Pragmatic Research on Diuretic Management in Early BPD (PRIMED) Pilot

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PROJECT SUMMARY/ABSTRACT Bronchopulmonary dysplasia (BPD) is the most frequent adverse outcome among infants born at <30 weeks gestation and is associated with adverse respiratory and neurodevelopmental outcomes. Early BPD includes a component of alveolar and interstitial edema resulting in reduced lung compliance. Some evidence suggests that the use of loop diuretics, such as furosemide, in preterm infants > 3 weeks of age improves pulmonary mechanics and oxygenation after 1 week of treatment; however, the evidence is weak because most studies were not conducted in the current treatment era characterized by widespread surfactant and antenatal corticosteroid use and data focuses mainly on short-term outcomes. Furthermore, diuretics have a range of side effects including electrolyte abnormalities, osteopenia, potential ototoxicity, and nephrocalcinosis. Despite weak evidence for their effectiveness and concerns over safety, diuretics are commonly used. There is a need to strengthen the evidence-base regarding diuretic use in BPD with data that answers the current, relevant clinical questions—whether an individual patient in the current treatment era will derive short- term benefits from the treatment and whether the treatment is safe and effective in the long-term. We designed a clinical trial that addresses prevailing clinical attitudes that some infants clinically benefit or are “responders” by including a run-in period that examines individual patient short-term response using an innovative N-of-1 trial design while also answering questions about the longer-term efficacy and safety of chronic diuretic use by following the run-in N-of-1 trial with a placebo-controlled, parallel group randomized controlled trial (RCT) of chronic diuretics among responders. The objective of this R34 application is to obtain necessary and sufficient information to enable final decisions about the approach of the larger clinical trial through the following specific aims: Aim 1: Estimate the number of responder infants available to enter the parallel group RCT phase of the trial after the N-of-1 trial run-in period and Aim 2: Evaluate provider and parent willingness to randomize responders to assess the potential dropout rate between run-in and randomization. Accomplishing these aims is particularly important because the use of a formal N-of-1 trial design as a run-in to a parallel group RCT is a unique and cutting-edge approach. Upon completion of these aims, this pilot will provide a detailed understanding of the extent to which participants are able to complete the N-of-1 trial and it will supply data on the percent of patients identified as “responders.” This will enable a more accurate assessment of the available sample size entering the parallel group RCT phase of the trial. The pilot will also provide the data necessary to determine the expected dropout rate between the run-in and parallel group RCT phases due to reluctance to randomize a “responder” to furosemide or placebo. Together this information will enable informed decisions about the larger trial sample size and the design of the N-of-1 run-in phase, and it will be of value for others planning studies of diuretics and BPD management strategies.