Clinical Trial Results:
HELP Study ExtensionTM: An Open-Label Study to Evaluate the Long-Term Safety and Efficacy of DX-2930 for Prevention Against Acute Attacks of Hereditary Angioedema (HAE)
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Summary
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EudraCT number |
2015-005255-27 |
Trial protocol |
GB DE IT |
Global end of trial date |
31 Oct 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
09 May 2020
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First version publication date |
09 May 2020
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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 |
DX-2930-04
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02741596 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
IND: 116647 | ||
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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 Director, Shire, 1 866-842-5335, ClinicalTransparency@shire.com
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Scientific contact |
Study Director, Shire, 1 866-842-5335, ClinicalTransparency@shire.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001864-PIP01-15 | ||
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 |
31 Oct 2019
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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 |
31 Oct 2019
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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 the trial was to evaluate the long-term safety of repeated subcutaneous (SC) administrations of lanadelumab (DX-2930).
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Protection of trial subjects |
This study was conducted in accordance with International Council for Harmonisation of Good Clinical Practice, the principles of 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 |
26 May 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 |
United States: 147
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Country: Number of subjects enrolled |
Canada: 13
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Country: Number of subjects enrolled |
European Union: 39
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Country: Number of subjects enrolled |
Jordan: 13
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Worldwide total number of subjects |
212
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EEA total number of subjects |
0
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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) |
21
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Adults (18-64 years) |
180
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From 65 to 84 years |
11
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 43 sites across United States, Canada, Europe and Jorden between 26 May 2016 (first subject first visit) and 31 October 2019 (last subject last visit). | |||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 212 subjects were enrolled and received treatment in two groups (Rollover subjects [109] and Non-rollover subjects [103]). Subjects who rolled from the DX-2930-03 (2015-005255-27) study were in Rollover group and subjects who were directly enrolled into this DX-2930-04 study were in Non-rollover group. | |||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Rollover Subjects | |||||||||||||||||||||||||||||||||
Arm description |
Subjects who rolled from the DX-2930-03 (2015-005255-27) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after subjects reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Lanadelumab
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Investigational medicinal product code |
DX-2930
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Other name |
SHP643
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received SC injection DX-2930 for q2wks up to 924 days.
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Arm title
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Non-rollover Subjects | |||||||||||||||||||||||||||||||||
Arm description |
Subjects who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days). | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Lanadelumab
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Investigational medicinal product code |
DX-2930
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Other name |
SHP643
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received SC injection DX-2930 for q2wks up to 924 days.
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Baseline characteristics reporting groups
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Reporting group title |
Rollover Subjects
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Reporting group description |
Subjects who rolled from the DX-2930-03 (2015-005255-27) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after subjects reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Non-rollover Subjects
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Reporting group description |
Subjects who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Rollover Subjects
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Reporting group description |
Subjects who rolled from the DX-2930-03 (2015-005255-27) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after subjects reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations. | ||
Reporting group title |
Non-rollover Subjects
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Reporting group description |
Subjects who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days). | ||
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End point title |
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) [1] | ||||||||||||
End point description |
An adverse event (AE) was any untoward medical occurrence in a clinical trial subject whether or not it appeared to had a causal relationship with the treatment administered. Treatment-emergent AEs are defined as AEs with onset at the time of or following the first exposure to open-label DX-2930 in this study, or medical conditions present prior to the start of treatment but increasing in severity or relationship at the time of or following the start of treatment.
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End point type |
Primary
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End point timeframe |
From start of the study up to follow-up (Day 952)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical testing was performed for the primary end point. |
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End point title |
Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During the Treatment Period | ||||||||||||
End point description |
HAE attack was defined as a discrete episode during which the subject progressed from no angioedema to symptoms of angioedema. The treatment period investigator-confirmed HAE attack rate was calculated for each subject as the number of investigator-confirmed HAE attacks occurring during the treatment period (regular dosing stage of the treatment period for rollover subjects) divided by the number of days the subject contributed to the treatment period multiplied by 28 days. Rate of investigator-confirmed HAE attacks during the treatment period was reported. Safety population was analysed, which included all subjects who received any study drug after entering the DX-2930-04 study. Here, the number of subjects analyzed signifies subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Up to Day 924
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Rate of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks Requiring Acute Treatment During the Treatment Period | ||||||||||||
End point description |
HAE attack was defined as a discrete episode during which the subject progressed from no angioedema to symptoms of angioedema. Rate of investigator-confirmed HAE attacks requiring acute treatment for each subject as the number of investigator-confirmed HAE attacks occurring during the treatment period (regular dosing stage of the treatment period for rollover subjects) divided by the number of days the subject contributed to the treatment period multiplied by 28 days. Safety population was analysed, which included all subjects who received any study drug after entering the DX-2930-04 study. Here, the number of subjects analyzed signifies subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Up to Day 924
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Rate of Moderate or Severe Hereditary Angioedema (HAE) Attacks During the Treatment Period | ||||||||||||
End point description |
HAE attack was defined as a discrete episode during which the subject progressed from no angioedema to symptoms of angioedema. Moderate and severe investigator-confirmed HAE attacks were the attacks that were moderate or severe as per the HAE attack assessment and reporting procedures (HAARP) defined severity. The overall severity of attack was determined by the investigator using following definitions: mild (transient or mild discomfort), moderate (mild to moderate limitation in activity), severe (marked limitation in activity). Safety population was analysed, which included all subjects who received any study drug after entering the DX-2930-04 study. Here, the number of subjects analysed signifies subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Up to Day 924
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Rate of High-Morbidity Hereditary Angioedema (HAE) Attacks During the Treatment Period | ||||||||||||
End point description |
HAE attack was defined as a discrete episode during which the subject progressed from no angioedema to symptoms of angioedema. High-morbidity Hereditary Angioedema (HAE) attack was defined as any attack that had at least one of the following characteristics: severe, resulted in hospitalization (except hospitalization for observation lesser than [<] 24 hours), hemodynamically significant (systolic blood pressure <90 millimetre of mercury [mmHg], required intravenous hydration, or associated with syncope or near-syncope) or laryngeal edema. Number of high-morbidity HAE attacks during the treatment period was analysed and reported using the methods for the overall number of investigator-confirmed HAE attacks with the exception of the monthly line graphs. Safety population was analysed, which included all subjects who received any study drug after entering the DX-2930-04 study. Here the number of subjects analysed signifies subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Up to Day 924
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time to First Investigator-Confirmed Hereditary Angioedema (HAE) Attacks During in Rollover Subjects | ||||||||||||
End point description |
HAE attack was defined as a discrete episode during which the subject progressed from no angioedema to symptoms of angioedema. Time to first investigator-confirmed HAE attack was calculated from the time of first open-label dose to the start time of the first investigator-confirmed HAE attack. Time to the first investigator-confirmed HAE attack was analysed and reported only in rollover safety population. Rollover Safety Population was analysed, which included subset of subjects who participated in the DX-2930-03 (2015-005255-27) study and received any study drug after entering the DX-2930-04 study (that is any exposure to open-label DX-2930).
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End point type |
Secondary
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End point timeframe |
Up to Day 924
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| Notes [2] - End point was planned only for rollover subjects. hence, non-rollover subjects were not evaluated. |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From start of study drug administration up to follow-up (Day 952)
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
Rollover Subjects
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Reporting group description |
Subjects who rolled from the DX-2930-03 (2015-005255-27) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after subjects reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Non-Rollover Subjects
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Reporting group description |
Subjects who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 Jun 2016 |
The tertiary objective to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) profile of lanadelumab was clarified to indicate administration would be SC.
Three additional tertiary objectives were added to obtain more comprehensive information:
* To evaluate safety and efficacy in the non-rollover population of switching from from long-term prophylactic (LTP) treatment to lanadelumab
* To evaluate breakthrough attack characteristics while receiving lanadelumab compared to historical baseline
* To evaluate subject experience with self-administration of lanadelumab including ease of SC administration of lanadelum
The number of non-rollover subjects was increased from at least 50 subjects up to a maximum of 100 subjects. Enrollment of subjects 12 to 17 years age was revised to be at least 15 including the estimated 10 rollover subjects from Study DX-2930-03 (2015-005255-27). Therefore, the total enrollment for the study was updated to be at least 150, but not more than 250.
The study was extended in duration from 6 months to approximately 1 year and subsequently the number of doses of study drug a subject could receive was increased.
Study Activities Schedule was revised to accommodate study assessments at dosing Visits 14 through 26. Follow-up visits (following end of treatment) are now occurring at Days 264, 378, and 392 (Visits 27, 28, and 29).
Efficacy endpoints were revised from mean rates to number of attacks.
The study was extended in duration from 6 months to approximately 1 year and subsequently the number of doses of study drug a subject could receive was increased.
Efficacy endpoints were revised from mean rates to number of attacks.
The efficacy evaluation period was updated to begin at Day 0 instead of Day 14 to be consistent with the intent-to-treat analysis principle. |
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20 Jan 2017 |
Clarified that subjects in Study DX-2930-03 (2015-005255-27) can be consented for enrollment in Study DX-2930-04 on or after Day 168 of Study DX-2930-03 (2015-005255-27).
Removed remnant text regarding the requirement to complete a 2-week washout period before entering the treatment period for non-rollover subjects on LTP for HAE. Washout period does not exist for non-rollover subjects.
Removed safety analysis category called “pretreatment group” since a pretreatment period does not exist in this study. |
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29 Jun 2017 |
A new tertiary objective and related measurement have been added to evaluate exploratory biomarker(s) of angioedema disease-state bioactivity in blood. Additional biomarker assessments have been added to the study to evaluate the effect of lanadelumab on disease activity.
A new tertiary efficacy objective and related measurement have been added to better understand the clinical response to rescue medications while on lanadelumab therapy.
* Objective: To assess the clinical response of rescue medications for the treatment of acute angioedema attacks while on lanadelumab therapy (applicable for subjects >= 18 years of age)
* Measurement: Subject response to rescue medications.
A new tertiary objective was added to assess subjects’ satisfaction with lanadelumab.
* Objective: To assess treatment satisfaction
* Measurement: Treatment satisfaction was to be measured using the Treatment Satisfaction Questionnaire for Medication (TSQM-9). The TSQM-9 was to be a 9-item validated instrument.
The treatment period was extended from 12 to up to 30 months to accommodate the additional changes to the study described above.
The requirement that each attack be confirmed by the investigator within 72 hours for non-serious AE attacks was expanded to 7 calendar days.
Note: This refers only to confirmation of attacks, not reporting of serious adverse events (SAEs) or AEs. Electrocardiogram (ECG) were to be assessed through Day 364, at the end of the study, and when clinically required.
The following subgroup analysis was added to the statistical section for consistency with statistical analysis used in Study DX-2930-03 (2015-005255-27):
“History of laryngeal HAE attacks (history of laryngeal attack, no history of laryngeal attack).” |
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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 | |||
