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    Summary
    EudraCT Number:2020-001157-48
    Sponsor's Protocol Code Number:20HH5896
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-07-09
    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 ConcernedUK - MHRA
    A.2EudraCT number2020-001157-48
    A.3Full title of the trial
    Identifying a safe and tolerated dose of Imatinib for
    patients with Pulmonary Arterial Hypertension (PAH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    PIPAH study: Using imatinib (drug) in Pulmonary Arterial Hypertension
    A.3.2Name or abbreviated title of the trial where available
    Positioning Imatinib for Pulmonary Arterial Hypertension (PIPAH)
    A.4.1Sponsor's protocol code number20HH5896
    A.5.4Other Identifiers
    Name:N/ANumber:N/A
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorImperial College London
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationImperial College London
    B.5.2Functional name of contact pointMartin Wilkins
    B.5.3 Address:
    B.5.3.1Street AddressImperial College London
    B.5.3.2Town/ cityNIHR Imperial CRF
    B.5.3.3Post codeW12 0HS
    B.5.4Telephone number02033136101
    B.5.6E-mailm.wilkins@imperial.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 Imatinib mesilate
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz Ltd, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR, United Kingdom
    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 nameImatinib mesilate
    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 INNImatinib mesilate
    D.3.9.4EV Substance CodeAS1
    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
    Pulmonary Arterial Hypertension (Idiopathic, heritable, or assosicated with anorexigens)
    E.1.1.1Medical condition in easily understood language
    Pulmonary Arterial Hypertension is a condition in which blood pressure is increased in the arteries of the lungs
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10036727
    E.1.2Term Primary pulmonary hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10037400
    E.1.2Term Pulmonary hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10037400
    E.1.2Term Pulmonary hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10068739
    E.1.2Term Chronic thromboembolic pulmonary hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10050701
    E.1.2Term Congenital pulmonary hypertension
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10050701
    E.1.2Term Congenital pulmonary hypertension
    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 over-aching hypothesis is that there is a subgroup of patients, identifiable by genotype, with pulmonary arterial hypertension that will benefit from a safe and tolerated dose of Imatinib.

    Imatinib is thought to work by blocking a protein called platelet derived growth factor receptor B. There is a gene that regulates the blood levels of this protein, called the “PDGFRB”. Patients can be divided into 3 groups based on variants of this PDGFRB gene; the 3 groups are called CC, CT and TT. Patients with CC have higher levels of PDGFRB than patients with TT. It is possible that Imatinib works better in patients with CC than TT, and that patients who are in the CT group lie in between.

    The study has two parts.

    Part 1 will identify a maximum tolerated dose (MTD) of Imatinib in patients with pulmonary arterial hypertension. The MTD is defined by a dose with a 20% probability of leading to discontinuation of treatment for more than 5 consecutive days due to side effects.

    Part 2 will ev
    E.2.2Secondary objectives of the trial
    -Change in the six-minute walk test, a measure of exercise capacity
    -Change in echocardiogram (type of ultrasound heart test) values, a measure of how well the heart is working
    -Change in "BNP" blood test values, another measure of heart function
    -Change in Quality of Life scores

    The above refer to change from baseline at 24 weeks.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects aged between 18-75^ years old
    2. PAH which is idiopathic, heritable or associated with anorexigens
    3. Subjects homozygous at rs3816018 locus (PDGFRB genotype)*
    *genotyped through the National Cohort Study
    4. Resting mean pulmonary artery pressure >25 mmHg, Pulmonary
    capillary wedge pressure ≤15 mmHg, PVR >5 wood units, and
    normal or reduced cardiac output , as measured by right heart
    catheterisation (RHC) at entry
    5. Six-minute walking distance >50m at entry
    6. Stable on an unchanged PAH therapeutic regime comprising at least
    2 therapies licensed for PAH (any combination of endothelin receptor
    antagonist, phosphodiesterase inhibitor or prostacyclin analogue) for
    at least 1 month prior to screening
    7. Able to provide written informed consent prior to any study
    mandated procedures
    8. Women of child-bearing potential are eligible to participate, if they agree to use one of the following contraception methods:
    Abstinence OR
    Highly effective contraceptive methods with typical-use failure rate
    <1% i.e.
    • Male or female sterilisation and long-acting reversible contraceptive methods (intrauterine devices and implants)prior to the female subject's entry into the study
    • Progestogen-only injections if repeat rejections are documented as having been administered on schedule by a healthcare professional.

    ^The upper age limit stems from PAH Registries and previous clinical trials in the field.
    E.4Principal exclusion criteria
    1. Unable to provide informed consent and/or non-fluent speaker of the English language
    2. Hypersensitivity to Imatinib or to any of the excipients
    3. Clinically-significant renal disease (confirmed by creatinine clearance <30 ml/min per 1.73m2)
    4. Clinically-significant liver disease (confirmed by serum transaminases >3 times than upper normal limit)
    5. Patients receiving oral and/or parenteral anticoagulants
    6. Anaemia confirmed by haemoglobin concentration <10 g/dl
    7. History of thrombocytopenia
    8. Individuals known to have haemoglobinopathy sickle cell disease, thalassaemia
    9. Hospital admission related to PAH or change in PAH therapy within 3 months prior to screening
    10. History of left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:
    a. aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild aortic insufficiency, mild aortic stenosis, mild mitral stenosis, moderate mitral regurgitation
    b. Mechanical or bioprosthetic cardiac valve
    c. Pericardial constriction, effusion with tamponade physiology, or abnormal left atrial size.
    d. Restrictive or congestive cardiomyopathy
    e. Left ventricular ejection fraction ≤50% (measured in echocardiogram at screening)
    f. Symptomatic coronary disease
    g. Significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation
    h. Acutely decompensated left heart failure within 1 month of screening
    i. History of untreated obstructive sleep apnoea
    11. Evidence of significant lung disease on high-resolution CT (if available) or recent (performed within 12 months) lung function, where FEV1 < 50% predicted and FVC < 70% predicted, and DLCO (or TLCO) < 50% predicted if any CT abnormalities; judged by the Site Physician
    12. Patients with a history of uncontrolled systemic hypertension
    13. Acute infection (including eye, dental, and skin infections)
    14. Chronic inflammatory disease including HIV, and Hepatitis B
    15. Women of childbearing potential who are pregnant or breastfeeding
    16. Previous intracerebral haemorrhage
    17. Patients who have received an Investigational Medicinal Product (IMP) within 1 month before the baseline visit
    E.5 End points
    E.5.1Primary end point(s)
    From a statistical point of view, the study has two parts.

    Part 1: Discontinuation of the drug for more than 5 consecutive days due to Grade 2 or above Adverse Events defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (version .5.0, 2017), adapted for this study

    Part 2: The primary efficacy endpoint is a binary variable. For patients with a baseline PVR >1000 dynes·s·cm−5, success is defined by an absolute reduction in PVR of ≥300 dynes·s·cm−5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes·s·cm−5, success is a 30% reduction in PVR at 24 weeks.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 24 weeks of treatment.
    E.5.2Secondary end point(s)
    -Change in 6MWD at 24 weeks.
    -Change in right ventricular ejection fraction (RVEF) values, measured in echocardiogram (at screening visit and at 24 weeks).
    -Change in plasma brain natriuretic peptide (proNT-BNP) levels from baseline at 24 weeks.
    -Change in Quality of Life (QoL) scores from baseline at 24 weeks
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 24 weeks of treatment.
    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 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
    Trial to find the maximum tolerated dose of imatinib in patients with PAH.
    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 No
    E.8.1.1Randomised No
    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 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.8.3 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 concerned8
    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
    Subjects will be considered complete for the purpose of this study once they have completed all procedures of the Follow-up Tele-visit at the end of Week 28 (or 4 Weeks after early termination).

    The end of study the clinical trial is defined as the last visit of the last subject undergoing the trial.
    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 months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years4
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 13
    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 state43
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 43
    F.4.2.2In the whole clinical trial 43
    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)
    At Week 28 ±3 days (or 4 weeks after early termination), subjects will have a televisit. Patients will be off study drug for approx. 4 weeks. Concomitant medications and AEs will be recorded. Women of childbearing potential will have a urine pregnancy test at home. Patients who wish to continue having the IMP will be able to discuss this with their study doctor. Treatment beyond the 28-week period will lie under the PI and local hospital’s responsibilities and will not relate to the study.
    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 Decision2020-07-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-28
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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