Clinical Trial Results:
A Multi-center, Open-label Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Lanadelumab (SHP643) in Chinese Subjects with Hereditary Angioedema
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Summary
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EudraCT number |
2023-001105-31 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
28 Nov 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Jun 2024
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First version publication date |
09 Jun 2024
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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 |
SHP643-304
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05460325 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Takeda
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Sponsor organisation address |
95 Hayden Avenue, Lexington, United States, MA 02421
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Public contact |
Study Director, Takeda, trialdisclosures@takeda.com
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Scientific contact |
Study Director, Takeda, trialdisclosures@takeda.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 |
28 Nov 2023
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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 |
28 Nov 2023
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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 main purpose of this study is to evaluate the safety of repeated subcutaneous (SC) administrations of lanadelumab in Chinese participants with hereditary angioedema (HAE).
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Protection of trial subjects |
Each participant signed an informed consent form (ICF) before participating in the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Jun 2022
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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 |
China: 20
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Worldwide total number of subjects |
20
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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) |
1
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Adults (18-64 years) |
19
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants took part in the study at 4 investigative sites in China from 22 June 2022 to 28 November 2023. | ||||||
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Pre-assignment
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Screening details |
Total 20 participants with diagnosis of hereditary angioedema(HAE) were enrolled in Run-in Period of 4-8 weeks.Participants who experienced ≥1.0 investigator-confirmed HAE attack per 4 weeks during Run-in Period & who remained eligible per inclusion & exclusion criteria entered the 26-week lanadelumab Treatment Period to receive lanadelumab 300 mg. | ||||||
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Period 1
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Period 1 title |
Run-in Period (4 or up to 8 Weeks)
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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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Arm title
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Lanadelumab 300 mg | ||||||
Arm description |
Participants received lanadelumab 300 mg, subcutaneously (SC), once every two weeks (Q2W) for 26 weeks. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Lanadelumab
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Investigational medicinal product code |
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Other name |
SHP643, TAKHZYRO, TAK-743, DX-2930, Lanadelumab Injection, Lanadelumab-flyo
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Lanadelumab 300 mg was administered SC, Q2W for 26 weeks.
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Period 2
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Period 2 title |
Treatment Period (Weeks 1 to 26)
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Is this the baseline period? |
No | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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Lanadelumab 300 mg | ||||||
Arm description |
Participants received lanadelumab 300 mg, subcutaneously (SC), once every two weeks (Q2W) for 26 weeks. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Lanadelumab
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Investigational medicinal product code |
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Other name |
SHP643, TAKHZYRO, TAK-743, DX-2930, Lanadelumab Injection, Lanadelumab-flyo
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Participants received lanadelumab 300 mg, SC, Q2W.
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Period 3
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Period 3 title |
Safety Follow-up Period (Weeks 27 to 30)
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Is this the baseline period? |
No | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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Lanadelumab 300 mg | ||||||
Arm description |
Participants received lanadelumab 300 mg, subcutaneously (SC), once every two weeks (Q2W) for 26 weeks. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Lanadelumab
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Investigational medicinal product code |
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Other name |
SHP643, TAKHZYRO, TAK-743, DX-2930, Lanadelumab Injection, Lanadelumab-flyo
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Lanadelumab 300 mg was administered SC, Q2W for 26 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Lanadelumab 300 mg
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Reporting group description |
Participants received lanadelumab 300 mg, subcutaneously (SC), once every two weeks (Q2W) for 26 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Lanadelumab 300 mg
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Reporting group description |
Participants received lanadelumab 300 mg, subcutaneously (SC), once every two weeks (Q2W) for 26 weeks. | ||
Reporting group title |
Lanadelumab 300 mg
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Reporting group description |
Participants received lanadelumab 300 mg, subcutaneously (SC), once every two weeks (Q2W) for 26 weeks. | ||
Reporting group title |
Lanadelumab 300 mg
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Reporting group description |
Participants received lanadelumab 300 mg, subcutaneously (SC), once every two weeks (Q2W) for 26 weeks. | ||
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End point title |
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) [1] | ||||||||||||||||||
End point description |
TEAE=an adverse event (AE) with onset at the time of or following initial dosing with study drug (lanadelumab), or medical conditions present prior to the start of study drug but increasing in severity or relationship at the time of or following the start of treatment, up to the last follow-up visit. An SAE is any untoward clinical manifestation of signs, symptoms or outcomes whether considered related to investigational product or not and at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, congenital abnormality/birth defect, an important medical event. Hypersensitivity reactions and events of disordered coagulation were considered as AESIs. Adverse events were classified as HAE attack and non-HAE attack reported AEs and are categorized accordingly in this outcome measure. The FAS included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to end of study (up to Day 210)
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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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of Participants With Clinically Meaningful Changes in Clinical Laboratory Parameters [2] | ||||||
End point description |
Laboratory parameters included clinical chemistry, hematology, coagulation, urinalysis, and serology. Clinically meaningful laboratory parameters assessment was based on investigator interpretation. Number of participants with clinically meaningful changes in laboratory parameters (including clinical chemistry, hematology, coagulation, urinalysis, and serology) were reported. The Full Analysis Set (FAS) included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to end of study (up to Day 210)
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| Notes [2] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants With Clinically Meaningful Changes in Vital Sign Abnormalities [3] | ||||||
End point description |
Vital signs included measurement of blood pressure, heart rate, body temperature, and respiratory rate. Clinically meaningful vital signs assessment was based on investigator interpretation. Number of participants with clinically meaningful changes in vital signs were reported. The FAS included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to end of study (up to Day 210)
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| Notes [3] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants With Clinically Meaningful Changes in Electrocardiogram (ECG) [4] | ||||||
End point description |
ECG included heart rate, PR interval, QRS duration, QT interval, corrected QT interval (QTc) interval, QT corrected for heart rate by Fridericia's cube root formula (QTcF) interval, and QT corrected for heart rate by Bazett formula (QTcB) interval. Clinically meaningful ECG assessment was based on investigator interpretation. Number of participants with clinically meaningful changes in ECG were reported. The FAS included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to end of study (up to Day 210)
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| Notes [4] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants With Clinically Significant Physical Examination Abnormalities on Day 182 [5] | ||||||||||
End point description |
Physical examination findings by body system were classified as height and weight, general appearance, ears, nose and throat, head and neck, ophthalmological, respiratory, cardiovascular, abdomen, neurological, extremities, dermatological, and lymphatic. Number of participants with clinically significant changes in physical examination findings per investigator interpretation were reported. Only categories with at least one participant with event are reported. The FAS included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Primary
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End point timeframe |
Day 182
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| Notes [5] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Plasma Concentrations of Lanadelumab | ||||||||||||||||||||||
End point description |
The Pharmacokinetic (PK) Set included all participants in the FAS who had at least 1 evaluable post-dose PK concentration value. 'n' signifies the number of participants with data available for analyses at the specified timepoint.
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End point type |
Secondary
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End point timeframe |
Anytime on Days 0 and 210; and pre-dose on Days 14, 56, 98, 140, 182
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Plasma Kallikrein (pKal) Activity | ||||||||||||||||||||||
End point description |
pKal activity was measured by cleaved high molecular weight kininogen (cHMWK) level (i.e., plasma concentrations of cHMWK). The Pharmacodynamic (PD) Set included all participants in the FAS who had at least 1 evaluable post-dose PD concentration value. 'n' signifies the number of participants with data available for analyses at the specified timepoint.
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End point type |
Secondary
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End point timeframe |
Anytime on Days 0 and 210; and pre-dose on Days 14, 56, 98, 140, 182
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Number of Investigator-Confirmed HAE Attacks During the Efficacy Evaluation Period of Day 0 Through Day 182 | ||||||||
End point description |
An HAE attack was confirmed by following symptoms or signs consistent with an attack in at least one of the following locations: 1) Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region; 2) Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea; 3) Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx. Treatment period attack rate per month is calculated as the number of investigator-confirmed HAE attacks occurring during that treatment period divided by number of days the participant contributed to that treatment period multiplied by 28 days. The FAS included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Secondary
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End point timeframe |
Day 0 through Day 182
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Investigator-Confirmed HAE Attacks that Required Acute Treatment During the Efficacy Evaluation Period of Day 0 Through Day 182 | ||||||||
End point description |
HAE attack was confirmed by following symptoms consistent with attack in atleast 1 of following locations:1)Peripheral angioedema:cutaneous swelling in extremity,face,neck,torso,and/or genitourinary region;2)Abdominal angioedema:abdominal pain,with/without abdominal distention,nausea,vomiting/diarrhea;3)Laryngeal angioedema:stridor,dyspnea,difficulty speaking,difficulty swallowing,throat tightening/swelling of tongue,palate,uvula/larynx.Acute HAE attacks were managed per investigator’s usual care, including use of individualized acute therapy/rescue medications.Acute therapy/rescue medications included Firazyr,fresh frozen plasma(FFP)/other local standard of care.Treatment period attack rate per month=number of investigator-confirmed HAE attacks requiring acute treatment occurring during that treatment period divided by number of days participant contributed to that treatment period multiplied by 28 days.FAS included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Secondary
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End point timeframe |
Day 0 through Day 182
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Moderate or Severe Investigator-Confirmed HAE Attacks During the Efficacy Evaluation Period of Day 0 Through Day 182 | ||||||||
End point description |
The severity of the investigator-confirmed HAE attacks was defined per the HAE attack assessment and reporting procedures (HAARP) definitions: severe (marked limitation in activity, assistance required), moderate (mild to moderate limitation in activity, some assistance needed). Treatment period attack rate per month is calculated as the number of moderate or severe investigator-confirmed HAE attacks occurring during that treatment period divided by number of days the participant contributed to that treatment period multiplied by 28 days. The FAS included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Secondary
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End point timeframe |
Day 0 through Day 182
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Participants with Maximum Attack Severity During the Efficacy Evaluation Period of Day 0 Through Day 182 | ||||||||||||||
End point description |
Number of participants with maximum HAE attack severity during the efficacy evaluation period was assessed. HAE attack severity was calculated per participant based on the severity categories as follows: No attack, Mild, Moderate, and Severe. The FAS included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Secondary
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End point timeframe |
Day 0 through Day 182
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Time to First Investigator-confirmed HAE Attack During the Efficacy Evaluation Period of Day 0 Through Day 182 | ||||||||
End point description |
Time to the first investigator-confirmed HAE attack (days) was calculated from the date and time of the first dose of study drug for that efficacy evaluation period to the date and time of the first investigator-confirmed HAE attack after the first dose for the efficacy evaluation period. The time to the first HAE attack was summarized using Kaplan-Meier (KM) estimates. '99999' indicates that median and full range were not evaluable due to low number of participants with events. The FAS included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Secondary
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End point timeframe |
Day 0 through Day 182
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Participants who Achieved at Least 50%, 70%, 90%, and 100% Reduction in the Investigator-Confirmed Normalized Number of Attacks (NNA) per 4 Weeks Relative to the Run-in Period NNA | ||||||||||||||
End point description |
A run-in period of 4 weeks was included to determine the participant’s baseline attack rate. This period may be extended up to 8 weeks. The normalized number of investigator-confirmed HAE attacks during efficacy evaluation period was expressed as a monthly (28 days) HAE attack rate relative to the run-in period NNA. Number of participants who achieved at least 50 percent (%), 70%, 90% and 100% reduction in the investigator-confirmed NNA per 4 weeks relative to the run-in period normalized NNA for the efficacy evaluation periods was assessed. The FAS included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Secondary
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End point timeframe |
Day 0 through Day 182
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of Participants who Achieved NNA <1.0 per 4 Weeks for the Efficacy Evaluation Period of Day 0 Through Day 182 | ||||||
End point description |
The normalized number of investigator-confirmed HAE attacks during the efficacy evaluation period was expressed as a monthly (28 days) HAE attack rate. Attack rate was calculated for each participant as the number of attacks occurring during the specified period divided by the number of days the participant contributed to the specified period multiplied by 28 days. Number of participants who achieved NNA <1.0 per 4 weeks for the efficacy evaluation period were assessed. The FAS included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Secondary
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End point timeframe |
Day 0 through Day 182
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants who Achieved Investigator-confirmed HAE Attack-Free Status During the Efficacy Evaluation Period of Day 0 Through Day 182 | ||||||
End point description |
An HAE attack was confirmed by following symptoms or signs consistent with an attack in at least one of the following locations: 1) Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region; 2) Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea; 3) Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx. A participant was considered as attack free if the participant had no investigator-confirmed HAE attacks during the efficacy evaluation period. Number of participants who achieved attack-free status for the efficacy evaluation periods were assessed. The FAS included all participants who received at least 1 dose of lanadelumab (IP).
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End point type |
Secondary
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End point timeframe |
Day 0 through Day 182
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants With Neutralizing or Non-neutralizing Antidrug Antibodies (ADA) in Plasma | ||||||||||||||||||
End point description |
Number of participants with neutralizing or non-neutralizing ADA in plasma were assessed. The FAS included all participants who received at least 1 dose of lanadelumab (IP). 'n' signifies the number of participants with data available for analyses at the specified timepoint.
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End point type |
Secondary
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End point timeframe |
Anytime on Days 0 and 210; and pre-dose on Days 14, 56, 98, 140, 182
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Plasma Concentrations of Lanadelumab by Immunogenicity Result | ||||||||||||||||||||||||||||||||
End point description |
The effect of presence or absence of neutralizing or non-neutralizing ADA in plasma on the lanadelumab plasma concentrations was assessed. '9999' indicates that data was not available as no participants were analyzed at the specified time point. '99999' indicates that standard deviation (SD) was not estimable for a single participant. The PK set included all participants in the FAS who had at least 1 evaluable post-dose PK concentration value. 'n' signifies the number of participants with data available for analyses at the specified timepoint.
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End point type |
Secondary
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End point timeframe |
Anytime on Days 0 and 210; and pre-dose on Days 56, 98, 140, 182
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Plasma Kallikrein Activity cHMWK by Immunogenicity Result | ||||||||||||||||||||||||||||||||
End point description |
The effect of presence or absence of neutralizing or non-neutralizing ADA in plasma on the cHMWK levels was assessed. The PD set included all participants in the FAS who had at least 1 evaluable post-dose PD concentration value. '9999' indicates that data was not available as no participants were analysed at the specified time point. '99999' indicates that SD was not estimable for a single participant. 'n' signifies the number of participants with data available for analyses at the specified timepoint.
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End point type |
Secondary
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End point timeframe |
Anytime on Days 0 and 210; and pre-dose on Days 56, 98, 140, 182
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Number of Investigator-confirmed HAE Attacks by Immunogenicity Result and Efficacy Evaluation Period of Day 0 Through Day 182 | ||||||||||||
End point description |
Effect of presence or absence of neutralizing or non-neutralizing ADA in plasma on the number of investigator-confirmed HAE attacks during the efficacy evaluation periods was assessed. ''99999' indicates that SD was not estimable for a single participant. The FAS included all participants who received at least 1 dose of lanadelumab (IP). 'n' signifies the number of participants with data available for analyses at the specified timepoint.
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End point type |
Secondary
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End point timeframe |
Day 0 through Day 182
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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 the study upto follow up (up to Day 210)
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Adverse event reporting additional description |
The FAS included all participants who received at least 1 dose of lanadelumab (IP).
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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 |
26
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Reporting groups
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Reporting group title |
Lanadelumab 300 mg
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Reporting group description |
Participants received lanadelumab 300 mg, SC, Q2W for 26 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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12 Apr 2022 |
The following changes were made as per Amendment 1: 1) Updated text for the analyses and classification of safety parameters for clarification. 2) Clarified the requirements of repeating test or re-screening. 3) Updated exclusion criteria to indicate that use of long term prophylaxis (LTP) therapy for HAE within 2 weeks prior to entering the run-in period is exclusionary only for adult participants. 4) Added details of “injection report” and “diary card”; removed the “self-administration questionnaire” and “memory aid” to provide clear guidance of the study execution. 5) Added details of the alternatives could be followed during an unanticipated situations like coronavirus disease 2019 (COVID-19) outbreak. 6) Added the subsection of interactive response technology for the investigational product management tasks. 7) Added sentence that alternative approaches such as remote source data review via phone or video could be used for monitoring purpose. |
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08 Feb 2023 |
The following changes were made as per Amendment 2: 1) Added the potential to conduct an interim analysis when approximately 10 participants complete the 26-week treatment period and 4-week follow-up period. 2) Emphasized that for the adolescent participants(<18 years of age) enrolled in the study that reach 18 years of age during study periods, a consent using the most current version of the informed consent form by participant is required. 3) Emphasized that both AESI and SAE should be reported to sponsor or contract research organization (CRO) within 24 hours by investigator by adding AESI reporting requirement in administrative information. 4) Extended the time frame of screening from up to 2 weeks to up to 4 weeks for feasibility of study due to COVID-19. 5) Updated exclusion criteria to specify the requirement to exclude participants using any lanadelumab prior to the study. 6) Removed liver toxicity (EU specific risk) as an important potential risk. |
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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 | |||
