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

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ClinicalTrials.gov Identifier: NCT04393246
Recruitment Status : Not yet recruiting
First Posted : May 19, 2020
Last Update Posted : May 19, 2020
Sponsor:
Information provided by (Responsible Party):
Joseph Cheriyan, MD, Cambridge University Hospitals NHS Foundation Trust

Brief Summary:

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.

Reference:

Gralinski and Baric 2015. Molecular pathology of emerging coronavirus infections. J Pathol 2015: 235: 185-195; DOI: 10.1002/path.4454


Condition or disease Intervention/treatment Phase
COVID-19 Drug: EDP1815 Drug: Dapagliflozin Drug: Ambrisentan Other: Standard of care Phase 2 Phase 3

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1407 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: TACTIC-E is a randomised, parallel arm, open-label platform trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: mulTi-Arm Therapeutic Study in Pre-ICu Patients Admitted With Covid-19 - Experimental Drugs and Mechanisms (TACTIC-E)
Estimated Study Start Date : May 20, 2020
Estimated Primary Completion Date : January 20, 2021
Estimated Study Completion Date : May 20, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Ambrisentan

Arm Intervention/treatment
Active Comparator: Standard of care
Standard of care
Other: Standard of care
Regular standard of care for COVID-19 patients

Experimental: EDP1815
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
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.

Experimental: Dapagliflozin and Ambrisentan
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
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




Primary Outcome Measures :
  1. Time to incidence of the composite endpoint of: Death, Mechanical ventilation, ECMO, Cardiovascular organ support, or Renal failure [ Time Frame: up to Day 14 ]
    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


Secondary Outcome Measures :
  1. Change in biomarkers known to be associated with progression of COVID-19 compared to baseline [ Time Frame: 14 days ]
    Change in serum/plasma levels of IL-6, Ferritin, CRP, D-Dimer, neutrophil to lymphocyte ratio, and LDH compared to baseline

  2. Change in therapy-specific markers of pharmacodynamic response in patients receiving EDP1815 or Dapagliflozin+Ambrisentan compared to baseline [ Time Frame: 14 days ]
    For patients receiving EDP1815: change in serum/plasma levels of IL-8, TNF, IL-1β, IL-10, IL-17, IL-13 compared to baseline For patients receiving Dapagliflozin+Ambrisentan: change in serum/plasma levels of ET-1, TNF compared to baseline

  3. Change in clinical status as assessed on 7-point ordinal scale compared to baseline [ Time Frame: 14 days ]
    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

  4. Time to each of the individual endpoints of the composite primary outcome measure [ Time Frame: 14 days ]
    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

  5. Proportion of patients with adverse events of special interest in each treatment arm [ Time Frame: 14 days ]
    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

  6. Time to Sp02 >94% on room air [ Time Frame: 14 days ]
    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)

  7. Time to first negative SARS-CoV2 PCR [ Time Frame: 14 days ]
    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

  8. Duration of oxygen therapy [ Time Frame: 14 days ]
    The duration of oxygen therapy given to a patient, measured in days

  9. Duration of hospitalisation [ Time Frame: 14 days ]
    The duration of hospitalisation of a patient, measured in days

  10. All-cause mortality at day 28 [ Time Frame: 28 days ]
    The number of deaths recorded at 28 days irrespective of the cause

  11. Time to clinical improvement [ Time Frame: 14 days ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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)
  • Stage 4 severe chronic kidney disease or requiring dialysis (i.e. Cockcroft Gault estimated creatinine clearance < 30 ml /min)
  • 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.

Dapagliflozin- and Ambrisentan-Specific Exclusion Criteria:

  • Type 1 diabetes
  • Known idiopathic pulmonary fibrosis
  • Previous hospital admission with ketoacidosis
  • 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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04393246


Contacts
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Contact: Sonakshi Kadyan, BTech MRes 01223 349007 sonakshi.kadyan@addenbrookes.nhs.uk

Locations
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United Kingdom
Cambridge University Hospitals NHS Foundation Trust
Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
Contact: Sonakshi Kadyan, BTech MRes    01223 349007    sonakshi.kadyan@addenbrookes.nhs.uk   
Sponsors and Collaborators
Cambridge University Hospitals NHS Foundation Trust
Investigators
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Principal Investigator: Joseph Cheriyan, MBChB MA FRCP Cambridge University Hospitals NHS Foundation Trust
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Responsible Party: Joseph Cheriyan, MD, Consultant in Clinical Pharmacology, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT04393246    
Other Study ID Numbers: TACTIC-E
First Posted: May 19, 2020    Key Record Dates
Last Update Posted: May 19, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Ambrisentan
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs
Antihypertensive Agents