Brief Title
Evaluate Efficacy and Safety of "Kamada-AAT for Inhalation" in Patients With AATD
Official Title
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
Brief Summary
Alpha-antitrypsin (AAT) is a member of the serpin family of proteinase inhibitors and is to a
large extent responsible for restricting proteinases, notably neutrophil elastase, and
proteinase 3, which might otherwise attack the lung tissue. 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.
The current study population will consist of adult patients with congenital alpha-1
antitrypsin (AAT) deficiency who have moderate airflow limitation (forced expiratory volume
in 1 second 50% ≤ [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 study site for evaluation of lung function by blood tests and CT densitometry. In
addition the patients will be required to fill out a daily e-diary with details of the
inhalations and will also report their daily symptoms.
Study Phase
Phase 3
Study Type
Interventional
Primary Outcome
FEV1 post bronchodilator
Secondary Outcome
CT densitometry whole-lung 15th percentile lung density (PD15) at total lung capacity (TLC).
Condition
Alpha 1-Antitrypsin Deficiency
Intervention
Alpha 1-Antitrypsin
Study Arms / Comparison Groups
Inhaled AAT
Description: Daily inhalation of 80 mg/day "Kamada-AAT for Inhalation" for 104 weeks
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
220
Start Date
November 25, 2019
Completion Date
May 2023
Primary Completion Date
November 2022
Eligibility Criteria
Inclusion Criteria:
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. 50% ≤ 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. 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:
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), and/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.
Gender
All
Ages
18 Years - 65 Years
Accepts Healthy Volunteers
No
Contacts
Jan Stolk, Prof, ,
Location Countries
Netherlands
Location Countries
Netherlands
Administrative Informations
NCT ID
NCT04204252
Organization ID
Kamada-AAT (inhaled) 008
Responsible Party
Sponsor
Study Sponsor
Kamada, Ltd.
Collaborators
Syneos Health
Study Sponsor
Jan Stolk, Prof, Principal Investigator, LUMC
Verification Date
January 2020