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    Summary
    EudraCT Number:2019-001771-36
    Sponsor's Protocol Code Number:CHDR1755
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-06-13
    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 number2019-001771-36
    A.3Full title of the trial
    Assessment of Neublastin-Induced Skin and Sensory Alterations and Headache in Healthy Subjects and Migraine Patients
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Neublastin Challenge in Healthy Subjects and Migraine Patients
    A.4.1Sponsor's protocol code numberCHDR1755
    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 SponsorCentre for Human Drug Research
    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 supportRegeneron Pharmaceuticals, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCentre for Human Drug Research
    B.5.2Functional name of contact pointPrincipal Investigator
    B.5.3 Address:
    B.5.3.1Street AddressZernikedreef 8
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 CL
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715246400
    B.5.5Fax number+31715246499
    B.5.6E-mailclintrials@chdr.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 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 nameNeublastin
    D.3.2Product code BG00010
    D.3.4Pharmaceutical form Solution for 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 INNNEUBLASTIN
    D.3.9.3Other descriptive nameNEUBLASTIN
    D.3.9.4EV Substance CodeSUB119427
    D.3.10 Strength
    D.3.10.1Concentration unit µg/kg microgram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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) Yes
    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 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.IMP: 2
    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 nameNeublastin
    D.3.2Product code BG00010
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntradermal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNEUBLASTIN
    D.3.9.3Other descriptive nameNEUBLASTIN
    D.3.9.4EV Substance CodeSUB119427
    D.3.10 Strength
    D.3.10.1Concentration unit µg/kg microgram(s)/kilogram
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1 to 20
    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) Yes
    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 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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    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 placeboIntradermal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Migraine
    E.1.1.1Medical condition in easily understood language
    Migraine
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10027599
    E.1.2Term Migraine
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objectives
    1. To assess pruritus and rash after administration of Neublastin or placebo in healthy subjects and migraine patients (Parts A and B)
    2. To assess headache and other migraine-associated symptoms after administration of Neublastin or placebo in migraine patients (Part B)

    E.2.2Secondary objectives of the trial
    Secondary Objectives
    1. To assess Neublastin-induced mechanical and thermal sensory responses using nociceptive thresholds in healthy subjects and migraine patients (Parts A and B)
    2. To assess headache and other migraine-associated symptoms in healthy subjects upon administration of Neublastin or placebo (Part A)
    3. To assess changes in temperature perception upon administration of Neublastin or placebo in healthy subjects and migraine patients (Parts A and B)
    4. To characterize the pharmacokinetics (PK) profile of a single 50 µg/kg IV dose of Neublastin in healthy subjects and in migraine patients (Parts A and B)
    5. To characterize the safety and tolerability of a single 50 µg/kg IV dose of Neublastin in healthy subjects and in migraine patients (Parts A and B)
    6. To characterize the safety and tolerability of Neublastin administered intradermally (ID) in healthy subjects (Part A)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female from 18 to 55 years of age (inclusive) at screening visit.
    3. Body mass index (BMI) between 18 and 32 kg/m2, inclusive at screening, with a minimum weight of 50 kg at screening.
    4. Subject is judged by the investigator to be in good health based on medical history (except for migraine in patients participating in Part B) based on all available data prior to administration of initial dose of study drug.
    7. Able and willing to provide signed informed consent prior to any study-mandated procedure.

    Additional inclusion criteria Part B (episodic migraine patients):
    9. History of episodic migraine headaches with or without aura for ≥6 months as determined by a diagnosis provided by a neurologist.
    10. Migraine headaches should either fulfil criteria A and B for migraine without aura or criterion C (“Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition,” 2018).
    A. Headache has at least 2 of the following characteristics:
    • unilateral location
    • pulsating quality
    • moderate or severe pain intensity (≥4 on headache questionnaire)
    • aggravation by or causing avoidance of routine physical activity
    B. Experiences at least 1 of the following during headache:
    • nausea and/or vomiting
    • photophobia and phonophobia
    C. Headache described as mimicking usual migraine attack treated with triptan;
    11. Migraine frequency: ≥1 and ≤5 migraine days per month in each of the 3 months prior to screening.
    12. Migraine headaches should be responsive to treatment with non-steroidal anti-inflammatory agents (NSAIDs) and/or triptans.
    E.4Principal exclusion criteria
    1. History of clinically significant cardiovascular, immunological, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, dermatologic, neurological (except for migraine for patients in Part B) or psychiatric disease, as assessed by the investigator that may confound the results of the study or pose an additional risk to the subject by participation in the study.
    2. History of arterial or venous thrombotic or thromboembolic disease.
    3. History of stroke or transient ischemic attack.
    5. Recent history (within 1 year prior to screening) or presence of a clinically significant chronically painful condition or recent and unresolved acutely painful condition, except for migraine in Part B.
    6. History of drug or alcohol abuse (>14 units of alcohol per week) within a year prior to the screening visit.
    11. Use of anti-platelet or anti-coagulation therapy, including but not limited to daily aspirin (except for 81 mg daily doses), clopidogrel, prasugrel, ticagrelor, enoxaparin, apixaban, warfarin.
    14. Presence of HIV (HIV Ab), hepatitis B (HBsAg, HBAb) or Hepatitis C (HCV Ab) seropositivity at screening.
    15. Any malignancy within the past 5 years, except for basal cell or squamous epithelial carcinomas of the skin or carcinoma in situ of the cervix or anus, that have been resected, with no evidence of metastatic disease for 3 years.
    25. Use of concomitant medications, including non-prescription medication, nutritional and herbal supplements within 14 days or 5 and ½ half-lives (whichever is longer) prior to initial dose of study drug, except incidental use of paracetamol.
    Additional key exclusion criteria Part B (migraine patients):
    28. Greater than or equal to 6 migraine days per month in each of the last 3 months prior to screening.
    29. Other headache disorders (except for episodic tension-type headache <5 days/month).
    30. Greater than or equal to 5 headache days per month of any type/diagnosis (except migraine) in each of the last 3 months prior to screening.

    E.5 End points
    E.5.1Primary end point(s)
    Safety and tolerability endpoints
    Parts A and B, IV administration
    • The incidence of treatment-emergent serious adverse events throughout the duration of the study in healthy subjects and migraine patients challenged with a single 50 µg/kg IV dose of Neublastin compared to placebo
    Part A, ID administration
    • The incidence of treatment-emergent serious adverse events throughout the duration of the study in healthy subjects challenged with Neublastin or placebo administered ID

    Pharmacokinetic endpoints
    Parts A and B, IV administration
    The PK variable is the concentration of Neublastin in serum at each time point that sample is collected.
    6.3 Pharmacodynamic endpoints
    All parameters will be compared to baseline; baseline is defined as the last value prior to dosing.

    Primary Endpoints - Parts A and B
    Assessment of pruritus
    • The incidence of pruritus in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by items 1 and 2 on the Pruritus Assessment questionnaire
    • The severity of pruritus in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by item 3 (Pruritus Average NRS) and item 4 (Peak Pruritus NRS) on the Pruritus Assessment questionnaire
    • The duration of pruritus in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by item 1 on the 5-D Pruritus Scale questionnaire
    Assessment of rash
    • The incidence of rash in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Rash Assessment questionnaire
    • The area and severity of rash in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Eczema Area and Severity Index (EASI)
    • The area and severity of rash in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by patient-reported SCORing Atopic Dermatitis (PO SCORAD) score
    • Qualitative assessments of rash in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as observed from digital photography of rash
    • The incidence and severity of erythema in healthy subjects and migraine patients over a 28 day period after challenge with Neublastin or placebo (IV and ID) as measured by the Erythema index

    Primary Endpoints - Part B
    Assessment of headache in migraine patients
    • The incidence of headache in migraine patients over a 28-day period after challenge with Neublastin or placebo (IV) as measured by the Headache Assessment questionnaire
    • The severity (peak measurement) of headache in migraine patients over a 28 day period after challenge with Neublastin or placebo (IV) as measured by the Headache Assessment questionnaire
    • The duration of headache in migraine patients over a 28-day period after challenge with Neublastin or placebo (IV) as measured by the Headache Assessment questionnaire
    • The incidence of migraine-associated symptoms in migraine patients over a 28-day period after challenge with Neublastin or placebo (IV) as measured by the Headache Assessment questionnaire


    E.5.1.1Timepoint(s) of evaluation of this end point
    Day - 1 - EOS
    E.5.2Secondary end point(s)
    Secondary Endpoints - Parts A and B
    Nociceptive thresholds
    • The pain detection threshold (PDT) for heat-induced pain in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID)
    • The PDT for cold-induced pain in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID)
    • The PDT for pressure pain in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo as measured by using a local algometer for the ID group and a pressure cuff for the IV group
    • The pain tolerance threshold (PTT) for pressure pain in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo as measured by using a local algometer for the ID group and a pressure cuff for the IV group
    • The area of secondary hyperalgesia in healthy subjects over a 28 day period after challenge with Neublastin or placebo, for ID administration only, as measured by the Von Frey test
    Abnormal temperature perception
    • The incidence of abnormal temperature perception in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Abnormal Temperature Perception Assessment
    • The severity of abnormal temperature perception in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo as measured by the Abnormal Temperature Perception Assessment
    • The duration of abnormal temperature perception in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo as measured by the Abnormal Temperature Perception Assessment
    Pharmacokinetics
    • The concentration of Neublastin in serum after a single 50 µg/kg IV dose of Neublastin in healthy subjects and migraine patients at each time point that sample is collected
    Safety
    • The incidence of treatment-emergent serious adverse events throughout the duration of the study in healthy subjects and migraine patients challenged with a single 50 µg/kg IV dose of Neublastin compared to placebo

    Secondary Endpoints - Parts A
    Headache assessment in healthy subjects
    • The incidence of headache in healthy subjects over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Headache Assessment questionnaire
    • The severity (peak measurement) of headache in healthy subjects over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Headache Assessment questionnaire
    • The duration of headache in healthy subjects over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Headache Assessment questionnaire
    • The incidence of migraine-associated symptoms in healthy subjects over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Headache Assessment questionnaire
    Safety
    • The incidence of treatment-emergent serious adverse events throughout the duration of the study in healthy subjects challenged with Neublastin or placebo administered ID
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day - 1 - EOS
    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 Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Challenge-model
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Challenge model
    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 No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 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 years
    E.8.9.1In the Member State concerned months8
    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: 48
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state48
    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 Decision2019-06-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-16
    P. End of Trial
    P.End of Trial StatusOngoing
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