Alpha 1-Antitrypsin Deficiency
Conditions
Brief summary
The purpose of this study is to evaluate the effects of weekly augmentation therapy with ARALAST Fraction IV-1 (Fr IV-1) on epithelial lining fluid (ELF) alpha 1-proteinase inhibitor levels and other ELF analytes and to assess the safety of the treatment. Eligible subjects with a diagnosis of severe congenital alpha 1-antitrypsin deficiency will receive 8 consecutive weekly treatments with 60 mg/kg/week of functional ARALAST Fr IV-1 administered intravenously. The efficacy and safety assessments will include two bronchoscopies with bronchoalveolar lavage on study initiation and on study termination and multiple imaging and laboratory safety assessments. Each subject will participate for a minimum of 12 weeks.
Interventions
BIOLOGICALAlpha1-Proteinase Inhibitor
60 mg/kg, weekly, intravenous infusion
Sponsors
Baxalta now part of Shire
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed and dated informed consent. * Male or female 18 years of age or older. * Documented, endogenous serum α1-PI level \< 40 mg/dL measured at screening (unless otherwise approved by the Sponsor) after a minimum of 28-day washout of any prior replacement therapy (if applicable). * Phenotype Pi Z (which includes Pi\*Z/Z, Pi\*Z/Null, or Pi\*Malton/Z), or Pi\*Null/Null. * Pulmonary functions at screening meeting the following criteria: 1. Forced expiratory volume at 1 second (FEV1) \>= 50% of predicted value; or 2. FEV1 \> 35% of predicted value and diffusing capacity for carbon monoxide \> 45% of predicated value, with no supplemental oxygen therapy and \< 3 pulmonary exacerbations or bronchitis requiring antibiotics/corticosteroids within the past 12 months). * For any female of childbearing potential, a negative urine test for pregnancy within 7 days prior to the first bronchoalveolar lavage (BAL) visit and agreement to employ adequate birth control measures for the duration of the study. * No clinically significant abnormalities detected on a 12-lead electrocardiogram (ECG) performed at the screening visit (ECG previously obtained within the past 12 months may be used, if available). * Laboratory results obtained at the screening visit, meeting the following criteria: 1. Serum alanine aminotransferase (ALT) \<= 2 times upper limit of normal (ULN) 2. Serum aspartate aminotransferase (AST) \<= 2 times ULN 3. Serum total bilirubin \<= 2 times ULN 4. Proteinuria \< +2 on dipstick analysis 5. Serum creatinine \<= 1.5 times ULN 6. Absolute neutrophil count (ANC) \>= 1500 cells/mm3 7. Hemoglobin (Hgb) \>= 10.0 g/dL 8. Platelet count \>= 105/mm3 * If the subject is treated with respiratory medications, such as inhaled bronchodilators or inhaled corticosteroids, or other chronic medications for the treatment of the subjects´s other medical condition(s), the subject's medication doses were unchanged for at least 14 days prior to the baseline BAL visit.
Exclusion criteria
* Clinically significant pulmonary impairment, other than chronic pulmonary disease (COPD). * The subject has received any alpha 1 proteinase inhibitor (α1-PI) augmentation therapy (e.g., Prolastin, Zemaira, Aralast, or an investigational α1-PI, by any route including intravenous and inhaled) within 28 days prior to screening. * The subject has received an investigational drug or device within 1 month prior to screening, or the subject is currently receiving an investigational drug or device. If the subject receives another investigational drug or device after enrollment, the subjects is to be withdrawn from the trial. * Presence of clinical symptoms of any lower respiratory tract infection or acute pulmonary exacerbation within 14 days prior to screening. * The subject has a known selective Immunoglobulin A (IgA) deficiency (IgA level less than 15 mg/dL) and/or antibody against IgA. * The subject is pregnant or lactating, or intends to become pregnant during the course of the study. * The subject is not a suitable candidate for a BAL procedure. * Moderate or severe bronchiectasis (total daily sputum production \> 10 mL). * Clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance. * Prior history of adverse reaction to local anaesthetics, sedatives, pain control drugs, and other medication employed at the study center for perioperative care associated with the BAL procedure. * Long-term use of oral or parenteral glucocorticosteroid within 28 days prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Bronchoalveolar Lavage (BAL) Epithelial Lining Fluid (ELF) Alpha1-Proteinase Inhibitor (α1-PI) Level | BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks) | Median change BAL ELF antigenic α1-PI level the from baseline to post-treatment |
| Number of Changes in the Rate of Infusion | During 8 consecutive weeks of treatment | Number of decreases in the rate or discontinuations of infusion at 0.2 mL/kg/min |
| The Number of Adverse Events (AEs) Related to the Infusion of ARALAST Fr. IV 1 Administered at a Rate of 0.2 mL/kg/Min | During 8 consecutive weeks of treatment | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the α1-PI Plasma Level | Blood samples were collected at baseline and after 8 consecutive weeks of treatment | Mean change in the plasma level of α1-PI from baseline to post-treatment |
| Ratio of Post- to Pre-treatment BAL ELF Antineutrophil Elastase Capacity (ANEC) Levels | BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks) | Median ratio of post- to pre-treatment BAL ELF ANEC levels |
| Change in in the Ratio of BAL ELF α1-PI to Human Neutrophil Elastase (HNE) Complex Concentration | BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks) | Median change in the ratio of BAL ELF α1-PI to HNE complex concentration from baseline to post-treatment |
| Change in the Plasma Antineutrophil Elastase Capacity (ANEC) Level | Blood samples were collected at baseline and after 8 consecutive weeks of treatment | Mean change in the plasma ANEC level from baseline to post-treatment |
| Clinically Significant Changes in Vital Signs From Pre- to Post-Infusion | During 8 consecutive weeks of infusion | Clinically significant changes in vital signs from pre- to post-infusion are: • Heart rate: 25% increase above pre-infusion value • Blood pressure: ≥ 30 mm Hg change from pre-infusion blood pressure (systolic or diastolic) • Temperature: an increase in body temperature to \>38°C (\>100.4°F). If the pre-infusion body temperature was already \>38°C (\>100.4°F), then any further increase in body temperature by 1.1°C (1.98°F) or more was considered clinically significant. • Respiratory rate: 25% increase above pre-infusion value |
Other
| Measure | Time frame | Description |
|---|---|---|
| Ratio of Post- to Pre-treatment BAL ELF Total Neutrophil Elastase Level | BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks) | Median ratio of post- to pre-treatment BAL ELF Total Neutrophil Elastase Level |
| Change in the BAL ELF Tumor Necrosis Factor-alpha (TNF-α) From Baseline to Post-treatment | BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks) | Median change in the BAL ELF TNF-α from baseline to post-treatment |
| Change in the BAL ELF Free Neutrophil Elastase Level | BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks) | Median change in the BAL ELF Free Neutrophil Elastase Level from baseline to post-treatment |
| Ratio of Post- to Pre-treatment BAL ELF Interleukin 8 (IL-8) Level | BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks) | Median ratio of post- to pre-treatment BAL ELF IL-8 Level |
Countries
Australia, New Zealand
Participant flow
Recruitment details
Participants were recruited at 5 hospital sites in New Zealand and Australia. The period studied was 1 year and 2 months.
Pre-assignment details
21 participants enrolled: 4 were screen failures (i.e., did not meet inclusion/exclusion criteria), 3 were discontinued due to unevaluable baseline bronchoalveolar lavage (BAL) samples, and 1 subject withdrew consent prior to receiving investigational product.
Participants by arm
| Arm | Count |
|---|---|
| Participants Treated With ARALAST Fr. IV-1 | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Participants Treated With ARALAST Fr. IV-1 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 59.6 years |
| Region of Enrollment Australia | 8 Participants |
| Region of Enrollment New Zealand | 5 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 13 |
| serious Total, serious adverse events | 1 / 13 |
Outcome results
Primary
Change in Bronchoalveolar Lavage (BAL) Epithelial Lining Fluid (ELF) Alpha1-Proteinase Inhibitor (α1-PI) Level
Median change BAL ELF antigenic α1-PI level the from baseline to post-treatment
Time frame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Population: Per protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Per Protocol | Change in Bronchoalveolar Lavage (BAL) Epithelial Lining Fluid (ELF) Alpha1-Proteinase Inhibitor (α1-PI) Level | 0.28 μM |
p-value: 0.0195Wilcoxon signed rank test
Primary
Number of Changes in the Rate of Infusion
Number of decreases in the rate or discontinuations of infusion at 0.2 mL/kg/min
Time frame: During 8 consecutive weeks of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Per Protocol | Number of Changes in the Rate of Infusion | 0 infusions |
Primary
The Number of Adverse Events (AEs) Related to the Infusion of ARALAST Fr. IV 1 Administered at a Rate of 0.2 mL/kg/Min
Time frame: During 8 consecutive weeks of treatment
Population: Intent to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Per Protocol | The Number of Adverse Events (AEs) Related to the Infusion of ARALAST Fr. IV 1 Administered at a Rate of 0.2 mL/kg/Min | 0 adverse events |
Secondary
Change in in the Ratio of BAL ELF α1-PI to Human Neutrophil Elastase (HNE) Complex Concentration
Median change in the ratio of BAL ELF α1-PI to HNE complex concentration from baseline to post-treatment
Time frame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Population: No per protocol subject had both pre- and post-treatment analytes available, therefore no analysis could be performed on this outcome measure
Secondary
Change in the Plasma Antineutrophil Elastase Capacity (ANEC) Level
Mean change in the plasma ANEC level from baseline to post-treatment
Time frame: Blood samples were collected at baseline and after 8 consecutive weeks of treatment
Population: Per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Per Protocol | Change in the Plasma Antineutrophil Elastase Capacity (ANEC) Level | 9.46 μM | Standard Deviation 2.31 |
p-value: <0.0001paired t-tests
Secondary
Change in the α1-PI Plasma Level
Mean change in the plasma level of α1-PI from baseline to post-treatment
Time frame: Blood samples were collected at baseline and after 8 consecutive weeks of treatment
Population: Per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Per Protocol | Change in the α1-PI Plasma Level | 10.34 μM | Standard Deviation 2.5 |
p-value: <0.0001paired t-tests
Secondary
Clinically Significant Changes in Vital Signs From Pre- to Post-Infusion
Clinically significant changes in vital signs from pre- to post-infusion are: • Heart rate: 25% increase above pre-infusion value • Blood pressure: ≥ 30 mm Hg change from pre-infusion blood pressure (systolic or diastolic) • Temperature: an increase in body temperature to \>38°C (\>100.4°F). If the pre-infusion body temperature was already \>38°C (\>100.4°F), then any further increase in body temperature by 1.1°C (1.98°F) or more was considered clinically significant. • Respiratory rate: 25% increase above pre-infusion value
Time frame: During 8 consecutive weeks of infusion
Population: Intention to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Per Protocol | Clinically Significant Changes in Vital Signs From Pre- to Post-Infusion | 2 # Clinically significant events |
Secondary
Ratio of Post- to Pre-treatment BAL ELF Antineutrophil Elastase Capacity (ANEC) Levels
Median ratio of post- to pre-treatment BAL ELF ANEC levels
Time frame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Population: Per protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Per Protocol | Ratio of Post- to Pre-treatment BAL ELF Antineutrophil Elastase Capacity (ANEC) Levels | 1.22 μM |
Other Pre-specified
Change in the BAL ELF Free Neutrophil Elastase Level
Median change in the BAL ELF Free Neutrophil Elastase Level from baseline to post-treatment
Time frame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Population: Per protocol population with both pre- and post-treatment analytes available from BAL procedures
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Per Protocol | Change in the BAL ELF Free Neutrophil Elastase Level | 41.17 nM |
Other Pre-specified
Change in the BAL ELF Tumor Necrosis Factor-alpha (TNF-α) From Baseline to Post-treatment
Median change in the BAL ELF TNF-α from baseline to post-treatment
Time frame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Population: Per protocol population with both pre- and post-treatment analytes available from BAL procedures
Other Pre-specified
Ratio of Post- to Pre-treatment BAL ELF Interleukin 8 (IL-8) Level
Median ratio of post- to pre-treatment BAL ELF IL-8 Level
Time frame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Population: Per protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Per Protocol | Ratio of Post- to Pre-treatment BAL ELF Interleukin 8 (IL-8) Level | 1.46 pg/mL |
p-value: 0.4375Wilcoxon signed rank
Other Pre-specified
Ratio of Post- to Pre-treatment BAL ELF Total Neutrophil Elastase Level
Median ratio of post- to pre-treatment BAL ELF Total Neutrophil Elastase Level
Time frame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Population: Per protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Per Protocol | Ratio of Post- to Pre-treatment BAL ELF Total Neutrophil Elastase Level | 1.24 nM |
p-value: 0.1875Wilcoxon signed rank test