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Efficacy and Safety of Lanadelumab for Prevention Against Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH) and Acquired Angioedema (AAE) Due to C1-INH Deficiency

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ClinicalTrials.gov Identifier: NCT04206605
Recruitment Status : Active, not recruiting
First Posted : December 20, 2019
Last Update Posted : May 19, 2020
Sponsor:
Information provided by (Responsible Party):
Shire

Brief Summary:
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 and in adults with acquired angioedema (AAE) due to C1-INH deficiency.

Condition or disease Intervention/treatment Phase
Angioedema Drug: Lanadelumab Other: Placebo Phase 3

Detailed Description:

Study consists of 2 angioedema indication cohorts based on the population-specific study entry criteria: 1. non-histaminergic normal C1-INH angioedema indication cohort with 12 years of age and above participants, 2. AAE indication cohort with 30 years and above participants. Participants will be randomized 2:1 to receive repeated SC administrations of lanadelumab or placebo in a double-blind fashion within each of the 2 angioedema indication cohorts. In the non-histaminergic normal C1-INH angioedema indication cohort, randomization will be stratified by baseline angioedema attack rate (1 to less than (<) 2 attacks/4 weeks, and greater than (>=)2 attacks/4 weeks) and in the AAE indication cohort, randomization will be stratified by baseline angioedema attack rate only (1 to < 2 attacks/4 weeks, 2 to < 3 attacks/4 weeks, and >= 3 attacks/4 weeks).

23 APRIL 2020: Enrollment of new patients into this study has been paused due to the COVID-19 situation. The duration of this pause is dependent on the leveling and control of the COVID-19 pandemic.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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) and Acquired Angioedema (AAE) Due to C1-INH Deficiency
Actual Study Start Date : May 4, 2020
Estimated Primary Completion Date : March 3, 2023
Estimated Study Completion Date : March 3, 2023


Arm Intervention/treatment
Experimental: Lanadelumab
Participants will receive 300 milligrams (mg) of lanadelumab solution in a prefilled syringe (PFS) as subcutaneous (SC) injection into the abdomen once every 2 weeks (q2w) for 26 weeks.
Drug: Lanadelumab
Participants will receive 300 mg of lanadelumab solution in a PFS SC injection once every 2 weeks for 26 weeks.
Other Names:
  • SHP643
  • DX-2930
  • TAK- 743

Placebo Comparator: Placebo
Participants will receive 300 mg of placebo matched to lanadelumab SC injection into the abdomen once q2w for 26 weeks.
Other: Placebo
Participants will receive 300 mg of placebo matched to lanadelumab SC injection once every 2 weeks for 26 weeks.




Primary Outcome Measures :
  1. Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 [ Time Frame: Day 0 through Day 182 ]
    An angioedema attack is 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 will be assessed.


Secondary Outcome Measures :
  1. Number of Participants Achieving Attack-Free Status During the Treatment Period of Day 0 Through Day 182 [ Time Frame: Day 0 through Day 182 ]
    Number of participants achieving attack-free status during the treatment period of day 0 through day 182 will be assessed.

  2. Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182 [ Time Frame: Day 0 Through Day 182 ]
    Moderate attack is defined as grade 2 (some assistance may be needed, no or minimal medical intervention/therapy required), Severe attack is defined as grade 3 (some assistance usually required, medical intervention/therapy required, hospitalizations possible). Number of investigator-confirmed moderate or severe angioedema attacks during the treatment period of day 0 through day 182 will be assessed.

  3. Number of Investigator-Confirmed Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182 [ Time Frame: Day 70 through Day 182 ]
    Number of investigator-confirmed angioedema attacks during the presumed steady state period of day 70 through day 182 will be assessed.

  4. Number of Participants Achieving Attack-Free Status During the Presumed Steady State Period of Day 70 Through Day 182 [ Time Frame: Day 70 through Day 182 ]
    Number of participants achieving attack-free status during the presumed steady state period of day 70 through day 182 will be assessed.

  5. Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182 [ Time Frame: Day 70 through Day 182 ]
    Number of investigator-confirmed moderate or severe angioedema attacks during the presumed steady state period of day 70 through day 182 will be assessed.

  6. Number of Participants with Maximum Attack Severity During Presumed Steady State Period of Day 70 Through Day 182 [ Time Frame: Day 70 through Day 182 ]
    Number of participants with maximum attack severity during the presumed steady state period of day 70 through day 182 will be assessed.

  7. Number of Participants with Maximum Attack Severity During Treatment Period of Day 0 Through Day 182 [ Time Frame: Day 0 through Day 182 ]
    Number of participants with maximum attack severity during treatment period of day 0 through day 182 will be assessed.

  8. Time to First Angioedema Attack After Day 0 Through Day 182 [ Time Frame: Day 0 Through Day 182 ]
    The time to the first angioedema attack (days) after Day 0 for the efficacy evaluation period of Day 0 through Day 182 will be calculated from the date and time of the first dose of lanadelumab for the efficacy evaluation period (Day 0 through Day 182) to the date and time of the first in angioedema attack after the first dose for the efficacy evaluation period of Day 0 through Day 182.

  9. Time to First Angioedema Attack After Day 70 Through Day 182 [ Time Frame: Day 70 through Day 182 ]
    The time to the first angioedema attack (days) after Day 0 for the efficacy evaluation period of Day 70 through Day 182 will be calculated from the date and time of the first dose of lanadelumab for the efficacy evaluation period (Day 70 through Day 182) to the date and time of the first in angioedema attack after the first dose for the efficacy evaluation period of Day 70 through Day 182.

  10. 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 [ Time Frame: Day 0 Through Day 182 ]
    Efficacy evaluation period will consist of two periods: Day 0 (after study drug administration) through Day 182 (the end of treatment period), presumed steady-state period from Day 70 through Day 182. Run in period will be 4 weeks and may be extended up to 8 weeks to determine their baseline attack rate. The normalized number of investigator-confirmed angioedema attacks (NNA) during each efficacy evaluation period will be expressed as a monthly (28 days) angioedema attack rate. Number of participants achieving at least 50 percent (%), 70%, 90% and 100% reduction in the investigator-confirmed normalized number of attacks per 4 weeks during each of the efficacy evaluation periods relative to the observation period NNA will be assessed.

  11. Number of Participants Achieving Normalized Number of Attacks (NNA) Less than (<)1.0 per 4 weeks During Each of the Efficacy Evaluation Periods [ Time Frame: Day 0 Through Day 182, Day 70 through Day 182 ]
    The normalized number of investigator-confirmed angioedema attacks (NNA) during each efficacy evaluation period will be expressed as a monthly (28 days) angioedema attack rate. Number of participants achieving normalized number of attacks < 1.0 per 4 weeks during each of the efficacy evaluation periods will be assessed.

  12. Number of Participants with Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) [ Time Frame: From start of the study up to follow up (Day 196) ]
    A TEAE is defined as any event emerging or manifesting at or after the initiation of treatment with an investigational product (IP) or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the IP or medicinal product. A SAE is any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to investigational product 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 will include hypersensitivity reactions, events of disordered coagulation such as bleeding AESI, hypercoagulable AESI. Number of participants with TEAEs including AESI and SAE will be assessed.

  13. Plasma Concentrations of Lanadelumab [ Time Frame: Day 0, 4, 28, 56, 84, 112, 140, 168 and 182 ]
    Plasma Concentrations of lanadelumab will be assessed.

  14. Plasma Kallikrein (pKal) Activity [ Time Frame: Day 0, 4, 28, 56, 84, 112, 140, 168 and 182 ]
    Plasma Kallikrein activity will be measured by biomarker cleaved high molecular weight kininogen (cHMWK ) level to assess pharmacodynamics of lanadelumab.

  15. Number of Participants With Neutralizing or Non-neutralizing Antidrug Antibodies (ADA) in Plasma [ Time Frame: Day 0, 28, 56, 84, 112, 140, 168 and 182 ]
    Number of participants with neutralizing or non-neutralizing antidrug antibodies in plasma will be assessed.

  16. Change in Total Angioedema Quality of life (AE-QoL) Questionnaire Score During the Treatment Period of Day 0 Through Day 182 [ Time Frame: Day 0 through Day 182 ]
    The AE-QoL questionnaire is a self-administered validated instrument to assess health related (HR)QoL among participants with recurrent angioedema. The AE-QoL consists of 17 disease-specific quality-of-life items, to produce a total AEQoL score and 4 domain scores (functioning, fatigue/mood, fear/shame, and nutrition) and each of the 17 items has a five point response scale ranging from 1 (Never) to 5 (Very Often).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 or 30 years of age and older for participants with AAE due to C1-INH deficiency 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:

    • non-histaminergic angioedema with normal C1-INH
    • AAE due to C1-INH deficiency, as documented by a history of angioedema attacks at screening and occurrence of attack(s) during the observation period.
  • Participants with non-histaminergic normal C1-INH angioedema must also meet the specific inclusion criteria below unique to this study population:

    • 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 antigen and 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.
  • Participants with AAE due to C1-INH deficiency must also meet the specific inclusion criteria below unique to this study population:

    • 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.
    • No family history of angioedema or C1-INH deficiency.
    • Onset of angioedema symptoms and attacks after the age of 30 years.
  • Diagnostic testing results obtained during screening from a sponsor-approved central laboratory that confirm C1-INH function below 50% of normal (decreased functional C1-INH) and low C4 levels (below the normal range). Participants may be retested if results are incongruent with clinical history or believed by the investigator to be confounded by recent C1-INH use.
  • 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; 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).
  • If the participant 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 participant 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.
  • For participants with normal C1-INH angioedema only: use of any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 6 months 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.
  • 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 antifibrinolytics 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 angioedema attack must be resolved prior to the first dose 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.
  • Participants 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04206605


Locations
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United States, Alabama
Clinical Research Center of Alabama
Birmingham, Alabama, United States, 35209
United States, Arizona
Medical Research of Arizona a division of Allergy, Asthma & Immunology Associates, LTD
Scottsdale, Arizona, United States, 85251
United States, California
UCSD Angioedema Center
San Diego, California, United States, 92122
United States, Colorado
Asthma and Allergy Associates, PC
Colorado Springs, Colorado, United States, 80907
United States, Maryland
Institute for Asthma & Allergy, P.C.
Chevy Chase, Maryland, United States, 20815
United States, Michigan
University of Michigan Specialty Allergy Clinic and Food Allergy Clinic
Ann Arbor, Michigan, United States, 48106
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63414
United States, Ohio
Optimed Research, LTD
Columbus, Ohio, United States, 43235
Sponsors and Collaborators
Shire
Investigators
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Study Director: Study Director Shire
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Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT04206605    
Other Study ID Numbers: SHP643-303
First Posted: December 20, 2019    Key Record Dates
Last Update Posted: May 19, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. 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.
URL: https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Angioedema
Angioedemas, Hereditary
Vascular Diseases
Cardiovascular Diseases
Urticaria
Skin Diseases, Vascular
Skin Diseases
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Genetic Diseases, Inborn