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

Phase 4

Completed

Conditions: Emphysema
Alpha1-proteinase Inhibitor Deficiency

Interventions: Biological: Alpha1-proteinase inhibitor
Other: Placebo

Registration Number: NCT00261833

Lead Sponsor: CSL Behring

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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 180

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Zemaira®	Alpha1-proteinase inhibitor	-
Placebo	Placebo	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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 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.
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).
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.
Percent Change in Percent Predicted FEV1	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.