1.
Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial.
Anstrom, KJ, Noth, I, Flaherty, KR, Edwards, RH, Albright, J, Baucom, A, Brooks, M, Clark, AB, Clausen, ES, Durheim, MT, et al
Respiratory research. 2020;(1):68
Abstract
Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02759120.
2.
Stopping live vaccines after disease eradication may increase mortality.
Aaby, P, Benn, CS
Vaccine. 2020;(1):10-14
Abstract
Several live vaccines may have beneficial non-specific effects (NSEs) reducing mortality more than can be explained by the prevention of the target infection, a phenomenon which has been linked to innate immune training. Most randomised controlled trials (RCTs) of oral polio vaccine (OPV) and measles vaccine (MV) have shown a large reduction in mortality that must have been at least partly nonspecific because it was much larger than the reduction explained by prevention of the target disease. Hence, stopping a live vaccine after disease-eradication could have negative health effects if the potential beneficial NSEs are not considered. We reviewed one eradicated disease, smallpox, and two infections likely to be eradicated in coming decades, polio and measles. No study was made of unintended effects of stopping smallpox vaccination when it happened in 1980. We have subsequently documented in both Guinea-Bissau and Denmark that smallpox-vaccinated individuals continued to have a survival advantage long after smallpox had been eradicated. The few studies which have examined the effect of OPV on survival all suggest strong beneficial NSEs; in RCTs, OPV compared with inactivated polio vaccine (IPV) has been associated with non-specific reductions in morbidity. RCTs, natural experiments and observational studies have found strong beneficial NSEs for MV. Hence, the imminent eradication of polio and the planned stop of OPV in 2024 and the subsequent eradication of measles infection and the possible stop to live MV could have negative effects for child survival. Before live vaccines are phased out, potential unintended effects of stopping these vaccines should be thoroughly studied.