A Study of Long-Term Safety and Efficacy of Lanadelumab for Prevention of Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor

An Open-Label Study to Evaluate the Long-Term Safety and Efficacy of Lanadelumab for Prevention Against Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH)

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).

Study Overview

• Status: Completed
• Conditions: Angioedema
• Intervention / Treatment: Drug: Lanadelumab

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.

• Study Type: Interventional
• Enrollment (Actual): 73
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 1E4
      • Ottawa Allergy Research Corporation
  • Quebec
    • Québec, Quebec, Canada, G1V 4W2
      • Clinique Spécialisée en Allergie de la Capitale
• France
  • Paris, France, 75012
    • Hôpital Saint-Antoine
• Germany
  • Bayern
    • Muenchen, Bayern, Germany, 81675
      • Klinikum rechts der Isar der TU
  • Hessen
    • Frankfurt, Hessen, Germany, 60590
      • Klinikum der Johann Wolfgang Goethe-Universitaet pt
• Hungary
  • Budapest, Hungary, 1088
    • Semmelweis Egyetem
• Italy
  • Milano, Italy, 20157
    • Azienda Socio Sanitaria Territoriale Fatebenefratelli (Presidio Ospedale Sacco)
  • Napoli, Italy, 80131
    • Azienda Ospedaliera Universitaria "Federico II"
  • Salerno, Italy, 84131
    • Azienda Ospedaliera Universitaria OO. RR. S. Giovanni di Dio e Ruggi D'Aragona
  • Palermo Palermo
    • Palermo, Palermo Palermo, Italy, 90100
      • A.O. Ospedali riuniti Villa Sofia - Cervello,
• Japan
  • Hiroshima-Ken
    • Hiroshima-shi, Hiroshima-Ken, Japan, 734-8551
      • Hiroshima University Hospital
  • Hyogo-Ken
    • Kobe-shi, Hyogo-Ken, Japan, 650-0017
      • Kobe University Hospital
  • Kanagawa-Ken
    • Fujisawa-shi, Kanagawa-Ken, Japan, 251-0025
      • Clover Hospital
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam UMC
  • Groningen, Netherlands, 9713 GZ
    • Universitair Medisch Centrum Groningen
  • Utrecht, Netherlands, 3508 GA
    • UMC Utrecht
• Poland
  • Bialystok, Poland, 15-867
    • NZOZ Homeo Medicus, Poradnia Alergologiczna
  • Wroclaw, Poland, 53-201
    • "ALL-MED" Specjalistyczna Opieka Medyczna Filia
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Vizcaya
    • Barakaldo, Vizcaya, Spain, 48903
      • Hospital Universitario Cruces
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Clinical Research Center of Alabama
  • Arizona
    • Scottsdale, Arizona, United States, 85248
      • Medical Research of Arizona
  • California
    • San Diego, California, United States, 92122
      • UCSD Angioedema Center
    • Walnut Creek, California, United States, 94598
      • Allergy and Asthma Clinical Research Inc
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Asthma and Allergy Associates, PC
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • Kanarek Allergy, Asthma and Immunology
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Institute for Asthma & Allergy, P.C.
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • University of Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Washington University
  • Ohio
    • Cincinnati, Ohio, United States, 45236
      • Bernstein Clinical Research Center, LLC
    • Columbus, Ohio, United States, 43235
      • Optimed Research, LTD
  • Washington
    • Seattle, Washington, United States, 98115
      • Seattle Allergy & Asthma Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lanadelumab 300 mg Every 2 Weeks; Participants received 300 milligrams (mg) lanadelumab subcutaneous (SC) injection, every 2 weeks (Q2W) for up to 26 weeks with an option to switch to lanadelumab 300 mg every 4 weeks (Q4W) if attacks were well-controlled based on the investigator's discretion and consultation with the sponsor's medical monitor.	Drug: Lanadelumab; Lanadelumab SC injection; Other Names: SHP643; TAK-743; DX-2930

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From Day 0 up to Day 182
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.	From Day 183 up to Day 196

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From Day 0 up to Day 182
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.	From Day 0 up to Day 182
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.	From Day 0 up to Day 182
Pharmacokinetic (PK) Plasma Concentrations of Lanadelumab	The data was partitioned by dosing regimen and reported accordingly to appropriately attribute to each dosing regimen.	Predose on Days 0, 84, and 140 and postdose on Day 182
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.	Predose on Days 0, 84, and 140 and postdose on Day 182
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.	Predose on Days 0, 84, and 140 and postdose on Day 182
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.	Baseline (Day 0) up to end of treatment period (Day 182)
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.	Days 0, 14, 28, 42, 56, 70, 84, 98, 112, 126, 140, 154, and 168
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.	From Day 0 up to Day 196
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.	From Day 0 up to Day 182
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.	From Day 0 up to Day 182
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.	From Day 0 up to Day 182

Collaborators and Investigators

• Sponsor: Shire
• Collaborators: Takeda Development Center Americas, Inc.
• Investigators: Study Director: Study Director, Takeda Development Center Americas

Publications and helpful links

Helpful Links

• To obtain more information on the study, click here/on this link

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2021
• Primary Completion (Actual): May 5, 2023
• Study Completion (Actual): May 5, 2023

Study Registration Dates

• First Submitted: June 16, 2020
• First Submitted That Met QC Criteria: June 23, 2020
• First Posted (Actual): June 24, 2020

Study Record Updates

• Last Update Posted (Actual): June 17, 2024
• Last Update Submitted That Met QC Criteria: June 14, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary
• Other Study ID Numbers: TAK-743-3001; 2019-004823-20 (EudraCT Number); jRCT2051220001 (Registry Identifier: jRCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No