A Study of Lanadelumab in Teenagers and Adults to Prevent Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH)
Condition: Angioedema
MeSH terms: Angioedema; Angioedemas, Hereditary
Intervention: Placebo; Lanadelumab
Intervention description: Placebo-matching lanadelumab SC injection.; Lanadelumab solution in a PFS for injection.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 77.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: Drug Therapy

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.
    

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).