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    EudraCT Number:2015-000793-36
    Sponsor's Protocol Code Number:HighNxGHR
    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:2015-03-06
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2015-000793-36
    A.3Full title of the trial
    Effect of High-dose Target-controlled Naloxone Infusion on Pain and Hyperalgesia in Patients following Groin-Hernia-Repair.
    A companion study to: Pharmacokinetics of High-dose Target-controlled Naloxone Infusion.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The effect of high dose naloxon - an antidote of morphine - on pain sensitivity after groin hernia repair.
    Effekten af høj-dosis naloxon - et stof der ophæver morfins virkning - på smerte-overfølsomhed efter en lyskebrok operation
    A.3.2Name or abbreviated title of the trial where available
    High-dose Target-controlled Naloxone Infusion
    A.4.1Sponsor's protocol code numberHighNxGHR
    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 SponsorRigshospitalet, Copenhagen University Hospitals
    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 supportRigshospitalet, Copenhagen University Hospitals
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRigshospitalet, Copenhagen University Hospitals
    B.5.2Functional name of contact pointThomas K. Ringsted
    B.5.3 Address:
    B.5.3.1Street AddressBlegdamsvej 9
    B.5.3.2Town/ cityCopenhagen
    B.5.3.3Post code2100
    B.5.4Telephone number004535457618
    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. name Naloxon "B. Braun"
    D. of the Marketing Authorisation holderB. Braun Melsungen AG
    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 Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNALOXONE
    D.3.9.1CAS number 465-65-6
    D.3.9.4EV Substance CodeSUB09142MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4.0
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Groin hernia repair
    E.1.1.1Medical condition in easily understood language
    Groin hernia repair
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10049475
    E.1.2Term Chronic pain
    E.1.2System Organ Class 100000004867
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The principal aim of the study is to investigate whether the administration of naloxone, a selective mu-opioid receptor (MOR) antagonist, can re-introduce pain (at rest, during movement and in pressure-evoked condition) and hyperalgesia six to eight weeks after unilateral, primary, open groin hernia repair with mesh-implantation (GHR). A three-step the target-controlled-infusion (TCI) model is employed.
    E.2.2Secondary objectives of the trial
    not applicable
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetics of High-dose Target-controlled Naloxone Infusion. 2015-02-16 version 1.8
    Since the pharmacokinetics of naloxone and its main-metabolite
    (naloxone-3-glucuronide), at the dose-levels used in this study (below
    or equals 3.5 mg/kg), are unknown, we have added a subset of
    volunteer participants in order to investigate the pharmacokinetic
    construct validity of the target-controlled-infusion (TCI) model.
    E.3Principal inclusion criteria
    • Healthy male
    • Age above 18 yrs and below 65 yrs
    • Signed informed consent
    • Participants submitted to unilateral, primary inguinal, open groin hernia repair 6-8 weeks prior to study start.
    • Surgical procedure a.m. Lichtenstein.
    • Urin-sample without traces of opioids (morphine, methadon, buprenorphine, codeine, tramadol, ketobemidone, oxycodone, hydromorphone, dextromethorphan)
    • ASA I-II
    • Body mass index (BMI): 18 < BMI < 30 kg/m2
    E.4Principal exclusion criteria
    • Participants, who do not speak or understand Danish
    • Participants, who cannot cooperate with the investigation
    • Participants, who have had previous surgery in the groin region
    • Participants with pain at rest > 3 (NRS)
    • Activity-related pain in the surgical field > 5 (NRS)
    • Allergic reaction against morphine or other opioids (including naloxone),
    • Abuse of alcohol or drugs – according to investigator’s evaluation
    • Use of psychotropic drugs (exception of SSRI)
    • Neurologic or psychiatric disease
    • Chronic pain condition
    • Regular use of analgesic drugs
    • Skin lesions or tattoos in the assessment areas
    • Nerve lesions in the assessment sites (e.g., after trauma, disc herniation, etc.)
    • Use of prescription drugs one week before the trial
    • Use of over-the-counter drugs 48 hours before the trial
    E.5 End points
    E.5.1Primary end point(s)
    (Abbreviations: BL = baseline; NRS = numerical rating scale (pain; 0 to 10); NX = naloxone; PL = placebo; TCI = during target-controlled-infusion):
    1. The primary endpoint is based on a summated measure (SM) of resting pain (RP), movement-related pain (MP) and pressure evoked pain (PM). NRS(SM) = NRS(RP) + NRS(MP) + NRS(PM)

    2. the summed pain intensities (SPIs) are calculated as: (BL-SPI[NX]) and (TCI-SPI[NX]), and, (BL-SPI[PL]) and (TCI-SPI[PL]), where (TCI-SPI) indicate SM-value at highest obtainable TCI-step (Fig. 2)

    3. The summed pain intensity differences (SPIDs) are the differences: SPID[NX] = (TCI-SPI[NX]) – (BL-SPI[NX]) and SPID[PL] = (TCI-SPI[PL]) - (BL-SPI[PL])

    4. The primary endpoint is SPIDs
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline (pre-infusion; 0 min); Step 1 (TCI-infusion 1 [naloxone: 0.25 mg/kg]: 15 to 25 min); Step 2 (TCI-infusion 2 [naloxone: 0.75 mg/kg]: 39 to 49 min); Step 3 (TCI-infusion 3 [naloxone: 2.25 mg/kg]: 65 to 75 min).
    E.5.2Secondary end point(s)
    Pressure pain thresholds (PPT) by algometry at the surgical site compared to the contralateral site, secondary hyperalgesia/allodynia areas at surgical site and contralateral site, psychometrics (Hospital Anxiety and Depression Scale [HADS], Pain Catastrophizing Scale [PCS]) and ratings by Clinical Opiate Withdrawal Scale (COWS).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Pressure pain thresholds (PPT) and secondary hyperalgesia/allodynia areas are assessed Baseline (pre-infusion; 0 min); Step 1 (TCI-infusion 1: 15 to 25 min); Step 2 (TCI-infusion 2: 39 to 49 min); Step 3 (TCI-infusion 3: 65 to 75 min).

    Clinical Opiate Withdrawal Scale (COWS) assessments are made at Baseline (pre-infusion; 0 min); Step 1 (TCI-infusion 1: 13 to 15 min); Step 2 (TCI-infusion 2: 37 to 39 min); Step 3 (TCI-infusion 3: 63 to 65 min).

    Psychometrics (Hospital Anxiety and Depression Scale [HADS], Pain Catastrophizing Scale [PCS]) and ratings by Clinical Opiate Withdrawal Scale (COWS) are only assessed at Baseline (pre-infusion; 0 min).
    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 No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    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. 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 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 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
    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 months6
    E.8.9.1In the Member State concerned days
    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: 16
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients No
    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 state16
    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
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Department of Surgery
    G.4.3.4Network Country Denmark
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-04-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-08-08
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