Alpha1-proteinase Inhibitor Deficiency, Emphysema
Conditions
Keywords
Alpha1-proteinase inhibitor deficiency, Emphysema, Chronic augmentation and maintenance therapy
Brief summary
This is a randomized, placebo-controlled, double-blind, multicenter phase III/IV study to compare the efficacy and safety of Zemaira® with placebo in subjects with emphysema due to alpha1-proteinase inhibitor deficiency. The effect of Zemaira® on the progression of emphysema will be assessed by the decline of lung density, measured by computed tomography (CT).
Interventions
BIOLOGICALAlpha1-proteinase inhibitor
60 mg/kg body weight/week intravenous
OTHERPlacebo
Lyophilized preparation: 60 mg/kg body weight/week intravenous
Sponsors
CSL Behring
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 18 to 65 years of age and willing to sign informed consent. * Males and non-pregnant, non-lactating females whose screening pregnancy test is negative and who are using contraceptives methods deemed reliable by the investigator. * Diagnosis of alpha1-proteinase inhibitor (A1-PI) deficiency (serum A1-PI levels \< 11 μM or \< 80 mg/dL). This includes newly diagnosed subjects, previously untreated subjects, currently treated subjects, and subjects currently not on treatment therapy but on treatment in the past. * Subjects with emphysema and forced expiratory volume in 1 second (FEV1) ≥ 35% and ≤ 70% (predicted). * No signs of chronic or acute Hepatitis A, Hepatitis B, Hepatitis C or HIV infection (negative serologies for HIV and viral hepatitis). In case of positive serologies for viral hepatitis, vaccination status or negative IgM should be available.
Exclusion criteria
* Any relevant chronic diseases or history of relevant diseases (e.g., severe renal insufficiency) except respiratory or liver disease secondary to alpha1-proteinase inhibitor deficiency. Subjects with well-controlled, chronic diseases may be included after consultation with the treating physician and the sponsor. * Current evidence of alcohol abuse or history of abuse of illegal and/or legally prescribed drugs such as barbiturates, benzodiazepines, amphetamines, cocaine, opioids, and cannabinoids. * History of allergy, anaphylactic reaction, or severe systemic response to human plasma derived products, or known mannitol hypersensitivity, or history of prior adverse reaction to mannitol. * History of transfusion reactions. * Selective IgA deficiency. * Acute illness within one week prior to the first administration of the investigational medicinal product (IMP). Start of treatment after recovery is possible. * Current tobacco smoker (smoking has to be ceased at least 6 months prior study inclusion). Subjects with a positive cotinine test due to nicotine replacement therapy (e.g. patches, chewing gum) or snuff are eligible. * Conditions or behaviors that interfere with attending scheduled study visits in the opinion of the investigator. * History of non-compliance. * Administration of any other experimental new drug or participation in an investigation of a marketed product within one month prior to the screening visit date. * Inability to perform necessary study procedures. * Lung transplantation, lung volume reduction surgery or lobectomy or being on a waiting list for any such surgeries.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annual Rate of Change in Lung Density | Over a 2-year period | As measured by centralized, standardized computer tomographic (CT) lung densitometry. CT scans were acquired at 2 inspiration states: TLC (ie, full inspiration) and FRC (ie, full expiration). Results were adjusted for total lung volume and are presented as point estimates for the average rate of decline in each treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annual Rate of Pulmonary Exacerbations | Over a 2-year period | Primary diagnostic criteria for exacerbations were increased dyspnea, increased sputum volume, and increased sputum purulence. Supporting diagnostic criteria were upper respiratory tract infection, fever without other apparent cause, increased wheezing, and increased cough. For diagnosis, participants had to meet 2 of the 3 primary criteria or 1 primary criterion and 1 supporting criterion. The annual rate was based on the total number of exacerbations and the total number of participant study days for all participants in the specified analysis population and adjusted to 365.25 days. |
| Percent Change in FEV1 | From baseline to 2 years | Percent change from baseline to Month 24. |
| Time to First Pulmonary Exacerbation | Over a 2-year period | Primary diagnostic criteria for exacerbations were increased dyspnea, increased sputum volume, and increased sputum purulence. Supporting diagnostic criteria were upper respiratory tract infection, fever without other apparent cause, increased wheezing, and increased cough. For diagnosis, participants had to meet 2 of the 3 primary criteria or 1 primary criterion and 1 supporting criterion. |
| Change in Lung Density | From baseline to 2 years | Change from baseline to Month 24 as measured by centralized, standardized CT lung densitometry. CT scans were acquired at 2 inspiration states: TLC (ie, full inspiration) and FRC (ie, full expiration). Results were adjusted for total lung volume. |
| Change in Exercise Capacity | From baseline to 2 years | Exercise capacity was measured as distance walked, using the incremental shuttle walk test. Change from baseline to end of treatment (2 years) in exercise capacity was analysed using an analysis of covariance (ANCOVA). |
| Change in Patient-reported Symptoms | From baseline to 2 years | Patient-reported symptoms were measured using the symptoms score component of the St George's Respiratory Questionnaire (SGRQ). SGRQ scores range from 0 to 100, with higher scores indicating more limitations and negative values for change indicating improvement. Change from baseline to end of treatment (2 years) in SGRQ was analysed using an ANCOVA. |
| Percent Change in Percent Predicted FEV1 | From baseline to 2 years | Percent change from baseline to Month 24. |
| Percent Change in FEV1 Divided by Forced Vital Capacity | From baseline to 2 years | Percent change from baseline to Month 24. |
| Percent Change in DLCO | From baseline to 2 years | Percent change from baseline to Month 24. |
| Duration of Pulmonary Exacerbations Relative to Treatment Duration | Over a 2-year period | Defined as the percentage of total treatment duration across participants for 1) exacerbations overall, 2) antibiotic treatment for exacerbations, and 3) hospitalization for exacerbations. Primary diagnostic criteria for exacerbations were increased dyspnea, increased sputum volume, and increased sputum purulence. Supporting diagnostic criteria were upper respiratory tract infection, fever without other apparent cause, increased wheezing, and increased cough. For diagnosis, participants had to meet 2 of the 3 primary criteria or 1 primary criterion and 1 supporting criterion. |
| Severity of Pulmonary Exacerbations | Over a 2-year period | Defined as the number of participants requiring 1) antibiotic treatment for exacerbations, and 2) hospitalization for exacerbations. Primary diagnostic criteria for exacerbations were increased dyspnea, increased sputum volume, and increased sputum purulence. Supporting diagnostic criteria were upper respiratory tract infection, fever without other apparent cause, increased wheezing, and increased cough. For diagnosis, participants had to meet 2 of the 3 primary criteria or 1 primary criterion and 1 supporting criterion. Antibiotic treatment usage was reported by quarterly interval. |
| Frequency and Intensity of Adverse Events (AEs) | Over a 2-year period | Number of participants with at least one AE, and the number of participants with mild, moderate or severe AEs. AE intensity was defined as mild (does not interfere with routine activities), moderate (interferes with routine activities), or severe (impossible to perform routine activities). |
Other
| Measure | Time frame |
|---|---|
| Baseline Lung Density at Total Lung Capacity (TLC) and Forced Residual Capacity (FRC) | Baseline |
Countries
Australia, Canada, Czechia, Denmark, Estonia, Finland, Germany, Ireland, Poland, Romania, Russia, Sweden, United States
Participant flow
Recruitment details
This multicenter, multinational study enrolled participants at 28 study centers in Europe, North America, and Australia.
Pre-assignment details
Screening took place 1 to 4 weeks prior to the first dose of randomized investigational product (ie, either Zemaira® or placebo). A total of 208 participants were screened; 28 of these did not fulfill all eligibility criteria and were therefore screening failures.
Participants by arm
| Arm | Count |
|---|---|
| Zemaira® Alpha1-proteinase inhibitor: 60 mg/kg body weight/week intravenous | 93 |
| Placebo Lyophilized preparation: 60 mg/kg body weight/week intravenous | 87 |
| Total | 180 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 |
| Overall Study | Death | 1 | 3 |
| Overall Study | Lung transplantation | 1 | 1 |
| Overall Study | Missing reason | 1 | 0 |
| Overall Study | Not interested in being participant | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Suspicion of pulmonary cancer | 0 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 7 |
Baseline characteristics
| Characteristic | Zemaira® | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 53.81 years STANDARD_DEVIATION 6.193 | 52.40 years STANDARD_DEVIATION 7.812 | 53.13 years STANDARD_DEVIATION 7.374 |
| Baseline diffusion capacity of carbon monoxide (DLCO) | 13.6 mL/min/mmHg STANDARD_DEVIATION 5.3 | 15.0 mL/min/mmHg STANDARD_DEVIATION 5.6 | 14.3 mL/min/mmHg STANDARD_DEVIATION 5.5 |
| Baseline percent predicted forced expiratory volume in 1 second (FEV1) | 47.4 percentage STANDARD_DEVIATION 12.1 | 47.2 percentage STANDARD_DEVIATION 11.1 | 47.3 percentage STANDARD_DEVIATION 11.6 |
| Number of participants with ZZ genotype (A1-PI deficiency), or SZ, Z / Null or Other genotype Other | 6 participants | 3 participants | 9 participants |
| Number of participants with ZZ genotype (A1-PI deficiency), or SZ, Z / Null or Other genotype SZ | 2 participants | 0 participants | 2 participants |
| Number of participants with ZZ genotype (A1-PI deficiency), or SZ, Z / Null or Other genotype Z / Null | 2 participants | 1 participants | 3 participants |
| Number of participants with ZZ genotype (A1-PI deficiency), or SZ, Z / Null or Other genotype ZZ | 83 participants | 83 participants | 166 participants |
| Sex: Female, Male Female | 45 Participants | 37 Participants | 82 Participants |
| Sex: Female, Male Male | 48 Participants | 50 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 90 / 93 | 84 / 87 |
| serious Total, serious adverse events | 28 / 93 | 28 / 87 |
Outcome results
Primary
Annual Rate of Change in Lung Density
As measured by centralized, standardized computer tomographic (CT) lung densitometry. CT scans were acquired at 2 inspiration states: TLC (ie, full inspiration) and FRC (ie, full expiration). Results were adjusted for total lung volume and are presented as point estimates for the average rate of decline in each treatment group.
Time frame: Over a 2-year period
Population: All randomized participants with at least 1 valid CT scan.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Zemaira® | Annual Rate of Change in Lung Density | TLC + FRC combined | -1.50 g/L per year | Standard Error 0.22 |
| Zemaira® | Annual Rate of Change in Lung Density | TLC | -1.45 g/L per year | Standard Error 0.23 |
| Zemaira® | Annual Rate of Change in Lung Density | FRC | -1.55 g/L per year | Standard Error 0.24 |
| Placebo | Annual Rate of Change in Lung Density | TLC + FRC combined | -2.12 g/L per year | Standard Error 0.24 |
| Placebo | Annual Rate of Change in Lung Density | TLC | -2.19 g/L per year | Standard Error 0.25 |
| Placebo | Annual Rate of Change in Lung Density | FRC | -2.02 g/L per year | Standard Error 0.26 |
Comparison: Analysis of the annual rate of change in lung density (TLC+FRC combined) was a linear mixed model with country, inspiration state, time since baseline treatment, and treatment-by-time interaction as fixed effects and participant and participant-by-time interaction as random coefficients at a 1-sided significance level of 0.025.p-value: 0.02995% CI: [-0.024, 1.261]95% confidence interval
Comparison: Analysis of the annual rate of change in lung density (TLC) was a linear mixed model with country, time since baseline treatment, and treatment-by-time interaction as fixed effects and participant and participant-by-time interaction as random coefficients at a 1-sided significance level of 0.025.p-value: 0.01795% CI: [0.059, 1.42]95% confidence interval
Comparison: Analysis of the annual rate of change in lung density (FRC) was a linear mixed model with country, time since baseline treatment, and treatment-by-time interaction as fixed effects and participant and participant-by-time interaction as random coefficients at a 1-sided significance level of 0.025.p-value: 0.0995% CI: [-0.223, 1.18]95% confidence interval
Secondary
Annual Rate of Pulmonary Exacerbations
Primary diagnostic criteria for exacerbations were increased dyspnea, increased sputum volume, and increased sputum purulence. Supporting diagnostic criteria were upper respiratory tract infection, fever without other apparent cause, increased wheezing, and increased cough. For diagnosis, participants had to meet 2 of the 3 primary criteria or 1 primary criterion and 1 supporting criterion. The annual rate was based on the total number of exacerbations and the total number of participant study days for all participants in the specified analysis population and adjusted to 365.25 days.
Time frame: Over a 2-year period
Population: All participants with A1-PI deficiency who were included in the study and randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zemaira® | Annual Rate of Pulmonary Exacerbations | 1.70 exacerbations per participant year |
| Placebo | Annual Rate of Pulmonary Exacerbations | 1.42 exacerbations per participant year |
Secondary
Change in Exercise Capacity
Exercise capacity was measured as distance walked, using the incremental shuttle walk test. Change from baseline to end of treatment (2 years) in exercise capacity was analysed using an analysis of covariance (ANCOVA).
Time frame: From baseline to 2 years
Population: All participants with A1-PI deficiency who were included in the study, randomized, and had a baseline and at least one endpoint assessment available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zemaira® | Change in Exercise Capacity | 1.77 metre | Standard Error 13 |
| Placebo | Change in Exercise Capacity | 14.86 metre | Standard Error 13.5 |
Secondary
Change in Lung Density
Change from baseline to Month 24 as measured by centralized, standardized CT lung densitometry. CT scans were acquired at 2 inspiration states: TLC (ie, full inspiration) and FRC (ie, full expiration). Results were adjusted for total lung volume.
Time frame: From baseline to 2 years
Population: All participants with A1-PI deficiency who were included in the study, randomized, and had a baseline and at least 1 endpoint assessment available.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Zemaira® | Change in Lung Density | TLC + FRC combined | -2.33 g/L | Standard Error 0.45 |
| Zemaira® | Change in Lung Density | TLC (N=66 for placebo) | -2.22 g/L | Standard Error 0.47 |
| Zemaira® | Change in Lung Density | FRC | -2.44 g/L | Standard Error 0.5 |
| Placebo | Change in Lung Density | TLC (N=66 for placebo) | -3.54 g/L | Standard Error 0.52 |
| Placebo | Change in Lung Density | TLC + FRC combined | -3.37 g/L | Standard Error 0.5 |
| Placebo | Change in Lung Density | FRC | -3.33 g/L | Standard Error 0.56 |
Comparison: Analysis of the change in lung density (TLC+FRC combined) from baseline to Month 24 was a mixed effects analysis of covariance (ANCOVA) model with country, treatment, and baseline lung density as fixed effects and inspiration state as a repeated random effect at a 1-sided significance level of 0.025.p-value: 0.05895% CI: [-0.26, 2.34]95% confidence interval
Comparison: Analysis of the change in lung density (TLC) from baseline to Month 24 was a mixed effects ANCOVA model with country, treatment, and baseline lung density as fixed effects at a 1-sided significance level of 0.025.p-value: 0.02895% CI: [-0.03, 2.67]95% confidence interval
Comparison: Analysis of the change in lung density (FRC) from baseline to Month 24 was a mixed effects ANCOVA model with country, treatment, and baseline lung density as fixed effects as a repeated random effect at a 1-sided significance level of 0.025.p-value: 0.11595% CI: [-0.57, 2.34]95% confidence interval
Secondary
Change in Patient-reported Symptoms
Patient-reported symptoms were measured using the symptoms score component of the St George's Respiratory Questionnaire (SGRQ). SGRQ scores range from 0 to 100, with higher scores indicating more limitations and negative values for change indicating improvement. Change from baseline to end of treatment (2 years) in SGRQ was analysed using an ANCOVA.
Time frame: From baseline to 2 years
Population: All participants with A1-PI deficiency who were included in the study, randomized, and had a baseline and at least one endpoint assessment available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zemaira® | Change in Patient-reported Symptoms | -1.19 units on a scale | Standard Error 1.79 |
| Placebo | Change in Patient-reported Symptoms | -0.09 units on a scale | Standard Error 1.93 |
Secondary
Duration of Pulmonary Exacerbations Relative to Treatment Duration
Defined as the percentage of total treatment duration across participants for 1) exacerbations overall, 2) antibiotic treatment for exacerbations, and 3) hospitalization for exacerbations. Primary diagnostic criteria for exacerbations were increased dyspnea, increased sputum volume, and increased sputum purulence. Supporting diagnostic criteria were upper respiratory tract infection, fever without other apparent cause, increased wheezing, and increased cough. For diagnosis, participants had to meet 2 of the 3 primary criteria or 1 primary criterion and 1 supporting criterion.
Time frame: Over a 2-year period
Population: All participants with A1-PI deficiency who were included in the study and randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zemaira® | Duration of Pulmonary Exacerbations Relative to Treatment Duration | Exacerbations (n = 68, 59) | 77.2 percentage of total treatment duration | Standard Deviation 98.8 |
| Zemaira® | Duration of Pulmonary Exacerbations Relative to Treatment Duration | Antibiotic treatment (n = 59, 52) | 6.32 percentage of total treatment duration | Standard Deviation 6.75 |
| Zemaira® | Duration of Pulmonary Exacerbations Relative to Treatment Duration | Hospitalization (n = 19, 16) | 6.22 percentage of total treatment duration | Standard Deviation 8.79 |
| Placebo | Duration of Pulmonary Exacerbations Relative to Treatment Duration | Exacerbations (n = 68, 59) | 58.9 percentage of total treatment duration | Standard Deviation 109.1 |
| Placebo | Duration of Pulmonary Exacerbations Relative to Treatment Duration | Antibiotic treatment (n = 59, 52) | 5.55 percentage of total treatment duration | Standard Deviation 6.8 |
| Placebo | Duration of Pulmonary Exacerbations Relative to Treatment Duration | Hospitalization (n = 19, 16) | 2.16 percentage of total treatment duration | Standard Deviation 1.67 |
Secondary
Frequency and Intensity of Adverse Events (AEs)
Number of participants with at least one AE, and the number of participants with mild, moderate or severe AEs. AE intensity was defined as mild (does not interfere with routine activities), moderate (interferes with routine activities), or severe (impossible to perform routine activities).
Time frame: Over a 2-year period
Population: All participants receiving at least 1 infusion of either Zemaira® or placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zemaira® | Frequency and Intensity of Adverse Events (AEs) | At least 1 AE | 92 participants |
| Zemaira® | Frequency and Intensity of Adverse Events (AEs) | Mild AEs | 13 participants |
| Zemaira® | Frequency and Intensity of Adverse Events (AEs) | Moderate AEs | 54 participants |
| Zemaira® | Frequency and Intensity of Adverse Events (AEs) | Severe AEs | 25 participants |
| Placebo | Frequency and Intensity of Adverse Events (AEs) | Severe AEs | 27 participants |
| Placebo | Frequency and Intensity of Adverse Events (AEs) | At least 1 AE | 86 participants |
| Placebo | Frequency and Intensity of Adverse Events (AEs) | Moderate AEs | 43 participants |
| Placebo | Frequency and Intensity of Adverse Events (AEs) | Mild AEs | 16 participants |
Secondary
Percent Change in DLCO
Percent change from baseline to Month 24.
Time frame: From baseline to 2 years
Population: All participants with A1-PI deficiency who were included in the study, randomized, and had a baseline and at least one endpoint assessment available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zemaira® | Percent Change in DLCO | -3.16 percent change | Standard Error 1.96 |
| Placebo | Percent Change in DLCO | -1.85 percent change | Standard Error 2.03 |
Secondary
Percent Change in FEV1
Percent change from baseline to Month 24.
Time frame: From baseline to 2 years
Population: All participants with A1-PI deficiency who were included in the study, randomized, and had a baseline and at least one endpoint assessment available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zemaira® | Percent Change in FEV1 | -4.29 percent change | Standard Error 1.26 |
| Placebo | Percent Change in FEV1 | -2.06 percent change | Standard Error 1.3 |
Secondary
Percent Change in FEV1 Divided by Forced Vital Capacity
Percent change from baseline to Month 24.
Time frame: From baseline to 2 years
Population: All participants with A1-PI deficiency who were included in the study, randomized, and had a baseline and at least one endpoint assessment available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zemaira® | Percent Change in FEV1 Divided by Forced Vital Capacity | -2.68 percent change | Standard Error 1.36 |
| Placebo | Percent Change in FEV1 Divided by Forced Vital Capacity | 1.56 percent change | Standard Error 1.4 |
Secondary
Percent Change in Percent Predicted FEV1
Percent change from baseline to Month 24.
Time frame: From baseline to 2 years
Population: All participants with A1-PI deficiency who were included in the study, randomized, and had a baseline and at least one endpoint assessment available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zemaira® | Percent Change in Percent Predicted FEV1 | -4.16 percent change | Standard Error 1.27 |
| Placebo | Percent Change in Percent Predicted FEV1 | -1.90 percent change | Standard Error 1.31 |
Secondary
Severity of Pulmonary Exacerbations
Defined as the number of participants requiring 1) antibiotic treatment for exacerbations, and 2) hospitalization for exacerbations. Primary diagnostic criteria for exacerbations were increased dyspnea, increased sputum volume, and increased sputum purulence. Supporting diagnostic criteria were upper respiratory tract infection, fever without other apparent cause, increased wheezing, and increased cough. For diagnosis, participants had to meet 2 of the 3 primary criteria or 1 primary criterion and 1 supporting criterion. Antibiotic treatment usage was reported by quarterly interval.
Time frame: Over a 2-year period
Population: All participants with A1-PI deficiency who were included in the study and randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zemaira® | Severity of Pulmonary Exacerbations | Total hospitalizations | 13 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | 0 hospitalizations | 80 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | 1 hospitalization | 10 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | 2 hospitalizations | 1 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | 3 hospitalizations | 1 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | >3 hospitalizations | 1 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | Antibiotics: Day 1 to <Month 3 | 22 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | Antibiotics: Month 3 to <Month 6 | 29 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | Antibiotics: Month 6 to <Month 9 | 24 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | Antibiotics: Month 9 to <Month 12 | 21 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | Antibiotics: Month 12 to <Month 15 | 30 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | Antibiotics: Month 15 to <Month 18 | 21 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | Antibiotics: Month 18 to <Month 21 | 26 participants |
| Zemaira® | Severity of Pulmonary Exacerbations | Antibiotics: Month 21 to <Month 24 | 20 participants |
| Placebo | Severity of Pulmonary Exacerbations | Antibiotics: Month 12 to <Month 15 | 21 participants |
| Placebo | Severity of Pulmonary Exacerbations | Total hospitalizations | 9 participants |
| Placebo | Severity of Pulmonary Exacerbations | Antibiotics: Month 3 to <Month 6 | 20 participants |
| Placebo | Severity of Pulmonary Exacerbations | 0 hospitalizations | 78 participants |
| Placebo | Severity of Pulmonary Exacerbations | Antibiotics: Month 18 to <Month 21 | 15 participants |
| Placebo | Severity of Pulmonary Exacerbations | 1 hospitalization | 5 participants |
| Placebo | Severity of Pulmonary Exacerbations | Antibiotics: Month 6 to <Month 9 | 15 participants |
| Placebo | Severity of Pulmonary Exacerbations | 2 hospitalizations | 1 participants |
| Placebo | Severity of Pulmonary Exacerbations | Antibiotics: Month 15 to <Month 18 | 15 participants |
| Placebo | Severity of Pulmonary Exacerbations | 3 hospitalizations | 3 participants |
| Placebo | Severity of Pulmonary Exacerbations | Antibiotics: Month 9 to <Month 12 | 17 participants |
| Placebo | Severity of Pulmonary Exacerbations | >3 hospitalizations | 0 participants |
| Placebo | Severity of Pulmonary Exacerbations | Antibiotics: Month 21 to <Month 24 | 15 participants |
| Placebo | Severity of Pulmonary Exacerbations | Antibiotics: Day 1 to <Month 3 | 19 participants |
Secondary
Time to First Pulmonary Exacerbation
Primary diagnostic criteria for exacerbations were increased dyspnea, increased sputum volume, and increased sputum purulence. Supporting diagnostic criteria were upper respiratory tract infection, fever without other apparent cause, increased wheezing, and increased cough. For diagnosis, participants had to meet 2 of the 3 primary criteria or 1 primary criterion and 1 supporting criterion.
Time frame: Over a 2-year period
Population: All participants with A1-PI deficiency who were included in the study and randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zemaira® | Time to First Pulmonary Exacerbation | 0.60 Years |
| Placebo | Time to First Pulmonary Exacerbation | 0.73 Years |
Other Pre-specified
Baseline Lung Density at Total Lung Capacity (TLC) and Forced Residual Capacity (FRC)
Time frame: Baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zemaira® | Baseline Lung Density at Total Lung Capacity (TLC) and Forced Residual Capacity (FRC) | TLC | 45.5 g/L | Standard Deviation 15.8 |
| Zemaira® | Baseline Lung Density at Total Lung Capacity (TLC) and Forced Residual Capacity (FRC) | FRC | 47.6 g/L | Standard Deviation 15.7 |
| Placebo | Baseline Lung Density at Total Lung Capacity (TLC) and Forced Residual Capacity (FRC) | TLC | 48.9 g/L | Standard Deviation 15.5 |
| Placebo | Baseline Lung Density at Total Lung Capacity (TLC) and Forced Residual Capacity (FRC) | FRC | 50.7 g/L | Standard Deviation 15 |