Clinical Research Directory

Study to Evaluate Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) Long-term Safety and Efficacy in Subjects Without F508del

This study will evaluate the long-term safety, efficacy and pharmacodynamics of ELX/TEZ/IVA in participants with cystic fibrosis (CF) with at least 1 non-F508del ELX/TEZ/IVA-responsive CF transmembrane conductance regulator (CFTR) gene mutation.

MR Imaging of Lung in the Follow-up Assessment of Cystic Fibrosis

The aim of the study is to assess the diagnostic sensitivity of MRI to detect changes in Helbich-Bhalla scoring over time in patients with cystic fibrosis

Natural History of Noncirrhotic Portal Hypertension

Background: \- Noncirrhotic Portal Hypertension (NCPH) is caused by liver diseases that increase pressure in the blood vessels of the liver. It seems to start slowly and not have many warning signs. Many people may not even know that they have a liver disease. There are no specific treatments for NCPH. Objectives: \- To learn more about how NCPH develops over time. Eligibility: \- People age 12 and older who have NCPH or are at risk for getting it. In the past year, they cannot have had other types of liver disease that typically result in cirrhosis, liver cancer, or active substance abuse. Design: * Participants will have 2 screening visits. * Visit 1: to see if they have or may develop NCPH. * Medical history * Physical exam * Urine and stool studies * Abdominal ultrasound * Fibroscan. Sound waves measure liver stiffness. \<TAB\>- Visit 2: * Blood tests * Abdominal MRI * Echocardiogram * Questionnaire * Liver blood vessel pressure (hepatic venous portal gradient (HVPG)) measurement. This is done with a small tube inserted in a neck vein. * They may have a liver biopsy. * All participants will visit the clinic every 6 months for a history, physical exam, and blood tests. They will also repeat some of the screening tests yearly. * Participants with NCPH will also have: * Upper endoscopy test. A tube inserted in the mouth goes through the esophagus and stomach. * At least every 2 years: Esophagogastroduodenoscopy. * At least every 4 years: testing including HVPG measurements and liver biopsy. * Participants without NCPH will also have: * Liver biopsy and HVPG measurements to see if they have NCPH. * Every 2 years: abdominal MRI and stool studies. * The study will last indefinitely.

Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease

Healthy volunteers and patients with diseases that involve problems clearing mucus from the lungs will be examined and tested to better understand the reasons for recurring lung infections in these patients and to try to develop better ways to diagnose and treat them. The study will also try to identify the genes responsible for these diseases. Healthy volunteers 18 years of age and older and patients 2 years of age or older with suspected primary ciliary dyskinesia (PCD), variant cystic fibrosis (CF) or pseudohypoaldosteronism (PHA) may be eligible for this study. Patients enrolled in the Natural History Study of Nontuberculous Mycobacteria at NIH or other NIH natural history protocols may also be enrolled. Participants undergo the following tests and procedures during a 1-day visit at the NIH Clinical Center, as follows: All patients and normal volunteers have the following procedures: * Physical examination and review of medical and genetic history and family genetic history. * Lung function test and measurement of oxygen saturation level. * Nitric oxide measurement to measure the amount of nitric oxide production in the nose: A small tube is placed in the nose while the subject breathes through the mouth into a cardboard tube. All patients have the following additional procedures: * Blood tests for liver and kidney function, blood count, immunoglobulins and pregnancy test (where appropriate). * Blood test or buccal scrape (brushing the inside of the cheek) to obtain DNA to look for gene mutations that cause PCD, CF or PHA. * Scrape biopsy of cell lining the inside of the nose: A small toothpick-sized plastic stick with a tiny cup on the end is used to get nasal lining cells to look at the cilia (hair-like structures that move mucus). * Semen analysis (in some men) to test sperm tail function or structure. Patients suspected of having a variant of CF or PHA, including nontuberculous mycobacterial lung disease, have the following additional procedures: * Sweat chloride test: A medicine is placed on the arm to produce sweat; then, a very low level of electric current is applied for 5 to 12 minutes. Sweat is collected in a plastic tube and tested for salt content. * Blood draw for CF genetic testing, if necessary, and to measure levels of the enzyme trypsin. * Saliva collection to measure sodium and chloride content. * Nasal potential difference to measure the electrical activity of the cells lining the inside of the nose: A soft plastic tube filled with a salt solution is passed into the nasal passage and a sterile needle is placed under the skin of the arm. This test provides information about how the lining of the nose is able to get used to changes in temperature and humidity. (Normal volunteers also have this test.)

Rare CFTR Mutation Cell Collection Protocol (RARE)

Over 1,900 mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein are implicated in causing Cystic Fibrosis (CF). Potential therapies that directly target defective CFTR are being evaluated in important clinical trials, but most target the most common CFTR mutation F508del. Many patients with rare CF mutations are not able to participate in those studies. The RARE study is specifically designed for people with CF caused by rare mutations. Eligible rare mutations are listed below: • CF patients who are heterozygous for pre-mature stop codons as noted below: i. one allele must be a F508del ii. the other allele must be a pre-mature stop codon mutation • CF Patients with other genotypes that require Study PI permission: i. CF patients with two mutations that are not eligible for Trikafta ii. CF patients homozygous or heterozygous (other allele must be F508del) for rare mutations of special interest (e.g., 711+3A-\>G, 2789+5G-\>A, 3272-26A-\>G, 3849+10kbC-\>T). Other rare mutations will be considered on a case by case basis This is a multi-site, specimen collection study. Investigators will collect blood, intestinal cells and nasal cells from each participant. Cells from these specimens will be used to test future CFTR modulators to see if they might work for people with study eligible rare mutations. Having cells to test in the lab is an important first step in identifying potential new therapies for people with these mutations.

Evaluation of VX-121/Tezacaftor/Deutivacaftor in Cystic Fibrosis (CF) Participants 1 Through 11 Years of Age

The purpose of this study is to evaluate the pharmacokinetics, safety, tolerability and efficacy of VX-121/tezacaftor/deutivacaftor (VX-121/TEZ/D-IVA) in CF participants with at least 1 triple combination responsive (TCR) mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Tissue Bank for Pulmonary Diseases

The aim of this research study is to collect and store the specimens that are left over after patients undergo tests ordered by their physicians. These specimens will be used at a later time by researchers in the Pulmonary Division to develop a better understanding of pulmonary diseases or for the development of new treatments. Typical research studies that will be conducted on the stored tissue, fluid, or bacteria from the patient sample involve obtaining bacterial cultures, measurement of inflammatory markers, and examination of the characteristics of the tissue. Other similar tests may be done in the future; however, these tests have not all been determined at this time. It is important to note that no genetic testing will be performed on any samples that are obtained as part of this protocol.

Evaluation of VX-828 in Healthy Participants and in Participants With Cystic Fibrosis

The purpose of the study is to evaluate safety, tolerability, and pharmacokinetics of VX-828 and VX-828 in triple combination (TC) with Tezacaftor (TEZ)/ VX-118 or TEZ/ deutivacaftor (D-IVA) in healthy participants and VX-828 in combination with D-IVA with or without TEZ in participants with cystic fibrosis (CF).

A Phase 1/2 Study of VX-522 in Participants With Cystic Fibrosis (CF)

The purpose of this study is to evaluate the safety, and tolerability and efficacy of VX-522 in participants 18 years of age and older with cystic fibrosis and a cystic fibrosis transmembrane conductance regulator (CFTR) genotype not responsive to CFTR modulator therapy.

Role of Genetic Factors in the Development of Lung Disease

This study is designed to evaluate the genetics involved in the development of lung disease by surveying genes involved in the process of breathing and examining the genes in lung cells of patients with lung disease. The study will focus on defining the distribution of abnormal genes responsible for processes directly involved in different diseases affecting the lungs of patients and healthy volunteers. Optional CT Sub-study The standard CT scan will be compared to the low dose radiation CT scan for the 150 subjects enrolled in the sub-study to assess the variation between the two techniques. Specifically, the quantitative computer aided detection of lung CT abnormalities from LAM can be compared to assess whether low radiation dose CT exams is an alternative to conventional CT to monitor disease status. This optional sub-study will be offered to up to 100 adult subjects with lung disease and up to 50 children age 9 and older with CF. Children will not be enrolled in the optional CT sub-study unless they have had a standard CT scan for medical purposes to use in comparison. One additional low dose radiation CT scan of the chest may be done as part of this sub-study when these subjects have their next annual CT scan.

Correction of Nonsense Mutations in Cystic Fibrosis

The presence of a nonsense mutation leads to the rapid degradation of the carrier mRNA mutation by a mechanism called NMD (nonsense-mediated mRNA decay) \[6, 13\]. There are currently 3 main strategies at least for correcting nonsense mutations: exon skipping, inhibition of NMD and nonsense mutation readthrough. In the laboratory, we developed a strategy for correcting nonsense mutations combining inhibition of NMD and activation of translecture. For this purpose, we have constructed screening systems to identify NMD-inhibiting and/or readthrough enhancers. The molecules thus identified are then tested on cell lines and in murine models carrying a nonsense mutation. One of our goals is to select a set of molecules that can correct effectively nonsense mutations. For this we have to test these molecules on a great diversity of nonsense mutations. This work will: * determine if we can correct all the nonsense mutations tested with at least one of our molecules * determine what is common within a group of mutations corrected by a given molecule * be able to assign the parameters that make one mutation is corrected by one molecule and not or little by another. This study will therefore improve our theoretical knowledge on the recognition of premature stop codons but also to propose therapeutic approaches for the correction of nonsense mutations of the CFTR gene in cystic fibrosis in a targeted way for a patient.

Role of Body Fat Distribution in Metabolic and Pulmonary Decline in Cystic Fibrosis (ORBIT-CF)

Nutrition and body composition, the amount of muscle and fat in the body, has a role in overall health. This study wants to learn more about how nutrition and body composition affects health outcomes like glucose tolerance and lung function in patients with cystic fibrosis (CF) who are ages 16-30 years old. 60 adolescents and young adults with CF will be recruited, and 30 volunteers without cystic fibrosis. A total of 40 of these study participants with CF will be asked to return for annual study visits for 2 years after the first visit. The long-term goal of this study is to use the information collected to make decisions about future nutrition monitoring and interventions which help maintain optimal health for individuals with CF.

GLP-1 Agonist Therapy in Cystic Fibrosis-Related Glucose Intolerance

Diabetes is a major co-morbidity in pancreatic insufficient cystic fibrosis (PI-CF) and associated with worse outcomes. While reduced β-cell mass contributes to the insulin secretory defects that characterizes cystic fibrosis-related diabetes (CFRD), other modifiable determinants appear operative in the emergence and progression of abnormal glucose tolerance towards diabetes. Identifying interventions to preserve β-cell function are crucial for delaying and potentially preventing CFRD development. In this study, we hypothesize that weekly administration of the long-acting glucagon-like peptide-1 (GLP-1) agonist dulaglutide will improve defective early-phase insulin secretion and improve glucose tolerance during a mixed-meal tolerance test.

Trikafta Exercise Study in Cystic Fibrosis

Shortness of breath (dyspnea) during exercise is a major source of distress and is a commonly reported symptom in patients with cystic fibrosis (CF). A recent drug treatment option known as Trikafta, which contains elexacaftor, tezacaftor, and ivacaftor, may be used in patients with CF to help improve lung health. However, the effects of this combination therapy on dyspnea and exercise performance, a known predictor of survival in CF, are not clear. The investigators aim to understand the effects of Trikafta on these symptoms and to gain new insight into the potential health improvements in CF from using this treatment option.

FEED-Cystic Fibrosis (FEED-CF)

The goal of this study is to determine the extent to which excess dietary sugars serve as a precipitating factor in glucose intolerance in adults with cystic fibrosis (CF), a population at especially high risk for a unique form of diabetes (CF-related diabetes, CFRD) and with standard-of-care dietary recommendations (high-calorie, high-fat) that conflict with recommendations for other forms of diabetes. This trial will investigate if the typical high-sugar, high-fat CF diet plays a role in diabetes risk and visceral fat accumulation in people with CF. A total of 30 participants will get a low-added sugar, high-fat diet and the other 30 will get a standard CF diet with no sugar restrictions. Participants will be randomized to the diet group they are assigned. All foods will be provided for 8 weeks.

Dose Escalation Study Evaluating the Safety and Pharmacokinetics of VX-581 in Healthy Participants

The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of VX-581.

CF Bronchodilation

It is estimated that one in every 3,600 children in Canada has cystic fibrosis (CF). CF is a genetic disease that affects the glands that produce mucus and sweat. In CF, mucus production increases and the mucus becomes thick and sticky. This can block the airways, making it difficult to breathe. Mucus production also causes bacteria to grow, which can lead to infections in the lungs. Individuals with CF suffer from shortness of breath, wheezing, cough, and poor exercise capacity. There are limited treatment options to reduce shortness of breath in these individuals. Some medications known as bronchodilators are commonly prescribed to reduce breathlessness in patients with CF. These drugs help open the airways making it easier to breathe. Unfortunately, there is limited scientific proof that these drugs can reduce shortness of breath and improve exercise capacity in patients with CF. As a result, some experts have recommended that these drugs should not be prescribed for patients with CF. The purpose of this study is to examine the effects of a bronchodilator on shortness of breath, exercise performance, and breathing responses compared to a placebo drug in adults with CF.

Streamlined Treatment of Pulmonary Exacerbations in Pediatrics

The STOP PEDS RCT is a multicenter, parallel, open label randomized controlled trial evaluating the long-term (one year) and short-term safety and efficacy of two antibiotic treatment strategies for the management of outpatient pulmonary exacerbations (PEx) in the pediatric CF population.

Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of SPL84 in Patients With Cystic Fibrosis

The goal of this clinical trial is to learn if drug SPL84 is safe for adult patients with cystic fibrosis (CF). It will also learn if the drug works to treat works to treat CF with a specific mutation (3849 +10kb C--\>T). The purpose of this research study is to test the safety and effectiveness of multiple doses of the study drug, SPL84. Researchers will compare drug SPL84 to a placebo (a look-alike substance that contains no drug) to see if drug SPL84 is safe and if it works to treat CF. In cohorts 1-3, SPL84 will be tested as a monotherapy, and in Cohort 4, SPL84 will be tested in participants who are already stable on CFTR modulator therapy. Participants will take drug SPL84 or a placebo by inhalation every week for 9 weeks (cohorts 1-3) or 12 weeks (cohort 4) and visit the clinic approximately weekly for checkups and tests.

Sinus Disease in Young Children With Cystic Fibrosis

This is a prospective, observational study examining the impact of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators on chronic rhinosinusitis (CRS) and olfactory dysfunction (OD) in young children with cystic fibrosis (YCwCF). This study involves two groups: children 2-8 years old, inclusive at initial visit, receiving highly effective modulator therapy (HEMT), and a control group of children 2-8 years old, inclusive at initial visit, not receiving HEMT. Outcomes will include sinus magnetic resonance imaging (MRI) scans, olfactory tests, and quality of life surveys obtained over a two-year period.

Safety, Tolerability and Efficacy Study of ARCT-032 in People With Cystic Fibrosis

ARCT-032-02 is a Phase 2, open-label, multicenter, multiple-ascending dose study of ARCT-032 in adults with CF who are not eligible for CFTR modulator therapy or are not taking CFTR modulators due to drug intolerance, poor response, or lack of access to modulators.

Pharmacokinetics of Omadacycline in Cystic Fibrosis

The purpose of this study is to characterize the pharmacokinetics of intravenous and oral omadacycline in patients with cystic fibrosis.

A Study Assessing KB407 for the Treatment of Cystic Fibrosis

This study will evaluate safety and tolerability of ascending doses of nebulized KB407 in adults with cystic fibrosis.

Hyperpolarized 129Xe MR Imaging of Lung Function in Healthy Volunteers and Subjects With Pulmonary Disease

The purpose of this study is to develop and evaluate the usefulness of hyperpolarized (HP) 129Xe gas MRI for regional assessment of pulmonary function.