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    Summary
    EudraCT Number:2015-001195-21
    Sponsor's Protocol Code Number:SFK3
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-07-08
    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 ConcernedNorway - NOMA
    A.2EudraCT number2015-001195-21
    A.3Full title of the trial
    NoTOPain

    Novel Treatment Option for neuropathic Pain

    A randomized, cross-over, placebo-controlled, double-blind, single-center, phase II study of cetuximab in patients with treatment-refractory, non-malignant severe chronic neuropathic pain.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Erbitux against neuropathic pain
    A.3.2Name or abbreviated title of the trial where available
    NoTOPain
    A.4.1Sponsor's protocol code numberSFK3
    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 SponsorSørlandet Hospital
    B.1.3.4CountryNorway
    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 supportMerck Serono
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSørlandet Hospital
    B.5.2Functional name of contact pointChristian Kersten
    B.5.3 Address:
    B.5.3.1Street AddressPb 416
    B.5.3.2Town/ cityKristiansand
    B.5.3.3Post code4604
    B.5.3.4CountryNorway
    B.5.4Telephone number+4791339443
    B.5.6E-mailchristian.kersten@sshf.no
    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 Erbitux
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Serono
    D.2.1.2Country which granted the Marketing AuthorisationNorway
    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 nameErbitux
    D.3.4Pharmaceutical form Solvent for solution for 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 No
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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 placeboSolvent for solution for infusion
    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
    Neuropathic pain conditions, i.e. radiculopathy or Complex regional pain syndrome
    E.1.1.1Medical condition in easily understood language
    Neuropathic pain
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    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 is to determine whether a single infusion of cetuximab compared to placebo is effective in significantly reducing average daily neuropathic pain score measured over 5 days in patients with defined neuropathic pain.
    E.2.2Secondary objectives of the trial
    • To determine the number of patients who achieve 30% and 50% reductions (following cetuximab vs. placebo) of average daily neuropathic pain scores, measured over 5 days, compared to baseline.
    • To determine the difference in the average worst daily neuropathic pain score (following cetuximab vs. placebo), measured over 5 days, compared to baseline.
    • To determine the number of patients who achieve 30% and 50% reductions (following cetuximab vs. placebo) of average daily worst neuropathic pain scores, measured over 5 days, compared to baselinepatients.
    • Comparison of patient satisfaction with cetuximab and placebo for NP seven days after each infusion, using the Patient Global Impression of Change (PGICS) as the endpoint measure.
    • Comparison of overall mean reduction in BPI interference scores and total BPI scores (following cetuximab vs. placebo), compared to baseline.
    • To document safety and toxicity of cetuximab compared with placebo in patients with NP.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    All of the following conditions must apply for inclusion:

    • Signed informed consent and anticipated compliance with the treatment and study follow-up according to ICH GCP, and national/local regulations.
    • Pain defined as “definite” neuropathic pain, according to the Special Interest Group on Neuropathic Pain (NeuPSIG) guidelines or defined as “probable” NP, according to the NeuPSIG guidelines, if the confirmatory test (see figure 2) was a positive diagnostic test, i.e. positive finding on radiologic or neurophysiological testing. Complex regional pain syndrome (CRPS) can be included despite lack of an offending lesion, as long as the “Budapest criteria”1 are fulfilled:
    Clinical diagnostic criteria for complex regional pain syndrome
    1) Continuing pain, which is disproportionate to any inciting event
    2) Must report at least one symptom in three of the four following categories:
    Sensory: Reports of hyperalgesia and/or allodynia
    Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry
    Sudomotor/Edema: Reports of edema and/or sweating changes and/or sweating asymmetry
    Motor/Trophic: Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
    3) Must display at least one sign at time of evaluation in two or more of the following categories
    Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement)
    Vasomotor: Evidence of temperature asymmetry and/or skin color changes and/or asymmetry
    Sudomotor/Edema: Evidence of edema and/or sweating changes and/or sweating asymmetry
    Motor/Trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
    4) There is no other diagnosis that better explains the signs and symptoms.

    • Neuropathic Pain associated with compressive nerve states (including failed surgery) or CRPS (according to the “Budapest criteria”1
    • Pain Detect score of at least 13 with average pain intensity of at least 6 /10 over the last four weeks. In addition, a pain DETECT pattern indicating that the underlying NP is constantly present.
    • Worst pain intensity higher than 6 for five of seven days during the screening phase, according to BPI-sf as assessed by the referring physician.
    • The patient should be able to distinguish between the neuropathic pain and other pain conditions, including elements of nociceptive pain caused by the same disease process.
    • NP duration of between six and thirty months, deemed chronic and likely to be irreversible by clinical history and findings.
    • No new or increased neuropathic pain treatment for the last four weeks.
    • Standard medical treatments for the patients’ underlying condition or neuropathic pain must have been considered or tried and must, according to the opinion of the referring or a consulted pain specialist, be judged to be inappropriate or of insufficient potential efficacy.
    • Referring physician agreement to follow up the patient after study completion according to the best possible and available pain treatment and care.
    • Women of childbearing potential (WOCBP) and men must use an acceptable method of contraception# throughout the study, and for 30 days after the last study drug administration.
    • WOCBP must have a negative pregnancy blood (hCG) test within 7 days before each treatment period.
    • White blood cell count ≥ 3 × 109 with neutrophils ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L and hemoglobin ≥ 6.21 mmol/L (10 g/dL). Total bilirubin ≤ 1.5 × upper limit of reference range and AST and ALT ≤ 2.5 × upper limit of reference range within the last 28 days before inclusion.
    • Aged 18 or above
    E.4Principal exclusion criteria
    Patients will be excluded from the study if they meet any of the following criteria:

    • Neuropathic pain origin in the central nervous system.
    • Phantom limb pain or a significant component of nociceptive pain.
    • Ascending distal small fiber peripheral neuropathy.
    • Patients primarily experiencing pain ‘attacks’, i.e. pattern of neuropathic pain depicted in picture 3 of the painDETECT scheme.
    • Other pain state that may interfere with evaluation of the studied neuropathic pain condition.
    • Any underlying medical or psychiatric condition, clinical disorder or laboratory finding, which in the opinion of the investigator may interfere with study objectives.
    • Uncontrolled or unstable diabetes.
    • Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV), unstable angina pectoris, history of myocardial infarction within the last twelve months, significant arrhythmias
    • Severe cerebrovascular disease during the six months prior to inclusion.
    • Active and ongoing eye and skin disorders or newly diagnosed gastric ulcer that may interfere with the study treatment.
    • History of allergic reaction to any of the study treatment components, red meat or tick bites.
    • Previous treatment with any EGFR-pathway inhibitor.
    • Women who are pregnant or breastfeeding.
    • Participation in another clinical trial within the past 90 days.
    • Use of any investigational agent within 90 days prior to day 1 of study drug.
    • Known drug abuse/alcohol abuse, legal incapacity or limited legal capacity or any other reason that, in the opinion of the investigator precludes the subject from participating.
    E.5 End points
    E.5.1Primary end point(s)
    Mean difference in average daily pain scores
    E.5.1.1Timepoint(s) of evaluation of this end point
    4-8 days after infusion
    E.5.2Secondary end point(s)
    Number of patients who achieve 30% and 50% reductions (following cetuximab vs. placebo) of average daily neuropathic pain scores.
    E.5.2.1Timepoint(s) of evaluation of this end point
    4-8 days after infusion
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Prognostic markers
    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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months12
    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: 14
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 14
    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 state14
    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)
    We have planned an open-label infusion of Erbitux in the end of the trial and intend to guide the referring physician according to further treatment, dependent on the effect of Erbitux for the given patient.
    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 Decision2015-10-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-29
    P. End of Trial
    P.End of Trial StatusCompleted
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