Cystic Fibrosis
Conditions
Keywords
Cystic Fibrosis, Alpha1-proteinase inhibitor, Alpha1-antitrypsin
Brief summary
This was a randomized, double-blind, placebo-controlled, dose escalation study to assess the safety and tolerability of 100 mg and 200 mg of inhaled Alpha-1 HC administered once a day for three weeks in subjects aged 18 years and older with cystic fibrosis (CF). The treatment duration in this study was intended to provide multi-dose safety information prior to proceeding to longer durations of exposure.
Interventions
BIOLOGICALAlpha-1 HC 100 mg
Alpha-1 HC is a sterile, liquid preparation of purified alpha1-proteinase inhibitor prepared from pooled human plasma. Alpha-1 HC 100 mg inhaled once daily for 21 days for a total of 21 inhaled treatments.
BIOLOGICALPlacebo
Phosphate Buffer Saline with Polysorbate (placebo) composed of the same elements listed for Alpha-1 HC, minus the 50 mg/mL of Alpha-1 HC. Placebo inhaled once daily for 21 days for a total of 21 inhaled treatments.
BIOLOGICALAlpha-1 HC 200 mg
Alpha-1 HC is a sterile, liquid preparation of purified alpha1-proteinase inhibitor prepared from pooled human plasma. Alpha-1 HC 200 mg inhaled once daily for 21 days for a total of 21 inhaled treatments.
Sponsors
Grifols Therapeutics LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 years or older. * Documentation of CF diagnosis. * Have a pre-bronchodilator FEV1 ≥ 40% of predicted at Visit 1 and have a Visit 2 pre-investigational product FEV1 that is ≥ 40% of predicted and within ± 15% of the Visit 1 result. * Deemed by the Investigator to be a suitable candidate for serial collection of expectorated sputum.
Exclusion criteria
* Had a pulmonary exacerbation during the 4 weeks before screening (Visit 1) which required the initiation of new antibiotic treatment * Have a pulmonary exacerbation during the screening period (between Visit 1 and Visit 2) which requires the initiation of new antibiotic treatment * FEV1 \< 0.59 liters at the screening visit * Respiratory insufficiency with continuous supplemental oxygen therapy, or carbon dioxide retention * Elevated aspartate transaminase (AST) or alanine aminotransferase (ALT) that is ≥ 3 times the upper limit of normal for age and gender * Smoking during the past 6 months * Lung surgery during the past 2 years * Positive culture for Burkholderia cepacia or mycobacterium during the past two years. * Active allergic bronchopulmonary aspergillosis * Pre-treatment sputum collection at Visit 1 or Visit 2 (Randomization) characterized by problems such as inadequate sputum volume or quality. * Known selective Immunoglobulin A (IgA) deficiency with known antibody against IgA (anti-IgA antibody). * History of anaphylaxis or severe systemic response to any plasma-derived alpha1-proteinase inhibitor preparation or other blood product(s), or to polysorbates. * Use of chronic oral steroids during the study. Note: Inhaled corticosteroids that had been administered for at least 4 weeks prior to Visit 1 were permissible during the study. * Use of chronic, high dose ibuprofen therapy within 3 weeks of screening and at anytime during the study. * Chronic maintenance therapy with systemic antibiotics within 3 weeks of screening and through last dose of investigational product. * Use of leukotriene synthesis inhibitor (zileuton) or leukotriene receptor antagonists (montelukast, zafirlukast) within 3 weeks of screening and at anytime during the study. * Use of roflumilast within 3 weeks of screening and at any time during the study. * Initiation of a new chronic medication or dosage change of a chronic medication for treatment of cystic fibrosis (example: Kalydeco™ \[ivacaftor\]) within 3 weeks of screening (Visit 1).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | 3 weeks | adverse event frequency |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 3 | 3 weeks | FEV1 conducted before and after inhalation of the investigational product at study visits. |
| Percent Change From Baseline in Forced Vital Capacity (FVC) at Week 3 | 3 weeks | FVC conducted before and after inhalation of the investigational product |
Countries
United States
Participant flow
Recruitment details
A total of 41 subjects provided informed consent and were screened for the study. Eleven (11) subjects were screen failures, and a total of 30 subjects were randomized to one of three treatment groups: 200 mg or 100 mg of Alpha-1 HC or placebo daily.
Participants by arm
| Arm | Count |
|---|---|
| Alpha-1 HC 100 mg 100 mg of aerosolized Alpha-1 HC inhaled daily via nebulizer for 3 weeks.
Alpha-1 HC: Alpha-1 HC is a sterile, liquid preparation of purified alpha1-proteinase inhibitor prepared from pooled human plasma. | 10 |
| Alpha-1 HC 200 mg 200 mg of aerosolized Alpha-1 HC inhaled daily via nebulizer for 3 weeks.
Alpha-1 HC: Alpha-1 HC is a sterile, liquid preparation of purified alpha1-proteinase inhibitor prepared from pooled human plasma. | 10 |
| Placebo Placebo inhaled daily via nebulizer for 3 weeks. Placebo (phosphate buffer saline with polysorbate).
Placebo | 10 |
| Total | 30 |
Baseline characteristics
| Characteristic | Alpha-1 HC 100 mg | Alpha-1 HC 200 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 28.2 years STANDARD_DEVIATION 10.62 | 28.1 years STANDARD_DEVIATION 11.43 | 29.3 years STANDARD_DEVIATION 9.96 | 28.5 years STANDARD_DEVIATION 10.32 |
| Region of Enrollment United States | 10 participants | 10 participants | 10 participants | 30 participants |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 6 Participants | 20 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 8 / 10 | 6 / 10 |
| serious Total, serious adverse events | 1 / 10 | 1 / 10 | 1 / 10 |
Outcome results
Primary
Adverse Events
adverse event frequency
Time frame: 3 weeks
Population: Safety Population: included all subjects who received any dose of IP (included those withdrawn from treatment for any reason)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alpha-1 HC 100 mg | Adverse Events | 100 percentage of participants |
| Alpha-1 HC 200 mg | Adverse Events | 80 percentage of participants |
| Placebo | Adverse Events | 60 percentage of participants |
Other Pre-specified
Percent Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 3
FEV1 conducted before and after inhalation of the investigational product at study visits.
Time frame: 3 weeks
Population: Safety Population: included all subjects who received any dose of Investigational Product (included those withdrawn from treatment for any reason)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alpha-1 HC 100 mg | Percent Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 3 | 1.5 percent | Standard Deviation 5.2 |
| Alpha-1 HC 200 mg | Percent Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 3 | -2.1 percent | Standard Deviation 12.28 |
| Placebo | Percent Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 3 | 0.5 percent | Standard Deviation 5.91 |
Other Pre-specified
Percent Change From Baseline in Forced Vital Capacity (FVC) at Week 3
FVC conducted before and after inhalation of the investigational product
Time frame: 3 weeks
Population: Safety Population: included all subjects who received any dose of Investigational Product (included those withdrawn from treatment for any reason)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alpha-1 HC 100 mg | Percent Change From Baseline in Forced Vital Capacity (FVC) at Week 3 | 1.2 percent | Standard Deviation 5.23 |
| Alpha-1 HC 200 mg | Percent Change From Baseline in Forced Vital Capacity (FVC) at Week 3 | -2.3 percent | Standard Deviation 11.57 |
| Placebo | Percent Change From Baseline in Forced Vital Capacity (FVC) at Week 3 | -0.9 percent | Standard Deviation 3.73 |