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?

The purpose of this study is to validate and utilize a personalized medicine approach to identify potential treatments with current FDA approved CFTR modifiers for non-approved CF gene mutations. The study will perform ex vivo testing of CFTR function and current marketed CFTR modulating drugs on expanded nasal cells at Cincinnati Children's Human Nasal Epithelium (HNE) Core Laboratory. The results will be confirmed and translated into bedside care through an N of 1 trial to determine effectiveness of treatment.

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 makes CFTR Modulators unique for treating cystic fibrosis?

CFTR Modulators are unique because they target the underlying cause of cystic fibrosis by helping the defective CFTR protein function more effectively, unlike other treatments that only manage symptoms. This approach can improve lung function and reduce complications associated with the disease. ^{1 2 3 4 5}

What data supports the effectiveness of the drug CFTR Modulators, specifically Elexacaftor/Tezacaftor/Ivacaftor, for treating cystic fibrosis?

Research shows that the drug Elexacaftor/Tezacaftor/Ivacaftor improves lung function, quality of life, and reduces exacerbations (flare-ups) in people with cystic fibrosis. It is considered a highly effective treatment for the majority of patients with this condition. ^{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 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]

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]

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]

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]

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]

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]

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]

Citations

1. Netherlands pubmed.ncbi.nlm.nih.gov

Improved glucose tolerance after initiation of Elexacaftor / Tezacaftor / Ivacaftor in adults with cystic fibrosis. [2023]

2. Switzerland 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. [2023]

3. Chile pubmed.ncbi.nlm.nih.gov

[Tritherapy with cystic fibrosis transmembrane conductance regulator protein modulators in cystic fibrosis]. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

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

5. England pubmed.ncbi.nlm.nih.gov

Development of elexacaftor - tezacaftor - ivacaftor: Highly effective CFTR modulation for the majority of people with Cystic Fibrosis. [2021]

6. France pubmed.ncbi.nlm.nih.gov

(Re)moving the needle: prospects for all-oral treatment for multidrug-resistant tuberculosis. [2018]

7. France pubmed.ncbi.nlm.nih.gov

Long-term plasma pharmacokinetics of bedaquiline for multidrug- and extensively drug-resistant tuberculosis. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Comparison of levofloxacin versus moxifloxacin for multidrug-resistant tuberculosis. [2018]

9. Switzerland pubmed.ncbi.nlm.nih.gov

New and Repurposed Drugs for the Treatment of Active Tuberculosis: An Update for Clinicians. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Principles for designing future regimens for multidrug-resistant tuberculosis. [2021]