E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult Patients with Congenital Alpha-1 Antitrypsin Deficiency with Moderate and Severe Airflow Limitation (40% ≤ FEV1 ≤ 80% of predicted; FEV1/SVC ≤ 70%), and with no history of two or more moderate or one or more severe exacerbations of COPD during the past year. |
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E.1.1.1 | Medical condition in easily understood language |
Treatment and management of adult patients with congenital Alpha Antitrypsin Deficiency. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10010331 |
E.1.2 | Term | Congenital, familial and genetic disorders |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary Objective (Double Blind) To assess the efficacy of Kamada-AAT for Inhalation administered at a dose of 80 mg daily vs. placebo, with efficacy measured by FEV1 post bronchodilator change from baseline at 104 weeks
OLE Objectives 1. To assess the long-term safety of Kamada-AAT for Inhalation for up to 208 weeks of treatment. 2. To assess the long-term efficacy of Kamada-AAT for Inhalation, as measured by FEV1 post bronchodilator for up to 208 weeks of treatment. 3. To assess the long-term efficacy of Kamada-AAT for Inhalation, as measured by CT densitometry change for up to 208 weeks of treatment. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives To assess the efficacy of Kamada-AAT for Inhalation administered at a dose of 80 mg daily vs placebo as measured by computed tomography (CT) densitometry change from baseline at 104 weeks. Safety Objective 1. To assess the safety of Kamada-AAT for Inhalation administered at a dose of 80 mg daily vs placebo 2. To assess the immunogenicity of Kamada-AAT for Inhalation and characterize the effect of Anti-drug antibodies (ADA) on drug levels in plasma.
First (Safety) Cohort Objective To assess the safety of Kamada-AAT for Inhalation administered at a dose of 80 mg vs placebo once daily during the first 24 weeks of treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Double-Blind Period 1. 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. 2. Serum AAT levels ≤ 11 µM at screening. 3. Lung disease with clinical evidence of airflow limitation (post bronchodilator FEV1/SVC≤70%) at screening. 4. 40% ≤ FEV1 ≤ 80% of predicted post-bronchodilator at screening. 5. Patients who are either naïve or washed out of any AAT treatment (by IV) for at least 8 weeks prior to randomization. 6. Age between 18 to 65 years inclusive at screening. 7. Able to read and sign informed consent and willing to participate in the study. 8. 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. 9. Study medication use for at least 20 out of the 28 days of run-in, as recorded in the study nebulization PARI Track data. 10. Demonstrated ability to complete eDiary for at least 20 out of the first 28 days of run-in.
Open-Label Period 1. Patients who completed 104 weeks of DB study treatment and attended the end of treatment visit. 2. 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. 3. Consenting to continue study participation in the OLE phase. 4. Agree to continue using contraceptive methods deemed reliable by the investigator for an additional 2 years, unless post-menopausal or surgically sterilized.
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E.4 | Principal exclusion criteria |
Double-Blind Period 1. Immunoglobulin A (IgA) absolute deficiency defined as serum IgA levels<0.05 g/L at screening. 2. History of life-threatening transfusion reaction(s), allergy, anaphylactic reaction, or systemic response to human plasma-derived products. 3. Two or more moderate or any severe exacerbation(s) within the year prior to the baseline visit. 4. A moderate exacerbation within 6 weeks prior to the baseline. 5. Use of oral or parenteral glucocorticoids in doses above 10 mg of prednisone daily or equivalent generics (substance and dose). 6. 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. 7. Hospitalization for any cause 6 weeks prior to screening. 8. History of lung or liver transplant. 9. On any thoracic or hepatic surgery waiting list. 10. Any lung surgery within the past two years (including bronchoscopic lung volume reduction). 11. Any smoking within the year prior to screening. 12. 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. 13. Acute or chronic hepatitis (hepatitis A, hepatitis B, hepatitis C,) or positive human immunodeficiency virus (HIV) serology. 14. 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. 15. Signs of significant abnormalities in ECG per investigator judgment at screening. 16. 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. 17. Previous exposure to inhaled AAT. 18. 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. 19. Inability to attend scheduled clinic visits and/or comply with study protocol. 20. 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 1. 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. 2. 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. 3. Any smoking within the DB study or since the DB study. 4. Pregnancy or lactation. 5. Participation in another clinical trial since termination of participation in the DB period. 6. Inability to attend scheduled clinic visits and/or comply with study protocol. 7. 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
DB period FEV1 (L) post bronchodilator change from baseline at 104 weeks.
OLE period 1. FEV1 (L) post bronchodilator change from DB baseline at OLE 104 weeks (total 208 weeks), and from OLE baseline at OLE 104 weeks (total 104 weeks of open label treatment), stratified by treatment during the DB part. 2. Change from DB at OLE 104 weeks (total 208 weeks of treatment), and from OLE baseline at OLE 104 weeks (total 104 weeks), in CT densitometry whole-lung 15th percentile lung density (PD15) at total lung capacity (TLC), stratified by treatment during the DB part. 3. Change from OLE baseline over 104 weeks of open-label treatment in Post bronchodilator FEV1 % of predicted, FEV1/FVC %, as well as in post bronchodilator volumes (body plethysmography) and diffusion (DLCO), stratified by treatment during the DB part. 4. BODE index score and 6MWT and MMRC dyspnea score from OLE baseline over 104 weeks of open-label treatment stratified by treatment during the DB part. 5. Quality of life score as measured by the COPD assessment tool (CAT) and EQ-5D-5L from OLE baseline over 104 weeks of open-label treatment, stratified by treatment during the DB part. 6. Desmosine level in plasma from OLE baseline over 104 weeks of open label treatment, stratified by treatment during the DB part. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
DB Period 1. Change from baseline over 104 weeks of treatment in CT densitometry whole-lung 15th percentile lung density (PD15) at total lung capacity (TLC). 2. Change from baseline over 104 weeks of treatment in Post bronchodilator spirometry measures a. FEV1 % of predicted b. FEV1/FVC % 3. Exacerbations; annual rate by severity and duration. 4. Change from Baseline over 104 weeks of treatment in 6 minute walk test (6MWT). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Prospective study, Followed by a 2-Year Open-Label Extension |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
New Zealand |
Australia |
United Kingdom |
Belgium |
Finland |
Ireland |
Netherlands |
Sweden |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 11 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 11 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |