Mucus Clearance Therapy for Primary Ciliary Dyskinesia

Overseen By Sara Abu-Nasser, DO

Age: Any Age

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of North Carolina, Chapel Hill

Must not be taking: Steroids, Beta antagonists, NSAIDs, others

Disqualifiers: Cardiovascular disease, Diabetes, Immunodeficiency, others

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

Compensation: Varies

Number of Visits: 4

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires participants to stop taking certain medications that may impact the study results, including steroids, beta antagonists, non-steroidal anti-inflammatory agents, beta-blocking medications, multivitamins, Vitamin C or E, and herbal medications. There is a specific period of 4 days before the treatment visit during which some of these medications should not be taken.

What data supports the effectiveness of the treatment for mucus clearance in Primary Ciliary Dyskinesia?

The study on adrenergic stimulation showed that similar drugs can enhance mucus clearance in the airways, suggesting that treatments like Albuterol and Salbutamol, which are adrenergic agonists, may help improve mucus clearance in conditions like Primary Ciliary Dyskinesia. ^{1 2 3 4 5}

Is Mucus Clearance Therapy using Tc-99m sulfur colloid safe for humans?

There is a report of an allergic reaction in a patient after injecting Tc-99m sulfur colloid, suggesting that while generally used safely, there may be rare allergic reactions. ^{1 5 6 7 8}

How does the mucus clearance treatment for primary ciliary dyskinesia differ from other treatments?

This treatment is unique because it involves the use of a nebulized epithelial sodium channel (ENaC) blocker, idrevloride, which helps improve lung function by blocking sodium channels to keep mucus hydrated and easier to clear, unlike other treatments that may not target this specific mechanism. ^{1 3 4 9 10}

What is the purpose of this trial?

The purpose of this study is to measure mucociliary clearance (MCC) in groups of subjects with the disease Primary Ciliary Dyskinesia (PCD) caused by mutations in different genes, and compare to healthy subjects. Some of these genes are associated with a milder clinical phenotype. This study seeks to determine if the milder phenotype is a result of mutations in a set of specific genes. The hypothesis is that subjects with PCD caused by mutations in the milder group will maintain a low, but significant rate of mucociliary clearance, while patients with mutations in genes in the more severe group will have a complete absence of mucociliary clearance. These studies will help inform future treatment strategies.

Research Team

Lawrence Ostrowski, PhD

Principal Investigator

University of North Carolina at Chapel Hil

Eligibility Criteria

This trial is for adults over 18 with Primary Ciliary Dyskinesia (PCD) due to specific genetic mutations. Participants need a confirmed PCD diagnosis, normal lung function tests, and no other lung diseases like asthma or cystic fibrosis. Women must not be pregnant unless they've had certain surgeries.

Inclusion Criteria

Subjects must have an FVC, FEV1 and FVC/FEV1 of at least 80% of predicted. Subjects who fall out of the normal range will be offered a copy of the test to share with their personal physician.

Forced Expiratory Volume (FEV1) of at least 30 percent of predicted

I am not pregnant or have had a hysterectomy with oophorectomy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 day

1 visit (in-person)

Baseline Measurement

Participants undergo baseline mucociliary clearance measurement using radiolabeled Tc99m-sulfur colloid and gamma imaging

60 minutes

1 visit (in-person)

Post-Albuterol Measurement

Participants receive Albuterol and undergo further mucociliary clearance measurement

60 minutes

1 visit (in-person)

Cough Clearance Measurement

Participants perform cough clearance assessment over a 30-minute period using gamma imaging

30 minutes

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the study procedures

1 day

Treatment Details

Interventions

• Albuterol
• Technetium99m - Sulfur Colloid (Tc99m-SC)

Trial Overview The study measures how well mucus clears from the lungs in PCD patients with different gene mutations compared to healthy people. It aims to see if some genes cause milder symptoms by allowing some mucociliary clearance versus none at all, which could guide future treatments.

Participant Groups

Group I: Genotypes associated mild phenotype Active Control 2 Interventions

Subjects with 2 confirmed mutations in RSPH1, Radial Spoke Head Component 9 (RSPH9), Radial Spoke Head Component 4A (RSPH4a), or Dynein Axonemal Heavy Chain 11 (DNAH11). This group may also include subjects with mutations in newly identified genes that are associated with a milder clinical phenotype.

Group II: Genotypes associated with severe phenotype Active Control 2 Interventions

Subjects with 2 confirmed mutations in DNAH5, Dynein Axonemal Intermediate Chain 1 (DNAI1), Coiled-Coil Domain Containing 39 (CCDC39), or Coiled-Coil Domain Containing 40 (CCDC40). This group may also include subjects with mutations in newly identified genes that are associated with a more severe clinical phenotype.

Group III: Healthy Control Active Control 2 Interventions

Healthy subjects with no pre-existing lung disease.

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a study involving halothane-anesthetized dogs, bronchial retention of submicrometer technetium-99m-labeled sulfur colloid particles was found to be 8.5% at 3 hours and 1.5% at 24 hours post-deposition, indicating that most particle clearance occurs within the first 3 hours.

The study demonstrated that clearance mechanisms differ between particle types: sulfur colloid particles cleared primarily through mucociliary transport, while unbound technetium-99m pertechnetate cleared more rapidly via transepithelial absorption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retention of insoluble particles after local intrabronchial deposition in dogs. Lay, JC., Berry, CR., Kim, CS., et al.[2017]

Inhalation of terbutaline sulphate, an adrenergic agonist, did not significantly enhance the clearance of particles from the bronchioles in 10 healthy subjects, indicating that this treatment may not be effective for stimulating mucociliary transport in the smallest airways.

The study suggests that mucociliary transport is not a major mechanism for clearing mucus from bronchioles, implying that other mechanisms may play a more critical role in mucus clearance in these areas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of adrenergic stimulation on clearance from small ciliated airways in healthy subjects. Svartengren, K., Philipson, K., Svartengren, M., et al.[2019]

Mucociliary transport can be effectively evaluated using inhaled technetium-99m labeled sulfur colloid to measure clearance rates.

In a case study of a patient with recurrent sinusitis and infertility, abnormal mucociliary clearance suggested a potential diagnosis of Kartagener syndrome, highlighting the importance of this assessment in understanding respiratory conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abnormal mucociliary transport study in a patient with Kartagener syndrome. Taylor, RE.[2016]

In a study of 30 cystic fibrosis patients and 12 normal subjects, it was found that mucociliary clearance (MCC) was significantly improved in normal subjects with higher inspiratory flow rates, indicating that airflow can enhance lung function.

The measurement of MCC was highly reproducible in cystic fibrosis patients, suggesting that this method could be reliably used to assess lung function over time in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mucociliary clearance in patients with cystic fibrosis and in normal subjects. Regnis, JA., Robinson, M., Bailey, DL., et al.[2006]

The radiation dose to the lung from Tc-99m sulfur colloid aerosol for ventilation studies ranges from 0.34 to 2.5 rads for the ciliated airway epithelium, indicating a variable exposure depending on the specific area of the lung.

In comparison, the lung parenchyma receives a slightly lower radiation dose of 0.31 rads, suggesting that while the aerosol is used for diagnostic purposes, it does expose lung tissues to measurable radiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation dose calculations for inhalation of Tc-99m sulfur colloid radioaerosol. Prato, FS., Vinitski, S.[2013]

The mixture of technetium Tc 99m sulfur colloid and lidocaine hydrochloride remains stable for up to eight hours, showing no significant changes in pH (4.5-5.5) or radiochemical purity (98.9% to 99.9%).

Storage of the mixture did not affect the radioactivity retained by filtration or increase particle size, indicating that this combination can be safely prepared and used within this time frame.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stability of a mixture of technetium Tc 99m sulfur colloid and lidocaine hydrochloride. Dura, JV., Hinkle, GH.[2019]

A patient experienced an allergic reaction after receiving an injection of 99Tcm sulfur colloid for a liver scan, indicating a potential sensitivity to this specific radiopharmaceutical.

The allergic reaction did not occur with a different radiopharmaceutical, 99Tcm polyphosphate, suggesting that the stabilizer in the sulfur colloid may be responsible for the allergic response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse reaction to 99Tcm sulfur colloid in a routine examination. A case report. Krasnokuki, D., Brufman, G., Löwinger, E., et al.[2015]

The study involved nine healthy, nonsmoking adults and demonstrated that tracheobronchial deposition and clearance of inhaled aerosols were highly reproducible under controlled conditions.

Acute exposure to 5 ppm sulfur dioxide did not significantly affect mucociliary clearance in these subjects, although there was a minor transient change observed after one hour, indicating that short-term exposure may have limited impact on airway clearance mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sulfur dioxide and tracheobronchial clearance in man. Wolff, RK., Dolovich, M., Rossman, CM., et al.[2019]

The nasal mucociliary transport test using 99mTc-albumin colloid is a highly sensitive screening tool for primary ciliary dyskinesia (PCD), correctly identifying all 8 cases of PCD in a study of 55 children.

While the test is effective at ruling out PCD (100% negative predictive value), it has low specificity (55%), meaning it may incorrectly indicate PCD in some cases with other conditions, such as secondary ciliary dyskinesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mucociliary transport using 99mTc-albumin colloid: a reliable screening test for primary ciliary dyskinesia. De Boeck, K., Proesmans, M., Mortelmans, L., et al.[2018]

In a phase 2 trial involving 123 participants with primary ciliary dyskinesia, treatment with the ENaC blocker idrevloride combined with hypertonic saline showed a significant improvement in lung function compared to hypertonic saline alone, with an average increase in ppFEV1 of 1.0 percentage points.

The treatment was found to be safe, with adverse events similar across all treatment groups, although cough and oropharyngeal pain were more common with idrevloride and hypertonic saline treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of the epithelial sodium channel blocker idrevloride in people with primary ciliary dyskinesia (CLEAN-PCD): a multinational, phase 2, randomised, double-blind, placebo-controlled crossover trial. Ringshausen, FC., Shapiro, AJ., Nielsen, KG., et al.[2023]

References

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

Retention of insoluble particles after local intrabronchial deposition in dogs. [2017]

2. England pubmed.ncbi.nlm.nih.gov

Effect of adrenergic stimulation on clearance from small ciliated airways in healthy subjects. [2019]

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

Abnormal mucociliary transport study in a patient with Kartagener syndrome. [2016]

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

Mucociliary clearance in patients with cystic fibrosis and in normal subjects. [2006]

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

Radiation dose calculations for inhalation of Tc-99m sulfur colloid radioaerosol. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Stability of a mixture of technetium Tc 99m sulfur colloid and lidocaine hydrochloride. [2019]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse reaction to 99Tcm sulfur colloid in a routine examination. A case report. [2015]

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

Sulfur dioxide and tracheobronchial clearance in man. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Mucociliary transport using 99mTc-albumin colloid: a reliable screening test for primary ciliary dyskinesia. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of the epithelial sodium channel blocker idrevloride in people with primary ciliary dyskinesia (CLEAN-PCD): a multinational, phase 2, randomised, double-blind, placebo-controlled crossover trial. [2023]