Angioedema
Conditions
Brief summary
The purpose of this study is to evaluate the long-term safety and efficacy of repeated subcutaneous (SC) administration of lanadelumab in adolescents and adults with non-histaminergic angioedema with normal C1-inhibitor who completed study SHP643-303 (NCT04206605).
Detailed description
This study consists of 26-week treatment period (Day 0 to Day 182) and a 2-week follow-up period. Participants who completed the double-blind treatment period at Day 182 of Study SHP643-303 (NCT04206605) will enroll into this extension study.
Interventions
DRUGLanadelumab
Lanadelumab SC injection
Sponsors
Takeda Development Center Americas, Inc.
Shire
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females, 12 years of age and older diagnosed with non-histaminergic normal C1-INH angioedema at the time of enrollment into the antecedent Study SHP643-303 (NCT04206605). * Participants must have completed the treatment period (through Visit 26/Day 182) of Study SHP643-303 (NCT04206605) without reporting a clinically significant TEAE that would preclude subsequent exposure to lanadelumab. * Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures. * Males, or non-pregnant, non-lactating females who are of child-bearing potential and who agree to be abstinent or agree to comply with the applicable contraceptive requirements of this protocol for the duration of the study; or females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months. * The participant (or the participant's parent/legal guardian, if applicable) has provided written informed consent approved by the institutional review board/research ethics board/ethics committee (IRB/REB/EC) at any time prior to study start. If the participant is a minor (i.e. lesser then (\<) 18 years of age), have a parent/legal guardian who is informed of the nature of the study provide written informed consent (i.e. permission) for the minor to participate in the study before any study-specific procedures are performed. Assent will be obtained from minor participants.
Exclusion criteria
* Discontinued from Study SHP643-303 (NCT04206605) after enrollment but before Visit 26 for any reason. * Presence of important safety concerns identified in Study SHP643-303 (NCT04206605) that would preclude participation in this study. * Dosing with an investigational product (IP, not including IP defined in antecedent Study SHP643-303 \[NCT04206605\]) or exposure to an investigational device within 4 weeks prior to Day 0. * Participants has a known hypersensitivity to the investigational product or its components. * Have any condition (surgical or medical) that, in the opinion of the investigator or sponsor, may compromise their safety or compliance, preclude the successful conduct of the study, or interfere with interpretation of the results (e.g. significant pre-existing illness or other major comorbidities that the investigator considers may confound the interpretation of study results).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | From Day 0 up to Day 182 | TEAE: Any event emerging or manifesting at or after initiation of treatment with investigational product (IP) or medicinal product or any existing event that worsens in either intensity or frequency following exposure to IP or medicinal product including clinically meaningful findings in laboratory safety tests, vital signs, weight, and electrocardiogram (ECG) findings. SAE: Any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to IP 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. AESI included hypersensitivity reactions, events of disordered coagulation such as bleeding AESI, hypercoagulable AESI. TEAEs were classified and reported as angioedema attack and non-angioedema attack adverse events in this outcome measure. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | From Day 183 up to Day 196 | TEAE: Any event emerging or manifesting at or after initiation of treatment with investigational product (IP) or medicinal product or any existing event that worsens in either intensity or frequency following exposure to IP or medicinal product including clinically meaningful findings in laboratory safety tests, vital signs, weight, and electrocardiogram (ECG) findings. SAE: Any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to IP 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. AESI included hypersensitivity reactions, events of disordered coagulation such as bleeding AESI, hypercoagulable AESI. TEAEs were classified and reported as angioedema attack and non-angioedema attack adverse events in this outcome measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of High-Morbidity Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 | From Day 0 up to Day 182 | A high-morbidity angioedema attack was defined as any attack that has at least one of the following characteristics: severe, results in hospitalization (except hospitalization for observation \<24 hours), hemodynamically significant (systolic blood pressure (BP) \<90 millimetres of mercury (mmHg), requires intravenous hydration, or associated with syncope or near-syncope) or laryngeal. |
| Pharmacokinetic (PK) Plasma Concentrations of Lanadelumab | Predose on Days 0, 84, and 140 and postdose on Day 182 | The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen. |
| Plasma Kallikrein (pKal) Activity | Predose on Days 0, 84, and 140 and postdose on Day 182 | Plasma kallikrein activity was measured by biomarker cleaved high molecular weight kininogen (cHMWK) with factor XIIa activation level to assess the pharmacodynamics of lanadelumab. The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen. |
| Number of Participants With Neutralizing Antidrug Antibodies (ADA) in Plasma | Predose on Days 0, 84, and 140 and postdose on Day 182 | Number of participants with positive ADA including evaluation of neutralizing antibodies in plasma was assessed. As pre-specified in the statistical analysis plan (SAP), data for this outcome measure was collected and analyzed as a single group irrespective of dosing regimen. |
| Change From Baseline in Total Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at End of Treatment Period | Baseline (Day 0) up to end of treatment period (Day 182) | The AE-QoL questionnaire is self-administered validated instrument to assess health related (HR)QoL among participants with recurrent angioedema(including hereditary angioedema\[HAE\]). It consists of 17 disease-specific QOL items, to produce total AE-QoL score & 4 domain scores(functioning,fatigue/mood,fear/shame,nutrition) each of 17 items had 5-point response scale ranging from 1(Never) to 5(Very Often). It was scored according to developers' guidelines to produce 4 domain scores yielding total score. The raw total score(mean of all item scores) was rescaled using linear transformations into final percentage scores ranging 0-100, based on maximum possible score, where higher score, greater QoL impairment. Negative change from Baseline indicates better QoL. Baseline: Last non-missing value prior to first exposure to study drug(based on date or date/time). As pre-specified in SAP, data for this outcome measure was collected and analyzed as single group irrespective of dosing regimen. |
| Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 | From Day 0 up to Day 182 | An angioedema attack was defined as the symptoms or signs consistent with an attack in at least 1 of the following locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Number of investigator-confirmed angioedema attacks during the treatment period of Day 0 through Day 182 was assessed. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | From Day 0 up to Day 196 | TEAE: Any event emerging or manifesting at or after initiation of treatment with investigational product (IP) or medicinal product or any existing event that worsens in either intensity or frequency following exposure to IP or medicinal product including clinically meaningful findings in laboratory safety tests, vital signs, weight, and electrocardiogram (ECG) findings. SAE: Any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to IP 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. AESI included hypersensitivity reactions, events of disordered coagulation such as bleeding AESI, hypercoagulable AESI. TEAEs were classified and reported as angioedema attack and non-angioedema attack adverse events in this outcome measure. |
| Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 in Participants Who Switched Dosing Regimen | From Day 0 up to Day 182 | An angioedema attack was defined as the symptoms or signs consistent with an attack in at least 1 of the following locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Number of investigator-confirmed angioedema attacks during the treatment period of Day 0 through Day 182 was assessed. |
| Number of Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 in Participants Who Switched Dosing Regimen | From Day 0 up to Day 182 | The overall severity of angioedema attack was determined by the site using following definitions: mild (transient or mild discomfort), moderate (mild to moderate limitation in activity), severe (marked limitation in activity). Number of moderate or severe angioedema attacks during the treatment period of Day 0 through Day 182 was assessed. |
| Number of High-Morbidity Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 in Participants Who Switched Dosing Regimen | From Day 0 up to Day 182 | A high-morbidity angioedema attack was defined as any attack that has at least one of the following characteristics: severe, results in hospitalization (except hospitalization for observation \<24 hours), hemodynamically significant (systolic BP \<90 mmHg, requires intravenous hydration, or associated with syncope or near-syncope) or laryngeal. |
| Number of Participants With Any Pause During Injection | Days 0, 14, 28, 42, 56, 70, 84, 98, 112, 126, 140, 154, and 168 | An injection report was completed by the participant (or parent/caregiver) following each dose administration of lanadelumab injection used during the treatment period and any kind of pause during injection was captured. Categories with at least one participant with event are reported. |
| Number of Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 | From Day 0 up to Day 182 | The overall severity of angioedema attack was determined by the site using following definitions: mild (transient or mild discomfort), moderate (mild to moderate limitation in activity), severe (marked limitation in activity). Number of moderate or severe angioedema attacks during the treatment period of Day 0 through Day 182 was assessed. |
Countries
Canada, France, Germany, Hungary, Italy, Japan, Netherlands, Poland, Spain, United States
Participant flow
Recruitment details
A total of 73 participants took part in the study at 34 investigative sites in Canada, France, Germany, Hungary, Italy, Japan, Netherlands, Poland, Spain, and the United States from 05 February 2021 to 05 May 2023.
Pre-assignment details
Participants with a diagnosis of non-histaminergic angioedema rolled over from the study SHP643-303 (NCT04206605) to receive lanadelumab 300 mg every 2 weeks (Q2W) of whom 2 participants switched to lanadelumab 300 mg at a reduced frequency of every 4 weeks (Q4W) for some time during the study.
Participants by arm
| Arm | Count |
|---|---|
| Lanadelumab 300 mg Q2W Participants received 300 mg lanadelumab SC injection, Q2W for up to 26 weeks with an option to switch to lanadelumab 300 mg Q4W if attacks were well-controlled based on the investigator's discretion and consultation with the sponsor's medical monitor. | 73 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Lanadelumab 300 mg Q2W |
|---|---|
| Age, Continuous | 43.7 years STANDARD_DEVIATION 12.63 |
| Body Mass Index (BMI) | 29.23 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 7.972 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Height | 166.75 centimeters (cm) STANDARD_DEVIATION 8.938 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 64 Participants |
| Region of Enrollment Canada | 5 Participants |
| Region of Enrollment France | 1 Participants |
| Region of Enrollment Germany | 3 Participants |
| Region of Enrollment Hungary | 2 Participants |
| Region of Enrollment Italy | 7 Participants |
| Region of Enrollment Japan | 4 Participants |
| Region of Enrollment Netherlands | 3 Participants |
| Region of Enrollment Poland | 6 Participants |
| Region of Enrollment Spain | 3 Participants |
| Region of Enrollment United States | 39 Participants |
| Sex: Female, Male Female | 59 Participants |
| Sex: Female, Male Male | 14 Participants |
| Weight | 81.52 kilograms (kg) STANDARD_DEVIATION 23.129 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 73 | 0 / 2 |
| other Total, other adverse events | 65 / 73 | 1 / 2 |
| serious Total, serious adverse events | 7 / 73 | 1 / 2 |
Outcome results
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up
TEAE: Any event emerging or manifesting at or after initiation of treatment with investigational product (IP) or medicinal product or any existing event that worsens in either intensity or frequency following exposure to IP or medicinal product including clinically meaningful findings in laboratory safety tests, vital signs, weight, and electrocardiogram (ECG) findings. SAE: Any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to IP 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. AESI included hypersensitivity reactions, events of disordered coagulation such as bleeding AESI, hypercoagulable AESI. TEAEs were classified and reported as angioedema attack and non-angioedema attack adverse events in this outcome measure.
Time frame: From Day 183 up to Day 196
Population: The SFAS included all participants who received any study drug after entering this study (i.e., any exposure to open-label lanadelumab). The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | Any TEAEs: Non-Angioedema Attack | 4 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | Any TEAEs: Angioedema Attack | 19 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | AESI: Non-Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | AESI: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | Any SAEs: Non-Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | Any SAEs: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | Any SAEs: Non-Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | Any TEAEs: Non-Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | AESI: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | Any TEAEs: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | Any SAEs: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Follow-up | AESI: Non-Angioedema Attack | 0 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period
TEAE: Any event emerging or manifesting at or after initiation of treatment with investigational product (IP) or medicinal product or any existing event that worsens in either intensity or frequency following exposure to IP or medicinal product including clinically meaningful findings in laboratory safety tests, vital signs, weight, and electrocardiogram (ECG) findings. SAE: Any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to IP 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. AESI included hypersensitivity reactions, events of disordered coagulation such as bleeding AESI, hypercoagulable AESI. TEAEs were classified and reported as angioedema attack and non-angioedema attack adverse events in this outcome measure.
Time frame: From Day 0 up to Day 182
Population: The SFAS included all participants who received any study drug after entering this study (i.e., any exposure to open-label lanadelumab). The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | Any TEAEs: Non-Angioedema Attack | 55 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | Any TEAEs: Angioedema Attack | 61 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | AESI: Non-Angioedema Attack | 1 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | AESI: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | Any SAEs: Non-Angioedema Attack | 5 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | Any SAEs: Angioedema Attack | 3 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | Any SAEs: Non-Angioedema Attack | 1 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | Any TEAEs: Non-Angioedema Attack | 1 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | AESI: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | Any TEAEs: Angioedema Attack | 1 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | Any SAEs: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) During Treatment Period | AESI: Non-Angioedema Attack | 0 Participants |
Secondary
Change From Baseline in Total Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at End of Treatment Period
The AE-QoL questionnaire is self-administered validated instrument to assess health related (HR)QoL among participants with recurrent angioedema(including hereditary angioedema\[HAE\]). It consists of 17 disease-specific QOL items, to produce total AE-QoL score & 4 domain scores(functioning,fatigue/mood,fear/shame,nutrition) each of 17 items had 5-point response scale ranging from 1(Never) to 5(Very Often). It was scored according to developers' guidelines to produce 4 domain scores yielding total score. The raw total score(mean of all item scores) was rescaled using linear transformations into final percentage scores ranging 0-100, based on maximum possible score, where higher score, greater QoL impairment. Negative change from Baseline indicates better QoL. Baseline: Last non-missing value prior to first exposure to study drug(based on date or date/time). As pre-specified in SAP, data for this outcome measure was collected and analyzed as single group irrespective of dosing regimen.
Time frame: Baseline (Day 0) up to end of treatment period (Day 182)
Population: The SFAS included all participants who received any study drug after entering this study (i.e., any exposure to open-label lanadelumab). Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lanadelumab 300 mg Q2W | Change From Baseline in Total Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at End of Treatment Period | -12.73 score on a scale | Standard Deviation 20.696 |
Secondary
Number of High-Morbidity Angioedema Attacks During the Treatment Period of Day 0 Through Day 182
A high-morbidity angioedema attack was defined as any attack that has at least one of the following characteristics: severe, results in hospitalization (except hospitalization for observation \<24 hours), hemodynamically significant (systolic blood pressure (BP) \<90 millimetres of mercury (mmHg), requires intravenous hydration, or associated with syncope or near-syncope) or laryngeal.
Time frame: From Day 0 up to Day 182
Population: The SFAS included all participants who received any study drug after entering this study (i.e., any exposure to open-label lanadelumab). The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanadelumab 300 mg Q2W | Number of High-Morbidity Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 | 232 angioedema attacks |
| Lanadelumab 300 mg Q4W | Number of High-Morbidity Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 | 1 angioedema attacks |
Secondary
Number of High-Morbidity Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 in Participants Who Switched Dosing Regimen
A high-morbidity angioedema attack was defined as any attack that has at least one of the following characteristics: severe, results in hospitalization (except hospitalization for observation \<24 hours), hemodynamically significant (systolic BP \<90 mmHg, requires intravenous hydration, or associated with syncope or near-syncope) or laryngeal.
Time frame: From Day 0 up to Day 182
Population: The RD-SFAS Set was a subset of the SFAS Set and included participants who switched from lanadelumab 300 mg Q2W to a lanadelumab 300 mg Q4W dosing regimen as recorded on the Dose Frequency Modification electronic case report form. The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanadelumab 300 mg Q2W | Number of High-Morbidity Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 in Participants Who Switched Dosing Regimen | 0 angioedema attacks |
| Lanadelumab 300 mg Q4W | Number of High-Morbidity Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 in Participants Who Switched Dosing Regimen | 1 angioedema attacks |
Secondary
Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182
An angioedema attack was defined as the symptoms or signs consistent with an attack in at least 1 of the following locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Number of investigator-confirmed angioedema attacks during the treatment period of Day 0 through Day 182 was assessed.
Time frame: From Day 0 up to Day 182
Population: The SFAS included all participants who received any study drug after entering this study (i.e., any exposure to open-label lanadelumab). The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanadelumab 300 mg Q2W | Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 | 595 angioedema attacks |
| Lanadelumab 300 mg Q4W | Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 | 2 angioedema attacks |
Secondary
Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 in Participants Who Switched Dosing Regimen
An angioedema attack was defined as the symptoms or signs consistent with an attack in at least 1 of the following locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Number of investigator-confirmed angioedema attacks during the treatment period of Day 0 through Day 182 was assessed.
Time frame: From Day 0 up to Day 182
Population: The RD-SFAS Set was a subset of the SFAS Set and included participants who switched from lanadelumab 300 mg Q2W to a lanadelumab 300 mg Q4W dosing regimen as recorded on the Dose Frequency Modification electronic case report form. The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanadelumab 300 mg Q2W | Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 in Participants Who Switched Dosing Regimen | 0 angioedema attacks |
| Lanadelumab 300 mg Q4W | Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 in Participants Who Switched Dosing Regimen | 2 angioedema attacks |
Secondary
Number of Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182
The overall severity of angioedema attack was determined by the site using following definitions: mild (transient or mild discomfort), moderate (mild to moderate limitation in activity), severe (marked limitation in activity). Number of moderate or severe angioedema attacks during the treatment period of Day 0 through Day 182 was assessed.
Time frame: From Day 0 up to Day 182
Population: The SFAS included all participants who received any study drug after entering this study (i.e., any exposure to open-label lanadelumab). The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanadelumab 300 mg Q2W | Number of Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 | 391 angioedema attacks |
| Lanadelumab 300 mg Q4W | Number of Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 | 2 angioedema attacks |
Secondary
Number of Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 in Participants Who Switched Dosing Regimen
The overall severity of angioedema attack was determined by the site using following definitions: mild (transient or mild discomfort), moderate (mild to moderate limitation in activity), severe (marked limitation in activity). Number of moderate or severe angioedema attacks during the treatment period of Day 0 through Day 182 was assessed.
Time frame: From Day 0 up to Day 182
Population: The RD-SFAS Set was a subset of the SFAS Set and included participants who switched from lanadelumab 300 mg Q2W to a lanadelumab 300 mg Q4W dosing regimen as recorded on the Dose Frequency Modification electronic case report form. The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanadelumab 300 mg Q2W | Number of Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 in Participants Who Switched Dosing Regimen | 0 angioedema attacks |
| Lanadelumab 300 mg Q4W | Number of Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 in Participants Who Switched Dosing Regimen | 2 angioedema attacks |
Secondary
Number of Participants With Any Pause During Injection
An injection report was completed by the participant (or parent/caregiver) following each dose administration of lanadelumab injection used during the treatment period and any kind of pause during injection was captured. Categories with at least one participant with event are reported.
Time frame: Days 0, 14, 28, 42, 56, 70, 84, 98, 112, 126, 140, 154, and 168
Population: The SFAS included all participants who received any study drug after entering this study (i.e., any exposure to open-label lanadelumab). Number analyzed is the number of participants with data available for analysis at the specified time point. The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 28 | 5 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 98 | 1 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 56 | 3 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 112 | 2 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 14 | 5 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 126 | 2 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 70 | 4 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 140 | 3 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 42 | 3 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 154 | 2 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 84 | 4 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 168 | 1 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Any Pause During Injection | Day 0 | 3 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 168 | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 0 | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 14 | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 28 | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 42 | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 56 | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 70 | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 84 | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 98 | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 112 | 1 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 126 | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 140 | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Any Pause During Injection | Day 154 | 0 Participants |
Secondary
Number of Participants With Neutralizing Antidrug Antibodies (ADA) in Plasma
Number of participants with positive ADA including evaluation of neutralizing antibodies in plasma was assessed. As pre-specified in the statistical analysis plan (SAP), data for this outcome measure was collected and analyzed as a single group irrespective of dosing regimen.
Time frame: Predose on Days 0, 84, and 140 and postdose on Day 182
Population: The SFAS included all participants who received any study drug after entering this study (i.e., any exposure to open-label lanadelumab). Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lanadelumab 300 mg Q2W | Number of Participants With Neutralizing Antidrug Antibodies (ADA) in Plasma | Day 0 | 2 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Neutralizing Antidrug Antibodies (ADA) in Plasma | Day 84 | 2 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Neutralizing Antidrug Antibodies (ADA) in Plasma | Day 140 | 3 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Neutralizing Antidrug Antibodies (ADA) in Plasma | Day 182 | 4 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen
TEAE: Any event emerging or manifesting at or after initiation of treatment with investigational product (IP) or medicinal product or any existing event that worsens in either intensity or frequency following exposure to IP or medicinal product including clinically meaningful findings in laboratory safety tests, vital signs, weight, and electrocardiogram (ECG) findings. SAE: Any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to IP 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. AESI included hypersensitivity reactions, events of disordered coagulation such as bleeding AESI, hypercoagulable AESI. TEAEs were classified and reported as angioedema attack and non-angioedema attack adverse events in this outcome measure.
Time frame: From Day 0 up to Day 196
Population: The RD-SFAS Set was a subset of the SFAS Set and included participants who switched from lanadelumab 300 mg Q2W to a lanadelumab 300 mg Q4W dosing regimen as recorded on the Dose Frequency Modification electronic case report form. The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | Any TEAEs: Non-Angioedema Attack | 2 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | Any TEAEs: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | AESI: Non-Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | AESI: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | Any SAEs: Non-Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | Any SAEs: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | Any SAEs: Non-Angioedema Attack | 1 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | Any TEAEs: Non-Angioedema Attack | 1 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | AESI: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | Any TEAEs: Angioedema Attack | 1 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | Any SAEs: Angioedema Attack | 0 Participants |
| Lanadelumab 300 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) in Participants Who Switched Dosing Regimen | AESI: Non-Angioedema Attack | 0 Participants |
Secondary
Pharmacokinetic (PK) Plasma Concentrations of Lanadelumab
The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.
Time frame: Predose on Days 0, 84, and 140 and postdose on Day 182
Population: The Pharmacokinetic (PK) Set included all participants in the SFAS who had at least 1 evaluable postdose PK concentration value. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanadelumab 300 mg Q2W | Pharmacokinetic (PK) Plasma Concentrations of Lanadelumab | Day 84 | 17021.002 nanograms per milliliter (ng/mL) | Standard Deviation 10116.5279 |
| Lanadelumab 300 mg Q2W | Pharmacokinetic (PK) Plasma Concentrations of Lanadelumab | Day 182 | 18799.596 nanograms per milliliter (ng/mL) | Standard Deviation 12054.1105 |
| Lanadelumab 300 mg Q2W | Pharmacokinetic (PK) Plasma Concentrations of Lanadelumab | Day 140 | 21138.057 nanograms per milliliter (ng/mL) | Standard Deviation 12076.9186 |
| Lanadelumab 300 mg Q2W | Pharmacokinetic (PK) Plasma Concentrations of Lanadelumab | Day 0 | 14419.068 nanograms per milliliter (ng/mL) | Standard Deviation 13208.1952 |
| Lanadelumab 300 mg Q4W | Pharmacokinetic (PK) Plasma Concentrations of Lanadelumab | Day 140 | 4944.010 nanograms per milliliter (ng/mL) | — |
| Lanadelumab 300 mg Q4W | Pharmacokinetic (PK) Plasma Concentrations of Lanadelumab | Day 84 | 7047.860 nanograms per milliliter (ng/mL) | — |
| Lanadelumab 300 mg Q4W | Pharmacokinetic (PK) Plasma Concentrations of Lanadelumab | Day 0 | NA nanograms per milliliter (ng/mL) | — |
| Lanadelumab 300 mg Q4W | Pharmacokinetic (PK) Plasma Concentrations of Lanadelumab | Day 182 | 14573.340 nanograms per milliliter (ng/mL) | — |
Secondary
Plasma Kallikrein (pKal) Activity
Plasma kallikrein activity was measured by biomarker cleaved high molecular weight kininogen (cHMWK) with factor XIIa activation level to assess the pharmacodynamics of lanadelumab. The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.
Time frame: Predose on Days 0, 84, and 140 and postdose on Day 182
Population: The Pharmacodynamic (PD) Set included all participants in the SFAS who had at least 1 evaluable postdose PD concentration value. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanadelumab 300 mg Q2W | Plasma Kallikrein (pKal) Activity | Day 0 | 15.306 percentage of cHMWK | Standard Deviation 15.2413 |
| Lanadelumab 300 mg Q2W | Plasma Kallikrein (pKal) Activity | Day 84 | 17.586 percentage of cHMWK | Standard Deviation 9.2437 |
| Lanadelumab 300 mg Q2W | Plasma Kallikrein (pKal) Activity | Day 140 | 17.238 percentage of cHMWK | Standard Deviation 9.159 |
| Lanadelumab 300 mg Q2W | Plasma Kallikrein (pKal) Activity | Day 182 | 15.515 percentage of cHMWK | Standard Deviation 9.2074 |
| Lanadelumab 300 mg Q4W | Plasma Kallikrein (pKal) Activity | Day 182 | 37.100 percentage of cHMWK | — |
| Lanadelumab 300 mg Q4W | Plasma Kallikrein (pKal) Activity | Day 0 | NA percentage of cHMWK | — |
| Lanadelumab 300 mg Q4W | Plasma Kallikrein (pKal) Activity | Day 140 | 44.700 percentage of cHMWK | — |
| Lanadelumab 300 mg Q4W | Plasma Kallikrein (pKal) Activity | Day 84 | 21.600 percentage of cHMWK | — |