A Study of Lanadelumab (SHP643) in Chinese Participants With Hereditary Angioedema (HAE)
Study Details
Study Description
Brief Summary
The main aim of this study is to evaluate the safety of lanadelumab in Chinese participants with HAE.
Participants will be treated with a subcutaneous injection of lanadelumab every two weeks for 26 weeks. During the study, each participant will make 16 visits to study clinics.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Lanadelumab 300 mg Participants will receive lanadelumab 300 milligram (mg), subcutaneously, once every 2 weeks (Q2W) from Day 0 to Day 182 (26 weeks). |
Drug: Lanadelumab
Lanadelumab subcutaneous injection.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Up to Day 210]
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.
- Number of Participants With Adverse Events of Special Interest (AESIs) [Up to Day 210]
Hypersensitivity reactions and events of disordered coagulation will be considered as AESIs. Number of participants with AESIs will be reported.
- Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameter [Up to Day 210]
Clinical laboratory parameter includes hematology, clinical chemistry, coagulation, and urinalysis. Number of participants with clinically significant changes in clinical laboratory parameter will be reported.
- Number of Participants With Clinically Significant Changes in Vital Sign Parameter [Up to Day 210]
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 12-Lead Electrocardiogram (ECG) Values [Up to Day 210]
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 [Up to Day 210]
Number of participants with clinically significant changes in physical examination will be reported.
Secondary Outcome Measures
- Plasma Concentrations of Lanadelumab [At Days 0 and 210; and pre-dose at Days 14, 56, 98, 140, 182]
Plasma concentrations of lanadelumab will be assessed.
- Plasma Kallikrein (pKal) Activity [At Days 0 and 210; and pre-dose at Days 14, 56, 98, 140, 182]
pKal activity will be measured by biomarker cleaved high molecular weight kininogen (cHMWK ) level.
- Number of Investigator-Confirmed HAE Attacks During the Efficacy Evaluation Periods [Day 0 through Day 182; Day 70 through Day 182]
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.
- Number of Investigator-Confirmed HAE Attacks Requiring Acute Treatment During the Efficacy Evaluation Periods [Day 0 through Day 182; Day 70 through Day 182]
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.
- Number of Moderate or Severe Investigator-Confirmed HAE Attacks During the Efficacy Evaluation Periods [Day 0 through Day 182; Day 70 through Day 182]
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.
- Number of Participants with Maximum Attack Severity During the Efficacy Evaluation Periods [Day 0 through Day 182; Day 70 through Day 182]
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.
- Time to First HAE Attack for the Efficacy Evaluation Period of Day 0 Through Day 182 [Day 0 through Day 182]
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.
- Time to First HAE Attack for the Efficacy Evaluation Period of Day 70 Through Day 182 [Day 70 through Day 182]
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.
- Number of Participants Achieving Attack-Free Status for the Efficacy Evaluation Periods [Day 0 through Day 182; Day 70 through Day 182]
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.
- Number of Participants Achieving at Least 50 %, 70% and 90% Reduction in the Investigator-Confirmed Normalized Number of Attacks (NNA) per 4 Weeks Relative to the Run-in Period NNA for the Efficacy Evaluation Periods [Day 0 through Day 182; Day 70 through Day 182]
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.
- Number of Participants Achieving NNA Less than (<) 1.0 per 4 Weeks for the Efficacy Evaluation Periods [Day 0 through Day 182; Day 70 through Day 182]
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 Antidrug Antibodies (ADA) in Plasma [At Days 0 and 210; and pre-dose at Days 56, 98, 140, 182]
Number of participants with neutralizing or non-neutralizing ADA in plasma will be assessed.
- Effect of Presence or Absence of Neutralizing or Non-neutralizing Antidrug Antibodies (ADA) in Plasma on Lanadelumab Plasma Concentrations [At Days 0, 56, 98, 140, 182 and 210]
The effect of presence or absence of neutralizing or non-neutralizing ADA in plasma on the lanadelumab plasma concentrations will be assessed.
- Effect of Presence or Absence of Neutralizing or Non-neutralizing Antidrug Antibodies (ADA) in Plasma on cHMWK Levels [At Days 0, 56, 98, 140, 182 and 210]
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 Antidrug Antibodies (ADA) in Plasma on Number of Investigator-confirmed HAE Attacks During the Efficacy Evaluation Periods [Day 0 through Day 182; Day 70 through Day 182]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Be of Chinese descent, defined as born in China and having Chinese parents and Chinese maternal and paternal grandparents.
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The participant is male or female and greater than or equal to (>=) 12 years of age at the time of informed consent.
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Documented diagnosis of HAE Type I or Type II based upon all of the following:
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Documented clinical history consistent with HAE (subcutaneous [SC] or mucosal, nonpruritic swelling episodes without accompanying urticaria).
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Diagnostic testing results obtained during screening by a laboratory (approved by the sponsor) that confirm HAE Type I or Type II: C1 esterase inhibitor (C1-INH) functional level <40% of the normal level. Participants with functional C1-INH level 40% to 50% of the normal level may be enrolled if they also have a C4 level below the normal range. Participants may begin participating in the run-in period before these diagnostic results are available. Participants may be re-tested if results are incongruent with clinical history or believed by the investigator to be confounded by recent long-term prophylaxis (LTP) use.
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At least one of the following: Age at reported onset of first angioedema symptoms less than or equal to (<=) 30 years, a family history consistent with HAE Type I or Type II, or C1q within normal range.
- Attack rate:
• At the time of enrollment, participants must experience at least 1 investigator-confirmed HAE attack per 4 weeks during the run-in period.
- The participant (or the participant's parent/legal guardian, if applicable) has provided written informed consent approved by the institutional review board (IRB)/ institutional ethical committee (IEC).
• If the participant is an adult, be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.
OR
• If the participant is a minor (that is <18 years of age), have a parent/legal guardian who is informed of the nature of the study provide written informed consent (that is, permission) for the minor to participate in the study before any study-specific procedures are performed. Assent will be obtained from minor participants.
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Males, or non-pregnant, non-lactating females who are fertile and sexually active 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 postmenopausal for at least 12 months.
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Agree to adhere to the protocol-defined schedule of assessments and procedures.
Exclusion Criteria:
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Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema, HAE with normal C1 esterase inhibitor (C1-INH) (also known as HAE Type III), idiopathic angioedema, or recurrent angioedema associated with urticaria.
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Participation in a prior lanadelumab study.
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Dosing with investigational drug or exposure to an investigational device within 4 weeks prior to entering to screening.
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Exposure to angiotensin-converting enzyme inhibitors or any estrogen-containing medications with systematic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to screening.
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Exposure to androgens (that is, danazol, methyltestosterone, testosterone) within 2 weeks prior to entering the run-in period.
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Use of LTP therapy (defined as continued use) for HAE (C1-INH, attenuated androgens, or anti-fibrinolytics) for adult participants within 2 weeks prior to entering the run-in period. Adolescent participants (>=12 to <18 years of age) who are on LTP therapy for HAE are allowed to enter the study.
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Use of short-term prophylaxis for HAE 7 days prior to entering the run-in period. Short-term prophylaxis is defined as fresh frozen plasma (FFP), C1-INH, attenuated androgens, or antifibrinolytics used to avoid angioedema complications from medically indicated procedures. Note: Currently, C1-INH therapies are not available in China.
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Any of the following liver function abnormalities: alanine aminotransferase (ALT) greater than (>)3* upper limit of normal (ULN), or aspartate aminotransferase (AST)
3* ULN or bilirubin >2* ULN (unless the bilirubin is a result of Gilbert's syndrome).
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Pregnancy or breast feeding.
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Participant has any condition that in the opinion of the investigator or sponsor, may compromise their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results (example, history of substance abuse or dependence, significant pre-existing illnesses or major comorbidity the investigator considers may confound the interpretation of the study results).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | The Second Affiliated Hospital of Guangzhou Medical University | Guangzhou | Guangdong | China | 510260 |
| 2 | Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology | Wuhan | Hubei | China | 430030 |
| 3 | Yantai Yuhuangding Hospital | Yantai | Shandong | China | 264000 |
| 4 | Peking Union Medical College Hospital | Beijing | China | 100730 |
Sponsors and Collaborators
- Takeda
Investigators
- Study Director: Study Director, Takeda
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SHP643-304