We have presented the study protocol and data analysis plans for the first phase II, multicentre randomised clinical trial that will test the efficacy and safety of a promising ALI prevention agent. Specifically, we have hypothesised that early administration of ASA to hospitalised patients who are at high risk of ALI, will be safe and will reduce the likelihood of progression to the full ALI phenotype. Secondarily, this investigation will glean important mechanistic data on ASA's impact on the pathways believed important in ALI pathogenesis as well as the potential value of relevant biomarkers in the prediction of subsequent development of ALI. Finally, the results of this study will provide essential information on both the scientific merit and feasibility of a larger, phase III trial testing the role of ASA in the prevention of lung injury.
The persistent difficulty in translating promising preclinical therapies into the clinical setting has fostered interest in the potential development of effective ALI prevention strategies. Indeed, prevention of ALI has been identified as a key strategic priority for invested parties such as the NHLBI.31
However, implementation of protocols aiming to test potential ALI prevention strategies have been historically hindered by an inability to accurately predict who is at risk for ALI. Moreover, the typically short interval between risk exposure and development of ALI as well as the small proportion of patients who progress to the full ALI phenotype following an ALI-related exposure has limited the feasibility of ALI prevention studies. In addition, the historic lack of standardisation for numerous important co-interventions that confound the associations of interest (eg, ventilator management, transfusion and resuscitation practices) has also limited our ability to test preventative strategies.
To this end, the recently validated LIPS score is a key element of the herein described study protocol.8
Specifically, the LIPS score is expected to facilitate the identification of patients at greatest risk of progressing to ALI (an LIPS score ≥4 is expected to identify a subgroup of patients who have a risk of progressing to ALI that is greater than 18%). In addition, it is notable that this ALI risk assessment tool was validated using data collected within the first 6 h after the initial evaluation in the ED. In an ALI prevention protocol such as described herein, where the time to randomisation is limited to 12 h from presentation to the ED, the ability to accurately determine risk for ALI in such a time-efficient manner is critical.
A second notable strength of the current protocol is expected to be the implementation of the CLIP for standardising important co-interventions that may otherwise confound our association of interest (ASA and ALI). During the period between hospital admission and the development of ALI, healthcare delivery factors (timely treatment of infection and shock, appropriate administration of fluid and transfusion therapies, prevention of aspiration, avoidance of large tidal volume ventilation), may be as important as individual biology in determining ALI development and outcome.32–39
Moreover, a recent survey noted wide variation in clinical practices such as the existence of a sepsis protocol, use of low tidal volume ventilation, positive end-expiratory pressure and restrictive transfusion practices, between hospitals and among the ED, ICU and operating room within hospitals.40
Thus, to effectively investigate preventive strategies in ALI, the standardisation of care delivery during the early phase of hospitalisation would appear critical. Indeed, the ARDSNet investigators have repeatedly shown the value of standardisation of clinical processes for ALI patients in clinical trials, allowing for determination of incremental benefit of new interventions.41
In the current investigation, standardisation of care with best practices will help to reduce variability in the rates of ALI and the intensity of lung injury (noise) due to inconsistencies in care delivery. The result is expected to be an increased chance of seeing a beneficial clinical or biological effect from ASA and a better assessment of the potential side effects of ASA in this population.
Although the multicentre randomised clinical trial design, availability of a time-efficient risk assessment tool (LIPS score) and the standardisation of important co-interventions with CLIP, as well as the robust study support and quality control offered through Metadata Rave, are clear strengths of the current study protocol, several important limitations with the planned investigation are worth being noted. Lung injury may be present at study entry even as clinical criteria for ALI are not fulfilled. Though a formal diagnosis of prevalent ALI is exclusionary, the molecular machinery will have been clearly set in motion in many of the study participants. Therefore, the study may be more accurately characterised as a prevention/early treatment trial rather than a pure prevention trial. Nonetheless, we have attempted to focus on the early period of ALI development by mandating a short interval from hospital presentation to randomisation (12 h) and a similarly short interval from hospital presentation to administration of the first study dose (24 h). In addition, the study will exclude patients who presented to an outside hospital ED more than 12 h before arrival at the enrolling site's facility. The study will also exclude those with ALI on hospital presentation or prior to randomisation as well as those who are receiving mechanical ventilation through a tracheostomy tube prior to the current hospital admission (patient who is ventilator dependent) or those with a history of interstitial lung disease with chronic pulmonary infiltrates that may mimic ALI.
A second limitation relates to the intervention of ASA administration. Specifically, it is now well documented that more than 10% of the population will have a variable response to ASA or at least some form of ASA resistance.17
These patients may not benefit from ASA, even if ASA can modulate the development of lung injury. However, as part of this study, we will measure plasma thromboxane, a sensitive indicator of ASA resistance, to determine the prevalence of ASA resistance in patients at high risk of ALI. As such, sensitivity analyses, stratifying study participants by ASA resistance (as determined by changes in thromboxane levels), may allow us to determine whether the effect of ASA on ALI development is isolated to those susceptible to the actions of ASA. A related concern is the potential influence of concomitant medications that may impact on ASA's ability to prevent or mitigate ALI (eg, statins and corticosteroids). To address this concern, we will be collecting detailed information on concomitant medications and, when necessary, appropriate statistical adjustments will be made.
A third potential limitation with this study relates to a previously recognised major barrier to ALI prevention studies, namely feasibility. First and foremost, a substantial proportion of the target population may be expected to be receiving ASA on presentation to the ED, an exclusion criteria for the current protocol. Notably, however, our preliminary work suggests that upwards of two-thirds of the target population was not on ASA prior to admission. We also note that over the 3 months of the initial LIPS,8
there were 800 patients who fulfilled study inclusion criteria of LIPS score ≥4 and did not fulfil the exclusion criteria of pre-existing ASA use, prevalent ALI and elective surgery. Therefore, we believe that with 14 proposed sites and 2 years of planned enrolment, we will successfully meet our enrolment goals of 400 total patients. Also relating to feasibility, it is possible that some sites will be challenged by the short time interval allowed for patient enrolment as well as the short time to study drug administration. Though a valid concern, we believe the use of the LIPS score and the robust support offered through Metadata Rave will greatly facilitate the enrolment and randomisation procedures such that sites will indeed be successful in meeting these time-sensitive challenges.
A fourth and final limitation which deserves mention relates to the potential toxicity of the intervention of interest. Generally, ASA is well tolerated even in acutely ill, hospitalised patients in whom ASA is often continued during the hospitalisation. As an example, in a study of ASA use up to the time of cardiac surgery, its continuation was not associated with an increased need for transfusion therapies.43
Nevertheless, there may be injury associated with the administration of ASA. To address this concern, patients at risk for major complications from ASA therapy have been excluded from the study. Multiple stopping criteria for patients who experience adverse events have also been incorporated into the protocol. In addition, the more complete understanding of the safety profile of an intervention of interest is an important goal of all phase II trials. In this regard, the information gleaned from this study, adverse events included, is necessary to help decide on the merits of proceeding to a phase III clinical trial.