Connecting Research to Clinical Trials for Better Therapies: Cystic Fibrosis Therapeutic Development Network Coordinating Center
The Center for Respiratory Biology and Therapeutics is part of the Cystic Fibrosis Foundation Therapeutic Development Network (TDN) and home to its national coordinating center (TDNCC).
The TDN is a nationwide clinical trials network funded by grants from the Cystic Fibrosis Foundation. The network facilitates safe, rapid and coordinated evaluation of new and existing treatments for people with cystic fibrosis (CF).
The coordinating center, co-led by Seattle Children’s Drs. Nicole Hamblett and Christopher Goss, manages the operational infrastructure for the network and provides a range of services required for managing CF clinical studies, including biostatistics, clinical data management and clinical trial management. The TDNCC also manages network communications and data systems; coordinates development and implementation of network policy and procedures; provides project management support for the TDN and its committees; and manages network meetings.
Assisting Sponsors
With extensive experience in planning and conducting CF clinical research, the TDNCC engages with industry sponsors to provide protocol development expertise. Early collaboration and advice provides support for sponsors prior to the submission of their study protocols to the TDN scientific review process.
Our Expertise
The TDNCC leadership has broad expertise in CF, including the design and analysis of clinical trials in an orphan disease setting. Additionally, we are involved in the development of new clinical outcome measures for CF, including the validation of biomarkers to enable early evaluation of new therapies.
Key Studies
The strength of the TDNCC lies in our unparalleled experience in setting up and managing CF studies and our intimate knowledge of the CF research community. Our funding comes a variety of sources, including the Cystic Fibrosis Foundation, the National Institutes of Health and the Food and Drug Administration.
A few of our current and past studies and journal articles:
PROMISE Study
Highly effective CFTR modulator drug therapy is increasingly available to those with CF. Multiple observational research studies are now being conducted to better understand the impacts of this important therapeutic milestone on long-term outcomes, patient care needs and future research priorities. PROMISE is a large, multidisciplinary academic study focused on the broad impacts of starting elexacaftor/tezacaftor/ivacaftor in the U.S. population age 6 years and older. The many areas of investigation and rationale for each are discussed by organ systems, along with recognition of remaining important questions that will not be addressed by this study alone. Knowledge gained through this and multiple complementary studies around the world will help to understand important health outcomes, clinical care priorities and research needs for a large majority of people treated with these or similarly effective medications targeting the primary cellular impairment in CF.
STOP2 Study
People with CF experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. The STOP2 study (Standardized Treatment of Pulmonary Exacerbations 2) aimed to test differing durations of intravenous antimicrobials for CF exacerbations. STOP2 was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7 to 10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days' total antimicrobial duration; all others were randomized to 14 or 21 days' duration. The study found that among adults with CF with early treatment improvement during exacerbation, ppFEV1 after 10 days of intravenous antimicrobials was not inferior to 14 days. For those with less improvement after one week, 21 days was not superior to 14 days. The STOP360 research study is currently open for patients with CF who are 6 years and older.
SIMPLIFY Study
The care for individuals with CF with at least one F508del mutation will greatly change as a result of the unparalleled clinical benefits observed with the new triple-combination CFTR (CF transmembrane regulator)-modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI). Incorporating ETI into the standard of care creates new motivation and opportunity to consider reductions in overall treatment burden and evaluate whether other chronic medications can now be safely discontinued without loss of clinical benefit. SIMPLIFY is a master protocol poised to test the impact of discontinuing versus continuing two commonly used chronic therapies in people with CF who are at least 12 years of age or older and stable on ETI therapy. The protocol comprises two concurrent randomized, controlled trials designed to evaluate the independent short-term effects of discontinuing hypertonic saline or dornase alfa, enabling individuals on both therapies to participate in one or both trials. The primary objective for each trial is to determine whether discontinuing treatment is noninferior to continuing treatment after establishment of ETI, as measured by the six-week absolute change in the percent-predicted forced expiratory volume in one second. In both trials, stopping therapy was found to be comparable to continuing therapy with respect to the six-week change in ppFEV1. This study was uniquely positioned to provide timely evidence on whether the daily treatment burden can be reduced among individuals on CFTR-modulator therapy.
Journal Article
Advancing the pipeline of cystic fibrosis clinical trials: a new roadmap with a global trial network perspective
The growing use of modulator therapies aimed at restoring cystic fibrosis transmembrane conductance regulator (CFTR) protein function in people with cystic fibrosis has fundamentally altered clinical trial strategies needed to advance new therapeutics across an orphan disease population that is now divided by CFTR modulator eligibility. The development of a robust pipeline of nucleic acid-based therapies (NABTs) — initially directed towards the estimated 10% of the cystic fibrosis population who are genetically ineligible for, or intolerant of, CFTR modulators — is dependent on the optimization of restricted trial participant resources across multiple development programs, a challenge that will preclude the use of gold standard placebo-controlled trials. Advancement of a full pipeline of symptomatic therapies across the entire cystic fibrosis population will be challenged by smaller effect sizes and uncertainty regarding their clinical importance in a growing modulator-treated population with more mild and stable pulmonary disease. In this Series paper, we aim to lay the foundation for clinical trial strategy and community partnership that must deviate from established and familiar precedent to advance the future pipeline of cystic fibrosis therapeutics.