Extension Study of Zemaira® i.v. Administration in Subjects With Emphysema Due to alpha1-proteinase Inhibitor Deficiency.

An Open-label, Non-controlled, Multicenter, Multinational Study to Evaluate the Efficacy and Safety of Zemaira® Administration in Chronic Augmentation and Maintenance Therapy in Subjects With Emphysema Due to alpha1-proteinase Inhibitor Deficiency Who Completed Clinical Study CE1226_4001

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).

Study Overview

• Status: Completed
• Conditions: Emphysema; Alpha 1-proteinase Inhibitor Deficiency
• Intervention / Treatment: Biological: Alpha1- proteinase inhibitor [human]

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • Darlinghurst, Australia, 2010
    • Study Site
  • Nedlands, Australia, 6009
    • Study Site
  • New Lambton, Australia, 2305
    • Study Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Study Site
  • Victoria
    • Fitzroy, Victoria, Australia, 3065
      • Study Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6J1S3
      • Study Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Study Site
  • Ontario
    • Toronto, Ontario, Canada, M5T 2S8
      • Study Site
• Czech Republic
  • Praha 4 - Krc, Czech Republic, 14059
    • Study Site
• Denmark
  • Arhus C, Denmark, 8000
    • Study Site
  • Hellerup, Denmark, 2900
    • Study Site
• Estonia
  • Tartu, Estonia, 51014
    • Study Site
• Finland
  • Oulu, Finland, 90220
    • Study Site
• Germany
  • Essen, Germany, 45239
    • Study Site
  • Heidelberg, Germany, 69126
    • Study Site
  • Nürnberg, Germany, 90419
    • Study Site
• Ireland
  • Dublin, Ireland, 9
    • Study Site
• Poland
  • Krakow, Poland, 31-066
    • Study Site
  • Warsaw, Poland, 01-138
    • Study Site
• Romania
  • Bucuresti, Romania, 011026
    • Study Site
• Sweden
  • Malmo, Sweden, 20502
    • Study Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zemaira®	Biological: Alpha1- proteinase inhibitor [human]; Lyophilized preparation of 60 mg/kg body weight intravenously once per week; Other Names: Zemaira®; Respreeza®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From baseline to 2 years
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.	From baseline to 2 years
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.	From baseline to 2 years
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
Percent Change in Lung Function as Measured by Percent Predicted FEV1		From baseline up to 2 years
Number of Subjects With Pulmonary Exacerbations		Up to 2 years
Annual Rate in Subject Years of Pulmonary Exacerbations	Annual exposure-adjusted incidence rate of pulmonary exacerbations.	Up to 2 years
Time to First Pulmonary Exacerbation		Up to 2 years
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.	From baseline up to 2.5 years

Collaborators and Investigators

• Sponsor: CSL Behring

Publications and helpful links

General Publications

• Greulich T, Chlumsky J, Wencker M, Vit O, Fries M, Chung T, Shebl A, Vogelmeier C, Chapman KR, McElvaney NG; RAPID Trial Group. Safety of biweekly alpha1-antitrypsin treatment in the RAPID programme. Eur Respir J. 2018 Nov 29;52(5):1800897. doi: 10.1183/13993003.00897-2018. Print 2018 Nov.
• McElvaney NG, Burdon J, Holmes M, Glanville A, Wark PA, Thompson PJ, Hernandez P, Chlumsky J, Teschler H, Ficker JH, Seersholm N, Altraja A, Makitaro R, Chorostowska-Wynimko J, Sanak M, Stoicescu PI, Piitulainen E, Vit O, Wencker M, Tortorici MA, Fries M, Edelman JM, Chapman KR; RAPID Extension Trial Group. Long-term efficacy and safety of alpha1 proteinase inhibitor treatment for emphysema caused by severe alpha1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE). Lancet Respir Med. 2017 Jan;5(1):51-60. doi: 10.1016/S2213-2600(16)30430-1. Epub 2016 Dec 2. Erratum In: Lancet Respir Med. 2017 Feb;5(2):e13.
• Chapman KR, Burdon JG, Piitulainen E, Sandhaus RA, Seersholm N, Stocks JM, Stoel BC, Huang L, Yao Z, Edelman JM, McElvaney NG; RAPID Trial Study Group. Intravenous augmentation treatment and lung density in severe alpha1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Jul 25;386(9991):360-8. doi: 10.1016/S0140-6736(15)60860-1. Epub 2015 May 27.

Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: April 29, 2008
• First Submitted That Met QC Criteria: April 30, 2008
• First Posted (Estimate): May 1, 2008

Study Record Updates

• Last Update Posted (Estimate): August 15, 2016
• Last Update Submitted That Met QC Criteria: July 13, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Emphysema; Alpha1-proteinase inhibitor deficiency; Chronic augmentation and maintenance therapy; Emphysema due to Alpha 1-proteinase inhibitor deficiency
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Liver Diseases; Genetic Diseases, Inborn; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Subcutaneous Emphysema; Pulmonary Emphysema; Emphysema; Alpha 1-Antitrypsin Deficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Serine Proteinase Inhibitors; Trypsin Inhibitors; Protease Inhibitors; Alpha 1-Antitrypsin
• Other Study ID Numbers: CE1226_3001; 1466 (CSL Behring); 2007-007129-38 (EudraCT Number)