2 research outputs found
Additional file 1: of Fluid strategies and outcomes in patients with acute respiratory distress syndrome, systemic inflammatory response syndrome and sepsis: a protocol for a systematic review and meta-analysis
Medline search strategy. Modified versions of this strategy will be used for other databases
Repair of acute respiratory distress syndrome by stromal cell administration in COVID-19 (REALIST-COVID-19): a structured summary of a study protocol for a randomised, controlled trial
Objectives: The primary objective of the
study is to assess the safety of a single intravenous infusion of Mesenchymal
Stromal Cells (MSCs) in patients with Acute Respiratory Distress Syndrome
(ARDS) due to COVID-19. Secondary objectives are to determine the effects of
MSCs on important clinical outcomes, as described below.Trial design: REALIST
COVID 19 is a randomised, placebo-controlled, triple blinded trial.Participants: The
study will be conducted in Intensive Care Units in hospitals across the United
Kingdom. Patients with moderate to severe ARDS as defined by the Berlin
definition, receiving invasive mechanical ventilation and with a diagnosis of
COVID-19 based on clinical diagnosis or PCR test will be eligible. Patients
will be excluded for the following reasons: more than 72 hours from the onset of
ARDS; age < 16 years; patient known to be pregnant; major trauma in previous
5 days; presence of any active malignancy (other than non-melanoma skin
cancer); WHO Class III or IV pulmonary hypertension; venous thromboembolism
currently receiving anti-coagulation or within the past 3 months; patient
receiving extracorporeal life support; severe chronic liver disease (Child-Pugh
> 12); Do Not Attempt Resuscitation order in place; treatment withdrawal
imminent within 24 hours; prisoners; declined consent; non-English speaking
patients or those who do not adequately understand verbal or written
information unless an interpreter is available; previously enrolled in the
REALIST trial.Intervention and
comparator: Intervention: Allogeneic donor CD362 enriched
human umbilical cord derived mesenchymal stromal cells (REALIST ORBCEL-C)
supplied as sterile, single-use cryopreserved cell suspension of a fixed dose
of 400 x106 cells in 40ml volume, to be diluted in Plasma-Lyte 148 to a
total volume of 200mls for administration. Comparator (placebo): Plasma-Lyte
148 Solution for Infusion (200mls). The cellular product (REALIST ORBCEL-C) was
developed and patented by Orbsen Therapeutics.Main outcomes: The
primary safety outcome is the incidence of serious adverse events. The primary
efficacy outcome is Oxygenation Index (OI) at day 7. Secondary outcomes
include: OI at days 4 and 14; respiratory compliance, driving pressure and PaO2/FiO2 ratio
(PF ratio) at days 4, 7 and 14; Sequential Organ Failure Assessment (SOFA)
score at days 4, 7 and 14; extubation and reintubation; ventilation free days
at day 28; duration of mechanical ventilation; length of ICU and hospital stay;
28-day and 90-day mortality.Randomisation: After
obtaining informed consent, patients will be randomised via a centralised
automated 24-hour telephone or web-based randomisation system (CHaRT, Centre
for Healthcare Randomised Trials, University of Aberdeen). Randomisation will
be stratified by recruitment centre and by vasopressor use and patients will be
allocated to REALIST ORBCEL-C or placebo control in a 1:1 ratio.Blinding
(masking): The investigator, treating physician, other
members of the site research team and participants will be blinded. The cell
therapy facility and clinical trials pharmacist will be unblinded to facilitate
intervention and placebo preparation. The unblinded individuals will keep the
treatment information confidential. The infusion bag will be masked at the time
of preparation and will be administered via a masked infusion set.Numbers to be
randomised (sample size): A sample size of 60 patients
with 30 patients randomised to the intervention and 30 to the control group. If
possible, recruitment will continue beyond 60 patients to provide more accurate
and definitive trial results. The total number of patients recruited will
depend on the pandemic and be guided by the data monitoring and ethics
committee (DMEC).Trial status: REALIST
Phase 1 completed in January 2020 prior to the COVID-19 pandemic. This was an
open label dose escalation study of REALIST ORBCEL-C in patients with ARDS. The
COVID-19 pandemic emerged as REALIST Phase 2 was planned to commence and the
investigator team decided to repurpose the Phase 2 trial as a COVID-19 specific
trial. This decision was discussed and approved by the Trial Steering Committee
(TSC) and DMEC. Submissions were made to the Research Ethics Committee (REC)
and MHRA to amend the protocol to a COVID-19 specific patient population and the
protocol amendment was accepted by the REC on 27th March 2020 and MHRA on
30th March 2020 respectively. Other protocol changes in this amendment
included an increase in the time of onset of ARDS from 48 to 72 hours,
inclusion of clinical outcomes as secondary outcomes, the provision of an
option for telephone consent, an indicative sample size and provision to
continue recruitment beyond this indicative sample size. The current protocol
in use is version 4.0 23.03.2020 (Additional file 1). Urgent Public Health
status was awarded by the NIHR on 2 April 2020 and the trial opened to
recruitment and recruited the first participant the same day. At the time of
publication the trial was open to recruitment at 5 sites across the UK (Belfast
Health and Social Care Trust, King's College London, Guys and St Thomas'
Hospital London, Birmingham Heartlands Hospital and the Queen Elizabeth
Hospital Birmingham) and 12 patients have been recruited across these sites.
Additional sites are planned to open and appropriate approvals for these are
being obtained. It is estimated recruitment will continue for 6 months.Trial
registration: ClinicalTrials.gov NCT03042143 (Registered
3 Feb 2017). EudraCT 2017-000585-33 (Registered 28 Nov 2017). Full protocol: The full protocol (version
4.0 23.03.2020) is attached as an additional file, accessible from the Trials
website (Additional file 1). In the interest of expediting dissemination of
this material, the familiar formatting has been eliminated; this Letter serves
as a summary of the key elements of the full protocol. The study protocol has
been reported in accordance with the Standard Protocol Items: Recommendations
for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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