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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
CSL Behring
ClinicalTrials.gov Identifier:
NCT00261833
First received: December 2, 2005
Last updated: January 11, 2015
Last verified: January 2015
  Purpose

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).


Condition Intervention Phase
Alpha1-proteinase Inhibitor Deficiency
Emphysema
Biological: Alpha1-proteinase inhibitor
Other: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by CSL Behring:

Primary Outcome Measures:
  • Annual Rate of Change in Lung Density [ Time Frame: Over a 2-year period ] [ Designated as safety issue: No ]
    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:
  • Annual Rate of Pulmonary Exacerbations [ Time Frame: Over a 2-year period ] [ Designated as safety issue: No ]
    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 [ Time Frame: From baseline to 2 years ] [ Designated as safety issue: No ]
    Percent change from baseline to Month 24.

  • Time to First Pulmonary Exacerbation [ Time Frame: Over a 2-year period ] [ Designated as safety issue: No ]
    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 [ Time Frame: From baseline to 2 years ] [ Designated as safety issue: No ]
    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 [ Time Frame: From baseline to 2 years ] [ Designated as safety issue: No ]
    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 [ Time Frame: From baseline to 2 years ] [ Designated as safety issue: No ]
    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) [ Time Frame: Over a 2-year period ] [ Designated as safety issue: Yes ]
    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 Percent Predicted FEV1 [ Time Frame: From baseline to 2 years ] [ Designated as safety issue: No ]
    Percent change from baseline to Month 24.

  • Percent Change in FEV1 Divided by Forced Vital Capacity [ Time Frame: From baseline to 2 years ] [ Designated as safety issue: No ]
    Percent change from baseline to Month 24.

  • Percent Change in DLCO [ Time Frame: From baseline to 2 years ] [ Designated as safety issue: No ]
    Percent change from baseline to Month 24.

  • Duration of Pulmonary Exacerbations Relative to Treatment Duration [ Time Frame: Over a 2-year period ] [ Designated as safety issue: No ]
    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 [ Time Frame: Over a 2-year period ] [ Designated as safety issue: No ]

    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.



Other Outcome Measures:
  • Baseline Lung Density at Total Lung Capacity (TLC) and Forced Residual Capacity (FRC) [ Time Frame: Baseline ] [ Designated as safety issue: No ]

Enrollment: 180
Study Start Date: March 2006
Study Completion Date: September 2012
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Zemaira® Biological: Alpha1-proteinase inhibitor
60 mg/kg body weight/week intravenous
Other Name: Zemaira®
Placebo Comparator: Placebo Other: Placebo
Lyophilized preparation: 60 mg/kg body weight/week intravenous

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00261833

  Show 28 Study Locations
Sponsors and Collaborators
CSL Behring
Investigators
Study Director: Senior Director Immonology & Pulmonology, Clinical R&D CSL Behring
  More Information

Additional Information:
No publications provided by CSL Behring

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: CSL Behring
ClinicalTrials.gov Identifier: NCT00261833     History of Changes
Other Study ID Numbers: CE1226_4001, 1449, 2005-003459-12
Study First Received: December 2, 2005
Results First Received: November 2, 2014
Last Updated: January 11, 2015
Health Authority: United States: Food and Drug Administration
Australia: Department of Health and Ageing Therapeutic Goods Administration
Canada: Ethics Review Committee
Canada: Health Canada
Czech Republic: Ethics Committee
Czech Republic: State Institute for Drug Control
Denmark: Danish Medicines Agency
Denmark: Ethics Committee
Denmark: The Danish National Committee on Biomedical Research Ethics
Estonia: The State Agency of Medicine
Finland: Ethics Committee
Finland: Finnish Medicines Agency
Germany: Ethics Commission
Germany: Paul-Ehrlich-Institut
Ireland: Irish Medicines Board
Ireland: Medical Ethics Research Committee
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Romania: National Medicines Agency
Sweden: Medical Products Agency

Keywords provided by CSL Behring:
Alpha1-proteinase inhibitor deficiency
Emphysema
Chronic augmentation and maintenance therapy

Additional relevant MeSH terms:
Alpha 1-Antitrypsin Deficiency
Alpha 1-Antitrypsin
Emphysema
Pulmonary Emphysema
Digestive System Diseases
Genetic Diseases, Inborn
Liver Diseases
Lung Diseases
Lung Diseases, Obstructive
Pathologic Processes
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Subcutaneous Emphysema
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Serine Proteinase Inhibitors
Trypsin Inhibitors

ClinicalTrials.gov processed this record on August 31, 2015