Ivacaftor for Chronic Sinusitis

Overseen By Norma Miller, RN

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Alabama at Birmingham

Must not be taking: CP3A inhibitors

Disqualifiers: Asthma, Transplantation, Immunodeficiency, others

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 4 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests ivacaftor, a medication, to determine its effectiveness for chronic sinusitis, a condition characterized by inflamed sinuses causing pain and stuffiness. The study will compare the effectiveness of ivacaftor combined with standard treatments, such as nasal sprays and antibiotics, against those treatments alone. Researchers aim to assess whether ivacaftor is safe and can improve symptoms and reduce sinus infections. Suitable participants have experienced chronic sinusitis, undergone sinus surgery, and recently had a sinus infection with specific bacteria. As an Early Phase 1 trial, this research focuses on understanding how ivacaftor works in people, offering participants a chance to contribute to groundbreaking medical research.

Do I need to stop my current medications to join the trial?

You may need to stop taking certain medications if they are moderate or strong CP3A inhibitors, as these are not allowed in the trial. For other medications, the trial protocol does not specify, so it's best to discuss with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ivacaftor is generally safe for people with cystic fibrosis (CF) who have a specific genetic mutation. One study found ivacaftor to be a safe and effective treatment for patients aged 6 and older with this mutation. Another study confirmed the long-term safety of ivacaftor for CF patients in the United States.

Although this study focuses on a different condition, chronic sinusitis, previous findings suggest that ivacaftor is well-tolerated when used as directed. Each condition and patient may respond differently, so discussing any concerns with a healthcare professional is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for chronic sinusitis, which typically involve topical nasal steroid sprays and culture-directed antibiotics, ivacaftor offers a unique approach. Ivacaftor is a medication traditionally used for cystic fibrosis, and it works by enhancing the function of a specific protein involved in fluid regulation within cells. Researchers are excited about ivacaftor because it targets the underlying cellular mechanisms, potentially offering a more effective solution for managing sinusitis symptoms. This novel mechanism of action could lead to better long-term outcomes for patients with chronic sinusitis.

What evidence suggests that ivacaftor might be an effective treatment for chronic sinusitis?

Research has shown that Ivacaftor can alleviate long-term sinus problems in individuals with cystic fibrosis. One study demonstrated that Ivacaftor improved sinus health as observed on CT scans, balanced nasal electrical activity and acidity, and relieved sinus symptoms after ten months. Other studies have found that combining Ivacaftor with other medications led to fewer flare-ups and better results on CT scans and endoscopies. These findings suggest Ivacaftor might help clear sinus issues by improving the function of the CFTR protein, which regulates salt and water levels in cells. In this trial, participants will receive either standard care treatment or standard care combined with Ivacaftor. While these results are promising, they primarily apply to individuals with cystic fibrosis, necessitating further research for those without the condition. ^{2 6 7 8 9}

Who Is on the Research Team?

Bradford Woodworth, MD

Principal Investigator

University of Alabama at Birmingham

Are You a Good Fit for This Trial?

This trial is for adults with chronic sinusitis who've had sinus surgery, can undergo specific nasal tests, and have a recent CT scan showing sinus issues. They must not be pregnant or breastfeeding, have normal liver and kidney function, and not be on certain other medications.

Inclusion Criteria

I had surgery that exposed my maxillary and ethmoid sinuses.

My recent CT scan shows changes in my mucosa, bones, or has air fluid levels.

You have tested positive for certain types of bacteria within the last 30 days.

Exclusion Criteria

Your blood has high levels of creatinine.

I am currently on medication that strongly affects my liver's ability to process drugs.

I have had an organ or bone marrow transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Treatment

Participants receive standard of care treatment with or without ivacaftor for 30 days

4 weeks

3 visits (in-person) on Day 1, Day 14, and Day 30

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Ivacaftor
• Standard of Care Treatment

Trial Overview The study is testing Ivacaftor's safety and effectiveness in treating chronic sinusitis compared to standard care. It will check if the drug improves chloride secretion in the sinuses, reduces inflammation/infection markers, and betters disease-specific quality of life scores.

How Is the Trial Designed?

Group I: standard of care treatment + ivacaftor Experimental Treatment 2 Interventions

topical nasal steroid spray and culture-directed antibiotics + ivacaftor 150 mg tablet

Group II: standard of care treatment Placebo Group 1 Intervention

topical nasal steroid spray and culture-directed antibiotics

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

Approved in United States as Kalydeco for:

• Cystic fibrosis in patients aged 4 months and older who have one mutation in the CFTR gene that is responsive to ivacaftor

Approved in European Union as Kalydeco for:

• Cystic fibrosis in patients aged 4 months and older who have one mutation in the CFTR gene that is responsive to ivacaftor

Approved in Canada as Kalydeco for:

• Cystic fibrosis in patients aged 4 months and older who have one mutation in the CFTR gene that is responsive to ivacaftor

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

In a study of 10 adults with HIV and talaromycosis, the use of efavirenz significantly reduced the exposure levels of itraconazole and its active metabolite, hydroxyitraconazole, by 86% and 84%, respectively, indicating a strong drug-drug interaction.

Despite the administration of itraconazole, the trough concentrations were below the recommended therapeutic level when taken with efavirenz, suggesting that this combination may compromise the effectiveness of talaromycosis treatment and requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug-drug interaction between itraconazole capsule and efavirenz in adults with HIV for talaromycosis treatment. Kaewpoowat, Q., Chaiwarith, R., Yasri, S., et al.[2021]

Ivacaftor (KALYDECO™) has been shown to enhance the function of various mutant CFTR proteins that are associated with cystic fibrosis, particularly those with mild defects in processing or channel conductance, based on in vitro studies using Fischer rat thyroid cells.

This study suggests that ivacaftor could be a versatile treatment option for patients with different CFTR mutations, potentially allowing for better patient stratification in clinical studies to assess its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. Van Goor, F., Yu, H., Burton, B., et al.[2022]

In a study of 43 adult cystic fibrosis patients, treatment with elexacaftor-tezacaftor-ivacaftor led to significant improvements in sinonasal symptoms, as measured by the SNOT-22 questionnaire, with scores decreasing from 34.8 to 24.4 (p = 0.000003).

Patients who had previously used other CFTR modulators experienced even greater improvements in both sinonasal and respiratory symptoms, indicating that prior treatment may enhance the efficacy of this new therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of highly effective modulator treatment on sinonasal symptoms in cystic fibrosis. DiMango, E., Overdevest, J., Keating, C., et al.[2022]

A 75-year-old male patient with Aspergillus flavus-induced chronic hypertrophic pachymeningitis was successfully treated with itraconazole (ITCZ), showing that it can be effective for this condition, especially after other antifungal treatments failed.

Pharmacokinetic analysis revealed that despite lower serum levels of ITCZ compared to healthy adults, the successful treatment was likely due to increased distribution to tissues from the unbound form of the drug, highlighting the importance of monitoring albumin levels in evaluating drug concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serum itraconazole and hydroxyitraconazole concentrations and interaction with digoxin in a case of chronic hypertrophic pachymenigitis caused by Aspergillus flavus. Mochizuki, M., Murase, S., Takahashi, K., et al.[2019]

A new solid dispersion formulation of docetaxel, combined with a pharmacokinetic booster (ritonavir), showed similar pharmacokinetic parameters to the traditional docetaxel premix solution in a Phase I clinical trial, indicating it can effectively improve oral bioavailability.

ModraDoc001 15 mg capsules demonstrated advantages such as lower inter-individual variability in drug exposure and improved dosing accuracy, making it a potentially safer and more reliable option for chronic oral chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical development and preliminary clinical testing of an oral solid dispersion formulation of docetaxel (ModraDoc001). Moes, JJ., Koolen, SL., Huitema, AD., et al.[2018]

In a study involving 16 patients with advanced solid tumors, the novel docetaxel tablet formulation ModraDoc006, when taken with ritonavir, showed that a high-fat meal slightly increased docetaxel exposure but decreased ritonavir levels, indicating that food intake can influence drug absorption.

Despite these changes, the overall effect of a high-fat meal on docetaxel exposure was minimal, suggesting that a light meal would likely not impact the treatment's effectiveness, with the most common side effects being mild diarrhea and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours. Vermunt, MAC., de Weger, VA., Janssen, JM., et al.[2021]

Ivacaftor significantly improves lung function and weight in patients with Cystic Fibrosis who have a type III mutation, by enhancing CFTR channel activity and chloride transport.

In a case report of a 17-year-old patient, ivacaftor led to complete resolution of sinus opacification and reduced sinonasal symptoms after 5 months, suggesting potential benefits for sinonasal health in Cystic Fibrosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivacaftor and sinonasal pathology in a cystic fibrosis patient with genotype deltaF508/S1215N. Vreede, CL., Berkhout, MC., Sprij, AJ., et al.[2016]

Itraconazole (ICZ) effectively inhibits the production of the inflammatory chemokine CXCL10 in oral fibroblasts stimulated by TNF-α, suggesting its potential as an anti-inflammatory treatment for Th1-mediated oral inflammatory diseases.

Unlike fluconazole (FLZ), ICZ also reduces the mRNA levels of other chemokines (CXCL9 and CXCL11) and inhibits the phosphorylation of c-JUN, a signaling protein involved in CXCL10 production, highlighting its unique mechanism of action in modulating inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Itraconazole inhibits TNF-α-induced CXCL10 expression in oral fibroblasts. Ohta, K., Ishida, Y., Fukui, A., et al.[2016]

In a study of 34 individuals with cystic fibrosis, treatment with elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) led to rapid improvement in sinonasal symptoms within just 7 days, with effects lasting for at least 180 days.

Objective measures, such as endoscopic findings and CT scans, showed significant improvements in nasal polyps and sinus health, indicating that ELX/TEZ/IVA effectively addresses chronic rhinosinusitis associated with cystic fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elexacaftor-Tezacaftor- Ivacaftor improves sinonasal outcomes in cystic fibrosis. Stapleton, AL., Kimple, AJ., Goralski, JL., et al.[2023]

The ciprofloxacin- and ivacaftor-releasing biodegradable sinus stent (CISS) demonstrated sustained drug release over 21 days without an initial burst, ensuring prolonged antibiotic action.

In vitro tests showed that the CISS significantly reduced biofilm formation of Pseudomonas aeruginosa compared to bare stents and controls, indicating its potential effectiveness in preventing bacterial infections in sinus treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In-vitro evaluation of a ciprofloxacin- and ivacaftor-coated sinus stent against Pseudomonas aeruginosa biofilms. Cho, DY., Lim, DJ., Mackey, C., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4310814/

Medical reversal of chronic rhinosinusitis in a cystic fibrosis ... Results. Ivacaftor treatment reversed CT findings of CF sinus disease, increased nasal voltage and pH and resolved sinus symptoms after ten months of therapy.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03439865

Ivacaftor for Acquired CFTR Dysfunction in Chronic ... The purpose of this pilot study is to explore wither ivacaftor in refractory CRS patients will demonstrate safety and tolerability; restore CFTR-mediated ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9470769/

IVACAFTOR IMPROVES SINONASAL OUTCOMES IN ... Objective measures of disease including endoscopic and CT findings improved with ELX/TEZ/IVA. Keywords: highly effective modulator therapy, sinus disease, ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S019607092400022X

Efficacy of Elexacaftor–Tezacaftor–Ivacaftor on chronic ... Elexacaftor-Tezacaftor-Ivacaftor was associated with fewer acute exacerbations of chronic rhinosinusitis, and a significant improvement of chronic ...

5. jamanetwork.com jamanetwork.com/journals/jamaotolaryngology/fullarticle/2808807

Elexacaftor-Tezacaftor-Ivacaftor Therapy for Chronic Sinus ... This cohort study found that use of ETI therapy was associated with improved CRS outcomes in participants with CF as quantified by improved sinus CT scans.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02722057

NCT02722057 | A Study to Confirm the Long-term Safety ... The purpose of this study is to confirm the long-term safety and effectiveness of Kalydeco® (ivacaftor) in US CF patients with the R117H-CFTR mutation <18 years ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6734927/

an open-label, single-arm study Ivacaftor is a safe, effective treatment for cystic fibrosis (CF) in patients aged ≥6 years with a CFTR gating mutation.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10485743/

Elexacaftor-Tezacaftor-Ivacaftor Therapy for Chronic Sinus ... Treatment of individuals with CF using ETI therapy was associated with improved chronic sinus disease and clinical outcomes.

9. news.vrtx.com news.vrtx.com/news-releases/news-release-details/data-follow-study-kalydecotm-ivacaftor-showed-durable

Data From Follow-Up Study of KALYDECO™ (ivacaftor ... Data From Follow-Up Study of KALYDECO™ (ivacaftor) Showed Durable Improvements in Lung Function and Other Measures of Disease in People with Cystic Fibrosis Who ...