A Study of Lanadelumab in Teenagers and Adults to Prevent Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH)

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.

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).