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    Summary
    EudraCT Number:2018-002093-42
    Sponsor's Protocol Code Number:SHP643-301
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-07-10
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2018-002093-42
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to assess the safety of Lanadelumab to prevent episodes of severe swelling in children
    A.3.2Name or abbreviated title of the trial where available
    Safety, Pharmacokinetics, and Pharmacodynamics Study of Lanadelumab to Prevent Hereditary Angioedema
    A.4.1Sponsor's protocol code numberSHP643-301
    A.5.4Other Identifiers
    Name:IND Number Number:116647
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorShire (Shire is now part of Takeda)
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDyax Corp., a Takeda Company
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda Pharmaceutical Company Limited
    B.5.2Functional name of contact pointRobert Bradley
    B.5.3 Address:
    B.5.3.1Street Address300 Shire Way
    B.5.3.2Town/ cityLexington
    B.5.3.3Post codeMA 02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number+17814821638
    B.5.6E-mailrobert.bradley@takeda.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Takhzyro
    D.2.1.1.2Name of the Marketing Authorisation holderShire Pharmaceuticals Ireland, Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/15/1551
    D.3 Description of the IMP
    D.3.1Product nameLanadelumab
    D.3.2Product code TAK743; SHP643
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLANADELUMAB
    D.3.9.1CAS number 1426055-14-2
    D.3.9.2Current sponsor codeTAK743; SHP643
    D.3.9.3Other descriptive nameDX-2930
    D.3.9.4EV Substance CodeSUB189058
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hereditary Angioedema (HAE)
    E.1.1.1Medical condition in easily understood language
    HAE is a long-term and life-threatening disease. HAE manifests clinically as unpredictable, intermittent attacks of edema of the face, larynx, gastrointestinal tract, limbs and/or genitalia
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level PT
    E.1.2Classification code 10019860
    E.1.2Term Hereditary angioedema
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level LLT
    E.1.2Classification code 10075280
    E.1.2Term Hereditary angioedema attack
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to evaluate the safety and pharmacokinetics (PK) of lanadelumab in children (2 to <12 years of age) with HAE.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are:
    • To evaluate the clinical outcomes of lanadelumab in preventing HAE attacks in children (2 to <12 years of age) with HAE.
    • To characterize the pharmacodynamics (PD) of lanadelumab in children (2 to <12 years of age) with HAE.
    • To assess the immunogenicity of chronically administered lanadelumab and its effect on PK, PD, clinical outcomes, and safety.

    The exploratory objectives are:
    • To evaluate the effect of lanadelumab on health-related quality of life (HRQoL).
    • To evaluate the effect of lanadelumab on exploratory biomarker(s) of angioedema disease-state bioactivity.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Be a child (male or female) 2 to <12 years of age at the time of screening.
    2. Documented diagnosis of HAE (Type I or II) based upon both of the following:
    • Documented clinical history consistent with HAE (SC or mucosal, nonpruritic swelling episodes without accompanying urticaria);
    • Diagnostic testing results obtained during screening from a sponsor-approved central laboratory that confirm C1-INH functional level <40% of the normal level. Subjects with functional C1-INH level 40-50% of the normal level may be enrolled if they also have a C4 level below the normal range. With prior sponsor approval, subjects 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 C1 inhibitor use.
    3. A historical baseline HAE attack rate of at least 1 attack per 3 months. Note: In addition, subjects who experience ≥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.
    4. Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
    5. 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).
    6. 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 30 days after the final study visit.
    E.4Principal exclusion criteria
    1. 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.
    2. Dosing with an investigational drug or exposure to an investigational device within 4 weeks prior to screening.
    3. Be pregnant or breastfeeding.
    4. Have initiated androgen treatment (eg, stanozolol, danazol, oxandrolone, methyltestosterone, and testosterone) within 2 weeks prior to entering the observation period.
    5. 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.
    6. Have any active infectious illness or fever defined as an oral temperature >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 Treatment Period A.
    7. Have any HAE attack that is not resolved prior to the first dose of study drug in Treatment Period A.
    8. Have any of the following liver function test abnormalities: alanine aminotransferase (ALT) >3x upper limit of normal (ULN), or aspartate aminotransferase (AST) >3x ULNl, or total bilirubin >2x ULN (unless the bilirubin elevation is a result of Gilbert’s syndrome).
    9. 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).
    10. Subject has a known hypersensitivity to the investigational product or its components.
    E.5 End points
    E.5.1Primary end point(s)
    Measures of safety include:
    • Adverse events including SAEs and AESI.
    • Clinical laboratory testing (hematology, clinical chemistry, coagulation)
    • Vital signs including blood pressure, heart rate, body temperature, and respiratory rate.

    Measures of PK include:
    • Plasma concentrations of lanadelumab
    • PK parameters in plasma, by age group, will be determined by a modelling and simulation approach and reported separately:
    o Cmax,ss: Maximum observed concentration at steady state
    o Cavg,ss: Average concentration over dosing interval at steady state
    o Ctrough,ss: Predose concentration at steady state
    o tmax: Time to reach Cmax in plasma
    o AUCtau,ss: Area under the concentration-time curve over the dosing interval at steady state
    o t½: Terminal half-life
    o CL/F: Apparent clearance
    o V/F: Apparent volume of distribution

    E.5.1.1Timepoint(s) of evaluation of this end point
    • 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]).
    E.5.2Secondary end point(s)
    • Normalized number of investigator-confirmed HAE attacks.
    • Time to the first attack, ie, duration that a subject is attack-free until their first attack.
    • Normalized number of investigator-confirmed HAE attacks requiring acute therapy use.
    • Normalized number of moderate or severe investigator-confirmed HAE attacks.
    • Normalized number of high morbidity investigator-confirmed HAE attacks.
    • Characteristics of investigator-confirmed HAE attacks, including duration, severity, attack location, and rescue medication use.
    • Achievement of attack-free status.
    • Plasma kallikrein activity (as measured by cHMWK level).
    E.5.2.1Timepoint(s) of evaluation of this end point
    • 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]).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Information not present in EudraCT
    E.8.5The trial involves multiple Member States Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    United States
    Germany
    Hungary
    Spain
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The Study Completion Date is defined as the date on which the last subject in the study completes the final protocol-defined assessment(s). This includes the follow-up visit or contact, whichever is later.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 20
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 20
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Pediatric patients
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 9
    F.4.2.2In the whole clinical trial 20
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The sponsor agrees to provide Post-Trial Access of investigational drug (lanadelumab) to paediatric patients following the conclusion of the SHP643-301 study where there is compelling ethical rationale for eligible clinical trial patients who have derived a measurable medical benefit from the drug.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-10-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-10-30
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