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A Pilot Study of Alpha-1-Antitrypsin (AAT) in Steroid Refractory Acute Graft vs Host Disease

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ClinicalTrials.gov Identifier: NCT01700036
Recruitment Status : Completed
First Posted : October 4, 2012
Results First Posted : January 5, 2018
Last Update Posted : November 27, 2018
Sponsor:
Collaborators:
CSL Behring
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
University of Michigan Rogel Cancer Center

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Graft vs Host Disease
Intervention Drug: Alpha-1-Antitrypsin (AAT)
Enrollment 40
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Treatment Arm
Hide Arm/Group Description

Alpha-1-Antitrypsin (AAT) for the treatment of Steroid Refractory Acute Graft vs Host Disease.

Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28. A second course of treatment will not be given.

Period Title: Overall Study
Started 40
Completed 40
Not Completed 0
Arm/Group Title Treatment Arm
Hide Arm/Group Description

Alpha-1-Antitrypsin (AAT) for the treatment of Steroid Refractory Acute Graft vs Host Disease.

Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28. A second course of treatment will not be given.

Overall Number of Baseline Participants 40
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 40 participants
59
(18 to 70)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants
Female
13
  32.5%
Male
27
  67.5%
1.Primary Outcome
Title Percentage of Patients That Respond to Treatment
Hide Description

To estimate the proportion of patients with steroid refractory acute Graft vs Host Disease) GvHD who respond (achieve either PR or CR) to Alpha-1 Antitrypsin (AAT) at a dose of 60mg/kg twice weekly for 8 doses

Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy.

Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.

Time Frame 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Treatment Arm
Hide Arm/Group Description:
Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.
Overall Number of Participants Analyzed 40
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
65
(48 to 79)
2.Secondary Outcome
Title Percentage of Patients Who Achieve a Complete Response to Treatment
Hide Description

To estimate the proportion of patients in complete remission without additional therapy at four weeks after the last dose of AAT

Complete remission is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.

Time Frame 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Treatment Arm
Hide Arm/Group Description:
Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.
Overall Number of Participants Analyzed 40
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
35
(21 to 52)
3.Secondary Outcome
Title Percentage of Patients With Documented Infection
Hide Description To estimate the incidence of infection during and following treatment of steroid refractory acute GVHD with AAT
Time Frame 30 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Treatment Arm
Hide Arm/Group Description:
Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.
Overall Number of Participants Analyzed 40
Measure Type: Number
Unit of Measure: percentage of patients
32.5
4.Secondary Outcome
Title The Percentage of Patients Alive at 6 Months for Patients in CR or PR
Hide Description

Survival at 6 months in patients receiving AAT treatment for steroid refractory acute GVHD for patients that achieved a CR or PR.

Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy.

Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.

Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
40 patients were enrolled and 26 patients achieved a CR or PR.
Arm/Group Title Treatment Arm
Hide Arm/Group Description:
Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.
Overall Number of Participants Analyzed 26
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of patients
50
(34 to 73)
5.Secondary Outcome
Title Mean Fold Change in Plasma Biomarkers
Hide Description The fold change in levels of plasma biomarkers IL-6, TNF-alpha and ST2 will be measured pre-treatment and after the administration of AAT treatment for steroid refractory GvHD.
Time Frame Baseline, 2 weeks, and 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Treatment Arm
Hide Arm/Group Description:
Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.
Overall Number of Participants Analyzed 40
Mean (Standard Error)
Unit of Measure: fold change from baseline
IL-6 Fold Change at 2 weeks 6.3  (3.6)
IL-6 Fold Change at 4 weeks 4  (1.9)
TNF-alpha Fold Change at 2 weeks 1.7  (0.8)
TNF-alpha Fold Change at 4 weeks 1.1  (0.2)
ST2 Fold Change at 2 weeks 1.2  (0.4)
ST2 Fold Change at 4 weeks 1.5  (0.7)
6.Secondary Outcome
Title Mean Plasma Levels for Alpha-1-Antitrypsin (AAT)
Hide Description Plasma levels of Alpha-1-Antitrypsin(AAT)will be measured.
Time Frame 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Treatment Arm
Hide Arm/Group Description:
Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.
Overall Number of Participants Analyzed 40
Mean (Standard Error)
Unit of Measure: mg/dl
AAT levels at two weeks 196.8  (11.91)
AAT levels at 4 weeks 214.8  (18.62)
Time Frame Patients will be followed for adverse events for 30 days after the last dose of the study drug.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Treatment Arm
Hide Arm/Group Description Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.
All-Cause Mortality
Treatment Arm
Affected / at Risk (%)
Total   8/40 (20.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Treatment Arm
Affected / at Risk (%) # Events
Total   11/40 (27.50%)    
Blood and lymphatic system disorders   
Disseminated intravascular coagulation   1/40 (2.50%)  1
Thrombotic thrombocytopenic purpura   1/40 (2.50%)  1
Gastrointestinal disorders   
Colitis   1/40 (2.50%)  1
Lower gastrointestinal hemorrhage   1/40 (2.50%)  1
General disorders   
Multi-organ failure   1/40 (2.50%)  1
Immune system disorders   
Immune system disorder   2/40 (5.00%)  2
Infections and infestations   
Bladder infection   1/40 (2.50%)  1
Hepatic infection   1/40 (2.50%)  1
Infection   1/40 (2.50%)  1
Sepsis   2/40 (5.00%)  2
Investigations   
Blood bilirubin increased   1/40 (2.50%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Neoplasms benign, malignant and unspecified   1/40 (2.50%)  1
Respiratory, thoracic and mediastinal disorders   
Hypoxia   1/40 (2.50%)  1
Respiratory failure   3/40 (7.50%)  4
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Treatment Arm
Affected / at Risk (%) # Events
Total   31/40 (77.50%)    
Blood and lymphatic system disorders   
Anemia   4/40 (10.00%)  4
Disseminated intravascular coagulation   1/40 (2.50%)  1
Thrombotic thrombocytopenic purpura   3/40 (7.50%)  3
Cardiac disorders   
Atrial fibrillation   1/40 (2.50%)  1
Sinus bradycardia   1/40 (2.50%)  1
Sinus tachycardia   1/40 (2.50%)  1
Supraventricular tachycardia   1/40 (2.50%)  1
Gastrointestinal disorders   
Abdominal pain   1/40 (2.50%)  1
Ascites   1/40 (2.50%)  1
Colitis   1/40 (2.50%)  1
Diarrhea   1/40 (2.50%)  1
Gastrointestinal disorder   1/40 (2.50%)  1
Lower gastrointestinal hemorrhage   3/40 (7.50%)  3
General disorders   
Fever   2/40 (5.00%)  2
Multi-organ failure   1/40 (2.50%)  1
Immune system disorders   
Immune system disorder   2/40 (5.00%)  2
Infections and infestations   
Bladder infection   1/40 (2.50%)  1
Device related infection   1/40 (2.50%)  1
Enterocolitis infectious   1/40 (2.50%)  1
Hepatic infection   1/40 (2.50%)  1
Infection   11/40 (27.50%)  16
Kidney infection   1/40 (2.50%)  2
Lung infection   1/40 (2.50%)  1
Mucosal infection   1/40 (2.50%)  1
Sepsis   3/40 (7.50%)  3
Skin infection   2/40 (5.00%)  3
Urinary tract infection   3/40 (7.50%)  3
Injury, poisoning and procedural complications   
Spinal fracture   2/40 (5.00%)  2
Investigations   
Alanine aminotransferase increased   1/40 (2.50%)  1
Blood bilirubin increased   6/40 (15.00%)  6
Lymphocyte count decreased   5/40 (12.50%)  6
Lymphocyte count increased   1/40 (2.50%)  1
Neutrophil count decreased   1/40 (2.50%)  1
Platelet count decreased   5/40 (12.50%)  7
White blood cell decreased   3/40 (7.50%)  3
Metabolism and nutrition disorders   
Anorexia   1/40 (2.50%)  1
Hyperglycemia   7/40 (17.50%)  7
Hyperkalemia   1/40 (2.50%)  1
Hypoalbuminemia   3/40 (7.50%)  3
Hyponatremia   1/40 (2.50%)  1
Musculoskeletal and connective tissue disorders   
Generalized muscle weakness   1/40 (2.50%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Neoplasms benign, malignant and unspecified   1/40 (2.50%)  1
Nervous system disorders   
Encephalopathy   1/40 (2.50%)  1
Nervous system disorder   1/40 (2.50%)  1
Psychiatric disorders   
Delirium   2/40 (5.00%)  2
Renal and urinary disorders   
Acute kidney injury   1/40 (2.50%)  1
Hematuria   1/40 (2.50%)  1
Urinary retention   1/40 (2.50%)  1
Respiratory, thoracic and mediastinal disorders   
Dyspnea   2/40 (5.00%)  2
Hypoxia   4/40 (10.00%)  4
Pneumonitis   2/40 (5.00%)  2
Respiratory failure   3/40 (7.50%)  4
Skin and subcutaneous tissue disorders   
Rash maculo-papular   2/40 (5.00%)  2
Vascular disorders   
Hypertension   2/40 (5.00%)  2
Hypotension   1/40 (2.50%)  1
Thromboembolic event   2/40 (5.00%)  2
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Dr. Pavan Reddy, MD
Organization: University of Michigan Cancer Center
Phone: 734-936-8785
Responsible Party: University of Michigan Rogel Cancer Center
ClinicalTrials.gov Identifier: NCT01700036     History of Changes
Other Study ID Numbers: umcc 2012.043
HUM 67889 ( Other Identifier: University of Michigan IRBMED )
First Submitted: October 2, 2012
First Posted: October 4, 2012
Results First Submitted: November 2, 2017
Results First Posted: January 5, 2018
Last Update Posted: November 27, 2018