Infant Study of Inhaled Saline in Cystic Fibrosis (ISIS)

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: 7% Hypertonic Saline (HS); Drug: 0.9% Isotonic Saline (IS)

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
• Enrollment (Actual): 321
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • BC Children's Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University / Lucile S. Packard Children's Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital and Northwestern University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University / Johns Hopkins Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan / C.S. Mott Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University in St. Louis
    • St. Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska
  • New York
    • Buffalo, New York, United States, 14222
      • Women and Children's Hospital of Buffalo
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital, Pulmonary Division
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15201
      • Children's Hospital of Pittsburgh
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia - Pediatric Respiratory Medicine
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital & Regional Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 4 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Active treatment group; 7% Hypertonic Saline administered via inhalation twice daily for 48 ± 4 weeks	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 Names: Hyper-Sal™, inhaled saline
ACTIVE_COMPARATOR: Control group; 0.9% Isotonic Saline administered via inhalation twice daily for 48 ± 4 weeks	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 Names: Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The rate of protocol-defined pulmonary exacerbations requiring treatment with oral, inhaled or intravenous antibiotics between subjects randomized to HS and IS	during the 48 week treatment period

Secondary Outcome Measures

Outcome Measure	Time Frame
Symptoms by parent home questionnaire administered weekly	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	over the 48 week treatment period
Standardized cough score assessed at study visits	during the 48 week treatment period
Change in weight, height, resting respiratory rate, and room air oxygen saturation	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	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)	over the 48 week treatment period

Collaborators and Investigators

• Sponsor: CF Therapeutics Development Network Coordinating Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Cystic Fibrosis Foundation
• Investigators: 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

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (ACTUAL): October 1, 2011
• Study Completion (ACTUAL): November 1, 2011

Study Registration Dates

• First Submitted: July 1, 2008
• First Submitted That Met QC Criteria: July 1, 2008
• First Posted (ESTIMATE): July 3, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): February 12, 2013
• Last Update Submitted That Met QC Criteria: February 11, 2013
• Last Verified: February 1, 2013

More Information

Terms related to this study

• Keywords: Cystic Fibrosis; hypertonic saline; inhaled saline
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: ISIS002; U01HL092931 (NIH); U01HL092932 (NIH)