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    Summary
    EudraCT Number:2022-002669-13
    Sponsor's Protocol Code Number:87RI21_0052
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-08-30
    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 ConcernedFrance - ANSM
    A.2EudraCT number2022-002669-13
    A.3Full title of the trial
    The PENTO protocol in Medication-related osteonecrosis of the jaw (MRONJ): a single-center phase IIa trial
    Le protocole PENTO dans l’ostéochimionécrose des maxillaires : Essai de phase IIa monocentrique
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The PENTO protocol in Medication-related osteonecrosis of the jaw (MRONJ)
    Le protocole PENTO dans l’ostéochimionécrose des maxillaires
    A.3.2Name or abbreviated title of the trial where available
    PENTO
    A.4.1Sponsor's protocol code number87RI21_0052
    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 SponsorLimoges University Hospital
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLimoges University Hospital
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLimoges University Hospital
    B.5.2Functional name of contact pointLoïc MARAIS
    B.5.3 Address:
    B.5.3.1Street Address2, avenue Martin Luther King
    B.5.3.2Town/ cityLimoges
    B.5.3.3Post code87042
    B.5.3.4CountryFrance
    B.5.4Telephone number+33(0)555 058 911
    B.5.6E-maildri@chu-limoges.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name PENTOXIFYLLINE
    D.2.1.1.2Name of the Marketing Authorisation holderPENTOXIFYLLINE MYLAN L.P. 400 mg
    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.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPentoxifylline
    D.3.9.1CAS number 6493-05-6
    D.3.9.4EV Substance CodeSUB09705MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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 Yes
    D.2.1.1.1Trade name TOCOPHEROL
    D.2.1.1.2Name of the Marketing Authorisation holderTOCO 500 mg
    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.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameALPHA-TOCOPHEROL
    D.3.9.4EV Substance CodeSUB16355MIG
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Medication-related osteonecrosis of the jaw (MRONJ)
    ostéochimionécrose (OCN) des maxillaires
    E.1.1.1Medical condition in easily understood language
    Medication-related osteonecrosis of the jaw (MRONJ)
    ostéochimionécrose (OCN) des maxillaires
    E.1.1.2Therapeutic area Diseases [C] - Mouth and tooth diseases [C07]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level LLT
    E.1.2Classification code 10084881
    E.1.2Term Medication-related osteonecrosis of jaw
    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
    The primary objective is to evaluate the proportion of healing (defined as an area of bone exposure (ABE) < 5 mm) in patients receiving PENTO in osteochimionecrosis at 12 months
    L’objectif principal est d’évaluer la proportion de guérison (définie par une zone d’exposition osseuse (EBA) < 5 mm) chez des patients bénéficiant du PENTO dans l’ostéochimionécrose à 12 mois
    E.2.2Secondary objectives of the trial
    The secondary objectives are :
    - to describe the evolution of the modified SOMA score
    - to describe the nutritional parameters evolution,
    - to follow the EBA evolution,
    - to evaluate the treatment tolerance (description of adverse events) at 12 months.
    Les objectifs secondaires sont de :
    - Décrire l’évolution du score SOMA modifié sur 12 mois
    - Décrire l’évolution de paramètres nutritionnels sur 12 mois
    - Suivre l’évolution de l’EBA sur 12 mois
    - D’évaluer la tolérance du traitement par le recueil des événements indésirables sur 12 mois
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age greater than or equal to 18 years
    - Current or past treatment with bisphosphonates (oral or IV) and/or targeted therapies (denosumab, bevacizumab)
    - Signs and symptoms for more than 8S with confirmation that the signs and symptoms are not of dental origin
    - AAOMS Stage 2 MRONJ
    - For patients of childbearing age, contraception is required (excluding periodic abstinence, withdrawal, lactational amenorrhea, spermicide alone)
    - Age supérieur ou égal à 18 ans
    -Traitement actuel ou passé par bisphosphonates et/ou thérapies ciblées. Il s’agit de :
    - Bisphosphonates per os : etidronate, tiludronate, alendronate, risédronate, ibandronate
    - Bisophosphonates IV : pamidronate, ibandronate, zolédronate
    - Denosumab : Ac monoclonal humain anti-RANKL (voie sous-cutanée)
    - Bevacizumab : Ac anti-VEGF (voie IV)
    - Signes et symptômes depuis plus de 8S avec confirmation que les signes et symptômes ne sont pas d’origine dentaire
    - OCN de stade 2 selon l’AAOMS : os exposé ou nécrotique; ou fistule muqueuse s’étendant jusqu’à l’os avec des preuves d’infection (écoulement purulent); ces patients sont symptomatiques
    -Pour les patientes en âge de procréer, nécessité d’une contraception (à l'exclusion des méthodes suivantes : abstinence périodique, retrait, aménorrhée lactationnelle, spermicide seul)
    E.4Principal exclusion criteria
    - History of head or neck radiotherapy or maxilla metastases
    - Patients who have received treatment in the past (PENTO or PENTOCLO protocol)
    - Patients who have undergone surgery for their MRONJ within the last 3 months
    - Pregnant or wishing to be pregnant, breastfeeding
    - Patient under palliative care
    - Patient with hypersensitivity to pentoxifylline or tocopherol or to an excipient
    - History of hypersensitivity reaction to penicillins, cephalosporins, or other beta-lactams (or dalacin if applicable)
    - History of jaundice/hepatic injury related to amoxicillin/clavulanic acid
    - Patient taking oral anticoagulants, or with a history of major bleeding or bleeding disorders
    - Patients with a history of hepatic failure, renal failure (Cl < 30 mL/min), hypotension (SBP (systolic blood pressure) < 90 mmHg)
    - Patient with hypotension (SBP < 90 mmHg)
    - Refusal to participate in the study
    - Patient participating in other interventional research that may interfere with the conduct of this research
    - Patient unable to understand the protocol
    - Patient under curatorship or guardianship
    - Antécédent de radiothérapie de la tête ou du cou ou de métastases des maxillaires
    - Patient ayant déjà reçu le traitement dans le passé (protocole PENTO ou PENTOCLO)
    - Patient ayant subi une chirurgie dans le cadre de son OCN dans les 3 derniers mois
    - Patiente enceinte ou souhaitant l’être, allaitante
    - Patient pris en charge en soins palliatifs
    - Patient présentant une hypersensibilité à la pentoxifylline ou au tocopherol ou à un excipient
    - Antécédent de réaction d’hypersensibilité aux pénicillines, aux céphalosporines ou à d’autres bêta-lactamines (ou à la dalacine le cas échéant)
    - Antécédent d'ictère/atteinte hépatique lié à l'amoxicilline/acide clavulanique
    - Patient prenant des anticoagulants oraux, ou ayant des antécédents de saignement majeur ou de troubles de la coagulation
    - Patient avec un antécédent d’insuffisance hépatique ou rénale ou d’hypotension artérielle
    - Patient présentant une hypotension artérielle (PAS < 90 mmHg)
    - Refus de participer à l’étude
    - Patient participant à une autre recherche interventionnelle susceptible d’interférer avec le déroulement de cette recherche
    - Patient en incapacité de comprendre le protocole
    - Patient sous curatelle ou tutelle ou sous sauvegarde de justice
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is healing as defined by an exposure bone area (EBA) less than 5 mm at 12 months. It will be expressed as the percentage of patients who achieved healing (EBA < 5 mm) at 12 months
    guérison définie par une zone d’exposition osseuse (EBA) < 5 mm à 12 mois
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months after treatment
    E.5.2Secondary end point(s)
    • The evolution of the modified SOMA score (qualitative and quantitative items) over 12 months: 0 -> 26 :
    Subjective:
    - Pain (occasional/minimal, intermittent/tolerate, persistent/intense, refractory)
    - Chewing (difficult with solids, with soft food, gastrostomy)
    Objective:
    - Bone exposure (minimal ulceration, < 2 cm, 2-4 cm, > 4 cm/fracture)
    - Trismus (minimal, 1-2 cm mouth opening, 0.5-1 cm, < 0.5cm)
    Management:
    - Pain (occasional, regular non-morphine treatment, regular morphine treatment, surgery)
    - Bone exposure (mouthwash, antibiotic therapy, debridement/HBO)
    Analytic:
    - Mandibular radiography (doubts, heterogeneous, sequestration, fracture)
    • Evolution of nutritional parameters over 12 months:
    - Patient's weight and BMI
    - Albuminemia in g/L (nomes 35-50 g/L)
    - Pre-albuminemia in mg/L (norms 250-350 mg/L)
    • Dimension and evolution of ABE (clinical) over 12 months:
    - Quantitative assessment: D dimension = major axis measurement of mucosal loss
    - Evolution: Relative regression D (= (D at x months - D at inclusion)/D at inclusion)
    • Collection of adverse events over 12 months, according to their nature, severity, severity (mild, moderate, severe) and causality
    • L’évolution du SOMA score modifié (items qualitatifs et quantitatifs) sur 12 mois : 0 -> 26 :
    Subjective :
    - Douleur (occasionnelle/minimale, intermittente/tolérable, persistante/intense, réfractaire)
    - Mastication (difficile avec les solides, avec une alimentation molle, gastrostomie)
    Objective :
    - Exposition osseuse (ulcération minime, < 2 cm, 2-4 cm, > 4 cm/fracture)
    - Trismus (minime, 1 à 2 cm d’ouverture buccale, 0,5-1 cm, < 0,5cm)
    Management :
    - Douleur (occasionnelle, traitement non morphinique régulier, traitement morphinique régulier, chirurgie)
    - Exposition osseuse (bains de bouche, antibiothérapie, débridement/HBO)
    Analytic :
    - Radiographie mandibulaire (doutes, hétérogène, séquestre, fracture)
    • Evolution des paramètres nutritionnels sur 12 mois :
    - Poids et IMC du patient
    - Albuminémie en g/L (nomes 35-50 g/L)
    - Pré-albuminémie en mg/L (normes 250-350 mg/L)
    • Dimension et évolution d l’EBA (clinique) sur 12 mois :
    - Evaluation quantitative : dimension D = mesure grand axe de la perte de substance muqueuse
    - Evolution : Régression relative D (= (D à x mois – D à l’inclusion)/D à l’inclusion)
    • Recueil des événements indésirables survenus sur 12 mois, en fonction de leur nature, de leur gravité, de leur sévérité (léger, modéré, sévère) et de leur causalité
    E.5.2.1Timepoint(s) of evaluation of this end point
    12 months
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months25
    E.8.9.1In the Member State concerned days7
    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: 16
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    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 state17
    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)
    possibility of continuing PENTO treatment outside the protocol, at the investigator's discretion.
    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 Decision2022-11-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-10-21
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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