Alpha 1-proteinase Inhibitor Deficiency, Emphysema
Conditions
Keywords
Alpha1-proteinase inhibitor deficiency, Chronic augmentation and maintenance therapy, Emphysema, Emphysema due to Alpha 1-proteinase inhibitor deficiency
Brief summary
This study is a continuation of the placebo-controlled study CE1226\_4001 (NCT00261833) to evaluate the efficacy and safety of Zemaira® intravenous (i.v). administration in subjects with emphysema due to alpha1-proteinase inhibitor deficiency. The long-term verification of a disease-modifying benefit of Zemaira® on the progression of emphysema will be assessed by volume-adjusted lung density, measured yearly by computed tomography (CT).
Interventions
BIOLOGICALAlpha1- proteinase inhibitor [human]
Lyophilized preparation of 60 mg/kg body weight intravenously once per week
Sponsors
CSL Behring
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects who have completed the 2-year treatment and observation period in the Phase 3/4 Zemaira® CE1226\_4001 study (NCT00261833) and are willing to sign informed consent * Males, and non-pregnant, non-lactating females, whose screening pregnancy test is negative and who are using contraceptive methods deemed reliable by the investigator
Exclusion criteria
* Individuals residing in the US * Current evidence of alcohol abuse or abuse of 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 * Current tobacco smoker (smoking must be discontinued for at least 6 months prior to study participation) * 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 * Inability to perform necessary study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Change of Adjusted Lung Density | Up to 2 years | As measured by centralized, standardized computer tomographic (CT) lung densitometry. CT scans were acquired at 2 inspiration states: TLC (Total Lung Capacity; ie, full inspiration) and FRC (Functional Residual Capacity; ie, full expiration). Results were adjusted for total lung volume and are presented as point estimates for the average rate of decline in the early start and delayed start subgroups from a linear random regression model with country, inspiration state (only for 'TLC and FRC state'), time (time elapsed since Day 1 \[CE1226\_4001\]), treatment and treatment by time interaction as fixed effects and subject and subject by time interaction as random coefficients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Adjusted Lung Density | From baseline to 2 years | Percent change from baseline to 2 years 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 and are presented as point estimates for the average percent change in the early start and delayed start subgroups from an analysis of covariance (ANCOVA) model with country, treatment, and baseline lung density as fixed effects and inspiration state as a repeated random effect. The baseline is the last assessment from the preceding study CE1226\_4001. |
| Change in Subject-reported Symptoms | From baseline to 2 years | Patient-reported symptoms were measured using the St George's Respiratory Questionnaire (SGRQ). SGRQ total, symptoms, activity and impact scores range from 0 to 100, with higher scores indicating more limitations, and change from baseline below zero (0) is favorable, indicating improvement. |
| Percent Change in Lung Function as Measured by Forced Expiratory Volume in 1 Second (FEV1) | From baseline up to 2 years | — |
| Percent Change in Lung Function as Measured by Ratio of FEV1/FVC (Forced Vital Capacity) | From baseline up to 2 years | — |
| Absolute Change in Adjusted Lung Density | From baseline to 2 years | Absolute change from baseline to 2 years 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 and are presented as point estimates for the average absolute change in the early start and delayed start subgroups from an analysis of covariance (ANCOVA) model with country, treatment, and baseline lung density as fixed effects and inspiration state as a repeated random effect. The baseline is the last assessment from the preceding study CE1226\_4001. |
| Number of Subjects With Pulmonary Exacerbations | Up to 2 years | — |
| Annual Rate in Subject Years of Pulmonary Exacerbations | Up to 2 years | Annual exposure-adjusted incidence rate of pulmonary exacerbations. |
| Time to First Pulmonary Exacerbation | Up to 2 years | — |
| Percentage of Subjects With Treatment Emergent Adverse Events | From baseline up to 2.5 years | Percentage of subjects with treatment-emergent adverse events (TEAEs): overall, by severity, by relatedness, by seriousness, and which occurred within 24 hours of Zemaira administration. |
| Percent Change in Lung Function as Measured by Percent Predicted FEV1 | From baseline up to 2 years | — |
Countries
Australia, Canada, Czechia, Denmark, Estonia, Finland, Germany, Ireland, Poland, Romania, Sweden
Participant flow
Recruitment details
This multicenter study was conducted at 22 centers in Europe, Canada, and Australia. Alpha1-proteinase inhibitor (A1-PI) deficient individuals with emphysema, who had completed the 2-year treatment and observation periods in study CE1226\_4001, except those participating in the USA, were invited to participate in study CE1226\_3001.
Pre-assignment details
Subjects who had participated in the CE1226\_4001 study, met the inclusion and exclusion criteria, and signed the informed consent were included in study CE1226\_3001.
Participants by arm
| Arm | Count |
|---|---|
| Zemaira® Alpha1- proteinase inhibitor \[human\]: Lyophilized preparation of 60 mg/kg body weight intravenously once per week | 140 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Adverse event, serious fatal | 1 |
| Overall Study | Drug abuse | 1 |
| Overall Study | Lung transplant | 1 |
| Overall Study | Travel/Vacation | 1 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Zemaira® |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 130 Participants |
| Region of Enrollment Australia | 17 participants |
| Region of Enrollment Canada | 25 participants |
| Region of Enrollment Czech Republic | 2 participants |
| Region of Enrollment Denmark | 35 participants |
| Region of Enrollment Estonia | 2 participants |
| Region of Enrollment Finland | 3 participants |
| Region of Enrollment Germany | 15 participants |
| Region of Enrollment Ireland | 19 participants |
| Region of Enrollment Poland | 4 participants |
| Region of Enrollment Romania | 1 participants |
| Region of Enrollment Sweden | 17 participants |
| Sex: Female, Male Female | 61 Participants |
| Sex: Female, Male Male | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 137 / 140 |
| serious Total, serious adverse events | 51 / 140 |
Outcome results
Primary
Rate of Change of Adjusted Lung Density
As measured by centralized, standardized computer tomographic (CT) lung densitometry. CT scans were acquired at 2 inspiration states: TLC (Total Lung Capacity; ie, full inspiration) and FRC (Functional Residual Capacity; ie, full expiration). Results were adjusted for total lung volume and are presented as point estimates for the average rate of decline in the early start and delayed start subgroups from a linear random regression model with country, inspiration state (only for 'TLC and FRC state'), time (time elapsed since Day 1 \[CE1226\_4001\]), treatment and treatment by time interaction as fixed effects and subject and subject by time interaction as random coefficients.
Time frame: Up to 2 years
Population: Intention-to-treat (ITT) population. Subjects may not have been included in all efficacy analyses because of missing efficacy assessments.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Zemaira® (Early Start) | Rate of Change of Adjusted Lung Density | TLC + FRC combined | -1.632 g/L per year | Standard Error 0.2824 |
| Zemaira® (Early Start) | Rate of Change of Adjusted Lung Density | TLC | -1.627 g/L per year | Standard Error 0.2743 |
| Zemaira® (Early Start) | Rate of Change of Adjusted Lung Density | FRC | -1.658 g/L per year | Standard Error 0.3186 |
| Zemaira® (Delayed Start) | Rate of Change of Adjusted Lung Density | TLC + FRC combined | -1.352 g/L per year | Standard Error 0.2961 |
| Zemaira® (Delayed Start) | Rate of Change of Adjusted Lung Density | TLC | -1.256 g/L per year | Standard Error 0.2891 |
| Zemaira® (Delayed Start) | Rate of Change of Adjusted Lung Density | FRC | -1.482 g/L per year | Standard Error 0.3346 |
Comparison: Analysis of the annual rate of change in lung density (for TLC + FRC combined) was a linear random regression model with country, inspiration state, time since Day 1 \[CE1226\_4001\], and treatment-by time interaction as fixed effects and subject and subject-by-time interaction as random coefficients at a 1-sided significance level of 0.025.p-value: =0.75295% CI: [-1.089, 0.53]Regression, Linear
Comparison: Analysis of the annual rate of change in lung density (for TLC) was a linear random regression model with country, time since Day 1 \[CE1226\_4001\], and treatment-by-time interaction as fixed effects and subject and subject-by-time interaction as random coefficients at a 1-sided significance level of 0.025.p-value: =0.82395% CI: [-1.159, 0.417]Regression, Linear
Comparison: Analysis of the annual rate of change in lung density (for FRC) was a linear random regression model with country, time since Day 1 \[CE1226\_4001\], and treatment-by-time interaction as fixed effects and subject and subject-by-time interaction as random coefficients at a 1-sided significance level of 0.025.p-value: =0.64895% CI: [-1.09, 0.738]Regression, Linear
Secondary
Absolute Change in Adjusted Lung Density
Absolute change from baseline to 2 years 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 and are presented as point estimates for the average absolute change in the early start and delayed start subgroups from an analysis of covariance (ANCOVA) model with country, treatment, and baseline lung density as fixed effects and inspiration state as a repeated random effect. The baseline is the last assessment from the preceding study CE1226\_4001.
Time frame: From baseline to 2 years
Population: ITT population. Subjects may not have been included in all efficacy analyses because of missing efficacy assessments.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Zemaira® (Early Start) | Absolute Change in Adjusted Lung Density | TLC + FRC combined, n = 64, 60 | -3.031 g/L | Standard Error 0.5888 |
| Zemaira® (Early Start) | Absolute Change in Adjusted Lung Density | TLC, n = 64, 59 | -2.971 g/L | Standard Error 0.5826 |
| Zemaira® (Early Start) | Absolute Change in Adjusted Lung Density | FRC, n = 64, 60 | -2.934 g/L | Standard Error 0.6671 |
| Zemaira® (Delayed Start) | Absolute Change in Adjusted Lung Density | TLC + FRC combined, n = 64, 60 | -2.502 g/L | Standard Error 0.6142 |
| Zemaira® (Delayed Start) | Absolute Change in Adjusted Lung Density | TLC, n = 64, 59 | -2.485 g/L | Standard Error 0.6142 |
| Zemaira® (Delayed Start) | Absolute Change in Adjusted Lung Density | FRC, n = 64, 60 | -2.953 g/L | Standard Error 0.6993 |
Comparison: Analysis of the change in lung density (for TLC + FRC combined) from baseline to 2 years was analyzed using an ANCOVA model with country, treatment, and baseline lung density as fixed effects and inspiration state as a repeated random effect.p-value: 0.52695% CI: [-2.179, 1.12]ANCOVA
Comparison: Analysis of the change in lung density (for TLC) from baseline to 2 years was analyzed using an ANCOVA model with country, treatment, and baseline lung density as fixed effects.p-value: 0.55895% CI: [-2.126, 1.154]ANCOVA
Comparison: Analysis of the change in lung density (for FRC) from baseline to 2 years was analyzed using an ANCOVA model with country, treatment, and baseline lung density as fixed effects.p-value: 0.98495% CI: [-1.858, 1.895]ANCOVA
Secondary
Annual Rate in Subject Years of Pulmonary Exacerbations
Annual exposure-adjusted incidence rate of pulmonary exacerbations.
Time frame: Up to 2 years
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zemaira® (Early Start) | Annual Rate in Subject Years of Pulmonary Exacerbations | 1.71 Exacerbations/subject year |
| Zemaira® (Delayed Start) | Annual Rate in Subject Years of Pulmonary Exacerbations | 1.39 Exacerbations/subject year |
Secondary
Change in Subject-reported Symptoms
Patient-reported symptoms were measured using the St George's Respiratory Questionnaire (SGRQ). SGRQ total, symptoms, activity and impact scores range from 0 to 100, with higher scores indicating more limitations, and change from baseline below zero (0) is favorable, indicating improvement.
Time frame: From baseline to 2 years
Population: ITT population. Subjects may not have been included in all efficacy analyses because of missing efficacy assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zemaira® (Early Start) | Change in Subject-reported Symptoms | Total score, n = 62, 56 | 1.185 units on a scale (change from baseline) | Standard Deviation 13.624 |
| Zemaira® (Early Start) | Change in Subject-reported Symptoms | Symptoms score, n = 67, 58 | 6.601 units on a scale (change from baseline) | Standard Deviation 22.29 |
| Zemaira® (Early Start) | Change in Subject-reported Symptoms | Activity score, n = 67, 57 | 0.55 units on a scale (change from baseline) | Standard Deviation 14.1429 |
| Zemaira® (Early Start) | Change in Subject-reported Symptoms | Impact score, n = 65, 57 | -0.22 units on a scale (change from baseline) | Standard Deviation 15.8999 |
| Zemaira® (Delayed Start) | Change in Subject-reported Symptoms | Impact score, n = 65, 57 | 1.626 units on a scale (change from baseline) | Standard Deviation 13.5699 |
| Zemaira® (Delayed Start) | Change in Subject-reported Symptoms | Total score, n = 62, 56 | 1.499 units on a scale (change from baseline) | Standard Deviation 12.0507 |
| Zemaira® (Delayed Start) | Change in Subject-reported Symptoms | Activity score, n = 67, 57 | 2.831 units on a scale (change from baseline) | Standard Deviation 14.0013 |
| Zemaira® (Delayed Start) | Change in Subject-reported Symptoms | Symptoms score, n = 67, 58 | 0.728 units on a scale (change from baseline) | Standard Deviation 19.2189 |
Secondary
Number of Subjects With Pulmonary Exacerbations
Time frame: Up to 2 years
Population: ITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zemaira® (Early Start) | Number of Subjects With Pulmonary Exacerbations | Overall (at least 1 exacerbation) | 63 participants |
| Zemaira® (Early Start) | Number of Subjects With Pulmonary Exacerbations | Severe exacerbation | 17 participants |
| Zemaira® (Early Start) | Number of Subjects With Pulmonary Exacerbations | Moderate exacerbation | 60 participants |
| Zemaira® (Early Start) | Number of Subjects With Pulmonary Exacerbations | Neither moderate or severe exacerbation | 21 participants |
| Zemaira® (Early Start) | Number of Subjects With Pulmonary Exacerbations | No exacerbation | 13 participants |
| Zemaira® (Delayed Start) | Number of Subjects With Pulmonary Exacerbations | Neither moderate or severe exacerbation | 17 participants |
| Zemaira® (Delayed Start) | Number of Subjects With Pulmonary Exacerbations | No exacerbation | 16 participants |
| Zemaira® (Delayed Start) | Number of Subjects With Pulmonary Exacerbations | Overall (at least 1 exacerbation) | 48 participants |
| Zemaira® (Delayed Start) | Number of Subjects With Pulmonary Exacerbations | Moderate exacerbation | 46 participants |
| Zemaira® (Delayed Start) | Number of Subjects With Pulmonary Exacerbations | Severe exacerbation | 11 participants |
Secondary
Percentage of Subjects With Treatment Emergent Adverse Events
Percentage of subjects with treatment-emergent adverse events (TEAEs): overall, by severity, by relatedness, by seriousness, and which occurred within 24 hours of Zemaira administration.
Time frame: From baseline up to 2.5 years
Population: Safety population comprises all subjects who were included in the study and who received at least 1 dose of Zemaira during study CE1226\_3001.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zemaira® (Early Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Any serious TEAE | 36.8 percentage of subjects |
| Zemaira® (Early Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Any TEAE | 100 percentage of subjects |
| Zemaira® (Early Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Mild TEAE | 19.7 percentage of subjects |
| Zemaira® (Early Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Moderate TEAE | 50.0 percentage of subjects |
| Zemaira® (Early Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Severe TEAE | 30.3 percentage of subjects |
| Zemaira® (Early Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Any treatment related TEAE | 14.5 percentage of subjects |
| Zemaira® (Early Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Any TEAE within 24 hours | 86.8 percentage of subjects |
| Zemaira® (Delayed Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Any serious TEAE | 35.9 percentage of subjects |
| Zemaira® (Delayed Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Severe TEAE | 29.7 percentage of subjects |
| Zemaira® (Delayed Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Any TEAE | 96.9 percentage of subjects |
| Zemaira® (Delayed Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Any TEAE within 24 hours | 79.7 percentage of subjects |
| Zemaira® (Delayed Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Mild TEAE | 15.6 percentage of subjects |
| Zemaira® (Delayed Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Any treatment related TEAE | 10.9 percentage of subjects |
| Zemaira® (Delayed Start) | Percentage of Subjects With Treatment Emergent Adverse Events | Moderate TEAE | 51.6 percentage of subjects |
Secondary
Percent Change in Adjusted Lung Density
Percent change from baseline to 2 years 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 and are presented as point estimates for the average percent change in the early start and delayed start subgroups from an analysis of covariance (ANCOVA) model with country, treatment, and baseline lung density as fixed effects and inspiration state as a repeated random effect. The baseline is the last assessment from the preceding study CE1226\_4001.
Time frame: From baseline to 2 years
Population: ITT population. Subjects may not have been included in all efficacy analyses because of missing efficacy assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zemaira® (Early Start) | Percent Change in Adjusted Lung Density | TLC and FRC combined, n = 64, 60 | -6.741 Percent change from baseline | Standard Deviation 1.4031 |
| Zemaira® (Early Start) | Percent Change in Adjusted Lung Density | TLC, n = 64, 59 | -6.825 Percent change from baseline | Standard Deviation 1.4286 |
| Zemaira® (Early Start) | Percent Change in Adjusted Lung Density | FRC, n = 64, 60 | -6.494 Percent change from baseline | Standard Deviation 1.5027 |
| Zemaira® (Delayed Start) | Percent Change in Adjusted Lung Density | TLC and FRC combined, n = 64, 60 | -7.035 Percent change from baseline | Standard Deviation 1.4671 |
| Zemaira® (Delayed Start) | Percent Change in Adjusted Lung Density | TLC, n = 64, 59 | -6.674 Percent change from baseline | Standard Deviation 1.5061 |
| Zemaira® (Delayed Start) | Percent Change in Adjusted Lung Density | FRC, n = 64, 60 | -8.281 Percent change from baseline | Standard Deviation 1.5752 |
Comparison: Analysis of the percent change in lung density (for TLC + FRC combined) from baseline to 2 years was analyzed using an ANCOVA model with country, treatment, and baseline lung density as fixed effects and inspiration state as a repeated random effect.p-value: 0.88395% CI: [-3.645, 4.233]ANCOVA
Comparison: Analysis of the percent change in lung density (for TLC) from baseline to 2 years was analyzed using an ANCOVA model with country, treatment, and baseline lung density as fixed effects.p-value: 0.94195% CI: [-4.172, 3.87]ANCOVA
Comparison: Analysis of the percent change in lung density (for FRC) from baseline to 2 years was analyzed using an ANCOVA model with country, treatment, and baseline lung density as fixed effects.p-value: 0.40495% CI: [-2.44, 6.014]ANCOVA
Secondary
Percent Change in Lung Function as Measured by Forced Expiratory Volume in 1 Second (FEV1)
Time frame: From baseline up to 2 years
Population: ITT population. Subjects may not have been included in all efficacy analyses because of missing efficacy assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zemaira® (Early Start) | Percent Change in Lung Function as Measured by Forced Expiratory Volume in 1 Second (FEV1) | -8.610 Percent change from baseline | Standard Deviation 12.9541 |
| Zemaira® (Delayed Start) | Percent Change in Lung Function as Measured by Forced Expiratory Volume in 1 Second (FEV1) | -8.666 Percent change from baseline | Standard Deviation 10.9057 |
Secondary
Percent Change in Lung Function as Measured by Percent Predicted FEV1
Time frame: From baseline up to 2 years
Population: ITT population. Subjects may not have been included in all efficacy analyses because of missing efficacy assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zemaira® (Early Start) | Percent Change in Lung Function as Measured by Percent Predicted FEV1 | -7.165 Percent change from baseline | Standard Deviation 13.2053 |
| Zemaira® (Delayed Start) | Percent Change in Lung Function as Measured by Percent Predicted FEV1 | -6.958 Percent change from baseline | Standard Deviation 11.0846 |
Secondary
Percent Change in Lung Function as Measured by Ratio of FEV1/FVC (Forced Vital Capacity)
Time frame: From baseline up to 2 years
Population: ITT population. Subjects may not have been included in all efficacy analyses because of missing efficacy assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zemaira® (Early Start) | Percent Change in Lung Function as Measured by Ratio of FEV1/FVC (Forced Vital Capacity) | 0.560 Percent change from baseline | Standard Deviation 12.9685 |
| Zemaira® (Delayed Start) | Percent Change in Lung Function as Measured by Ratio of FEV1/FVC (Forced Vital Capacity) | -5.441 Percent change from baseline | Standard Deviation 10.8993 |
Secondary
Time to First Pulmonary Exacerbation
Time frame: Up to 2 years
Population: ITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zemaira® (Early Start) | Time to First Pulmonary Exacerbation | 0.405 years |
| Zemaira® (Delayed Start) | Time to First Pulmonary Exacerbation | 0.602 years |