Stage 1 Study of ARALAST NP and GLASSIA in A1PI Deficiency

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Chronic Obstructive Pulmonary Disease, Alpha1-antitrypsin Deficiency

Intervention / Treatment
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* 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%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age at the time of screening 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). 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). Clinically evident mild-moderate chronic obstructive pulmonary disease (COPD) (according to GOLD criteria for diagnosis) at the time of screening. 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. 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. 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. Participant is willing and able to comply with the requirements of the protocol. Exclusion Criteria: Known ongoing or history of clinically significant pulmonary impairment other than emphysema/ COPD. 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). Known ongoing or history of cor pulmonale. Known resting partial pressure of carbon dioxide (PaCO2) levels of > 45 mmHg. Clinically significant congestive heart failure with New York Heart Association (NYHA) Class III/IV symptoms. The participant has received an organ transplant, has undergone major lung surgery, or is currently on a transplant list. 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). 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. 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). 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). 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). 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. Known severe immunoglobulin A (IgA) deficiency (ie, IgA level < 8 mg/dL at screening). Known history of hypersensitivity following infusions of human blood or blood components (eg, human immunoglobulins or human albumin). Presence of clinically significant laboratory abnormalities at the screening 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. 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. Participant is a family member or employee of the investigator. If female, participant is pregnant or nursing at the time of enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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) |