takeda/studies/attachments/Plain_Language_Summary_-_English_BWA02PI

Plain Language Summary - English

takeda/studies/attachments/SHP643-304-clinical-study-report-redact.pdf

CSR Synopsis - English

The main aim of this study is to evaluate the safety of lanadelumab in Chinese
participants with HAE.

Participants will be treated with lanadelumab for 26 weeks.

A Study of Lanadelumab (SHP643) in Chinese Participants With Hereditary Angioedema (HAE)

Hereditary Angioedema (HAE)

Lanadelumab

A Multi-center, Open-label Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Lanadelumab (SHP643) in Chinese Subjects With Hereditary Angioedema

TEAE is defined as 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. A participant could
be counted in more than one category.

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.

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.

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.

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.

pKal activity was measured by cleaved high molecular weight kininogen (cHMWK) level
(i.e., plasma concentrations of cHMWK).

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.

An HAE attack was confirmed by following symptoms/signs consistent with an attack in
atleast 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/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.Acute HAE
attacks were managed per the investigator's usual care, including use of individualized
acute therapy/rescue medications.Acute therapy/rescue medications included Firazyr, fresh
frozen plasma (FFP), or other local standard of care.Treatment period attack rate per
month is calculated as the number of investigator-confirmed HAE attacks requiring acute
treatment occurring during that treatment period divided by number of days the
participant contributed to that treatment period multiplied by 28 days.

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.

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.

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.

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.

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 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.

Number of participants with neutralizing or non-neutralizing ADA in plasma were assessed.

The effect of presence or absence of neutralizing or non-neutralizing ADA in plasma on
the lanadelumab plasma concentrations was assessed.

The effect of presence or absence of neutralizing or non-neutralizing ADA in plasma on
the cHMWK levels was assessed.

The number of investigator-confirmed HAE attacks during the efficacy evaluation period
was expressed as a normalized monthly (4 weeks, i.e., 28 days). 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 effect of presence or
absence of neutralizing or non-neutralizing ADA in plasma on the investigator-confirmed
HAE attacks during the efficacy evaluation period was assessed.

Participants received lanadelumab 300 milligrams (mg), subcutaneously (SC), once every 2
weeks (Q2W) from Day 0 to Day 182 (26 weeks).

The main aim of this study is to evaluate the safety of lanadelumab in Chinese participants
      with HAE.

      Participants will be treated with lanadelumab for 26 weeks.

The Second Affiliated Hospital of Guangzhou Medical University

Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology

Yantai Yuhuangding Hospital

Peking Union Medical College Hospital

TEAE is defined as 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. A 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. Number of participants with TEAEs and SAEs will be reported.

Hypersensitivity reactions and events of disordered coagulation will be considered as AESIs. Number of participants with AESIs will be reported.

Clinical laboratory parameter includes hematology, clinical chemistry, coagulation, and urinalysis. Number of participants with clinically significant changes in clinical laboratory parameter will be reported.

Vital signs includes blood pressure (BP), heart rate (HR), body temperature, and respiratory rate. Number of participants with clinically significant changes in vital sign parameter will be reported.

Number of participants with clinically significant changes in 12-lead ECG values will be reported.

Number of participants with clinically significant changes in physical examination will be reported.

Plasma concentrations of lanadelumab will be assessed.

pKal activity will be measured by biomarker cleaved high molecular weight kininogen (cHMWK) level.

An HAE attack will be 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. Efficacy evaluation period will consist of 2 periods: Day 0 (after study drug administration) through Day 182 and presumed steady-state period from Day 70 through Day 182. Number of investigator-confirmed HAE attacks during the efficacy evaluation periods will be reported.

An HAE attack will be 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. Efficacy evaluation period will consist of 2 periods: Day 0 (after study drug administration) through Day 182 and presumed steady-state period from Day 70 through Day 182. Number of investigator-confirmed HAE attacks requiring acute treatment during the efficacy evaluation periods will be reported.

The severity of the Investigator-Confirmed HAE attacks is 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). Efficacy evaluation period will consist of 2 periods: Day 0 (after study drug administration) through Day 182 and presumed steady-state period from Day 70 through Day 182. Number of moderate or severe investigator-confirmed HAE attacks during the efficacy evaluation periods will be reported.

Maximum HAE attack severity is the most severe attack reported by the participant. Efficacy evaluation period will consist of 2 periods: Day 0 (after study drug administration) through Day 182 and presumed steady-state period from Day 70 through Day 182. Number of participants with maximum attack severity during the efficacy evaluation periods will be reported.

The time to the first HAE attack (days) after Day 0 for the efficacy evaluation period of Day 0 through Day 182 will be calculated from the date and time of the first dose of lanadelumab for the efficacy evaluation period (Day 0 through Day 182) to the date and time of the first in HAE attack after the first open-label dose for the efficacy evaluation period of Day 0 through Day 182. The time to the first HAE attack will be summarized using Kaplan-Meier (KM) estimates.

The time to the first HAE attack (days) after Day 0 for the efficacy evaluation period of Day 70 through Day 182 will be calculated from the date and time of the first dose of lanadelumab for the efficacy evaluation period (Day 70 through Day 182) to the date and time of the first in HAE attack after the first open-label dose for the efficacy evaluation period of Day 70 through Day 182. The time to the first HAE attack will be summarized using KM estimates.

An HAE attack will be 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. Efficacy evaluation period will consist of 2 periods: Day 0 (after study drug administration) through Day 182 and presumed steady-state period from Day 70 through Day 182. Number of participants achieving attack-free status for the efficacy evaluation periods will be assessed.

Run in period will be 4 weeks and may be extended up to 8 weeks to determine their baseline attack rate. The normalized number of investigator-confirmed HAE attacks during efficacy evaluation period will be expressed as a monthly (28 days) HAE attack rate. Efficacy evaluation period will consist of 2 periods: Day 0 (after study drug administration) through Day 182 and presumed steady-state period from Day 70 through Day 182. Number of participants achieving at least 50 percent (%), 70% and 90% reduction in the investigator-confirmed NNA per 4 weeks relative to the run-in period normalized NNA for the efficacy evaluation periods will be assessed.

The normalized number of investigator-confirmed HAE attacks during each efficacy evaluation period will be expressed as a monthly (28 days) HAE attack rate. Efficacy evaluation period will consist of 2 periods: Day 0 (after study drug administration) through Day 182 and presumed steady-state period from Day 70 through Day 182. Number of participants achieving NNA <1.0 per 4 weeks for the efficacy evaluation periods will be assessed.

Number of participants with neutralizing or non-neutralizing ADA in plasma will be assessed.

The effect of presence or absence of neutralizing or non-neutralizing ADA in plasma on the lanadelumab plasma concentrations will be assessed.

The effect of presence or absence of neutralizing or non-neutralizing ADA in plasma on the cHMWK levels will be assessed.

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 will be assessed.

Participants will receive lanadelumab 300 milligram (mg), subcutaneously, once every 2 weeks (Q2W) from Day 0 to Day 182 (26 weeks).

A Study of Lanadelumab (SHP643) in Chinese Participants With Hereditary Angioedema (HAE)

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