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    The EU Clinical Trials Register currently displays   43974   clinical trials with a EudraCT protocol, of which   7312   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2012-005696-14
    Sponsor's Protocol Code Number:6451
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-08-14
    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 ConcernedUK - MHRA
    A.2EudraCT number2012-005696-14
    A.3Full title of the trial
    A phase 3 randomised non-inferiority trial to evaluate the use of imatinib, nilotinib and ponatinib in patients with newly-diagnosed chronic phase chronic myeloid leukaemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    SPIRIT 3 - a phase 3 randomised trial to evaluate the most effective way to use drug treatments in newly diagnosed early stage chronic myeloid leukaemia (cancer of blood which starts in bone marrow) patients
    A.3.2Name or abbreviated title of the trial where available
    SPIRIT 3 - study to evaluate best use of TKIs in chronic phase CML
    A.4.1Sponsor's protocol code number6451
    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 SponsorNewcastle upon Tyne Hospitals NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAriad Pharmaceuticals
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNewcastle University
    B.5.2Functional name of contact pointProfessor Stephen O'Brien
    B.5.3 Address:
    B.5.3.1Street AddressAcademic Haematology
    B.5.3.2Town/ cityWilliam Leech Building
    B.5.3.3Post codeNE2 4HH
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0191 282 0904
    B.5.5Fax number0191 376 0748
    B.5.6E-mailstephen.o'brien@ncl.ac.uk
    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 Glivec
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameGlivec
    D.3.4Pharmaceutical form Film-coated 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 INNimatinib mesilate
    D.3.9.1CAS number 220127-57-1
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100 to 400
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Tasigna
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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/3/06/375
    D.3 Description of the IMP
    D.3.1Product nameTasigna
    D.3.4Pharmaceutical form Capsule, hard
    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 INNnilotinib hydrochloride monohydrate
    D.3.9.1CAS number 641571-10-0
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 nameponatinib
    D.3.2Product code AP24534
    D.3.4Pharmaceutical form Film-coated 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 INNponatinib
    D.3.9.1CAS number 1114544-31-8
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15 to 45
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic phase Chronic Myeloid Leukaemia
    E.1.1.1Medical condition in easily understood language
    early stages of myeloid (bone marrow) leukaemia (blood cancer) which originates in the bone marrow.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10052065
    E.1.2Term Chronic phase chronic myeloid leukaemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The study aims to see if treatment with imatinib is as good as treatment with nilotinib when patients in either group who are not doing so well switch to ponatinib. The response to treatment is measured in the blood and tests will look for leukaemic cells.
    E.2.2Secondary objectives of the trial
    We are looking at survival in the group of patients who start on imatinib compared to the group of patients who start on nilotinib five years after they first start treatment. We would like to know the numbers of patients who start on either imatinib or nilotinib who are able to reduce or stop treatment and maintain control of their leukaemia. The study also aims to see how cost effective the use of these particular drugs can be to the NHS. Imatinib will soon be available to the NHS at a much lower price than it is now and also in comparison to nilotinib it is likely to be much cheaper for a number of years to come. Ponatinib (which will be supplied free of charge to trial patients) may be used to help patients that started on imatinib or nilotinib to gain the best response possible and it might be that reducing the dose of any of these drugs to half or being able to permanently stop them will be of great long-term benefit to the NHS in terms of cost. We will look at safety
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients ≥ 18 years of age. 2. Patients must fulfill all of the following: i) be diagnosed with chronic phase CML confirmed by blood morphology and RT-PCR for BCR-ABL. ii) be enrolled within 3 months of initial diagnosis of chronic phase CML (date of RT-PCR confirming presence of BCR-ABL) iii) be in confirmed chronic phase ie: a) < 15% blasts in blood (manual differential) b) < 30% blasts plus promyelocytes in blood c) < 20 % basophils in blood d) ≥ 100 x 109 /L platelets e) no evidence of extramedullary leukaemic involvement, with the exception of hepatosplenomegaly 3.Written voluntary informed consent.
    E.4Principal exclusion criteria
    1. Any prior treatment for CML with any TKI (eg imatinib, dasatinib, nilotinib, bosutinib, ponatinib); busulphan, IFN-alpha, homoharringtonine, cytosine arabinoside, any other investigational agents. 2. Patients who have received prior CML chemotherapy including regimens used in peripheral blood progenitor cells (PBPCs) mobilisation for haematopoietic progenitor-cell transplantation. (collection of unmobilised PBPCs is allowed at diagnosis). 3. Patients who have had any form of prior haematopoietic stem cell transplant (autograft or allograft). 4. Patients with an ECOG Performance Status Score ≥ 3 5. Patients with serum bilirubin, SGOT/AST, SGPT/ALT or creatinine concentrations > 2.0 x upper limit of normal (ULN) 6. Patients with serum amylase or lipase > 1.5 x ULN, history of acute pancreatitis within 1 year of study, history of chronic pancreatitis, or uncontrolled hypertriglyceridaemia (triglycerides > 450 mg/dL) 7. Patients with significant uncontrolled or active cardiovascular disease, specifically including, but not restricted to a) myocardial infarction, unstable angina and/or congestive heart failure within 6 months prior to study; and b) history of clinically significant atrial arrhythmia; or any ventricular arrhythmia. 8. Patients taking medications known to be associated with Torsade de Pointes (eg amiodarone, azithromycin, chloroquine, citalopram, domperidone, erythromycin, quinidine, sotalol, thioridazine) 9. Patients with known uncontrolled hypertension; systolic blood pressure > 140mm Hg and/or diastolic blood pressure > 90mm Hg 10. Patients with a known INR or PTT > 1.5 x ULN, with the exception of patients on treatment with oral anticoagulants, or patients with a known bleeding disorder. Baseline testing of INR is not required. 11. Patients with uncontrolled medical disease such as diabetes mellitus, thyroid dysfunction, neuropsychiatric disorders or infection. 12. Patients who have undergone major surgery within 4 weeks of starting trial IMP. 13. Patients who are: a) pregnant b) breast feeding c) of childbearing potential without a negative pregnancy test prior to starting trial IMP and d) male or female of childbearing potential unwilling to use barrier contraceptive precautions throughout the trial (postmenopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential). 14. Patients with a history of another malignancy either currently or within the past five years (with the exception of basal cell skin carcinoma in situ). 15. Patients with a history of non-compliance to medical regimens or patients who can envisage being unable to complete the study for any reason. 16. Patients unwilling to receive trial drug via a home delivery method.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is major molecular response (MMR, MR3) at 3 years on study in group I and group N. Group I is all patients who were initially randomised to imatinib and group N is all patients who were initially randomised to nilotinib (regardless of whether they subsequently switched to ponatinib).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Three years from start of participation in trial.
    E.5.2Secondary end point(s)
    Overall survival (OS), progression free survival (PFS) and event free survival (EFS) at 5 years in group I (started on imatinib) vs group N (started on nilotinib). Assessment of the number of patients at 5 years in group I (started on imatinib) vs group N (started on nilotinib) who are in the following categories (MR3 will include PCR undetectable): - No dose reduction at 3 years (stage 3); on full dose, not in MR3 - No dose reduction at 3 years (stage 3); on full dose, in (late) MR3 - Underwent unsuccessful dose reduction at 3 years (stage 3); on full dose, not in MR3 - Underwent successful dose reduction at 3 years (stage 3); on reduced dose in MR3 - Underwent successful dose reduction at 3 years (stage 3); off treatment in MR3 - PCR undetectable regardless of current therapy The incremental cost per quality-adjusted life-year gained (incremental cost effectiveness ratio or ICER) over 5 years in group I and group N and extrapolated over the estimated patient life time. Assessment of the costs to the NHS and personal social services of the alternative regimens over 5 years and extrapolated over the estimated patient life time. Treatment failure due to resistance or intolerance in group I and group N. To assess the safety and tolerability of imatinib, nilotinib and ponatinib.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Overall survival, progression free survival and event free survival will be assessed at 5 years. Secondary endpoints that focus on patients who have switched treatment to ponatinib will be assessed at 5 years, focussing on their status at 3 years of the trial.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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 Yes
    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) Yes
    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 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 concerned163
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years10
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years10
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 600
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 400
    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 No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state1000
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1000
    F.4.2.2In the whole clinical trial 1000
    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)
    Both imatinib and nolitinib are NICE approved for first-line treatment of chronic phase CML. Unless either of these drugs are withdrawn from market for an unpredictable reason such as for safety reasons, these drugs will remain routinely available to patients. Ariad have agreed to supply ponatinib to patients who switch to this treatment as part of the study protocol for a minimum of 5 years after the last patient is entered in to the trial. …..
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-09-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-09
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2016-09-16
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