Stage 1 Study of ARALAST NP and GLASSIA in A1PI Deficiency

• Sponsor: Baxalta now part of Shire (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02722304
• Collaborator: Baxalta Innovations GmbH, now part of Shire (Industry)
• Enrollment: 7
• Locations: 17
• Arms: 5
• Actual Duration (Months): 22.4
• Patients Per Site: 0.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease; Alpha1-antitrypsin Deficiency	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%	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: Nov 2, 2016
• Actual Primary Completion Date: Sep 14, 2018
• Actual Study Completion Date: Sep 14, 2018

Arms and Interventions

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 Alpha1-Proteinase Inhibitor (Human) A1PI
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 Alpha1-Proteinase Inhibitor (Human) A1PI
Placebo Comparator: Placebo Human Albumin 2%	Biological: Human Albumin 2%; Human albumin 2% (by appropriate dilution with normal saline solution)

Outcome Measures

Primary Outcome Measures

1. Rate of Change in Lung Density Based on Group 1 (ARALAST NP) Versus Placebo, Group 3 and Group 4 (GLASSIA) Versus Placebo [Baseline, Early termination of the study (approximately 22 months)]

   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.

Secondary Outcome Measures

1. Rate of Change in Lung Density for Each Treatment Group [Baseline, Early termination of the study (approximately 22 months)]

   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.

2. Mean Steady State Trough Concentration of Antigenic and Functional Alpha1-Proteinase Inhibitor (A1PI) for ARALAST NP and GLASSIA at Each Dose Level [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 was reported.

3. Number of Events With Related and Unrelated Serious and Non-Serious Treatment Emergent Adverse Event (TEAE) [From start of study treatment up to early termination of the study (approximately 22 months)]

   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.

4. Percentage of Participants With Related and Unrelated Serious and Non-Serious Treatment Emergent Adverse Events (TEAE's) [From start of study treatment up to early termination of the study (approximately 22 months)]

   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.

5. Number of Events With Temporally Related Serious and Non-Serious Treatment Emergent Adverse Events (AEs) [From start of study treatment up to early termination of the study (approximately 22 months)]

   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.

6. Percentage of Participants With Temporally Related Serious and Non-Serious Treatment Emergent Adverse Events (AEs) [From start of study treatment up to early termination of the study (approximately 22 months)]

   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.

7. Number of Events With Suspected Adverse Reactions or Serious and Non-Serious Adverse Reactions (ARs) [From start of study treatment up to early termination of the study (approximately 22 months)]

   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.

8. Percentage of Participants With Suspected Adverse Reactions or Serious and Non-Serious Adverse Reactions (ARs) [From start of study treatment up to early termination of the study (approximately 22 months)]

   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.

9. Percentage of Participants With at Least One Infusion Rate Change or Infusion Interruption or Stopped Due to AEs [From start of study treatment up to early termination of the study (approximately 22 months)]

   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.

10. Number of Participants Who Developed Anti-A1PI Antibodies Following Treatment With ARALAST NP or GLASSIA [Baseline, Early termination of the study (approximately 22 months)]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 PiZ/Z, PiZ/Null, PiMalton/Z, PiNull/Null, or other rare genotypes (except PIMS, PIMZ, 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.

1. 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).

2. 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).

3. 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).

4. 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.

5. Known severe immunoglobulin A (IgA) deficiency (ie, IgA level < 8 mg/dL at screening).

6. Known history of hypersensitivity following infusions of human blood or blood components (eg, human immunoglobulins or human albumin).

7. Presence of clinically significant laboratory abnormalities at the screening

8. 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.

9. 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.

10. Participant is a family member or employee of the investigator.

11. If female, participant is pregnant or nursing at the time of enrollment.

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Baxalta now part of Shire
• Baxalta Innovations GmbH, now part of Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Jun 21, 2016
• Statistical Analysis Plan - Jan 19, 2019

More Information

Publications

None provided.

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT02722304
• Other Study ID Numbers: 460503
• First Posted: Mar 30, 2016
• Last Update Posted: May 13, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Additional relevant MeSH terms: Alpha 1-Antitrypsin Deficiency; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Protease Inhibitors; Alpha 1-Antitrypsin

Study Results

Participant Flow

Recruitment Details	The study was conducted at 4 study centers in the United States (3) and Australia (1) between 02 November 2016 (first participant first visit) and 14 September 2018 (last participant last visit).
Pre-assignment Detail	A total of 22 participants were screened for entry of study, of these, 15 participants were considered screen failures. Remaining 7 participants were enrolled and randomized in the study.

Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)	ARALAST NP 120 mg/kg (Group 2)	GLASSIA 60 mg/kg (Group 3)	GLASSIA 120 mg/kg (Group 4)	Placebo (Group 5)
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of ARALAST NP IV infusion for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.
Period Title: Overall Study
STARTED	1	0	2	2	2
Treated	1	0	1	1	2
COMPLETED	0	0	0	0	0
NOT COMPLETED	1	0	2	2	2

Baseline Characteristics

Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)	ARALAST NP 120 mg/kg (Group 2)	GLASSIA 60 mg/kg (Group 3)	GLASSIA 120 mg/kg (Group 4)	Placebo (Group 5)	Total
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of ARALAST NP IV infusion for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.	Total of all reporting groups
Overall Participants	1	0	1	1	2	5
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.0 (NA)	65.0 (NA)	68.0 (NA)	46.0 (4.24)	57.4 (10.83)
Sex: Female, Male (Count of Participants)
Female	1 100%	1 Infinity	1 100%	2 200%	5 250%
Male	0 0%	0 NaN	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 NaN	0 0%	0 0%	0 0%
Not Hispanic or Latino	1 100%	1 Infinity	1 100%	2 200%	5 250%
Unknown or Not Reported	0 0%	0 NaN	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 NaN	0 0%	0 0%	0 0%
Asian	0 0%	0 NaN	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 NaN	0 0%	0 0%	0 0%
Black or African American	0 0%	0 NaN	0 0%	0 0%	0 0%
White	1 100%	1 Infinity	1 100%	2 200%	5 250%
More than one race	0 0%	0 NaN	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 NaN	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Rate of Change in Lung Density Based on Group 1 (ARALAST NP) Versus Placebo, Group 3 and Group 4 (GLASSIA) Versus Placebo
Description	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.
Time Frame	Baseline, Early termination of the study (approximately 22 months)

Outcome Measure Data

Analysis Population Description

Study was early terminated due to low and slow rate of enrollment, hence, data was not collected for this efficacy endpoint.

Arm/Group Title	ARALAST NP 60 mg/kg Versus Placebo	GLASSIA 60 mg/kg Versus Placebo	GLASSIA 120 mg/kg Versus Placebo
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion and 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion and 6 ml/kg BW/week of placebo (human albumin two %) in normal saline for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion and 6 ml/kg BW/week of placebo (human albumin two %) in normal saline for a total of 96 weeks.
Measure Participants	0	0	0

2. Secondary Outcome

Title	Rate of Change in Lung Density for Each Treatment Group
Description	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.
Time Frame	Baseline, Early termination of the study (approximately 22 months)

Outcome Measure Data

Analysis Population Description

Study was early terminated due to low and slow rate of enrollment, hence, data was not collected for this efficacy endpoint.

Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)	GLASSIA 60 mg/kg (Group 3)	GLASSIA 120 mg/kg (Group 4)	Placebo (Group 5)
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.
Measure Participants	0	0	0	0

3. Secondary Outcome

Title	Mean Steady State Trough Concentration of Antigenic and Functional Alpha1-Proteinase Inhibitor (A1PI) for ARALAST NP and GLASSIA at Each Dose Level
Description	Mean steady state trough concentration of antigenic and functional alpha1-proteinase inhibitor (a1pi) for ARALAST NP and GLASSIA at each dose level was reported.
Time Frame	Baseline, Early termination of the study (approximately 22 months)

Outcome Measure Data

Analysis Population Description

Study was early terminated due to low and slow rate of enrollment, hence, data was not collected for this efficacy endpoint.

Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)	GLASSIA 60 mg/kg (Group 3)	GLASSIA 120 mg/kg (Group 4)	Placebo (Group 5)
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.
Measure Participants	0	0	0	0

4. Secondary Outcome

Title	Number of Events With Related and Unrelated Serious and Non-Serious Treatment Emergent Adverse Event (TEAE)
Description	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.
Time Frame	From start of study treatment up to early termination of the study (approximately 22 months)

Outcome Measure Data

Analysis Population Description

SAS included all participants who had received any amount of IP or placebo, regardless of protocol deviations or non-adherence to the study procedures. Analysis was performed according to the treatment regimen received regardless of the randomized treatment regimen.

Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)	GLASSIA 60 mg/kg (Group 3)	GLASSIA 120 mg/kg (Group 4)	Placebo (Group 5)
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.
Measure Participants	1	1	1	2
Serious TEAE: Events Related to IP	0	0	0	0
Non-serious TEAE: Events Related to IP	0	0	0	19
Serious TEAE: Events Related to SP	0	0	0	0
Non-serious TEAE: Events Related to SP	0	0	0	1
Serious TEAE: Unrelated Events	0	0	0	0
Non-serious TEAE: Unrelated Events	2	0	0	5

5. Secondary Outcome

Title	Percentage of Participants With Related and Unrelated Serious and Non-Serious Treatment Emergent Adverse Events (TEAE's)
Description	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.
Time Frame	From start of study treatment up to early termination of the study (approximately 22 months)

Outcome Measure Data

Analysis Population Description

SAS included all participants who had received any amount of IP or placebo, regardless of protocol deviations or non-adherence to the study procedures. Analysis was performed according to the treatment regimen received regardless of the randomized treatment regimen.

Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)	GLASSIA 60 mg/kg (Group 3)	GLASSIA 120 mg/kg (Group 4)	Placebo (Group 5)
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.
Measure Participants	1	1	1	2
Serious TEAE: Related to IP	0 0%	0 NaN	0 0%	0 0%
Non-Serious TEAE: Related to IP	0 0%	0 NaN	0 0%	50 5000%
Serious TEAE: Related to SP	0 0%	0 NaN	0 0%	0 0%
Non-Serious TEAE: Related to SP	0 0%	0 NaN	0 0%	50 5000%
Serious TEAE: Unrelated	0 0%	0 NaN	0 0%	0 0%
Non-Serious TEAE: Unrelated	100 10000%	0 NaN	0 0%	100 10000%

6. Secondary Outcome

Title	Number of Events With Temporally Related Serious and Non-Serious Treatment Emergent Adverse Events (AEs)
Description	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.
Time Frame	From start of study treatment up to early termination of the study (approximately 22 months)

Outcome Measure Data

Analysis Population Description

SAS included all participants who had received any amount of IP or placebo, regardless of protocol deviations or non-adherence to the study procedures. Analysis was performed according to the treatment regimen received regardless of the ( randomized treatment regimen.

Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)	GLASSIA 60 mg/kg (Group 3)	GLASSIA 120 mg/kg (Group 4)	Placebo (Group 5)
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.
Measure Participants	1	1	1	2
Temporally Serious TEAE Related to IP	0	0	0	0
Temporally Non-Serious TEAE Related to IP	0	0	0	17

7. Secondary Outcome

Title	Percentage of Participants With Temporally Related Serious and Non-Serious Treatment Emergent Adverse Events (AEs)
Description	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.
Time Frame	From start of study treatment up to early termination of the study (approximately 22 months)

Outcome Measure Data

Analysis Population Description

SAS included all participants who had received any amount of IP or placebo, regardless of protocol deviations or non-adherence to the study procedures. Analysis was performed according to the treatment regimen received regardless of the randomized treatment regimen.

Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)	GLASSIA 60 mg/kg (Group 3)	GLASSIA 120 mg/kg (Group 4)	Placebo (Group 5)
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.
Measure Participants	1	1	1	2
Temporally Serious TEAE Related to IP	0 0%	0 NaN	0 0%	0 0%
Temporally Non-Serious TEAE Related to IP	0 0%	0 NaN	0 0%	50 5000%

8. Secondary Outcome

Title	Number of Events With Suspected Adverse Reactions or Serious and Non-Serious Adverse Reactions (ARs)
Description	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.
Time Frame	From start of study treatment up to early termination of the study (approximately 22 months)

Outcome Measure Data

Analysis Population Description

SAS included all participants who had received any amount of investigational product (IP) or placebo, regardless of protocol deviations or non-adherence to the study procedures. Analysis was performed according to the treatment regimen received regardless of the randomized treatment regimen.

Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)	GLASSIA 60 mg/kg (Group 3)	GLASSIA 120 mg/kg (Group 4)	Placebo (Group 5)
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.
Measure Participants	1	1	1	2
Suspected ARs or Non-serious ARs	1	0	0	24
Suspected ARs or Serious ARs	0	0	0	0

9. Secondary Outcome

Title	Percentage of Participants With Suspected Adverse Reactions or Serious and Non-Serious Adverse Reactions (ARs)
Description	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.
Time Frame	From start of study treatment up to early termination of the study (approximately 22 months)

Outcome Measure Data

Analysis Population Description

SAS included all participants who had received any amount of IP or placebo, regardless of protocol deviations or non-adherence to the study procedures. Analysis was performed according to the treatment regimen received regardless of the randomized treatment regimen.

Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)	GLASSIA 60 mg/kg (Group 3)	GLASSIA 120 mg/kg (Group 4)	Placebo (Group 5)
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.
Measure Participants	1	1	1	2
Suspected ARs or Non-serious ARs	100 10000%	0 NaN	0 0%	50 5000%
Suspected ARs or Serious ARs	0 0%	0 NaN	0 0%	0 0%

10. Secondary Outcome

Title	Percentage of Participants With at Least One Infusion Rate Change or Infusion Interruption or Stopped Due to AEs
Description	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.
Time Frame	From start of study treatment up to early termination of the study (approximately 22 months)

Outcome Measure Data

Analysis Population Description

SAS included all participants who had received any amount of IP or placebo, regardless of protocol deviations or non-adherence to the study procedures. Analysis was performed according to the treatment regimen received regardless of the randomized treatment regimen.

Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)	GLASSIA 60 mg/kg (Group 3)	GLASSIA 120 mg/kg (Group 4)	Placebo (Group 5)
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.
Measure Participants	1	1	1	2
Participants with at Least 1 Infusion Rate Change	0 0%	0 NaN	0 0%	50 5000%
Participantswith at Least 1 Infusion Interruption	0 0%	0 NaN	0 0%	50 5000%

11. Secondary Outcome

Title	Number of Participants Who Developed Anti-A1PI Antibodies Following Treatment With ARALAST NP or GLASSIA
Description	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.
Time Frame	Baseline, Early termination of the study (approximately 22 months)

Outcome Measure Data

Analysis Population Description

SAS included all participants who had received any amount of IP or placebo, regardless of protocol deviations or non-adherence to the study procedures. Analysis was performed according to the treatment regimen received regardless of the randomized treatment regimen.

Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)	GLASSIA 60 mg/kg (Group 3)	GLASSIA 120 mg/kg (Group 4)	Placebo (Group 5)
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.	Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.	Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.
Measure Participants	1	1	1	2
Count of Participants [Participants]	0 0%	0 NaN	0 0%	0 0%

Adverse Events

Time Frame	From start of study treatment up to early termination of the study (approximately 22 months)
Adverse Event Reporting Description	Study was terminated early. One arm/ group (ARALAST NP 120 mg/kg (Group 2)) did not have any participants randomized to it at the time of the study termination. Therefore there are zero participants at risk. This applies to the following fields, below for the ARALAST NP 120 mg/kg (Group 2) arm/group: - participants at risk for Serious Adverse Events - participants at risk for All-Cause Mortality - participants at risk for Other (Not Including Serious) Adverse Events
Arm/Group Title	ARALAST NP 60 mg/kg (Group 1)		ARALAST NP 120 mg/kg (Group 2)		GLASSIA 60 mg/kg (Group 3)		GLASSIA 120 mg/kg (Group 4)		Placebo (Group 5)
Arm/Group Description	Participants received 60 milligram per kilogram body weight per week (mg/kg BW/week) of ARALAST NP intravenous (IV) infusion for a total of 96 weeks.		Participants received 120 mg/kg BW/week of ARALAST NP IV infusion for a total of 96 weeks.		Participants received 60 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.		Participants received 120 mg/kg BW/week of GLASSIA IV infusion for a total of 96 weeks.		Participants received 6 milliliter per kilogram body weight per week (ml/kg BW/week) of placebo (human albumin two percent [%]) in normal saline for a total of 96 weeks.
All Cause Mortality
	ARALAST NP 60 mg/kg (Group 1)		ARALAST NP 120 mg/kg (Group 2)		GLASSIA 60 mg/kg (Group 3)		GLASSIA 120 mg/kg (Group 4)		Placebo (Group 5)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/0 (NaN)		0/1 (0%)		0/1 (0%)		0/2 (0%)
Serious Adverse Events
	ARALAST NP 60 mg/kg (Group 1)		ARALAST NP 120 mg/kg (Group 2)		GLASSIA 60 mg/kg (Group 3)		GLASSIA 120 mg/kg (Group 4)		Placebo (Group 5)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/0 (NaN)		0/1 (0%)		0/1 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	ARALAST NP 60 mg/kg (Group 1)		ARALAST NP 120 mg/kg (Group 2)		GLASSIA 60 mg/kg (Group 3)		GLASSIA 120 mg/kg (Group 4)		Placebo (Group 5)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)		0/1 (0%)		0/1 (0%)		2/2 (100%)
Eye disorders
Right Eye Retinal Detachment	1/1 (100%)	1	0/0 (NaN)	0	0/1 (0%)	0	0/1 (0%)	0	0/2 (0%)	0
Gastrointestinal disorders
DIARRHOEA	1/1 (100%)	1	0/0 (NaN)	0	0/1 (0%)	0	0/1 (0%)	0	0/2 (0%)	0
General disorders
site conditions/ Catheter site rash/ MILD RASH AT THE SITE OF TAPE USED AT IV CANNULA SITE	0/1 (0%)	0	0/0 (NaN)	0	0/1 (0%)	0	0/1 (0%)	0	1/2 (50%)	1
Nervous system disorders
Headache	0/1 (0%)	0	0/0 (NaN)	0	0/1 (0%)	0	0/1 (0%)	0	1/2 (50%)	13
Nausea	0/1 (0%)	0	0/0 (NaN)	0	0/1 (0%)	0	0/1 (0%)	0	1/2 (50%)	6
Reproductive system and breast disorders
Vaginal haemorrhage/ PER VAGINAL BLEEDING	0/1 (0%)	0	0/0 (NaN)	0	0/1 (0%)	0	0/1 (0%)	0	1/2 (50%)	3
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease/ COPD EXACERBATION	0/1 (0%)	0	0/0 (NaN)	0	0/1 (0%)	0	0/1 (0%)	0	1/2 (50%)	1
Skin and subcutaneous tissue disorders
CONTACT DERMATITIS	0/1 (0%)	0	0/0 (NaN)	0	0/1 (0%)	0	0/1 (0%)	0	1/2 (50%)	1

Limitations/Caveats

The Data Monitoring Committee (DMC) reviewed the available efficacy and safety data and unanimously recommended to terminate the study. The decision was based on the very low number of enrollees, and the slow rate of participant enrollment.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.