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    Summary
    EudraCT Number:2019-003577-25
    Sponsor's Protocol Code Number:1907V921F
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2022-12-13
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2019-003577-25
    A.3Full title of the trial
    A Phase 1/2, Multicentre, Open-label Study to Evaluate the
    Pharmacokinetics, Safety, and Tolerability of Naldemedine in Paediatric
    Patients Who Are Receiving or Who Are About to Receive Treatment with Opioids
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical research study to assess if naldemedine is safe and tolerable when
    admininstered to paediatric patients (patients under the age of 18) who
    are receiving or about to receive treatment with a class of drugs called opioids
    A.3.2Name or abbreviated title of the trial where available
    Study of the Pharmacokinetics and Safety of Naldemedine in Paediatric Patients receiving Opioids
    A.4.1Sponsor's protocol code number1907V921F
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/379/2021
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorShionogi B.V.
    B.1.3.4CountryNetherlands
    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 supportShionogi & Co. Ltd
    B.4.2CountryJapan
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationShionogi B.V.
    B.5.2Functional name of contact pointRegulatory Affairs Department
    B.5.3 Address:
    B.5.3.1Street Address5th floor, 33 Kingsway
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeWC2B 6UF
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailregulatory.affairs@shionogi.eu
    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 Rizmoic
    D.2.1.1.2Name of the Marketing Authorisation holderShionogi B.V.
    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 namenaldemedine 0.2 mg film-coated tablets
    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 INNNaldemedine Tosylate
    D.3.9.1CAS number 1345728-04-2
    D.3.9.2Current sponsor codeS-297995B
    D.3.9.3Other descriptive nameNaldemedine tosylate (USAN) Naldemedine (USAN) Naldemedine tosilate (JAN)
    D.3.9.4EV Substance CodeSUB177220
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.2
    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.3.1Product nameNaldemedine 0.2mg/g powder for oral suspension
    D.3.4Pharmaceutical form Powder for oral suspension
    D.3.4.1Specific paediatric formulation Yes
    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 INNNaldemedine Tosylate
    D.3.9.1CAS number 1345728-04-2
    D.3.9.2Current sponsor codeS-297995B
    D.3.9.3Other descriptive nameNaldemedine tosylate (USAN) Naldemedine (USAN) Naldemedine tosilate (JAN)
    D.3.9.4EV Substance CodeSUB177220
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.2
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Opioid induced constipation
    E.1.1.1Medical condition in easily understood language
    Constipation resulting from treatment with a class of drugs called opioids
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 24.0
    E.1.2Level LLT
    E.1.2Classification code 10071128
    E.1.2Term Opioid induced constipation
    E.1.2System Organ Class 10017947 - Gastrointestinal 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 evaluate the pharmacokinetics, safety and tolerability of naldemedine in paediatric patients who are receiving or who are about to receive treatment with opioids
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of naldemedine after a single oral dose of naldemedine in paediatric patients who are receiving or who are about to receive opioids.
    To evaluate the PK of naldemedine after multiple, once daily oral doses of naldemedine through population PK in paediatric patients who are receiving or who are about to receive opioids.
    To evaluate the palatability of naldemedine powder for oral suspension and the ability to swallow naldemedine tablets.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients ≥ 2 years of age and < 18 years of age at the time of the signing of the informed consent form.
    2. Patients with cancer or non-cancer pain who are receiving (or who are about to receive) acute or chronic treatment with opioids
    3. Have either newly diagnosed constipation, a history of constipation treated with laxatives, or expected to develop constipation after opioid treatment.
    4. Patients able to remain in the clinic for blood sampling for at least 12 hours following the first study intervention dose and able to return for blood sampling at the 24-hour time point.
    5. Patients able to comply with meal, tobacco, and concomitant medication restrictions
    6. BMI within approximately the 3rd to 97th percentile for their age according to the World Health Organization (WHO) Child Growth Standard
    7 a. Male Patients: Based on the Clinical Trials Facilitation and Coordination Group (CTFG) guidance, no contraception measures are required for male patients because naldemedine is not genotoxic and is categorized ‘unlikely’ for the risk of human teratogenicity/foetotoxicity.
    7 b. Female patients: A female patient is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies:
    - Is a woman of nonchildbearing potential (WONCBP)
    OR
    - Is a woman of childbearing potential (WOCBP) and using an
    acceptable contraceptive method as described in protocol, during the treatment period and for 30 days following the last dose of study drug . The investigator should evaluate the potential for contraceptive method failure (eg. noncompliance, recently initiated) in relationship to the first dose of study drug.
    - A WOCBP must have a negative highly sensitive pregnancy test (urine or
    serum as required by local regulations) at screening and within 24 hours of
    the first dose of naldemedine.
    - If a urine test cannot be confirmed as negative (e.g., an ambiguous
    result), a serum pregnancy test is required. In such cases, the patient
    must be excluded from participation if the serum pregnancy result is
    positive.
    - Additional requirements for pregnancy testing during and after study
    intervention as per protocol.
    8. Each patient’s parent/legal guardian must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
    E.4Principal exclusion criteria
    1. Patients with a history of a GI neoplasm or an ongoing GI-related issue or any
    recent (within last 1 year) or planned GI tract surgery
    2. Patients with signs or symptoms of GI obstruction or patients with recurrent obstruction who may be at increased risk of GI perforation.
    3. Patients who are unable to eat/swallow or have need of a nasogastric tube.
    4. Patients who have reported no bowel movements for 7 consecutive days at the time of obtaining informed consent or on the initial day of study intervention administration (Study Day 1)
    5. Patients with a history of more than 1 week of CTCAE Grade 3 neutropenia or
    thrombocytopenia with clinical sequelae
    6. Patients who need mechanical ventilation
    7. Patients who have severe CTCAE Grade 3 or above hepatic or renal impairment including end-stage renal disease requiring haemodialysis, as determined by the investigator
    8. Patients that have any progressive neurological disorders or potential disruption to the blood-brain barrier (e.g., primary brain malignancies, CNS metastases, active multiple sclerosis, etc.) considering the risk of opioid withdrawal or reduced analgesia.
    9. Patients who have a history of hypersensitivity to naldemedine or any of its ingredients.
    10. Patients who have previously received naldemedine.
    11. Patients currently receiving their first cycle of chemotherapy
    12. Patients currently participating in another study of an investigational drug product or have received another investigational drug product within 30 days or 5 half-lives, whichever is longer, before baseline
    13. Positive pregnancy test for female patients of childbearing potential
    E.5 End points
    E.5.1Primary end point(s)
    To evaluate the pharmacokinetics (PK) of naldemedine and nor-naldemedine after a single oral dose of naldemedine
    -- PK parameters using standard non-compartmental method, e.g. Cmax, Tmax, AUC, AUC0-last, AUC0-inf, λz, t1/2,z of naldemedine and nor-naldemedine; and CL/F, MRT, and Vz/F for naldemedine only, and metabolic ratio of Cmax of nor-naldemedine to Cmax of naldemedine [MRM/U, Cmax] andmetabolic ratio of AUC of nor-naldemedine to AUC of naldemedine [MRM/U, AUC] for nor-naldemedine only
    E.5.1.1Timepoint(s) of evaluation of this end point
    7 days
    E.5.2Secondary end point(s)
    To evaluate the safety and tolerability of naldemedine after a single oral dose of naldemedine
    -- Using results of physical examinations (including assessment of opioid withdrawal symptoms and pain intensity), vital signs, 12-lead ECGs, safety laboratory tests, treatment-emergent adverse events (TEAEs), treatment-related TEAEs,including gastrointestinal (GI) events, and
    serious adverse events (SAEs) on Study Days 1 through 7
    To evaluate the PK of naldemedine after multiple, once daily oral doses of naldemedine through population PK
    -- using Results of population PK analysis
    PK parameters using population PK analysis (e.g. Cmax, Tmax, AUC0-τ, accumulation ratio for Cmax calculated as ratio of Day 7 to Day 1 Cmax (RCmax), and accumulation ratio for AUC calculated as ratio of Day 7 to Day 1 AUC (RAUC) for naldemedine only
    To evaluate the palatability of naldemedine powder for oral suspension and the ability to swallow naldemedine tablets
    --using results of self-reported visual analogue scale (VAS) for palatability assessments of naldemedine powder for oral suspension for patients ≥ 6 years of age
    -- Results of investigator’s or patient’s parent/legal guardian assessment of palatability of naldemedine powder for oral suspension for patients ≥ 2 years to < 6 years of age, and, if possible, patients’ self-assessment using a VAS with facial hedonic scale
    -- Results of self-reported ease of swallowing of naldemedine tablets
    E.5.2.1Timepoint(s) of evaluation of this end point
    To evaluate the safety and tolerability of naldemedine after a single oral dose of naldemedine: Days 1 through 7
    To evaluate the PK of naldemedine after multiple, once daily oral doses of naldemedine through population PK: ratio of Day 7 to Day 1
    To evaluate the palatability of naldemedine powder for oral suspension and the ability to swallow naldemedine tablets: during the study
    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 No
    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 No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    This is a Phase 1/2 study but not within E.7.1.1 or E7.1.2 groups
    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 Yes
    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.8.2.4Number of treatment arms in the trial1
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    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
    Bosnia and Herzegovina
    North Macedonia
    Albania
    Armenia
    Belgium
    France
    Italy
    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
    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 months2
    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 months2
    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: 24
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 16
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 8
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 15
    F.4.2.2In the whole clinical trial 24
    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)
    Shionogi is unable to proceed further with submission of the compassionate use program for patients that have completed the study 1907V921F in Belgium due to the specified regulatory conditions being different to those indicated in our protocol. For patients that may require continuation of naldemedine after study completion, Shionogi advise the PI to consider following the local procedure that is available for urgent situations as outlined by the Health Authority.
    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 Decision2023-01-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-05-24
    P. End of Trial
    P.End of Trial StatusCompleted
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