A Prospective Phase III Multi-center, 2-Year 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%), Followed by a 2-Year Open-Label Extension

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Kamada Ltd.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

25 Oct 2019 → 28 Feb 2026

Decision date (initial)

2024-09-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Kamada Ltd.

External identifiers

EU CT number

2024-516054-21-00

EudraCT number

2019-000602-30

ClinicalTrials.gov

NCT04204252

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Safety

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.

Secondary objectives 3

1. 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.
2. Safety Objective: To assess the safety of Kamada-AAT for Inhalation administered at a dose of 80 mg daily vs placebo.
3. Safety Objectives: To assess the immunogenicity of Kamada-AAT for Inhalation and characterize the effect of anti-drug antibodies (ADA) on drug levels in plasma.

Conditions and MedDRA coding

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.

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Double-Blind Period: Diagnosis of severe AAT deficiency, i.e. patients with either Pi(ZZ), Pi(Z/Null), or Pi(Null/Null) genotypes.
2. Double-Blind Period: Serum AAT levels ≤ 11 μM at screening.
3. Double-Blind Period: Lung disease with clinical evidence of airflow limitation (post bronchodilator FEV1/SVC≤70%) at screening.
4. Double-Blind Period: 40% ≤ FEV1 ≤ 80% of predicted post-bronchodilator at screening.
5. Double-Blind Period: Patients who are either naïve or washed out of any AAT treatment for at least 8 weeks prior to randomization.
6. Double-Blind Period: Age between 18 to 65 years inclusive at screening.
7. Double-Blind Period: Able to read and sign informed consent and willing to participate in the study.
8. 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.
9. 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.
10. Double-Blind Period: Demonstrated ability to complete eDiary for at least 20 out of the first 28 days of run-in.
11. Open-Label Period: Patients who completed 104 weeks of DB study treatment and attended the end of treatment visit.
12. 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.
13. Open-Label Period: Consenting to continue study participation in the OLE phase.
14. 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 26

1. Double-Blind Period: Immunoglobulin A (IgA) absolute deficiency defined as serum IgA levels<0.05 g/L at screening.
2. Double-Blind Period: History of life-threatening transfusion reaction(s), allergy, anaphylactic reaction, or systemic response to human plasma-derived products.
3. Double-Blind Period: Two or more moderate or any severe exacerbation(s) within the year prior to the baseline visit.
4. Double-Blind Period: A moderate exacerbation within 6 weeks prior to the baseline.
5. Double-Blind Period: Use of oral or parenteral glucocorticoids in doses above 10 mg of prednisone daily or equivalent generics (substance and dose).
6. 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.
7. Double-Blind Period: Hospitalization for any cause 6 weeks prior to screening.
8. Double-Blind Period: History of lung or liver transplant.
9. Double-Blind Period: On any thoracic or hepatic surgery waiting list.
10. Double-Blind Period: Any lung surgery within the past two years (including bronchoscopic lung volume reduction).
11. Double-Blind Period: Any smoking within the year prior to screening.
12. 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.
13. Double-Blind Period: Acute or chronic hepatitis (hepatitis A, hepatitis B, hepatitis C,) or positive human immunodeficiency virus (HIV) serology.
14. 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.
15. Double-Blind Period: Signs of significant abnormalities in ECG per investigator judgment at screening.
16. 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.
17. 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.
18. Double-Blind Period: Inability to attend scheduled clinic visits and/or comply with study protocol.
19. 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.
20. 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.
21. 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.
22. Open-Label Period: Any smoking within the DB study or since the DB study.
23. Open-Label Period: Pregnancy or lactation.
24. Open-Label Period: Participation in another clinical trial since termination of participation in the DB period.
25. Open-Label Period: Inability to attend scheduled clinic visits and/or comply with study protocol.
26. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. FEV1 (L) post bronchodilator change from baseline at 104 weeks.

Secondary endpoints 4

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 over 104 weeks of treatment; annual rate by severity and duration.
4. Change from Baseline over 104 weeks of treatment in 6 minute walk test (6MWT).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Kamada Ltd.

Sponsor organisation

Kamada Ltd.

Address

2 Holzman Haim Street

City

Rehovot

Postcode

7670402

Country

Israel

Scientific contact point

Organisation

Kamada Ltd.

Contact name

Orit Pinchuk

Public contact point

Organisation

Kamada Ltd.

Contact name

Orit Pinchuk

Third parties 10

Locations

5 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 28 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications