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    Summary
    EudraCT Number:2015-002624-31
    Sponsor's Protocol Code Number:NL53861.068.15
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-11-16
    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 number2015-002624-31
    A.3Full title of the trial
    Intravenous immunoglobulin therapy for small fiber neuropathy: a randomised, double-blind, placebo-controlled study on efficacy and safety.
    Intraveneuze immunoglobulinen voor de behandeling van dunnevezelneuropathie: een gerandomiseerde, dubbelblinde, placebo-gecontroleerde studie naar effectiviteit en veiligheid.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Intravenous immunoglobulin therapy for small fiber neuropathy: a randomised, double-blind, placebo-controlled study on efficacy and safety.
    Intraveneuze immunoglobulinen voor de behandeling van dunnevezelneuropathie: een gerandomiseerde, dubbelblinde, placebo-gecontroleerde studie naar effectiviteit en veiligheid.
    A.3.2Name or abbreviated title of the trial where available
    IVIg in SFN
    IVIg bij DVN
    A.4.1Sponsor's protocol code numberNL53861.068.15
    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 SponsorMaastricht UMC
    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 supportGrifols
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMaastricht UMC
    B.5.2Functional name of contact pointC.G. Faber
    B.5.3 Address:
    B.5.3.1Street AddressP. Debyelaan 25
    B.5.3.2Town/ cityMaastricht
    B.5.3.3Post code6202 AZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031433877059
    B.5.5Fax number0031433877055
    B.5.6E-mailc.faber@mumc.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 Gamunux 10%
    D.2.1.1.2Name of the Marketing Authorisation holderGrifols
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameGamunex
    D.3.2Product code 726788
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    Intravenous 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) 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) Yes
    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 placeboSolution 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
    Skin-biopsy proven small fiber neuropathy without an underlying cause
    Huidbiopt bewezen dunnevezelneuropathie zonder bekende onderliggende oorzaak.
    E.1.1.1Medical condition in easily understood language
    Skin-biopsy proven small fiber neuropathy without an underlying cause
    Huidbiopt bewezen dunnevezelneuropathie zonder bekende onderliggende oorzaak.
    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
    To evaluate the efficacy of IVIg treatment (4 courses of treatment, 3 weeks apart) compared to placebo by assessing changes on the mean weekly level of peak pain intensity (PI-NRS) compared to baseline scores.
    Evaluatie van de effectiviteit van IVIG behandeling (4 behandelingen, 3 weken ertussen) in vergelijking met een placebo, door the kijken naar het verschil in het gemiddelde wekelijkse niveau van de maximale pijn intensiteit (PI-NRS) in vergelijking met de baseline.
    E.2.2Secondary objectives of the trial
    Corneal confocal microscopy, pain intensity, pain qualities, and other SFN related complaints, daily and social functioning, as well as quality of life will be assessed.
    Safety: adverse events, vital signs and laboratory values outside the normal range
    Cornea confocale microscopie, pijnintensiteit, pijnkwaliteit en andere DVN gerelateerde klachten, dagelijks en sociaal functioneren en de kwaliteit van leven.
    Veiligheid: advese events, vitale kenmerken en laboratorium onderzoek buiten de normaalwaarden.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • 18 years or older.
    • Skin-biopsy proven idiopathic SFN or idiopathic painful neuropathy with predominantly SFN pattern
    • Pain intensity rated ≥ 5 on the PI-NRS (maximum pain) or on the neuropathic pain scale,36,37 question number 1 for at least 12 weeks before the study as declared by each patient to the best of their knowledge; if available, medical records of each patient will be consulted on the reported pain intensity.
    • Each subject will receive an information leaflet and an informed consent form. Subjects must give informed consent by signing and dating prior to study entry.
    • Eligible patients must be willing to complete all study-related activities and examination required by the protocol
    E.4Principal exclusion criteria
    • Are unable or unwilling to provide written informed consent.
    • Have predominant clinical picture of large nerve fiber involvement (i.e., weakness, loss of vibration sense, hypo-/areflexia).
    • Had treatment with IVIg or any other immunomodulatory/immunosuppressive agents (e.g., steroids) within the last 12 weeks prior to the date of informed consent.
    • Have an underlying cause of SFN (diabetes, SCN9A/10A/11A mutations, hypothyroidism, renal failure, vitamin B12 deficiency, monoclonal gammopathy, alcohol abuse (more than 5 IU/day), malignancies, drugs that cause neuropathy (e.g. chemotherapy, amiodarone, propafenone)).
    • Have a history of anaphylaxis or severe systemic response to immunoglobulin or with a blood product.
    • Have cardiac insufficiency (NYHA III/IV), cardiomyopathy, significant cardiac dysrhythmia requiring treatment, unstable or advanced ischemic heart disease, or history of congestive heart failure, severe hypertension (diastolic blood pressure >120 mmHg or systolic >170 mmHg).
    • Are females who are pregnant, breast-feeding, or if of childbearing potential, or unwilling to practice adequate contraception throughout the study.
    • Have known hyperviscosity.
    • Have a history of renal insufficiency or high serum creatinine levels (MDRD <30).
    • Have known selective IgA deficiency.
    • Have conditions whose symptoms and effects could alter protein catabolism and/or IgG utilization (e.g. protein-losing enteropathies, nephrotic syndrome).
    • Have a known hypercoagulable state.
    • Are mentally challenged adult subjects unable to give independent informed consent.
    • The use of pain (analgesic/anti-neuropathic) medication is allowed, but only if dosages are remained unchanged for at least 30 days prior to randomization. A change in dosage of these drugs will not be allowed throughout the study.
    E.5 End points
    E.5.1Primary end point(s)
    Comparison of the percentage of responder subjects between the two treatment groups from the first randomization during 12 weeks. A patient withdrawing from the study will be recorded as treatment failure for their randomization arm.
    E.5.1.1Timepoint(s) of evaluation of this end point
    During the complete length of the study (12 weeks)
    E.5.2Secondary end point(s)
    • The daily pain intensity (defined as the mean pain experienced during the day: from waking up to 6 pm), the nocturnal pain intensity (6 pm until waking up), and the average of these two will also be assessed using the PI-NRS, twice a week.51
    • Change of painful symptoms will be compared to baseline using the patients’ global impression of change (PGIC) on a 7-point Likert scale. Subsequent scores of the PGIC are 1) “worse than ever”; 2) “much worse”; 3) “little worse”; 4) “no change”; 5)”little improved”; 6) “much improved”; 7)”completely resolved”. “Completely resolved” and “much improved” are considered as a relevant improvement. Clinically relevant pain reduction on PGIC for pain will be defined as score 6 (“much improved”) or 7 (“completely resolved”).52,53
    • The Rasch-transformed 13 items SFN symptoms inventory questionnaire (RT-SFN-SIQ) highlights sensory symptoms, pain and autonomic complaints.16 Differences between the two arms will be examined using its score obtained after interval transformation using the Rasch method.54,55
    • The amount of pain medication used during the trial will be registered in the pain diary and will be used to compare the impact of the treatment versus placebo arms.
    • Patients will be requested to register (in a pain diary) the frequency and duration of occurrence and duration (in hours)) of non-medical rescue activities as well, such as using cooling/heating and forced resting.
    • Pain relief will also be captured on a daily basis using a 5-point Likert-scale: 0: no relief, 1: slight, 2: moderate, 3: good, and 4: complete relief. This is according to the IMMPACT recommendations.53
    • The neuropathic pain scale (NPS) will also be recorded to determine the various pain qualities.37
    • Daily Sleep Interference Scale (DSIS) will also be completed by subject twice a week on waking (11-point numerical scale ranging from 0 (pain does not interfere with sleep) to 10 (pain completely interferes with sleep)).
    • Rasch-built Overall disability Outcome Scale specifically designed for SFN (SFN-RODS): the SFN-RODS is the only clinimetrically evaluated scale at the activity and participation level for assessing outcome in this disorder. Its incorporation will be providing data on its possible responsiveness.56
    • The Short Form 36 Health Survey (SF-36) is a generic quality of life measure.
    E.5.2.1Timepoint(s) of evaluation of this end point
    During the complete length of the study (12 weeks)
    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 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) Yes
    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 Yes
    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.8.5The 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
    The subject is finished with the trial after 6 months. We will include 60 patients.
    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 months
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 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 state60
    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)
    Possibly that this treatment can be continued in the future.
    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 Decision2015-11-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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