Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration (REALIST) (REALIST)
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|ClinicalTrials.gov Identifier: NCT03042143|
Recruitment Status : Recruiting
First Posted : February 3, 2017
Last Update Posted : January 17, 2019
|First Submitted Date ICMJE||February 1, 2017|
|First Posted Date ICMJE||February 3, 2017|
|Last Update Posted Date||January 17, 2019|
|Actual Study Start Date ICMJE||January 7, 2019|
|Estimated Primary Completion Date||July 2020 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT03042143 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration (REALIST)|
|Official Title ICMJE||Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration (REALIST): An Open Label Dose Escalation Phase 1 Trial Followed by a Randomized, Double-blind, Placebo-controlled Phase 2 Trial|
|Brief Summary||Acute Respiratory Distress Syndrome (ARDS) causes the lungs to fail due to the collection of fluid in the lungs (pulmonary oedema). ARDS is common in severely ill patients in Intensive Care Units and is associated with a high mortality and a high morbidity in those who survive. There is a large economic burden with direct healthcare costs, but also indirectly due to the impact on the carer and patient through the patients inability to return to full time employment. There is little evidence for effective drug (pharmacological) treatment for ARDS. There is increasing information that mesenchymal stem cells (MSCs) might be important in treating ARDS. REALIST will investigate if a single infusion of MSCs will help in the treatment of ARDS. The first step will be to first of all determine what dose of MSCs is safe and then divide patients suffering from ARDS into two groups, one of which will get MSCs and the other a harmless dummy (or placebo) infusion, who will then be followed up to determine if lung function improves. If effective this may lead to further research to determine if MSCs are effective in patients with ARDS. This project will also provide new information about mechanisms in the development of ARDS leading, potentially, to other new treatments|
The role of MSCs as a novel treatment in ARDS. Mesenchymal Stem Cells (MSCs) are a mononuclear cell population that have the potential to differentiate into multiple lineages, and bone, cartilage and adipocyte cells in particular. Cell-based therapies have been termed the "next pillar of Medicine". MSCs constitute an innovative approach with substantial therapeutic promise for ARDS. MSCs possess several favorable biological characteristics, including convenient isolation, ease of expansion in culture while maintaining genetic stability, minimal immunogenicity and feasibility for allogenic transplantation.
MSCs reduce inflammation and enhance bacterial clearance during rodent and murine bacterial pneumonia, and augment repair of the animal and human lung. Large animal studies have also replicated these beneficial effects. Bone marrow derived (BM) hMSCs decreased acute lung injury (ALI), without producing organ toxicity, in endotoxin injured pigs. Two randomised small phase 1 studies of plastic adherent MSCs in patients with ARDS have taken place. In Japan, investigators used adipose-derived plastic adherent cells in a small cohort (n=12) of patients with ARDS randomized 1:1 to MSCs or placebo: showing that the cells were safe and well-tolerated in this patient group, and were associated with reduced plasma levels of the alveolar epithelial cell injury marker SP-D. In the US Matthay has completed the phase 1 START trial, using a dose escalation study of plastic adherent bone marrow derived MSCs, in patients with moderate to severe ARDS. START showed that marrow derived MSCs at similar doses to those proposed in this study are safe and well-tolerated, (n=9), with a trend to reduced lung injury in the group treated with the highest (10x106cells/kg) compared with the lower doses, 1-5x106cells/kg.
In young people (aged 16-17 years) and adult patients with moderate to severe ARDS, human umbilical cord derived CD362 enriched MSCs, (REALIST ORBCEL-C cells) are safe and improve important surrogate clinical outcomes.
The phase 1 trial is an open label dose escalation pilot study in which cohorts of subjects with moderate to severe ARDS will receive increasing doses of a single infusion of Realist Orbcel-C in a 3+3 design. We initially plan 3 cohorts with 3 subjects/cohort. Planned doses for the 3 cohorts pending absence of safety concerns are 100 x 10^6 cells, 200 x 10^6 cells and 400 x 10^6 cells. Initially 3 cohorts with 3 subjects/cohort.
After 7 days of follow-up for all study subjects in the phase 1 study is available the TMG will review the data and propose a cell dose for the phase 2 trial. This recommendation will be submitted to the DMEC for approval prior to initiating the phase 2 trial. For planning purposes, the phase 2 trial has been designed using the 400 x 10^6 cells, dose assuming it will be the maximal tolerated dose.
The phase 2 trial is a randomized, double-blind, allocation concealed placebo-controlled study using the 400x10^6 cell dose of Realist Orbcel-C or the maximal tolerable dose as determined by the DMEC in patients with moderate to severe ARDS.
To assess the safety of a single intravenous infusion of REALIST ORBCEL-C cells in patients with ARDS.
In patients with moderate to severe ARDS to determine the effect of a single intravenous infusion of REALIST ORBCEL-C cells on:
Patients will be prospectively screened daily. All patients with ARDS will be entered into a screening log. If the patient is not recruited the reason will be recorded. A fully anonymised minimal dataset will be recorded on these patients (age, gender, APACHE II score, worst P/F ratio at time of assessment, reasons for non-enrolment and vital status). APACHE II score and vital status will be collected using anonymised linkage to the ICNARC database through a defined CMP number (or equivalent). This will allow comparison to identify that the study population is representative of the overall cohort of patients. This information is required to establish an unbiased study population and to ensure the study can be reported in keeping with CONSORT guidelines (www.consort-statement.org).
Informed consent procedure:
The study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki. The chief investigator (CI) (or designee) is responsible for ensuring that informed consent for trial participation is given by each patient or a legal representative. An appropriately trained doctor or nurse may take consent. The person taking informed consent must be GCP trained, suitably qualified and experienced and have been delegated this duty on the delegation log. Appropriate signatures and dates must be obtained on the informed consent documentation prior to collection of trial data and administration of the trial drug. If no consent is given a patient cannot be randomised into the trial. The incapacitating nature of the condition precludes obtaining prospective informed consent from participants. In this situation informed consent will be sought from a Personal Legal Representative or Professional Legal representative.
Personal legal representative consent:
Informed consent will be sought from the patient's personal legal representative (Per LR) who may be a relative, partner or close friend. The Per LR will be informed about the trial by the responsible clinician or a member of the research team and provided with a copy of the covering statement for the Per LR with an attached participant information sheet (PIS) and asked to give an opinion as to whether the patient would object to taking part in such medical research. If the Per LR decides that the patient would have no objection to participating in the trial the Per LR will be asked to sign the Per LR consent form which will then be countersigned by the person taking consent. The original will be retained in the trial site file and a copy given to the Per LR and another copy placed in the patients' medical records.
Professional legal representative consent:
As the patient is unable to give informed consent and no Per LR is available, a doctor who is not connected with the conduct of the trial may act as a professional legal representative (Prof LR). The doctor will be informed about the trial by the responsible clinician or a member of the research team and given a copy of the PIS. If the doctor decides that the patient is suitable for entry into the trial that doctor will be asked to sign the professional legal representative consent form. The original will be retained in the trial site file and a copy given to the Prof LR and another copy placed in the patients' medical records.
Retrospective patient consent:
Patients will be informed of their participation in the trial by the responsible clinician or a member of the research team once the patient regain capacity to understand the details of the trial. The responsible clinician or a member of the research team will discuss the study with the patient and the patient will be given a copy of the PIS to keep. The patient will be asked for consent to participate in the trial and to sign the consent to continue form which will then be countersigned by the person taking consent. The original will be retained in the trial site file and a copy given to the patient and another copy placed in the patients' medical records. Where consent to continue is not obtained, consent from the legal representative will remain valid. If the patient refuses consent, permission to use data collected to that point and to access medical records for trial data will be requested from the patient.
Withdrawal of consent:
Patients may withdraw or be withdrawn (by Per LR or Prof LR) from the trial at any time without prejudice.
In the event of a request to withdraw from the study, the researcher will determine which elements of the trial are to be withdrawn from the following possibilities and this will be documented:
Consent will also be requested to use the samples collected to that point.
Investigational medicinal product
The Investigational Medicinal Products are:
Storage, thawing and reconstitution of Orbcel-C cells:
Trial guidelines will provide detailed information regarding the protocol for storage, thawing and reconstitution, and administration of the cell product Orbcel-C and placebo.
The study drug will be commenced as soon as possible following reconstitution and within 6 hours.
Study drug termination criteria:
Study drug will be continued until one of the following is met:
Study drug compliance:
Any omission of the study drug will be recorded in the CRF to monitor compliance.
Study drug accountability:
The site clinical trials pharmacist and cell therapy facility staff will maintain full accountability for the study drug received, prepared and dispensed to patients in ICU. Records will be kept allowing traceability between the cell donor and the IMP recipient. Drug administration will be recorded on the patient's prescription chart.
Study drug return and destruction:
Any partially used study drug should be disposed of/destroyed at the site in accordance with Trial guidelines and local biological waste management policies.
Unused product should disposed of/destroyed under the supervision of the site clinical trials pharmacist. Records of return and destruction will be maintained.
The NICTU will provide training to site staff on trial processes and procedures including CRF completion and data collection. Within the NICTU the clinical data management process is governed by SOPs to ensure standardisation and adherence to International Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines and regulatory requirements. Data is to be entered onto the electronic database as per the CRF entry timelines. On-site monitoring visits during the trial will check: (i) the accuracy of the data entered into the CRF, (ii) entries against source documents alongside adherence to the protocol, (iii) trial specific procedures and (iv) Good Clinical Practice (GCP). This monitoring will be carried out as per the trial specific Monitoring Plan. Changes to data will be recorded and fully auditable. Data errors will be documented and corrective actions implemented. Data validation will be implemented and discrepancy reports will be generated following data entry to identify data that may be out of range or inconsistent, or protocol deviations, based on data validation checks programmed into the clinical trial database. For routinely collected clinical data the NHS record will be the source document and for study specific measurements the CRF will be the source document.
The PI (or designee) will collect all data and record this in the CRF. Each participant will be allocated a unique participant study number at trial entry, and this, and initials, will be used to identify him or her on the CRF for the duration of the trial. Data will be collected from the time of trial entry until hospital discharge. Trial data will be entered onto a CRF and processed electronically as per NICTU SOPs and the study specific Data Management Plan (DMP). Submitted data will be reviewed for completeness and entered onto a secure, backed-up custom database. Due care will be taken to ensure data safety and integrity, and compliance with GDPR and the Data Protection Act 2018. Data queries will be raised electronically. The designated site staff will be required to respond to these queries within 2 weeks and send them back to the CTU after the queries have been reviewed and signed by the CI/delegated staff member. Any amended information will then be entered in the study database. A copy of the signed data query form should be retained with the CRF at the investigator site.
If the participant is transferred to another hospital the PI or designated member of the site study team will liaise with the receiving hospital to ensure complete data capture as per CRF instruction. If this is not possible, the primary outcome must be collected as a minimum. CRFs are to be submitted to the CTU as per the CRF submission schedule. Data censorship for each trial will occur 90 days post randomisation.
Analysis Population The primary analysis will be conducted on all outcome data obtained from all participants regardless of protocol adherence, i.e. intention to treat analysis.
It is possible that some enrolled subjects may not be treated with study drug. Therefore a secondary analysis of the all-treated population analysis will be undertaken.
For the Phase 1 trial no formal statistical analysis will be performed on safety data. The primary analysis will be descriptive and will focus on adverse events. The number of pre specified cell infusion associated events will also be reported. Descriptive analysis of pulmonary and non-pulmonary organ function will also be undertaken. We plan to publish the data from the phase 1 study.
The maximal tolerated dose up to 400x10^6cells will be proposed by the TMG and approved by the DMEC prior to use in the Phase 2 randomised controlled clinical trial.
For the Phase 2 trial, adverse events will be reported as for the Phase 1 study. For continuously distributed outcomes, differences between groups will be tested using independent samples t-tests and analysis of covariance with transformations of variables to normality if appropriate, or non-parametric equivalents. Chi-square tests (or Fisher's Exact tests) will be used for categorical variables. A p value of 0.05 will be considered as significant.
Correlations between changes in the biological markers measured and physiological and clinical outcomes will be assessed by appropriate graphical and statistical methods including Pearson's (or Spearman's) correlation coefficient.
A final analysis and report of the Phase 1 study is planned following the last patient's 90 day follow up. A final analysis and report of the phase 2 study is planned following the last patient's 90 day follow up. The 2 year follow up data will be published thereafter and will be an important long term outcome. A detailed statistical analysis plan will be written and approved by the independent DMEC prior to any analysis.
All the power calculations and methodology for data analysis have been confirmed by the trial statistician from the Northern Ireland Clinical Trials Unit (NICTU).
Every effort will be made to minimise missing baseline and outcome data in this trial. The level and pattern of the missing data in the baseline variables and outcomes will be established by forming appropriate tables and the likely causes of any missing data will be investigated. This information will be used to determine whether the level and type of missing data has the potential to introduce bias into the analysis results for the proposed statistical methods, or substantially reduce the precision of estimates related to treatment effects. If necessary, these issues will be dealt with using multiple imputation or Bayesian methods for missing data as appropriate.
The phase 1 trial will recruit up to 18 participants.
Although the primary focus of the phase 2 trial is safety, there is, however, power to detect a difference in physiological outcomes.
The primary efficacy outcome measure will be the difference in oxygenation index (OI) between the ORBCEL-C and placebo treated groups at day 7. Based on our data from a recently completed clinical trial in ARDS, the mean (standard deviation; SD) OI at day 7 in patients with ARDS is 62(51)cmH2O/kPa . To allow 1:1 recruitment (ORBCEL-C vs placebo) a sample size of 56 subjects will have 80% power at a two-tailed significance level of 0.05 using a two-sample t-test to detect a clinically significant difference of 39 cmH2O/kPa in OI between groups. In a previous phase 2 study of similar size, we have found that an intervention can demonstrate a change in OI of a similar magnitude confirming a treatment effect of this size can be achieved .
Although we anticipate few withdrawals or loss to follow-up we have allowed for this in the sample size calculation. In previous UK multicentre studies in the critically ill <3% withdrew consent or were lost to follow-up [4, 65]. Therefore, a conservative drop-out rate of 5% has been estimated and the study will require a total of 60 patients (30 patients in the ORBCEL-C and 30 in the placebo group).
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 1
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
The phase 1 trial is an open label dose escalation pilot study in which cohorts of subjects with moderate to severe ARDS will receive increasing doses of a single infusion of Realist Orbcel-C in a 3+3 design. Initially 3 cohorts with 3 subjects/cohort.
After 7 days of follow-up for all study subjects in the phase 1 study is available the TMG will review the data and propose a cell dose for the phase 2 trial. This recommendation will be submitted to the DMEC for approval prior to initiating the phase 2 trial.
The phase 2 trial is a randomized, double-blind, allocation concealed placebo-controlled study using the maximal tolerable dose as determined by the DMEC in patients with moderate to severe ARDS.
Primary Purpose: Treatment
The cell therapy facility and clinical trials pharmacist will be unblinded. The unblinded individuals will keep the treatment information confidential and will not discuss or release information on treatment allocation to the patient, the investigator, or other unauthorized personnel.
As in prior studies of MSCs, the infusion bag containing either the cell product or placebo will be masked at the time of preparation in the clinical site's cell therapy facility so that the contents of the infusion bag are not visible to the investigators or to the clinicians who are administering the study drug. The contents of the infusion bag will be administered through a masked infusion set.
|Condition ICMJE||Acute Respiratory Distress Syndrome|
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||October 2022|
|Estimated Primary Completion Date||July 2020 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||16 Years and older (Child, Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Listed Location Countries ICMJE||United Kingdom|
|Removed Location Countries|
|NCT Number ICMJE||NCT03042143|
|Other Study ID Numbers ICMJE||16154DMcA-AS|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Professor Danny McAuley, Belfast Health and Social Care Trust|
|Study Sponsor ICMJE||Belfast Health and Social Care Trust|
|PRS Account||Belfast Health and Social Care Trust|
|Verification Date||January 2019|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP