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    Summary
    EudraCT Number:2013-000201-23
    Sponsor's Protocol Code Number:reflect01
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-05-30
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2013-000201-23
    A.3Full title of the trial
    A randomised clinical trial evaluating the effect of remifentanil vs fentanyl
    during cardiac surgery on the incidence of chronic thoracic pain.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Two commonly used anesthesia during cardiac surgery (remifentanil and
    fentanyl) will be compared; the effect of these anesthesia on the
    development of chronic thoracic pain will be measured.
    A.3.2Name or abbreviated title of the trial where available
    REFLECT
    A.4.1Sponsor's protocol code numberreflect01
    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 SponsorSt. Antonius Ziekenhuis
    B.1.3.4CountryNetherlands
    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 supportSt. Antonius Hospital
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSt. Antonius Hospital
    B.5.2Functional name of contact pointClinical Pharmacy department
    B.5.3 Address:
    B.5.3.1Street AddressKoekoekslaan 1
    B.5.3.2Town/ cityNieuwegein
    B.5.3.3Post code3435 CM
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31306092612
    B.5.5Fax number0031306093080
    B.5.6E-mailc.knibbe@antoniusziekenhuis.nl
    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 Remifentanil HCL 2 mg vial
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline BV
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameRemifentanil HCL
    D.3.4Pharmaceutical form Powder for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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 RoleComparator
    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 Fentanyl 100 ug = 2 ml vial
    D.2.1.1.2Name of the Marketing Authorisation holderBipharma
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameFentanyl
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Fentanyl 500 ug = 10 ml vial
    D.2.1.1.2Name of the Marketing Authorisation holderBipharma
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameFentanyl
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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
    chronic thoracic pain after cardiac surgery via sternotomy
    E.1.1.1Medical condition in easily understood language
    chronic thoracic pain (pain on chest) after cardiac surgery
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]
    MedDRA Classification
    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 of this study is to determine the influence of intra-operative use of remifentanil versus fentanyl on the percentage of patients with chronic pain one year after cardiac surgery.
    E.2.2Secondary objectives of the trial
    -percentage of patients with chronic thoracic pain and their mean NRS scores three months and six months after cardiac surgery. - effect on the quality of life (QoL) and on the use of analgesics three months, six months and one year after surgery
    - pain thresholds will be measured, evaluating the difference in postoperative pain threshold (three days and one year after surgery) compared to preoperative pain threshold (baseline), using quantitative sensory testing.
    - other aspects in the postoperative period, e.g. NRS scores, postoperative consumption of analgesics, length of ICU- and hospital stay, safety parameters of remifentanil
    - influence of genetic variances involved in pain sensitivity (e.g. GCH-1, WDF-4, ZNF, MC1R) and in pharmacokinetics and pharmacodynamics of opiates (e.g. UGT, MRP, OPRM1, COMT) will be investigated.
    - cost-effectiveness analysis alongside the RCT with a 12 month follow-up will be performed.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    All patients living in Utrecht and surroundings undergoing cardiac surgery via sternotomy, including a CABG and/or valve replacement, admitted to the ICU or PACU in the St. Antonius hospital, between 18 and 85 years old, weighing between 45 and 140 kg, written informed consent.
    E.4Principal exclusion criteria
    - Pregnancy/ breastfeeding
    - Language barrier
    - History of drug abuse
    - Neurologic condition such as peripheral neuropathy
    - Known morphine or paracetamol allergy
    - BMI > 35 kg/m2
    E.5 End points
    E.5.1Primary end point(s)
    The percentage of patients reporting chronic thoracic pain one year after cardiac surgery.
    E.5.1.1Timepoint(s) of evaluation of this end point
    one year after cardiac surgery
    E.5.2Secondary end point(s)
    - The percentage of patients reporting chronic thoracic pain three months and six months after cardiac surgery
    - The mean NRS score of patients with chronic thoracic pain three months and six months after cardiac surgery.
    - The quality of life (QoL) three months, six months and one year after surgery.
    - The difference in postoperative pain thresholds three days and one year after cardiac surgery compared to the preoperative pain threshold (baseline)
    - The use of analgesics three months, six months and one year after cardiac surgery.
    - The percentage of patients with at least one NRS-score of ≥ 4 at rest during ICU and hospital stay
    - The mean NRS per patient at rest during ICU stay
    - The required amounts of analgesics (morphine/paracetamol) during hospital stay
    - Length of ICU and hospital stay
    - Total administered amount of remifentanil and fentanyl
    - Total medical costs during one year, including costs of hospitalization days (ICU and non-ICU) and costs of medications
    - Productivity costs during one year (i.e., foregone paid and unpaid work and reduced productivity while at work)
    - Cost-effectiveness, expressed as incremental costs per case of chronic pain at 12 months after cardiac surgery avoided and incremental costs per quality-adjusted life-year (QALY) gained
    - Safety parameters of remifentanil; such as nausea, constipation, respiratory depression, duration of ventilation, hallucinations, delirium, Glascow Coma Scale, renal function)
    - Genetic variances involved in pain sensitivity (e.g. GCH-1, WDF-4, ZNF, MC1R) and pharmacokinetics and pharmacodynamics of opiates (e.g. UGT, MRP, OPRM1, COMT)
    E.5.2.1Timepoint(s) of evaluation of this end point
    peri- and postoperative period, 3 months, 6 months and 1 year after cardiac surgery
    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 No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 Yes
    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) Yes
    E.8.2.2Placebo No
    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
    End of the trial is approximately one year after the last patient's visit for cardiac surgery.
    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 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: 63
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 63
    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 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 state126
    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 Decision2013-05-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-08-30
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-04-25
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