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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to study how well individuals with Primary Ciliary Dyskinesia (PCD), a condition affecting mucus movement in the lungs, can clear mucus. Researchers compare individuals with PCD caused by different gene mutations to determine if specific genes result in milder symptoms. The trial employs Albuterol (also known as Salbutamol or Ventolin) and a special imaging agent, Technetium99m - Sulfur Colloid (Tc99m-SC), to measure mucus movement. It suits those with PCD and known genetic mutations or healthy individuals without lung issues. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

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.

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

Research has shown that albuterol is usually well-tolerated. Studies have found that using inhaled albuterol regularly for six weeks does not harm lung function or increase airway sensitivity. Many individuals with breathing issues, such as those with Primary Ciliary Dyskinesia (PCD), use bronchodilators, including albuterol, without serious side effects.

Technetium 99m Sulfur Colloid (Tc99m-SC) often helps doctors assess lung and organ function. While generally safe, one report noted an allergic reaction in a patient, suggesting that rare allergies may occur. Overall, this treatment is considered safe and is commonly used in medical imaging tests.

In summary, both albuterol and Tc99m-SC have been safely used in many patients, but like any medical treatment, there is always a small chance of side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the mucus clearance therapy for Primary Ciliary Dyskinesia (PCD) because it combines Albuterol and Technetium99m - Sulfur Colloid (Tc99m-SC) to enhance mucus clearance in a novel way. Unlike standard treatments that mainly focus on managing symptoms with medications like antibiotics or chest physiotherapy, this approach uses Albuterol, a bronchodilator, to open the airways and improve respiratory function. Additionally, the use of Tc99m-SC, a radiopharmaceutical, allows for better visualization and measurement of mucus clearance, potentially offering a more targeted and effective treatment method. This combination could lead to more precise and efficient management of PCD, which is why it's generating excitement among researchers.

What evidence suggests that this trial's treatments could be effective for Primary Ciliary Dyskinesia?

Research has shown that albuterol, one of the treatments in this trial, can help some children with primary ciliary dyskinesia (PCD). One study found that 18.1% of children with PCD responded well to bronchodilator treatment, including albuterol. Albuterol relaxes the muscles in the airways, making breathing easier.

Technetium99m - Sulfur Colloid (Tc99m-SC) is another component of this trial, used to evaluate how well mucus is cleared from the lungs in PCD patients. This assessment helps doctors understand the severity of the condition. While Tc99m-SC does not treat PCD, it aids in evaluating how the disease affects the lungs. ^{2 6 7 8 9}

Who Is on the Research Team?

Lawrence Ostrowski, PhD

Principal Investigator

University of North Carolina at Chapel Hil

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/10669686/

The effect of regular salbutamol on lung function and ... Conclusion: Our data have shown that salbutamol, inhaled regularly for 6 weeks, did not cause either a decline in lung function or an increase in bronchial ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0012369215486337

The Effect of Regular Salbutamol on Lung Function and ... Our data have shown that salbutamol, inhaled regularly for 6 weeks, did not cause either a decline in lung function or an increase in bronchial responsiveness ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10789254/

Bronchodilator responsiveness in children with primary ciliary ... A positive BD response was seen in 86 out of 474 (18.1%) of the pulmonary function tests from 82 children with primary ciliary dyskinesia. BD ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05932316

Evaluating Bronchodilator Response in Patients With ... Many systemic diseases can cause bronchiectasis: cystic fibrosis (CF), primary ciliary dyskinesia (PCD), primary immune deficiencies (PID) and idiopathic ...

5. mdpi.com mdpi.com/2077-0383/14/19/6808

Primary Ciliary Dyskinesia—Current Diagnostic and ... Physical exercise caused a significant increase in PEFR in children with PCD, greater than that observed after salbutamol inhalation. These results suggest that ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12525432/

Primary Ciliary Dyskinesia—Current Diagnostic and ... Available data indicate that dynein protein defects disrupt the structure of the dynein arms, which in turn leads to immotility or hypokinesia ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04901715

Functional Studies of Novel Genes Mutated in Primary ... The purpose of this study is to measure mucociliary clearance (MCC) in groups of subjects with the disease Primary Ciliary Dyskinesia (PCD) caused by ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9699262/

Reversible Bronchial Obstruction in Primary Ciliary Dyskinesia Of the 46 patients who completed bronchodilator spirometry, 29 (63%) were regularly using bronchodilators and inhaled corticosteroids.

9. publications.ersnet.org publications.ersnet.org/content/erj/51/3/1702221

Are inhaled corticosteroids prescribed rationally in primary ... Although ICS are safe, high doses such as were prescribed to many PCD children, carry an increased risk of systemic side-effects, including adrenal suppression ...