Absorptive Clearance After Inhaled Osmotics in Cystic Fibrosis

• ClinicalTrials.gov Identifier: NCT01223183
• Recruitment Status: Completed
• First Posted: October 18, 2010
• Results First Posted: February 5, 2018
• Last Update Posted: November 29, 2018
• Sponsor: University of Pittsburgh
• Information provided by (Responsible Party): Tim Corcoran, University of Pittsburgh

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Drug: hypertonic saline (7%); Drug: isotonic saline	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Subjects inhale isotonic saline on one imaging day and 7% hypertonic on the other. The order is randomized. There is a period of 5-24 days between imaging days.
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Absorptive Clearance After Inhaled Osmotics in Cystic Fibrosis
• Study Start Date: September 2010
• Actual Primary Completion Date: December 2012
• Actual Study Completion Date: December 2012

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: isotonic saline then hypertonic 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.	Drug: hypertonic saline (7%); single treatment by inhalation; Drug: isotonic saline; single treatment by inhalation
Active Comparator: hypertonic saline then 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.	Drug: hypertonic saline (7%); single treatment by inhalation; Drug: isotonic saline; single treatment by inhalation

Outcome Measures

Primary Outcome Measures :

1. Absorptive Clearance Rate After Isotonic Saline Inhalation [ Time Frame: 80 minutes after radiopharmaceutical inhalation ]
   The absorption rate of Indium 111 diethylenetriaminepentaacetic acid (In-DTPA) in the airways after the inhalation of isotonic saline
2. Absorptive Clearance Rate After Hypertonic Saline Inhalation [ Time Frame: 80 minutes after radiopharmaceutical inhalation ]
   The absorption rate of In-DTPA after the inhalation of hypertonic saline
3. Mucociliary Clearance Rate After Isotonic Saline Inhalation [ Time Frame: 80 minutes after radiopharmaceutical inhalation ]
   The clearance rate of Tc-SC after the inhalation of isotonic saline
4. Mucociliary Clearance Rate After Hypertonic Saline Inhalation [ Time Frame: 80 minutes after radiopharmaceutical inhalation ]
   The clearance rate of Tc-SC after the inhalation of hypertonic saline

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

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)

Contacts and Locations

Locations

United States, Pennsylvania

University of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15213

Sponsors and Collaborators

University of Pittsburgh

Investigators

• Principal Investigator: Tim Corcoran, PhD; University of Pittsburgh

More Information

Additional Information:

PACCM aerosol research 

Publications of Results:

Locke LW, Myerburg MM, Markovetz MR, Parker RS, Weber L, Czachowski MR, Harding TJ, Brown SL, Nero JA, Pilewski JM, Corcoran TE. Quantitative imaging of airway liquid absorption in cystic fibrosis. Eur Respir J. 2014 Sep;44(3):675-84. doi: 10.1183/09031936.00220513. Epub 2014 Apr 17.

Other Publications:

Corcoran TE, Thomas KM, Myerburg MM, Muthukrishnan A, Weber L, Frizzell R, Pilewski JM. Absorptive clearance of DTPA as an aerosol-based biomarker in the cystic fibrosis airway. Eur Respir J. 2010 Apr;35(4):781-6. doi: 10.1183/09031936.00059009. Epub 2009 Aug 28.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Locke LW, Myerburg MM, Weiner DJ, Markovetz MR, Parker RS, Muthukrishnan A, Weber L, Czachowski MR, Lacy RT, Pilewski JM, Corcoran TE. Pseudomonas infection and mucociliary and absorptive clearance in the cystic fibrosis lung. Eur Respir J. 2016 May;47(5):1392-401. doi: 10.1183/13993003.01880-2015. Epub 2016 Mar 23.

• Responsible Party: Tim Corcoran, PhD, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT01223183
• Other Study ID Numbers: PRO09080375
• First Posted: October 18, 2010
• Results First Posted: February 5, 2018
• Last Update Posted: November 29, 2018
• Last Verified: November 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Tim Corcoran, University of Pittsburgh:

cystic fibrosis; nuclear medicine; aerosol; nebulizer

Additional relevant MeSH terms:

Cystic Fibrosis; Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases