Clinical trial NCT01619657: Preventive Inhalation of Hypertonic Saline in Infants With Cystic Fibrosis
Official title: Randomized, Double-blind, Controlled Pilot Study on Safety of Hypertonic Saline as Preventive Inhalation Therapy in Newborns and Infants With Cystic Fibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cystic Fibrosis Lung Disease
Keywords: Cystic Fibrosis
Hypertonic Saline
Infant
Newborn
Prevention
Lead sponsor: Heidelberg University
Sponsor class: OTHER
Collaborators: name: German Center for Lung Research
First posted: 2012-06-14
Enrollment: 42
Sex: ALL
Maximum age (years): 4
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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).

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of patients in both treatment groups with adverse events (AEs) and serious adverse events (SAEs)
timeFrame: during the 52 week treatment period
Secondary outcomes:
measure: Rate of protocol-defined pulmonary exacerbations
timeFrame: during the 52 week treatment period
measure: Time to first pulmonary exacerbation in both treatment groups
timeFrame: during the 52 week treatment period
measure: Proportion of children with morphological and/or functional changes due to CF lung disease at baseline and after 1 year of inhalation
timeFrame: during the 52 week treatment period
measure: Extent and severity of bronchial dilatation
timeFrame: during the 52 week treatment period
measure: Proportion of children with impairments in lung function
timeFrame: during the 52 week treatment period
measure: Severity of impairment in lung function test
timeFrame: during the 52 week treatment period
measure: Health-related quality of life
timeFrame: during the 52 week treatment period
measure: Change in anthropometric and basic respiratory parameters
timeFrame: during the 52 week treatment period
measure: Proportion of patients with new isolation of CF pathogen
timeFrame: during the 52 week treatment period
measure: Time to first isolation of a CF pathogen
timeFrame: during the 52 week treatment period
Other outcomes:
Locations:
city: Heidelberg
country: Germany
facility: University Children's Hospital Heidelberg, Cystic Fibrosis Centre
state: Baden-Württemberg
city: Gießen
country: Germany
facility: University Hospital Gießen and Marburg GmbH
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Lübeck
country: Germany
facility: University Children's Hospital Schleswig-Holstein
Study officials:
affiliation: University Hospital Heidelberg
name: Marcus A Mall, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.