Safety and Tolerability Trial of Inhaled Alpha1-Proteinase Inhibitor (Human), Hydrophobic Chromatography Process (Alpha-1 HC) in Subjects With Cystic Fibrosis
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Alpha-1 HC 100 mg 100 mg of aerosolized Alpha-1 HC inhaled daily via nebulizer for 3 weeks. |
Biological: Alpha-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.
Other Names:
|
| Experimental: Alpha-1 HC 200 mg 200 mg of aerosolized Alpha-1 HC inhaled daily via nebulizer for 3 weeks. |
Biological: Alpha-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.
Other Names:
|
| Placebo Comparator: Placebo Placebo inhaled daily via nebulizer for 3 weeks. Placebo (phosphate buffer saline with polysorbate). |
Biological: Placebo
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.
|
Outcome Measures
Primary Outcome Measures
- Adverse Events [3 weeks]
adverse event frequency
Other Outcome Measures
- 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
Eligibility Criteria
Criteria
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
- 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).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | The University of Alabama at Birmingham | Birmingham | Alabama | United States | 35233 |
| 2 | National Jewish Hospital | Denver | Colorado | United States | 80206 |
| 3 | Children's Hospital Boston | Boston | Massachusetts | United States | 02115 |
| 4 | UNC at Chapel Hill | Chapel Hill | North Carolina | United States | 27599 |
| 5 | Rainbow Babies and Children's Hospital | Cleveland | Ohio | United States | 44106 |
| 6 | Medical University of South Carolina | Charleston | South Carolina | United States | 29425 |
Sponsors and Collaborators
- Grifols Therapeutics LLC
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- T6005-201
Study Results
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. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Alpha-1 HC 100 mg | Alpha-1 HC 200 mg | Placebo |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | Placebo inhaled daily via nebulizer for 3 weeks. Placebo (phosphate buffer saline with polysorbate). Placebo |
| Period Title: Overall Study | |||
| STARTED | 10 | 10 | 10 |
| COMPLETED | 10 | 10 | 10 |
| NOT COMPLETED | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Alpha-1 HC 100 mg | Alpha-1 HC 200 mg | Placebo | Total |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | Placebo inhaled daily via nebulizer for 3 weeks. Placebo (phosphate buffer saline with polysorbate). Placebo | Total of all reporting groups |
| Overall Participants | 10 | 10 | 10 | 30 |
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
28.2
(10.62)
|
28.1
(11.43)
|
29.3
(9.96)
|
28.5
(10.32)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
8
80%
|
6
60%
|
6
60%
|
20
66.7%
|
| Male |
2
20%
|
4
40%
|
4
40%
|
10
33.3%
|
| Region of Enrollment (participants) [Number] | ||||
| United States |
10
100%
|
10
100%
|
10
100%
|
30
100%
|
Outcome Measures
| Title | Adverse Events |
|---|---|
| Description | adverse event frequency |
| Time Frame | 3 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: included all subjects who received any dose of IP (included those withdrawn from treatment for any reason) |
| Arm/Group Title | Alpha-1 HC 100 mg | Alpha-1 HC 200 mg | Placebo |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | Placebo inhaled daily via nebulizer for 3 weeks. Placebo (phosphate buffer saline with polysorbate). Placebo |
| Measure Participants | 10 | 10 | 10 |
| Number [percentage of participants] |
100
1000%
|
80
800%
|
60
600%
|
| Title | Percent Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 3 |
|---|---|
| Description | FEV1 conducted before and after inhalation of the investigational product at study visits. |
| Time Frame | 3 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: included all subjects who received any dose of Investigational Product (included those withdrawn from treatment for any reason) |
| Arm/Group Title | Alpha-1 HC 100 mg | Alpha-1 HC 200 mg | Placebo |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | Placebo inhaled daily via nebulizer for 3 weeks. Placebo (phosphate buffer saline with polysorbate). Placebo |
| Measure Participants | 10 | 10 | 10 |
| Mean (Standard Deviation) [percent] |
1.5
(5.20)
|
-2.1
(12.28)
|
0.5
(5.91)
|
| Title | Percent Change From Baseline in Forced Vital Capacity (FVC) at Week 3 |
|---|---|
| Description | FVC conducted before and after inhalation of the investigational product |
| Time Frame | 3 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: included all subjects who received any dose of Investigational Product (included those withdrawn from treatment for any reason) |
| Arm/Group Title | Alpha-1 HC 100 mg | Alpha-1 HC 200 mg | Placebo |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | Placebo inhaled daily via nebulizer for 3 weeks. Placebo (phosphate buffer saline with polysorbate). Placebo |
| Measure Participants | 10 | 10 | 10 |
| Mean (Standard Deviation) [percent] |
1.2
(5.23)
|
-2.3
(11.57)
|
-0.9
(3.73)
|
Adverse Events
| Time Frame | 3 weeks | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Alpha-1 HC 100 mg | Alpha-1 HC 200 mg | Placebo | |||
| Arm/Group Description | 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. | 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. | Placebo inhaled daily via nebulizer for 3 weeks. Placebo (phosphate buffer saline with polysorbate). Placebo | |||
All Cause Mortality |
||||||
| Alpha-1 HC 100 mg | Alpha-1 HC 200 mg | Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Alpha-1 HC 100 mg | Alpha-1 HC 200 mg | Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/10 (10%) | 1/10 (10%) | 1/10 (10%) | |||
| Gastrointestinal disorders | ||||||
| ABDOMINAL PAIN | 0/10 (0%) | 0 | 1/10 (10%) | 1 | 0/10 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| PULMONARY EXACERBATION/ | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
Other (Not Including Serious) Adverse Events |
||||||
| Alpha-1 HC 100 mg | Alpha-1 HC 200 mg | Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 10/10 (100%) | 8/10 (80%) | 6/10 (60%) | |||
| Gastrointestinal disorders | ||||||
| MOUTH ULCERATION | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| VOMITING | 0/10 (0%) | 0 | 1/10 (10%) | 1 | 0/10 (0%) | 0 |
| ABDOMINAL PAIN UPPER | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| General disorders | ||||||
| CHEST DISCOMFORT | 0/10 (0%) | 0 | 2/10 (20%) | 2 | 1/10 (10%) | 1 |
| FATIGUE | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| CHEST PAIN | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| CHILLS | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| PAIN | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| PYREXIA | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 2/10 (20%) | 2 |
| Infections and infestations | ||||||
| ORAL HERPES | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| SINUSITIS | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| UPPER RESPIRATORY TRACT INFECTION | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| OTITIS EXTERNA | 0/10 (0%) | 0 | 1/10 (10%) | 1 | 0/10 (0%) | 0 |
| OTITIS MEDIA | 0/10 (0%) | 0 | 1/10 (10%) | 1 | 0/10 (0%) | 0 |
| Investigations | ||||||
| BLOOD CREATININE INCREASED | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| BLOOD PRESSURE INCREASED | 0/10 (0%) | 0 | 1/10 (10%) | 1 | 0/10 (0%) | 0 |
| BREATH SOUNDS ABNORMAL | 0/10 (0%) | 0 | 1/10 (10%) | 1 | 0/10 (0%) | 0 |
| C-REACTIVE PROTEIN INCREASED | 0/10 (0%) | 0 | 2/10 (20%) | 2 | 0/10 (0%) | 0 |
| FORCED EXPIRATORY VOLUME DECREASED | 0/10 (0%) | 0 | 1/10 (10%) | 1 | 0/10 (0%) | 0 |
| PHYSICAL EXAMINATION ABNORMAL | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| PULMONARY FUNCTION TEST DECREASED | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| SPUTUM ABNORMAL | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||
| DECREASED APPETITE | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| ARTHRALGIA | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| BACK PAIN | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| FLANK PAIN | 0/10 (0%) | 0 | 1/10 (10%) | 1 | 1/10 (10%) | 1 |
| Nervous system disorders | ||||||
| DIZZINESS | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| SINUS HEADACHE | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| Psychiatric disorders | ||||||
| DEPRESSION | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| Reproductive system and breast disorders | ||||||
| ENDOMETRIOSIS | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| BRONCHIAL SECRETION RETENTION | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| BRONCHOSPASM | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| COUGH | 3/10 (30%) | 3 | 1/10 (10%) | 1 | 1/10 (10%) | 1 |
| DRY THROAT | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| DYSPNOEA | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| HAEMOPTYSIS | 4/10 (40%) | 4 | 1/10 (10%) | 1 | 1/10 (10%) | 1 |
| OROPHARYNGEAL PAIN | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 2/10 (20%) | 2 |
| PHARYNGEAL ERYTHEMA | 0/10 (0%) | 0 | 1/10 (10%) | 1 | 0/10 (0%) | 0 |
| PHARYNGEAL OEDEMA | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| PULMONARY CONGESTION | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| PULMONARY EXACERBATION | 1/10 (10%) | 1 | 3/10 (30%) | 3 | 0/10 (0%) | 0 |
| RALES | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| RESPIRATORY TRACT IRRITATION | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| RHINITIS ALLERGIC | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| RHONCHI | 0/10 (0%) | 0 | 0/10 (0%) | 0 | 1/10 (10%) | 1 |
| SPUTUM INCREASED | 1/10 (10%) | 1 | 1/10 (10%) | 1 | 1/10 (10%) | 1 |
| THROAT IRRITATION | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| WHEEZING | 3/10 (30%) | 3 | 1/10 (10%) | 1 | 0/10 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||
| ALOPECIA | 0/10 (0%) | 0 | 1/10 (10%) | 1 | 0/10 (0%) | 0 |
| PHOTOSENSITIVITY REACTION | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 0/10 (0%) | 0 |
| RASH MACULAR | 0/10 (0%) | 0 | 1/10 (10%) | 1 | 0/10 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Site may publish results from the Study, after providing Sponsor thirty days' notice prior to submitting a manuscript or other materials related to the Study to any outside party. At Sponsors' request, Site will remove any Confidential Information (other than Study results), and Site will upon Sponsors' request, delay publication or presentation for a period of up to one hundred twenty days to allow Sponsor to protect its interests in any Sponsor Inventions.
Results Point of Contact
| Name/Title | Henry Li, PhD |
|---|---|
| Organization | Grifols Therapeutics Inc. |
| Phone | 919-316-6042 |
| henry.li@grifols.com |
- T6005-201