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    Summary
    EudraCT Number:2020-003280-26
    Sponsor's Protocol Code Number:IMB101-005
    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:2020-09-11
    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 number2020-003280-26
    A.3Full title of the trial
    A Dose-Ranging Pharmacodynamic Study to Evaluate the Effects of IMB-1018972 on Myocardial Energetics, Metabolism, and Function in Patients with Type 2 Diabetes
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A research study to learn about the effects of IMB-1018972, to try and help your heart cell use energy more efficiently, to find the best dose, and to see how safe it is. This is for patients who may be at risk for a heart condition known as diabetic cardiomyopathy (DbCM) as a complication of a type 2 diabetes mellitus (T2DM).
    A.3.2Name or abbreviated title of the trial where available
    To evaluate IMB-1018972 on cardiac energetics in patients with T2D.
    A.4.1Sponsor's protocol code numberIMB101-005
    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 SponsorImbria Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    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 supportImbria Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationImbria Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointKaren Jauregi
    B.5.3 Address:
    B.5.3.1Street Address265 Franklin Street, Suite #1702
    B.5.3.2Town/ cityBoston
    B.5.3.3Post codeMA 02110
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1617675-4060
    B.5.5Fax number+1617675-4061
    B.5.6E-mailkj@imbria.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.3.2Product code IMB-1018972
    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 INNNot assigned
    D.3.9.2Current sponsor codeIMB-1018972
    D.3.9.3Other descriptive nameIMB-1018972 trihydrochloride monohydrate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 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.3.2Product code IMB-1018972
    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 INNNot assigned
    D.3.9.2Current sponsor codeIMB-1018972
    D.3.9.3Other descriptive nameIMB-1018972 trihydrochloride monohydrate
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboModified-release capsule, hard
    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
    Diabetic Cardiomyopathy (DbCM)
    E.1.1.1Medical condition in easily understood language
    Diabetes (Type 2)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10012647
    E.1.2Term Diabetic cardiomyopathy
    E.1.2System Organ Class 10007541 - Cardiac 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 primary objective is to evaluate and characterise the dose-response relationship for short-term administration of IMB-1018972 on the myocardial phosphocreatine/adenosine triphosphate (PCr/ATP) ratio, a measure of cardiac energetic reserve, by 31P-magnetic resonance spectroscopy (MRS) at rest and during dobutamine stress.
    E.2.2Secondary objectives of the trial
    -The secondary objectives are the following:
    • To assess the potential dose-response relationship of IMB-1018972 on cardiac systolic and diastolic function, measured by cardiac magnetic resonance (CMR) and transthoracic echocardiography (TTE);
    • To measure cardiac systolic augmentation to dobutamine stress by CMR;
    • To assess the potential dose-response relationship of IMB-1018972 on myocardial pyruvate dehydrogenase (PDH) flux inferred by the [13C]bicarbonate/[1 13C]pyruvate ratio measured by hyperpolarized [1-13C]pyruvate MRS (in all patients in Cohort A [Stage 1] and in up to 12 patients from Cohort B [Stage 2]); and
    • To evaluate the safety and tolerability of repeat oral doses of IMB-1018972 in patients with DbCM.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of written informed consent before any screening procedures;
    2. Male or female aged ≥18 and ≤75 years at screening;
    3. Must agree to adequate contraception requirements as follows:
    a. WOCBP must have a negative serum pregnancy test at screening and a negative pregnancy test (serum or urine) on the day of baseline pre-dose (Stage 1 and Stage 2), at Visit 5 pre dose (Stage 2 only), and at the end of study (EOS)/safety follow-up visit or early termination (Stage 1 and Stage 2);
    b. WOCBP must agree to use dual methods of contraception, including 1 highly effective and 1 effective method of contraception, from the day of first dosing until 3 months after the last administration of test product; and
    c. Male patients must use an effective barrier method of contraception if sexually active with a WOCBP, from the day of first dosing until 3 months after the last administration of test product;
    4. Must agree not to donate sperm or ova from the day of first dosing until 3 months after last dosing;
    5. Women not of childbearing potential must be either surgically sterile (hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before screening) or postmenopausal, defined as spontaneous amenorrhea for at least 2 years with follicle-stimulating hormone (FSH) in the postmenopausal range at screening;
    6. Must be able and willing to comply with all study procedures and requirements.
    7. Diagnosis of T2D;
    8. Elevated HbA1c defined as ≥6.5% (≥48 mmol/mol);
    9. Elevated BMI defined as ≥30 kg/m2;
    10. Preserved LVEF (defined as ≥50%); and
    11. If on oral hypoglycaemic (anti-diabetic) therapy, no change in therapy over the past 3 months.
    E.4Principal exclusion criteria
    1. BMI >40 kg/m2;
    2. Uncontrolled hypertension (defined as resting blood pressure >180/90 mmHg) at screening;
    3. Standard contraindication(s) to magnetic resonance scanning;
    4. More than mild to moderate valvular heart disease per Investigator’s judgement;
    5. Persistent or permanent atrial fibrillation;
    6. History of sustained ventricular tachycardia or cardiac arrest;
    7. Exertional angina or intermittent claudication;
    8. Known significant obstructive coronary artery disease per Investigator’s judgement;
    9. Absolute or significant contraindication to dobutamine infusion, including: phaeochromocytoma, LV outflow tract obstruction, untreated hyperthyroidism, severe hypotension, aortic dissection, or large aneurysm;
    10. History of stroke, transient ischaemic attack, acute coronary syndrome, myocardial infarction, peripheral vascular disease, diagnosis of NYHA functional class III or IV heart failure, hospitalization for heart failure, or any arterial revascularisation procedure (including coronary artery bypass grafting) within 6 months before screening;
    11. Presence of indwelling cardiac device (pacemaker, cardiac resynchronisation therapy, and/or implantable cardioverter defibrillator);
    12. Significant hepatic impairment defined as total bilirubin and/or alanine aminotransferase and/or aspartate aminotransferase >2 x upper limit of the normal;
    13. Moderate or severe renal impairment defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 of body surface area;
    14. History of Parkinson disease, Parkinsonian symptoms, restless leg syndrome, or other related movement disorders;
    15. Known allergy, intolerance, or absolute contraindication to TMZ or nicotinic acid;
    16. Concomitant use within the last 1 month of TMZ, nicotinic acid (at prescription/therapeutic dose), perhexiline, meldonium, or ranolazine;
    17. Any use of insulin and/or SGLT2 inhibitors;
    18. History of alcohol abuse or drug addiction within the previous 5 years;
    19. Pregnant, or planning pregnancy or lactation;
    20. Participation in another clinical study involving a test product or medical device within 28 days (or 5 half-lives of the test product, whichever is longer), prior to first dosing;
    21. Any medical or surgical condition that may interfere with the patient’s participation in the clinical study, significantly interfere with the interpretation of the results, or put the patient at significant risk, according to the Investigator’s judgment, from study participation; or
    22. For those in Cohort B, prior participation in Stage 1 of this study.
    23. Known hypersensitivity to IMB-1018972, mannitol, hypromellose, magnesium stearate and pre-gelatinized corn starch (other ingredients of placebo and active).
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoint:
    • Resting cardiac PCr/ATP ratio at rest measured by 31P-MRS at baseline and at each dose level of IMB-1018972; and
    • Change in cardiac PCr/ATP ratio with dobutamine stress (ie, dobutamine stress induced drop in PCr/ATP ratio from its resting value at the same time point) measured by 31P-MRS at baseline and at each dose level of IMB 1018972.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy endpoints are planned for Stage 2 data. In addition, where appropriate, pooled efficacy data from Stage 1 (ie, reflecting data with 200 mg BID IMB-1018972 given for the same treatment duration) and Stage 2 will be examined.
    E.5.2Secondary end point(s)
    1. Change in 31P-MRS-derived cardiac PCr/ATP ratio compared to baseline at each dose level at rest and during dobutamine stress;

    2. CMR-derived cardiac functional measures:
    o Cardiac output and index augmentation to dobutamine stress;
    o Left ventricle ejection fraction (LVEF) augmentation to dobutamine stress;
    o LV end-systolic volume (LVESV) and LVESV index reduction with dobutamine stress; and
    o Cardiac diastolic function, specifically peak absolute LV diastolic filling rate and peak ventricular filling rate normalised to cavity size (ie, end-diastolic volume [EDV]), both derived from LV volume-time curves;

    •3. TTE-derived cardiac functional measures:
    o LV global longitudinal strain from LV strain analysis;
    o Cardiac diastolic function evaluated by E/e’ ratio from the medial, lateral, and mean values using mitral inflow Doppler and tissue Doppler imaging; and
    o LV untwist quantification including peak untwisting velocity by torsion analysis; and

    4. In those undergoing hyperpolarized [1 13C]pyruvate MRS cardiac imaging, cardiac PDH flux defined as [13C]bicarbonate/[1-13C]pyruvate ratio after a standardised glucose load.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At baseline and at each dose level of IMB-1018972.
    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 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 Yes
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    different doses of the study drug.
    E.8.2.4Number of treatment arms in the trial3
    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 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
    The End of Study is defined as the date of the last protocol-specified visit/assessment (including telephone contact) for the last patient in the study.
    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 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 21
    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 state36
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 36
    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 Decision2020-11-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-11-09
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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