Clinical Trial Results:
A double-blind, randomized, placebo-controlled, cross-over study to evaluate the clinical efficacy and safety of subcutaneous administration of human plasma-derived C1-esterase inhibitor in the prophylactic treatment of hereditary angioedema
Summary
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EudraCT number |
2013-000916-10 |
Trial protocol |
GB HU IT ES CZ |
Global end of trial date |
12 Oct 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
17 Nov 2016
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First version publication date |
17 Nov 2016
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CSL830_3001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01912456 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
CSL Behring
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Sponsor organisation address |
Emil-von-Behring-Strasse 76, Marburg, Germany, 35041
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Public contact |
Trial Disclosure Manager, CSL Behring GmbH, clinicaltrials@cslbehring.com
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Scientific contact |
Trial Disclosure Manager, CSL Behring GmbH, clinicaltrials@cslbehring.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
04 Dec 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Oct 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate the clinical efficacy of subcutaneous (SC) CSL830 in the prophylactic treatment of hereditary angioedema (HAE). To compare the clinical efficacy of 2 doses of SC CSL830.
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Protection of trial subjects |
This study was carried out in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, standard operating procedures for clinical research and development at CSL Behring and any other relevant procedures and applicable international and national regulatory requirements. The study protocol and all amendments were approved by the Independent Ethics Committee / Institutional Review Board of the participating centers. Before undergoing Screening procedures for possible enrollment into the study, the subjects’ legally acceptable representative was informed, in an understandable form, about the nature, scope, and possible consequences of the study.
The investigator was responsible for obtaining a subject’s legally acceptable representative written informed consent to participate in the study. The investigator could cease study treatment and withdraw the subject, or the subject could withdraw himself from participation in the study at any time. If a subject was withdrawn from the study or further participation was declined, the subject would continue to have access to medical care and would be treated according to routine medical practice, but would no longer receive the investigational medicinal product.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 Dec 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 1
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Country: Number of subjects enrolled |
Canada: 8
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Country: Number of subjects enrolled |
Israel: 9
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Country: Number of subjects enrolled |
Romania: 1
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Country: Number of subjects enrolled |
United States: 54
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Country: Number of subjects enrolled |
Spain: 4
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Country: Number of subjects enrolled |
United Kingdom: 3
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Country: Number of subjects enrolled |
Czech Republic: 1
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Country: Number of subjects enrolled |
Hungary: 4
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Country: Number of subjects enrolled |
Italy: 5
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Worldwide total number of subjects |
90
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EEA total number of subjects |
18
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
7
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Adults (18-64 years) |
76
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From 65 to 84 years |
7
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
115 subjects were screened and 90 were randomized/enrolled | ||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Period 1
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Investigator, Carer, Assessor, Subject | ||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo high/CSL830 (40) | ||||||||||||||||||||||||||||||||||||||||
Arm description |
In Period 1, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
A high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks
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Arm title
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CSL830 (40)/placebo high | ||||||||||||||||||||||||||||||||||||||||
Arm description |
In Period 1, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
CSL830
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Investigational medicinal product code |
CSL830
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Other name |
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Pharmaceutical forms |
Powder and solution for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
A low-volume dose of C1-esterase inhibitor (40 IU/kg) will be administered subcutaneously twice a week for up to 16 weeks
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Arm title
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Placebo low/CSL830 (60) | ||||||||||||||||||||||||||||||||||||||||
Arm description |
In Period 1, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
A low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks
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Arm title
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CSL830 (60)/placebo low | ||||||||||||||||||||||||||||||||||||||||
Arm description |
In Period 1, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
CSL830
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Investigational medicinal product code |
CSL830
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Other name |
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Pharmaceutical forms |
Powder and solution for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
A high-volume dose of C1-esterase inhibitor (60 IU/kg) will be administered subcutaneously twice a week for up to 16 weeks
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Period 2
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Period 2 title |
Period 2
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | ||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo high/CSL830 (40) | ||||||||||||||||||||||||||||||||||||||||
Arm description |
In Period 1, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
CSL830
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Investigational medicinal product code |
CSL830
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Other name |
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Pharmaceutical forms |
Powder and solution for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
A low-volume dose of C1-esterase inhibitor (40 IU/kg) will be administered subcutaneously twice a week for up to 16 weeks
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Arm title
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CSL830 (40)/Placebo high | ||||||||||||||||||||||||||||||||||||||||
Arm description |
In Period 1, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
A high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks
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Arm title
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Placebo low/CSL830 (60) | ||||||||||||||||||||||||||||||||||||||||
Arm description |
In Period 1, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
CSL830
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Investigational medicinal product code |
CSL830
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Other name |
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Pharmaceutical forms |
Powder and solution for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
A high-volume dose of C1-esterase inhibitor (60 IU/kg) will be administered subcutaneously twice a week for up to 16 weeks
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Arm title
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CSL830 (60)/Placebo low | ||||||||||||||||||||||||||||||||||||||||
Arm description |
In Period 1, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
A low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks
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Baseline characteristics reporting groups
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Reporting group title |
Placebo high/CSL830 (40)
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Reporting group description |
In Period 1, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
CSL830 (40)/placebo high
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Reporting group description |
In Period 1, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo low/CSL830 (60)
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Reporting group description |
In Period 1, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
CSL830 (60)/placebo low
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Reporting group description |
In Period 1, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo high/CSL830 (40)
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Reporting group description |
In Period 1, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks. | ||
Reporting group title |
CSL830 (40)/placebo high
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Reporting group description |
In Period 1, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks. | ||
Reporting group title |
Placebo low/CSL830 (60)
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Reporting group description |
In Period 1, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks. | ||
Reporting group title |
CSL830 (60)/placebo low
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Reporting group description |
In Period 1, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks. | ||
Reporting group title |
Placebo high/CSL830 (40)
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Reporting group description |
In Period 1, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks. | ||
Reporting group title |
CSL830 (40)/Placebo high
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Reporting group description |
In Period 1, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks. | ||
Reporting group title |
Placebo low/CSL830 (60)
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Reporting group description |
In Period 1, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks. | ||
Reporting group title |
CSL830 (60)/Placebo low
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Reporting group description |
In Period 1, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks. | ||
Subject analysis set title |
CSL830 (40) - ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The ITT Population consisted of all subjects who provided informed consent / assent and were randomized, regardless of whether they received investigational product.
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Subject analysis set title |
CSL830 (60) - ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The ITT Population consisted of all subjects who provided informed consent / assent and were randomized, regardless of whether they received investigational product.
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Subject analysis set title |
Placebo high - ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The ITT Population consisted of all subjects who provided informed consent / assent and were randomized, regardless of whether they received investigational product.
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Subject analysis set title |
Placebo Low - ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The ITT Population consisted of all subjects who provided informed consent / assent and were randomized, regardless of whether they received investigational product.
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Subject analysis set title |
CSL830 (40) - Safety
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The Safety Population consisted of all subjects who provided informed consent / assent, were randomized, and received at least 1 dose (or partial dose) of investigational product.
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Subject analysis set title |
CSL830 (60) - Safety
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The Safety Population consisted of all subjects who provided informed consent / assent, were randomized, and received at least 1 dose (or partial dose) of investigational product.
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Subject analysis set title |
Placebo high - Safety
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The Safety Population consisted of all subjects who provided informed consent / assent, were randomized, and received at least 1 dose (or partial dose) of investigational product.
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Subject analysis set title |
Placebo low - Safety
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The Safety Population consisted of all subjects who provided informed consent / assent, were randomized, and received at least 1 dose (or partial dose) of investigational product.
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End point title |
Time-normalized number of hereditary angioedema attacks | ||||||||||||||||||||
End point description |
The time normalized number of HAE attacks as reported by the investigator per subject was calculated as:
•The total number of HAE attacks per subject and per treatment period / length of stay of subject in treatment period (days),
Where length of stay of subject in treatment period was calculated as:
•Date of last day of subject in treatment period – date of first day of Week 3 of subject in treatment period + 1.
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End point type |
Primary
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End point timeframe |
During the treatment phase, up to 28 weeks
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Statistical analysis title |
Within-subject analysis - Placebo Low /CSL830 (60) | ||||||||||||||||||||
Comparison groups |
Placebo Low - ITT v CSL830 (60) - ITT
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Number of subjects included in analysis |
85
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
-0.12
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.14 | ||||||||||||||||||||
upper limit |
-0.09 | ||||||||||||||||||||
Notes [1] - Because of the crossover design, each subject was randomized to receive both the 60 IU/kg CSL830 and Placebo Low Volume treatments in consecutive treatment periods. Therefore, the subjects in each treatment period are the same subjects and data for all 45 subjects in the ITT population are included in this mixed model analysis. |
|||||||||||||||||||||
Statistical analysis title |
Within-subject analysis - CSL830 (40)/Placebo High | ||||||||||||||||||||
Comparison groups |
CSL830 (40) - ITT v Placebo high - ITT
|
||||||||||||||||||||
Number of subjects included in analysis |
87
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [2] | ||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
-0.08
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.11 | ||||||||||||||||||||
upper limit |
-0.05 | ||||||||||||||||||||
Notes [2] - Because of the crossover design, each subject was randomized to receive both the 40 IU/kg CSL830 and Placebo High Volume treatments in consecutive treatment periods. Therefore, the subjects in each treatment period are the same subjects and data for all 45 subjects in the ITT population are included in this mixed model analysis. |
|||||||||||||||||||||
Statistical analysis title |
Between-subject analysis - CSL830 (40)/CSL830 (60) | ||||||||||||||||||||
Comparison groups |
CSL830 (40) - ITT v CSL830 (60) - ITT
|
||||||||||||||||||||
Number of subjects included in analysis |
86
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [3] | ||||||||||||||||||||
P-value |
= 0.114 | ||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
-0.02
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.05 | ||||||||||||||||||||
upper limit |
0.01 | ||||||||||||||||||||
Notes [3] - Because of the crossover design, each subject was randomized to receive both CSL830 and Placebo treatments in consecutive treatment periods. Therefore, the subjects in each treatment period are the same subjects and data for all 90 subjects in the ITT population are included in this mixed model analysis. |
|
|||||||||||||
End point title |
Percentage of subjects with a ≥ 50% reduction in the number of hereditary angioedema attacks | ||||||||||||
End point description |
The percentage reduction (%) in the time normalized number of HAE attacks was calculated as:
•100 x [1 – (the time normalized number of HAE attacks when treated with CSL830) / (the time normalized number of HAE attacks when treated with placebo)].
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
During the treatment phase, up to 28 weeks
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Between-subject analysis - CSL830 (40)/CSL830 (60) | ||||||||||||
Comparison groups |
CSL830 (60) - ITT v CSL830 (40) - ITT
|
||||||||||||
Number of subjects included in analysis |
82
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
Wilson CI - calculation of percentages | ||||||||||||
Parameter type |
difference in the percentages | ||||||||||||
Point estimate |
13.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.8 | ||||||||||||
upper limit |
29.7 |
|
|||||||||||||||||||||
End point title |
Time-Normalized Number of Uses of Rescue Medication | ||||||||||||||||||||
End point description |
|||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
During the treatment phase, up to 28 weeks
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Within-subject analysis - Placebo Low/CSL830 (60) | ||||||||||||||||||||
Comparison groups |
CSL830 (60) - ITT v Placebo Low - ITT
|
||||||||||||||||||||
Number of subjects included in analysis |
85
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [4] | ||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
-0.12
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.15 | ||||||||||||||||||||
upper limit |
-0.09 | ||||||||||||||||||||
Notes [4] - Because of the crossover design, each subject was randomized to receive both the 60 IU/kg CSL830 and Placebo Low Volume treatments in consecutive treatment periods. Therefore, the subjects in each treatment period are the same subjects and data for all 45 subjects in the ITT population are included in this mixed model analysis. |
|||||||||||||||||||||
Statistical analysis title |
Within-subject analysis - CSL830 (40)/Placebo High | ||||||||||||||||||||
Comparison groups |
CSL830 (40) - ITT v Placebo high - ITT
|
||||||||||||||||||||
Number of subjects included in analysis |
87
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [5] | ||||||||||||||||||||
P-value |
= 0.018 | ||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
-0.15
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.26 | ||||||||||||||||||||
upper limit |
-0.03 | ||||||||||||||||||||
Notes [5] - Because of the crossover design, each subject was randomized to receive both the 40 IU/kg CSL830 and Placebo High Volume treatments in consecutive treatment periods. Therefore, the subjects in each treatment period are the same subjects and data for all 45 subjects in the ITT population are included in this mixed model analysis. |
|||||||||||||||||||||
Statistical analysis title |
Between-subject analysis - CSL830 (40)/CSL830 (60) | ||||||||||||||||||||
Comparison groups |
CSL830 (40) - ITT v CSL830 (60) - ITT
|
||||||||||||||||||||
Number of subjects included in analysis |
86
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [6] | ||||||||||||||||||||
P-value |
= 0.31 | ||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
-0.03
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.07 | ||||||||||||||||||||
upper limit |
0.02 | ||||||||||||||||||||
Notes [6] - Because of the crossover design, each subject was randomized to receive both CSL830 and Placebo treatments in consecutive treatment periods. Therefore, the subjects in each treatment period are the same subjects and data for all 90 subjects in the ITT population are included in this mixed model analysis. |
|
|||||||||||||||||||||
End point title |
Percentage of subjects with adverse events (AEs) within 24 hours of C1-esterase inhibitor or placebo administration | ||||||||||||||||||||
End point description |
|||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Within 24 hours of C1-esterase inhibitor or placebo administration
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Percentage of subjects with AEs or other specified safety events | ||||||||||||||||||||
End point description |
The percentage of subjects experiencing the following during treatment with CSL830 and placebo: unsolicited AEs, serious AEs, suspected adverse drug reactions, increased risk scores for deep vein thrombosis and pulmonary embolism, thromboembolic events, inhibitory anti C1 INH antibodies, or clinically significant abnormalities in laboratory assessments.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
During the treatment phase, up to 32 weeks
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Percentage of subjects experiencing solicited local AEs (Injection site reactions) | ||||||||||||||||||||
End point description |
The percentage of subjects experiencing solicited local AEs (discomfort [eg, pain, burning], swelling, bruising, or itching at the investigational product injection site) during treatment with CSL830 and placebo.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
During the treatment phase, up to 32 weeks
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Investigational product injections resulting in solicited local AEs (Injection site reactions) | ||||||||||||||||||||
End point description |
The rate/injection of injections of C1-esterase inhibitor or placebo that were followed by solicited local AEs (discomfort [eg, pain, burning], swelling, bruising, or itching at the investigational product injection site) during treatment with CSL830 and placebo. Rate/Injection = Number of events/number of injections.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
During the treatment phase, up to 32 weeks
|
||||||||||||||||||||
|
|||||||||||||||||||||
Notes [7] - 1307 total number of injections within treatment [8] - 1320 total number of injections within treatment [9] - 1290 total number of injections within treatment [10] - 1164 total number of injections within treatment |
|||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
During the treatment phase, up to 32 weeks.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The Safety Population consisted of all subjects who provided informed consent / assent, were randomized, and received at least 1 dose (or partial dose) of investigational product.
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.0
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
CSL830 (40)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
CSL830 (60)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo high
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo low
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
20 Feb 2014 |
The study design has been revised so that subjects are not required to discontinue use of their medication for hereditary angioedema (HAE) prophylaxis at entry into the Run-in Period.
The inclusion criteria have been revised to permit the inclusion of subjects who have used a stable regimen of oral medication for prophylaxis against HAE attacks (ie, androgens, tranexamic acid, progestins) within 3 months of the Screening Visit and who do not plan to change that regimen during the study.
The exclusion criteria have been revised to exclude:
a. Subjects with body weight < 40 kilograms
b. Subjects who have used intravenous C1-esterase inhibitor (C1-INH) for routine prophylaxis against HAE attacks (ie, administered every 3 or 4 days) within 3 months of the Screening Visit or who plan to use intravenous C1-INH for routine prophylaxis against HAE attacks during the study.
c. Subjects who are unable to have their HAE adequately managed pharmacologically with on demand treatment, administered either independently or with assistance.
Secondary safety and tolerability endpoints have been added.
The planned statistical analyses have been revised:
a. New sub-group analyses have been included.
b. A description of missing data handling has been added.
c. The lower bound of the 95% confidence interval for the responder rate of the combined active treatment group has been added. The lower bound is 33%.
d. Additional details have been included to support statistical analyses.
The list of permitted on-study medications has been revised to allow the use of medications (eg, intravenous C1-INH) for the pre-procedure prevention of acute HAE attacks during the study. |
||
11 Dec 2014 |
The protocol has undergone administrative revisions to more clearly convey the joint intent of the Steering Committee, the Data Safety Monitoring Board, and CSL Behring regarding study conduct as pertains to the stopping, restarting, and termination rules. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |