Zemaira in Subjects With Emphysema Due to Alpha1-Proteinase Inhibitor Deficiency

Study Overview
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Brief Summary
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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).

Official Title
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A Randomized, Placebo-Controlled, Double-Blind, Multicenter Phase III/IV Study to Compare the Efficacy and Safety of 60mg/kg Body Weight of Zemaira® Weekly I.V. Administration With Placebo Weekly I.V. Administration in Chronic Augmentation and Maintenance Therapy in Subjects With Emphysema Due to Alpha1-Proteinase Inhibitor Deficiency

Conditions
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Alpha1-proteinase Inhibitor Deficiency, Emphysema

Intervention / Treatment
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* Biological: Alpha1-proteinase inhibitor
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zemaira®<br> | Biological: Alpha1-proteinase inhibitor<br>* 60 mg/kg body weight/week intravenous<br>* Other names: Zemaira®;|
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* Lyophilized preparation: 60 mg/kg body weight/week intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Over a 2-year period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Over a 2-year period | 
| Percent Change in FEV1 | Percent change from baseline to Month 24. | From baseline to 2 years | 
| 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. | Over a 2-year period | 
| 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. | From baseline to 2 years | 
| 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). | From baseline to 2 years | 
| 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. | From baseline to 2 years | 
| 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). | Over a 2-year period | 
| Percent Change in Percent Predicted FEV1 | Percent change from baseline to Month 24. | From baseline to 2 years | 
| Percent Change in FEV1 Divided by Forced Vital Capacity | Percent change from baseline to Month 24. | From baseline to 2 years | 
| Percent Change in DLCO | Percent change from baseline to Month 24. | From baseline to 2 years | 
| 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. | Over a 2-year period | 
| 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. | Over a 2-year period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alpha1-proteinase inhibitor deficiency, Emphysema, Chronic augmentation and maintenance therapy