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    Summary
    EudraCT Number:2016-004419-11
    Sponsor's Protocol Code Number:SC35
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-12-08
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2016-004419-11
    A.3Full title of the trial
    Safety and efficacy of interleukin-1 inhibitor anakinra for the amelioration of fever during neutropenia and mucositis in patients with multiple myeloma receiving an autologous hematopoietic stem cell transplantation after high-dose melphalan.
    Veiligheid en effectiviteit van interleukine-1-remmer anakinra ter preventie van mucositis en koorts tijdens neutropenie bij patiënten met multipel myeloom die een autologe stamceltransplantatie ondergaan na hoge-dosis melfalan.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Anakinra as prevention of mucositis and fever in patients with a stem cell transplantation
    Anakinra ter preventie van darmslijmvliesontsteking en koorts bij patiënten met een stamceltransplantatie
    A.3.2Name or abbreviated title of the trial where available
    AFFECT-1
    AFFECT-1
    A.4.1Sponsor's protocol code numberSC35
    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 SponsorRadboud university medical center
    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 supportRadboud Institute of Health Sciences
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRadboud university medical center
    B.5.2Functional name of contact pointTrialbureau Hematologie-Oncologie
    B.5.3 Address:
    B.5.3.1Street AddressGeert Grooteplein Zuid 8
    B.5.3.2Town/ cityNijmegen
    B.5.3.3Post code6525 GA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31243614794
    B.5.5Fax number+31243668205
    B.5.6E-mailtrialbureauhemat-onco@radboudumc.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 Kineret
    D.2.1.1.2Name of the Marketing Authorisation holderSwedish Orphan Biovitrum AB
    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.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNANAKINRA
    D.3.9.1CAS number 143090-92-0
    D.3.9.2Current sponsor codeANAKINRA
    D.3.9.3Other descriptive nameANAKINRA
    D.3.9.4EV Substance CodeSUB05500MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Mucositis and febrile neutropenia
    Mucositis en febriele neutropenie
    E.1.1.1Medical condition in easily understood language
    Inflammation of the lining (mucosa) of the digestive tract
    Fever during neutropenia
    Darmslijmvliesontsteking
    Koorts tijdens neutropenie
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10028127
    E.1.2Term Mucositis
    E.1.2System Organ Class 100000004867
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10016288
    E.1.2Term Febrile neutropenia
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the safety and efficacy of anakinra in patients with multiple myeloma receiving high-dose melphalan (HDM) in the preparation for an autologous hematopoietic stem cell transplantation (SCT).
    Het primaire doel van het onderzoek is om de veiligheid en effectiveiteit van anakinra te onderzoeken bij patiënten met een multipel myeloom, die behandeling met hoge-dosis melfalan (HDM) ontvangen in de voorbereiding voor een autologe stamceltransplantatie.
    E.2.2Secondary objectives of the trial
    Secondary objectives are the gathering of blood and microbiota samples for translational research.
    Secundaire doelen zijn het verkrijgen van bloed- en microbiota-monsters voor translationeel onderzoek.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Aged ≥ 18 years
    - Diagnosed with multiple myeloma
    - Scheduled to receive an autologous SCT after myeloablative therapy with high-dose melphalan
    - Managed with a central venous catheter (triple- or quadruple lumen)
    - Is able and willing to participate
    - Has provided written informed consent
    - Has a negative tuberculosis Quantiferon test
    - Has negative serology for active hepatitis B and C
    - Has negative serology for HIV
    - Has no known hypersensitivity to Escherichia coli derived products or any components of anakinra
    - Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation (during treatment with study medication), and for 30 days after the last dose.
    - Leeftijd ≥ 18 jaar
    - Gediagnosticeerd met multipel myeloom
    - Gepland om een autologe stamceltransplantatie te ontvangen na myeloablatieve therapie met hoge-dosis melfalan
    - Wordt behandeld via centraal veneuze catheter (CVC) (triple- of quadruple lumen)
    - Kan en wil deelnemen
    - Schriftelijk informed consent
    - Heeft een negatieve tuberuclose-Quantiferon-test
    - Heeft negatieve serologie voor actieve Hepatitis B en C
    - Heeft negatieve HIV-serologie
    - Heeft geen bekende overgevoeligheid voor eiwitten geproduceerd met behulp van Escherichia coli of andere componenten van anakinra
    - Vrouwen in de vruchtbare leeftijd en mannen moeten akkoord gaan met het gebruiken van adequate anticonceptie (hormoon- of barrière-methode, abstinentie) voorafgaand aan inclusie, tijdens deelname (tijdens behandeling met studiemedicatie) en tot 30 dagen na de laste dosis.
    E.4Principal exclusion criteria
    - Inability to understand the nature and extent of the trial and the procedures required
    - Enrolment in any other investigational treatment study or use of an investigational agent during the stem cell transplantation (this means studies in multiple myeloma regarding induction or maintenance treatment are permitted).
    - Women who are pregnant or nursing
    - Diagnosed with amyloidosis or light-chain deposition disease
    - ALT or AST greater than 2.0 x upper limit of normal (ULN) of the local laboratories values.
    - Bilirubin levels greater than 2.0 x upper limit of normal (ULN) of the local laboratories values, except for benign non-malignant indirect hyperbilirubinemia such as Gilbert syndrome
    - Impaired renal function with eGFR <40 ml/min
    - Received a live vaccine during the 3 months prior to baseline visit
    - Recent use of IL-1 inhibitor, such as anakinra, rilonacept or canakinumab, within three months prior to baseline visit
    - Treatment with TNF inhibiting agents (such as etanercept, adalimumab, infliximab, certolizumab and golimumab).
    - Uncontrolled bacterial or viral infections, or fungal infections, at the start of therapy
    - Documented colonization with highly resistant microorganisms (HRMOs, in Dutch: BRMO’s), prior to registration, or detected during screening procedures
    - Documented colonization with methicillin-resistant Staphylococcus aureus (MRSA), prior to registration
    - Subjects who are not able to receive antibacterial prophylaxis with quinolones (because of hypersensitivity)
    - Subjects with an active solid malignancy prior to registration, with the exception of cutaneous basal or squamous cell carcinomas
    - History of mycobacterial infection.
    - Subjects with intrinsic disorders of the gastro-intestinal (GI) tract, including, but not limited to: Crohn’s disease, ulcerative colitis, celiac disease, short bowel syndrome.
    - Subject has any concurrent medical or psychiatric condition or disease that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
    - Onvermogen tot het begrip van de aard en omvang van het onderzoek en de vereiste procedures
    - Deelname in een andere studie met onderzoeksbehandeling of gebruik van onderzoeksmedicatie tijdens de periode van stamceltransplantatie (dit betekent dat multipel myeloom-studies over inductie- of onderhoudsbehandeling zijn toegestaan)
    - Vrouwen die zwanger zijn of borstvoeding geven
    - Gediagnosticeerd met amyloïdose of light-chain deposition disease
    - ALAT of ASAT hoger dan 2,0 x de bovengrens van normaal van lokale laboratoriumwaarden
    - Bilirubine hoger dan 2,0 x de bovengrens van normaal van de lokale laboratoriumwaarden, uitgezonderd benigne indirecte hyperbilirubinemie zoals het syndroom van Gilbert
    - Verminderde nierfunctie met eGFR <40 ml/min
    - Heeft een levend-verzwakt vaccin ontvangen in de 3 maanden voor baseline
    - Recent gebruik van IL-1-remmer, zoals anakinra, reilonacept of canakinumab, in de 3 maanden voor baseline
    - Behandeling met TNF-alfa-remmers (zoals etancercept, adalimumab, infliximab, certolizumab en golimumab)
    - Ongecontroleerde bacteriële of virale infecties, of infecties met schimmels, voorafgaand aan de behandeling
    - Gedocumenteerde kolonisatie met bijzonder resistente micro-organismen (BRMO’s) voorafgaand aan registratie, of vastgesteld tijdens screening
    - Gedocumenteerde kolonisatie met methicilline-resistente Staphylococcus aureus (MRSA), voorafgaand aan registratie
    - Personen die geen antibacteriële profylaxe met quinolonen kunnen ontvangen (vanwege overgevoeligheid)
    - Personen met een actieve solide maligniteit voorafgaand aan registratie, uitgezonderd cutane basaalcel- of plaveiselcelcarcinomen
    - Mycobacteriële infectie in de voorgeschiedenis
    - Personen met intrinsieke aandoeningen van het maag-darmkanaal, waaronder de ziekte van Crohn, colitis ulcerosa, coeliakie en short bowel syndrome.
    - Personen met een gelijktijdige medische of psychiatrische aandoening die waarschijnlijk zal interfereren met de studieprocedures of –resultaten, of die naar de mening van de onderzoeker een gevaar zouden vormen voor deelname aan de studie
    E.5 End points
    E.5.1Primary end point(s)
    Establish the safety of anakinra as well as the maximum tolerated dose (MTD).
    Het vaststellen van de veiligheid van anakinra, evenals de maximaal getolereerde dosis.
    E.5.1.1Timepoint(s) of evaluation of this end point
    DLTs will be evaluated during and after treatment of every subject. Overall safety and maximum tolerated dose will be evaluated at the end of the study.
    DLT's worden geëvalueerd tijdens en na behandeling van elke proefpersoon. Algehele veiligheid en de maximaal getolereerde dosis worden aan het eind van de studie geëvalueerd.
    E.5.2Secondary end point(s)
    - Incidence of fever during neutropenia
    - Incidence of mucositis-related fever
    - Maximum CRP level on day +9-10
    - Daily mean CRP level
    - Intestinal mucositis as measured by the area-under-the-curve of reciprocal citrulline levels
    - Clinical mucositis as determined by the daily mouth and gut scores
    - Days with fever ((≥ 38.2° C)
    - Days with fever (≥ 38.5° C)
    - Mean daily morning temperature
    - Area under the curve of daily morning temperature
    - Incidence of bloodstream infections i.e. bacteremia
    - Type of bloodstream infections
    - Incidence of persistently positive blood cultures on day +4
    - Quality of life according to the EORTC QLQ-C30
    - Severity of fatigue as the score measured by the validated FACIT-Fatigue scale
    - Short term overall survival (100 days and 1 year)
    - Length of hospital stay in days
    - Use of systemic antimicrobial agents (incidence and duration)
    - Use of analgesic drugs (incidence and duration)
    - Use of total parenteral nutrition (TPN) (incidence and duration)
    - De incidentie van febriele neutropenie
    - De incidentie van mucositis-gerelateerde koorts
    - Het maximale CRP-niveau op dag +9-10
    - Het dagelijks gemiddelde CRP-niveau
    - Intestinale mucositis zoals gemeten via de area-under-the-curve van reciproke citrulline-niveau's
    - Klinische mucositis zoals vastgesteld m.b.v. de daily mouth score en daily gut score.
    - Dagen met koorts (≥ 38,2° C)
    - Dagen met koorts (≥ 38,5° C)
    - Gemiddelde dagelijkse ochtendtemperatuur
    - Incidentie van bloedbaan-infecties (bacteriëmie)
    - Type bacteriëmieën
    - Incidentie van aanhoudend positieve bloedkweken op dag +4
    - Kwaliteit van leven volgens de EORTC quality of life-questionnaire (QLQ) C30
    - Ernst van vermoeidheid volgens de score van de FACIT-Fatigue-vragenlijst
    - Korte-termijnsoverleving (100 dagen en 1 jaar)
    - Duur van ziekenhuisopname
    - Gebruik van systemische antimicrobiële middelen (incidentie en duur)
    - Gebruik van pijnstilling (incidentie en duur)
    - Gebruik van totale parenterale voeding (incidentie en duur)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety-related endpoints will be evaluated after treatment is completed. Other endpoints will be evaluated after all subjects have finished that part of the study.
    Eindpunten gerelateerd aan veiligheid worden geëvalueerd nadat de behandeling is afgerond. Overige eindpunten worden geëvalueerd nadat alle proefpersonen dat deel van de studie hebben afgerond.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    open, dose-finding trial
    open, dose-finding trial
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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
    Last visit of the last subject (LVLS)
    Laatste polikliniek-bezoek van laatste proefpersoon.
    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 months3
    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: 18
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 18
    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 state18
    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.
    Geen.
    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 Decision2016-12-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-04-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-04-02
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