimental group

Description:

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.

Treatment:

Biological: Allogeneic SARS-CoV-2 VSTs