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    Summary
    EudraCT Number:2014-001006-18
    Sponsor's Protocol Code Number:D5136C00007
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-05-18
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-001006-18
    A.3Full title of the trial
    Multicenter, open-label, randomised, pharmacokinetic (PK) and pharmacodynamic (PD) dose-ranging Phase II study of ticagrelor followed by a double-blind, randomised, parallel-group, placebo-controlled 4 weeks extension phase in paediatric patients with sickle cell disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A pharmacokinetic (PK) and pharmacodynamic (PD) dose-ranging Phase II study of ticagrelor followed by a 4 weeks extension phase in paediatric patients with sickle cell disease
    A.4.1Sponsor's protocol code numberD5136C00007
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02214121
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/298/2015
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    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 supportAstraZenenca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    B.5.2Functional name of contact pointInformation Center
    B.5.3 Address:
    B.5.3.1Street AddressN/A
    B.5.3.2Town/ cityN/A
    B.5.3.3Post codeN/A
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018002369933
    B.5.6E-mailinformation.center@astrazeneca.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameticagrelor
    D.3.2Product code AZD6140
    D.3.4Pharmaceutical form Granules for oral suspension
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNticagrelor
    D.3.9.1CAS number 274693-27-5
    D.3.9.2Current sponsor codeAZD6140
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number45
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboGranules for oral suspension
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Investigation of platelet aggregation in paediatric patients with sickle cell disease
    E.1.1.1Medical condition in easily understood language
    In children diagnosed with sickle cell disease, to study the effects of study treatment on platelets and blood vessel blockage.
    E.1.1.2Therapeutic area Body processes [G] - Genetic Phenomena [G05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10040644
    E.1.2Term Sickle cell disease
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To characterise the relationship between ticagrelor dose and inhibition of platelet aggregation in paediatric patients with Sickle Cell Disease (SCD), using PK-PD modelling, to support dose selection for Phase III
    E.2.2Secondary objectives of the trial
    To determine the PK properties of ticagrelor in paediatric patients with Sickle Cell Disease (SCD) and to assess impact of weight, age and other demographic on the ticagrelor pharmacokinetics

    Investigation of efficacy of ticagrelor vs. placebo in paediatric patients with SCD in reducing:
    Number of Vaso-occlusive crises (VOC)

    Days hospitalized for VOC or other complications of SCD
    Days with pain (ages ≥4 years only)
    Intensity of pain (ages ≥4 years only)
    Days of analgesic use (ages ≥4 years only)
    Days of opioid analgesic use
    Days of absence from school or work (ages ≥6 years only)

    To assess safety and tolerability of single and multiple doses of ticagrelor in paediatric patients with SCD

    To determine the percent of patients with haemorrhagic events requiring medical intervention.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Children aged ≥2 to <18 years of age and body weight >16 kg diagnosed with homozygous sickle cell (HbSS) or sickle beta-zero-thalassaemia (HbS/β0)
    2.If treated with an anti-sickling agent such as hydroxyurea, the weight adjusted dose must be stable for 1 month before enrolment
    E.4Principal exclusion criteria
    1.Previous history of transient ischemic attack (TIA) or clinically overt cerebrovascular accident (CVA) (ischemic or haemorrhagic), severe head trauma, intracranial haemorrhage, intracranial neoplasm, arteriovenous malformation, aneurysm, or proliferative retinopathy
    2.Findings on TCD: Current or previous values for time averaged mean of the maximum velocity (TAMMV) that are Conditional or Abnormal*.
    Conditional TAMMV values are ≥153 cm/sec using imaging TCD (TCDi) technique (corresponding to ≥170 cm/sec by the non-imaging technique). Both the middle cerebral artery and the internal carotid artery should be considered. Abnormal TAMMV values are ≥180 cm/sec using TCDi (corresponding to ≥200 cm/sec by the non-imaging technique) and are an indication for chronic transfusions because of a high stroke risk. Any other criteria that would locally be considered as TCD indications for chronic transfusion would also exclude the patient.
    3.Undergoing treatment with chronic RBC transfusion therapy
    4.Use of non-steroidal anti-inflammatory drugs (NSAIDs) >3 days per week
    5.Receiving chronic treatment with anticoagulants or antiplatelet drugs that cannot be discontinued.
    6.Moderate or severe hepatic impairment, defined as Child-Pugh Class B or C,or renal failure requiring dialysis
    7.Active pathological bleeding or increased risk of bleeding complications according to Investigator
    8.Risk of bradycardic events (known sick sinus syndrome or second or third degree atrioventricular block)
    9.Concomitant oral or intravenous therapy with strong CYP3A4 inhibitors, CYP3A4 substrates with narrow therapeutic indices, or strong CYP3A4 inducers
    10.Surgical procedure planned to occur during the study
    11.Patients who are currently pregnant or breastfeeding, or planning to become pregnant during the study
    12.Known hypersensitivity or contraindication to ticagrelor
    E.5 End points
    E.5.1Primary end point(s)
    P2Y12 reaction units (PRU), Maximum plasma concentration (Cmax), Area under the plasma concentration time curve (AUC)
    E.5.1.1Timepoint(s) of evaluation of this end point
    PRU:Pre-dose, 2, 6 h post-dose at Visit 2 and 3 (after single dosing); Pre-dose, 2h post-dose at Visit 4 (after repeated dosing)
    Cmax and AUC: Visits 2,3, and 4
    E.5.2Secondary end point(s)
    Concentrations of Ticagrelor an its active metabolite

    Efficacy endpoints: number of Vaso-occlusive crises, number of Vaso-occlusive crises requiring hospitalization or emergency department visits, days hospitalized for complications of sickle cell disease, days with pain, intensity of pain, days of analgesic use, days of opioid analgesic use, days of absence from school or work

    Safety endpoints: AEs/Serious Adverse Events (SAE)s, Vital signs, laboratory safety samples, Haemorrhagic events
    E.5.2.1Timepoint(s) of evaluation of this end point
    Ticagrelor concentration: 1, 2, 4, 6 h post-dose at Visit 2 and 3 (after single dosing); Pre-dose, 1, 2h post-dose at Visit 4 (after repeated dosing).

    Efficacy endpoints: during 4 weeks of study treatment starting from randomization in Part B.

    Safety endpoints: vital signs at all study visits (1-9), laboratory samples at Visits 1, 4 and 9, SAEs from enrollment until Visit 9 and AEs, haemorrhagic events from randomization (Visit 2) until Visit 9.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    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 Yes
    E.8.1.7.1Other trial design description
    Part A is open label and Part B is double blind part
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    Egypt
    Ghana
    Italy
    Kenya
    Lebanon
    South Africa
    Turkey
    United Kingdom
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months8
    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 months8
    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: 50
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    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 Yes
    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
    Children aged>2-<18 need ICF from the parent/both parents//legal guardian (according to local regulations) and assent from the child/adolescent (where required by local regulations).
    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 14
    F.4.2.2In the whole clinical trial 50
    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)
    None
    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 Decision2016-07-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-02-27
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