Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT02326350 |
| Other study ID # |
14043DMcA-AS |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
February 6, 2015 |
| Est. completion date |
November 23, 2018 |
Study information
| Verified date |
March 2019 |
| Source |
Belfast Health and Social Care Trust |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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 their inability to return to full time employment.
There is little evidence for effective drug (pharmacological) treatment for ARDS. Blood cells
called platelets have increasingly been recognized to play a key role in the development of
ARDS. There is increasing information that aspirin, a drug which is widely used to treat
heart disease, might be important in treating ARDS. We plan to test if aspirin will help in
the treatment of ARDS. To do this we will divide patients suffering from ARDS into two
groups, one of which will get aspirin and the other a harmless dummy (or placebo) tablet who
will then be followed up to determine if lung function improves. If effective this may lead
to further research to determine if aspirin is 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.
Description:
The role of aspirin as a novel therapy for ARDS.
Aspirin inhibits cyclo-oxygenase enzymes, therefore preventing the formation of lipid
mediators including thromboxane A2 (TxA2) and pro-inflammatory prostaglandins from
arachidonic acid. TxA2 is required for platelet degranulation and aggregation. Production of
pro-inflammatory prostaglandins from arachidonic acid is mediated by cyclo-oxygenase-2
(COX-2), an enzyme induced in inflammatory and endothelial cells by cytokines, growth factors
and bacterial products including lipopolysaccharide (LPS). Prostaglandin E2 (PGE2) is a key
downstream pro-inflammatory product of COX-2 activation. It can act in an auto and paracrine
fashion on local inflammatory and parenchymal cells to increase intracellular cyclic
adenosine mono-phosphate (cAMP), drive nuclear translocation of NFκB and thus the production
of many pro-inflammatory cytokines, including TNFα and IL-8. Aspirin can also induce the
production of a lipoxin (aspirin-triggered 15-epi-lipoxin A4, also known as ATL). Lipoxins
are a group of anti-inflammatory eicosanoids derived from arachidonic acid which act via the
lipoxin A4 receptor (LXA4R) on leucocytes to inhibit free-radical formation, and reduce
activation of the proinflammatory transcription factors AP-1 and NFκB, all of which are
implicated in the development of ARDS.
Hypothesis.
Treatment with aspirin is safe and improves important surrogate clinical outcomes in adult
patients with ARDS.
Trial objectives.
To conduct a randomised, double-blind, allocation concealed, placebo-controlled phase 2 trial
of aspirin as a treatment for ARDS.
To study the biological effects of aspirin on pulmonary and systemic inflammatory responses,
epithelial and endothelial function and injury and lipid inflammatory mediators.
Population.
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, this will ensure
the study can be reported in keeping with CONSORT guidelines (www.consort-statement.org).
Routinely collected patient demographics will also be collected on these patients. This will
allow comparison to identify that the study population is representative of the overall
cohort of patients. We have an established and effective system in place to screen and
identify patients with ARDS.
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) 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. 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 they will be asked to sign two copies of the Per LR consent form
which will then be countersigned by the person taking consent. The Per LR will retain one
copy of the signed consent form. The second copy will be photocopied and the photocopy placed
in the patients' medical records whilst the original will be retained in the trial site file.
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 they will be asked to sign two copies of the
professional legal representative consent form. The doctor will retain one copy of the signed
consent form. The second copy will be photocopied and the photocopy placed in the patient's
medical records; the original will be retained in the trial site file.
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 they 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 two copies of the consent to
continue form which will then be countersigned by the person taking consent. The patient will
retain one copy of the signed consent form. The second copy will be photocopied and the
photocopy placed in the patient's medical records whilst the original will be retained in the
trial site file.
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 and consent will be requested to use the data collected to that point. If a
patient or Per LR requests termination of the trial drug during the treatment period, the
drug will be stopped but the patient will continue to be followed-up as part of the trial. If
a patient or a Per LR withdraws consent during trial treatment, the trial drug will be
stopped but permission will be sought to access medical records for data related to the
trial. If a patient or Per LR wishes to withdraw from the trial after completion of trial
treatment, permission to access medical records for trial data will be sought.
Randomisation.
Patients in the STAR study are eligible for co-enrolment in other non-CTIMP studies, this
will be decided on a case by case basis.
Randomisation procedure.
The clinical trials pharmacist will be provided with a randomisation schedule which has been
generated by the CTU. After informed consent, the researcher will contact the clinical trials
pharmacist who will allocate the next sequential number as per the randomisation schedule.
Randomisation will be stratified by vasopressor use. The clinical trials pharmacist will
dispense the trial drugs. Study drug will be dispensed as per local pharmacy guidelines.
Aspirin and placebo study drug will have an identical appearance. The researcher will then
register the recruited patient with the CTU.
Study procedures for unblinding.
The investigator or treating physician may unblind a participant's treatment assignment in
the case of an emergency, when knowledge of the study treatment is essential for the
appropriate clinical management or welfare of the subject. Should a treating clinician
require emergency unblinding, they should contact the clinical trials pharmacist at the Royal
Victoria Hospital during working hours or if out of working hours the on call pharmacist for
the Belfast Health and Social Care Trust for emergency unblinding. Following this and once
the patient is stable, all reasonable efforts should then be made to contact the CI or
co-Investigators who will be contactable via an emergency contact telephone number The date
and reason for the unblinding must be recorded in the CRF.
Study drug
Treatment regimen.
Subjects will be randomised to receive aspirin 75mg capsule or a placebo capsule enterally
for up to 14 days. Subjects will be randomised in a 1:1 ratio using blocks of variable size.
The first dose of the study drug will ideally be administered within 4 hours of randomisation
and subsequent doses will be as close to 10 am as possible starting on the following calendar
day.
Study drug compliance.
Any omission of the study drug will be recorded in the CRF to monitor compliance.
Study drug accountability.
The clinical trials pharmacist will be responsible for maintaining records of the study drug
dispensed to patients in ICU including dates, quantity, lot number and expiry date. Drug
administration will be recorded on the patient's prescription chart.
Study drug return and destruction.
At the end of the treatment period any remaining unused drug will be returned to the hospital
pharmacy. Destruction of trial medication will be in accordance with pharmacy department's
standard operating procedures (SOPs) and hospital waste management policy. A record of
destruction will be maintained.
Standardised management.
All patients will receive standardised management with regards to nutrition, antibiotic
policy, fluid management and weaning. Patients will be managed using a standardised
mechanical ventilation protocol aiming for tidal volumes of 6 ml/kg ideal body weight.
The influence of other treatments provided to critically ill patients will be minimised as
the study will be undertaken in a single centre where standardised care is delivered based on
evidence based local guidelines.
Data collection and recording.
All data for an individual patient will be collected by the CI or their delegated nominees
and recorded in the CRF. CRFs are to be submitted to the CTU as per the CRF Submission
Schedule.
Patient identification in the CRF will be through their unique Subject Number allocated at
the time of randomisation and initials. Data will be collected from the time the patient is
considered for entry into the trial through to their discharge from hospital.
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 the
Data Protection Act 1998.
Data censorship will occur after 90 days post randomisation.
Training Issues.
To ensure accurate, complete and reliable data, the CTU will do the following:
- Be available for consultation with the trial personnel by mail, telephone and/or fax.
- Review and evaluate CRF data, detect errors in data collection and request data
verification.
Data management.
Following the submission of CRFs to the CTU, the data will be processed as per the CTU SOPs.
Data queries will be generated for site staff as required to clarify data or request missing
information. The designated site staff will be required to respond to these queries within 2
weeks and send them back to the CTU after they 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.
Data storage.
All essential documentation and trial records will be stored by the CI in conformance with
the applicable regulatory requirements and access to stored information will be restricted to
authorised personnel.
Statistical considerations.
Sample size.
The primary outcome measure will be the difference in OI between the aspirin 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. A
sample size of 56 subjects (28 in each group) will have 80% power at a two-tailed
significance level of 0.05 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 our previous single centre study of simvastatin in ARDS there
were no withdrawals. In a multi-centre UK study of pulmonary artery catheters in ICU patients
(PAC-Man), no patients were lost to follow up, and only 3% withdrew consent after recovering
competency. This is in keeping with our local data. Therefore a drop-out rate of 5% has been
estimated and the study will require a total of 60 patients (30 in each group).
Statistical analysis.
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 secondary analysis excluding patients
identified to have aspirin resistance will also be undertaken. The study will be analysed
with an intention to treat so all randomised patients will be included in the analysis. 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 Spearmans) correlation coefficient.
A single final analysis is planned at the end of the trial.
