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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,167
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.
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.
Regular standard of care for COVID-19 patients
Cambridge University Hospitals NHS Foundation Trust
Cambridge, Cambridgeshire, United Kingdom
RECRUITINGTime 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
Time frame: up to Day 14
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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 14 days
Duration of oxygen therapy
The duration of oxygen therapy given to a patient, measured in days
Time frame: 14 days
Duration of hospitalisation
The duration of hospitalisation of a patient, measured in days
Time frame: 14 days
All cause mortality at day 28
The number of deaths recorded at 28 days irrespective of the cause
Time frame: 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
Time frame: 14 days
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