Clinical Trial Results:
A randomized, placebo-controlled, double-blind Phase III study of the efficacy and safety of recombinant human C1 inhibitor for the treatment of acute attacks in patients with hereditary angioedema
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Summary
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EudraCT number |
2005-000206-31 |
Trial protocol |
IT GB ES |
Global end of trial date |
13 Nov 2007
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Dec 2018
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First version publication date |
06 Dec 2018
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Other versions |
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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 |
C1 1304-01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00262301 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Pharming Technologies BV
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Sponsor organisation address |
Darwinweg 24, Leiden, Netherlands,
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Public contact |
Anurag Relan, MD, Pharming Technologies BV, +31 715247400, medical-information@pharming.com
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Scientific contact |
Anurag Relan, MD, Pharming Technologies BV, +31 715347400, medical-information@pharming.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 |
13 Nov 2007
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
13 Nov 2007
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Global end of trial reached? |
Yes
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Global end of trial date |
13 Nov 2007
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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 efficacy of rhC1INH in the treatment of acute angioedema attacks in patients with HAE.
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Protection of trial subjects |
Patients developing a life-threatening attack after randomization or after the administration of study medication were to be treated with any treatment procedure as deemed necessary by the investigator, in the patients best interests.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Jul 2004
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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 |
Spain: 2
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Italy: 26
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Country: Number of subjects enrolled |
Israel: 1
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Country: Number of subjects enrolled |
Romania: 2
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Worldwide total number of subjects |
32
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EEA total number of subjects |
31
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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) |
1
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Adults (18-64 years) |
27
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From 65 to 84 years |
4
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients with a clinically confirmed diagnosis of HAE were recruited for the study. Patients who presented to the clinic with an acute angioedema attack with 5 hours of onset were to be randomized. | |||||||||
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Pre-assignment
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Screening details |
In total: 177 screened patients, 159 eligible, 34 randomized, 32 treated. | |||||||||
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Period 1
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Period 1 title |
Double-blind Phase (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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rhC1INH RCT-phase | |||||||||
Arm description |
- | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Recombinant human C1 inhibitor
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Investigational medicinal product code |
rhC1INH
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Other name |
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
rhC11NH at 100 U/kg dosage
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Arm title
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Saline | |||||||||
Arm description |
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Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Saline
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Saline at 100 U/kg dosage
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Baseline characteristics reporting groups
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Reporting group title |
Double-blind Phase
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Reporting group description |
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End points reporting groups
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Reporting group title |
rhC1INH RCT-phase
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Reporting group description |
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Reporting group title |
Saline
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Reporting group description |
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End point title |
Time to Beginning of Relief of Symptoms in RCT-phase | ||||||||||||
End point description |
The primary efficacy variable was time to beginning of relief of symptoms assessed using the overall severity VAS score. For the primary endpoint, the time of beginning of relief of symptoms was the first timepoint at which the overall severity VAS score decreased by at least 20 mm with respect to baseline, at any eligible location.
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End point type |
Primary
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End point timeframe |
up to 48 hours after study drug administration in RCT-phase
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Statistical analysis title |
Time to beginning of relief | ||||||||||||
Comparison groups |
rhC1INH RCT-phase v Saline
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Number of subjects included in analysis |
32
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0294 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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End point title |
Time to Minimal Symptoms in RCT-phase | ||||||||||||
End point description |
Time to minimal symptoms, where ‘minimal symptoms’ was defined as an overall severity VAS score of <20 mm in severity of symptoms for all anatomical locations of an attack.
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End point type |
Secondary
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End point timeframe |
Up to 48 hours after study drug administration
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events for each arm with onset dates within 7 days of study drug administration have been listed
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
9.1
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Reporting groups
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Reporting group title |
rhC1INH in RCT-phase
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Reporting group description |
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Reporting group title |
Saline
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 3% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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19 May 2004 |
Amendment 1 included the following changes to the original protocol:
• Changes were made to the inclusion criteria
• A description of the differential diagnosis was added
• The randomization method was changed
• The type of blood sampling tubes for the diagnostic purpose and immunogenicity analyses were changed
• The cleaved C1INH, C4b/c and PAP complex assays were removed
• Amylase was added to the routine biochemistry measurements
• The Time 20 minutes time point on Day 1 was changed to 45 minutes
• The schedule of assessments was updated
• An independent data monitoring committee was formed
• The last question in the VAS was updated
• Additional minor corrections and clarifications. |
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23 Oct 2006 |
• Changes were made to the method of preparation and administration of the study drug
• Additional Investigator sites were added
• The follow up window was made larger
• The AE section was updated to include text that conformed to European regulations
• In addition some administrative changes were made.
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16 Nov 2006 |
• The discharge criteria were changed to allow patients to be discharged between 4 and 12 hours after treatment if they had no or minimal symptoms
• An OLE to the study was added to allow patients who had been treated for a previous attack to be treated again
• Day 7 was removed from the study
• Treatment with plasma-derived C11NH or fresh frozen plasma was changed so that it was only not allowed within 7 days prior to treatment with rhC1INH compared to the 2 weeks in the original protocol.
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10 May 2007 |
An interim analysis was added. The interim analysis was to be conducted once 26 patients had been treated. |
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03 Aug 2007 |
The IDMC concluded that “continuation of the trial in view of the current interim analysis is not appropriate and we would support a decision of Pharming to discontinue the trial”.
Therefore the Sponsor stopped the randomized, Saline-controlled arm of the trial. The open label-treatment extension of the study was continued for all eligible patients to collect additional safety data. Open-label treatment was extended to all of the screened patients meeting inclusion and exclusion criteria. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
