Alpha 1-Antitrypsin Deficiency
Conditions
Keywords
alpha 1 proteinase inhibitor, alpha1 proteinase inhibitor, congenital emphysema, replacement therapy
Brief summary
The goal of this trial was to explore the utility of evaluating emphysema progression through CT scans measuring lung density during a 2 year period of weekly infusions of either placebo or human alpha-1-antitrypsin (AAT; Prolastin®). Exacerbation data recorded in patient diaries were also collected. All efficacy data were analyzed for potential use in evaluating Prolastin efficacy in this and other clinical trials.
Detailed description
This is a one to one randomized, placebo-controlled, clinical, exploratory study with the aim of collecting information on possible clinical endpoints i.e., the progression of emphysema by lung density measurements with CT scan and frequency of exacerbations that could be used for a subsequent placebo controlled clinical trial. Progression of disease will be investigated in 80 patients with alpha-1-antitrypsin deficiency, who will be treated with human alpha-1-antitrypsin (AAT; Prolastin®) or placebo weekly for two years to analyze the effect of treatment on lung density and exacerbations. Targeted augmentation therapy with weekly infusions of Prolastin® will be a dose of 60 mg/kg body weight (range of 51.72 to 71.43 mg per kg body weight). Therefore, this study focuses on several questions: * Is the 15th percentile point calculated by analysis of CT lung histograms a useful endpoint for clinical trials in AAT deficiency? * Is quantitation of exacerbations in AAT-deficient patients a useful endpoint for clinical trials in AAT deficiency? * Are there significant differences between the treatments in favor of Prolastin®?
Interventions
Weekly infusion of 60 mg/kg body weight for 2 years
DRUGAlbumin (Human) 20%, United States Pharmacopeia (USP)
Weekly infusion for 2 years. Albumin (Human) 20% will be diluted with 5% glucose to a final concentration of 2.0%.
Sponsors
Grifols Therapeutics LLC
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Patient with pulmonary emphysema due to severe congenital AAT deficiency of phenotype protease inhibitor Z (PiZ) or other rare genotypes (not MS, MZ or SZ) and AAT serum level \< 11 microns (µM) or \< 80 mg/dL (status to be confirmed by phenotyping and genotyping) * Inspiratory capacity (VC - ERV) \> 1.2 L and forced expiratory volume at one second (FEV1) \< 80% of predicted value post bronchodilator * FEV1/VC \< 70% of predicted value post-bronchodilator or transfer factor of carbon monoxide (KCO) \< 80% of predicted value post-bronchodilator * History of at least one exacerbation in the past 2 years * Written informed consent
Exclusion criteria
* FEV1 \< 25% of predicted value post-bronchodilator * Augmentation therapy for more than one month with plasma-derived human alpha 1-antitrypsin (AAT) within the last 2 years * History of lung transplant * Any lung surgery within the past 2 years * On any thoracic surgery waiting list * Diagnosis of liver cirrhosis * Severe concomitant disease * Active pulmonary infection/exacerbations within the last month * Active smoking during the last 6 months or plasma positive for cotinine * Body weight \< 42 kg or \> 92 kg * Pregnancy or lactation * Women of child-bearing potential without adequate contraception
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Progression Rate of Emphysema Determined by Change in 15th Percentile of Lung Density Measured by Annual CT Scan of the Whole Lung | 24 or 30 months |
Secondary
| Measure | Time frame |
|---|---|
| The Frequency of Exacerbations as Determined by Patient Diary. | 24 or 30 months |
| The Deterioration of the Lung Function Will be Assessed by Measurement of the Change in Forced Expiratory Volume at One Second (FEV1) and Transfer Factor of Carbon Monoxide (KCO) | 24 or 30 months |
| Change in Lung Density at Each Visit as Measured by Computed Tomography | 24 or 30 months |
| Mortality | 24 or 30 months |
| Quality of Life With a Disease Specific Instrument, the St. George's Respiratory Questionnaire | 24 or 30 months |
| Duration and Severity of the Exacerbations | 24 or 30 months |
Countries
Denmark, Sweden, United Kingdom
Participant flow
Recruitment details
Multicenter study with 3 sites in Denmark, Sweden, and the United Kingdom.
Participants by arm
| Arm | Count |
|---|---|
| Prolastin (60 mg/kg Body Weight) | 38 |
| Placebo | 39 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Disease progression | 0 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lung transplantation | 1 | 2 |
| Overall Study | Too ill to attend visit | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Prolastin (60 mg/kg Body Weight) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 34 Participants | 67 Participants |
| Age, Continuous | 54.68 years STANDARD_DEVIATION 8.29 | 55.26 years STANDARD_DEVIATION 9.68 | 54.97 years STANDARD_DEVIATION 9.03 |
| Region of Enrollment Denmark | 18 participants | 17 participants | 35 participants |
| Region of Enrollment Sweden | 8 participants | 8 participants | 16 participants |
| Region of Enrollment United Kingdom | 12 participants | 14 participants | 26 participants |
| Severity of COPD at baseline Mild | 1 participants | 2 participants | 3 participants |
| Severity of COPD at baseline Moderate | 10 participants | 8 participants | 18 participants |
| Severity of COPD at baseline None | 2 participants | 2 participants | 4 participants |
| Severity of COPD at baseline Severe | 19 participants | 20 participants | 39 participants |
| Severity of COPD at baseline Very Severe | 6 participants | 7 participants | 13 participants |
| Sex: Female, Male Female | 13 Participants | 23 Participants | 36 Participants |
| Sex: Female, Male Male | 25 Participants | 16 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 37 / 38 | 38 / 39 |
| serious Total, serious adverse events | 9 / 38 | 15 / 39 |
Outcome results
Primary
The Progression Rate of Emphysema Determined by Change in 15th Percentile of Lung Density Measured by Annual CT Scan of the Whole Lung
Time frame: 24 or 30 months
Population: The modified Intent-To-Treat Population was defined as all subjects in the Intent-To-Treat (ITT) Population (all randomized subjects) who had a valid baseline CT scan and at least one valid post-baseline CT scan measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prolastin (60 mg/kg Body Weight) | The Progression Rate of Emphysema Determined by Change in 15th Percentile of Lung Density Measured by Annual CT Scan of the Whole Lung | Baseline | 47.980 g/L | Standard Deviation 19.072 |
| Prolastin (60 mg/kg Body Weight) | The Progression Rate of Emphysema Determined by Change in 15th Percentile of Lung Density Measured by Annual CT Scan of the Whole Lung | Endpoint | 45.085 g/L | Standard Deviation 19.433 |
| Prolastin (60 mg/kg Body Weight) | The Progression Rate of Emphysema Determined by Change in 15th Percentile of Lung Density Measured by Annual CT Scan of the Whole Lung | Change from Baseline | -2.895 g/L | Standard Deviation 4.739 |
| Placebo | The Progression Rate of Emphysema Determined by Change in 15th Percentile of Lung Density Measured by Annual CT Scan of the Whole Lung | Baseline | 45.477 g/L | Standard Deviation 16.949 |
| Placebo | The Progression Rate of Emphysema Determined by Change in 15th Percentile of Lung Density Measured by Annual CT Scan of the Whole Lung | Endpoint | 41.354 g/L | Standard Deviation 16.26 |
| Placebo | The Progression Rate of Emphysema Determined by Change in 15th Percentile of Lung Density Measured by Annual CT Scan of the Whole Lung | Change from Baseline | -4.124 g/L | Standard Deviation 4.147 |
Comparison: The main effect ANCOVA model includes the change from baseline to endpoint as the dependent variable, treatment and center as fixed factors, change in logarithm of total lung volume and baseline measurement as covariates.p-value: 0.049ANCOVA
Secondary
Change in Lung Density at Each Visit as Measured by Computed Tomography
Time frame: 24 or 30 months
Secondary
Duration and Severity of the Exacerbations
Time frame: 24 or 30 months
Secondary
Mortality
Time frame: 24 or 30 months
Secondary
Quality of Life With a Disease Specific Instrument, the St. George's Respiratory Questionnaire
Time frame: 24 or 30 months
Secondary
The Deterioration of the Lung Function Will be Assessed by Measurement of the Change in Forced Expiratory Volume at One Second (FEV1) and Transfer Factor of Carbon Monoxide (KCO)
Time frame: 24 or 30 months
Secondary
The Frequency of Exacerbations as Determined by Patient Diary.
Time frame: 24 or 30 months