R01HD105678

A Phase III Randomized Controlled Trial of Azithromycin for RSV-Induced Respiratory Failure in Children

Lung disease caused by respiratory syncytial virus (RSV) is associated with substantial short and long-term morbidity for infants and children. Despite this far-reaching disease burden, current management is limited. Developing an effective intervention for acute infection with RSV would have an enormous impact on the public health of children.

Matrix metalloproteinase (MMP)-9 is a protease that has been implicated in RSV pathogenesis. Azithromycin (AZM) is a commonly used macrolide antibiotic with a well-known safety profile that has immunomodulatory effects that have been beneficial against other inflammatory airway diseases and may work through an MMP-9-based mechanism of action.

We completed a Phase II, randomized controlled trial (RCT) of high-dose AZM [20 mg/kg (IV) x 3 days], and demonstrated that the treatment was safe and associated with decreased hospital length of stay and decreased endotracheal MMP-9 concentrations in mechanically-ventilated children. Taken together, these data provide compelling evidence that justifies a multi-centered Phase III RCT to determine the effectiveness of AZM.

The overarching hypothesis of the ARRC trial (AZM Treatment for RSV-Induced Respiratory Failure in Children) is that administration of AZM during acute, RSV-induced respiratory failure will be beneficial, mediated through an MMP-9 pathway. To test this overall hypothesis, we have developed a research network of pediatric critical care physicians to enroll 370 children in a double-masked placebo-controlled RCT of high-dose AZM.

Inclusion criteria will be age less than 2 years and acute respiratory failure secondary to RSV infection requiring ICU admission with intensive respiratory support [defined as mechanical ventilation, non-invasive bi-level positive airway pressure (BiPAP), continuous positive end-expiratory pressure (CPAP), or high-flow nasal cannula (HFNC) therapy of > 1L/kg/min of flow]. Exclusion criteria include previous use of AZM within 7 days, cardiac arrhythmias, chronic home ventilation/oxygenation, and immunosuppressive conditions.

We will test the following aims:

1. High-dose AZM administration will result in decreased length of hospital stay, decreased duration of oxygen therapy, and decreased ICU length of stay. Enrolled patients will be administered high-dose AZM or placebo, receive all other therapies based on standard American Academy of Pediatrics guidelines for RSV infection, and outcomes will be assessed.

2. Administration of high-dose AZM will result in a reduced number of wheezing episodes over 12 months after primary infection and the time to the first wheezing episode.

3. Nasal markers of MMP-9 driven lung inflammation will be decreased in patients receiving AZM and predictive of outcome.

Successful completion of this impactful grant application will determine the effectiveness of AZM on the recovery of children with severe RSV infection. A positive result from this trial will represent a paradigm shift in the management of severe RSV infection, as the first successful treatment for acute and post-RSV related respiratory exacerbation and has the potential to identify novel biomarkers of disease outcome.

University Of Alabama At Birmingham

TO CONDUCT AND SUPPORT LABORATORY RESEARCH, CLINICAL TRIALS, AND STUDIES WITH PEOPLE THAT EXPLORE HEALTH PROCESSES. NICHD RESEARCHERS EXAMINE GROWTH AND DEVELOPMENT, BIOLOGIC AND REPRODUCTIVE FUNCTIONS, BEHAVIOR PATTERNS, AND POPULATION DYNAMICS TO PROTECT AND MAINTAIN THE HEALTH OF ALL PEOPLE. TO EXAMINE THE IMPACT OF DISABILITIES, DISEASES, AND DEFECTS ON THE LIVES OF INDIVIDUALS. WITH THIS INFORMATION, THE NICHD HOPES TO RESTORE, INCREASE, AND MAXIMIZE THE CAPABILITIES OF PEOPLE AFFECTED BY DISEASE AND INJURY. TO SPONSOR TRAINING PROGRAMS FOR SCIENTISTS, DOCTORS, AND RESEARCHERS TO ENSURE THAT NICHD RESEARCH CAN CONTINUE. BY TRAINING THESE PROFESSIONALS IN THE LATEST RESEARCH METHODS AND TECHNOLOGIES, THE NICHD WILL BE ABLE TO CONDUCT ITS RESEARCH AND MAKE HEALTH RESEARCH PROGRESS UNTIL ALL CHILDREN, ADULTS, FAMILIES, AND POPULATIONS ENJOY GOOD HEALTH. THE MISSION OF THE NICHD IS TO ENSURE THAT EVERY PERSON IS BORN HEALTHY AND WANTED, THAT WOMEN SUFFER NO HARMFUL EFFECTS FROM REPRODUCTIVE PROCESSES, AND THAT ALL CHILDREN HAVE THE CHANCE TO ACHIEVE THEIR FULL POTENTIAL FOR HEALTHY AND PRODUCTIVE LIVES, FREE FROM DISEASE OR DISABILITY, AND TO ENSURE THE HEALTH, PRODUCTIVITY, INDEPENDENCE, AND WELL-BEING OF ALL PEOPLE THROUGH OPTIMAL REHABILITATION.

93.865 - Child Health and Human Development Extramural Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

Birmingham, Alabama 352940004 United States

Single Zip Code

NICHD Research Project Grant (R01 - Clinical Trial Required) (PA-18-480)

Amendment Since initial award the total obligations have increased 353% from $734,504 to $3,324,945.