CFTR Modulators for Cystic Fibrosis

(Nof1 Trial)

Overseen By Rory OShaughnessy, MPH

Age: Any Age

Sex: Any

Trial Phase: Academic

Sponsor: Children's Hospital Medical Center, Cincinnati

Must be taking: CFTR modulators

Must not be taking: CYP3A inducers/inhibitors, Prednisone

Disqualifiers: Pregnancy, Unstable CF pathogens, Diabetes, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

Duration: 4 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests treatments for cystic fibrosis using drugs known as CFTR modulators. The aim is to determine which drugs work best for individuals with rare CF gene mutations. Researchers will assess how these drugs affect cells from participants’ nasal passages and then confirm results with personalized care. Individuals with cystic fibrosis and a rare CF gene mutation are well-suited for this trial. As an unphased trial, it offers participants a unique opportunity to contribute to groundbreaking research that could lead to personalized treatment options.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use certain drugs like CYP3A inducers or inhibitors (e.g., voriconazole, fluconazole, rifampin) or prednisone over 20mg daily. It's best to discuss your current medications with the trial team.

What prior data suggests that these CFTR modulators are safe for use in this study?

Research has shown that CFTR modulators are generally safe for people with cystic fibrosis. Studies have found that drugs like elexacaftor/tezacaftor/ivacaftor are usually well-tolerated. People taking them have reported better lung function and other health improvements over time.

In one study, patients who took elexacaftor/tezacaftor/ivacaftor for 24 months did not experience any serious side effects. Another study confirmed the long-term safety of these medications.

Overall, current evidence suggests that CFTR modulators are safe and effective for treating cystic fibrosis. Most people handle them well, and serious side effects are rare. ^{1 2 3 4 5}

Why are researchers excited about this trial?

CFTR modulators are unique because they target the underlying cause of cystic fibrosis rather than just alleviating symptoms. Most current treatments focus on managing symptoms or complications of the disease, like lung infections and digestive issues, without addressing the root problem. CFTR modulators work by correcting the malfunctioning protein caused by cystic fibrosis, potentially improving lung function and quality of life. Researchers are excited about these treatments because they offer a more targeted approach, which could lead to better outcomes for patients.

What evidence suggests that CFTR Modulators could be effective for Cystic Fibrosis?

Research has shown that CFTR modulators treat cystic fibrosis by correcting the faulty protein caused by CFTR gene mutations. One study with 307 participants demonstrated that the medication Elexacaftor-Tezacaftor-Ivacaftor, also known as Trikafta, led to significant health improvements for 18 different CFTR mutations. Another study with 422 participants found similar benefits for 64 CFTR mutations. Real-world data from 494 patients using these modulators also showed fewer hospital visits and emergencies. These findings suggest that CFTR modulators, which participants in this trial may receive, can greatly improve health outcomes for people with cystic fibrosis. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for individuals with Cystic Fibrosis who have rare CFTR gene mutations and are at least 6 years old, meeting age-specific criteria for different modulator drugs. They must not have had changes in their chronic CF therapies in the last 28 days, have an FEV1 > 50% predicted, and no history of organ transplantation or conditions that could risk their safety.

Inclusion Criteria

I am at least 4 months old.

I am 6 years or older and eligible for the drug according to FDA guidelines.

I am at least 12 years old.

Exclusion Criteria

Lactating

Your blood clotting time is more than 1.5 times the normal level.

Your white blood cell count is very high or your absolute neutrophil count is very low.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Run-in

Subjects undergo a 14-day run-in period before the observational block

2 weeks

1 visit (in-person)

Observational

28-day block of non-treatment observation

4 weeks

2 visits (in-person)

Washout

14-day washout period following the observational block

2 weeks

1 visit (in-person)

Treatment

28-day block of modulator treatment

4 weeks

2 visits (in-person)

Washout

14-day washout period following the treatment block

2 weeks

1 visit (in-person)

Follow-up

14-day follow-up period before study completion

2 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• CFTR Modulators

Trial Overview The study tests FDA-approved CFTR modulators on nasal cells to see if they work for non-approved CF gene mutations. It involves lab testing followed by personalized 'N-of-1' trials where each participant's response to treatment is closely monitored to assess effectiveness.

How Is the Trial Designed?

Group I: CFTR modulator or other therapies Experimental Treatment 1 Intervention

CFTR modulator or active therapy

CFTR Modulators is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Trikafta for:

• Cystic fibrosis in patients aged 2 years and older who have at least one copy of the F508del mutation in the CFTR gene or another mutation that is responsive to treatment with TRIKAFTA

Approved in European Union as Kaftrio for:

• Cystic fibrosis in patients aged 2 years and older who have at least one copy of the F508del mutation in the CFTR gene or another mutation that is responsive to treatment with Kaftrio

Approved in Canada as Trikafta for:

• Cystic fibrosis in patients aged 2 years and older who have at least one copy of the F508del mutation in the CFTR gene or another mutation that is responsive to treatment with TRIKAFTA

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Published Research Related to This Trial

In a study involving 182 patients with multidrug-resistant tuberculosis (MDR-TB), both levofloxacin (LFX) and moxifloxacin (MXF) showed similar effectiveness in achieving negative sputum cultures after 3 months of treatment, with 88.3% and 90.5% conversion rates, respectively.

The incidence of adverse drug reactions was low and comparable between the two groups, with 7.7% in the LFX group and 5.2% in the MXF group, indicating that both medications are generally safe for use in treating MDR-TB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of levofloxacin versus moxifloxacin for multidrug-resistant tuberculosis. Koh, WJ., Lee, SH., Kang, YA., et al.[2018]

A 14-year-old female patient with severe cystic fibrosis showed significant improvements in quality of life and lung function after starting therapy with Elexacaftor-Tezacaftor-Ivacaftor (ETI), with FVC and FEV1 increasing by 21% and 20% at 45 days, and 22% and 27% at 365 days, respectively.

The patient also experienced a notable improvement in nutritional status, with an increase in weight-for-BMI from 1.6 to 5.6 kg during the first six months, and no adverse effects were reported during the treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Tritherapy with cystic fibrosis transmembrane conductance regulator protein modulators in cystic fibrosis]. Fielbaum Colodro, O., Vidal Grell, A., Méndez Yarur, A., et al.[2023]

Elexacaftor-tezacaftor-ivacaftor is a newly approved triple-combination therapy for cystic fibrosis that significantly improves lung function, quality of life, and reduces exacerbations in patients aged 12 and older with at least one F508del mutation in the CFTR gene, surpassing existing treatments.

While the therapy shows promising efficacy, common side effects include rash and headache, and liver function monitoring is advised; however, about 10% of the cystic fibrosis population remains ineligible for this or any CFTR modulation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elexacaftor-Tezacaftor-Ivacaftor: The First Triple-Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapy. Ridley, K., Condren, M.[2020]

Fewer than 20% of patients with multidrug-resistant tuberculosis (MDR-TB) are currently receiving treatment, highlighting the urgent need for improved treatment programs.

New drugs like bedaquiline and delamanid offer hope for MDR-TB, but to be effective, future treatment regimens must be designed to be shorter, simpler, and more tolerable, following eight key principles to enhance their clinical effectiveness and ease of use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Principles for designing future regimens for multidrug-resistant tuberculosis. Brigden, G., Nyang'wa, BT., du Cros, P., et al.[2021]

In a study involving 16 patients with cystic fibrosis (PwCF) on Trikafta® therapy, downregulation of matrix metalloprotease 9 (MMP9) was observed in those who responded well to the treatment, suggesting it may serve as a biomarker for therapy efficacy.

The study indicates that the NF-kB pathway may regulate MMP9 levels, providing insights into the molecular mechanisms that could explain the variability in clinical responses to Trikafta®, which could inform future personalized medicine approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of Plasmatic Matrix Metalloprotease 9: A Promising New Tool for Understanding the Variable Clinical Responses of Patients with Cystic Fibrosis to Cystic Fibrosis Transmembrane Conductance Regulator Modulators. Capraro, M., Pedrazzi, M., De Tullio, R., et al.[2023]

The development of the triple combination CFTR modulator elexacaftor-tezacaftor-ivacaftor is a significant advancement in cystic fibrosis treatment, potentially benefiting over 90% of patients by improving their health outcomes.

Survival rates for cystic fibrosis have dramatically increased from an average of 10 years in the 1960s to approximately 50 years today, highlighting the success of modern therapies and comprehensive care in managing the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of elexacaftor - tezacaftor - ivacaftor: Highly effective CFTR modulation for the majority of people with Cystic Fibrosis. Middleton, PG., Taylor-Cousar, JL.[2021]

All-oral treatment regimens for multidrug-resistant tuberculosis (MDR-TB) could significantly improve patient care by eliminating painful daily injections, which are currently part of standard treatment and fail in about half of cases.

Drugs like bedaquiline, delamanid, and linezolid show strong bactericidal activity and have limited prior population exposure, making them suitable candidates for effective all-oral MDR-TB regimens, potentially enhancing treatment adherence and reducing costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

(Re)moving the needle: prospects for all-oral treatment for multidrug-resistant tuberculosis. Milstein, M., Brzezinski, A., Varaine, F., et al.[2018]

In a study of 13 patients treated with bedaquiline (BDQ) for multidrug-resistant tuberculosis, the median treatment duration was 11 months, and plasma concentrations indicated good drug efficacy and safety, with no significant drug interactions observed.

BDQ was still detectable in one patient’s plasma 200 days after treatment ended, which raises concerns about the potential for drug resistance due to prolonged presence in the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term plasma pharmacokinetics of bedaquiline for multidrug- and extensively drug-resistant tuberculosis. Perrineau, S., Lachâtre, M., Lê, MP., et al.[2019]

The lengthy treatment duration and challenges like poor patient adherence and drug resistance highlight the urgent need for new TB therapies, leading to the largest drug development portfolio in TB history.

Several promising drug candidates, including bedaquiline and delamanid, are being considered for future TB regimens, with ongoing research into their pharmacokinetics and clinical effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New and Repurposed Drugs for the Treatment of Active Tuberculosis: An Update for Clinicians. Aguilar Diaz, JM., Abulfathi, AA., Te Brake, LH., et al.[2023]

In a cohort study of 33 adults with cystic fibrosis, treatment with the triple CFTR modulator Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) led to significant improvements in glucose tolerance, with nearly half of the patients showing better glucose control after about 6 months of treatment.

The study also found significant reductions in blood glucose levels during an oral glucose tolerance test and improvements in HbA1c levels, suggesting that ELX/TEZ/IVA may enhance metabolic health in cystic fibrosis patients without increasing insulin secretion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved glucose tolerance after initiation of Elexacaftor / Tezacaftor / Ivacaftor in adults with cystic fibrosis. Steinack, C., Ernst, M., Beuschlein, F., et al.[2023]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK610228/

Elexacaftor-Tezacaftor-Ivacaftor and Ivacaftor (Trikafta) - NCBI Study 124 (N = 307; 18 CFTR mutations) and Study 16 (N = 422; 64 CFTR mutations) demonstrated that ELX-TEZ-IVA resulted in clinically meaningful improvements in ...

2. jmcp.org jmcp.org/doi/10.18553/jmcp.2023.29.6.599

Real-world outcomes and direct care cost before and after ... Among 494 commercially insured members diagnosed with cystic fibrosis, a meaningful decrease in hospitalizations, emergency department visits, ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1569199325014675

LONGITUDE: An observational study of the long-term ... LONGITUDE is an observational, registry-based cohort study using data from the UK CF Registry to evaluate outcomes of ELX/TEZ/IVA in people aged ≥6 years.

4. cff.org cff.org/managing-cf/cftr-modulator-therapies

CFTR Modulator Therapies Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein made by the CFTR gene.

5. cda-amc.ca cda-amc.ca/sites/default/files/DRR/2025/SR0837-Combined_Review.pdf

Elexacaftor-Tezacaftor-Ivacaftor and Ivacaftor (Trikafta) NCT04378153: Impact of discontinuing chronic therapies in people with cystic fibrosis on highly effective CFTR modulator therapy (SIMPLIFY). ClinicalTrials ...

6. 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 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11965699/

Improved Clinical Outcomes With Elexacaftor/Tezacaftor/ ... Overall, lung function, SwCl, PEx rate, CFQ‐R scores and BMI improved after 24 months of ETI treatment. ETI was well tolerated, and none of the ...

8. thelancet.com thelancet.com/journals/eclinm/article/PIIS2589-5370(25)00409-2/fulltext?rss=yes

Elexacaftor-tezacaftor-ivacaftor in people with cystic ... Elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis harbouring two CFTR Class I variants: real-world data from the French ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S1569199323000668

Real-world safety and effectiveness of elexacaftor ... Phase 3 clinical trials showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in people with cystic fibrosis (CF) with ≥1 ...

10. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40209082/

Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/ ... These results confirm the favorable long-term safety profile and durable disease-modifying clinical benefits of ELX/TEZ/IVA in adolescents and adults with CF.