Clinical trial NCT04206605: A Study of Lanadelumab in Teenagers and Adults to Prevent Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH)
Official title: A Phase 3, Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Efficacy and Safety of Lanadelumab for Prevention Against Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Angioedema
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Takeda Development Center Americas, Inc.
First posted: 2019-12-20
Enrollment: 77
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main aim of this study is to check if repeated subcutaneous (SC) injections of lanadelumab can prevent angioedema attacks in teenagers and adults with non-histaminergic angioedema with normal C1-INH. Another aim is to check if they tolerate the repeated SC injections.

Participants will receive a SC injection of lanadelumab every two weeks for 26 weeks. The first two doses of lanadelumab will be given at the study clinic. Once a participant (and/or parent/caregiver) has been appropriately trained, lanadelumab can be self-injected. Visits to the study clinic are planned for the first, third and fourth week and then every 4 weeks.

Detailed description: This study consists of non-histaminergic normal C1-INH angioedema population with 12 years of age and above. Participants will be randomized 2:1 to receive repeated SC administrations of lanadelumab or placebo in a double-blind fashion. Randomization will be stratified based on baseline angioedema attack rate (1 to less than (\<) 2 attacks/4 weeks, and greater than (\>=) 2 attacks/4 weeks), as well as subtype (known mutations, family history and unknown mutation, idiopathic).

Eligibility criteria: Inclusion Criteria:

The Participant will not be considered eligible for the study without meeting all of the applicable population criteria below.

* Males and females, 12 years of age and older for participants with non-histaminergic normal C1-INH angioedema at the time of signing of the informed consent form (ICF).
* Documented clinical history of recurrent attacks of angioedema in the absence of wheals/urticaria.
* Investigator-confirmed diagnosis of non-histaminergic bradykinin-mediated angioedema with normal C1-INH as documented by a history of angioedema attack(s) at screening and occurrence of attacks during the observation period:

  * History of recurrent angioedema with at least an average of 1 angioedema attack per 4 weeks prior to screening and this attack rate must be confirmed during the observation period while treated with chronic high-dose antihistamine (cetirizine 40 milligram per day \[mg/day\] or equivalent high-dose second-generation antihistamine medication).
  * Diagnostic testing results obtained during screening from a sponsor-approved central laboratory that confirm C1-INH function \>= 50 percent (%) of normal and C4 level not below the normal range. With prior sponsor approval, participants may be retested during the observation period if results are incongruent with clinical history.
  * Clinical history of not responding to high-dose antihistamine treatment (cetirizine 40 mg/day or equivalent high-dose second-generation antihistamine medication), which must be confirmed during the observation period with at least 1 angioedema attack per 4 weeks with chronic high-dose antihistamine treatment and no significant difference (as assessed by the investigator and in consultation with the sponsor's medical monitor, as necessary) from the historic attack rate without high-dose antihistamine treatment.
* Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
* Participants \>= 18 years of age must be willing to use icatibant as the rescue medication during the observation and treatment period. During the observation period, participants need to be treated with icatibant for at least 2 angioedema attacks or at least 1 moderate or severe attack. In the opinion of the investigator, participants with no response to icatibant for acute angioedema attacks in the past medical history/screening, or no improvement or worsened attack severity 2 hours after icatibant treatment during the observation period (based on totality of assessments), will not be included. Note: For participants 12 to \< 18 years of age, standard of care therapy per local protocols should be provided.
* 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. Female participants of childbearing potential must have a negative serum pregnancy test at screening and must be willing to undergo pregnancy tests throughout the study. Females of non-childbearing potential are defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months.
* The participants (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).
* If the participants 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 participants is a minor (i.e. \< 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

The participant will be excluded from the study if any of the following exclusion criteria are met.

* Concomitant diagnosis of Type I or Type II HAE, or recurrent angioedema associated with urticaria.
* Dosing with any investigational drug or exposure to an investigational device within 4 weeks prior to screening.
* Exposure to angiotensin-converting enzyme (ACE) inhibitors or rituximab within 6 months prior to screening.
* Use of any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to screening.
* Response to omalizumab (prophylactic) or corticosteroid (acute/prophylactic) or epinephrine (acute) or anti-leukotrienes (prophylactic) treatments in the past.
* Use of long-term prophylactic therapy for HAE, e.g. C1-INH, attenuated androgens (e.g. danazol, methyltestosterone, testosterone), or anti-fibrinolytics within 2 weeks prior to entering the observation period as long as the investigator determines that doing so would not place the participant at any undue safety risk, and that the participant is at least 18 years of age.
* Any exposure to prophylactic plasma kallikrein inhibitors prior to screening.
* Use of short-term prophylaxis for HAE within 7 days prior to entering the observation period. Short-term prophylaxis is defined as C1-INH, attenuated androgens, or anti-fibrinolytics used to avoid angioedema complications from medically indicated procedures.
* Have any active infectious illness or fever defined as an oral temperature greater than (\>) 38°C (100.4°F), tympanic \> 38.5°C (101.3°F), axillary \> 38°C (100.4°F), or rectal/core \> 38.5°C (101.3°F) within 24 hours prior to the first dose of study drug in the treatment period.
* Any of the following liver function test abnormalities: alanine aminotransferase (ALT) \> 3x upper limit of normal, or aspartate aminotransferase (AST) \> 3x upper limit of normal, or total bilirubin \> 2x upper limit of normal (unless the bilirubin elevation is a result of Gilbert's syndrome).
* Pregnancy or breast feeding.
* Participant has a known hypersensitivity to the investigational product or its components.
* Have any uncontrolled underlying medical condition which would require treatment adjustment during the study treatment period that, in the opinion of the investigator or sponsor, may confound the results of the safety assessments or may place the participant at risk. Participants with stable treatment for at least 3 months prior to screening and NOT expecting any change to their treatment regimen for 6 months during the study treatment period, will not be excluded.
* 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).

Primary outcomes:
measure: Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182
timeFrame: Day 0 through Day 182
Secondary outcomes:
measure: Number of Participants Achieving Attack-Free Status During the Treatment Period of Day 0 Through Day 182
timeFrame: Day 0 through Day 182
measure: Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182
timeFrame: Day 0 Through Day 182
measure: Number of Investigator-Confirmed Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182
timeFrame: Day 70 through Day 182
measure: Number of Participants Achieving Attack-Free Status During the Presumed Steady State Period of Day 70 Through Day 182
timeFrame: Day 70 through Day 182
measure: Number of Participants With Maximum Attack Severity During Treatment Period of Day 0 Through Day 182
timeFrame: Day 0 through Day 182
measure: Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182
timeFrame: Day 70 through Day 182
measure: Number of Participants With Maximum Attack Severity During Presumed Steady State Period of Day 70 Through Day 182
timeFrame: Day 70 through Day 182
measure: Time to First Angioedema Attack After Day 0 Through Day 182
timeFrame: Day 0 Through Day 182
measure: Time to First Angioedema Attack After Day 70 Through Day 182
timeFrame: Day 70 through Day 182
measure: Number of Participants Achieving at Least 50 %, 70%, 90% and 100% Reduction in the Investigator-Confirmed Normalized Number of Attacks (NNA) Per 4 Weeks During Each of the Efficacy Evaluation Periods Relative to the Observation Period NNA
timeFrame: Day 0 Through Day 182
measure: Number of Participants Achieving Normalized Number of Attacks (NNA) Less Than (<)1.0 Per 4 Weeks During Each of the Efficacy Evaluation Periods
timeFrame: Day 0 through Day 182, Day 70 through Day 182
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs)
timeFrame: From the first study drug administration up to follow-up (Day 196)
measure: Plasma Concentrations of Lanadelumab
timeFrame: Pre-dose and post-dose at Days 0, 4, 14, 28, 56, 84, 112, 140, 168 and 182
measure: Plasma Kallikrein (pKal) Activity
timeFrame: Pre-dose and post-dose at Days 4, 14, 28, 56, 84, 112, 140, 168 and 182
measure: Number of Participants With Neutralizing or Non-neutralizing Antidrug Antibodies (ADA) in Plasma
timeFrame: Pre-dose and post-dose at Days 28, 56, 84, 112, 140, 168 and 182
measure: Number of Participants With Change in Total Angioedema Quality of Life (AE-QoL) Questionnaire Score During the Treatment Period of Day 0 Through Day 182
timeFrame: Baseline through Day 182
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Clinical Research Center of Alabama
state: Alabama
city: Scottsdale
country: United States
facility: Medical Research of Arizona
state: Arizona
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: Santa Monica
country: United States
facility: AIRE Medical of Los Angeles
state: California
city: Walnut Creek
country: United States
facility: Allergy and Asthma Clinical Research Inc
state: California
city: Colorado Springs
country: United States
facility: Asthma and Allergy Associates, PC
state: Colorado
city: Tampa
country: United States
facility: University of South Florida Asthma, Allergy & Immunology
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Overland Park
country: United States
facility: Kanarek Allergy, Asthma and Immunology
state: Kansas
city: Chevy Chase
country: United States
facility: Institute for Asthma & Allergy - Chevy Chase
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Fair Lawn
country: United States
facility: Jay M Kashkin, MD Allergy, Asthma and Immunology
state: New Jersey
city: Charlotte
country: United States
facility: Clinical Research of Charlotte
state: North Carolina
city: Cincinnati
country: United States
facility: Bernstein Clinical Research Center, LLC
state: Ohio
city: Columbus
country: United States
facility: Optimed Research, LTD
state: Ohio
city: Layton
country: United States
facility: Tanner Clinic
state: Utah
city: Seattle
country: United States
facility: Seattle Allergy & Asthma Research Institute
state: Washington
city: Ottawa
country: Canada
facility: Ottawa Allergy Research Corporation
state: Ontario
city: Québec
country: Canada
facility: Clinique Specialisee en Allergie de la Capitale
state: Quebec
city: Isere
country: France
facility: CHU Grenoble Alpes, service de médecine interne, bureau de recherche clinique
city: Paris
country: France
facility: Service médecine interne, hôpital Saint Antoine
city: Frankfurt
country: Germany
facility: Klinikum der Johann Wolfgang Goethe-Universitaet
state: Hessen
city: Mainz
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz
state: Rheinland Pfalz
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig AoeR
state: Sachsen
city: Munich
country: Germany
facility: Klinikum rechts der Isar der TUM, HNO Klinik und Poliklinik
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Milano
country: Italy
facility: Azienda Socio Sanitaria Territoriale Fatebenefratelli (Presidio Ospedale Sacco)
city: Napoli
country: Italy
facility: DAI di Medicina Interna, Immunologia Clinica, Patologia Clinica, Malattie Infettive
city: Salerno
country: Italy
facility: Azienda Ospedaliera Universitaria OO. RR. S. Giovanni di Dio e Ruggi D'Aragona
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Hyogo
country: Japan
facility: Kobe University Hospital
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Bialystok
country: Poland
facility: NZOZ Homeo Medicus, Poradnia Alergologiczna
city: Wroclaw
country: Poland
facility: "ALL-MED" Specjalistyczna Opieka Medyczna Medyczny Instytut Badawczy
city: L'Hospitalet de Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge
state: Barcelona
city: Vigo
country: Spain
facility: Complexo Hospitalario Universitario de Vigo
state: Pontevedra
city: Barakaldo
country: Spain
facility: Hospital Universitario Cruces
state: Vizcaya
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: