Clinical trial NCT04393246: mulTi-Arm Therapeutic Study in Pre-ICu Patients Admitted With Covid-19 - Experimental Drugs and Mechanisms
Official title: mulTi-Arm Therapeutic Study in Pre-ICu Patients Admitted With Covid-19 - Experimental Drugs and Mechanisms (TACTIC-E)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: COVID-19
Lead sponsor: Cambridge University Hospitals NHS Foundation Trust
Sponsor class: OTHER
First posted: 2020-05-19
Enrollment: 454
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: TACTIC-E is a randomised, parallel arm, open-label platform trial
Primary purpose: TREATMENT

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. 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: 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.

Eligibility 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 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

Primary outcomes:
measure: Time to incidence of the composite endpoint of: Death, Mechanical ventilation, ECMO, Cardiovascular organ support, or Renal failure
timeFrame: up to Day 14
Secondary outcomes:
measure: Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: IL-6
timeFrame: 14 days
measure: Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: ferritin
timeFrame: 14 days
measure: Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: c-reactive protein (CRP)
timeFrame: 14 days
measure: Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: D-dimer
timeFrame: 14 days
measure: Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: neutrophil/lymphocyte ratio
timeFrame: 14 days
measure: Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: lactate dehydrogenase (LDH)
timeFrame: 14 days
measure: Change in clinical status as assessed on 7-point ordinal scale compared to baseline
timeFrame: 14 days
measure: Time to each of the individual endpoints of the composite primary outcome measure
timeFrame: 14 days
measure: Proportion of patients with adverse events of special interest in each treatment arm
timeFrame: 14 days
measure: Time to Sp02 >94% on room air
timeFrame: 14 days
measure: Time to first negative SARS-CoV2 PCR
timeFrame: 14 days
measure: Duration of oxygen therapy
timeFrame: 14 days
measure: Duration of hospitalisation
timeFrame: 14 days
measure: All-cause mortality at day 28
timeFrame: 28 days
measure: Time to clinical improvement
timeFrame: 14 days
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
state: Cambridgeshire
Study officials:
affiliation: Cambridge University Hospitals NHS Foundation Trust
name: Joseph Cheriyan, MBChB MA FRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gralinski LE, Baric RS. Molecular pathology of emerging coronavirus infections. J Pathol. 2015 Jan;235(2):185-95. doi: 10.1002/path.4454.
citation: Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
citation: Lu IN, Kulkarni S, Fisk M, Kostapanos M, Banham-Hall E, Kadyan S, Bond S, Norton S, Cope A, Galloway J, Hall F, Jayne D, Wilkinson IB, Cheriyan J. muLTi-Arm Therapeutic study in pre-ICu patients admitted with Covid-19-Experimental drugs and mechanisms (TACTIC-E): A structured summary of a study protocol for a randomized controlled trial. Trials. 2020 Jul 31;21(1):690. doi: 10.1186/s13063-020-04618-2.