Efficacy and Safety of Human Alpha1-Proteinase Inhibitor Inhalation in Adults with Congenital Alpha-1 Antitrypsin Deficiency and Moderate to Severe Airflow Limitation
- Trial ID
- 2024-516054-21-00
- Protocol
- KamadaAATInhaled008
- Sponsor
- Kamada Ltd.
Trial statistics
Objectives
The primary objective of this study is to evaluate the **efficacy** of Kamada-AAT for Inhalation, administered at a dose of 80 mg daily, compared to placebo. The efficacy is measured by the change in forced expiratory volume in one second (**FEV1**) post-bronchodilator from baseline at 104 weeks. This is clinically relevant as it assesses the potential of Kamada-AAT to improve lung function in adult patients with congenital Alpha-1 Antitrypsin Deficiency, a condition characterized by moderate and severe airflow limitation.
Secondary objectives include:
- Assessing the efficacy of Kamada-AAT for Inhalation by measuring computed tomography (**CT**) densitometry change from baseline at 104 weeks.
- Evaluating the safety of Kamada-AAT for Inhalation at the same dosage compared to placebo.
- Assessing the immunogenicity of Kamada-AAT for Inhalation and characterizing the effect of anti-drug antibodies (**ADA**) on drug levels in plasma.
Participants
The clinical trial involved a total of **112 participants** diagnosed with **Congenital Alpha-1 Antitrypsin Deficiency** exhibiting moderate to severe airflow limitation, characterized by a post-bronchodilator FEV1 between 40% and 80% of the predicted value and an FEV1/SVC ratio of 70% or less. The study population comprised both male and female adults aged 18 to 65 years, with no significant history of two or more moderate or one or more severe exacerbations of COPD in the past year. Participants were selected based on their ability to complete an eDiary and their willingness to adhere to contraceptive methods if applicable. The trial included individuals who were either naïve to or had been washed out of any AAT treatment for at least eight weeks prior to randomization. The selection criteria ensured that participants had serum AAT levels of 11 μM or less at screening and demonstrated clinical evidence of airflow limitation. The study population was characterized by a diverse range of lifestyle factors, although specific details regarding diet, physical activity, or habits were not provided by the sponsor.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the efficacy and safety of **Kamada-AAT for Inhalation** in adult patients with **congenital alpha-1 antitrypsin deficiency** and moderate to severe airflow limitation. The trial is structured into two main phases: a 2-year double-blind period followed by a 2-year open-label extension. The primary objective is to assess the efficacy of the treatment by measuring the change in FEV1 post-bronchodilator from baseline at 104 weeks. Secondary endpoints include changes in CT densitometry, spirometry measures, exacerbation rates, and the 6-minute walk test over the same period.
Participants will be involved in the study for a total of four years, with the initial double-blind phase lasting two years. The trial begins with a screening visit to confirm eligibility based on specific inclusion criteria, such as genotype and lung function parameters. Participants must demonstrate the ability to complete an eDiary and adhere to study medication use during a run-in period. Following successful screening, participants are randomized to receive either the active treatment or placebo, administered via the **eFlow® Nebuliser System**.
Study visits are scheduled at regular intervals throughout the trial to monitor safety, efficacy, and adherence. These include baseline assessments, periodic follow-up visits, and an end-of-study visit at the conclusion of the double-blind phase. Participants who complete the double-blind phase and meet the criteria are eligible to continue into the open-label extension, where all receive the active treatment. Conditions for early termination from the study include non-compliance with study procedures, adverse events, or withdrawal of consent.
Treatment
The clinical trial involves the administration of **Kamada-AAT for Inhalation**, an experimental medication formulated as an **inhalation solution**. The active substance in this medication is the **human alpha1-proteinase inhibitor**, which is derived from protein sources. The medication is administered via **inhalation use** using the eFlow® Nebuliser System, a device that has received CE marking. The prescribed dosage for the trial is 80 mg per day, with a maximum treatment period of 238 days. The trial aims to evaluate the efficacy and safety of this treatment in adult patients with congenital alpha-1 antitrypsin deficiency, characterized by moderate to severe airflow limitation.
In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind study. The placebo is designed to mimic the **Kamada-AAT for Inhalation** in appearance and administration method but does not contain the active substance. The placebo is administered under the same conditions as the experimental medication to ensure the integrity of the study's blinding process. The use of a placebo allows for a controlled comparison to assess the true efficacy of the **Kamada-AAT for Inhalation**.
Efficacy
The efficacy of "Kamada-AAT for Inhalation" in treating adult patients with **Congenital Alpha-1 Antitrypsin Deficiency** will be assessed in a Phase III, multi-center, placebo-controlled, double-blind clinical trial. The primary endpoint for evaluating efficacy is the change in Forced Expiratory Volume in one second (FEV1) post-bronchodilator from baseline at 104 weeks. Secondary endpoints include changes from baseline over 104 weeks in CT densitometry whole-lung 15th percentile lung density (PD15) at total lung capacity (TLC), post-bronchodilator spirometry measures such as FEV1 % of predicted and FEV1/FVC %, the annual rate of exacerbations by severity and duration, and changes in the 6-minute walk test (6MWT).
Efficacy parameters will be measured and collected at specified intervals throughout the study duration, with the primary endpoint assessed at the 104-week mark. The study will utilize validated spirometry tests to measure FEV1 and other lung function parameters. The eFlow® Nebuliser System will be employed for the administration of the inhalation solution. Data collection will be conducted in a manner consistent with clinical trial standards, ensuring the reliability and validity of the results. The trial is designed to provide comprehensive data on the efficacy of the treatment over a two-year period, followed by an open-label extension phase for further evaluation.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Double-Blind Period: Diagnosis of severe AAT deficiency, i.e. patients with either Pi(ZZ), Pi(Z/Null), or Pi(Null/Null) genotypes.
- Double-Blind Period: Serum AAT levels ≤ 11 μM at screening.
- Double-Blind Period: Lung disease with clinical evidence of airflow limitation (post bronchodilator FEV1/SVC≤70%) at screening.
- Double-Blind Period: 40% ≤ FEV1 ≤ 80% of predicted post-bronchodilator at screening.
- Double-Blind Period: Patients who are either naïve or washed out of any AAT treatment for at least 8 weeks prior to randomization.
- Double-Blind Period: Age between 18 to 65 years inclusive at screening.
- Double-Blind Period: Able to read and sign informed consent and willing to participate in the study.
- Double-Blind Period: 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.
- Double-Blind Period: Study medication use for at least 20 out of the 28 days of run-in, as recorded in the study nebulization PARI Track data.
- Double-Blind Period: Demonstrated ability to complete eDiary for at least 20 out of the first 28 days of run-in.
- Open-Label Period: Patients who completed 104 weeks of DB study treatment and attended the end of treatment visit.
- Open-Label Period: Patients who completed the DB period and attended follow-up visits are eligible for the OLE provided that they comply with all other OLE eligibility criteria.
- Open-Label Period: Consenting to continue study participation in the OLE phase.
- Open-Label Period: Agree to continue using contraceptive methods deemed reliable by the investigator for an additional 2 years, unless post‐menopausal or surgically sterilized.
Exclusion Criteria
- Double-Blind Period: Immunoglobulin A (IgA) absolute deficiency defined as serum IgA levels<0.05 g/L at screening.
- Double-Blind Period: History of life-threatening transfusion reaction(s), allergy, anaphylactic reaction, or systemic response to human plasma-derived products.
- Double-Blind Period: Two or more moderate or any severe exacerbation(s) within the year prior to the baseline visit.
- Double-Blind Period: A moderate exacerbation within 6 weeks prior to the baseline.
- Double-Blind Period: Use of oral or parenteral glucocorticoids in doses above 10 mg of prednisone daily or equivalent generics (substance and dose).
- Double-Blind Period: 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.
- Double-Blind Period: Hospitalization for any cause 6 weeks prior to screening.
- Double-Blind Period: History of lung or liver transplant.
- Double-Blind Period: On any thoracic or hepatic surgery waiting list.
- Double-Blind Period: Any lung surgery within the past two years (including bronchoscopic lung volume reduction).
- Double-Blind Period: Any smoking within the year prior to screening.
- Double-Blind Period: 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.
- Double-Blind Period: Acute or chronic hepatitis (hepatitis A, hepatitis B, hepatitis C,) or positive human immunodeficiency virus (HIV) serology.
- Double-Blind Period: 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.
- Double-Blind Period: Signs of significant abnormalities in ECG per investigator judgment at screening.
- Double-Blind Period: 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.
- Double-Blind Period: 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.
- Double-Blind Period: Inability to attend scheduled clinic visits and/or comply with study protocol.
- Double-Blind Period: Any other factor that, in the opinion of the investigator, would prevent the patient from complying with the requirements of the protocol.
- Open-Label Period: Any adverse event(s) in the DB period and/or medical condition that, in the opinion of the investigator, might prevent the patient from safely participating in the OLE period of the study, including but not limited to: a. Occurrence of a life-threatening allergy, anaphylactic reaction, or systemic response to human plasma derived products. b. Received lung transplant, entered a waiting list for lung transplantation, or underwent lung surgery. The investigator should consult the sponsor before inclusion of any patient with a significant condition if the investigator believes that it will not pose an unacceptable risk for the patient.
- Open-Label Period: Evidence of alcohol abuse or history of alcohol abuse or illegal and/or legally prescribed drugs, within the DB study or since the DB study.
- Open-Label Period: Any smoking within the DB study or since the DB study.
- Open-Label Period: Pregnancy or lactation.
- Open-Label Period: Participation in another clinical trial since termination of participation in the DB period.
- Open-Label Period: Inability to attend scheduled clinic visits and/or comply with study protocol.
- Open-Label Period: Any other factor that, in the opinion of the investigator, would prevent the patient from complying with the requirements of the protocol or would jeopardize the safety of the patient.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 28 Oct 2019 | 13 |
 Finland | Not Recruiting | 28 Oct 2019 | 10 |
 Ireland | Not Recruiting | 28 Oct 2019 | 10 |
 The Netherlands | Not Recruiting | 28 Oct 2019 | — |
 Sweden | Not Recruiting | 28 Oct 2019 | 25 |
| Netherlands | — | — | 50 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Kamada-AAT for Inhalation | Test | INHALATION SOLUTION | INHALATION USE | 80 | 238 | PRD11482029 |
Placebo for “Kamada-AAT for Inhalation” | Placebo | N/A | — | — | — | N/A |