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    Summary
    EudraCT Number:2014-003237-25
    Sponsor's Protocol Code Number:POPPIV4.022.07.16
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-07-20
    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 ConcernedUK - MHRA
    A.2EudraCT number2014-003237-25
    A.3Full title of the trial
    A blinded randomised placebo-controlled trial investigating the efficacy of morphine analgesia for procedural pain in infants
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Does morphine provide effective pain relief during painful procedures performed in newborn babies as part of their essential medical care?
    A.3.2Name or abbreviated title of the trial where available
    Is morphine an effective analgesic for procedural pain in infants?
    A.4.1Sponsor's protocol code numberPOPPIV4.022.07.16
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN82342359
    A.5.4Other Identifiers
    Name:EudraCT NumberNumber:2014-003237-25
    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 SponsorUniversity of Oxford
    B.1.3.4CountryUnited Kingdom
    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 supportThe Wellcome Trust
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportNational Institute of Health Research
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Oxford
    B.5.2Functional name of contact pointMs Heather House
    B.5.3 Address:
    B.5.3.1Street AddressClinical Trials and Research Governance, Joint Research Office, Block 60, Churchill Hospital
    B.5.3.2Town/ cityOxford
    B.5.3.3Post codeOX3 7LE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01865572224
    B.5.5Fax number01865572228
    B.5.6E-mailheather.house@admin.ox.ac.uk
    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 nameMorphine sulphate Oral solution 200mcg in 1mL
    D.3.2Product code n/a
    D.3.4Pharmaceutical form Oral solution
    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 INNmorphine sulphate 200mcg in 1ml oral solution
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 placeboOral solution
    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
    Screening for Retinopathy of Prematurity is an essential yet painful routine test that is performed multiple times in infants who are born prematurely. Premature infants also regularly require heel lance for blood tests. We will conduct a randomised placebo-controlled trial to examine whether morphine is an effective analgesic for these procedures.
    E.1.1.1Medical condition in easily understood language
    Preterm babies regularly require eye exams and blood tests, both of which are considered painful procedures. We will test morphine compared with placebo for both these procedures.
    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
    To test whether administration of morphine reduces clinical pain scores (PIPP-R) compared with a placebo (inactive solution) 30 seconds after an eye examination to test for retinopathy of prematurity (ROP).

    To test whether administration of morphine reduces pain-related brain activity compared with a placebo (inactive solution) following a clinically-essential heel lance.


    E.2.2Secondary objectives of the trial
    To test whether administration of morphine improves clinical stability after ROP screening in the 6-hour and 24-hour period following the start of the examclinical intervention (heel lance followed by retinopathy of prematurity (ROP) screening).

    To test whether administration of morphine reduces clinical pain scores (PIPP-R) and motor reflex withdrawal activity compared with a placebo (inactive solution) following a clinically-essential heel lance compared with a placebo (inactive solution).


    To test whether administration of morphine is safe by determining whether it results in episodes of respiratory depression or hypotension that require intervention compared with a placebo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The study will be conducted in the neonatal unit at the John Radcliffe Hospital, Oxford.

    Inclusion Criteria
    • Participants will be in-patients on the neonatal unit at the John Radcliffe Hospital, Oxford.
    • Infants born less than 32 weeks’ gestation or birth weight <1501 g
    • At the time of study, infants will be between 34 and 42 weeks gestational age (GA) and will be studied if they require a clinical heel lance and retinopathy of prematurity (ROP) screening on the same test occasion. We will study infants during a single test occasion when they are greater than or equal to 34 weeks’ gestation.
    Infants for whom parents/guardians have given written informed consent for inclusion in the trial.
    Parents/guardians have consented to inclusion in the trial.Senior clinician considers inclusion in trial to be medically appropriate.
    E.4Principal exclusion criteria
    Exclusion Criteria:

    • intraventricular haemorrhage > grade II
    • short bowel syndrome
    • receiving nil by mouth due to documented gut pathology
    • received opiates in the last 72 hours
    • received other analgesics or sedatives in the last 24 hours
    • previously documented episode of morphine sensitivity
    • congenital malformation or genetic condition known to affect neurological development
    • born to mothers who regularly use opiates during pregnancy or while breastfeeding or expressing breast milk.
    E.5 End points
    E.5.1Primary end point(s)
    Primary outcome measure: Clinical pain score (PIPP-R) score 30seconds after ROP screening.
    Co-primary outcome measure: Magnitude of nociceptive-specific brain activity evoked by heel lance.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary outcome measure: 30 seconds after ROP screening
    Co-primary outcome measure: Immediately following heel lance
    E.5.2Secondary end point(s)
    (1) Clinical stability in the 6-hour and 24-hour period following the start of the clinical intervention (heel lance followed by ROP screening). (Clinical stability assessment is calculated from pulse oximetry and blood pressure recordings and the need for increased respiratory support.)

    (2) Premature infant pain profile-Revised (PIPP-R) score and amplitude of reflex withdrawal following heel lance.

    (3) Drug safety will be assessed by calculating the number of incidences of apnoea that require intervention using NeoPuff or ‘bag and mask’ and the number of incidences of hypotension that requires treatment with inotropes in the 24-hour period following the administration of the IMP or placebo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    (1) Clinical stability: 24-hours after ROP screening.

    (2) Premature infant pain profile-revised (PIPP-R) score and amplitude of reflex withdrawal: immediately following heel lance.

    (3) Drug safety: 24-hour period following the administration of the IMP or placebo.
    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 No
    E.6.5Efficacy No
    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 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.8.4.1Number of sites anticipated in Member State concerned1
    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
    The end of the trial is defined as the point after data has been collected from the last participant in the study and once the database has been locked.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days16
    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: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F.1.1.2.1Number of subjects for this age range: 78
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 78
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    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 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 state156
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 156
    F.4.2.2In the whole clinical trial 156
    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)
    Routine care will continue to be provided in the Neonatal Unit after the 48 hour trial period.
    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 Thames Valley CLRN
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-08-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-03-15
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