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    The EU Clinical Trials Register currently displays   43614   clinical trials with a EudraCT protocol, of which   7207   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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    EudraCT Number:2013-002948-91
    Sponsor's Protocol Code Number:1315V9232
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-05-08
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2013-002948-91
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Naldemedine in the Treatment of Opioid-induced Constipation in Subjects with Non-malignant Chronic Pain Receiving Opioid Therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Naldemedine in the Treatment of Opioid-induced Constipation in Subjects with Non-malignant Chronic Pain Receiving Opioid Therapy
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code number1315V9232
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01993940
    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 SponsorShionogi 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 supportShionogi Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedpace
    B.5.2Functional name of contact pointDirector, Clinical Operation
    B.5.3 Address:
    B.5.3.1Street AddressStirling University Innovation Park, Beta Centre, Unit 16
    B.5.3.2Town/ cityStirling
    B.5.3.3Post codeFK9 4NF
    B.5.3.4CountryUnited Kingdom
    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 nameNaldemedine
    D.3.2Product code S-297995
    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
    D.3.9.1CAS number 1345728-04-2
    D.3.9.2Current sponsor codeORG16240
    D.3.9.3Other descriptive nameNALDEMEDINE
    D.3.9.4EV Substance CodeSUB126248
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 placeboFilm-coated tablet
    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
    Opioid-induced Constipation in Subjects with Non-malignant Chronic Pain Receiving Opioid Therapy
    E.1.1.1Medical condition in easily understood language
    Opioid-induced Constipation
    E.1.1.2Therapeutic area Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10071128
    E.1.2Term Opioid induced constipation
    E.1.2System Organ Class 100000004856
    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 efficacy of naldemedine compared to placebo without concomitant laxative treatment in subjects with non-malignant chronic pain receiving a stable opioid regimen and having OIC
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of naldemedine on the frequency of spontaneous bowel movements (SBMs)
    To evaluate the safety and tolerability of naldemedine
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects aged 18 to 80 years inclusive at the time of informed consent
    2. Subjects must have non-malignant chronic pain treated with opioids for at least 3 months and must have OIC
    3. Subjects must be treated with a stable opioid regimen at a total daily dose on average of ≥ 30 mg equivalents of oral morphine sulfate for at least 1 month prior to Screening
    4. Subjects must not be currently using laxatives or must be willing to discontinue laxative use (e.g., stool softener, bulking agents, gastrointestinal tract stimulants/prokinetic agents, suppositories, enemas or other medications/agents used to treat constipation) at the time of Screening and must be willing to use only the rescue laxatives provided throughout the study duration
    5. Subjects must meet the following 3 criteria based on the Bowel Movement and Constipation Assessment (BMCA) Diary collected via eDiary over a 14 consecutive day qualifying period during the 28 day Screening Period:
    a. No more than 4 SBMs total over the 14 consecutive day qualifying period. In addition, no more than 3 SBMs in a given week of the qualifying period.
    b. Experience one or more of the following bowel symptoms in 25% or more of BMs:
    1. Presence of straining
    2. Lumpy or hard stools
    3. Sensation of incomplete evacuation
    4. Sensation of anorectal obstruction/blockage
    c. Subjects must have at least 78% compliance with daily completion of eDiary entries (i.e., make 11 of 14 diary completions) during the 14 consecutive day qualification period
    6. Males will be either sterile for 6 months prior to Screening (e.g., vasectomy) or agree to use an approved method of contraception (use of a condom with spermicide from the start of the Screening visit until 28 days after the last dose of IMP)
    7. Females must be non-pregnant, non-lactating, and either postmenopausal (defined as cessation of regular menstrual periods for at least 1 year if ≥ 50 years old or 2 years if < 50 years old with follicle-stimulating hormone (FSH) confirmation), surgically sterile by hysterectomy, bilateral oophorectomy or agree to use a highly effective (with failure rates < 1%/year) technique of birth control from Screening visit until 28 days after the last dose of IMP, such as:
    a. hormonal implants, injectables, combined oral contraceptives
    b. intrauterine contraceptive devices
    c. barrier method of contraception (condom or occlusive cap [diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository or condom in combination with tubal ligation)
    8. Subjects who are not currently sexually active (abstinent) must agree to use one of the above-mentioned methods if they become sexually active while participating in the study
    9. Females of child bearing potential must have a negative serum pregnancy test at the Screening visit and a negative urine pregnancy test at Visit 2 (Day 1), prior to dosing
    10. Able to understand and willing to sign an informed consent form prior to Screening, and comply with all study procedures and requirements
    E.4Principal exclusion criteria
    1. Evidence of significant structural abnormalities of the gastrointestinal tract (GI)
    a. history of bowel obstructions, strictures
    b. history of bowel surgery such as bowel resection or bariatric surgeries
    2. Evidence of active medical diseases affecting bowel transit such as ileus, uncontrolled hypothyroidism, irritable bowel syndrome (IBS), inflammatory bowel disease (ulcerative colitis, Crohn’s disease, diverticulitis), fecal incontinence
    3. History or presence of pelvic disorders that may be a cause of constipation
    4. Surgery (except for minor procedures) within 60 days of Screening, or planned surgery during study treatment that would influence pain or bowel function or preclude completion of the study
    5. History of chronic constipation prior to starting analgesic medication or any potential non-opioid cause of bowel dysfunction that may be a major contributor to the constipation (e.g., mechanical gastrointestinal obstruction)
    6. Severe constipation that has not been appropriately managed such that the subject is at immediate risk of developing serious complications of constipation. This includes subject who have reported no bowel movements for 7 consecutive days prior to and during the Screening Period
    7. Subjects who have never taken laxatives for the treatment of OIC
    8. Initiation of a new bowel regimen or prokinetic agent, or significant change in diet supplement use, or exercise regimens within 28 days of the Screening visit
    9. History of active treatment for cancer within the last 2 years (except for basal cell or squamous cell carcinoma of the skin that have been successfully resected or tamoxifen [Nolvadex®] and raloxifene [Evista®] when being used for prevention of breast cancer)
    10. Abnormal laboratory tests at Screening:
    a. >2 × upper limit of normal (ULN) for alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
    b. >1.5 × ULN for total bilirubin
    c. >1.5 × ULN for serum creatinine
    11. Subjects with a significant comorbid medical condition(s) to the extent that study participation may not be in the subject’s best interest or that may interfere with study compliance/completion. Comorbid conditions may include cardiovascular, respiratory, hepatic, renal, endocrine dysfunction, or a history of human immunodeficiency (HIV)
    12. Subjects who have significant cardiovascular (CV) risk such as presence or suspected presence of unstable coronary artery disease, myocardial infarction (MI), stroke or transient ischemic attack (TIA) within 3 months of Screening
    13. Presence of any medical or psychiatric condition that, in the opinion of the Investigator, may compromise the ability of the subject to understand and comply with the study protocol or provide informed consent to participate in the study
    14. Positive result for serologic test for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) or active hepatitis A virus (HAV)
    15. Current use of any prohibited medication listed in Section 6.2.5 including opioid antagonists, partial agonists or mixed agonist/antagonists
    16. Any history of illegal drug use in the last 2 years, documented misuse of prescribed medications or a positive urine drug screen (unless the positive drug substance has been prescribed)
    17. Any allergic reaction to opioids or known or suspected hypersensitivity to naltrexone hydrochloride, methylnaltrexone bromide, naloxone hydrochloride, alvimopan or any other opioid antagonist
    18. Treatment with an IMP within 2 months prior to the Screening visit
    19. Prior participation in naldemedine trials
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint will be the proportion of responders where a responder is defined as having 9 positive response weeks or more out of the 12-week Treatment Period and 3 positive response weeks out of the last 4 weeks of the 12-week Treatment Period. A positive response week will be defined as ≥ 3 SBMs per week and an increase from baseline of ≥ 1 SBM per week for that week.
    SBM is defined as a BM that occurs without the use of a rescue laxative medication during the 24 hours prior to the BM. However, a BM occurring within 24 hours after rescue laxative therapy will not be considered a SBM.
    Any number of SBMs rated on the Bristol Stool Scale as 1 within a 2 hour period will be counted as a single SBM.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    E.5.2Secondary end point(s)
    Mean change in the frequency of SBMs per week from baseline to the first four weeks of the Treatment Period
    • Mean change in the frequency of SBMs per week without straining from baseline to the last two weeks of the Treatment Period
    • Mean change in the frequency of SBMs per week from baseline to each two weeks of the Treatment Period
    E.5.2.1Timepoint(s) of evaluation of this end point
    1 - Week 4
    2 - Last two weeks of the Treatment Period
    3 - Every two weeks
    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 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. 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) 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 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 EEA30
    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
    Czech Republic
    United Kingdom
    United States
    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
    Last Visit Last Subject (LVLS)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial 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: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 290
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 170
    F.4.2.2In the whole clinical trial 540
    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)
    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 Decision2014-08-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-04-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-06-09
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