mulTi-Arm Therapeutic Study in Pre-ICu Patients Admitted With Covid-19 - Experimental Drugs and Mechanisms

Study Overview
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Brief Summary
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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. A trial arm (UNI911) with the IMP Niclosamide was added to the protocol with one patient recruited into this arm. Following an AESI and after discussions between the funder and the Sponsor the arm was stopped.

Detailed Description
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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.

Official Title
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mulTi-Arm Therapeutic Study in Pre-ICu Patients Admitted With Covid-19 - Experimental Drugs and Mechanisms (TACTIC-E)

Conditions
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COVID-19

Intervention / Treatment
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* Drug: EDP1815
* Drug: Dapagliflozin
* Drug: Ambrisentan
* Other: Standard of care


Participation Criteria
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Eligibility Criteria
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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 Is able to swallow capsules/tablets 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

Ages Eligible for Study
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Minimum Age: 18 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: TACTIC-E is a randomised, parallel arm, open-label platform trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of care<br>Standard of care | Other: Standard of care<br>* Regular standard of care for COVID-19 patients<br>|
| Experimental: EDP1815<br>1.6 x 10^11 cells dosage-in-capsule orally twice per day for up to 7 days (with the option to extend up to 14 days), on top of standard of care | Drug: EDP1815<br>* 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.<br>|
| Experimental: Dapagliflozin and Ambrisentan<br>Ambrisentan 5mg tablet orally once per day for up to a maximum of 14 days and Dapagliflozin 10mg tablet orally once per day for up to a maximum of 14 days, on top of standard of care | Drug: Dapagliflozin<br>* 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)<br>* Other names: Forxiga;Drug: Ambrisentan<br>* 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.<br>* Other names: Letairis, Volibris, Pulmonext;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to incidence of the composite endpoint of: Death, Mechanical ventilation, ECMO, Cardiovascular organ support, or Renal failure | Number of days taken for occurrence of one of the following events: 1. Death 2. Mechanical ventilation 3. Extracorporeal membrane oxygenation (ECMO) 4. Cardiovascular organ support (balloon pump or inotropes/vassopressors) 5. Renal failure (estimated creatinine clearance (by Cockcroft-Gault formula) <15 ml /min/1.73m^2), haemofiltration or dialysis | up to Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: IL-6 | Change in patient blood levels of IL-6 compared to baseline, measured in pg/mL | 14 days | 
| Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: ferritin | Change in patient blood levels of ferritin compared to baseline, measured in ng/mL | 14 days | 
| Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: c-reactive protein (CRP) | Change in patient blood levels of CRP compared to baseline, measured in mg/L | 14 days | 
| Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: D-dimer | Change in patient blood levels of D-dimer compared to baseline, measured in ng/mL | 14 days | 
| Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: neutrophil/lymphocyte ratio | Change in patient blood levels of neutrophil/lymphocyte ratio compared to baseline | 14 days | 
| Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: lactate dehydrogenase (LDH) | Change in patient blood levels of lactate dehydrogenase (LDH) compared to baseline, measured in U/L | 14 days | 
| Change in clinical status as assessed on 7-point ordinal scale compared to baseline | The clinical status of the patients is assessed using 7-point ordinal scale as follows: 1 = Death, 2 = Mechanical ventilation, 3 = Non-invasive or high flow oxygen, 4 = Low flow oxygen, 5 = Hospitalised - no oxygen, 6 = Discharged - normal activities not resumed, 7 = Discharged - normal activities resumed | 14 days | 
| Time to each of the individual endpoints of the composite primary outcome measure | Number of days taken for occurrence of each of the following events: 1. Death 2. Mechanical ventilation 3. Extracorporeal membrane oxygenation (ECMO) 4. Cardiovascular organ support (balloon pump or inotropes/vassopressors) 5. Renal failure (estimated creatinine clearance (by Cockcroft-Gault formula) <15 ml /min/1.73m^2), haemofiltration or dialysis | 14 days | 
| Proportion of patients with adverse events of special interest in each treatment arm | The proportion of patients in each treatment arm that experience adverse events of special interest, defined as: Diabetic ketoacidosis in patients on Ambrisentan & Dapagliflozin, New peripheral oedema in patients on Ambrisentan & Dapagliflozin arm | 14 days | 
| Time to Sp02 >94% on room air | The time taken to achieve blood oxygen saturation levels above 94% in patients on room air, measured in hours/days (chronically hypoxic individuals will be excluded from this analysis) | 14 days | 
| Time to first negative SARS-CoV2 PCR | The amount of time between a patient's first positive SARS-CoV2 PCR test and a patient's first negative SARS-CoV2 PCR test, measured in days | 14 days | 
| Duration of oxygen therapy | The duration of oxygen therapy given to a patient, measured in days | 14 days | 
| Duration of hospitalisation | The duration of hospitalisation of a patient, measured in days | 14 days | 
| All-cause mortality at day 28 | The number of deaths recorded at 28 days irrespective of the cause | 28 days | 
| Time to clinical improvement | The time to clinical improvement for a patient, defined as: >2 point improvement from Day 1 on the 7-point ordinal scale, measured in days | 14 days |