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, forwhich there is no currently approved treatment other than supportive care. Urgentinvestigation 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 biologicalsurrogates of efficacy which may support further development and deployment of candidatetherapies in larger scale trials of COVID-19 positive patients receiving normal standardof care.Given the spectrum of clinical disease, community based infected patients or hospitalisedpatients can be included. Products requiring parenteral administration will only beinvestigated 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 computedtomography (CT) scan or requiring supplemental oxygen and c) hospitalised requiringassisted ventilation. Participants may be recruited from all three of these cohorts,depending on the experimental therapy, its route of administration and mechanism ofaction. The relevant cohort(s) for any given therapy will be detailed in thetherapy-specific appendix.Candidate therapies can be added to the protocol and previous candidates removed fromfurther investigation as evidence emerges. The trial will be monitored by an independentData Monitoring Committee (DMC) to ensure patient safety.Each candidate cohort will include a small cohort of patients randomised to candidatetherapy 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 sizecalculations are not appropriate.
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.
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.
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.
NHS Lothian
Edinburgh, United Kingdom
Investigator: Kev Dhaliwal
Contact: 01312426579
Kev.Dhaliwal@ed.ac.uk
Annya Bruce, PhD
01312429180
Annya.Bruce@ed.ac.uk
Kevin Dhaliwal
01312429180
kev.dhaliwal@ed.ac.uk
Kev Dhaliwal, Principal Investigator
University of Edinburgh