Preventive Inhalation of Hypertonic Saline in Infants With Cystic Fibrosis (PRESIS)

Randomized, Double-blind, Controlled Pilot Study on Safety of Hypertonic Saline as Preventive Inhalation Therapy in Newborns and Infants With Cystic Fibrosis

The purpose of this study is to assess whether 6% hypertonic saline (HS) is a safe and effective preventive therapy in newborns and infants with cystic fibrosis (CF).

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis Lung Disease
• Intervention / Treatment: Drug: 6% Hypertonic Saline (HS), 4mL; Drug: 0.9% Isotonic Saline (IS), 4mL

Detailed Description

Cystic fibrosis (CF) remains one of the most common lethal genetic diseases in Europe and North America. Despite a substantial increase in life expectancy over the past decades, many CF patients still die during young adulthood due to chronic progressive CF lung disease that is caused by defective fluid transport by airway epithelia causing dehydration of airway surfaces, which in turn leads to impaired mucociliary clearance, chronic airway mucus obstruction, inflammation and infection. Recent evidence from studies in a mouse model of CF lung disease suggest that preventive improvement of airway surface hydration may be an effective treatment of early and reversible mucus obstruction and inflammation, and thus delay or ameliorate progressive damage in lungs of CF patients. Hypertonic saline (HS) is an osmotic agent that improves airway surface hydration, and inhalation of 6% HS is already an established, safe, and effective maintenance therapy that improves mucociliary clearance and lung function, and reduces pulmonary exacerbations in older children (> 6 years) and adults with chronic CF lung disease and fixed lung damage. However, the effect of HS as a preventive therapy has not been studied, and no other therapies are available for preventive improvement of airway dehydration and mucociliary dysfunction in CF.

This investigator initiated clinical trial is a monocentric, randomized, double-blind, controlled pilot study on safety and efficacy of a preventive and early inhalation with HS in newborns and infants with CF who are diagnosed in the newborn period either by CF newborn screening (CF-NBS) or for another reason (e.g. meconium ileus) and are younger than 4 months of age at the time of enrolment. Participating patients will be randomized to 6% HS or 0.9% isotonic saline (IS) as active comparator. In both groups, patients will inhale their study solution twice daily over 52 weeks. At the beginning, during and at the end of the study, different measurements will be undertaken to determine effects of HS on safety, radiologic and/or functional alterations of the lung, number of exacerbations, time to first detection of a CF pathogen, and health-related quality of life. We expect that the results of this study will provide first evidence on the safety and efficacy of a preventive therapy that improves airway surface hydration and targets a CF basic defect and may thus delay and/or ameliorate chronic damage of the lungs of patients with CF.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Gießen, Germany, 35392
    • University Hospital Giessen and Marburg GmbH
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Lübeck, Germany, 23538
    • University Children's Hospital Schleswig-Holstein
  • Baden-Württemberg
    • Heidelberg, Baden-Württemberg, Germany, 69120
      • University Children's Hospital Heidelberg, Cystic Fibrosis Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 4 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Confirmed diagnosis of CF established in neonatal period either via CF newborn screening (NBS) or because of symptoms typical for CF (e.g. meconium ileus), positive family history or positive prenatal screening and fulfilling at least one of the following three criteria:

   • sweat chloride ≥ 60mEq/L
   • two CF causing mutations of CFTR gen
   • alterations of transepithelial potential difference of nasal or rectal epithelia typical for CF.
2. Age at enrolment is 0 to 4 months.
3. Patient's and parent's ability to comply with medication use, study visits, and study procedures is judged by the investigator (therefore parents have to understand the character of the study and individual consequences).
4. Participation in this study is voluntary. Only patients, whose parents or legal guardians gave written consent, are included.

Exclusion Criteria:

1. Born < 30 weeks gestation.
2. Prolonged mechanical ventilation in the first 3 months of life.
3. A significant medical disease or condition other than CF likely to interfere with the child's ability to complete the entire protocol.
4. Previous major surgery except for meconium ileus.
5. Other major organ dysfunction, excluding pancreatic or hepatic dysfunction or another condition due to cystic fibrosis.
6. Physical findings that would compromise the safety of the subject or the quality of the study data as determined by investigator.
7. History of adverse reaction to sedation.
8. Known hypersensitivity to study treatment.
9. Participation in other interventional studies at the same time.

Criteria, which lead to a displacement of the procedures in sedation until the child has recovered:

• Clinically significant upper airway obstruction as determined by investigator (e.g. severe laryngomalacia, markedly enlarged tonsils, significant snoring, diagnosed obstructive sleep apnoea).
• Acute intercurrent respiratory infection, defined as an increase in cough, wheezing, or respiratory rate with onset in 2 weeks preceding visit.
• Oxygen saturation <95% before initial pulmonary function test or initial MRI.
• Severe gastroesophageal reflux, defined as persistent frequent emesis despite anti-reflux therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hypertonic Saline; Inhalation with 6% Hypertonic Saline twice daily over 1 year	Drug: 6% Hypertonic Saline (HS), 4mL; Administered via inhalation twice daily for 52 weeks. The delivery system is a PARI LC SPRINT® Junior nebulizer with a baby bend, size-adapted PARI® Baby face mask size 0-3, connection tubing (2.2m) and a PARI JuniorBOY® SX compressor.; Other Names: MucoClear® 6%
Active Comparator: Isotonic Saline; Inhalation with 0.9% Isotonic Saline twice daily over 1 year	Drug: 0.9% Isotonic Saline (IS), 4mL; Administered via inhalation twice daily for 52 weeks. The delivery system is a PARI LC SPRINT® Junior nebulizer with a baby bend, size-adapted PARI® Baby face mask size 0-3, connection tubing (2.2m) and a PARI JuniorBOY® SX compressor.; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients in both treatment groups with adverse events (AEs) and serious adverse events (SAEs)	Safety of inhalation with HS and IS in newborns and infants with CF assessed by proportion of adverse events (AEs) and serious adverse events (SAEs)	during the 52 week treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of protocol-defined pulmonary exacerbations	Rate of protocol-defined pulmonary exacerbations requiring treatment with oral, inhaled or intravenous antibiotics between subjects randomized to HS and IS	during the 52 week treatment period
Time to first pulmonary exacerbation in both treatment groups		during the 52 week treatment period
Proportion of children with morphological and/or functional changes due to CF lung disease at baseline and after 1 year of inhalation	Proportion of children with morphological and/or functional changes due to CF lung disease at baseline and after 1 year of inhalation according to magnetic resonance imaging (MRI) chest score and chest x-ray (CXR) Chrispin-Norman score in both groups (HS vs. IS)	during the 52 week treatment period
Extent and severity of bronchial dilatation	Extent and severity of bronchial dilatation after MRI and CXR scores at baseline and after 1 year of inhalation in both groups	during the 52 week treatment period
Proportion of children with impairments in lung function	Proportion of children with impairments in lung function determined via multiple breath washout at baseline, after 3, 6, 9, and 12 months of inhalation in both groups	during the 52 week treatment period
Severity of impairment in lung function test	Severity of impairment in lung function test at baseline, after 3, 6, 9, and 12 months of inhalation in both groups	during the 52 week treatment period
Health-related quality of life	Health-related quality of life as assessed by scores from Cystic Fibrosis Questionnaire - Revised Parent Report (CFQ-R, German version), administered quarterly	during the 52 week treatment period
Change in anthropometric and basic respiratory parameters	Change in weight, height, body mass-index, weight-for-height, resting respiratory rate, and room air oxygen saturation	during the 52 week treatment period
Proportion of patients with new isolation of CF pathogen	Among participants from whom Pseudomonas aeruginosa or other CF pathogens were not isolated from respiratory cultures prior to enrolment, the proportion from whom these organisms are isolated from clinically collected respiratory cultures	during the 52 week treatment period
Time to first isolation of a CF pathogen	Time to acquisition of a CF pathogen is going to be compared between both treatment groups	during the 52 week treatment period

Collaborators and Investigators

• Sponsor: Heidelberg University
• Collaborators: German Center for Lung Research
• Investigators: Principal Investigator: Marcus A Mall, MD, University Hospital Heidelberg

Publications and helpful links

General Publications

• Stahl M, Wielputz MO, Ricklefs I, Dopfer C, Barth S, Schlegtendal A, Graeber SY, Sommerburg O, Diekmann G, Husing J, Koerner-Rettberg C, Nahrlich L, Dittrich AM, Kopp MV, Mall MA. Preventive Inhalation of Hypertonic Saline in Infants with Cystic Fibrosis (PRESIS). A Randomized, Double-Blind, Controlled Study. Am J Respir Crit Care Med. 2019 May 15;199(10):1238-1248. doi: 10.1164/rccm.201807-1203OC.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): October 1, 2017

Study Registration Dates

• First Submitted: June 12, 2012
• First Submitted That Met QC Criteria: June 12, 2012
• First Posted (Estimate): June 14, 2012

Study Record Updates

• Last Update Posted (Actual): October 26, 2017
• Last Update Submitted That Met QC Criteria: October 25, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Cystic Fibrosis; Prevention; Infant; Hypertonic Saline; Newborn
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Lung Diseases; Pulmonary Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: UKH-PIHSNC-1