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    The EU Clinical Trials Register currently displays   37219   clinical trials with a EudraCT protocol, of which   6124   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2016-002584-33
    Sponsor's Protocol Code Number:CINC424C2301
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-10-20
    Trial 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 - BfArM
    A.2EudraCT number2016-002584-33
    A.3Full title of the trial
    A phase III randomized open-label multi-center study of ruxolitinib vs. best available therapy in patients with corticosteroid-refractory acute graft vs. host disease after allogenic stem cell transplantation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and efficacy of ruxolitinib versus best available therapy in patients with corticosteroid-refractory acute graft vs. host disease after allogeneic stem cell transplantation
    A.4.1Sponsor's protocol code numberCINC424C2301
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/349/2017
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    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 supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma GmbH
    B.5.2Functional name of contact pointMedizinischer Infoservice (MCC)
    B.5.3 Address:
    B.5.3.1Street AddressRoonstrasse 25
    B.5.3.2Town/ cityNürnberg
    B.5.3.3Post code90429
    B.5.3.4CountryGermany
    B.5.4Telephone number +49 1802 232300
    B.5.5Fax number +49 911 27312160
    B.5.6E-mailinfoservice.novartis@novartis.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 Jakavi
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRuxolitinib
    D.3.2Product code INC424
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    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 INNruxolitinib
    D.3.9.1CAS number 1092939-17-7
    D.3.9.2Current sponsor codeINC424
    D.3.9.3Other descriptive nameRUXOLITINIB PHOSPHATE
    D.3.9.4EV Substance CodeSUB32897
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    corticosteroid-refractory acute graft vs. host disease after allogeneic stem cell transplantation
    E.1.1.1Medical condition in easily understood language
    acute Graft versus host disease
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10066260
    E.1.2Term Acute graft versus host disease
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10066262
    E.1.2Term Acute graft versus host disease in skin
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10066264
    E.1.2Term Acute graft versus host disease in intestine
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10066263
    E.1.2Term Acute graft versus host disease in liver
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of the trial is to compare the efficacy of ruxolitinib with best available therapy in patients with corticosteroid refractory acute Graft vs. Host Disease by assessing the overall response rate (either complete or partial response without requiring additional systemic therapies) based on organ stage scoring.
    E.2.2Secondary objectives of the trial
    The key secondary objectif of the trial is to measure the durable response rate of patients who are corticosteroid refractory acute graft vs. host disease and to compare those patients treated with ruxolitinib vs. best available therapy.
    The other secondary objectives relate to further measurements comparing patients treated with ruxolitinib vs. best available therapy:
    Their survival over a 2 year time period.
    Whether steroids are successfully tapered to lower doses.
    Whether they develop chronic graft vs. host disease, and other standard transplant outcomes including control of their underlying hematologic disease for which the transplant was performed.
    The safety of ruxolitinib and best available therapy.
    Measurements of each patient’s reported quality of life will be compared in patients treated with ruxolitinib vs. best available therapy for their corticosteroid refractory acute graft vs. host disease.
    To estimate the rate of Best Overall Response (BOR)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Have undergone alloSCT from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or
    cord blood. Recipients of non- myeloablative, myeloablative, and reduced intensity conditioning are eligible
    - Clinically diagnosed Grades II to IV acute GvHD as per standard criteria occurring after alloSCT requiring systemic immune suppressive
    therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening.
    - Confirmed diagnosis of corticosteroid refractory aGvHD (confirmed within 48h prior to study treatment start) defined as:
    • Patients administered high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) and either:
    • Progressing based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,
    OR
    • Failure to achieve at a minimum partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,
    OR
    • Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria:
    • Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 mg/kg/day (or equivalent prednisone dose ≥2.5 mg/kg/day)
    OR
    • Failure to taper the methylprednisolone dose to <1 mg/kg/day (or equivalent prednisone dose <1.25 mg/kg/day) for a minimum 7 days.
    E.4Principal exclusion criteria
    - Has received more than one systemic treatment for steriod refractory aGvHD,
    - Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features (as defined by Jagasia, et al. 2015)
    - Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection.
    Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
    - Evidence of uncontrolled viral infection including CMV, EBV, HHV-6, HBV, or HCV based on assessment by the treating physicial.
    - Presence of relapsed primary malignancy, or who have been treated for relapse after the alloHSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.
    Other protocol-defined inclusion/exclusion criteria may apply.
    E.5 End points
    E.5.1Primary end point(s)
    Overall Response Rate (ORR)
    • ORR is defined as the proportion of patients with a best overall response defined as complete response or partial response without requirement for additional systemic therapy for an early progression, mixed response, or non response.
    E.5.1.1Timepoint(s) of evaluation of this end point
    28 Days
    E.5.2Secondary end point(s)
    1. Durable Overall Response Rate
    o Proportion of all patients in each arm who achieve a complete response (CR) or partial response (PR) at Day 28 and maintain a CR or PR at Day 56.
    2.Proportion of patients who achieved OR (CR+PR) at Day 14.
    3. Duration of response
    o DOR is the time from first response until aGvHD progression or the date of additional systemic therapies for aGvHD.
    4. Cumulative steroid dose
    o Weekly cumulative steroid dose for each subject up to Day 56 or end of treatment
    5. Overall Survival (OS)
    o OS is defined as the time from the date of randomization to the date of death due to any cause.
    6. Event-free survival
    o Event-free survival, defined as the time from the date of randomization to the date of hematologic disease relapse/progression, graft failure, or death due to any cause.
    7. Failure-Free survival (FFS)
    o FFS is defined as the time from the date of randomization to date of hematologic disease relapse/progression, non- relapse mortality, or addition of new systemic aGvHD treatment.
    8. Non Relapse Mortality (NRM)
    o NRM is defined as the time from date of randomization to date of death not preceded by hematologic disease relapse/progression
    9. Malignancy Relapse/Progression (MR)
    o MR is defined as the time from date of randomization to hematologic malignancy relapse/progression.
    Calculated for patients with underlying hematologic malignant disease.
    10. Incidence of cGvHD
    o cGvHD, defined as the diagnosis of any cGvHD including mild, moderate, severe
    11.Best Overall Response (BOR), defined as proportion of patients who
    achieved RO(CR+PR) at any time pointup to and including D28 and
    before the start of additional systemic therapy for aGvHD
    12. Pharmacokinetics (PK) of ruxolitinib in Steroid Refractory -acute GvHD patients
    o Ruxolitinib plasma concentrations after a single dose and at steady state.
    13. Exposure-response relationship of ruxolitinib in SR-aGvHD
    o Pharmacokinetics (exposure) and efficacy (ORR, OS or other relevant
    endpoints) relationship. Pharmacokinetics (exposure) and safety (AEs) relationship.
    14. Patient Reported Outcomes (PROs): Change in FACT-BMT from baseline, only in adults
    15. Patient Reported Outcomes (PROs): Change in EQ-5D-5L from baseline
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Day 56
    2. Day 14
    3. Up to 24 weeks
    4. 56 Days
    5. Up to 24 months
    6. Up to 24 months
    7. Up to 24 months
    8. Up to 24 months
    9. Up to 24 months
    10. Up to 24 months
    11. Up to Day 28
    12. 168 Days
    13. 168 Days
    14. Baseline, Up to 30 day follow-up visit
    15. Baseline, Up to 30 day follow-up visit
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    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 Yes
    E.8.1.1Randomised Yes
    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 Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Best available therapy (BAT)
    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 concerned21
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA104
    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
    Argentina
    Australia
    Austria
    Bulgaria
    Canada
    Czech Republic
    Denmark
    France
    Germany
    Greece
    Hong Kong
    Hungary
    Israel
    Italy
    Japan
    Korea, Republic of
    Netherlands
    Norway
    Poland
    Portugal
    Russian Federation
    Saudi Arabia
    Spain
    Sweden
    Taiwan
    Turkey
    United Kingdom
    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
    End of Study (EoS) will occur when all patients have reached Month 24 (2 years from randomization), unless the patient withdraws consent.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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: 15
    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) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 281
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 226
    F.4.2.2In the whole clinical trial 308
    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)
    Patients who are still receiving ruxolitinib at their end of study
    (approximately 2 years from randomization), and deriving clinical
    benefit from ruxolitinib as assessed by the Investigator, will be given
    the possibility to continue ruxolitinib outside the study from another
    source, where permitted by and in accordance to local laws and
    regulations.
    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 Decision2016-12-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-01-23
    P. End of Trial
    P.End of Trial StatusOngoing
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