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    Summary
    EudraCT Number:2012-005627-32
    Sponsor's Protocol Code Number:IIVOP
    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:2014-03-25
    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 number2012-005627-32
    A.3Full title of the trial
    A randomised, double blind, placebo controlled crossover study of the influence of the HCN channel blocker ivabradine in a healthy volunteer pain model - an enriched population study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The influence of ivabradine on the symptoms of neuropathic pain in a healthy volunteer pain model (IIVOP)
    A.3.2Name or abbreviated title of the trial where available
    The influence of ivabradine in a healthy volunteer pain model
    A.4.1Sponsor's protocol code numberIIVOP
    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 SponsorCambridge University Hospitals NHS Foundation Trust and the University of Cambridge
    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 supportMedical Research Council
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportServier
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCCTU Cambridge University Hospitals NHS Foundation Trust
    B.5.2Functional name of contact pointCarrie Bayliss
    B.5.3 Address:
    B.5.3.1Street AddressCambridge University Hospitals NHS Foundation Trust, Level 6 Coton House, Box 401,
    B.5.3.2Town/ cityAddenbrooke's Hospital, Hills Road, Cambridge
    B.5.3.3Post codeCB2 0QQ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01223348158
    B.5.5Fax number01223596471
    B.5.6E-mailcctu@addenbrookes.nhs.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 Yes
    D.2.1.1.1Trade name Procorolan
    D.2.1.1.2Name of the Marketing Authorisation holderLes Laboratories Servier
    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 nameIvabradine
    D.3.4Pharmaceutical form 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 INNIvabradine
    D.3.9.1CAS number 148849-67-6
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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 placeboTablet
    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
    Neuropathic Pain
    E.1.1.1Medical condition in easily understood language
    Nerve Pain
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10054095
    E.1.2Term Neuropathic pain
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    We will examine whether ivabradine reduces the intensity of sensitisation induced by capsaicin. Application of capsaicin cream to the skin causes a reddening of the skin, and an increased sensitivity within the area the cream is applied (the primary hyperalgesia area) and in surrounding areas (the secondary hyperalgesia area). Changes in sensitivity can be assessed using quantitative sensory testing (QST). This will be an enriched population study, meaning that we will only include participants who respond to capsaicin. This will be determined at the screening visit.

    The principle research objective is to investigate whether ivabradine reduces the area of secondary punctate mechanical hyperalgesia induced by capsaicin (a change in normal sensation to a von Frey hair or pin prick stimulator).
    E.2.2Secondary objectives of the trial
    The secondary research objectives will be to determine the effect of ivabradine on secondary hyperalgesia using a variety of other thresholds measured using quantitative sensory testing (QST).

    The intensity of capsaicin-induced flare will also be assessed using manual tracing, infrared thermography, or laser Doppler imaging.

    In the primary area we will assess the warm sensation threshold (WST) and the heat pain threshold (HPT). Other thresholds will be determined such as mechanical pain thresholds (MPT) using a weighted hair called a von Frey hair or a pinprick stimulator to apply increasing forces. Thermal and mechanical hyperalgesia will be determined as the change in threshold from baseline to post-capsaicin application, and compared between treatment arms.

    We will map the area of sensitivity as the area in which volunteers feel changes in normal sensation to light stroking with a cotton bud, soft brush or air puff (known as the area of mechanical allodynia).

    We will
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Volunteers who have given written informed consent to participate
    - Volunteers who can communicate fluently in English
    - Male or female
    - Aged 18-64 years
    - Absence of any chronic pain medicine
    - Volunteers in good general health, including a body mass index (BMI) in the range of 19-35
    - Volunteers with a normal resting 12-lead standard ECG including (measured for 1 minute on lead D2): normal sinus rhythm; 60 bpm ≤ HR on resting ECG; PR interval ≤ 210ms; QTcB ≤ 430ms for men and ≤ 450ms for women; QRS duration ≤ 120ms; the results of ECG recordings will be included in the CRF
    - Women of child bearing potential must use hormonal based contraception for the duration of the trial and 1 week following the end of their trial participation
    E.4Principal exclusion criteria
    - Volunteers with 1 arm
    - Pre-existing pain on either forearm
    - Previous surgery or tattoo on either forearm
    - History of disease associated with neuropathy
    - Volunteers who are allergic to ivabradine or capsaicin
    - History of personal or familial Long QT Syndrome
    - History of cardiac dysrhythmia
    - Use of CYP3A4 inhibitors such as ketoconazole, itraconazole, macrolide antibiotics and the anti-retrovirals nelfinavir, nefazodone and ritonavir.
    - Use of CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin or St John’s Wort etc.)
    - Use of QT interval prolonging medicinal products (e.g. quinidine, disopyramide or pimozide etc.)
    - Volunteers with any rash or broken skin on the arm where the capsaicin will be applied
    - Volunteers with lactose intolerance, as the placebo and ivabradine tablets contain lactose
    - Volunteers with a resting heart rate of 59 beats per minute or less at screening
    - Volunteers who are pregnant or breast feeding
    - Female volunteers of childbearing potential who refuse to use hormonal contraceptive measures for the duration of the trial as listed in section 11.5 of the protocol
    - Male volunteers who refuse to use adequate contraceptive measures for the duration of the trial as listed in section 11.5 of the protocol
    - Volunteers who have an underlying medical condition such as migraine or epilepsy which may affect the trial findings
    - Volunteers who smoke (≥5 cigarettes/day), take recreational drugs or consume more than the recommended allowance of alcohol units per week (21 units per week for males and 14 units per week for females)
    - Participants who are not willing to abstain from drinking beverages containing quinine, caffeine and/or xanthine for 24 hours prior to the trial visit
    - Volunteers who produce a positive result in a urine screen for drugs of abuse or who are known or suspected to be drug-dependent (sedatives, hypnotics, tranquilizers or any other addictive agent)
    - Volunteers who produce a positive result in an alcohol breath test
    - Volunteers currently participating in any interventional trial, have participated in an interventional trial within 16 weeks of screening or are currently participating in a non-interventional trial which participating in this trial would impact upon
    - Volunteers who, in the opinion of the PI, have a clinically relevant abnormality or medical history that is deemed to make the participant ineligible because of a safety concern.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the area of punctate mechanical hyperalgesia in capsaicin-responders.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Change from baseline value (pre-capsaicin) to post-capsaicin value on the screening capsaicin visit.

    Change from baseline value (pre-capsaicin) to post-capsaicin value (taken 1.5 hours following drug/placebo administration on the two trial visits)
    E.5.2Secondary end point(s)
    Endpoints will be summarised for all subjects from data obtained during the screening capsaicin session for standard reference values of capsaicin-induced hyperalgesia and comparison between capsaicin responders and non-responders. Endpoints will be summarised and compared between placebo and ivabradine treatment arms for data obtained during the two trial visits.

    • Pain score measured using a 100mm visual analogue scale (VAS)
    • Temperature thresholds in an area of sensitised skin including cold sensation threshold, warm sensation threshold, heat pain threshold and cold pain threshold. Thermal hyperalgesia will be determined as the change in threshold from baseline to post-capsaicin, and compared between treatment arms.
    • Mechanical thresholds in an area of sensitised skin including mechanical pain threshold. The magnitude of mechanical hyperalgesia will be determined as the change in threshold from baseline to post-capsaicin, and compared between treatment arms
    • The area of mechanical sensitisation determined using light brushing of the skin (tactile allodynia).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Change from baseline value (pre-capsaicin) to post-capsaicin value on the screening capsaicin visit.

    Change from baseline value (pre-capsaicin) to post-capsaicin value (taken 1.5 hours following drug/placebo administration on the two trial visits)
    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 Yes
    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 Yes
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Enriched population
    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.8.5.1Number of sites anticipated in the EEA1
    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
    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 months6
    E.8.9.1In the Member State concerned days1
    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 days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    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) Yes
    F.1.2.1Number of subjects for this age range: 72
    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 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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 24
    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)
    Not applicable
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-04-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-06-12
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2016-03-28
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