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    Summary
    EudraCT Number:2018-003672-12
    Sponsor's Protocol Code Number:TM005
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-11-28
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2018-003672-12
    A.3Full title of the trial
    A 24-week phase 2, double-blind, randomized, placebo-controlled, single-centre safety and efficacy study to evaluate overall safety and tolerability of co-administration of tesofensine and metoprolol in subjects with hypothalamic injury-induced obesity (HIO), and with a 24-week open-label extension, in total 48 weeks
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 24-week phase 2, double-blind, placebo-controlled, single-centre safety and efficacy study to evaluate overall safety and tolerability of co-administration of tesofensine and metoprolol in subjects with obesity caused by an injury in hypothalamus (HIO), and with a 24-week open-label extension, in total 48 weeks
    Et 24 ugers fase 2, dobbelt-blindet, randomiseret, placebokontrolleret, enkelt center sikkerhed- og effekt-forsøg med henblik på at vurdere sikkerhed og tolerabilitet af co-administration af tesofensine og Metoprolol hos forsøgsdeltagere med overvægt forårsaget af skade i hypothalamus (HIO), og med en 24 ugers åben forlænget behandling, i alt 48 uger
    A.4.1Sponsor's protocol code numberTM005
    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 SponsorSaniona A/S
    B.1.3.4CountryDenmark
    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 supportSaniona A/S
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSaniona A/S
    B.5.2Functional name of contact pointKim Krogsgaard
    B.5.3 Address:
    B.5.3.1Street AddressBaltorpvej 154
    B.5.3.2Town/ cityBallerup
    B.5.3.3Post codeDK-2750
    B.5.3.4CountryDenmark
    B.5.4Telephone number+4520148384
    B.5.6E-mailkim.krogsgaard@saniona.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.3.1Product nameTesofensine
    D.3.2Product code NS2330
    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 INNTesofensine
    D.3.9.2Current sponsor codeNS2330
    D.3.9.4EV Substance CodeSUB20754
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.00050
    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 Yes
    D.2.1.1.1Trade name Metoprololsuccinat "Orion"
    D.2.1.1.2Name of the Marketing Authorisation holderOrion Corporation
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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.3.4Pharmaceutical 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 INNMetoprolol
    D.3.9.3Other descriptive nameMETOPROLOL SUCCINATE (PH. EUR.)
    D.3.9.4EV Substance CodeSUB176597
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    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
    Hypothalmic injury-induced obesity (HIO)
    E.1.1.1Medical condition in easily understood language
    Obesity caused by an injury in hypothalamus
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10013367
    E.1.2Term Disorders of the pituitary gland and its hypothalamic control
    E.1.2System Organ Class 100000004860
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To examine overall safety and tolerability of co-administration of 0.5 mg tesofensine/50 mg metoprolol treatment over 24 weeks in subjects with HIO
    E.2.2Secondary objectives of the trial
    • To examine the effect on satiety, appetite, body weight, body composition, quality of life, craving for something sweet, salty, savory and fatty, thirst, glycaemic control and lipid profile, HR and BP from from Baseline to week 24, from Baseline to week 48 and from week 24 to week 48 following co-administration of 0.5 mg tesofensine/50 mg metoprolol treatment in subjects with HIO.
    • To establish profile of trough values of tesofensine, its N-desmethyl-metabolite (NS2360) and metoprolol following co-administration of 0.5 mg tesofensine/50 mg metoprolol treatment in subjects with HIO.
    • To evaluate the effect on BP and HR from Baseline to week 24 by 24 hours (24H) home monitoring of BP and 48 H home monitoring of HR.
    • To evaluate overall safety and tolerability from week 24 to week 48 following co-administration of 0.5 mg tesofensine/50 mg metoprolol treatment in subjects with HIO.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Informed consent obtained before any trial-related activities
    2. Males and females, aged 18-75
    3. Confirmed diagnosis of HIO
    4. BMI ≥27 kg/m2 (where overweight is related to the HIO)
    5. Well managed and stable substitution of hypopituitarism >2 months as judged by the investigator
    6. Normal blood pressure or well managed hypertension (only if dose of BP medication(s) has been stable for >2 months)
    7. Type 2 diabetes is allowed, but the following criteria must be met:
    • HbA1c < 86 mmol/mol
    • Subjects taking GLP-1 analogues must have been on stable dose for >3 months
    • Fasting plasma glucose <11.0 mmol/l measured on site
    E.4Principal exclusion criteria
    1. BP ≥160/90 mmHg
    2. HR ≥ 90, <50 bpm
    3. Hypersensitivity to tesofensine/metoprolol or any component of the products
    4. Type 1 diabetes, Cushings disease, acromegaly, hypophysitis, infiltrative diseases or Prader-Willi syndrome
    5. Heart failure New York Heart Association (NYHA) level II or greater, decompensated heart failure
    6. Previous myocardial infarction or stroke within the last 5 years
    7. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other DSM-III disorders, or any other psychiatric condition, which in the investigator’s opinion will interfere significantly with study compliance
    8. Physical impairment, which in the investigator’s opinion will interfere significantly with study compliance
    9. Any clinically significant cardiac arrhythmia
    10. Treatment with calcium channel blockers and beta blockers
    11. Concomitant use of monoaminooxidase inhibitors
    12. Use of recreational medication
    13. Bulimia or anorexia nervosa
    14. Any agent used for weight loss in the past 3 months, except GLP-1 compounds
    15. Untreated hypo- or hyperthyroidism
    16. Clinically significant liver (>3x ULN) and/or kidney impairment
    17. More than 5% weight loss within the last 3 months
    18. Subject is pregnant or lactating or intends to become pregnant or is of childbearing potential and not using an adequate contraceptive method (Spiral or hormonal contraception, birth control pills, implant, transdermal patch, vaginal ring or depot injection)
    19. Male subjects not agreeing to use a condom without spermicide or oil-containing products (e.g., lubricants) during sexual activity with female partners of childbearing potential throughout the trial until at least 8 weeks after the last administration of IMP
    20. Any contraindication for metoprolol according to the Summary of Product Characteristics (SmPC), e.g. severe peripheral arterial disease, untreated pheochromocytoma, concomitant intravenous administration of calcium antagonists of verapamil and diltiazem, due to the risk of hypotension, AV conduction disturbances, or left ventricular insufficiency
    21. Subject has lactose intolerance or a rare hereditary problem of fructose intolerance, glucose galactose malabsorption or sucrase isomaltase insufficiency
    22. Subject is unable to understand and communicate in Danish language or to understand the protocol requirements, instructions and study-related restrictions, the nature, scope and possible consequences of the clinical study or is unlikely to comply with the study requirements; e.g., uncooperative attitude and improbability of completing the clinical study
    23. PHQ-9 (Patient Health Questionnaire):
    a. If a score of at least 5 in question 1 and 2 coming from the area of “More than half the days” or Nearly every day” or
    b. PHQ-9 score ≥ 10 when counts from questions 3-5 have been subtracted or
    c. If a tic in question 6 in “More than half the days” or “Nearly every day” or
    d. Any score > 0 on question 9 at screening and baseline
    24. Any suicidal behaviour within the past 30 days since screening
    25. Subject has been enrolled in another clinical study within the past three months
    26. Any other clinically meaningful condition, which in the opinion of the investigator, would make participation potentially unsafe
    E.5 End points
    E.5.1Primary end point(s)
    Safety and tolerability will be judged from all safety data collected in the period, including number and type of treatment emergent adverse events, laboratory data, blood pressure and heart rate.
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 weeks.
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints:
    • Change in satiety and appetite using the CSS Baseline to week 24, from Baseline to week 48 and from week 24 to week 48
    • Change in body weight from Baseline to week 24, from Baseline to week 48 and from week 24 to week 48
    • Change in body composition i.e. body fat and lean body mass by Dual-energy X-ray absorptiometry (DEXA) from Baseline to week 24, from Baseline to week 48 and from week 24 to week 48
    • Change in quality of life by the use of the SF-36 questionnaire from Baseline to week 24, from Baseline to week 48 and from week 24 to week 48
    • Change in craving for something sweet, salty, savory and fatty by the use of Visual Analogue Scale (VAS) scales from Baseline to week 24, from Baseline to week 48 and from week 24 to week 48
    • Change in thirst by the use of a VAS scale from Baseline to week 24, from Baseline to week 48 and from week 24 to week 48
    • Change on glycaemic control and lipid profile from Baseline to week 24, from Baseline to week 48 and from week 24 to week 48
    • Change in waist circumference from Baseline to week 24, from Baseline to week 48 and from week 24 to week 48

    Secondary safety and PK endpoints:
    • Change on HR and BP from Baseline to week 48 and from week 24 to week 48
    • Trough values of tesofensine, Metropolol and N-desmethyl-metabolite (NS2360)
    - Active arm: the first 24 weeks and then continuously up to week 48.
    - Placebo arm: start of treatment at week 25 and then continuously up to week 48.
    • Change of 24H BP/48H HR and QT from Baseline to V5 and V8 and from V5 to V8 measured by home monitoring
    • Number and type of AE’s from week 24 to week 48
    E.5.2.1Timepoint(s) of evaluation of this end point
    Weeks 24 and 48.
    For trough values:
    - Active arm: the first 24 weeks and then continuously up to week 48.
    - Placebo arm: start of treatment at week 25 and then continuously up to week 48.
    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 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 No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Double-blind, randomized, placebo-controlled with an open-label extension
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    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 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
    LVLS
    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 months0
    E.8.9.1In the Member State concerned days0
    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: 22
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 state25
    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 Decision2019-01-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-10-16
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