Cystic Fibrosis
Conditions
Keywords
Cystic fibrosis, Infants, Children, Pulmozyme, Pulmonary function, Computed tomography
Brief summary
This is a study to find out whether Pulmozyme is effective for clearing mucus from the airways of children with cystic fibrosis less than 3 ½ years of age.
Detailed description
Pulmozyme is given using a nebulizer and is now widely used in older children and adults with cystic fibrosis. In adults and older children, studies have shown that daily use of Pulmozyme improves lung function and decreases the number of lung infections requiring hospital treatment. Pulmozyme has been approved by the Food and Drug Administration for use in children over 5 years old and adults with cystic fibrosis. Pulmozyme has also been approved by the FDA for use in children with cystic fibrosis less than 5 years old based upon studies showing that it is safe in this age group and that it does get into the airway tubes as well in infants and toddlers as it does in older children and adults. Currently Pulmozyme is not widely used in children with cystic fibrosis younger than 5 years because no study has clearly shown that inhaling Pulmozyme daily improves lung function or improves clearance of mucus from the airway tubes in very young children. This study will measure whether Pulmozyme improves lung function and mucous clearance from the lungs in children with cystic fibrosis less than 3 ½ years of age. This study will compare Pulmozyme to a placebo. During the study infants and young children with cystic fibrosis will be treated with Pulmozyme for 6 months and placebo for 6 months. The study medicines will be inhaled at home once a day from a nebulizer for a period of one year. Half of the children will be treated with Pulmozyme for the first 6 months of the study and half will receive the placebo. At the 6 month point the group receiving Pulmozyme will be changed to the placebo and the group receiving placebo will be changed to Pulmozyme. The order of the 6 month treatment periods is randomized. This study is blinded. The study doctor and his staff will not know who is receiving Pulmozyme or placebo at any time during the study. Whether Pulmozyme works will be measured using infant lung function tests and by doing a special 3-D x-ray of the child's chest (a high resolution CT or HRCT) at the beginning of the study, at 6 months and at 12 month after starting study. The study will not change the regular clinical care.
Interventions
DRUGRecombinant Human DNase (Pulmozyme)
2.5 mg in 3 ml diluent delivered by nebulization given daily for 6 months with 3 ml diluent placebo delivered by nebulization given daily for 6 months
DRUGPlacebos
2.5 ml sterile solution (8.77 mg/ml sodium chloride, 0.15 mg/ml calcium chloride, pH 7.0 +/- 2.0) delivered daily by nebulization for 6 months, either preceding or following 6 months of Pulmozyme depending on randomization of the subject
Sponsors
Genentech, Inc.
Nationwide Children's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Months to 30 Months
Healthy volunteers
No
Inclusion criteria
* Age \< 30 months * Diagnosis of CF based on clinical features consistent with CF as well as 1 of the 2 following criteria: a) two sweat chlorides \>60 mEq/L (by quantitative pilocarpine iontophoresis), b) genotype with 2 identifiable mutations consistent with CF. * Informed consent by parent or legal guardian
Exclusion criteria
* Previous treatment with Pulmozyme * Hospitalization or treatment with IV antibiotics with 14 days of initial study visit * Acute intercurrent respiratory infection, defined as any of the following symptoms within the preceding 48 hours: 1) fever \> 38 degrees C, 2) new onset of coryza or other upper respiratory symptoms, 3) increase in cough, wheezing, or respiratory rate * History of adverse reaction to sedation * Oxyhemoglobin saturation \<90% on room air * Severe upper airway obstruction as determined by site PI (severe laryngomalacia, markedly enlarged tonsils, significant snoring, diagnosed obstructive sleep apnea) * Hemodynamically significant congenital heart disease or diagnosed arrhythmias * History of hemoptysis * History of previous pulmonary air leak (pneumothorax) * Diagnosed seizure disorder necessitating current anticonvulsive therapy. A history of febrile seizures is not an exclusion criterion. * Use of Investigational drug(s) within 60 days or 5 half-lives of enrollment in this study. * Known allergy to Chinese Hamster Ovary-derived biological products or any component of the placebo or active drug formulations.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Chest CT (High Resolution Computed Tomography (HRCT) Score) | 6 months | Change in Total HRCT Score from initiation of intervention to 6 months Modified Maffessanti HRCT Scoring System Airways 1. Bronchial Wall Thickening:1 = mild, 2 = moderate, 3 = severe 2. Bronchiectasis:1 = mild, 2 = moderate, 3 = severe 3. Axial extent of 1 or 2: 1 = central/middle, 2 = also periphery 4. Regional extent of 1 or 2: x 1 if \< 50 %, x 2 if \> 50 % 5. Gas trapping score:0 if 1 sub-segment, 1 if \< 25 %, 2 if 25 - 50 %, 3 if 50 - 75 %, 4 if \> 75 % Multiply (# 1 + # 2 + # 3) by # 4 then add # 5 Parenchyma 1. Airspace disease: 0 = none, 1 = present 2. Ground glass opacity: 0 = none, 1 = present 3. Mucous Plugging: 0 = none, 1 = present Total Score = Airway + Parenchymal Scores for RUL, LUL, RLL, and LLL Sections. The Total Score ranges from 12 to 92, with higher scores indicating greater impairment. Maximum Score = 4 x 23 = 92 |
| Infant Pulmonary Function Tests (FEV0.5) | 6 months | Change in FEV0.5 from initiation of intervention to 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Antibiotic Treatment Days | per 6 month interval | Total number of days treated with IV, oral or nebulized antibiotics over 6 initial month interval |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nebulized rhDNAse Then Placebo once daily nebulized rhDNAse
Recombinant Human DNase (Pulmozyme): Comparison of 2.5 mg in 3 ml diluent delivered by nebulization given daily for 6 months then 3 ml diluent placebo delivered by nebulization given daily for 6 months | 12 |
| Placebo Then Nebulized rhDNAse once daily nebulized vehicle
Recombinant Human DNase (Pulmozyme): Comparison of 3 ml diluent placebo delivered by nebulization given daily for 6 months then 2.5 mg in 3 ml diluent delivered by nebulization given daily for 6 months | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Nebulized rhDNAse Then Placebo | Placebo Then Nebulized rhDNAse | Total |
|---|---|---|---|
| Age, Continuous | 23.3 weeks STANDARD_DEVIATION 11.9 | 48.3 weeks STANDARD_DEVIATION 36.7 | 41.8 weeks STANDARD_DEVIATION 31.6 |
| Region of Enrollment United States | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 4 Participants | 8 Participants | 12 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 12 | 11 / 12 |
| serious Total, serious adverse events | 1 / 12 | 0 / 12 |
Outcome results
Primary
Chest CT (High Resolution Computed Tomography (HRCT) Score)
Change in Total HRCT Score from initiation of intervention to 6 months Modified Maffessanti HRCT Scoring System Airways 1. Bronchial Wall Thickening:1 = mild, 2 = moderate, 3 = severe 2. Bronchiectasis:1 = mild, 2 = moderate, 3 = severe 3. Axial extent of 1 or 2: 1 = central/middle, 2 = also periphery 4. Regional extent of 1 or 2: x 1 if \< 50 %, x 2 if \> 50 % 5. Gas trapping score:0 if 1 sub-segment, 1 if \< 25 %, 2 if 25 - 50 %, 3 if 50 - 75 %, 4 if \> 75 % Multiply (# 1 + # 2 + # 3) by # 4 then add # 5 Parenchyma 1. Airspace disease: 0 = none, 1 = present 2. Ground glass opacity: 0 = none, 1 = present 3. Mucous Plugging: 0 = none, 1 = present Total Score = Airway + Parenchymal Scores for RUL, LUL, RLL, and LLL Sections. The Total Score ranges from 12 to 92, with higher scores indicating greater impairment. Maximum Score = 4 x 23 = 92
Time frame: 6 months
Population: Subjects will include children with CF \< 30 months old and never treated with Pulmozyme. Patients available for recruitment will include 12 newly diagnosed children \<30 months old from Nationwide Children's Hospital and 4 from Dayton Children's.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebulized rhDNAse | Chest CT (High Resolution Computed Tomography (HRCT) Score) | 3.7 Score points | Standard Deviation 21.1 |
| Nebulized Saline | Chest CT (High Resolution Computed Tomography (HRCT) Score) | 6.1 Score points | Standard Deviation 9.5 |
Primary
Infant Pulmonary Function Tests (FEV0.5)
Change in FEV0.5 from initiation of intervention to 6 months
Time frame: 6 months
Population: Children \< 30 months of age with cystic fibrosis who were given either the study drug followed by the placebo or given placebo followed by study drug. Data is not available for the second period, as the PI has retired and is no longer associated with NCH.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebulized rhDNAse | Infant Pulmonary Function Tests (FEV0.5) | -0.1 z score | Standard Deviation 1.1 |
| Nebulized Saline | Infant Pulmonary Function Tests (FEV0.5) | -0.2 z score | Standard Deviation 1 |
Secondary
Antibiotic Treatment Days
Total number of days treated with IV, oral or nebulized antibiotics over 6 initial month interval
Time frame: per 6 month interval
Population: Subjects included children \< 30 months of age who were newly diagnosed with Cystic Fibrosis. Subjects were recruited from Nationwide Children's (AKA Columbus Children's) and Dayton Children's Hospitals.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebulized rhDNAse | Antibiotic Treatment Days | 31.7 days | Standard Deviation 24.5 |
| Nebulized Saline | Antibiotic Treatment Days | 36.3 days | Standard Deviation 20.1 |