Clinical trial NCT04390464: mulTi-Arm Therapeutic Study in Pre-ICu Patients Admitted With Covid-19 - Repurposed Drugs (TACTIC-R)
Official title: mulTi-Arm Therapeutic Study in Pre-ICu Patients Admitted With Covid-19 - Repurposed Drugs (TACTIC-R)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: COVID19
Lead sponsor: Cambridge University Hospitals NHS Foundation Trust
Sponsor class: OTHER
First posted: 2020-05-15
Enrollment: 1167
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: TACTIC-R is a randomised, parallel arm, open-label platform trial.
Primary purpose: TREATMENT

Brief summary: TACTIC-R is a randomised, parallel arm, open-label platform trial for investigating potential treatment 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 COVID19 appears to be due to a later, exaggerated, host immune response. 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. Therefore, this study proposes to assess the efficacy of immunomodulatory agents that target dysregulated immune response that drive the severe lung, and other organ, damage. The medications investigated for efficacy in this trial are Baricitinib and Ravulizumab.

Detailed description: TACTIC-R will assess the efficacy of the immunomodulatory agents Baricitinib and Ravulizumab as potential treatments for COVID-19 disease against Standard of Care alone. These agents target the dysregulated immune response that drives the severe lung, and other organ, damage frequently seen during COVID-19 infection. This trial will compare these immunomodulatory agents to Standard of Care over a 14-day treatment period, with follow-up at 28 and 90 days. Patients will be randomised in a 1:1:1 ratio across treatments.

TACTIC-R 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.

TACTIC-R will also iterate an algorithm for use of clinical and biochemical phenotyping to:

1. Stratify patients to therapeutic arms according to probability of efficacy
2. Identify early indicators of failure of therapeutic strategy.

By collecting samples for genomics, transcriptomics, proteomics and immunological phenotyping, parallel studies associated with TACTIC-R will investigate host susceptibility factors for development of severe COVID-19-related disease and predictive biomarkers of response to therapeutic strategy.

Eligibility criteria: Inclusion Criteria

To be included in the trial the participant must:

1. Be aged 18 and over
2. Have clinical picture strongly suggestive of COVID-19-related (with/without positive COVID-19 test) AND

   * Risk count (as defined below) \>3 OR
   * ≥ 3 if risk count includes "Radiographic severity score \>3"
3. Be considered an appropriate subject for intervention with immunomodulatory in the opinion of the supervising clinician
4. Be able to be maintained on venous thromboembolism prophylaxis or current maintenance therapy during inpatient dosing period, according to local guidelines

Exclusion Criteria

The presence of any of the following will preclude participant inclusion:

1. Inability to supply direct informed consent or assent from Next of Kin or Independent Healthcare Provider on behalf of patient
2. Mechanical ventilation at time of prior to dosing
3. Contraindications to study drugs, including hypersensitivity to the active substances or any of the excipients
4. Currently on any of the study investigational medicinal products
5. Known unresolved Neisseria meningitidis infection
6. Unwilling to be vaccinated against Neisseria meningitidis or receive prophylactic antibiotic cover until 2 weeks after vaccination
7. Known active tuberculosis (no blood screening required)
8. Known active Hepatitis B or C (no blood screening required); active varicella zoster
9. Concurrent participation in any interventional clinical trial including COVID-19-related disease trials (observational studies allowed)
10. Patient moribund at presentation or screening
11. Pregnancy at screening (or unwillingness to adhere to pregnancy advice in protocol)
12. Unwillingness to adhere to breastfeeding advice in protocol
13. Either alanine transaminase or aspartate transaminase (ALT or AST) \> 5 times the upper limit of normal
14. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. Cockcroft Gault estimated creatinine clearance \< 30 ml /min/1.73 m\^2)
15. Currently receiving probenecid or chronic IVIG treatment
16. 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.

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 clinical status as assessed on 7-point ordinal scale compared to baseline
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: Frances Hall Hall, FRCP (UK), D.Phil
role: PRINCIPAL_INVESTIGATOR
References:
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: Kulkarni S, Fisk M, Kostapanos M, Banham-Hall E, Bond S, Hernan-Sancho E, Norton S, Cheriyan J, Cope A, Galloway J, Hall F, Jayne D, Wilkinson IB. Repurposed immunomodulatory drugs for Covid-19 in pre-ICu patients - mulTi-Arm Therapeutic study in pre-ICu patients admitted with Covid-19 - Repurposed Drugs (TACTIC-R): A structured summary of a study protocol for a randomised controlled trial. Trials. 2020 Jul 8;21(1):626. doi: 10.1186/s13063-020-04535-4.