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    Summary
    EudraCT Number:2018-000446-19
    Sponsor's Protocol Code Number:1720302
    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:2020-12-15
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-000446-19
    A.3Full title of the trial
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Center Trial to Evaluate the Efficacy and Safety of a Single Treatment of DaxibotulinumtoxinA for Injection in Adults with Isolated Cervical Dystonia (ASPEN-1).
    Sperimentazione di Fase 3, randomizzata, in doppio cieco, controllata con placebo, a gruppi paralleli, multicentrica, per valutare l'efficacia e la sicurezza di un singolo trattamento di DaxibotulinumtoxinA per iniezione negli adulti con distonia cervicale isolata (ASPEN-1).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to investigate the effectiveness and safety of DaxibotulinumtoxinA for Injection in subjects with Isolated Cervical Dystonia (ASPEN-1).
    Uno studio clinico per valutare l'efficacia e la sicurezza di DaxibotulinumtoxinA per iniezione in soggetti con distonia cervicale isolata (ASPEN-1).
    A.3.2Name or abbreviated title of the trial where available
    ASPEN-1
    ASPEN-1
    A.4.1Sponsor's protocol code number1720302
    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 SponsorRevance Therapeutics, Inc
    B.1.3.4CountryUnited States
    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 supportRevance Therapeutics Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRevance Therapeutics Inc.
    B.5.2Functional name of contact pointRegulatory Affairs Manager
    B.5.3 Address:
    B.5.3.1Street Address7555 Gateway Blvd.
    B.5.3.2Town/ cityNewark
    B.5.3.3Post codeCA 94560
    B.5.3.4CountryUnited States
    B.5.4Telephone number+15107423655
    B.5.6E-mailczee@revance.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 nameDaxibotulinumtoxinA per iniezione
    D.3.2Product code [RT002]
    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.3.9.1CAS number 93384-43-1
    D.3.9.2Current sponsor code.
    D.3.9.3Other descriptive nameBOTULINUM TOXIN TYPE A
    D.3.9.4EV Substance CodeSUB13117MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number125 to 250
    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 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 placeboPowder 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
    Cervical Dystonia
    Distonia Cervicale
    E.1.1.1Medical condition in easily understood language
    Cervical Dystonia
    Distonia Cervicale
    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 21.0
    E.1.2Level LLT
    E.1.2Classification code 10064124
    E.1.2Term Cervical dystonia
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the efficacy of a high and low dose of DAXI for injection
    (250 U; 125 U) relative to placebo, and to each other, in adults with
    moderate to severe, isolated Cervical Dystonia (CD)
    Per confrontare l'efficacia di una dose alta e bassa di DAXI per iniezione
    (250 U; 125 U) rispetto al placebo e tra loro, negli adulti con
    distonia cervicale (CD) isolata da moderata a grave.
    E.2.2Secondary objectives of the trial
    - To establish duration of effect for DAXI for injection
    - To assess safety and immunogenicity of DAXI for injection
    - Stabilire la durata dell'effetto per DAXI per iniezione
    - Valutare la sicurezza e l'immunogenicità del DAXI per l'iniezione
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adults, 18 to 80 years of age
    2. Meets diagnostic criteria for isolated CD (idiopathic; dystonic symptoms localized to the head, neck, shoulder areas) with at least moderate severity at Baseline (Day 1), defined as a TWSTRS-total score of at least 20, with at least 15 on the TWSTRS-Severity subscale, at least 3 on the TWSTRS-Disability subscale, and at least 1 on the TWSTRS-Pain subscale
    3. Written informed consent including authorization to release health information
    1. Adulti, dai 18 agli 80 anni
    2. Soddisfa i criteri diagnostici per la CD isolata (idiopatica, sintomi distonici localizzati alla testa, al collo, alle spalle) con gravità almeno moderata al basale (giorno 1), definito come un punteggio totale TWSTRS di almeno 20, con almeno 15 sulla sottoscala TWSTRS-Severity, almeno 3 sulla sottoscala TWSTRS-Disability e almeno 1 sulla sottoscala TWSTRS-Pain
    3. Consenso informato scritto inclusa l'autorizzazione a divulgare informazioni sanitarie
    E.4Principal exclusion criteria
    1. Cervical dystonia attributable to an underlying etiology
    2. Predominant retrocollis or anterocollis CD
    3. Significant dystonia in other body areas, or is currently being treated with BoNT for dystonia in areas other than those associated with isolated CD
    4. Severe dysphagia (Grade 3 or 4 on the Dysphagia Severity Scale) at Screening or Baseline
    5. Any neuromuscular neurological conditions that place the subject at increased risk of morbidity with exposure to BoNT, including peripheral motor neuropathic diseases
    6. Previous treatment with any BoNT product for any condition within the 14 weeks prior Screening
    7. Botulinum neurotoxin treatment-experienced subjects who have historically required <100 U of Botox or its equivalent to treat CD symptoms
    8. Botulinum neurotoxin treatment-experienced subjects who had suboptimal or no treatment response to the most recent BoNTA injection for CD, as determined by the investigator, or history of primary or secondary non-response to BoNTA injections, known to have neutralizing antibodies to BoNTA, or have a history of botulinum toxin type B injection for CD due to non-response or suboptimal response to BoNTA
    9. Use of deep brain stimulation, or intrathecal baclofen for dystonia
    10. Subjects on oral medications for focal dystonia or neuroleptics for psychiatric conditions, who have not been stable on their regimen for at least 4 weeks prior to Screening
    11. Neurological abnormalities in the neck other than CD
    12. Previous neck surgery, phenol injection to the neck muscles, myotomy or denervation surgery in the neck/shoulder region
    13. Profound atrophy of cervical musculature, or cervical contractures or cervical spinal deformity leading to marked limitation on passive range of motion
    14. Use of aminoglycoside antibiotics, polymyxins, lincosamides or other agents that might interfere with neuromuscular transmission within 14 days prior to Screening
    15. Women of child bearing potential (WOCBP), who have a positive pregnancy test at Screening, or do not agree to use an effective method of birth control during the course of the study
    16. Female, who is pregnant or nursing
    17. Screening 12-lead ECG with exclusionary conduction criteria of corrected QT interval: QTcF interval > 450 msec (males) or > 470 msec (females), heart block, or ventricular tachycardia
    18. History of severe (stage 3) chronic obstructive pulmonary disease, or unstable pulmonary disease within 30 days prior to Screening
    19. History of chronic or recurrent hypokalemia, or serum potassium < 2.5 mEq/L or mmol/L on chemistry at Screening
    20. History of congestive heart failure, (New York Heart Association Class III or IV), Torsade de Pointe (TdP), and/or Long QT Syndrome,
    21. Participants in an investigational drug or device study within the last 30 days prior to Screening
    22. Active skin infections at the injection sites which would put the subject at increased risk of morbidity with BoNT injections
    23. Presence of any blood coagulation disorder, or on anticoagulation treatment with international normalized ratio (INR) > 3.5
    24. Any acute illnesses or medical conditions including cognitive impairment (e.g., dementia), significant psychiatric illnesses (e.g., major depressive or bipolar disorder) or symptoms (e.g., suicidal ideation, psychosis) that are not stable, and in the investigator's opinion, could put the subject at increased risk of morbidity, confound the study results, or interfere significantly with the subject's participation in the study.
    1. Distonia cervicale attribuibile ad una eziologia di base
    2. Prevalentemente CD retrocollis o anterocollis
    3. Distonia significativa in altre aree del corpo o attualmente trattata con BoNT per la distonia in aree diverse da quelle associate a CD isolata
    4. Disfagia grave (Grado 3 o 4 sulla scala di gravità della disfagia) allo screening o al basale
    5. Qualsiasi condizione neuromuscolare neurologica che pone il soggetto ad aumentato rischio di morbidità con l'esposizione a BoNT, comprese le patologie neuropatiche motorie periferiche
    6. Trattamento precedente con qualsiasi prodotto BoNT per qualsiasi condizione entro 14 settimane prima dello screening
    7. Soggetti con esperienza di trattamento con neurotossina botulinica che hanno storicamente richiesto <100 U di Botox o il suo equivalente per trattare i sintomi della CD
    8. Soggetti con esperienza di trattamento con neurotossina botulinica che hanno avuto una risposta subottimale o senza trattamento alla più recente iniezione di BoNTA per CD, come determinato dallo sperimentatore, o anamnesi di non risposta primaria o secondaria alle iniezioni di BoNTA, noto per avere anticorpi neutralizzanti per BoNTA , o con una storia di tossina botulinica di tipo B iniettata per CD a causa di una mancata risposta o di una risposta subottimale a BoNTA
    9. Uso della stimolazione cerebrale profonda o baclofene intratecale per la distonia
    10. Soggetti su farmaci orali per distonia focale o neurolettici per condizioni psichiatriche, che non sono stati stabili sul loro regime almeno 4 settimane prima dello screening
    11. Anomalie neurologiche nel collo diverse dallaCD
    12. Precedente intervento chirurgico al collo, iniezione di fenolo ai muscoli del collo, miotomia o intervento chirurgico di denervazione nella regione collo/spalla
    13. Atrofia profonda della muscolatura cervicale, o contratture cervicali o deformità spinali cervicali che portano a marcate limitazioni sulla gamma passiva di movimento
    14. Uso di antibiotici aminoglicosidici, polimixine, lincosammidi o altri agenti che potrebbero interferire con la trasmissione neuromuscolare entro 14 giorni prima dello screening
    15. Donne potenzialmente fertili (WOCBP), che hanno un test di gravidanza positivo allo Screening, o che non accettano di utilizzare un metodo di controllo delle nascite efficace nel corso dello studio
    16. Femmina, che è incinta o che allatta
    17. Screening ECG a 12 derivazioni con criteri di conduzione esclusivi dell'intervallo QT corretto : intervallo QTcF> 450 msec (maschi) o> 470 msec (femmine), blocco cardiaco o tachicardia ventricolare
    18. Storia di malattia polmonare ostruttiva cronica grave (stadio 3) o malattia polmonare instabile entro 30 giorni prima dello screening
    19. Anamnesi di ipokaliemia cronica o ricorrente o potassio sierico <2.5 mEq / L o mmol / L in chimica allo Screening
    20. Storia di insufficienza cardiaca congestizia, (New York Heart Association di classe III o IV), Torsade de Pointe (TdP) e / o sindrome del QT lungo,
    21. Partecipanti a uno studio sperimentale su farmaci o dispositivi negli ultimi 30 giorni precedenti allo screening
    22. Infezioni cutanee attive nei siti di iniezione che metterebbero il soggetto ad aumentato rischio di morbilità con iniezioni di BoNT
    23. Presenza di qualsiasi disturbo della coagulazione del sangue o trattamento anticoagulante con rapporto normalizzato internazionale (INR)> 3.5
    24. Qualsiasi malattia acuta o condizione medica comprendente deterioramento cognitivo (ad es. Demenza), malattie psichiatriche significative (ad esempio, disturbo depressivo maggiore o bipolare) o sintomi (ad esempio ideazione suicidaria, psicosi) non stabili e secondo il parere dello sperimentatore, potrebbe mettere il soggetto ad aumentato rischio di morbilità, confondere i risultati dello studio o interferire in modo significativo con la partecipazione del soggetto allo studio.
    E.5 End points
    E.5.1Primary end point(s)
    The average of the change from baseline in TWSTRS-total score at Weeks 4 and 6.
    La media del cambiamento rispetto al basale nel punteggio totale TWSTRS alle settimane 4 e 6
    E.5.1.1Timepoint(s) of evaluation of this end point
    It will be assessed at weeks 4 and 6
    Sarà valutato alle settimane 4 e 6
    E.5.2Secondary end point(s)
    • Change from baseline in TWSTRS-total score (all post-treatment timepoints)
    • Duration of effect, defined as time (number of weeks) from treatment to loss of at least 80% of the peak treatment effect achieved at Weeks 4 and 6 (i.e., the target TWSTRS score)
    • Percentage of subjects with at least "moderate" (a 2-point) improvement on CGIC at Week 4 or 6
    • Percentage of subjects with at least "moderate" (a 2-point) improvement on PGIC at Week 4 or 6
    • Safety, which includes adverse events (AEs), presence of serum neutralizing antibodies to BoNTA and novel excipient RTP004, hematology, serum chemistry, urinalysis, ECG, vital signs, physical and neurologic examinations, and clinically significant changes in pulmonary function by spirometry (FEV1 / FVC)
    • Cambiamento rispetto al basale nel punteggio totale TWSTRS (tutti i timepoint successivi al trattamento)
    • Durata dell'effetto, definita come tempo (numero di settimane) dal trattamento alla perdita di almeno l'80% dell'effetto di picco del trattamento raggiunto alle settimane 4 e 6 (cioè il punteggio TWSTRS target)
    • Percentuale di soggetti con almeno un miglioramento "moderato" (a 2 punti) su CGIC alla settimana 4 o 6
    • Percentuale di soggetti con almeno un miglioramento "moderato" (a 2 punti) su PGIC alla settimana 4 o 6
    • Sicurezza, che include eventi avversi (AE), presenza di anticorpi neutralizzanti sierici per BoNTA e nuovi eccipienti RTP004, ematologia, chimica del siero, analisi delle urine, ECG, segni vitali, esami fisici e neurologici e cambiamenti clinicamente significativi della funzione polmonare mediante spirometria ( FEV1 / FVC)
    E.5.2.1Timepoint(s) of evaluation of this end point
    It will be assessed at Week 6.
    Sarà valutato alla settimana 6
    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 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 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA36
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Canada
    Czechia
    France
    Germany
    Hungary
    Italy
    Poland
    Spain
    United Kingdom
    United States
    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 end of study is defined as LVLS or procedure (EU and non EU).
    La fine dello studio è definita come LVLS o procedura (UE e non UE).
    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 months4
    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 months4
    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: 210
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 300
    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
    Nessuno
    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 Decision2019-01-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-16
    P. End of Trial
    P.End of Trial StatusOngoing
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