Efficacy and Safety of Lanadelumab for Prevention Against Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH)
Efficacy and Safety 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 safety and efficacy of repeated subcutaneous
 (SC) administrations of lanadelumab in preventing angioedema attacks in adolescents and
 adults with non-histaminergic angioedema with normal C1-INH.
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).
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 greater than or equal to (>=) 50
 percent (%) of normal and normal C4. 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 less than (<) 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).