Stage 1 Study of ARALAST NP and GLASSIA in A1PI Deficiency

A Stage 1, Prospective, Randomized, Placebo-Controlled, Double- Blind Study to Evaluate the Safety and Efficacy of Alpha1-Proteinase Inhibitor (A1PI) Augmentation Therapy in Subjects With A1PI Deficiency and Chronic Obstructive Pulmonary Disease (COPD)

The purpose of this study is to conduct a pilot study to evaluate the safety and efficacy of weekly administration of Alpha1-Proteinase Inhibitor (A1PI) augmentation therapy in subjects with A1PI deficiency and emphysema/ chronic obstructive pulmonary disease (COPD).

Study Overview

• Status: Terminated
• Conditions: Chronic Obstructive Pulmonary Disease; Alpha1-antitrypsin Deficiency
• Intervention / Treatment: Biological: ARALAST NP 60 mg/kg; Biological: ARALAST NP 120 mg/kg; Biological: GLASSIA 60 mg/kg; Biological: GLASSIA 120 mg/kg; Biological: Human Albumin 2%

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Fitzroy, Victoria, Australia, 34741
      • St Vincent's Hospital Melbourne
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • LHSC - Victoria Hospital
    • Toronto, Ontario, Canada, M5T 3A9
      • Inspiration Research Limited
• United States
  • Arizona
    • Peoria, Arizona, United States, 85381
      • Phoenix Medical Research Institute, LLC
  • California
    • Newport Beach, California, United States, 92663
      • Newport Native MD, Inc
  • Florida
    • Kissimmee, Florida, United States, 34741
      • Pulmonary Disease Specialists, P.A., / PDS Research
    • Miami, Florida, United States, 33144
      • L&C Professional Medical Research Institute
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Health System
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health
    • Michigan City, Indiana, United States, 46360
      • La Porte County Institute for Clinical Research, Inc.
  • New York
    • Fayetteville, New York, United States, 13066
      • Pulmonary Health Physicians
  • North Carolina
    • Gastonia, North Carolina, United States, 28054
      • Clinical Research of Gastonia
    • Winston-Salem, North Carolina, United States, 27103
      • Southeastern Research Center LLC
  • Texas
    • Allen, Texas, United States, 75013
      • Metroplex Pulmonary and Sleep Center
    • Houston, Texas, United States, 77065
      • Houston Pulmonary and Sleep Associates
    • San Antonio, Texas, United States, 78258
      • Element Research Group
    • The Woodlands, Texas, United States, 77005
      • Renovatio Clinical-Respiratory & Sleep Disorders Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. ≥18 years of age at the time of screening
2. Endogenous plasma Alpha1-Proteinase Inhibitor (A1PI) level <8 μM at any time during the Screening period for treatment-naïve participants, or following 4-weeks minimum wash-out from previous augmentation therapy in treatment-experienced participants. The screening plasma A1PI level may be repeated if a participant obtains an exclusionary value that is suspected to be due to inadequate washout of A1PI).
3. Participant has documented A1PI genotype of Pi*Z/Z, Pi*Z/Null, Pi*Malton/Z, Pi*Null/Null, or other rare genotypes (except PI*MS, PI*MZ, or PI*SZ).
4. Clinically evident mild-moderate chronic obstructive pulmonary disease (COPD) (according to GOLD criteria for diagnosis) at the time of screening.
5. If the participant is treated with any respiratory medications including inhaled bronchodilators, inhaled corticosteroids, or systemic corticosteroids (e.g. prednisone ≤ 10 mg/day or its equivalent), the doses of the participant's medications have remained stable for at least 28 days prior to screening.
6. No clinically significant abnormalities (other than emphysema, bronchitis or bronchiectasis) detected via a chest computed tomography (CT) or chest X-ray at the time of screening.
7. If female of childbearing potential, participant must have a negative pregnancy test at screening and agree to employ adequate birth control measures for the duration of the study.
8. Participant is willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

1. Known ongoing or history of clinically significant pulmonary impairment other than emphysema/ COPD.
2. The participant is experiencing lower respiratory infection (LRTI)/acute pulmonary exacerbation (APE) at the time of enrollment (signing Informed consent form (ICF)). Participant may be rescreened after both clinical resolution of LRTI/APE and having also remained stable for at least 4 weeks after the end of LRTI/APE).
3. Known ongoing or history of cor pulmonale.
4. Known resting partial pressure of carbon dioxide (PaCO2) levels of > 45 mmHg.
5. Clinically significant congestive heart failure with New York Heart Association (NYHA) Class III/IV symptoms.
6. The participant has received an organ transplant, has undergone major lung surgery, or is currently on a transplant list.
7. Known history of ongoing malignancy (other than adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix).

8. Smoker or participant that has ceased smoking for less than one year prior to screening whose levels of cotinine are outside of the normal range of a nonsmoker.

   All participants must agree to refrain from smoking throughout the course of the study.

9. The participant is receiving long-term therapy (> 28 days) of parenteral corticosteroids or oral corticosteroids at doses greater than 10 mg/day of prednisone or its equivalent).
10. The participant is receiving long-term round-the-clock oxygen supplementation (other than temporary for acute COPD exacerbation, or supplemental oxygen (O2) with continuous positive airway pressure [CPAP], or bi-level positive airway pressure [BiPAP] during the day).
11. Participant has contraindications for CT (e.g. body weight and/or body size exceeding the weight and gantry size limits specified by the manufacturer of the CT scanner, inability to lie flat in the CT scanner, claustrophobia, metal prosthesis or pacemaker in the chest wall or upper extremity that would impact lung density assessment).
12. Participant is unwilling or unable to modify bronchodilator medications for 6 hours for short acting β2 agonists, 24 hours for long-acting β2 agonists, and 48 hours for long acting anticholinergics prior to the scheduled quantitative CT scan.
13. Known severe immunoglobulin A (IgA) deficiency (ie, IgA level < 8 mg/dL at screening).
14. Known history of hypersensitivity following infusions of human blood or blood components (eg, human immunoglobulins or human albumin).
15. Presence of clinically significant laboratory abnormalities at the screening
16. The participant has a clinically significant medical, psychiatric, or cognitive illness, is a recreational drug/alcohol user, or has any other uncontrolled medical condition (eg, unstable angina, transient ischemic attack, uncontrolled hypertension) that, in the opinion of the investigator, would affect participant's safety or compliance or confound the results of the study.
17. Participant has been exposed to another IP within 28 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study.
18. Participant is a family member or employee of the investigator.
19. If female, participant is pregnant or nursing at the time of enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ARALAST NP 60 mg/kg; 60 mg/kg body weight/week	Biological: ARALAST NP 60 mg/kg; ARALAST NP is an Alpha1-Proteinase Inhibitor (A1PI) augmentation therapy; Other Names: Alpha1-Proteinase Inhibitor (Human); A1PI; Alpha1-Proteinase Inhibitor
Experimental: ARALAST NP 120 mg/kg; 120 mg/kg body weight/week	Biological: ARALAST NP 120 mg/kg; ARALAST NP is an Alpha1-Proteinase Inhibitor (A1PI) augmentation therapy; Other Names: Alpha1-Proteinase Inhibitor (Human); A1PI; Alpha1-Proteinase Inhibitor
Experimental: GLASSIA 60 mg/kg; 60 mg/kg body weight/week	Biological: GLASSIA 60 mg/kg; GLASSIA is an Alpha1-Proteinase Inhibitor (A1PI) augmentation therapy; Other Names: Alpha1-Proteinase Inhibitor (Human); A1PI; Alpha1-Proteinase Inhibitor
Experimental: GLASSIA 120 mg/kg; 120 mg/kg body weight/week	Biological: GLASSIA 120 mg/kg; GLASSIA is an Alpha1-Proteinase Inhibitor (A1PI) augmentation therapy; Other Names: Alpha1-Proteinase Inhibitor (Human); A1PI; Alpha1-Proteinase Inhibitor
Placebo Comparator: Placebo; Human Albumin 2%	Biological: Human Albumin 2%; Human albumin 2% (by appropriate dilution with normal saline solution)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Change in Lung Density Based on Group 1 (ARALAST NP) Versus Placebo, Group 3 and Group 4 (GLASSIA) Versus Placebo	Rate of change in lung density was assessed by computed tomography (CT) densitometry. Computed Tomography (CT) scans was used to measure lung density as a quantitative assessment of emphysema progression and treatment efficacy at each of the study visits. CT lung density at the 15th percentile (PD15) is the threshold below which 15% of the voxels have lower densities, and was used as the parameter for estimating the rate of lung density decline. Rate of change in lung density based on Group 1 (ARALAST NP) versus Placebo, Group 3 and Group 4 (GLASSIA) versus Placebo were reported. The safety analysis set used for all the efficacy parameter assessment.	Baseline, Early termination of the study (approximately 22 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Change in Lung Density for Each Treatment Group	Rate of change in lung density was assessed by computed tomography (CT) densitometry for each treatment group. Computed Tomography (CT) scans was used to measure lung density as a quantitative assessment of emphysema progression and treatment efficacy at each of the study visits. The safety analysis set used for all the efficacy parameter assessment.	Baseline, Early termination of the study (approximately 22 months)
Mean Steady State Trough Concentration of Antigenic and Functional Alpha1-Proteinase Inhibitor (A1PI) for ARALAST NP and GLASSIA at Each Dose Level	Mean steady state trough concentration of antigenic and functional alpha1-proteinase inhibitor (a1pi) for ARALAST NP and GLASSIA at each dose level was reported.	Baseline, Early termination of the study (approximately 22 months)
Number of Events With Related and Unrelated Serious and Non-Serious Treatment Emergent Adverse Event (TEAE)	An Adverse event (AE) was defined as any untoward medical occurrence in a participant administered an IP that does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as AEs with a start date on or after the first dose of double-blind investigational product or a start date before the date of the first dose of double-blind investigational product that increased in severity or after the date of the first dose. TEAE related to Investigational Product (IP) and Study Procedures (SP) were considered. A non-serious AE is an AE that does not meet the criteria of an SAE. Number of events with related and unrelated serious and non-serious TEAE were reported.	From start of study treatment up to early termination of the study (approximately 22 months)
Percentage of Participants With Related and Unrelated Serious and Non-Serious Treatment Emergent Adverse Events (TEAE's)	An Adverse event (AE) was defined as any untoward medical occurrence in a participant administered an IP that does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as AEs with a start date on or after the first dose of double-blind investigational product or a start date before the date of the first dose of double-blind investigational product that increased in severity or after the date of the first dose. A non-serious AE is an AE that does not meet the criteria of an SAE. TEAE related to IP and Study Procedures were considered. Percentage of participants with related and unrelated serious and non-serious TEAE were reported.	From start of study treatment up to early termination of the study (approximately 22 months)
Number of Events With Temporally Related Serious and Non-Serious Treatment Emergent Adverse Events (AEs)	An Adverse event (AE) was defined as any untoward medical occurrence in a participant administered an IP that does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as AEs with a start date on or after the first dose of double-blind investigational product or a start date before the date of the first dose of double-blind investigational product that increased in severity or after the date of the first dose. A non-serious AE is an AE that does not meet the criteria of an SAE. TEAEs were temporally related to treatment administration (ie, occurred within 72 hours following the end of the infusion). TEAE Related to IP were considered.	From start of study treatment up to early termination of the study (approximately 22 months)
Percentage of Participants With Temporally Related Serious and Non-Serious Treatment Emergent Adverse Events (AEs)	An Adverse event (AE) was defined as any untoward medical occurrence in a participant administered an IP that does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as AEs with a start date on or after the first dose of double-blind investigational product or a start date before the date of the first dose of double-blind investigational product that increased in severity or after the date of the first dose. A non-serious AE is an AE that does not meet the criteria of an SAE. TEAEs were temporally related to treatment administration (ie, occurred within 72 hours following the end of the infusion). TEAE Related to IP were considered.	From start of study treatment up to early termination of the study (approximately 22 months)
Number of Events With Suspected Adverse Reactions or Serious and Non-Serious Adverse Reactions (ARs)	An Adverse Reactions (ARs) plus suspected adverse reaction is any adverse event which met any of the following criteria: an adverse event that began during infusion or within 72 hours following the end of IP infusion; an adverse event considered by either the investigator and/or the sponsor to be possibly or probably related to IP administration; an adverse event for which causality assessment was missing or indeterminate. Adverse reaction included both serious and non-serious ARs.	From start of study treatment up to early termination of the study (approximately 22 months)
Percentage of Participants With Suspected Adverse Reactions or Serious and Non-Serious Adverse Reactions (ARs)	An Adverse Reactions (AR) plus suspected adverse reaction is any adverse event which met any of the following criteria: an adverse event that began during infusion or within 72 hours following the end of IP infusion; an adverse event considered by either the investigator and/or the sponsor to be possibly or probably related to IP administration; an adverse event for which causality assessment was missing or indeterminate. Adverse reaction included both serious and non-serious ARs.	From start of study treatment up to early termination of the study (approximately 22 months)
Percentage of Participants With at Least One Infusion Rate Change or Infusion Interruption or Stopped Due to AEs	An Adverse event (AE) was defined as any untoward medical occurrence in a participant administered an IP that does not necessarily have a causal relationship with the treatment. Number of infusions for which the infusion rate was reduced and/or the infusion interrupted or stopped due to adverse events (AEs) were reported.	From start of study treatment up to early termination of the study (approximately 22 months)
Number of Participants Who Developed Anti-A1PI Antibodies Following Treatment With ARALAST NP or GLASSIA	Number of participants who developed anti- A1PI antibodies following treatment with ARALAST NP or GLASSIA were reported. Anti-A1PI binding antibody were determined for the samples that tested positive or negative at each assessment time point.	Baseline, Early termination of the study (approximately 22 months)

Collaborators and Investigators

• Sponsor: Baxalta now part of Shire
• Collaborators: Baxalta Innovations GmbH, now part of Shire

Study record dates

Study Major Dates

• Study Start (Actual): November 2, 2016
• Primary Completion (Actual): September 14, 2018
• Study Completion (Actual): September 14, 2018

Study Registration Dates

• First Submitted: March 23, 2016
• First Submitted That Met QC Criteria: March 28, 2016
• First Posted (Estimate): March 30, 2016

Study Record Updates

• Last Update Posted (Actual): May 13, 2021
• Last Update Submitted That Met QC Criteria: April 17, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Liver Diseases; Genetic Diseases, Inborn; Subcutaneous Emphysema; Emphysema; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Alpha 1-Antitrypsin Deficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Serine Proteinase Inhibitors; Trypsin Inhibitors; Protease Inhibitors; Alpha 1-Antitrypsin
• Other Study ID Numbers: 460503

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: De-identified individual participant data from this particular study will not be shared as there is a reasonable likelihood that individual patients could be re-identified (due to the limited number of study participants).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes