Infant Study of Inhaled Saline in Cystic Fibrosis (ISIS)

• ClinicalTrials.gov Identifier: NCT00709280
• Recruitment Status: Completed
• First Posted: July 3, 2008
• Last Update Posted: February 12, 2013
• Sponsor: CF Therapeutics Development Network Coordinating Center
• Collaborators: Cystic Fibrosis Foundation; National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): CF Therapeutics Development Network Coordinating Center

Tracking Information

• First Submitted Date: July 1, 2008
• First Posted Date: July 3, 2008
• Last Update Posted Date: February 12, 2013
• Study Start Date: April 2009
• Actual Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: May 11, 2009): The rate of protocol-defined pulmonary exacerbations requiring treatment with oral, inhaled or intravenous antibiotics between subjects randomized to HS and IS [ Time Frame: during the 48 week treatment period ]
• Original Primary Outcome Measures (submitted: July 1, 2008): The average change in functional residual capacity (FRC) measured by plethysmography during infant pulmonary function testing (iPFT) [ Time Frame: over the 48 week treatment period ]

Current Secondary Outcome Measures (submitted: November 24, 2009)

• Symptoms by parent home questionnaire administered weekly [ Time Frame: during the 48 week treatment period ]
• Health-related quality of life as assessed by scores from Cystic Fibrosis Questionnaire-Revised Parent Report (CFQ-R), administered quarterly [ Time Frame: over the 48 week treatment period ]
• Standardized cough score assessed at study visits [ Time Frame: during the 48 week treatment period ]
• Change in weight, height, resting respiratory rate, and room air oxygen saturation [ Time Frame: over the 48 week treatment period ]
• Among participants from whom Pseudomonas aeruginosa (Pa) and other CF pathogens were not isolated from respiratory cultures prior to enrollment, the proportion from whom these organisms are isolated from clinically collected respiratory cultures [ Time Frame: measured at baseline and at 48 weeks ]
• Pulmonary function indices measured at baseline and 48 weeks in infants 4 to 15 months of age at enrollment participating in infant pulmonary function testing (N = 100, selected sites) [ Time Frame: over the 48 week treatment period ]

Original Secondary Outcome Measures (submitted: July 1, 2008)

• The number of protocol-defined pulmonary exacerbations requiring treatment with oral, inhaled or intravenous antibiotics [ Time Frame: over the 48 week treatment period ]
• Rates of adverse events, withdrawal, adherence to treatment, new isolation of CF pathogens from respiratory cultures, resting respiratory rate, and room air oxygen saturations [ Time Frame: over the 48 week treatment period ]
• The rate of protocol-defined intolerance to the test dose of HS [ Time Frame: at the Screening Visit ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Infant Study of Inhaled Saline in Cystic Fibrosis
• Official Title: Infant Study of Inhaled Saline in Cystic Fibrosis
• Brief Summary: The purpose of this study is to assess whether 7% hypertonic saline (HS) is an effective and safe therapy in infants and young children with CF.

Detailed Description

A growing body of evidence supports the importance of intervention in Cystic Fibrosis (CF) lung disease during infancy and early childhood, in order to potentially delay or prevent irreversible lung disease. Yet, aside from antimicrobial therapies, the CF community has no clinical trial evidence base with which to guide pulmonary therapies in children <6 years of age. Hypertonic Saline (HS) is the most attractive chronic maintenance therapy to investigate in these young children because it addresses defective mucociliary clearance, an early step in the cascade of events leading to CF lung disease that is expected to be abnormal prior to the onset of airway infection and inflammation.

This study is a randomized, parallel group, controlled trial to assess the efficacy and safety of 7% HS inhaled twice daily for 48 weeks among young children with CF 4 to < 60 months of age at enrollment. The primary hypothesis is that, compared to isotonic saline (IS), HS will decrease the number of protocol-defined pulmonary exacerbations during the 48 week treatment period. The results of the proposed trial may for the first time provide evidence for early initiation of HS, which, by improving mucociliary clearance, may delay or hinder the cycle of infection and inflammation responsible for progressive airway damage in CF lung disease.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Cystic Fibrosis

Intervention

• Drug: 7% Hypertonic Saline (HS)
  Administered via inhalation twice daily for 48 ± 4 weeks. The delivery system is a PARI Sprint Junior nebulizer with a PARI Baby face mask or mouthpiece driven by a PARI Pro Neb compressor.
  Other Name: Hyper-Sal™, inhaled saline
• Drug: 0.9% Isotonic Saline (IS)
  Administered via inhalation twice daily for 48 ± 4 weeks. The delivery system is a PARI Sprint Junior nebulizer with a PARI Baby face mask or mouthpiece driven by a PARI Pro Neb compressor.
  Other Name: Normal saline

Study Arms

• Experimental: Active treatment group
  7% Hypertonic Saline administered via inhalation twice daily for 48 ± 4 weeks
  Intervention: Drug: 7% Hypertonic Saline (HS)
• Active Comparator: Control group
  0.9% Isotonic Saline administered via inhalation twice daily for 48 ± 4 weeks
  Intervention: Drug: 0.9% Isotonic Saline (IS)

Publications *

• Rosenfeld M, Ratjen F, Brumback L, Daniel S, Rowbotham R, McNamara S, Johnson R, Kronmal R, Davis SD; ISIS Study Group. Inhaled hypertonic saline in infants and children younger than 6 years with cystic fibrosis: the ISIS randomized controlled trial. JAMA. 2012 Jun 6;307(21):2269-77. doi: 10.1001/jama.2012.5214.
• Subbarao P, Stanojevic S, Brown M, Jensen R, Rosenfeld M, Davis S, Brumback L, Gustafsson P, Ratjen F. Lung clearance index as an outcome measure for clinical trials in young children with cystic fibrosis. A pilot study using inhaled hypertonic saline. Am J Respir Crit Care Med. 2013 Aug 15;188(4):456-60. doi: 10.1164/rccm.201302-0219OC.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 14, 2010): 321
• Original Estimated Enrollment (submitted: July 1, 2008): 150
• Actual Study Completion Date: November 2011
• Actual Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Months to 59 Months (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT00709280
• Other Study ID Numbers: ISIS002; U01HL092931 ( U.S. NIH Grant/Contract ); U01HL092932 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: CF Therapeutics Development Network Coordinating Center
• Study Sponsor: CF Therapeutics Development Network Coordinating Center

Collaborators

• Cystic Fibrosis Foundation
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Stephanie Davis, MD; University of North Carolina, Chapel Hill
• Principal Investigator: Margaret Rosenfeld, MD, MPH; Children's Hospital and Regional Medical Center
• Principal Investigator: Felix Ratjen, MD, PhD; University of Toronto Hospital for Sick Children

• PRS Account: CF Therapeutics Development Network Coordinating Center
• Verification Date: February 2013