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    Summary
    EudraCT Number:2016-000592-24
    Sponsor's Protocol Code Number:MR308-3501
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-12-10
    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 number2016-000592-24
    A.3Full title of the trial
    A Randomized, Double-Blind, Multicenter, Placebo- and active Comparator-Controlled Study to evaluate Efficacy and Safety of MR308 in the Treatment of Acute Pain After Third Molar Tooth Extraction (STARDOM1).
    Studio multicentrico, randomizzato, in doppio cieco, controllato con placebo e con comparatore attivo, per valutare l'efficacia e la sicurezza dell'MR308 nel trattamento del dolore acuto dopo l'estrazione del terzo molare (STARDOM1).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and Safety in a randomised acute pain study of MR308:
    STARDOM1.
    Efficacia e sicurezza dell'MR308 in uno studio randomizzato sul dolore acuto:
    STARDOM1.
    A.3.2Name or abbreviated title of the trial where available
    STARDOM1
    STARDOM1
    A.4.1Sponsor's protocol code numberMR308-3501
    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 SponsorMUNDIPHARMA RESEARCH GMBH & CO. KG
    B.1.3.4CountryGermany
    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 supportMundipharma Research GmbH & Co. KG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMundipharma Research GmbH & Co. KG
    B.5.2Functional name of contact pointClinical trial contact
    B.5.3 Address:
    B.5.3.1Street AddressHoehenstr. 10
    B.5.3.2Town/ cityLimburg
    B.5.3.3Post code65549
    B.5.3.4CountryGermany
    B.5.4Telephone number00496431701453
    B.5.5Fax number00496431701453
    B.5.6E-mailbarbara.riechert@mundipharma-rd.eu
    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 nameMR308 Tablet 100 mg
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTramadol hydrochloride Celecoxib
    D.3.9.2Current sponsor codeMR308 Co-crystal
    D.3.9.3Other descriptive nameCTC cocrystal
    D.3.9.4EV Substance CodeSUB04927MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMR308 Tablet 150 mg
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTramadol hydrochloride Celecoxib
    D.3.9.2Current sponsor codeMR308 Co-crystal
    D.3.9.3Other descriptive nameCTC cocrystal
    D.3.9.4EV Substance CodeSUB04927MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.IMP: 3
    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 Zydol 50 mg capsules
    D.2.1.1.2Name of the Marketing Authorisation holderGrünenthal Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTramadol hydrochloride
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameTRAMADOL HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB04927MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute pain after third molar tooth extraction; dental procedure must have involved extraction of at least two impacted third molars requiring bone removal. If only two impacted third molars are extracted, they must be ipsilateral and both required bone removal under local anaesthesia.
    Dolore acuto dopo estrazione di terzo molare; la procedura dentale deve comprendere l'estrazione di almeno due terzi molari inclusi che richieda la rimozione di tessuto osseo. Se solamente due terzi molari inclusi verranno estratti, dovranno essere omolaterali ed entrambi dovranno richiedere la rimozione di tessuto osseo in anestesia locale.
    E.1.1.1Medical condition in easily understood language
    Treatment of acute pain after third molar tooth extraction.
    trattamento del dolore acuto dopo estrazione di terzo molare
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10066714
    E.1.2Term Acute pain
    E.1.2System Organ Class 100000004867
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the efficacy of MR308 doses in the Treatment of acute moderate to severe pain. Efficacy will be assessed by showing
    superiority of MR308 doses over Placebo and non-inferiority compared with Tramadol, followed by superiority over Tramadol based on teeth sum of pain intesity differences over 0-4 hours (SPID4).
    Dimostrare l'efficacia di dosi MR308 nel trattamento del dolore acuto da moderato a severo. L'efficacia sarà valutata dimostrando la superiorità delle dosi di MR308 rispetto al placebo e la non inferiorità rispetto al Tramadolo, seguita dalla superiorità rispetto al Tramadolo basata sulla differenze tra le somme delle intensità di dolore calcolate su 0-4 ore (SPID4)
    E.2.2Secondary objectives of the trial
    To compare the effficacy of MR308 doses versus Tramadol and Placebo based on the secondary efficacy endpoints. To compare the safety and tolerability of MR308 doses versus Tramadol and Placebo.
    Comparare l'efficiacia delle dosi MR308 rispetto a Tramadol e Placebo basandosi su endpoint secondari di sicurezza e tollerabilità.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    2.0-Mon Jul 04 00:00:00 CEST 2016-pharmacogenomic sub-study-Pharmacogenomic samples will be collected and stored at the Sponsors designated storage repository to provide a resource for future genomic analysis, which will examine why subjects may respond differently to certain drugs by analysing genetic markers. The identification of genetic biomarkers underlying variability in drug efficacy or safety endpoints may be particularly valuable to inform drug labelling and ultimately optimise patient therapy. For example, variations in genes involved in the metabolism of drug compounds e.g. Cytochrome P450 2D6, can have an influence on the bioavailability of the compounds which could lead to an increased level of side effects or an alteration of drug efficacy. Therefore some drugs may be more effective in certain subject groups or they may cause more side effects in certain subjects depending on their genetic make up.
    2.0-Mon Jul 04 00:00:00 CEST 2016-Sottostudio di farmacogenomica-Tutti i soggetti arruolati nello studio verranno considerati arruolati nello studio secondario di farmacogenomica sponsorizzato da
    Mundipharma Research GmbH & Co. KG.
    I campioni farmacogenomici verranno raccolti e conservati presso gli archivi dello Sponsor designati e costituiranno una risorsa per le analisi genomiche future, le quali esamineranno le ragioni per cui è possibile che i soggetti rispondano in maniera diversa a determinati farmaci tramite l’analisi dei marcatori genetici.
    L’identificazione dei biomarcatori genetici, alla base della variabilità relativa all’efficacia del farmaco o agli endpoint di sicurezza potrebbe rivelarsi particolarmente utile alle indicazioni sulle etichette dei farmaci e, in ultima analisi, all’ottimizzazione della terapia dei pazienti. Ad esempio, le variazioni nei geni che coinvolgono il metabolismo dei composti dei farmaci come il citocromo P450 2D6 possono influenzare la biodisponibilità dei composti, che potrebbe determinare un incremento degli effetti indesiderati o un alterazione dell’efficacia del farmaco. Pertanto, alcuni farmaci potrebbero risultare maggiormente efficaci in determinati gruppi di soggetti, oppure provocare più effetti indesiderati in altri soggetti, a seconda delle caratteristiche genetiche individuali.
    E.3Principal inclusion criteria
    Only subjects meeting all of the following inclusion criteria will be considered for study inclusion:
    1. Male/female subjects ≥ 18 years on the day of consent.
    2. Willing and able to provide written informed consent for this study.
    3. Subjects must have a planned elective dental procedure i.e. extraction of at least two impacted third molars (one of them must be mandibular) requiring bone removal, within 28 days after the Screening Visit. If only two impacted third molars are extracted, they must be ipsilateral and require bone removal.
    4. If a female is of child-bearing potential, she must be using highly effective methods of contraception throughout the study, not breastfeeding, and have negative pregnancy tests prior to receiving IMP. A highly effective method of birth control is defined as one which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs (Intrauterine Device, hormonal), sexual abstinence or vasectomised partner).
    5. Good general health as judged by Investigators on the basis of medical history and physical examination.
    6. Willingness to comply with the study procedures and requirements.
    Additional Inclusion Criteria after Surgery:
    1. Third molar extractions completed without any immediate complication.
    2. Tolerating oral fluids, no uncontrolled nausea/vomiting and ready to take oral analgesia.
    3. The subject is alert and calm, spontaneously pays attention to caregiver, e.g. RASS = 0 (Sessler et al., 2002 & Ely et al., 2003).
    4. Subjects with moderate or severe pain (qualifying PI-VAS score ≥ 45mm and < 70mm or ≥ 70mm) as a result of an oral surgical procedure under local anaesthesia and/or sedation*. This must be measured within a maximum of 6 hours after the end of the surgical procedure.
    * Randomisation within one pain group may be temporarily closed, please see section 11.4 for further details.
    Solo i soggetti in grado di soddisfare tutti i criteri seguenti potranno essere considerati idonei all’arruolamento:
    1. Soggetti di sesso maschile/femminile che, al giorno del consenso, abbiano compiuto 18 anni.
    2. Soggetti che abbiano la volontà nonché la facoltà di fornire un consenso informato scritto relativo alla partecipazione al presente studio.
    3. I soggetti dovranno sottoporsi a una procedura odontoiatrica liberamente scelta, ossia l’estrazione di almeno due terzi molari malati (uno dei quali deve essere mandibolare) che richiedono la rimozione ossea entro 28 giorni dalla visita di screening. Se vengono estratti solo due terzi molari malati, essi devono essere ipsilaterali e necessitare della rimozione ossea.
    4. Se un soggetto di sesso femminile è in età fertile, sarà tenuto a utilizzare metodi contraccettivi ad alta efficacia durante tutto il periodo di partecipazione allo studio, non potrà allattare e dovrà risultare negativo al test di gravidanza prima di ricevere la dose di Prodotto medicinale sperimentale. Un metodo altamente efficace di controllo delle nascite è un metodo con un tasso di fallimento basso (ovvero, meno dell’1% all’anno) se utilizzato in modo affidabile e corretto, come sterilizzazione, impianti, preparazioni iniettabili, contraccettivi orali combinati, alcuni dispositivi intrauterini (IUD), astinenza sessuale o un partner sterilizzato.
    5. Essere in uno stato di salute buono, in base a quanto stabilito dagli Sperimentatori mediante anamnesi medica ed esame obiettivo.
    6. Volontà di rispettare le procedure e i requisiti relativi allo studio.
    Criteri di inclusione aggiuntivi in seguito all’intervento chirurgico:

    1. Estrazioni del terzo molare completate senza eventuali complicazioni immediate.
    2. Tolleranza di liquidi orali, nessuna nausea/vomito non controllati e preparati ad assumere una dose di analgesico.
    3. Il soggetto è vigile e calmo; presta attenzione spontaneamente al caregiver, ovvero RASS = 0 (Sessler et al., 2002 & Ely et al., 2003).
    4. Soggetti con dolori gravi o moderati (Punteggio PI-VAS ammissibile compreso tra 45 mm e
    <70 mm oppure >70 mm) in seguito a procedura chirurgica sotto anestesia locale e/o sedazione*. Tale valore dovrà essere misurato entro un massimo di 6 ore dal termine della procedura chirurguca.

    * La randomizzazione all’interno di un gruppo di dolore potrebbe essere temporaneamente chiusa; per ulteriori dettagli, consultare la sezione 11.4.
    E.4Principal exclusion criteria
    Subjects having any of the following criteria must not be included in the study.
    1. Any abnormal laboratory value that is clinically significant in the opinion of Investigator that would compromise the safety of the subject in the study.
    2. Any recent history of frequent nausea or vomiting, dizziness within the last 3 months regardless of etiology.
    3. Subjects having any medical condition or treatment that is either a warning or contraindication as per the SmPC of tramadol (e.g. selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, MAO inhibitors (within 14 days before taking IMP), antipsychotics, anticonvulsant and other seizure threshold-lowering medicinal products),, celecoxib (e.g. increased risk of post-operative bleeding, active peptic ulceration, GI
    bleeding or inflammatory bowel disease) or paracetamol.
    4. Known sensitivity and/or contraindication to tramadol, celecoxib, paracetamol, sulfonamides, opioids, NSAIDS, COX-2 inhibitors, or related
    compounds or formulation excipients as well as severe hypersensitivity reactions (e.g. angioedema) to any drugs.
    5. Subjects who are known to have had inadequate pain relief from paracetamol, tramadol or celecoxib.
    6. Subjects requiring any medication which is prohibited as per section prohibited medication.
    7. Subjects who are in the Investigators opinion considered at increased risk of post-operative complications e.g. major dental infection/abscess.
    8. Any history of drug or alcohol abuse, misuse, physical or psychological dependence, mood changes, sleep disturbance and functional capacity
    which have an impact on pain perception.
    9. Significant neurological or psychiatric disorders including mental instability (unrelated to the pain) that could interfere with pain assessment; other pain that might impair the assessment of the nociceptive pain.
    10. Any medical history of significant and/or inadequately controlled cardiovascular (uncontrolled high blood pressure, high risk of cardiovascular events, severe heart failure), pulmonary, hematologic, (including coagulopathy/bleeding disorders), neurological (e.g. subjects with epilepsy or those susceptible to seizures), , liver disease (e.g.
    severe hepatic impairment), kidney disease (e.g. impaired renal function in subjects taking diuretics, ACE-inhibitors, or angiotensin II antagonists), endocrine, immunologic, dermatologic painful conditions or any other conditions that may compromise the ability of the subject to
    participate in the study or might interfere with drug absorption, distribution, metabolism or excretion.
    11. Previous randomisation in this study.
    12. Subjects who participated in a clinical research study involving a new chemical entity or an experimental drug within 30 days of study
    entry (defined as the start of the Screening Period).
    13. Subjects who were treated regularly with opioid analgesic or NSAIDs within 30 days prior to screening or who have received a long-acting
    NSAID within three days prior to the start of the surgery.
    14. Subjects who have received any analgesic medication (e.g. NSAIDs, oral opioid preparations etc.) other than short-acting preoperative or
    intraoperative local anaesthetic agents within 12 hours before the start of the surgery or peri operatively until randomisation.
    15. Subjects who are incapable of complying with the protocol.
    Additional Exclusion Criteria after Surgery:
    1. Serious complication during surgery and up to randomisation, including:
    • Post-operative primary and secondary bleed that cannot be controlled.
    • Subjects who did not had the third molar extraction completed as planned.
    2. Post-operative medications or treatments that can have an analgesic effect or cause sedation or have amnesic effect are not permitted as these may interfere with the study assessments. These include use of ice packs, corticosteroids, nitrous oxide, benzodiazepines, alcohol, hypnotics, analgesics, opioids, other psychotropic medicinal products
    and any other analgesia except the provided study treatments
    3. If in the Investigators opinion there are any factors that may confound the analysis of the study regarding efficacy and safety (e.g. a PI-VAS score greater than 90).
    I soggetti che soddisfano uno qualsiasi dei criteri seguenti verranno esclusi dallo studio.
    1. Qualsiasi valore anomalo verificatosi in laboratorio clinicamente significativo secondo il parere dello Sperimentatore, tale da poter compromettere la sicurezza del paziente durante lo studio.
    2. Recente anamnesi di nausea, vomito o vertigini frequenti negli ultimi 3 mesi indipendentemente dall’eziologia.
    3. Sogg. con condizioni o trattamenti medici che implicano avvertenza o controindicazione in base all’RCP del tramadolo (vale a dire, inibitori selettivi della ricaptazione della serotonina (SSRI), inibitore della ricaptazione della serotonina-norepinefrina (SNRI), antidepressivi triociclici, MAO inibitori (entro 14 giorni prima di ricevere la dose del Prodotto medicinale sperimentale), antipsicotici, anticonvulsivo e altri prodotti medicinali di abbassamento della soglia convulsiva), celecobix (ovvero, aumento del rischio di emorragie postoperatorie, ulcera peptica attiva, emorragia gastrointestinale o malattie infiammatorie croniche intestinali) o del paracetamolo.
    4. Sensibilità nota e/o controindicazione a tramadolo, celecoxib, paracetamolo, sulfonamidi, oppioidi, FANS, inibitori della COX-2 o ai relativi composti o eccipienti della formulazione, nonché reazioni di ipersensibilità grave (ad es., angioedema) a qualsiasi farmaco.
    5. Sogg. che non hanno ottenuto un’adeguata riduzione del dolore tramite l’assunzione di paracetamolo, tramadolo o celecoxib.
    6. Sogg. che richiedono eventuali terapie vietate, di cui alla sezione relativa alle terapie non consentite.
    7. Sogg. che, secondo il parere dello Sperim., sono considerati ad elevato rischio di complicazioni postoperatorie, quali forme gravi di infezioni dentali/ascessi.
    8. Anamnesi di abuso di farmaci o alcol, uso improprio, dipendenza fisica o psicologica, cambiamenti di umore, disturbi del sonno e capacità funzionale che hanno un impatto sulla percezione del dolore.
    9. Sogg. con disordini neurologici o psichiatrici significativi, compresa l’instabilità mentale (non imputabile al dolore) che potrebbero interferire con la valutazione del dolore; oppure altri tipi di dolore in grado di pregiudicare la valutazione del dolore nocicettivo.
    10. Anamnesi medica di malattia cardiovascolare importante e/o non adeguatamente controllata (pressione arteriosa elevata non controllata, rischio elevato di eventi cardiovascolari, insuffic. cardiaca grave), malattia polmonare, malattia ematologica (tra cui coagulopatia/disturbi emorragici), malattia neurologica (ad es., soggetti affetti da epilessia o predisposti a crisi convulsive), malattia epatica (ad es., insuffic. epatica grave), malattia renale (ad es., insuffic. renale in sogg. che assumono diuretici, ACE-inibitori o antagonisti dell’angiotensina II), malattia endocrina, malattia immunologica, malattia dermatologica dolorosa o altre patologie che possono compromettere la capacità del sogg. di partecipare allo studio o interferire con l’assorbimento, la distribuzione, il metabolismo o l’escrezione dei farmaci.
    11. Precedente randomizzazione nel presente studio.
    12. I sogg. che hanno preso parte a uno studio di sperimentazione clinico riguardo a una nuova sostanza chimica o un farmaco sperimentale entro
    30 giorni dall’adesione allo studio (definito come Periodo di screening).
    13. Sogg. che sono stati trattati regolarmente con analgesici a base di oppioidi o FANS nei 30 giorni precedenti lo screening o che hanno ricevuto FANS a lunga durata d’azione nei tre giorni precedenti l’inizio dell’intervento chirurgico.
    14. Sogg. che sono stati sottoposti a terapie a base di sostanze analgesiche (ad esempio, FANS, preparazioni a base di oppioidi, e così via) diverse da agenti anestetici locali preoperatori e intraoperatori a breve durata entro 12 ore dall’inizio dell’intervento chirurgico o perioperativamente fino alla randomizzazione.
    15. Sogg. incapaci di rispettare il protocollo.
    Criteri di esclusione aggiuntivi in seguito all’intervento chirurgico:

    1. Complicazioni gravi verificatesi durante l’intervento chirurgico e fino alla randomizzazione, compresi:
    • Emorragie postoperatorie primarie e secondarie che non possono essere controllate.
    • Soggetti che non hanno completato l’estrazione del terzo molare come previsto.
    2. Farmaci o trattamenti postoperatori che possono determinare effetti analgesici o causare sedazione o ancora provocare effetti amnesici non sono consentiti in quanto potrebbero interferire con la valutazione dello studio. Tali terapie includono l’utilizzo di impacchi di ghiaccio, corticosteroidi, protossido di azoto, benzodiazepine, alcol, sostanze ipnotiche, analgesiche, a base di oppioidi, altri prodotti medicinali psicotropi e qualuque altro analgesico ad eccezione dei trattamenti dello studio forniti
    3. Nel caso in cui, secondo il parere dello Sperimentatore, vi siano eventuali fattori che potrebbero confondere le analisi dello studio in relazione all’efficacia. e alla sicur. (ad es. punteggio PI-VAS > 90
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the Sum of Pain Intensity Differences over 0-4 hours (SPID4). SPID4 is derived as the weighted Sum of Pain Intensity Differences (baseline pain – current pain), measured at different time points via the PI-VAS. Time between two consecutive measurements will be used for weighting. Larger values indicate larger
    pain relief.
    L’endpoint di efficacia primario è rappresentato dalla Sum of Pain Intensity Differences nell’arco di 0-4 ore (SPID4). SPID4 deriva dalla somma ponderata delle differenze di intensità del dolore (dolore a livello basale - dolore attuale), misurata in diversi punti temporali tramite PI-VAS. Il tempo tra due misurazioni consecutive verrà utilizzato per la ponderazione. Valori più ampi indicano un sollievo dal dolore maggiore.
    E.5.1.1Timepoint(s) of evaluation of this end point
    0-4 hours (SPID4)
    0-4 hours (SPID4)
    E.5.2Secondary end point(s)
    1. 50% responder at 4 hours, defined as subjects with a reduction in
    pain intensity (PI-VAS) from 0 hours at 4 hours of at least 50%.
    2. Use of at least one dose of rescue medication during the first 4 hours.

    Other secondary endpoints:
    1. SPID over 0-12 hours, 0-24 hours, 0-48 hours and 0-72 hours.
    2. Pain (PI-VAS) at each post-dose time point.
    3. Pain Relief (PAR) at each post-dose time point.
    4. Total Pain Relief (TOTPAR) over 0-4 hours, 0-12 hours, 0-24 hours, 0-
    48 hours and 0-72 hours, defined as the sum of respective PAR,
    weighted with the time between two consecutive measurements.
    5. Worst pain as per PI-VAS experienced by subjects in 24 and 48 hours
    from first IMP intake.
    6. Responder based on PI-VAS
    • 50% responder, based on PI-VAS at 12, 24, 48 and 72 hours.
    • 30% responder, based on PI-VAS at 4, 12, 24, 48 and 72 hours.
    7. Time to 30% and time to 50% response based on PI-VAS.
    8. Time to perceptible pain relief and time to meaningful pain relief.
    9. Rescue medication use.
    • Average dose of rescue medication per 24 hours.
    • Time to first intake of rescue medication.
    10. EQ-5D-5L at 4, 24, 48, and 72 hours.
    1.Il 50% dei soggetti che rispondono a 4 ore vengono definiti come i soggetti con una riduzione dell’intensità del dolore (PI-VAS) da 0 a 4 ore per almeno il 50%.
    2. Utilizzo di almeno una dose di farmaco di soccorso durante
    le prime 4 ore.

    Ulteriori endpoint secondari:
    1. SPID su 0-12 ore, 0-24 ore, 0-48 ore e 0-72 ore.
    2. Dolore (PI-VAS) a ciascun punto temporale dopo il dosaggio.
    3. Sollievo dal dolore (PAR) a ciascun punto temporale dopo il dosaggio.
    4. sollievo dal dolore totale (TOTPAR) nell’arco di 0-4 ore, 0-12 ore, 0-24 ore, 0¬48 ore e 0-72 ore, definito come la somma del rispettivo PAR, ponderato con il tempo tra due misurazioni consecutive.
    5. Dolore più grave di cui alla PI-VAS sperimentato dai soggetti in 24 e 48 ore dalla prima somministrazione del Prodotto medicinale sperimentale.
    6. Soggetti che rispondono alla terapia sulla base della PI-VAS
    • 50% dei soggetti che rispondono alla terapia sulla base della PI-VAS a 12, 24, 48 e 72 ore.
    • 30% dei soggetti che rispondono alla terapia sulla base della PI-VAS a 4, 12, 24, 48 e 72 ore.
    7. Tempo al 30% e al 50% di risposta sulla base della PI-VAS.
    8. Tempo al sollievo dal dolore percepibile e tempo al sollievo significativo.
    9. Uso della terapia di soccorso.
    • Dose media dei farmaci di soccorso per 24 ore.
    • Tempo alla prima somministrazione dei farmaci di soccorso.
    EQ-5D-5L a 4, 24, 48 e 72 ore.
    E.5.2.1Timepoint(s) of evaluation of this end point
    see above
    vedere sopra
    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) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial5
    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 EEA34
    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
    Canada
    France
    Germany
    Hungary
    Italy
    Japan
    Poland
    Spain
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months15
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months15
    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.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 765
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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 state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 565
    F.4.2.2In the whole clinical trial 765
    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 Decision2017-03-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-22
    P. End of Trial
    P.End of Trial StatusCompleted
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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