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    Summary
    EudraCT Number:2019-003948-71
    Sponsor's Protocol Code Number:D-FR-59011-002
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-10-21
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-003948-71
    A.3Full title of the trial
    AN INTEGRATED PHASE I/II, MULTICENTRE, DOUBLE-BLIND, RANDOMISED, DYSPORT AND PLACEBO-CONTROLLED, DOSE ESCALATION AND DOSE-FINDING STUDY TO EVALUATE THE SAFETY AND EFFICACY OF IPN59011 IN THE TREATMENT OF ADULT UPPER LIMB SPASTICITY
    Studio di fase I/II integrata, di intensificazione e di determinazione della dose, multicentrico, randomizzato, in doppio cieco, controllato verso Dysport e placebo per valutare la sicurezza e l’efficacia di IPN59011 nel trattamento della spasticità degli arti superiori in età adulta
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study investigating single injection of new botulinum toxin to determine safety and efficacy for treating spasticity in the upper limb
    Studio per determinare la sicurezza e l’efficacia di iniezioni singole di tossina botulinica per il trattamento della spasticità del tronco superiore
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberD-FR-59011-002
    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 SponsorIPSEN INNOVATION
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportIpsen Innovation
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIpsen Innovation
    B.5.2Functional name of contact pointNeuroscience Therapeutic Area, R&D
    B.5.3 Address:
    B.5.3.1Street AddressZ.I de Courtaboeuf, 5 Avenue du Canada
    B.5.3.2Town/ cityLes Ulis Cedex
    B.5.3.3Post code91940
    B.5.3.4CountryFrance
    B.5.4Telephone number0033160922000
    B.5.5Fax number0033160929461
    B.5.6E-mailct-application@ipsen.com
    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 nameIPN59011
    D.3.2Product code [IPN59011]
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeIPN59011
    D.3.10 Strength
    D.3.10.1Concentration unit ng nanogram(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 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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 RoleComparator
    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 Dysport
    D.2.1.1.2Name of the Marketing Authorisation holderIpsen Pharma
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameDysport
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTOSSINA BOTULINICA DI CLOSTRIDIUM BOTULINUM TIPO A
    D.3.9.1CAS number 93384-43-1
    D.3.9.2Current sponsor codeDysport
    D.3.9.4EV Substance CodeSUB77183
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typetoxin
    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 placeboPowder and solvent for solution for injection
    D.8.4Route of administration of the placeboIntramuscular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Upper limb spasticity after stroke or traumatic brain injury
    Spasticità del tronco superiore dopo infarto o danno cerebrale traumatico
    E.1.1.1Medical condition in easily understood language
    Medical condition where Upper limb muscles are tight or in spasm after stroke or traumatic brain injury and needs to be relaxed
    Condizione medica nella quale i muscoli del tronco superiore sono contratti o hanno spasmi dopo un infarto o un danno cerebrale traumatico e hanno la necessità di essere rilassati
    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 LLT
    E.1.2Classification code 10041416
    E.1.2Term Spasticity
    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
    Stage 1
    • To assess the safety and tolerability of increasing doses of a single treatment of IPN59011 in subjects with the clenched fist pattern compared with Dysport and placebo, and to select two dose levels for further investigation in Stage 2 based on safety and efficacy criteria.
    Stage 2
    • To determine the safety of two doses of IPN59011 selected after Stage 1, for the treatment of AUL spasticity in subjects with the flexed elbow pattern (mandatory of the two permitted clinical patterns in Stage 2) compared with Dysport at the peak of treatment effect, and to select the lowest dose which is safe and effective and providing 6-month duration of response for further investigation in Stage 3.
    Stage 3
    • To determine the safety of one total dose of IPN59011 selected from Stage 2 for the treatment of AUL spasticity in subjects with several clinical patterns on the adducted/rotated shoulder pattern (mandatory clinical pattern in Stage 3) compared with Placebo.
    Stadio 1: Valutare la sicurezza e la tollerabilità di dosi crescenti di un singolo trattamento con IPN59011 in soggetti con pattern caratterizzato da mano chiusa a pugno rispetto a Dysport® e al placebo, nonché selezionare due livelli di dose da esaminare in modo più approfondito nello Stadio 2 sulla base dei criteri di sicurezza e di efficacia.
    Stadio 2: Determinare la sicurezza delle due dosi di IPN59011 selezionate dopo lo Stadio 1 per il trattamento della spasticità degli arti superiori nell'adulto in soggetti con pattern caratterizzato da gomito flesso (il pattern clinico obbligatorio tra i due consentiti nello Stadio 2) rispetto a Dysport al picco di effetto del trattamento, nonché selezionare la dose più bassa che risulti sicura ed efficace e determini una durata della risposta di 6 mesi per l’esecuzione di ulteriori indagini nello Stadio 3.
    E.2.2Secondary objectives of the trial
    All Stages
    • To evaluate PD characteristics of IPN59011 for the treatment of subjects with AUL spasticity in the corresponding PTMG per stage by using MAS to assess the:
    - time to onset,
    - peak of effect,
    - time to peak, and
    - duration of effect.
    • To assess the efficacy of IPN59011 overtime compared with Dysport and/or placebo in reducing upper limb muscle tone in hemiparetic subjects as measured by MAS in the corresponding PTMG.
    • To compare the PD profile of IPN59011 to Dysport including duration of treatment response as measured by MAS in the corresponding PTMG.
    • To evaluate the Physician's Global Assessment (PGA) of overall treatment response as assessed by the investigator.
    • To evaluate the treatment benefit as assessed by the subject using Patient Global Impression of change (PGI-C).
    • To assess the presence of IPN59011 and BoNT-A antibodies and titers (binding and neutralising).
    Tutti gli stadi
    • Valutare le caratteristiche farmacodinamiche (PD) di IPN59011 per il trattamento di soggetti con spasticità degli arti superiori in età adulta nel corrispondente gruppo muscolare bersaglio primario (PTMG, Primary Target Muscle Group) in base allo stadio, utilizzando la scala di Ashworth modificata (MAS, Modified Ashworth Scale) al fine di determinare:
    • tempo di insorgenza;
    • picco di effetto;
    • tempo per il raggiungimento del picco;
    • durata dell’effetto.
    • Valutare l’efficacia di IPN59011 nel corso del tempo rispetto a Dysport e/o al placebo nel ridurre il tono muscolare dell'arto superiore in soggetti con emiparesi secondo la scala MAS nel PTMG corrispondente.
    • Confrontare il profilo PD di IPN59011 con quello di Dysport, compresa la durata della risposta al trattamento secondo la scala MAS nel PTMG corrispondente.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must fulfil all the following criteria to be included in the study:
    (1) Provision of written informed consent prior to any study related procedures.
    (2) Female and male subjects between:
    • For Stage 1: 18 and 65 years of age, inclusive.
    • For Stage 2 and Stage 3: 18 and 70 years of age, inclusive.
    (3) Have spastic hemiparesis following stroke or TBI.
    (4) Are at least 6 months post-stroke or TBI.
    (5) Have never received BoNT or if previously treated, should have received their last injection of any commercialised BoNT-A or B at least 4 months prior to study Baseline.
    (6) Have a MAS score =2 in the PTMG to be injected:
    • For Stage 1: subjects should have a clenched fist with a MAS score =2 in the extrinsic finger flexors.
    • For Stage 2: subjects should have one or more clinical pattern(s) in addition to flexed elbow with a MAS score =2 in elbow flexors.
    • For Stage 3: subjects should have two or more clinical pattern(s) in addition to adducted/rotated shoulder with a MAS score =2 in adducted/rotated shoulder flexors.
    (7) Should also be eligible to receive a total recommended dose 1000 U Dysport in the upper limb for Stage 2.
    (8) Angle of spasticity =5° in the PTMG to be injected.
    (9) Should not have any fixed contractures as defined by:
    • Complete fingers extension with XV1 =160°
    • Complete wrist extension with XV1 =90°
    • Complete elbow extension with XV1 =160°
    (10) Physical therapy, occupational therapy, splinting, use of benzodiazepine, and muscle relaxants had to be stable from at least 30 days preceding the study Baseline until the end of the study.
    (11) Subjects in good health (i.e. absence of any uncontrolled systemic disease or other significant medical condition) as determined by medical history, physical and neurological examinations, clinical laboratory studies, electrocardiograms (ECGs), vital signs, and Investigator's judgement prior to randomisation.
    Per essere inclusi nello studio i soggetti dovranno soddisfare tutti i criteri riportati di seguito:
    (1) Rilascio del consenso informato scritto prima di qualsiasi procedura correlata allo studio.
    (2) Sesso femminile e maschile, con età compresa:
    • Per lo Stadio 1: tra i 18 e i 65 anni, inclusi.
    • Per gli Stadi 2 e 3: tra i 18 e i 70 anni, inclusi.
    (3) Emiparesi spastica secondaria a ictus o a trauma cranico.
    (4) Almeno 6 mesi dall’ictus o dal trauma cranico.
    (5) Soggetti mai sottoposti a trattamento con BoNT o, se già trattati con BoNT, al basale dello studio devono essere trascorsi almeno 4 mesi dall’ultima iniezione di qualsiasi BoNT-A o B commercializzata.
    (6) Punteggio MAS =2 nel PTMG in cui praticare l’iniezione:
    • Per lo Stadio 1: i soggetti devono presentare una mano chiusa a pugno con un punteggio MAS =2 nei flessori estrinseci delle dita.
    • Per lo Stadio 2: i soggetti devono presentare almeno un pattern clinico oltre al gomito flesso con un punteggio MAS =2 nei flessori del gomito.
    • Per lo Stadio 3: i soggetti devono presentare almeno due pattern clinici oltre alla spalla in adduzione/rotazione con un punteggio MAS =2 nei flessori della spalla in adduzione/rotazione.
    (7) Idoneità a ricevere una dose raccomandata totale di 1000 U di Dysport nell’arto superiore per lo Stadio 2.
    (8) Angolo di spasticità =5° nel PTMG in cui praticare l'iniezione.
    (9) Assenza di contratture fisse, da intendersi come:
    • Estensione completa delle dita con XV1 =160°
    • Estensione completa del polso con XV1 =90°
    • Estensione completa del gomito con XV1 =160°
    (10) Fisioterapia, terapia occupazionale, uso di tutori, di benzodiazepine e di miorilassanti, stabili da almeno 30 giorni prima del basale e fino alla fine dello studio.
    (11) Condizioni di buona salute (ovvero, assenza di malattie sistemiche non controllate o altre patologie significative) secondo quanto stabilito in base all’anamnesi, agli esami obiettivo e neurologico, agli studi di laboratorio clinici, agli elettrocardiogrammi (ECG), ai segni vitali e al giudizio dello sperimentatore prima della randomizzazione
    E.4Principal exclusion criteria
    Subjects will be excluded from the study if they meet any of the following criteria:
    (1) Likely treatment with any serotype of BoNT for any condition during the study.
    (2) Undergone previous surgery to treat spasticity in the affected upper limb.
    (3) Has initiated physiotherapy within 30 days prior to Baseline (if physiotherapy initiated more than 30 days prior to Baseline and ongoing, the therapy regimen should be maintained at the same frequency and intensity throughout the study if possible or at least up to post-injection 3-months).
    (4) Has received previous treatment with phenol and or alcohol in the targeted upper limb any time before the study.
    (5) Has been treated or is likely to be treated with intrathecal baclofen during the 30 days prior to study Baseline or during the course of the study.
    (6) Current or planned treatment with any medications that interfere either directly or indirectly with neuromuscular transmission, such as curare-like non-depolarising agents, lincosamides, polymyxins, anticholinesterases and aminoglycoside antibiotics, within 30 days prior to Baseline.
    (7) Use of concomitant therapy which, in the investigator's opinion, would interfere with the evaluation of the safety or efficacy of the study treatment, including medications affecting bleeding disorders, provided the International normalized ratio (INR) is controlled between 2 and 3 (antiplatelet agents and/or anticoagulants given for treatment or prevention of cardiovascular/cerebrovascular diseases).
    (8) Treatment with an experimental drug or use of any experimental device within 30 days prior to the study Baseline and during the conduct of the study.
    (9) Currently planned or a history of tendon lengthening surgery, significant contracture or muscle atrophy at target joint or muscle in the past 6 months prior to Screening.
    (10) Any medical condition (including severe dysphagia or airway disease) that may increase, in the opinion of the investigator, the likelihood of adverse events (AEs) related to BoNT treatment.
    (11) Known disease of the neuromuscular junction (e.g. Lambert-Eaton myasthenic syndrome, myasthenia gravis or amyotrophic lateral sclerosis etc.).
    (12) Has a history of hypersensitivity to the investigational medicinal products (or other BoNTs) or any excipient used in their formulation.
    (13) Infection at the injection site(s).
    (14) A history of drug or alcohol abuse.
    (15) Clinically diagnosed significant anxiety disorder, or any other significant psychiatric disorder (e.g. depression) that might interfere with the subject's participation in the study.
    (16) Inability to understand protocol procedures and requirements which, in the opinion of the investigator, could negatively impact on protocol compliance or inability or unwillingness to comply with the protocol.
    (17) Presence of any other condition (e.g. neuromuscular disorder or other disorder that could interfere with neuromuscular function), laboratory finding or circumstance that, in the judgement of the investigator, might increase the risk to the subject or decrease the chance of obtaining satisfactory data to achieve the objectives of the study.
    (18) Pregnant women, or women of childbearing potential not willing to practice a highly effective form of contraception method at the beginning of the study, for the duration of the study and for a minimum of 12 weeks following last administration of study treatment. Highly effective methods of contraception are defined as methods of birth control which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, intrauterine devices, or vasectomised partner. The double barrier method (condom and spermicide) may be considered an acceptable form of birth control if deemed appropriate for the subject by the Investigator.
    Saranno esclusi dallo studio i soggetti che soddisfano uno qualsiasi dei seguenti criteri:
    (1) Probabile trattamento con BoNT di qualsiasi sierotipo per qualunque condizione durante lo studio.
    (2) Precedenti interventi chirurgici per trattare la spasticità dell’arto superiore colpito.
    (3) Inizio della fisioterapia nei 30 giorni precedenti il basale (se la fisioterapia viene avviata a più di 30 giorni dal basale ed è in corso, il regime terapeutico deve essere mantenuto alla stessa frequenza e intensità nel corso dello studio, se possibile, o per almeno 3 mesi dopo l’iniezione).
    (4) Precedente trattamento con fenolo e/o alcol nell’arto superiore di interesse in qualsiasi momento prima dello studio.
    (5) Trattamento effettivo o probabile con baclofene per via intratecale nei 30 giorni precedenti il basale dello studio o nel corso dello studio stesso.
    (6) Trattamento in corso o programmato con qualsiasi medicinale che interferisca in modo diretto o indiretto con la trasmissione neuromuscolare, quali agenti non depolarizzanti simili ai curari, lincosamidi, polimixine, anticolinesterasici e antibiotici aminoglicosidici, nei 30 giorni precedenti il basale.
    (7) Uso di una terapia concomitante che, secondo l’opinione dello sperimentatore, interferirebbe con la valutazione della sicurezza o dell’efficacia del trattamento in studio, compresi i medicinali che influiscono sui disturbi della coagulazione, a condizione che il rapporto internazionale normalizzato (INR, International Normalized Ratio) sia controllato entro l’intervallo 2-3 (agenti antipiastrinici e/o anticoagulanti somministrati per il trattamento o la prevenzione dei disturbi cardiovascolari/cerebrovascolari).
    (8) Trattamento con un farmaco sperimentale o utilizzo di un dispositivo sperimentale nei 30 giorni precedenti il basale o nel corso dello studio.
    (9) Intervento di allungamento dei tendini, pregresso o programmato, contrattura importante o atrofia muscolare in corrispondenza di un’articolazione o di un muscolo di interesse nei 6 mesi precedenti lo Screening.
    (10) Qualsiasi condizione medica (compresa disfagia severa o malattia delle vie aeree severa) che, secondo il parere dello sperimentatore, potrebbe incrementare le probabilità che si sviluppino eventi avversi (AE) correlati al trattamento con BoNT.
    (11) Patologia nota della giunzione neuromuscolare (per es. sindrome miastenica di Lambert-Eaton, miastenia grave o sclerosi laterale amiotrofica ecc.).
    (12) Anamnesi positiva per ipersensibilità ai prodotti medicinali sperimentali (o ad altre BoNT) o a qualsiasi eccipiente usato nella loro formulazione.
    (13) Infezione in corrispondenza della/e sede/i di iniezione.
    (14) Anamnesi positiva per abuso di alcolici o stupefacenti.
    (15) Disturbo d’ansia significativo clinicamente diagnosticato o qualsiasi altro disturbo psichiatrico significativo (per es. depressione) che potrebbe interferire con la partecipazione del soggetto allo studio.
    (16) Incapacità di comprendere le procedure e i requisiti del protocollo che, secondo il parere dello sperimentatore, potrebbe influire negativamente sull’aderenza al protocollo oppure incapacità o riluttanza a rispettare il protocollo.
    (17) Presenza di qualsiasi altra condizione (per es. malattia neuromuscolare o altra patologia che potrebbe interferire con la funzione neuromuscolare), referto di laboratorio o circostanza che, secondo il giudizio dello sperimentatore, potrebbe incrementare il rischio per il soggetto o ridurre le probabilità di ottenere dati soddisfacenti per il conseguimento degli obiettivi dello studio.
    E.5 End points
    E.5.1Primary end point(s)
    All Stages- Safety
    • Incidence, severity and nature of TEAEs.
    • Incidence, severity and nature of AESIs
    • Vital signs (absolute values and change from Baseline).
    • Clinical laboratory evaluations (absolute and change from Baseline values).
    • Presence of BoNT-A and IPN59011 antibodies (binding and neutralising).
    • Abnormal Physical examination findings.
    Tutti gli stadi – Sicurezza
    • Incidenza, gravità e natura degli eventi avversi emersi durante il trattamento (TEAE, Treatment-Emergent Adverse Event).
    • Incidenza, gravità e natura degli eventi avversi di particolare interesse (AESI, Adverse Event of Special Interest).
    • Segni vitali (valori assoluti e variazione rispetto al basale).
    • Valutazioni cliniche di laboratorio (valori assoluti e variazione rispetto al basale).
    • Presenza di anticorpi diretti contro BoNT-A e IPN59011 (leganti e neutralizzanti).
    • Reperti anomali all’esame obiettivo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At each post treatment visit.
    Ad ogni visita post trattamento.
    E.5.2Secondary end point(s)
    All Stages
    • Change from Baseline to all post-treatment visits (except Day 22, telephone call) in MAS score in the PTMG.
    • Change from Baseline to all post-treatment visits in MAS score in all injected muscle groups.
    • PD characteristics of IPN59011 in the PTMG:
    - Time to onset - time to the response to treatment (a reduction of at least one grade in the MAS score).
    - Peak of effect - maximal decrease in the MAS score from Baseline.
    - Time to peak - time to reach the peak of effect (maximal decrease in the MAS score from Baseline).
    - Duration of effect - duration between time to onset and last timepoint with a response to treatment.
    • Response to treatment as measured by at least one grade reduction in MAS score in the PTMG from Baseline to all post-treatment visits.
    • Response to treatment as measured by at least one-grade reduction in MAS score in all injected muscles from Baseline to all post-treatment visits.
    • PGA score of overall treatment response at all post-treatment visits.
    • PGI-C (as assessed by the subject) in the spastic clinical pattern at all post-treatment visits.
    Stage 2
    • Change from Baseline to post-treatment Day 29 in MAS score in the PTMG (flexed elbow pattern).
    Note: if PD profile of IPN59011 in Stage 1 indicates a peak of effect different than Day 29, the endpoint in Stage 2 will be modified accordingly.
    • Change from Baseline to all post-treatment visits in the Tardieu Scale (TS) in the PTMG.
    Stage 3
    • Change from Baseline to post-treatment Day 29 in MAS score in the PTMG (adducted/rotated shoulder pattern).
    Note: if PD profile of IPN59011 in Stage 1 indicates a peak of effect different than Day 29, the endpoint in Stage 3 will be modified accordingly.
    • Change from baseline to all post-treatment visits in Disability Assessment Scale (DAS).
    • Reduction of pain in the shoulder (adducted/rotated pattern) using the Numeric Rating Scale (NRS).
    Tutti gli stadi
    • Variazioni rispetto al basale rilevate a tutte le visite post-trattamento (a eccezione del Giorno 22, telefonata) del punteggio MAS nel PTMG.
    • Variazione rispetto al basale rilevata a tutte le visite post-trattamento del punteggio MAS in tutti i gruppi muscolari in cui viene praticata l’iniezione.
    • Caratteristiche PD di IPN59011 nel PTMG:
    - Tempo di insorgenza – tempo alla risposta al trattamento (una riduzione di almeno un grado del punteggio MAS).
    - Picco di effetto – riduzione massima del punteggio MAS rispetto al basale.
    - Tempo al raggiungimento del picco – tempo per raggiungere il picco di effetto (riduzione massima del punteggio MAS rispetto al basale).
    - Durata dell’effetto – tempo intercorrente tra l’insorgenza e l’ultimo timepoint con una risposta al trattamento.
    • Risposta al trattamento misurata in base a una riduzione di almeno un grado del punteggio MAS nel PTMG dal basale a tutte le visite post-trattamento.
    • Risposta al trattamento misurata in base a una riduzione di almeno un grado del punteggio MAS in tutti i muscoli in cui è stata praticata l’iniezione dal basale a tutte le visite post-trattamento.
    • Punteggio PGA della risposta globale al trattamento a tutte le visite post-trattamento.
    • PGI-C (secondo la valutazione del soggetto) nel pattern clinico di spasticità a tutte le visite post-trattamento.
    Stadio 2
    • Variazione rispetto al basale rilevata al Giorno 29 post-trattamento del punteggio MAS nel PTMG (pattern a gomito flesso).
    Nota: se il profilo PD di IPN59011 nello Stadio 1 indica un picco di effetto diverso rispetto al Giorno 29, l’endpoint nello Stadio 2 sarà modificato di conseguenza.
    • Variazione rispetto al basale rilevata a tutte le visite post-trattamento della Scala di Tardieu (TS, Tardieu Scale) nel PTMG.
    Stadio 3
    • Variazione rispetto al basale rilevata al Giorno 29 post-trattamento del punteggio MAS nel PTMG (pattern con spalla in adduzione/rotazione).
    Nota: se il profilo PD di IPN59011 nello Stadio 1 indica un picco di effetto diverso rispetto al Giorno 29, l’endpoint nello Stadio 3 sarà modificato di conseguenza.
    • Variazione rispetto al basale rilevata a tutte le visite post-trattamento della scala di valutazione della disabilità (DAS, Disability Assessment Scale).
    • Riduzione del dolore a livello della spalla (pattern in adduzione/rotazione) utilizzando la scala di valutazione numerica (NRS, Numeric Rating Scale).
    E.5.2.1Timepoint(s) of evaluation of this end point
    At each post treatment visit.
    Ad ogni visita post trattamento.
    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 Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    dose escalation
    dose escalation
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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 Information not present in EudraCT
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial 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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 9
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 209
    F.4.2.2In the whole clinical trial 209
    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)
    standard of care
    standard of care
    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 Decision2020-10-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-15
    P. End of Trial
    P.End of Trial StatusOngoing
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