Our goals are to help develop evidence-based translational strategies and improved outcomes in the prevention and treatment of nontuberculous mycobacteria (NTM) in cystic fibrosis (CF), while training the next generation of CF investigators. This requires strong clinical core support to facilitate trials, and to disseminate clinical data and biological samples for translational studies.
The Clinical Research Core is led by Stacey Martiniano, MD at the Univesity of Colorado and Children's Hospital Colorado and Jerry Nick, MD at National Jewish Health. The Clinical Research Core supports RDP investigators in all aspects of clinical and translational research re;ated to NTM infection in CF. This includes assistance with study design, and implementation of trials through help with study coordination, screening, recruitment, biostatistical and bioinformatics support. Resources are available to collect, store and distribute data and samples, with a particular focus on biomarker development.
The Clinical Research Core is currently supporting three ongoing NTM trials at our Center:
Isolation of NTM from CF sputum is relatively common, and of uncertain significance, as clinical sequelae can range from undetectable to severe. In the context of CF, the diagnosis of NTM disease and the decision to treat currently requires more than one positive culture accompanied by evidence of accelerated clinical decline. Achieving a standardized diagnosis of NTM disease is essential for the conduct of therapeutic trials. The primary objective of this trial is to develop and test feasibility of a standardized diagnostic protocol to assist with identification of CF patients requiring treatment for NTM disease that is based on forthcoming guidelines from the CF Foundation (CFF) and the European CF Society (ECFS). The secondary object is to facilitate extensions of this diagnostic protocol to other CF Care Centers, utilizing data collection integrated within the CFF Patient Registry. Patients with a positive culture for NTM in the past year are eligible. The study’s primary endpoint is diagnosis of NTM disease at 6, 12, and 24-months following enrollment.
No NTM treatment protocol has been validated in the setting of CF. This primary objective of this trial is to develop and test the feasibility of a standardized treatment algorithm for confirmed disease by either Mycobacteria avium complex (MAC) or Mycobacteria abscessus complex (MABSC) that is also based on forthcoming CFF/ECFS guidelines. The secondary object is to facilitate extensions of this diagnostic protocol to other CF Care Centers, utilizing data collection integrated within the CFF Patient Registry. First-line treatment consists of combinations of 3 or 4 antibiotics, determined by the type of infection and severity of presentation. The algorithm also includes scheduled testing for medication-induced toxicities, as well as second- and third-line options in the setting of treatment failure. The primary endpoint is 12 months of negative NTM cultures following completion of therapy.
NTM pulmonary infections are difficult to treat and treatment failure is common, likely due in-part to sub-therapeutic drug levels. Clinical pharmacokinetics (PK) and pharmacodynamics (PD) have been shown to be altered in CF, however no specific studies have been performed for the antimycobacterial drugs in CF. The purpose of this study is to determine oral antimycobacterial drug PK and PD in patients with CF. Our hypothesis is that CF patients have altered drug absorption and metabolism leading to sub-therapeutic drug levels and that taking drugs with food and supplemental enzymes may improve drug levels by improving intestinal absorption. The aims of the proposal are (1) compare PK of oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus enzymes in 20 subjects with pancreatic insufficient CF to 10 healthy controls, (2) begin to investigate the influence of host characteristics and drug metabolism on the PK of antimycobaterial drugs, and (3) estimate an optimized dosing regimen for the antimycobacterial drugs against MAC. Upon completion of this study we will determine if and why PK of the antimycobacterial drugs are altered in CF. More importantly, we will develop CF-specific guidelines to achieve therapeutic goals with recommendations for drug dosing, enzyme use, and timing of therapeutic monitoring to be used for future treatment of NTM lung disease in CF.
The Clinical Research Core has extensive experience with designing and performing clinical studies, standardizing specimen collection, maintaining clinical and genetic databases, investigating novel biomarkers and providing biostatistical and bioinformatics support for CF investigators. In addition to the three NTM trials highlighted above, we are currently conducting over 60 additional clinical trials within the Colorado CF Center, including both CFF Therapeutic Development Network (TDN) multicenter treatment and observational studies, as well as investigator-initiated trials. In many studies we provide support in bioinformatics, biostatistics, patient recruitment and study coordination. Almost all studies have been performed in conjunction with the Colorado Clinical and Translational Sciences Institute (funded through an NIH CTSA).
The clinical environment at the Colorado CF Center provides a unique setting for NTM research. Our Care Center currently sees over 750 pediatric and adult patients at Children’s Hospital Colorado and National Jewish Health. This includes the largest cohort (n=160) of long-term CF survivors (over age 40 years old), which is a group that we believe reflects future trends for the CF population as a whole. Patients travel from throughout Colorado and the Mountain West region, stretching from the Canadian border to New Mexico, and from bordering states. Additionally, CF patients are referred from around the nation to our CF Center and to the National Jewish Health Mycobacteria Program for evaluation of NTM infection. Thus we encounter positive NTM cultures frequently from a diverse CF patient population.