mulTi-Arm Therapeutic Study in Pre-ICu Patients Admitted With Covid-19 - Repurposed Drugs (TACTIC-R) (TACTIC-R)

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.

Study Overview

• Status: Unknown
• Conditions: COVID19
• Intervention / Treatment: Other: Standard of care; Drug: Ravulizumab; Drug: Baricitinib

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.

• Study Type: Interventional
• Enrollment (Anticipated): 1167
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Recruiting
      • Cambridge University Hospitals NHS Foundation Trust
      • Contact: Elena Hernan Sanch0; Phone Number: 01223369824; Email: elena.hernansancho@addenbrookes.nhs.uk
      • Contact: Maria King; Phone Number: 07792173955; Email: maria.king@addenbrookes.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Standard of care	Other: Standard of care; Regular standard of care for COVID-19 patients
EXPERIMENTAL: Ravulizumab + Standard of care; Ravulizumab IV (adjusted to weight, Day 1 only)	Drug: Ravulizumab; Ravulizumab (Ultomiris, Alexion Pharmaceuticals) is a monoclonal antibody that binds to terminal complement protein C5 and prevents the complement-mediated destruction of cells. It is administered by intravenous infusion. Ravulizumab has a marketing authorisation in the UK for treating Paroxysmal Nocturnal Haemoglobinuria in adults.; Other Names: Ultomiris
EXPERIMENTAL: Baricitinib + Standard of care; Baricitinib PO OD (4mg, Days 1-14)	Drug: Baricitinib; Baricitinib is administered orally once daily. It is licensed for treatment of rheumatoid arthritis, it is a relatively fast acting disease modifying anti-rheumatic drug and has the potential to be scaled up for use for a pandemic.; Other Names: Olumiant

What is the study measuring?

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) 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 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 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
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
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: venous thromboembolism, new infections requiring antimicrobials	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	14 days
All cause mortality at day 28	The number of deaths recorded at 28 days irrespective of the cause	28 Days

Collaborators and Investigators

• Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Investigators: Principal Investigator: Frances Hall Hall, FRCP (UK), D.Phil, Cambridge University Hospitals NHS Foundation Trust

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 8, 2020
• Primary Completion (ANTICIPATED): May 7, 2021
• Study Completion (ANTICIPATED): May 1, 2022

Study Registration Dates

• First Submitted: May 8, 2020
• First Submitted That Met QC Criteria: May 14, 2020
• First Posted (ACTUAL): May 15, 2020

Study Record Updates

• Last Update Posted (ACTUAL): May 18, 2020
• Last Update Submitted That Met QC Criteria: May 14, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Ravulizumab
• Other Study ID Numbers: TACTIC-R

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No