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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group 1 | Experimental | Bronchial Deposition Intervention: Alpha1-Proteinase Inhibitor (Human) Dosage: 25 mg in lungs, one inhalation per day over 4 weeks |
|
| Group 2 | Experimental | Peripheral Deposition Intervention: Alpha1-Proteinase Inhibitor (Human) Dosage: 25 mg in lungs, one inhalation per day over 4 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Alpha1-Proteinase Inhibitor (Human) | Drug | 25 mg of Alpha1-Proteinase Inhibitor (Human) in the lungs, one inhalation per day over 4 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Free Elastase in Induced Sputum From Baseline to Week 4 | Baseline vs Week 4 |
| Measure | Description | 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Matthias Griese, MD | Kinderklinik und Kinderpoliklinik im Haunerschen Kinderspital | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17050563 | Result | Griese M, Latzin P, Kappler M, Weckerle K, Heinzlmaier T, Bernhardt T, Hartl D. alpha1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur Respir J. 2007 Feb;29(2):240-50. doi: 10.1183/09031936.00047306. Epub 2006 Oct 18. |
| Label | URL |
|---|---|
| FDA Approved Product Labeling Information | View source |
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Subjects inhaled saline once daily for 2 weeks during the Run-in Period.
This study was performed in 8 study centers in Germany.
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| ID | Title | Description |
|---|---|---|
| FG000 | Peripheral Deposition | Peripheral Deposition is achieved with a breathing maneuver consisting of slow and deep breaths |
| FG001 | Bronchial Deposition | Bronchial Deposition consists of inhalation of smaller volumes per breath at higher flow rates |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Peripheral Deposition | Peripheral Deposition is achieved with a breathing maneuver consisting of slow and deep breaths |
| BG001 | Bronchial Deposition | Bronchial Deposition consists of inhalation of smaller volumes per breath at higher flow rates |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Free Elastase in Induced Sputum From Baseline to Week 4 | 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). | Posted | Sep 2009 | Mean | Standard Deviation | ug/mL | Baseline vs Week 4 |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Peripheral Deposition | Peripheral Deposition is achieved with a breathing maneuver consisting of slow and deep breaths |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal Pain | Gastrointestinal disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Henry Li | Grifols Therapeutics | 1-800-520-2807 | henry.li@grifols.com |
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| ID | Term |
|---|---|
| D003550 | Cystic Fibrosis |
| ID | Term |
|---|---|
| D010182 | Pancreatic Diseases |
| D004066 | Digestive System Diseases |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D000515 | alpha 1-Antitrypsin |
| ID | Term |
|---|---|
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D015843 | Serpins |
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|
| 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 |
| Protocol Violation |
|
| No sputum, devise issues, exacerbation |
|
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Free Elastase during the Run-In Phase | Mean | Standard Deviation | µg/mL |
|
|
|
|
| Secondary | Change in Alpha-1-anti-trypsin (A1AT) Activity in Induced Sputum From Baseline at Week 4 | 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. | Posted | Mean | Standard Deviation | ug/mL | Baseline vs Week 4 |
|
|
|
| Secondary | Change in Total Immunoglobulin G (IgG) Fragments in Induced Sputum From Baseline at Week 4 | 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. | Posted | Mean | Standard Deviation | ug/mL | Baseline vs Week 4 |
|
|
|
| Secondary | Change in Total Bacterial Load in Induced Sputum From Baseline to Week 4 | 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. | Posted | Mean | Standard Deviation | CFU/g | Week 4 |
|
|
|
| Secondary | Change in Pseudomonas Load in Induced Sputum From Baseline at Week 4 | 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. | Posted | Mean | Standard Deviation | CFU/g | Baseline vs Week 4 |
|
|
|
| Secondary | Change in Neutrophil Number in Induced Sputum From Baseline at Week 4 | 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. | Posted | Mean | Standard Deviation | percentage of change | Baseline vs Week 4 |
|
|
|
| 0 |
| 37 |
| 10 |
| 37 |
| EG001 | Bronchial Deposition | Bronchial Deposition consists of inhalation of smaller volumes per breath at higher flow rates | 0 | 35 | 13 | 35 |
| Conjunctivitis Allergic | Eye disorders |
|
| Abdominal Pain | Gastrointestinal disorders |
|
| Diarrhoea | Gastrointestinal disorders |
|
| Gingivitis | Gastrointestinal disorders |
|
| Toothache | Gastrointestinal disorders |
|
| Fatigue | General disorders |
|
| Influenza like illness | General disorders |
|
| Pyrexia | General disorders |
|
| Nasopharyngitis | Infections and infestations |
|
| Sinusitis | Infections and infestations |
|
| Urinary Tract Infection | Infections and infestations |
|
| Back pain | Musculoskeletal and connective tissue disorders |
|
| Sleep disorder | Psychiatric disorders |
|
| Cough | Respiratory, thoracic and mediastinal disorders |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders |
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| Haemoptysis | Respiratory, thoracic and mediastinal disorders |
|
| Pruritis | Skin and subcutaneous tissue disorders |
|
| Vasculitis | Vascular disorders |
|
The investigator must send a draft manuscript of the publication or abstract to the sponsor thirty days in advance of submission in order to obtain approval prior to submission of the final version for publication. This will be reviewed promptly and approval will not be withheld unreasonably. In case of a difference of opinion between the sponsor and the Investigator(s), the contents of the publication will be discussed in order to find a solution which satisfies both parties.
| D030342 |
| Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D007232 | Infant, Newborn, Diseases |
| D010455 |
| Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000209 | Acute-Phase Proteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000510 | Alpha-Globulins |
| D012712 | Serum Globulins |
| D005916 | Globulins |