Evaluate Efficacy and Safety of Kamada-AAT for Inhalation in Patients With AATD

Study Overview
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Brief Summary
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The current study population will consist of adult patients with congenital alpha-1 antitrypsin (AAT) deficiency who have moderate or severe airflow limitation (forced expiratory volume in 1 second 40% ≤ [FEV1] ≤ 80% of predicted) and FEV1/slow vital capacity [SVC] ≤ 70% and who have not experienced two or more moderate or one or more severe exacerbations of COPD during the past year. A total of 220 patients will be recruited, and after 4 weeks practice inhaling saline with the nebulizer, will be randomized 1:1 to inhale either 80 mg/day Kamada-AAT for Inhalation or a placebo with identical appearance. Patients will be treated for 104 weeks and then followed up for a further 26 weeks. Over this time there will be 13 visits to the clinical site and in addition the patients will be required to fill out a daily e-diary.

Detailed Description
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Individuals with a genetic deficiency of alpha-1-antitrypsin (AATD) are at a significantly increased risk (80-100%) of developing emphysema. This study is designed to administer a solution of AAT by nebulizer so that patients can inhale the drug instead of requiring infusions as in current treatment. A significant advantage of inhalation is that the AAT is directly transferred to the lungs, which is the site most in need of the protein. Previous results show that in addition to the added convenience, three times higher concentrations of AAT can be achieved in the lungs by inhalation than by intravenous infusions. To date, more than 220 patients have completed Inhalation studies for several indications.

Official Title
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A Prospective Phase III Multi-center, Placebo Controlled, Double Blind Study to Evaluate the Efficacy and Safety of Kamada-AAT for Inhalation 80 mg Per Day in Adult Patients With Congenital Alpha-1 Antitrypsin Deficiency With Moderate and Severe Airflow Limitation (40% ≤ FEV1 ≤ 80% of Predicted; FEV1/SVC ≤ 70%)

Conditions
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Alpha 1-Antitrypsin Deficiency

Intervention / Treatment
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* Drug: Alpha 1-Antitrypsin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Diagnosis of severe AAT deficiency, i.e. patients with either Pi(ZZ), Pi(Z/Null), or Pi(Null/Null) genotypes confirmed by genotype blood test documented prior to screening. Serum AAT levels ≤ 11 µM at screening. Lung disease with clinical evidence of airflow limitation (post bronchodilator FEV1/SVC ≤ 70%) at screening. 40% ≤ FEV1 ≤ 80% of predicted post-bronchodilator at screening. Patients who are either naïve or washed out of any AAT treatment for at least 8 weeks prior to randomization. Age between 18 to 65 years inclusive at screening. Able to read and sign informed consent and willing to participate in the study. Males or non-pregnant, non-lactating females whose screening pregnancy test is negative, who are using contraceptive methods deemed reliable by the investigator, who are post-menopausal, or are surgically sterilized. High compliance during run in defined as study medication use and e-Diary compliance for at least 20 out of the 28 days of run in. Exclusion Criteria Immunoglobulin A (IgA) absolute deficiency defined as serum IgA levels < 0.05 g/L at screening. History of life-threatening transfusion reaction(s), allergy, anaphylactic reaction, or systemic response to human plasma-derived products. Two or more moderate or any severe exacerbation(s) within the year prior to the baseline visit. A moderate exacerbation within 6 weeks prior to the baseline. Use of oral or parenteral glucocorticoids in doses above 10 mg of prednisone daily or equivalent generics (substance and dose). Clinically significant inter-current illnesses (except for respiratory or liver disease secondary to AAT deficiency), including: cardiac, hepatic, renal, endocrine, neurological, hematological, neoplastic, immunological, skeletal, or other. Patients might be included after consultation with the treating physician and the sponsor if, in the opinion of the Investigator, their condition will not interfere with the safety, compliance or other aspects of this study. Hospitalization for any cause 6 weeks prior to screening. History of lung or liver transplant. On any thoracic or hepatic surgery waiting list. Any lung surgery within the past two years (including bronchoscopic lung volume reduction). Any smoking within the year prior to screening. Evidence of alcohol abuse or history of alcohol abuse, or use of illegal drugs and/or abuse of legally prescribed drugs in the last 5 years prior to screening. Acute or chronic hepatitis (hepatitis A, hepatitis B, hepatitis C), or positive human immunodeficiency virus (HIV) serology. Signs of significant abnormalities in serum hematology, serum chemistry, serum inflammatory / immunogenic markers and urinalysis per investigator judgment, taking into considerations the potential effects of the AAT deficiency. Signs of significant abnormalities in ECG per investigator judgment at screening. Presence of psychiatric/ mental disorder or any other medical disorder that might impair the patient's ability to give informed consent or to comply with the requirements of the study protocol. If, in the opinion of the Investigator, the condition will not interfere with the compliance or other aspects of this study, the patient might be included after consultation with the treating physician and the sponsor. Participation in another clinical trial involving investigational medication or interventional treatment within 30 days and/or last dose 5 half-lives prior to screening visit. Inability to attend scheduled clinic visits and/or comply with study protocol. Any other factor that, in the opinion of the investigator, would prevent the patient from 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Inhaled AAT<br>Daily inhalation of 80 mg/day Kamada-AAT for Inhalation for 104 weeks | Drug: Alpha 1-Antitrypsin<br>* Kamada's alpha 1-antitrypsin product given by inhalation using the eFlow® electronic nebulizer manufactured by PARI Pharma GmbH<br>* Other names: Kamada alpha 1-antitrypsin for inhalation;|
| Placebo Comparator: Placebo<br>Daily inhalation of a solution of NaCl in phosphate buffer solution with 0.01% TWEEN-80 | Drug: Placebo<br>* Preparation of NaCl in phosphate buffer solution with 0.01% TWEEN-80<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 post bronchodilator | Change from baseline in post bronchodilator FEV1 at 104 weeks | 104 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CT densitometry whole-lung 15th percentile lung density (PD15) at total lung capacity (TLC). | Change from baseline over 104 weeks of treatment in CT densitometry whole-lung 15th percentile lung density (PD15) at total lung capacity (TLC). | 104 weeks | 
| FEV1 % of predicted | Change from baseline over 104 weeks of treatment in FEV1 % of predicted | 104 weeks | 
| FEV1/FVC % | Change from baseline over 104 weeks of treatment in FEV1/FVC % | 104 weeks | 
| Exacerbations | Annual rate of exacerbations by severity and duration | 104 weeks | 
| 6 minute walk test | Change from Baseline in the distance walked in six minutes | 104 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inhaled Alpha 1-Antitrypsin Nebulizer