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A Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) Study of Lanadelumab to Prevent Hereditary Angioedema (HAE) Attacks in Pediatric Participants of 2 Years to Less Than (<) 12 Years of Age (SPRING)

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ClinicalTrials.gov Identifier: NCT04070326
Recruitment Status : Recruiting
First Posted : August 28, 2019
Last Update Posted : September 26, 2019
Sponsor:
Information provided by (Responsible Party):
Shire

Tracking Information
First Submitted Date  ICMJE August 26, 2019
First Posted Date  ICMJE August 28, 2019
Last Update Posted Date September 26, 2019
Actual Study Start Date  ICMJE August 30, 2019
Estimated Primary Completion Date December 17, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 26, 2019)
  • Number of Participants with Adverse Events Including Serious Adverse Events (SAE) and Adverse Events of Special Interest (AESI) [ Time Frame: From start of study treatment up to Follow up (Day 392) ]
    An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this investigational product 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 which results in death, is life-threatening, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, results in a congenital abnormality/birth defect, is an important medical event. Adverse events of special interest for this study are hypersensitivity reactions and disordered coagulation (hypercoagulability events and bleeding events).
  • Plasma Concentrations of Lanadelumab Over the Treatment Period [ Time Frame: Day 0 (Pre-dose), Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392 ]
    Plasma concentrations (cmax) of lanadelumab over the treatment period will be assessed.
  • Maximum Observed Concentration at Steady State (Cmax,ss) of Lanadelumab in Plasma [ Time Frame: Day 0 (Pre-dose), Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392 ]
    Maximum observed concentration at steady state (Cmax,ss) of lanadelumab in plasma will be assessed.
  • Average Concentration Over Dosing Interval at Steady State (Cavg,ss) of Lanadelumab in Plasma [ Time Frame: Day 0 (Pre-dose), Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392 ]
    Average concentration over Dosing interval at steady state (Cavg,ss) of lanadelumab in plasma will be assessed.
  • Predose Concentration at Steady State (Ctrough,ss) of Lanadelumab in Plasma [ Time Frame: Day 0 (Pre-dose), Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392 ]
    Predose concentration at steady state (Ctrough,ss) of lanadelumab in plasma will be assessed.
  • Time to Reach Maximum Observed Concentration (Cmax) (tmax)of Lanadelumab in Plasma [ Time Frame: Day 0 (Pre-dose), Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392 ]
    Time to reach Cmax (tmax) of lanadelumab in plasma will be assessed.
  • Area Under the Concentration-Time Curve Over the Dosing Interval at Steady State (AUCtau,ss) of Lanadelumab in Plasma [ Time Frame: Day 0 (Pre-dose), Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392 ]
    Area under the concentration-time curve over the dosing interval at steady state (AUCtau,ss) of lanadelumab in plasma will be assessed.
  • Terminal half-life (t1/2) of Lanadelumab in Plasma [ Time Frame: Day 0 (Pre-dose), Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392 ]
    Terminal half-life (t1/2) of lanadelumab in plasma will be assessed.
  • Apparent clearance (CL/F) of Lanadelumab [ Time Frame: Day 0 (Pre-dose), Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392 ]
    Apparent clearance (CL/F) of lanadelumab will be assessed.
  • Apparent Volume of Distribution (V/F) of Lanadelumab [ Time Frame: Day 0 (Pre-dose), Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392 ]
    Apparent volume of distribution (V/F) of lanadelumab will be assessed.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 26, 2019)
  • Normalized Number of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks During Overall Treatment Period [ Time Frame: From start of study treatment up to Follow up (Day 392) ]
    The normalized number of investigator-confirmed HAE attacks during each efficacy evaluation period will be expressed as a monthly HAE attack rate. A HAE 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). Overall treatment period of the study is from Day 0 (after start of study drug administration) through Day 364 (Week 52).
  • Normalized Number of Investigator-Confirmed HAE Attacks For Each Efficacy Evaluation Period Other Than the Overall Treatment Period [ Time Frame: Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364 ]
    Efficacy evaluation period consists of overall treatment period (Day 0 [after study drug administration] through Day 364 [Week 52]), treatment Period A (Day 0 [after study drug administration] through Day 182 [Week 26]), treatment Period B (Day 183 through Day 364 [Week 52]), overall presumed steady state period (Day 70 [Week 10] through Day 364 [Week 52]), presumed steady state period for treatment period A (Day 70 [Week 10] through Day 182 [Week 26]).
  • Time to the First Investigator-Confirmed Hereditary Angioedema (HAE) Attack for Each Evaluation Period [ Time Frame: Day 0 through Day 364, Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364 ]
    Time to the first investigator-confirmed HAE attack (days) for each efficacy evaluation period will be calculated from the date and time of the first dose of lanadelumab for that efficacy evaluation period to the date and time of the first investigator-confirmed HAE attack after the first open-label dose for that efficacy evaluation period. Efficacy evaluation period consists of overall treatment period (Day 0 [after study drug administration] through Day 364 [Week 52]), treatment Period A (Day 0 [after study drug administration] through Day 182 [Week 26]), treatment Period B (Day 183 through Day 364 [Week 52]), overall presumed steady state period (Day 70 [Week 10] through Day 364 [Week 52]), presumed steady state period for treatment period A (Day 70 [Week 10] through Day 182 [Week 26]).
  • Normalized Number of Hereditary Angioedema (HAE) Attacks Requiring Acute Treatment for Each Efficacy Evaluation Period [ Time Frame: Day 0 through Day 364, Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364 ]
    Efficacy evaluation period consists of overall treatment period (Day 0 [after study drug administration] through Day 364 [Week 52]), treatment Period A (Day 0 [after study drug administration] through Day 182 [Week 26]), treatment Period B (Day 183 through Day 364 [Week 52]), overall presumed steady state period (Day 70 [Week 10] through Day 364 [Week 52]), presumed steady state period for treatment period A (Day 70 [Week 10] through Day 182 [Week 26]).
  • Normalized Number of Moderate or Severe Investigator-Confirmed Hereditary Angioedema (HAE) Attacks for Each Efficacy Evaluation Period [ Time Frame: Day 0 through Day 364, Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364 ]
    Efficacy evaluation period consists of overall treatment period (Day 0 [after study drug administration] through Day 364 [Week 52]), treatment Period A (Day 0 [after study drug administration] through Day 182 [Week 26]), treatment Period B (Day 183 through Day 364 [Week 52]), overall presumed steady state period (Day 70 [Week 10] through Day 364 [Week 52]), presumed steady state period for treatment period A (Day 70 [Week 10] through Day 182 [Week 26]). Severe attack is defined as grade 3 (some assistance usually required, medical intervention/therapy required, hospitalizations possible), moderate attack is defined as grade 2 (some assistance may be needed, no or minimal medical intervention/therapy required).
  • Normalized Number of High Morbidity Investigator-Confirmed Hereditary Angioedema (HAE) Attacks for Each Efficacy Evaluation Period [ Time Frame: Day 0 through Day 364, Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364 ]
    Efficacy evaluation period consists of overall treatment period (Day 0 [after study drug administration] through Day 364 [Week 52]), treatment Period A (Day 0 [after study drug administration] through Day 182 [Week 26]), treatment Period B (Day 183 through Day 364 [Week 52]), overall presumed steady state period (Day 70 [Week 10] through Day 364 [Week 52]), presumed steady state period for treatment period A (Day 70 [Week 10] through Day 182 [Week 26]). A high morbidity HAE attack is defined as any attack that has at least one of the following characteristics: severe, results in hospitalization (except hospitalization for observation <24 hours), hemodynamically significant (systolic blood pressure <90, requires intravenous (IV) hydration or associated with syncope or near-syncope) or laryngeal.
  • Number of Participants with Characteristics of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks for Each Efficacy Evaluation Period [ Time Frame: Day 0 through Day 364, Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364 ]
    Characteristics of investigator-confirmed HAE attacks for each efficacy evaluation period includes duration, severity, attack location, and rescue medication use. Efficacy evaluation period consists of overall treatment period (Day 0 [after study drug administration] through Day 364 [Week 52]), treatment Period A (Day 0 [after study drug administration] through Day 182 [Week 26]), treatment Period B (Day 183 through Day 364 [Week 52]), overall presumed steady state period (Day 70 [Week 10] through Day 364 [Week 52]), presumed steady state period for treatment period A (Day 70 [Week 10] through Day 182 [Week 26]).
  • Number of Participants with Hereditary Angioedema (HAE) Attack-Free Status for Each Evaluation Period [ Time Frame: Day 0 through Day 364, Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364 ]
    The number of particpiants who are attack-free will be summarized for each efficacy evaluation period. Efficacy evaluation period consists of overall treatment period (Day 0 [after study drug administration] through Day 364 [Week 52]), treatment Period A (Day 0 [after study drug administration] through Day 182 [Week 26]), treatment Period B (Day 183 through Day 364 [Week 52]), overall presumed steady state period (Day 70 [Week 10] through Day 364 [Week 52]), presumed steady state period for treatment period A (Day 70 [Week 10] through Day 182 [Week 26]).
  • Plasma Kallikrein (pKal) Activity [ Time Frame: Day 0 (Pre-dose), Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392 ]
    pKal activity will be measured by biomarker cleaved high molecular weight kininogen (cHMWK )level to assess pharmacodynamics of lanadelumab.
  • Number of Participants with Positive Immunogenicity [ Time Frame: Day 0 (Pre-dose), Day 28, 84, 140, 182, 196, 252, 308, 364 and 392 ]
    Immunogenicity will be measured based on the presence or absence of neutralizing or non-neutralizing Anti-drug Antibody (ADA) in plasma.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) Study of Lanadelumab to Prevent Hereditary Angioedema (HAE) Attacks in Pediatric Participants of 2 Years to Less Than (<) 12 Years of Age
Official Title  ICMJE SPRING STUDY: An Open-Label, Multicenter, Phase 3 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Lanadelumab for Prevention Against Acute Attacks of Hereditary Angioedema (HAE) in Pediatric Subjects 2 to <12 Years of Age
Brief Summary The purpose of this phase 3, open-label, multicenter study is to evaluate the safety, PK, and PD of lanadelumab in children with age of 2 years to <12 years with Hereditary Angioedema (HAE).
Detailed Description This Study will consists of 52-week treatment period and a 4-week follow-up period. 52-week treatment period comprises of a 26-week treatment period A (Day 0 to Day 182) and a 26-week treatment period B (Day 183 to Day 364). Participants who complete treatment period A will immediately continue into treatment period B.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Hereditary Angioedema (HAE)
Intervention  ICMJE Drug: Lanadelumab
Participants will receive 150 mg dose of lanadelumab every 2 or 4 weeks, depending on the participants age, over the 52-week treatment period.
Other Names:
  • TAK-743
  • DX-2930
  • SHP643
Study Arms  ICMJE Experimental: Lanadelumab
Participants aged 2 years to < 6 years will receive lanadelumab at a dose of 150 milligrams (mg) for every 4 weeks (q4wks) with a total of 14 doses over 52-week treatment period and participants aged 6 years to <12 years will receive lanadelumab at a dose of 150 mg for every 2 weeks (q2wks) with a total of 27 doses over 52-week treatment period.
Intervention: Drug: Lanadelumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 26, 2019)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 17, 2021
Estimated Primary Completion Date December 17, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Be a child (male or female) 2 to lesser than (<) 12 years of age at the time of screening.
  • Documented diagnosis of HAE (Type I or II) based upon both of the following:

    1. Documented clinical history consistent with HAE (SC or mucosal, nonpruritic swelling episodes without accompanying urticarial).
    2. Diagnostic testing results obtained during screening from a sponsor- approved central laboratory that confirm C1-INH functional level <40 percent (%) of the normal level. Participants with functional C1 esterase inhibitor (C1-INH) level 40-50% of the normal level may be enrolled if they also have a complement4 (C4) level below the normal range. With prior sponsor approval, participants may be retested during the baseline observation period if results are incongruent with clinical history or believed by the investigator to be confounded by recent complement1 (C1) inhibitor use.
  • A historical baseline HAE attack rate of at least 1 attack per 3 months. Note: In addition,participants who experience greater than or equal to (>=)1.0 angioedema attacks per three months during the 12-week baseline observation period and who remain eligible per the inclusion criteria will enter the lanadelumab treatment period.
  • Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
  • Have a parent(s)/legal guardian who is informed of the nature of the study and can provide written informed consent for the child to participate in the study before any study-specific procedures are performed (with assent from the child when appropriate).
  • Females of childbearing potential must agree to be abstinent or agree to comply with the applicable contraceptive requirements of this protocol through the duration of the study from screening through 70 days after the final study visit.

Exclusion Criteria:

  • Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE), HAE with normal C1-INH, idiopathic angioedema, or recurrent angioedema associated with urticaria.
  • Dosing with an investigational drug or exposure to an investigational device within 4 weeks prior to screening.
  • Be pregnant or breastfeeding.
  • Have initiated androgen treatment (eg, stanozolol, danazol, oxandrolone, methyltestosterone, and testosterone) within 2 weeks prior to entering the observation period.
  • Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to screening.
  • Have any active infectious illness or fever defined as an oral temperature greater than (>) 38 degree celsius (°C) (100.4 fahrenheit [°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 treatment period A.
  • Have any HAE attack that is not resolved prior to the first dose of study drug in treatment period A.
  • Have any of the following liver function test abnormalities: alanine aminotransferase (ALT) >3x upper limit of normal (ULN), or aspartate aminotransferase (AST) >3x ULN, or total bilirubin >2x ULN (unless the bilirubin elevation is a result of Gilbert's syndrome).
  • Have any condition (any surgical or medical condition) 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 (eg, significant pre-existing illness or other major comorbidity that the investigator considers may confound the interpretation of study results).
  • Participant has a known hypersensitivity to the investigational product or its components.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 11 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Shire Contact +1 866 842 5335 ClinicalTransparency@shire.com
Listed Location Countries  ICMJE Canada,   Germany,   Hungary,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04070326
Other Study ID Numbers  ICMJE SHP643-301
2018-002093-42 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: 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
Responsible Party Shire
Study Sponsor  ICMJE Shire
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Study Director Shire
PRS Account Shire
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP