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Evaluate Efficacy and Safety of "Kamada-AAT for Inhalation" in Patients With AATD (InnovAATe)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04204252
Recruitment Status : Recruiting
First Posted : December 18, 2019
Last Update Posted : January 6, 2020
Sponsor:
Collaborator:
Syneos Health
Information provided by (Responsible Party):
Kamada, Ltd.

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.


Condition or disease Intervention/treatment Phase
Alpha 1-Antitrypsin Deficiency Drug: Alpha 1-Antitrypsin Drug: Placebos Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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 Airflow Limitation (50% ≤ FEV1 ≤ 80% of predicted; FEV1/SVC ≤ 70%)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Study will be conducted by a CRO and monitored by a DMC including unblinded personnel
Primary Purpose: Treatment
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
Actual Study Start Date : November 25, 2019
Estimated Primary Completion Date : November 2022
Estimated Study Completion Date : May 2023


Arm Intervention/treatment
Active Comparator: Inhaled AAT
Daily inhalation of 80 mg/day "Kamada-AAT for Inhalation" for 104 weeks
Drug: Alpha 1-Antitrypsin
Kamada's alpha 1-antitrypsin product given by inhalation using the eFlow® electronic nebulizer manufactured by PARI Pharma GmbH
Other Name: Kamada alpha 1-antitrypsin for inhalation

Placebo Comparator: Placebo
Daily inhalation of a solution of NaCl in phosphate buffer solution with 0.01% TWEEN-80
Drug: Placebos
Preparation of NaCl in phosphate buffer solution with 0.01% TWEEN-80
Other Name: Placebo




Primary Outcome Measures :
  1. FEV1 post bronchodilator [ Time Frame: 104 weeks ]
    Change from baseline in post bronchodilator FEV1 at 104 weeks


Secondary Outcome Measures :
  1. CT densitometry whole-lung 15th percentile lung density (PD15) at total lung capacity (TLC). [ Time Frame: 104 weeks ]
    Change from baseline over 104 weeks of treatment in CT densitometry whole-lung 15th percentile lung density (PD15) at total lung capacity (TLC).

  2. FEV1 % of predicted [ Time Frame: 104 weeks ]
    Change from baseline over 104 weeks of treatment in FEV1 % of predicted

  3. FEV1/FVC % [ Time Frame: 104 weeks ]
    Change from baseline over 104 weeks of treatment in FEV1/FVC %

  4. Exacerbations [ Time Frame: 104 weeks ]
    Annual rate of exacerbations by severity and duration

  5. 6 minute walk test [ Time Frame: 104 weeks ]
    Change from Baseline in the distance walked in six minutes


Other Outcome Measures:
  1. TEAEs [ Time Frame: 130 weeks ]
    Rate and severity of adverse events during treatment emergent adverse events (TEAEs), adverse events of special interest (AESIs) and serious adverse events (SAEs) during treatment and follow-up period [Safety Outcome]

  2. PiM [ Time Frame: 130 weeks ]
    Plasma M-type AAT specific (PiM) levels evaluated as function of exposure time, antibody response (positive vs. negative), and antibody titers

  3. ADA/nADA [ Time Frame: 130 weeks ]
    Rate and titers of binding and neutralizing AAT antibodies (ADA/nADA) in plasma [Safety Outcome]



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04204252


Locations
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Netherlands
Leiden University Medical Center (LUMC) Recruiting
Leiden, ZA, Netherlands, 2333
Contact: Lineke Punselie, SN/SC    +31715266376    l.w.p.punselie@lumc.nl   
Sponsors and Collaborators
Kamada, Ltd.
Syneos Health
Investigators
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Principal Investigator: Jan Stolk, Prof LUMC
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Responsible Party: Kamada, Ltd.
ClinicalTrials.gov Identifier: NCT04204252    
Other Study ID Numbers: Kamada-AAT (inhaled) 008
First Posted: December 18, 2019    Key Record Dates
Last Update Posted: January 6, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kamada, Ltd.:
Inhaled Alpha 1-Antitrypsin Nebulizer
Additional relevant MeSH terms:
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Alpha 1-Antitrypsin Deficiency
Respiratory Tract Diseases
Pathologic Processes
Liver Diseases
Digestive System Diseases
Lung Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema
Alpha 1-Antitrypsin
Protein C Inhibitor
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action