Cystic Fibrosis
Conditions
Brief summary
The objective of this trial is to determine the optimal region of the lung for depositing Prolastin (alpha-1 antitrypsin; AAT) by inhalation in order to treat cystic fibrosis (CF). The AKITA® nebulizer has settings which can be varied to target the inhaled drug to either the deep lung or to the upper airways in a one to one randomization. The study will measure how much of the activity of the enzyme elastase is inhibited by AAT.
Detailed description
The optimum deposition site (bronchial or peripheral) in CF patients for AAT will be investigated by measuring several parameters in induced sputum. The study will start with a 2 week run-in period in which the planned 60 patients inhale isotonic saline once daily. This period is followed by a 4 week treatment period where 30 patients inhale AAT for peripheral deposition and 30 patients inhale AAT for bronchial deposition. Six patients in each group will be asked to collect spontaneous sputum at home. Twenty-five milligrams of AAT will be deposited at one of the two target sites using the AKITA® device. The inhalation should take place in the evening between 18.00 and 23.00 h. Patients will inhale saline once daily for 2 weeks (run-in period) followed by 4 weeks of once daily inhalation of AAT. Induced sputum will be collected at visits to the clinic at the start of the run-in, at the start of AAT treatment, and at 2 and 4 weeks after the start of AAT treatment.
Interventions
25 mg of Alpha1-Proteinase Inhibitor (Human) in the lungs, one inhalation per day over 4 weeks.
Sponsors
Grifols Therapeutics LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
8 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient with diagnosis of CF * Age \>= 8 years * Forced expiratory volume at one second (FEV1) \> 25 % of predicted value * Free elastase activity checked at visit 1 must be positive (free elastolytic activity in the sample, 2 standard deviations above of the negative blank samples in the assay.) . * Patient must be positive at least 3 times for pseudomonas in the last 2 years * Patient must be positive for pseudomonas at Visit 1 * Patient must be able to perform reliable spirometry * Patient must be on stable concomitant therapy at least 2 weeks prior to visit 1 and during the study * Written informed consent of the patient or legal representative(s)
Exclusion criteria
* FEV1 \< 25% of predicted value post-bronchodilator * History of lung transplant * Any lung surgery within the past 2 years * On any thoracic surgery waiting list * Severe concomitant disease (serious malignant disease, congestive heart failure New York Heart Association (NYHA) III/IV, cor pulmonale with the need of oxygen therapy) * Severe liver cirrhosis with ascites, hypersplenism or grade III/IV esophageal varices. * Known selective immunoglobulin A (IgA) deficiency with known antibody against IgA (anti-IgA antibody) * Active pulmonary exacerbation within the 4 weeks prior to screening * Current Smoking * Pregnancy or lactation * Women of child-bearing age without adequate contraception * Any medical condition which the investigator feels will prohibit the patient from completing the trial * Participation in another clinical trial within 30 days prior to inclusion at visit 1
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Free Elastase in Induced Sputum From Baseline to Week 4 | Baseline vs Week 4 |
Secondary
| Measure | Time frame |
|---|---|
| Change in Alpha-1-anti-trypsin (A1AT) Activity in Induced Sputum From Baseline at Week 4 | Baseline vs Week 4 |
| Change in Total Immunoglobulin G (IgG) Fragments in Induced Sputum From Baseline at Week 4 | Baseline vs Week 4 |
| Change in Total Bacterial Load in Induced Sputum From Baseline to Week 4 | Week 4 |
| Change in Pseudomonas Load in Induced Sputum From Baseline at Week 4 | Baseline vs Week 4 |
| Change in Neutrophil Number in Induced Sputum From Baseline at Week 4 | Baseline vs Week 4 |
Participant flow
Recruitment details
This study was performed in 8 study centers in Germany.
Pre-assignment details
Subjects inhaled saline once daily for 2 weeks during the Run-in Period.
Participants by arm
| Arm | Count |
|---|---|
| Peripheral Deposition Peripheral Deposition is achieved with a breathing maneuver consisting of slow and deep breaths | 37 |
| Bronchial Deposition Bronchial Deposition consists of inhalation of smaller volumes per breath at higher flow rates | 35 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | No sputum, devise issues, exacerbation | 3 | 4 |
| Overall Study | Protocol Violation | 4 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Peripheral Deposition | Bronchial Deposition |
|---|---|---|---|
| Age, Categorical <=18 years | 20 Participants | 10 Participants | 10 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 52 Participants | 27 Participants | 25 Participants |
| Age, Continuous | 25.46 years STANDARD_DEVIATION 8.84 | 23.78 years STANDARD_DEVIATION 7.54 | 27.42 years STANDARD_DEVIATION 9.78 |
| Free Elastase during the Run-In Phase Absolute Change | -7.25 µg/mL STANDARD_DEVIATION 29.6 | -4.0 µg/mL STANDARD_DEVIATION 21.3 | -10.9 µg/mL STANDARD_DEVIATION 36.9 |
| Free Elastase during the Run-In Phase Week 0 | 36.2 µg/mL STANDARD_DEVIATION 36.9 | 36.6 µg/mL STANDARD_DEVIATION 35.9 | 35.9 µg/mL STANDARD_DEVIATION 38.8 |
| Free Elastase during the Run-In Phase Week 2 | 29.1 µg/mL STANDARD_DEVIATION 27 | 32.7 µg/mL STANDARD_DEVIATION 31.7 | 25.0 µg/mL STANDARD_DEVIATION 20.1 |
| Region of Enrollment Germany | 72 participants | 37 participants | 35 participants |
| Sex: Female, Male Female | 40 Participants | 21 Participants | 19 Participants |
| Sex: Female, Male Male | 32 Participants | 16 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 37 | 13 / 35 |
| serious Total, serious adverse events | 0 / 37 | 0 / 35 |
Outcome results
Primary
Change in Free Elastase in Induced Sputum From Baseline to Week 4
Time frame: Baseline vs Week 4
Population: Modified Intent-to-Treat Population (mITT) was all randomized subjects who received any amount of study medication and had at least one evaluation of the primary efficacy variable (free elastase in induced sputum) post baseline and at baseline (Visit 2).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Peripheral Deposition | Change in Free Elastase in Induced Sputum From Baseline to Week 4 | -7.42 ug/mL | Standard Deviation 29.96 |
| Bronchial Deposition | Change in Free Elastase in Induced Sputum From Baseline to Week 4 | 6.11 ug/mL | Standard Deviation 31.3 |
p-value: 0.197ANCOVA
Secondary
Change in Alpha-1-anti-trypsin (A1AT) Activity in Induced Sputum From Baseline at Week 4
Time frame: Baseline vs Week 4
Population: For Group 1, only 24 out of 28 subjects had applicable data to analyze. For Group 2, only 27 out of 28 subjects had applicable data to analyze.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Peripheral Deposition | Change in Alpha-1-anti-trypsin (A1AT) Activity in Induced Sputum From Baseline at Week 4 | 16741 ug/mL | Standard Deviation 33583 |
| Bronchial Deposition | Change in Alpha-1-anti-trypsin (A1AT) Activity in Induced Sputum From Baseline at Week 4 | 6469 ug/mL | Standard Deviation 18999 |
Secondary
Change in Neutrophil Number in Induced Sputum From Baseline at Week 4
Time frame: Baseline vs Week 4
Population: For Group 1, only 21 out of 28 subjects had applicable data to analyze. For Group 2, only 22 out of 28 subjects had applicable data to analyze.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Peripheral Deposition | Change in Neutrophil Number in Induced Sputum From Baseline at Week 4 | -20.8 percentage of change | Standard Deviation 30.3 |
| Bronchial Deposition | Change in Neutrophil Number in Induced Sputum From Baseline at Week 4 | -8.2 percentage of change | Standard Deviation 20.9 |
Secondary
Change in Pseudomonas Load in Induced Sputum From Baseline at Week 4
Time frame: Baseline vs Week 4
Population: For Group 1, only 24 out of 28 subjects had applicable data to analyze. For Group 2, all 28 subjects had applicable data to analyze.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Peripheral Deposition | Change in Pseudomonas Load in Induced Sputum From Baseline at Week 4 | -40.1 CFU/g | Standard Deviation 808.2 |
| Bronchial Deposition | Change in Pseudomonas Load in Induced Sputum From Baseline at Week 4 | -22.3 CFU/g | Standard Deviation 772.4 |
Secondary
Change in Total Bacterial Load in Induced Sputum From Baseline to Week 4
Time frame: Week 4
Population: For Group 1, only 24 out of 28 subjects had applicable data to analyze. For Group 2, all 28 subjects had applicable data to analyze.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Peripheral Deposition | Change in Total Bacterial Load in Induced Sputum From Baseline to Week 4 | 22673275.8 CFU/g | Standard Deviation 253455845.23 |
| Bronchial Deposition | Change in Total Bacterial Load in Induced Sputum From Baseline to Week 4 | 5021353.2 CFU/g | Standard Deviation 130686274.77 |
Secondary
Change in Total Immunoglobulin G (IgG) Fragments in Induced Sputum From Baseline at Week 4
Time frame: Baseline vs Week 4
Population: For Group 1, only 24 out of 28 subjects had applicable data to analyze. For Group 2, only 26 out of 28 subjects had applicable data to analyze.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Peripheral Deposition | Change in Total Immunoglobulin G (IgG) Fragments in Induced Sputum From Baseline at Week 4 | 0.005 ug/mL | Standard Deviation 1.1 |
| Bronchial Deposition | Change in Total Immunoglobulin G (IgG) Fragments in Induced Sputum From Baseline at Week 4 | -0.48 ug/mL | Standard Deviation 1.53 |