Phase II, Safety and Efficacy Study of Kamada-alpha-1-antitrypsin (AAT) for Inhalation

Study Overview
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Brief Summary
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To evaluate different doses of Kamada-AAT for Inhalation on the levels of alpha 1-proteinase inhibitor and other analytes in epithelial lining fluid (ELF) and serum and to assess the safety of the treatment in subjects with AAT Deficiency.

Official Title
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Phase II, Double-Blind, Placebo-Controlled Study to Explore the ELF and Plasma Concentration as Well as Safety of Inhaled Alpha-1 Antitrypsin in Alpha-1 Antitrypsin Deficiency Subjects

Conditions
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Alpha-1 Antitrypsin Deficiency

Intervention / Treatment
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* Drug: Kamada-AAT for Inhalation, 80mg
* Drug: Placebo
* Drug: Kamada-AAT for Inhalation, 160mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients between 18 and 65 years of age (inclusive). Able and willing to sign informed consent. Males, and non-pregnant, non-lactating females whose screening pregnancy test is negative and who are using contraceptive methods deemed reliable by the investigator or who are post-menopausal or surgically sterilized. Diagnosis of alpha1-antitrypsin deficiency [only individuals with a ZZ or Z null classification]. Forced expiratory volume in one second (FEV1) ≥ 50% of predicted post bronchodilator No respiratory exacerbations within 6 weeks of baseline. Subjects can be re-screened if exacerbations exist at the time of enrollment. No signs of chronic and/or acute Hepatitis A, Hepatitis B, Hepatitis C, HIV infection and Parvovirus B19, by NAT (for Parvovirus B19, nucleic acid testing (NAT) result must be < 10^4 IU/mL). No significant abnormalities in serum hematology, serum chemistry, serum inflammatory / immunogenic markers and urinalysis. No significant abnormalities in ECG. Not on intravenous augmentation therapy for at least 8 weeks prior to initial dosing with study drug/placebo and willing to forego intravenous augmentation therapy for the duration of the study. Exclusion Criteria: Clinically significant intercurrent illnesses (except for respiratory or liver disease secondary to AAT deficiency), including: cardiac, hepatic, renal, endocrine, neurological, hematological, neoplastic, immunological, skeletal or other) that in the opinion of the investigator, could interfere with the safety, compliance or other aspects of this study. Patients with well-controlled, chronic diseases could possibly be included after consultation with the treating physician and the sponsor. History of life threatening allergy, anaphylactic reaction, or systemic response to human plasma derived products. History of life threatening transfusion reactions. History of lung transplant. Current or previous (up to 8 weeks from baseline) use of AAT augmentation therapy or by any other route Current use of oral or parenteral glucocorticoids in doses exceeding 10mg of prednisone daily or equivalent generics (substance and dose). Any lung surgery within the past two years. On any thoracic surgery waiting list. Active smoking during the last 12 months from screening date. Pregnancy or lactation. Woman of child-bearing potential not taking adequate contraception deemed reliable by the investigator. Presence of psychiatric/ mental disorder or any other medical disorder which might impair the patient's ability to give informed consent or to comply with the requirements of the study protocol. Evidence of alcohol abuse or history of alcohol abuse or illegal and/or legally prescribed drugs. Immunoglobulin A (IgA) Deficiency. Inability to undergo bronchoscopy. Allergy to lidocaine or any other medicines used in the bronchoscopy process Exacerbation of chronic obstructive pulmonary disease (COPD) in the previous 6 weeks. Participation in another clinical trial involving investigational medication or interventional treatment within 30 days prior to baseline visit. Participation in observational clinical trial which involves any invasive procedure scheduled to occur during the AAT inhaled study period. If participating in an observational clinical trial that already completed all diagnostic procedures (e.g. liver biopsy), any adverse events (AEs) experienced must have returned to baseline within 30 days prior to baseline visit. Inability to attend scheduled clinic visits and/or comply with the study protocol. Any other factor that, in the opinion of the investigator, would prevent the patient form complying with the requirements of the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Kamada-AAT for Inhalation, 80mg<br>Daily inhalation of Kamada-AAT for Inhalation, 80mg | Drug: Kamada-AAT for Inhalation, 80mg<br> <br> |
| Placebo Comparator: Placebo<br>Placebo administered by inhalation daily | Drug: Placebo<br> <br> |
| Experimental: Kamada-AAT for Inhalation, 160mg<br>Daily inhalation of Kamada-AAT for Inhalation, 160mg | Drug: Kamada-AAT for Inhalation, 160mg<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Concentration of Antigenic Alpha-1 Antitrypsin (AAT) in the Lung Epithelial Lining Fluid (ELF) | Patients underwent bronchoalveolar lavage (BAL) prior to initiation of drug and then again after 3 months. Concentration of AAT in the BAL was measured by an enzyme linked immunosorbent assay (ELISA) specific for the normal form of AAT (piM). Urea was also measured in order to determine the dilution factor of the BAL fluid and calculate the concentration of AAT in the ELF. | 12 weeks from initiation of study drug | 
| Change From Baseline to 12 Weeks in the Concentration of Functional AAT (Alpha-1 Antitrypsin) in ELF | ITT population with baseline and 12 week values. Patients underwent bronchoalveolar lavage (BAL) prior to initiation of drug and then again after 3 months. Concentration of AAT in the BAL was measured by an antineutrophil elastase capacity (ANEC) assay. Urea was also measured in order to determine the dilution factor of the BAL fluid and calculate the concentration of AAT in the ELF. | 12 weeks from initiation of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Levels of M Specific AAT in Plasma (PiM) | Intention to treat (ITT) population with baseline and 12 week values.The median change from baseline to Week 12 in the levels of M-specific AAT (piM) in plasma was measured using a specific ELISA assay for M-specific AAT (piM) | 12 weeks from initiation of study drug | 
| Change From Baseline in AAT-neutrophil Elastase (NE) Complexes in ELF | Patients underwent a BAL procedure at baseline and 12 weeks and the fluid was analyzed to calculate the change from baseline in the concentration of complexes between AAT and neutrophil elastase in the ELF | 12 weeks from initiation of study drug |