Please select the eligibility criteria that correspond to the clinical trial below.
Title: Timing of Hypertonic Saline Inhalation Relative to Airways Clearance in Cystic Fibrosis
Brief Summary: Lung disease is the predominant cause of morbidity and mortality in Cystic Fibrosis (CF) with 80% of deaths resulting directly or indirectly from pulmonary disease. Abnormal airway clearance causes retention of mucus resulting in frequent chest infections. Physiotherapists use different techniques to help clear mucus from the lungs of patients with CF. Inhaled medications and airways clearance techniques (ACTs) are central to a CF patient's daily treatment and are often coordinated.

Burden of treatment is a common reason for non-adherence in this patient group, and streamlining of treatment timings is sought to optimize adherence whilst ensuring efficacy to an often complex daily regimen of inhaled bronchodilators, nebulizers and ACTs. A gap in the research exists as to the optimal timing of Hypertonic Saline (HTS) and ACT within the daily regimen. A study to show whether the timing of HTS around ACT is significant, can better inform patients and potentially allow more flexibility around their treatment regimen.

Lung Clearance Index (LCI) has shown good sensitivity to abnormalities in lung function compared with spirometry and has demonstrated a treatment effect in other trials. LCI may be a suitable tool therefore, to assess intervention strategies aimed at airways clearance in CF. This study aims to compare the effects ACTs after HTS inhalation versus ACTs during HTS inhalation as measured by LCI.

It is a randomized, crossover trial of ACTs after HTS inhalation compared with ACTs during HTS inhalation in adult CF patients during day 10-14 of a hospital admission for treatment of a pulmonary exacerbation. Patients will be randomized to receive 1 of the treatment session options on the first day and the reverse on the second day.

The primary objective of this study is to compare the change in LCI (a measure of lung function) at 90 minutes post treatment with ACTs after HTS inhalation compared with ACTs during HTS inhalation in adult CF patients.

LCI (lung clearance index) ACT (airway clearance technique) HTS (hypertonic saline)


Options:
A: Inclusion Criteria:

* Pass the inhalation test
* Chronic sputum production, at least ≥ 10 ml /24h
* Cystic Fibrosis (CF) diagnosed ( established by genotype or sweat sodium\>70 mmol/l or sweat chloride of\>60 mmol/l)
* Clinically stable at the time of recruitment (defined as no requirement for antibiotics or change in respiratory medication in the preceding 4 weeks)
* Trained in the use of autogenic drainage technique (at least 6 months)
* Inhaling hypertonic saline since at least 6 months
* To be able to provide written, informed consent and perform the protocol and the evaluations

Exclusion Criteria:

* Active massive hemoptysis during the previous 2 months
* Patient in transplantation or retransplantation list
* Patient already participating in another study at the same time
B: Inclusion Criteria:

* Has a diagnosis of CF via standard criteria
* Is aged 18 years or older
* Is capable of providing written informed consent in English to participate in the study.
* Has a forced expiratory volume in 1 second (FEV1) \>= 40% and \< 110% predicted normal for age, gender, and height at Screening.
* Has a body mass index (BMI) \< 30 kg/m2
* Can tolerate cessation of treatment with HS for 72 hours and rhDNase for 24 hours prior to each treatment visit until discharge from Visits 2 and 3.
* Can tolerate cessation of treatment with long-acting beta-agonists (LABAs) for 12 hours and short-acting beta-agonists (SABAs) for 6 hours prior to radioaerosol administration for each MCC measurement and at least until discharge from Visits 2 and 3
* Is on a stable medication regimen for at least 28 days before start of dosing and can continue such regimen for duration of study
* Tolerates the 30 minute administration of 7% HS by the tPAD device at screening without subjective intolerance, oxyhemoglobin desaturation, or significant change in spirometry (\>10% reduction from pre-dose value in FEV1, measured 30 minutes after completion of the aerosol administration)

Exclusion Criteria:

* Has evidence of an acute upper or lower respiratory infection or clinically significant illness at screening or within 28 days prior to the start of dosing
* Required an acute intervention with antibiotics (oral, inhaled, or IV) or systemic corticosteroids within the last 28 days for a respiratory illness
* Has a history of intolerance to a beta-agonist or hypertonic saline
* Has evidence of significant nasal obstruction that impairs the ability to breathe through the nose
* Has a clinical diagnosis of sleep apnea
* Has current symptoms of allergic rhinitis
* Is unable to maintain a stable dosage regimen of any concomitant medication throughout the duration of the trial.
* Has participated in a clinical drug or investigational device trial within the past 28 days
* Has a history of positive test for Burkholderia cepacia
* Has a present history of any clinically significant and uncontrolled neurologic, gastrointestinal, renal, hepatic, cardiovascular (including hyper/hypotension and tachy/bradycardia), psychological, pulmonary, metabolic, endocrine, or hematological disorder or disease, or any other major disorder or disease, in the opinion of the investigator
* Has a history of smoking within the last 12 months
* Is known to be pregnant, has a positive urine pregnancy test or is nursing (female subjects only)
* Should not participate in the study, in the opinion of the Principal or Clinical investigator
C: Inclusion Criteria:

* Diagnosis of CF by newborn screening or at least one clinical feature of CF, AND either: (a) A documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis or (b) A genotype with two identifiable CF-causing mutations
* Informed consent by parent or legal guardian
* Age 4 months to \< 60 months at Enrollment visit. If participating in Infant Pulmonary Function testing (selected sites), age 4 months to \< 16 months at Enrollment visit.
* Ability to comply with medication use, study visits, and study procedures as judged by the site investigator

Exclusion Criteria:

* Acute intercurrent respiratory infection, defined as an increase in cough, wheezing, or respiratory rate with onset in 1 week preceding Enrollment visit
* Acute wheezing at Enrollment visit (prior to HS test dose), or at Infant PFT visit (prior to infant pulmonary function testing), as applicable
* Oxygen saturation \< 95% (\< 90% in centers located above 4000 feet elevation) at Enrollment visit (prior to HS test dose) or at Infant PFT visit (prior to infant pulmonary function testing), as applicable
* Other major organ dysfunction, excluding pancreatic dysfunction
* Physical findings that would compromise the safety of the subject or the quality of the study data as determined by the site investigator
* Investigational drug use within 30 days prior to Enrollment visit, or within 30 days prior to Infant PFT visit as applicable
* Treatment with inhaled hypertonic saline at any concentration within 30 days of Enrollment visit, or within 30 days prior to Infant PFT visit as applicable
* Chronic lung disease not related to CF
* Intolerance of test dose of HS at Enrollment visit
* A sibling that has been randomized and is still enrolled in ISIS002

Additional Exclusion Criteria for Participation in Infant Pulmonary Function Testing:

* History of adverse reaction to sedation
* Clinically significant upper airway obstruction as determined by the Site Investigator (e.g. severe laryngomalacia, markedly enlarged tonsils, significant snoring, diagnosed obstructive sleep apnea)
* Severe gastroesophageal reflux, defined as persistent frequent emesis despite anti-reflux therapy
* Acute intercurrent respiratory infection, defined as an increase in cough, wheezing, or respiratory rate with onset in 2 weeks preceding visit
D: Inclusion Criteria:

1. Male or female patients with a documented diagnosis of CF aged ≥18 years.
2. Written informed consent.
3. At least day 10 - 14 of IV antibiotic therapy during a hospital admission for a pulmonary exacerbation.
4. Patients must be able to perform acceptable spirometric manoeuvres, according to the American Thoracic Society/ERS (ATS/ERS) standards (Miller, Hankinson et. al. 2005).
5. Patient with an FEV1% predicted of ≥ 40%predicted (Stanojevic, Wade et al. 2008).
6. Patients who are productive of sputum from screening visit to study visit 1 (≥10g over 24 hours).
7. Patients who have been prescribed HTS (Nebusal 7%) and have successfully completed a challenge test.
8. Any other chronic medication must have commenced therapy 4 weeks prior to screening and be willing to continue this therapy for the entire duration of the study.

Exclusion Criteria:

1. Day 1-9 of IV antibiotic therapy during a hospital admission.
2. Patients who are colonized with Burkholderia cepacia complex.
3. Patient who are HTS naive.
4. Patients who have an intolerance to HTS.
5. Patients who are currently participating in another study or have participated in another study with an investigational drug within one month of screening.
6. Clinically significant disease or medical condition other than CF or CF-related conditions that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data.

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Answer: D