“RIC in COVID-19” is a pilot, multi-center, randomized study designed to ascertain whether RIC decreases the severity of inflammatory markers associated with a “cytokine storm” score.
The study has been reviewed and approved with a favorable opinion from the United Kingdom National Research Ethics Service (NRES) (South Central – Berkshire Research Ethics Committee reference: 20/SC/0192). The study protocol is registered on the public trials database clinicaltrials.gov NCT04699227. This study has also received approval by the Ethics Committee of the State University of Campinas (CAAE: 33,709,320.4.0000.5404) and by the Human Research Ethics Committee, University of Cape Town, South Africa (HREC 407/2020).
A minimum of 55 non-critical adult patients with a confirmed diagnosis of COVID-19 will be consecutively enrolled into the study. The patients will be identified as those admitted to either The Royal Free (London UK), The Lister Hospital (Stevenage, UK), Hospital Estadual Sumaré (Sumaré, Brazil), or Groote Schuur Hospital (Cape Town, South Africa). After enrolment, patients will be randomized (n = 30 per group) in a 1:1 fashion to receive either RIC or sham-control intervention.
Patients will be included according to the following criteria:
Adult patients (≥ 18 to 80 years of age) with a diagnosis of COVID-19 infection, confirmed by positive PCR reaction.
Clinical features of respiratory distress, i.e., with respiratory rate > 30 bpm or use of accessory muscles; or
Peripheral oxygen saturation SaO2 < 95% or requiring oxygen supplementation, or
Clinically unwell with reduced mobility, raised temperature/heart rate, and/or deranged biochemical laboratory results.
Patients will be excluded on the basis of any of the following exclusion criteria:
Contraindication for the use of a brachial cuff on either arm;
Intercurrent disease with an expected life expectancy of less than 24 h;
Pregnant or breastfeeding women;
Bleeding disorder or platelet count below 50;
Currently enrolled in another research study;
End-stage renal disease requiring renal replacement therapy;
Chronic liver disease and/or ALT and AST ≥ 5 times the normal upper reference limit;
Significant immunodeficiency states: AIDS/HIV not on antiretroviral agents, solid organ transplants, bone marrow transplants, chronic use of immunomodulating therapy such as anti-TNF-α or corticosteroids with prednisone-equivalent dose ≥ 20 mg/day prior to COVID diagnosis;
Any active underlying malignancy;
Baseline stage C chronic heart failure or symptomatic chronic obstructive pulmonary disease.
Critical illness requiring invasive ventilation, including patients with:
The RIC protocol will consist of 3–4 cycles of cuff inflations to at least 20 mmHg above systolic blood pressure for 5 min with deflation to 0 mmHg for a further 5 min, which will be automatically administered by the pre-programmed CellAegis (Canada), or Segall (Denmark) autoRIC pneumatic device.
Patients randomized to the sham-control group will have 3–4 cycles of automated low-pressure cuff inflation to 20 mmHg for 5 min and deflation to 0 mmHg for a further 5 min, by a visually identical pneumatic device as used in the RIC protocol. Trial intervention will be performed daily up to 15 days or until either patient discharge or deterioration requiring critical care. The trial intervention will not delay or affect the patient’s clinical management in accordance with local center policies.
Randomization and Blinding
After enrolment, patients will be randomized 1:1 to receive either RIC or sham-control intervention. The research team who will perform the trial intervention will be unblinded as they will need to be informed of which protocol to administer to the patient. All subsequent analysis will be performed blinded to treatment.
The primary outcome is the level of inflammatory cytokines that are involved in the cytokine storm that can occur following SARS-CoV-2 infection. Venous blood will be collected following RIC administration (on the day of admission and every other day subsequently, when possible) and saved for the subsequent measurement of inflammatory markers such as C-reactive protein (CRP), TNF-α, IL-1β, IL-6, and D-dimer, in addition to cardiac biomarkers troponin T and NTpro-BNP.
Secondary endpoints include the following: [i] time to clinical deterioration (defined as time from randomization to mortality or worsening of the World Health Organization (WHO) Clinical Progression Scale — assessed by the increase of 2 points in this scale), [ii] serum IL-6 ≥ 80 pg/mL as a biomarker of severe clinical outcomes in COVID-19 infection, and [iii] cytokine storm score measured by area under the curve (AUC) serum TNF-α, IL-1β, IL-6, and CRP. The effect of plasma from COVID-19 patients on cardiac endothelial cells will also be evaluated as a secondary endpoint by measuring the survival of primary cardiac endothelial cells incubated with patient plasma .
Sample Size Calculations
Since there are no data available on the effect of RIC on the inflammatory response in COVID-19 patients and the objective of this pilot study is not to provide a formal assessment of efficacy, the sample size was established empirically in 55 individuals in a conservative expectation of a small standardized effect size (0.2).
Summary statistics will be provided by treatment group for demographic and baseline characteristics, which will be compared among treatment groups for the ITT population. Between-group differences in demographic and baseline characteristic will be tested using a chi-square test (for categorical variables) or a 1-way analysis of variance (ANOVA) model with treatment as a factor (for continuous variables). The significance of these tests will be used as an initial assessment for satisfactoriness of randomization. For continuous variables, changes from baseline to subsequent days of follow up will be considered outcomes. These outcomes will be compared according to the treatment groups adjusted to the baseline values using covariance analysis models (ANCOVA) or by rank analysis of covariance (RANCOVA) according to their distribution. The normality distribution will be investigated using normality tests such as histograms, kurtosis, asymmetry, Kolmogorov–Smirnov, and Shapiro–Wilk in order to select the appropriate tests to compare the data.
Data Management, Governance, and Funding
The trial is funded by the Thomson Family Charitable Trust and the Hatter Cardiovascular Institute and sponsored by University College London and by the Fundação de Apoio a Pesquisa do Estado de São Paulo (FAPESP). Data will be collected on a case report form (CRF) and managed using REDCap electronic data capture tools. REDCap  is a secure, web-based application designed to support validated and audited data capture for research studies. An independent data monitoring committee will be convened to monitor the progress and safety of the study.