TACTIC-E is a randomised, parallel arm, open-label platform trial for investigating potential treatments for COVID-19 disease. While SARS-CoV infection evades detection by the immune system in the first 24 hours of infection, it ultimately produces a massive immune system response in the subgroup of people who develop severe complications. Most tissue damage following infection with COVID-19 appears to be due to a later, exaggerated, host immune response (Gralinski and Baric 2015). This leads to lung and sometimes multi-organ damage. Most people who develop these severe complications still have virus present in their respiratory tract at the time-point when the disease starts to evolve. Immune modulation in the presence of active infection has potential to cause more harm than benefit. Safety considerations when studying immune modulation strategies are paramount. This study will assess the efficacy of a novel immunomodulatory agent and a novel combination of approved agents which may protect the patient against end-organ damage and modulate the pulmonary vascular response. This study will compare the novel therapeutic agent EDP1815 and a novel combination of the approved agents dapagliflozin and ambrisentan against Standard of Care.
TACTIC-E will assess the efficacy of the novel immunomodulatory agent EDP1815 and a
combination of the approved cardiovascular drugs dapagliflozin and ambrisentan as potential
treatments for COVID-19 disease against Standard of Care alone. These agents target the
dysregulated immune response that drive the severe lung, and other organ, damage frequently
seen during COVID-19 infection, with an aim to promote a positive vascular response to reduce
end-organ damage.
Treatment with EDP1815 will be for up to 7 days, with the option of extension to 14 days at
the discretion of the PI or their delegate, if the patient is felt to be clinically
responding to treatment, is tolerating treatment, and is judged to be likely to benefit from
a longer treatment course. Treatment with combination dapagliflozin and ambrisentan will be
for up to 14 days. Patients will be randomised in a 1:1:1 ratio across treatments.
TACTIC-E will use a platform design with interim analysis to make efficient decisions about
efficacy and futility (e.g. lack of efficacy and risk of harm) of the trial treatments. This
enables the trial to stop recruiting to arms early where a clear efficacy decision can be
made. It also allows for the addition of further arms.
Drug: EDP1815
EDP1815 is an orally administered pharmaceutical preparation of a single strain of Prevotella histicola isolated from the duodenum of a human donor. EDP1815 is currently in phase 2 clinical development and has European and US approval to initiate a multinational psoriasis study.
Drug: Dapagliflozin
Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT-2) inhibitor. Dapagliflozin is licensed for use in the UK for treatment of Type II diabetes. Since this trial is evaluating Dapagliflozin in an unlicensed indication, it is being carried out under a Clinical Trial Authorisation (CTA)
Other Name: Forxiga
Drug: Ambrisentan
Ambrisentan is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA). Ambrisentan was approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and indicated for the treatment of pulmonary arterial hypertension.
Other Name: Letairis, Volibris, Pulmonext
Other: Standard of care
Regular standard of care for COVID-19 patients
General Inclusion Criteria:
- Be aged 18 and over
- Have clinical picture strongly suggestive of COVID-19-related disease (with/without
positive COVID-19 test) AND
- Risk count (as defined below) >3 OR
- Risk count ≥3 if it includes "Radiographic severity score >3"
- Be hospitalized or eligible for hospitalization on clinical grounds
- Be considered an appropriate subject for intervention with immunomodulatory or other
disease modifying agents in the opinion of the investigator
General Exclusion Criteria:
- Inability to supply direct informed consent from patient or from Next of Kin or
Independent Healthcare Provider on behalf of patient
- Invasive mechanical ventilation at time of screening
- Contraindications to study drugs, including hypersensitivity to the active substances
or any of the excipients
- Currently on any of the study investigational medicinal products
- Concurrent participation in an interventional clinical trial (observational studies
allowed)
- Patient moribund at presentation or screening
- Pregnancy at screening
- Unwilling to stop breastfeeding during treatment period
- Known severe hepatic impairment (with or without cirrhosis)
- Requiring dialysis Cockcroft Gault estimated creatinine clearance < 30 ml /min/1.73m2
at screening
- Inability to swallow at screening visit
- Any medical history or clinically relevant abnormality that is deemed by the principal
investigator and/or medical monitor to make the patient ineligible for inclusion
because of a safety concern.
EDP1815-Specific Exclusion Criteria:
- Patient is taking a systemic immunosuppressive agent such as, but not limited to, oral
steroids, methotrexate, azathioprine, ciclosporin or tacrolimus, unless these are
given as part of COVID standard of care treatment.
- Patient has known primary or secondary B cell disorder
Dapagliflozin- and Ambrisentan-Specific Exclusion Criteria:
- Type 1 diabetes
- Known idiopathic pulmonary fibrosis
- Previous hospital admission with ketoacidosis
- Patients concurrently on other SGLT2 inhibitors
- History of symptomatic heart failure within 3 months of admission
- Sustained blood pressure below 100/70 mmHg at admission
- Metabolic acidosis defined as pH< 7.25 AND ketones > 3.0 mmol/L
- Alanine transaminase and/or aspartate transaminase (ALT and/or AST) > 3 times the
upper limit of normal (only one needs to be measured)
Risk Count
Patients will be given a Risk Count equal to the cumulative points received for the
following criteria (no = 0 points, yes = 1 point):
Male gender, Age > 40 years, Non-white ethnicity, Diabetes, Hypertension, Neutrophils >
8.0x10^9/L, CRP > 40mg/L, Radiographic severity score >3
Cambridge University Hospitals NHS Foundation Trust
Cambridge, Cambridgeshire, United Kingdom
Investigator: Heike Templin, BSc
Contact: 01223 250874
Heike.templin@addenbrookes.nhs.uk
Heike Templin, BSc
01223 250874
heike.templin@addenbrookes.nhs.uk
Joseph Cheriyan, MBChB MA FRCP, Principal Investigator
Cambridge University Hospitals NHS Foundation Trust