CFTR Modulator Therapy for Cystic Fibrosis

(HyPOINT Trial)

Not currently recruiting at 3 trial locations

Overseen By Kelly Thornton, BS

Age: < 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Children's Hospital Medical Center, Cincinnati

Must be taking: CFTR modulators

Disqualifiers: Metal implants, Claustrophobia, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 28

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to track lung health in people with Cystic Fibrosis (CF) using a special MRI scan that avoids radiation. The researchers aim to determine the effectiveness of the new triple combination CFTR modulator therapy, which improves lung function, by measuring changes in lung ventilation (airflow) with this MRI. Participants should have CF with at least one deltaF508 mutation and no recent changes in their CF treatments. The trial could lead to more personalized CF treatments in the future. As a Phase 4 trial, the treatment has already received FDA approval and proven effective, and this research helps understand its benefits for more patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does require that there be no changes in your chronic pulmonary medications or therapies in the 28 days before the first visit. This suggests you should continue your current medications without changes before starting the trial.

What is the safety track record for the CFTR modulator therapy?

Research has shown that CFTR modulator therapies, particularly triple combination treatments, are generally safe. Studies indicate they often lead to better health outcomes compared to other options, with side effects similar to those of standard treatments.

Some individuals have experienced breathing issues, such as chest tightness or difficulty breathing, which led them to discontinue the therapy. These side effects occurred in about 5% to 31% of participants, making them fairly common but not guaranteed. However, most individuals tolerate these therapies well, and their approval for treating cystic fibrosis suggests safety based on past research.

While more real-world data is being collected, the overall evidence supports that these treatments are generally safe. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about this trial because it's exploring innovative ways to track lung function in cystic fibrosis patients using advanced imaging techniques. Unlike traditional methods like spirometry and multiple-breath washout, which provide indirect measurements, the use of hyperpolarized 129Xe MRI directly visualizes how air moves through the lungs, offering a clearer picture of lung ventilation. This technique could lead to more precise monitoring of disease progression and treatment effects, potentially transforming how we evaluate and manage cystic fibrosis. By directly comparing this new imaging method with established tests, the trial aims to validate its use and potentially set a new standard for assessing lung function in this condition.

What evidence suggests that this trial's treatments could be effective for Cystic Fibrosis?

This trial will examine the effects of CFTR modulator therapy, specifically the combination of elexacaftor, tezacaftor, and ivacaftor, on patients with cystic fibrosis (CF). Studies have shown that this therapy significantly improves health for people with CF by enhancing breathing, digestion, and nutrition. Research also shows it reduces sweat chloride levels, indicating the treatment's effectiveness. Clinical data indicates that these drugs outperform placebo treatments and are as safe as other treatments. These findings suggest that the therapy effectively manages CF symptoms and enhances quality of life. ^{1 2 3 6 7}

Who Is on the Research Team?

Jason Woods, PhD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Are You a Good Fit for This Trial?

This trial is for people with Cystic Fibrosis who have at least one deltaF508 mutation. They must be able to follow the study schedule, give consent, and have been stable on certain CFTR modulators or not on any such therapy. Ages vary by phase: 6-18 for Phase 1 and 9-18 for Phase 2. Participants need normal organ function and no recent acute illness.

Inclusion Criteria

Written informed consent (and assent when applicable) obtained from subject or subject's legal representative

I can follow the study's schedule and requirements.

Exclusion Criteria

Any other condition that, in the opinion of the Site Investigator/designee, would preclude informed consent or assent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives

I am not pregnant or breastfeeding.

You cannot have metal implants or be claustrophobic for a standard MRI.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Baseline and Repeated 129Xe MRI Scanning

Implementation of a centralized analysis program of repeated 129Xe MRI scanning in CF patients with mild lung disease to define the intra-subject variability of the primary outcome ventilation defect percentage (VDP).

4 weeks

Multiple visits for MRI scanning

Phase 2: Observational Study with Triple-Combination Modulator Therapy

Patients assessed before and after the clinical initiation of triple-combination modulator therapy, with primary endpoint being the change of VDP after 28 days.

12 months

Visits at 28 days, 6 months, and 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Hyperpolarized Imaging

Trial Overview The trial tests a new way to monitor lung health in Cystic Fibrosis using MRI with hyperpolarized gas, which shows both structure and function of lungs without radiation. It aims to see if this can detect early changes better than current methods when starting triple combination CFTR modulator therapy.

How Is the Trial Designed?

Group I: Phase 1 Experimental Treatment 1 Intervention

Phase 1 will include implementation of a centralized analysis program of repeated 129Xe MRI scanning in CF patients with mild lung disease to define the intra-subject variability of the primary outcome ventilation defect percentage (VDP). Patients will undergo baseline 129Xe MRI scanning and repeated measurements the same day, as well as at 28 days (± 7 days). Phase 1 will establish the intra-subject reproducibility to facilitate future use of 129Xe MRI in multi-site studies. Furthermore, the reproducibility limits defined will inform the overall design of future studies and will compare to established pulmonary function and multiple-breath washout testing (via measurement of the lung clearance index, LCI).

Group II: Initiation of CFTR Modulator Experimental Treatment 1 Intervention

Phase 2 will be an observational study of patients assessed before and after the clinical initiation of triple-combination modulator therapy (after presumed FDA and Health Canada approval). The primary endpoint for Phase 2 is the change of VDP after 28 days of triple-combination modulator therapy. Within Phase 2, this study will also address how highly-effective modulator therapies affect lung function trajectories by measuring 129Xe MRI at 28 days (± 7 days), 6 months (± 28 days), and 12 months (± 28 days) after start of therapy (paralleling time points of the PROMISE study). Finally, to understand how 129Xe MRI can be used in combination with existing measures of lung function (e.g. spirometry, multiple breath washout), the investigators will directly compare the repeated data collected in both Phase 1 and Phase 2 to these established measures of lung function that are currently used in observational and interventional studies.

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

University of Virginia

Collaborator

Trials

802

Recruited

1,342,000+

University of Wisconsin, Madison

Collaborator

Trials

1,249

Recruited

3,255,000+

The Hospital for Sick Children

Collaborator

Trials

724

Recruited

6,969,000+

Published Research Related to This Trial

In a study involving 10 participants with mild cystic fibrosis, both dynamic 19F and hyperpolarized 129Xe MRI effectively detected ventilation abnormalities, but they provided different insights into lung function.

The results showed that while both imaging techniques identified ventilation defects, they were not entirely congruent, indicating that using both methods together can give a more comprehensive view of lung ventilation status in cystic fibrosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of single breath hyperpolarized 129 Xe MRI with dynamic 19 F MRI in cystic fibrosis lung disease. McCallister, A., Chung, SH., Antonacci, M., et al.[2021]

Hyperpolarized 129Xe MRI can effectively detect ventilation defects in pediatric patients with mild cystic fibrosis (CF), even when traditional measures like FEV1 show normal results, indicating its potential as a sensitive diagnostic tool.

In a study of 22 participants (11 healthy controls and 11 CF patients), the ventilation defect percentage (VDP) was significantly higher in CF patients (18.3%) compared to controls (6.4%), suggesting that 129Xe MRI may be a valuable method for monitoring lung function and disease progression in young CF patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperpolarized 129Xe for investigation of mild cystic fibrosis lung disease in pediatric patients. Thomen, RP., Walkup, LL., Roach, DJ., et al.[2022]

Real-world studies indicate that while CFTR modulator therapies for cystic fibrosis are generally well-tolerated, there may be a higher frequency of adverse events (AEs) and discontinuation compared to clinical trials, particularly with lumacaftor/ivacaftor (LUM/IVA) which showed more respiratory-related AEs.

All four CFTR modulators were associated with potential mental health and neurocognitive AEs, highlighting the need for systematic monitoring and the important role of pharmacists in managing these therapies and their side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review. Dagenais, RVE., Su, VCH., Quon, BS.[2022]

Highly effective modulator therapies (HEMTs) have significantly improved the management of cystic fibrosis, leading to better survival rates and health across multiple organ systems.

Despite their benefits, HEMTs are associated with serious adverse events, such as liver injury and neurocognitive symptoms, highlighting the need for long-term safety studies and careful monitoring in patients of all ages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trials and tribulations of highly effective modulator therapies in cystic fibrosis. Lieu, N., Prentice, BJ., Field, P., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8964016/

Efficacy and Safety of Triple Combination Cystic Fibrosis ... CFTR modulators in triple combination achieve better clinical results than placebo and active control, and result in comparable adverse events.

2. news.vrtx.com news.vrtx.com/news-releases/news-release-details/vertex-presents-new-data-across-portfolio-cystic-fibrosis

Vertex Presents New Data Across Portfolio of Cystic Fibrosis ... Data presented on outcomes following treatment with CFTR modulators add to growing body of evidence that reduced level of sweat chloride is ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2341287925001322

Advances in the treatment of cystic fibrosis: CFTR modulators Triple therapy with elexacaftor-tezacaftor-ivacaftor has been found to significantly improve respiratory, gastrointestinal and nutritional outcomes as well as ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11565698/

Modulator-refractory cystic fibrosis: Defining the scope and ... Consistent access and regular use of CFTR modulator therapy is a significant factor contributing to recurrent exacerbations. Recent studies ...

5. jmcp.org jmcp.org/doi/10.18553/jmcp.2023.29.6.599

Real-world outcomes and direct care cost before and after ... Data from the real-world setting show a doubling in CF per-person expenditures for privately insured patients from 2010 (pre-CFTR modulator ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1471489222000662

Current state of CFTR modulators for treatment of Cystic ... Phase 3 trials have generally shown reassuring safety profiles for CFTR modulators, with more real-world safety data emerging [44,103]. LFT abnormalities ...

7. mdpi.com mdpi.com/2077-0383/10/1/23

Real-World Safety of CFTR Modulators in the Treatment ... Chest tightness and/or dyspnea were the most common respiratory AEs to prompt discontinuation, with reported frequencies between from 5 to 31%. In one case ...