Absorptive Clearance After Inhaled Osmotics in Cystic Fibrosis

Phase 1

Completed

• Conditions: Cystic Fibrosis
• Interventions: Drug: hypertonic saline (7%); Drug: isotonic saline

• Registration Number: NCT01223183
• Lead Sponsor: University of Pittsburgh

Brief Summary

Blockage of the breathing tubes of the lungs by thick, sticky mucus is a major cause of lung problems for people with cystic fibrosis (CF). Many researchers now believe that people with CF absorb too much water from the insides of their lungs, and that the mucus in their lungs becomes so thick and sticky because there is not enough water in it. The investigators are trying to develop ways to measure how fast water is absorbed from the breathing tubes in the lung so that the investigators can more quickly test new medications that are being developed to fix this problem for CF patients. The investigators have already done studies showing that people with CF absorb a particular radioactive drug (Indium-111 diethylenetriaminepentaacetic acid or In-DTPA) from their lungs more quickly than people without CF. Now the investigators are trying to prove that the absorption of this drug is related to the absorption of water. The investigators measure the absorption of In-DTPA by delivering it in an aerosol (inhaled mist) along with another radioactive drug (Technetium 99m sulfur colloid or Tc-SC). This other drug helps us measure how much material is cleared from the lungs in other ways (like coughing) without being absorbed. In this study, the investigators will measure how the absorption of In-DTPA is affected by inhaling isotonic saline and hypertonic saline (salt water), both of which the investigators know affect the absorption of water in the airways.

Detailed Description

There is a substantial need for new biomarkers in the study of cystic fibrosis (CF) lung disease. Conventional endpoints, such as rate of FEV1 decline, require prolonged trials and large sample sizes to demonstrate therapeutic efficacy. Ideally such biomarkers would provide a quantitative window to the most basic aspects of CF pathophysiology, allowing for the development and evaluation of therapies prior to large scale clinical trials. The basic defect of CF lung disease occurs in the airways where dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium (ENaC) channels is thought to create an ionic gradient that causes excessive liquid absorption across the epithelium. This results in a dehydrated airway surface liquid (ASL) layer, defective mucociliary clearance, and an increased proclivity for infection and inflammation.

Aerosol-based methods have been developed to measure mucociliary clearance in the lung and used to demonstrate the efficacy of inhaled osmotic therapies. We have developed an aerosol technique to measure both mucociliary clearance and the absorptive clearance of a hydrophilic small molecule (diethylenetriaminepentaacetic acid or DTPA) in whole, central, and peripheral lung regions. We estimate DTPA absorption by delivering an aerosol containing both Indium 111 DTPA (In-DTPA) and Technetium 99m sulfur colloid (Tc-SC) to the airways. The clearance of each radiopharmaceutical is imaged independently and two separate clearance curves are calculated. In-DTPA is cleared through both absorption and mucociliary clearance while Tc-SC is cleared only through the mucociliary route. The difference between the clearance rates of the radiopharmaceuticals provides an estimate of In-DTPA absorption rate.

Our previous studies have demonstrated that absorption of In-DTPA occurs at a higher rate in central (airway dominated) lung zones of CF subjects compared to controls (42 vs. 32 %/hr, CF n= 9, control n=10, p=0.03). We believe that this increased In-DTPA absorption is being caused by the increased liquid absorption occurring in these airways, however there are other potential causes such as increase in tight junction permeability or epithelial denuding.

In this study we propose to measure In-DTPA absorption after the delivery of interventions known to affect liquid absorption in the airways to see if changes in In-DTPA absorption mirror the changes in liquid absorption known to be caused by the interventions.

Study Timeline

• Study Start: 2010-09
• Study First Submitted: 2010-10-14
• Study First Submitted QC: 2010-10-15
• Study First Posted: 2010-10-18
• Primary Completion: 2012-12
• Study Completion: 2012-12
• Results First Submitted: 2017-04-05
• Results First Submitted QC: 2017-07-24
• Results First Posted: 2018-02-05
• Status Verified: 2018-11
• Last Update Submitted: 2018-11-02
• Last Update Posted: 2018-11-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• age ≥ 18 years
• diagnosis of cystic fibrosis as determined by sweat test or genotype and clinical symptoms
• clinically stable as determined by the investigator (pulmonologist)

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Exclusion Criteria

• intolerant to hypertonic saline.
• FEV1%p <40% of predicted
• nursing mother
• positive urine pregnancy test
• unwilling to stop hypertonic saline therapy for 72 hours prior to each test day
• cigarette smoker (regular smoking within 6 months of study)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
isotonic saline then hypertonic saline	hypertonic saline (7%)	Subjects inhaled nebulized isotonic saline on study day 1, and then after a 5-24 day washout period, subjects inhaled nebulized 7% hypertonic saline on study day 2.
isotonic saline then hypertonic saline	isotonic saline	Subjects inhaled nebulized isotonic saline on study day 1, and then after a 5-24 day washout period, subjects inhaled nebulized 7% hypertonic saline on study day 2.
hypertonic saline then isotonic saline	hypertonic saline (7%)	Subjects inhaled nebulized 7% hypertonic saline on study day 1, and then after a 5-24 day washout period, subjects inhaled nebulized isotonic saline on study day 2.
hypertonic saline then isotonic saline	isotonic saline	Subjects inhaled nebulized 7% hypertonic saline on study day 1, and then after a 5-24 day washout period, subjects inhaled nebulized isotonic saline on study day 2.

Primary Outcome Measures

Name	Time	Method
Absorptive Clearance Rate After Isotonic Saline Inhalation	80 minutes after radiopharmaceutical inhalation	The absorption rate of Indium 111 diethylenetriaminepentaacetic acid (In-DTPA) in the airways after the inhalation of isotonic saline
Absorptive Clearance Rate After Hypertonic Saline Inhalation	80 minutes after radiopharmaceutical inhalation	The absorption rate of In-DTPA after the inhalation of hypertonic saline
Mucociliary Clearance Rate After Isotonic Saline Inhalation	80 minutes after radiopharmaceutical inhalation	The clearance rate of Tc-SC after the inhalation of isotonic saline
Mucociliary Clearance Rate After Hypertonic Saline Inhalation	80 minutes after radiopharmaceutical inhalation	The clearance rate of Tc-SC after the inhalation of hypertonic saline

Trial Locations

Locations (1)

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States