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    The EU Clinical Trials Register currently displays   40051   clinical trials with a EudraCT protocol, of which   6562   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2016-004432-38
    Sponsor's Protocol Code Number:CINC424D2301
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-09-19
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2016-004432-38
    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 chronic graft versus host disease after allogeneic stem cell transplantation
    III. fázisú, randomizált, nyílt elrendezésű, multicentrikus vizsgálat a ruxolitinib és a legjobb elérhető kezelés összehasonlítására kortikoszteroid-refrakter, krónikus graft versus host betegségben szenvedő betegeknél, allogén őssejtátültetést követően
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of efficacy and safety of ruxolitinib vs. best available therapy (BAT) in patients with corticosteroid refractory chronic graft versus host disease after bone marrow transplantation
    A.3.2Name or abbreviated title of the trial where available
    REACH 3
    A.4.1Sponsor's protocol code numberCINC424D2301
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma AG
    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 AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma AG
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressForum 1, Novartis Campus
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4056
    B.5.4Telephone number +41 61 32 41111
    B.5.5Fax number +41 61 32 48001
    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. name Jakavi
    D. 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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 chronic Graft vs Host Disease
    E.1.1.1Medical condition in easily understood language
    chronic Graft vs 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 10072158
    E.1.2Term Chronic 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 10072159
    E.1.2Term Chronic 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 10066261
    E.1.2Term Chronic 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 10072160
    E.1.2Term Chronic 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
    To compare the efficacy of ruxolitinib versus Investigator’s choice Best Available Therapy (BAT) in patients with moderate or severe SR-cGvHD assessed by Overall Response Rate (ORR) at the Cycle 7 Day 1 visit.
    E.2.2Secondary objectives of the trial
    Key Secondary:
    To compare the rate of failure free survival (FFS) and the change in the modified Lee cGvHD Symptom Scale score between treatment groups

    Other secondary:
    ● Best overall response (BOR)
    ● Estimate ORR at the end of Cycle 3
    ● Duration of response
    ● Overall survival
    ● Non-relapse mortality (NRM)
    ● Proportion of patients with ≥50% reduction in the daily steroid dose at Cycle 7 Day 1
    ● Proportion of patients who successfully tapered off all steroids at Cycle 7 Day 1
    ● Cumulative incidence of Malignancy Relapse/Recurrence (MR)
    ● Change in FACT-BMT and EQ-5D
    ● To assess pharmacokinetics of ruxolitinib
    ● Safety and tolerability of ruxolitinib and BAT
    ● Medical resource utilization
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ● Male or female patients ≥12 years old at the time of signing the ICF
    ● 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
    ● Evident myeloid and platelet engraftment: Absolute neutrophil count (ANC) >
    1000/mm3 and platelet count > 25,000/ mm3
    ● Patients with clinically diagnosed moderate to severe cGvHD according to NIH
    Consensus Criteria (Jagasia 2015) prior to randomization:
    ● Moderate cGvHD: At least one organ (not lung) with a score of 2, 3 or more
    organs involved with a score of 1 in each organ, or lung score of 1
    ● Severe cGvHD: at least 1 organ with a score of 3, or lung score of 2 or 3
    ● Patients currently receiving systemic or topical corticosteroids for the treatment of
    cGvHD for a duration of < 12 months prior to Cycle 1 Day 1 (if applicable), and have a
    confirmed diagnosis of steroid refractory cGvHD defined per 2014 NIH consensus
    criteria (Martin 2015) irrespective of the concomitant use of a calcineurin inhibitor, as
    ● A lack of response or disease progression after administration of minimum
    prednisone 1 mg/kg/day for at least 1 week (or equivalent), OR
    ● Disease persistence without improvement despite continued treatment with
    prednisone at >0.5 mg/kg/day or 1 mg/kg/every other day for at least 4 weeks (or equivalent), OR
    ● Increase to prednisone dose to >0.25 mg/kg/day after two unsuccessful attempts
    to taper the dose (or equivalent)
    ● Patient must accept to be treated with only one of the following BAT options on
    Cycle 1 Day 1. (Additions and changes are allowed during the course of the study,
    but only with BAT from the following BAT options): extracorporeal photopheresis
    (ECP), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR
    inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, ibrutinib
    E.4Principal exclusion criteria
    ● Patients who have received two or more systemic treatments (BAT) for cGvHD in addition to
    corticosteroids ± CNI for cGvHD
    ● Patients that transition from aGvHD to cGvHD
    without tapering off corticosteroids ± CNI and any systemic treatment
    ● Patients who were treated with prior JAK inhibitors for aGvHD; except when the
    patient achieved complete or partial response and has been off JAK inhibitor
    treatment for at least 8 weeks prior to Cycle 1 Day 1
    ● Failed prior alloSCT within the past 6 months from Cycle 1 Day 1
    ● Patients with relapsed primary malignancy, or who have been treated for relapse
    after the alloSCT was performed
    ● SR-cGvHD occurring after a non-scheduled donor lymphocyte infusion (DLI)
    administered for pre-emptive treatment of malignancy recurrence. Patients who
    have received a scheduled DLI as part of their transplant procedure and not for
    management of malignancy relapse are eligible
    ● Any corticosteroid therapy for indications other than cGvHD at doses >1
    mg/kg/day methylprednisolone or equivalent within 7 days of Cycle 1 Day 1
    E.5 End points
    E.5.1Primary end point(s)
    overall response rate (ORR) on Cycle 7 Day 1 after
    randomization, defined as the proportion of patients in
    each arm demonstrating a complete response (CR) or
    partial response (PR) without the requirement of
    additional systemic therapies for an earlier
    progression, mixed response or non-response.
    Scoring of response will be relative to the organ score
    at randomization.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Cycle 7 Day 1
    E.5.2Secondary end point(s)
    Key secondary:
    Composite time to event endpoint incorporating the following FFS events:
    i) relapse or recurrence of underlying disease or death due to underlying disease,
    ii) non-relapse mortality, or
    iii) addition or initiation of another systemic therapy for cGvHD

    Rate of patients with clinically relevant improvement of
    the modified Lee symptoms score at Cycle 7 Day 1.

    FFS will be used as the first key secondary endpoint for all regions except the US (ROW). The modified Lee symptom score will be used as the first key secondary
    endpoint for the US

    Other secondary:
    - Proportion of patients who achieved OR (CR+PR) at any time point (up Cycle 7 day 1 or the start of additional systemic therapy for cGvHD)
    - To estimate ORR at end of Cycle 3 Proportion of patients who achieved OR (CR+PR) at Cycle 4 Day 1.
    - Duration of Response Duration of response (DOR) is assessed for responders only
    - Overall survival, defined as the time from the date of randomization to the date of death due to any cause
    - Non-relapse mortality (NRM), defined as the time from date of randomization to date of death not preceded by underlying disease relapse/recurrence
    - Malignancy Relapse/Recurrence (MR) is defined as the time from date of randomization to hematologic malignancy relapse/recurrence
    - Change in FACT-BMT from baseline to each visit where measured.
    - Change in EQ-5D from baseline to each visit where measured
    - Pharmacokinetic parameters of ruxolitinib after a single dose and at steady state. Cmax, AUClast, and AUCinf. Other PK parameters are CL/F, Vz/F, Tmax and T1/2
    - Safety and tolerability including myelosuppression, infections, and bleeding will be assessed by monitoring the frequency, duration, and severity of Adverse Events including occurrence of any second primary malignancies, infections, by performing physical exams, and evaluating changes in vital signs from baseline, routine serum chemistry, hematology results and coagulation profile
    - Resources including duration and frequency of hospitalization, emergency room visits, additional outpatient office visits to general practitioner, specialist, and urgent care visits
    E.5.2.1Timepoint(s) of evaluation of this end point
    for all:
    Cycle 7 Day 1
    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 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 Yes
    E.6.13.1Other scope of the trial description
    medical resource utilization
    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. 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. 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA102
    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
    Czech Republic
    Korea, Republic of
    Russian Federation
    Saudi Arabia
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    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 end of study is defined as the earliest occurrence of one of the following:
    All patients have completed 39 cycles OR
    discontinued from the study OR
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    E.8.9.2In all countries concerned by the trial months9
    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: 30
    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. of subjects for this age range: 30
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 132
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 162
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 260
    F.4.2.2In the whole clinical trial 324
    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)
    Following completion of 39 cycles, if any patients are still receiving treatment and benefitting from ruxolitinib they will be transitioned to commercial product or to a local supply of ruxolitinib outside of the study. If commercial product/local supply is not available, the patient will be transitioned to the rollover protocol CINC424A2X01B or an alternative option.
    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 Decision2017-10-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-10-11
    P. End of Trial
    P.End of Trial StatusOngoing
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