Clinical Trial Results:
A Phase 3, Randomized, Double-blind, Placebo-controlled, Two-period, Three-sequence, Partial Crossover Study to Evaluate the Efficacy and Safety of Subcutaneous Administration of 2000 IU of C1 Esterase Inhibitor [Human] Liquid for Injection for the Prevention of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema
Summary
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EudraCT number |
2015-002478-19 |
Trial protocol |
DE HU ES |
Global end of trial date |
24 Jul 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Mar 2018
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First version publication date |
02 Mar 2018
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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 |
SHP616-300
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02584959 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Shire
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Sponsor organisation address |
300 Shire Way, Lexington, United States, MA 02421
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Public contact |
Study Physician, Shire, ClinicalTransparency@shire.com
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Scientific contact |
Study Physician, Shire, ClinicalTransparency@shire.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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
24 Jul 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
24 Jul 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Jul 2017
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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 |
The primary objective of this study was to demonstrate superior efficacy of SC administration of 2000 IU C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema attacks relative to placebo based on the normalized number of angioedema attacks (NNA) during a treatment period.
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Protection of trial subjects |
This study was conducted in accordance with the International Council for Harmonisation (ICH) of Good Clinical Practice, and consistent with the principles protecting clinical trial subjects that have their origin in the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
08 Jan 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Hungary: 4
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Country: Number of subjects enrolled |
Spain: 7
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Country: Number of subjects enrolled |
Romania: 8
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Country: Number of subjects enrolled |
Germany: 2
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Country: Number of subjects enrolled |
Israel: 10
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Country: Number of subjects enrolled |
United States: 46
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Country: Number of subjects enrolled |
Canada: 4
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Worldwide total number of subjects |
81
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EEA total number of subjects |
21
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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) |
3
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Adults (18-64 years) |
74
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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 |
This was a multicenter study conducted at 33 sites/centers in 7 countries: Unites States, Canada, Germany, Hungary, Israel, Spain, and Romania. | ||||||||||||||||||||
Pre-assignment
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Screening details |
Of the 81 subjects screened, 6 subjects failed to meet the randomization criteria and were not randomly assigned to a treatment sequence. All 75 randomly assigned subjects received at least 1 dose of the IP. | ||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
81 | ||||||||||||||||||||
Number of subjects completed |
75 | ||||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Failed to meet the randomization criteria: 6 | ||||||||||||||||||||
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, Monitor, Data analyst, Carer, Assessor, Subject | ||||||||||||||||||||
Blinding implementation details |
To maintain the blind, C1 esterase inhibitor [human] liquid for injection and placebo had an identical presentation, including its packaging and labeling, such that the contents of the glass vials within the prepackaged study kits were indistinguishable from each other. Independent external laboratory performing the PK/PD analyses kept the results in strict confidence until the study was unblinded. Some representatives of the sponsor were unblinded to review drug accountability.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Sequence A/B (SHP 616) | ||||||||||||||||||||
Arm description |
Subjects randomized to Sequence A/B received investigational product (SHP616) in treatment period 1. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
C1 esterase inhibitor [human] liquid
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Investigational medicinal product code |
SHP 616
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
2000 IU (4.0 ml) C1 esterase inhibitor [human] liquid was administered subcoutaneously twice weekly (every 3 or 4 days) for 14 weeks.
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Arm title
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Sequence B/A (Placebo) | ||||||||||||||||||||
Arm description |
Subjects randomized to Sequence B/A received Placebo in treatment period 1. | ||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||
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 |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo (4.0 ml) was administered subcutanously twice weekly (every 3 or 4 days) for 14 weeks.
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Arm title
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Sequence A/A (SHP 616) | ||||||||||||||||||||
Arm description |
Subjects randomized to Sequence A/A received investigational product (SHP616) in treatment period 1. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
C1 esterase inhibitor [human] liquid
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Investigational medicinal product code |
SHP 616
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
2000 IU (4.0 ml) C1 esterase inhibitor [human] liquid was administered subcoutaneously twice weekly (every 3 or 4 days) for 14 weeks.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Of the 81 subjects screened, 6 subjects failed to meet the randomization criteria and were not randomly assigned to a treatment sequence. All 75 randomly assigned subjects received at least 1 dose of the investigational product. |
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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, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||
Blinding implementation details |
To maintain the blind, C1 esterase inhibitor [human] liquid for injection and placebo had an identical presentation, including its packaging and labeling, such that the contents of the glass vials within the prepackaged study kits were indistinguishable from each other. Independent external laboratory performing the PK/PD analyses kept the results in strict confidence until the study was unblinded. Some representatives of the sponsor were unblinded to review drug accountability.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Sequence A/B (Placebo) | ||||||||||||||||||||
Arm description |
Subjects randomized to Sequence A/B received Placebo in treatment period 2. | ||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||
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 |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo (4.0 ml) was administered subcutanously twice weekly (every 3 or 4 days) for 14 weeks.
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Arm title
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Sequence B/A (SHP 616) | ||||||||||||||||||||
Arm description |
Subjects randomized to Sequence B/A received investigational product (SHP616) in treatment period 2. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
C1 esterase inhibitor [human] liquid
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Investigational medicinal product code |
SHP 616
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
2000 IU (4.0 ml) C1 esterase inhibitor [human] liquid was administered subcoutaneously twice weekly (every 3 or 4 days) for 14 weeks.
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Arm title
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Sequence A/A (SHP 616) | ||||||||||||||||||||
Arm description |
Subjects randomized to Sequence A/A received investigational product (SHP616) in treatment period 2. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
C1 esterase inhibitor [human] liquid
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Investigational medicinal product code |
SHP 616
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
2000 IU (4.0 ml) C1 esterase inhibitor [human] liquid was administered subcoutaneously twice weekly (every 3 or 4 days) for 14 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Sequence A/B (SHP 616)
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Reporting group description |
Subjects randomized to Sequence A/B received investigational product (SHP616) in treatment period 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sequence B/A (Placebo)
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Reporting group description |
Subjects randomized to Sequence B/A received Placebo in treatment period 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sequence A/A (SHP 616)
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Reporting group description |
Subjects randomized to Sequence A/A received investigational product (SHP616) in treatment period 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Sequence A/B (SHP 616)
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Reporting group description |
Subjects randomized to Sequence A/B received investigational product (SHP616) in treatment period 1. | ||
Reporting group title |
Sequence B/A (Placebo)
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Reporting group description |
Subjects randomized to Sequence B/A received Placebo in treatment period 1. | ||
Reporting group title |
Sequence A/A (SHP 616)
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Reporting group description |
Subjects randomized to Sequence A/A received investigational product (SHP616) in treatment period 1. | ||
Reporting group title |
Sequence A/B (Placebo)
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Reporting group description |
Subjects randomized to Sequence A/B received Placebo in treatment period 2. | ||
Reporting group title |
Sequence B/A (SHP 616)
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Reporting group description |
Subjects randomized to Sequence B/A received investigational product (SHP616) in treatment period 2. | ||
Reporting group title |
Sequence A/A (SHP 616)
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Reporting group description |
Subjects randomized to Sequence A/A received investigational product (SHP616) in treatment period 2. | ||
Subject analysis set title |
Safety set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects who received at least one dose of investigational product.
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Subject analysis set title |
Treatment A (SHP 616) Overall
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
All subjects who received treatment A (SHP 616).
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Subject analysis set title |
Treatment B (Placebo) Overall
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
All subjects who received treatment B (Placebo).
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Subject analysis set title |
Full analysis set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects in the safety set who received at least 1 postbaseline (eg, randomization) primary efficacy assessment.
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End point title |
Time-Normalized Number of Attacks (NNA) for participants during a treatment period [1] | ||||||||||||||||||||||||||||
End point description |
Time-normalized number of angioedema attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4x (number of attacks during treatment period)/(days of treatment period).
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End point type |
Primary
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End point timeframe |
Weeks 1 to 14 for treatment period 1 and 2
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Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Statistics are reported per overall treatment (SHP616 or Placebo) for this endpoint. |
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Statistical analysis title |
Difference in LS means | ||||||||||||||||||||||||||||
Statistical analysis description |
The LS means, 95% CIs, and p-values were based on a mixed effect linear model with period, sequence, use of prophylactic therapy with C1 INH at randomization, and treatment as fixed effects and subject nested within sequence as a random effect.
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Comparison groups |
Treatment A (SHP 616) Overall v Treatment B (Placebo) Overall
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Number of subjects included in analysis |
113
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Analysis specification |
Pre-specified
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Analysis type |
other [2] | ||||||||||||||||||||||||||||
P-value |
< 0.0001 [3] | ||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||
Parameter type |
Difference in LS means | ||||||||||||||||||||||||||||
Point estimate |
-2.32
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-2.895 | ||||||||||||||||||||||||||||
upper limit |
-1.744 | ||||||||||||||||||||||||||||
Notes [2] - Due to the cross-over design of the study the overall number of unique subjects in this analysis is 60. [3] - Sequence effect p-value=0.2997; Period effect p-value=0.8473; Prophylactic effect p-value=0.0009 |
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End point title |
Proportion of subjects meeting the criterion of at least 50% reduction in the NNA during the experimental injection treatment period relative to the placebo period | ||||||
End point description |
Time-Normalized Number of Attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4x (number of attacks during treatment period)/(days of treatment period).
Subjects with 0 attacks in the placebo period were excluded because a percent reduction could not be calculated. Analysis was done on subjects who were dosed in both treatment periods.
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End point type |
Secondary
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End point timeframe |
Weeks 1 to 14 for treatment period 1 and 2
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No statistical analyses for this end point |
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End point title |
The normalized number of attacks (NNA) during each treatment period excluding the first 2 weeks. [4] | ||||||||||||||||||||||||||||
End point description |
Time-Normalized Number of Attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4x (number of attacks during treatment period)/(days of treatment period).
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End point type |
Secondary
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End point timeframe |
Weeks 3 to 14 for treatment period 1 and 2
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Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Statistics are reported per overall treatment (SHP616 or Placebo) for this endpoint. |
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Statistical analysis title |
Difference in LS means | ||||||||||||||||||||||||||||
Statistical analysis description |
The LS means, 95% CIs, and p-values were based on a mixed effect linear model with period, sequence, use of
prophylactic therapy with C1 INH at randomization, and treatment as fixed effects and subject nested within sequence as a random effect.
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Comparison groups |
Treatment A (SHP 616) Overall v Treatment B (Placebo) Overall
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Number of subjects included in analysis |
110
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Analysis specification |
Pre-specified
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Analysis type |
other [5] | ||||||||||||||||||||||||||||
P-value |
< 0.0001 [6] | ||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||
Parameter type |
Difference in LS means | ||||||||||||||||||||||||||||
Point estimate |
-2.323
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-2.969 | ||||||||||||||||||||||||||||
upper limit |
-1.677 | ||||||||||||||||||||||||||||
Notes [5] - Due to the cross-over design of the study the overall number of unique subjects in this analysis is 60. [6] - Sequence effect p-value=0.2630; Period effect p-value=0.8792; Prophylactic effect p-value=0.0065 |
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End point title |
Proportion of subjects meeting the criterion of at least 50% reduction in the NNA during the experimental injection treatment period relativ to the placebo period excluding the first 2 weeks of each treatment period | ||||||
End point description |
Time-Normalized Number of Attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4x (number of attacks during treatment period)/(days of treatment period).
Subjects with 0 attacks in the placebo period were excluded because a percent reduction could not be calculated.
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End point type |
Secondary
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End point timeframe |
Weeks 3 to 14 for treatment period 1 and 2
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No statistical analyses for this end point |
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End point title |
Proportion of subjects meeting the criterion of at least 50% reduction in the NNA during the experimental injection treatment period relative to the pretreatment assessment. | |||||||||
End point description |
Subjects with 0 attacks at baseline were excluded because a percent reduction could not be calculated.
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End point type |
Secondary
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End point timeframe |
Weeks 1 to 14 for treatment period 1 and 2
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No statistical analyses for this end point |
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End point title |
Cumulative attack severity [7] | ||||||||||||||||||||||||||||
End point description |
Cumulative attack severity was defined as the summation of the maximum symptom severity recorded for each angioedema attack in a treatment period for each subject.
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End point type |
Secondary
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End point timeframe |
Weeks 1 to 14 for treatment period 1 and 2
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Notes [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Statistics are reported per overall treatment (SHP616 or Placebo) for this endpoint. |
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Statistical analysis title |
Difference in LS means | ||||||||||||||||||||||||||||
Statistical analysis description |
The LS means, 95% CIs,and p-values were based on a mixed effect linear model with period, sequence, use of
prophylactic therapy with C1 INH at randomization, and treatment as fixed effects and subject nested within sequence as a random effect.
Cumulative attack severity was the summation of the maximum symptom severity recorded for each angioedema attack in a treatment period for each subject.
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Comparison groups |
Treatment A (SHP 616) Overall v Treatment B (Placebo) Overall
|
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Number of subjects included in analysis |
113
|
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Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||
Analysis type |
other [8] | ||||||||||||||||||||||||||||
P-value |
< 0.0001 [9] | ||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||
Parameter type |
Differenece in LS means | ||||||||||||||||||||||||||||
Point estimate |
-4.881
|
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Confidence interval |
|||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||
lower limit |
-6.113 | ||||||||||||||||||||||||||||
upper limit |
-3.649 | ||||||||||||||||||||||||||||
Notes [8] - Due to the cross-over design of the study the overall number of unique subjects in this analysis is 60. [9] - Sequence effect p-value=0.2538; Period effect p-value=0.6213; Prophylactic effect p-value=0.0152 |
|
|||||||||||||||||||||||||||||
End point title |
Number of attack-free days [10] | ||||||||||||||||||||||||||||
End point description |
Attack-free days were normalized per month
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Weeks 1 to 14 for treatment period 1 and 2
|
||||||||||||||||||||||||||||
Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Statistics are reported per overall treatment (SHP616 or Placebo) for this endpoint. |
|||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
Statistical analysis title |
Difference in LS means | ||||||||||||||||||||||||||||
Statistical analysis description |
The LS means, 95% CIs, and p-values were based on a mixed effect linear model with period, sequence, use of
prophylactic therapy with C1 INH at randomization, and treatment as fixed effects and subject nested within sequence as a random effect.
|
||||||||||||||||||||||||||||
Comparison groups |
Treatment A (SHP 616) Overall v Treatment B (Placebo) Overall
|
||||||||||||||||||||||||||||
Number of subjects included in analysis |
113
|
||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||
Analysis type |
other [11] | ||||||||||||||||||||||||||||
P-value |
< 0.0001 [12] | ||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||
Parameter type |
Difference in LS means | ||||||||||||||||||||||||||||
Point estimate |
5.435
|
||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||
lower limit |
3.981 | ||||||||||||||||||||||||||||
upper limit |
6.889 | ||||||||||||||||||||||||||||
Notes [11] - Due to the cross-over design of the study the overall number of unique subjects in this analysis is 60. [12] - Sequence effect p-value=0.2629; Period effect p-value=0.2659, Phrophylactic effect p-value=0.0487 |
|
|||||||||||||||||||||||||||||
End point title |
Number of angioedema attacks requiring acute treatment [13] | ||||||||||||||||||||||||||||
End point description |
Angioedema attacks were normalized per month
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Weeks 1 to 14 for treatment period 1 and 2
|
||||||||||||||||||||||||||||
Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Statistics are reported per overall treatment (SHP616 or Placebo) for this endpoint. |
|||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
Statistical analysis title |
Difference in LS means | ||||||||||||||||||||||||||||
Statistical analysis description |
The LS means, 95% CIs, and p-values were based on a mixed effect linear model with period, sequence, use of
prophylactic therapy with C1 INH at randomization, and treatment as fixed effects and subject nested within sequence as a random effect.
|
||||||||||||||||||||||||||||
Comparison groups |
Treatment A (SHP 616) Overall v Treatment B (Placebo) Overall
|
||||||||||||||||||||||||||||
Number of subjects included in analysis |
113
|
||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||
Analysis type |
other [14] | ||||||||||||||||||||||||||||
P-value |
< 0.0001 [15] | ||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||
Parameter type |
Difference in LS means | ||||||||||||||||||||||||||||
Point estimate |
-2.175
|
||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||
lower limit |
-2.75 | ||||||||||||||||||||||||||||
upper limit |
-1.599 | ||||||||||||||||||||||||||||
Notes [14] - Due to the cross-over design of the study the overall number of unique subjects in this analysis is 60. [15] - Sequence effect p-value=0.3687; Period effect p-value=0.8883; Prophylactic effect p-value=0.0009 |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Safety and tolerability - Adverse Events, Injection Site Reactions and Immunogenicity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Treatment-emergent adverse events (TEAE) were counted by the treatment most recently taken when the event occurred. Subjects were counted once per category per treatment.
Injection site reactions (Erythema, Swelling, Cutaneous pain, Burning sensation, Itching/Pruritus, Warm sensation) were recorded on a designated eCRF page by the site personnel who monitored the local reaction for 1 hour after IP administration 5 times during each treatment period.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From day of first dose in week 1 to week 15 for treatment period 1 and 2
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
PK parameters: AUC (0-96) and AUC (0-t) for Functional C1 INH Binding Activity | ||||||||||||||||||
End point description |
AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days)
AUC(0-96) = AUC(0-tau)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
PK parameters: AUC (0-96) and AUC (0-t) for C1 INH Antigen Concentrations | ||||||||||||||||||
End point description |
AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days)
AUC(0-96) = AUC(0-tau)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
PK parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations | ||||||||||||||||||
End point description |
AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days)
AUC(0-96) = AUC(0-tau)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [16] - not calculated, 99999 was entered |
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
PK Parameters: Cmax and Cmin for Functional C1 INH Binding Activity | ||||||||||||||||||
End point description |
Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Within 15 min prior dosing at at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
PK Parameters: Cmax and Cmin for C1 INH Antigen Concentrations | ||||||||||||||||||
End point description |
Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Within 15 min prior dosing at at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
PK Parameters: Cmax and Cmin for Complement C4 Concentrations | ||||||||||||||||||
End point description |
Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Within 15 min prior dosing at at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [17] - not calculated, 99999 was entered |
|||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
PK Parameters: tmax | |||||||||||||||||||||
End point description |
tmax=time of maximum observed plasma concentration
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Within 15 min prior dosing at at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Notes [18] - n=5 for Complement C4 Concentration [19] - n=2 for Complement C4 Concentration (not calculated, 99999 was entered) |
||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Response to icatibant when administered for an acute attack | |||||||||||||||||||||
End point description |
||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Weeks 1 to 14 for each treatment period
|
|||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Assess disease activity as measured by the Angioedema Activity Score (AAS) | ||||||||||||
End point description |
The Least Square means, 95% confidence intervals and p-values are based on mixed effect linear model with period, sequence, use of prophylactic therapy with C1 INH at randomization and treatment as fixed effects and subject nested within sequence as a random effect.
The normalized 98-day Angioedema Activity Score (AAS) per month for a subject is calculated by (the sum of daily AAS within a treatment period/the number of days that a subject has AAS records within the treatment period)*30.4.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Weeks 1 to 14 for treatment period 1 and 2
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in least square means | ||||||||||||
Statistical analysis description |
The Least Square means, 95% confidence intervals and p-values are based on mixed effect linear model with period, sequence, use of prophylactic therapy with C1 INH at randomization and treatment as fixed effects and subject nested within sequence as a random effect.The normalized 98-day Angioedema Activity Score (AAS) per month for a subject is calculated by (the sum of daily AAS within a treatment period/the number of days that a subject has AAS records within the treatment period)*30.4.
|
||||||||||||
Comparison groups |
Treatment A (SHP 616) Overall v Treatment B (Placebo) Overall
|
||||||||||||
Number of subjects included in analysis |
113
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [20] | ||||||||||||
P-value |
< 0.0001 [21] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Difference in LS means | ||||||||||||
Point estimate |
-31.735
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-42.696 | ||||||||||||
upper limit |
-20.773 | ||||||||||||
Notes [20] - Due to the cross-over design of the study the overall number of unique subjects in this analysis is 60. [21] - Sequence effect p-value=0.3723; Period effect p-value=0.8735; Prophylactic effect p-value=0.0543 |
|
||||||||||||||||||||||||||||
End point title |
Subject experience with self-administration: Overall experience with the syringe | |||||||||||||||||||||||||||
End point description |
Self-administration survey was assessed in week 14 (visit 28 and 28b).
Visit 28 summarizes treatment period 1 of treatment sequence A/A and both treatment periods 1 and 2 of treatment sequences A/B and B/A. Visit 28b summarizes treatment period 2 of treatment sequence A/A.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Visit 28 (week 14) for period 1 and visit 28b (week 14) for period 2
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
Notes [22] - n=12 for Visit 28b [23] - not applicable for Visit 28b, 99999 was entered |
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Subject experience with self-administration: How many visit for confidence with self-administration | ||||||||||||||||||
End point description |
Self-administration survey was assessed in week 14 (visit 28 and 28b).
Visit 28 summarizes treatment period 1 of treatment sequence A/A and both treatment periods 1 and 2 of treatment sequences A/B and B/A. Visit 28b summarizes treatment period 2 of treatment sequence A/A.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Visit 28 (week 14) for period 1 and visit 28b (week 14) for period 2
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [24] - n=12 for Visit 28b [25] - not applicable for Visit 28b, 99999 was entered |
|||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||
End point title |
Subject experience with self-administration: Better long-term option for subject and preferred administration for subject | |||||||||||||||||||||||||||||||||
End point description |
Self-administration survey was assessed in week 14 (visit 28 and 28b).
Visit 28 summarizes treatment period 1 of treatment sequence A/A and both treatment periods 1 and 2 of treatment sequences A/B and B/A. Visit 28b summarizes treatment period 2 of treatment sequence A/A.
|
|||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
Visit 28 (week 14) for period 1 and visit 28b (week 14) for period 2
|
|||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
Notes [26] - n=12 for Visit 28b [27] - not applicable for Visit 28b, 99999 was entered |
||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Subject experience with self-administration: Subject's preference for administration | |||||||||||||||||||||||||||
End point description |
Self-administration survey was assessed in week 14 (visit 28 and 28b).
Visit 28 summarizes treatment period 1 of treatment sequence A/A and both treatment periods 1 and 2 of treatment sequences A/B and B/A. Visit 28b summarizes treatment period 2 of treatment sequence A/A.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Visit 28 (week 14) for period 1 and visit 28b (week 14) for period 2
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
Notes [28] - n=12 for Visit 28b [29] - not applicable for Visit 28b, 99999 was entered |
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Mean change in Angioedema Quality of Life Questionnaire Scores from baseline to week 13 [30] | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Absolute change calculated as visit score minus baseline per period. Baseline was dosing Day 1 visit, prior to investigational product administration/placebo, for each specific study period. Visit 1a was the baseline for period 1 and Visit 1b was the baseline for period 2.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
baseline (visit 1) to week 13 (visit 25) for period 1 and baseline (visit 1b) to week 13 (visit 25b) for period 2
|
|||||||||||||||||||||||||||||||||||||||||||||
Notes [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive statistics were collected for this endpoint. |
||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Adverse events were recorded from the time the informed consent was signed through 7 days after the last dose of investigational product (week 1 to 15 for treatment period 1 and 2).
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Treatment B (Placebo)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Treatment B (Placebo) Overall | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Treatment A (SHP 616)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Treatment A (SHP 616 ) Overall | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 |
||
22 Jul 2015 |
Inclusion of final clinical data from Study SHP616-103 was added, which was relevant to subject safety and the study rationale.
The baseline angioedema attack rate required for study inclusion was modified.
Updates were made to some study procedures or requirements (eg, parent/legal guardian/caregiver performing and/or assisting an adolescent subject, photographs and measurements of injection site reactions, longitudinal follow-up to test for
C1 INH antibody titers). |
||
03 Sep 2015 |
The inclusion and exclusion criteria regarding the attack rate and baseline
prophylactic therapy was modified.
A new exclusion criterion was added to prevent any changes of dose in hormonal products/therapies prior to study enrollment.
Self-administration was allowed in both treatment periods (1 and 2), under supervision and after receiving adequate training by the site or home health professional.
Clarification was added for the subjects who continued to have breakthrough attacks on the blinded IP despite receiving on-demand treatment for the management of angioedema attacks during the study.
Added a section to clarify nonpharmacologic treatments and procedures.
Added overall severity and duration assessment for injection site reactions.
Number of subjects randomly assigned in each of the 3 treatment sequences (A/B, B/A, A/A) was modified along with the statistical power calculations.
Removed “achieving a NNA <2.0” as a secondary efficacy endpoint. |
||
11 Jan 2016 |
Allowed subjects (adolescent or adult) the option to self-administer IP with or without supervision after receiving appropriate training by the investigator or designee. Adolescent subjects self-administering IP were supervised by a parent/legal guardian/caregiver (if home health professional and/or study site personnel was not present).
Subjects who elected to self-administer IP were instructed on IP transport, storage, treatment compliance, and retention of all used and unused product vials for drug accountability purposes. Written instructions on IP and self-administration procedures were provided to subjects at the screening or first dosing visit.
Revised schedule for assessment of SC injection site reactions during treatment periods 1 and 2; the assessments were to be less frequent and only occur when IP was administered at the investigative site. An overall assessment of the impact on
daily living and duration of injection sites reaction occurred at the last visit of each treatment period.
In order to prevent subjects from missing a scheduled dose of IP, additional guidance on the dosing interval was provided.
For subjects without documented C1 INH antigen level and/or C1 INH functional activity as part of eligibility criteria to confirm HAE diagnosis, a blood sample was collected at screening and sent to a local or central laboratory (as appropriate). |
||
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 |