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    Summary
    EudraCT Number:2014-000113-31
    Sponsor's Protocol Code Number:TED01RV
    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:2014-03-24
    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 number2014-000113-31
    A.3Full title of the trial
    A randomized, double-masked, placebo-controlled, efficacy and safety study of RV 001, an insulin-like growth factor-1 receptor (IGF-1R) antagonist antibody (fully human), administered every 3 weeks (q3W) by intravenous (iv) infusion in patients suffering from active thyroid eye disease (TED)
    Uno studio randomizzato, in doppio cieco, controllato verso placebo, di efficacia e sicurezza di RV 001, un anticorpo (interamente umano) antagonista del recettore insuline-like del fattore di crescita-1 (IGF-1R), somministrato ogni 3 settimane per infusione endovenosa in pazienti con malattia tiroidea oculare (thyroid eye disease – TED).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial looking at the safety of RV 001 and how well it works in treating thyroid eye disease. The trial drug or placebo is given intravenously (into a vein) every 3 weeks and allocation to the study drug is by chance.
    Uno studio di ricerca per valutare la sicurezza di RV 001 e come funziona nel trattamento della malattia tiroidea oculare. Il farmaco sperimentale o placebo viene somministrato per via endovenosa (in vena) ogni 3 settimane e l'assegnazione al farmaco in studio è casuale.
    A.4.1Sponsor's protocol code numberTED01RV
    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 SponsorRiver Vision Development Corporation
    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 supportRiver Vision Development Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPremier Research Group Ltd
    B.5.2Functional name of contact pointMerryn Collard
    B.5.3 Address:
    B.5.3.1Street Address1st Floor, Rubra 2, Mulberry Business Park
    B.5.3.2Town/ cityWokingham
    B.5.3.3Post codeRG41 2GY
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441189364507
    B.5.5Fax number+447880203237
    B.5.6E-mailmerryn.collard@premier-research.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 nameTeprotumumab
    D.3.2Product code RV 001
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    Intravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTeprotumumab
    D.3.9.1CAS number 103673-493-6
    D.3.9.2Current sponsor codeRV 001, RO4858696
    D.3.9.3Other descriptive nameRecombinant human anti-human insulin-like growth factor 1 receptor mAb
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Thyroid-Associated Ophthalmopathy / Graves' Ophthalmopathy
    Oftalmopatia Tiroidea / Oftlamopatia di Graves
    E.1.1.1Medical condition in easily understood language
    Thyroid Eye Disease
    Malattia Tiroidea Oculare
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    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 efficacy endpoint is the assessment of whether the patient is a responder or not at the end of the 6 month treatment phase.
    L’obiettivo primario dello studio è quello di valutare se il paziente risulta o meno responsivo alla fine dei 6 mesi di trattamento.
    E.2.2Secondary objectives of the trial
    Efficacy will be assessed by CAS (7 point scale), proptosis, motility restriction, clinical measures of severity, and Graves' Ophthalmopathy Quality of Life (GO-QOL) scale.
    L’efficacia sarà valutata in base al CAS (scala a 7 punti), alla proptosi, alla limitazione della motilità, ai livelli clinici di gravità e alla scala di valutazione della qualità della vita in presenza di oftalmopatia di Graves (Graves’ Ophthalmopathy Quality of Life, GO-QOL)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Aged 18-75 years (inclusive).
    2. Clinical diagnosis of Graves' disease associated with active TED with a clinical activity score (CAS) ≥ 4 (on the 7 point version of the scale) and moderate to severe TED according to the Clinical Severity Score (CSS) for the most severely affected eye.
    3. Fewer than 9 months from onset of TED as determined by patient records.
    4. No previous medical or surgical therapy for TED, excluding local supportive measures and oral steroids if the maximum cumulative dose is less than 1000 mg methylprednisolone or equivalent. There must be at least 6 weeks between last administration of steroids and study randomization.
    5. Patients must be euthyroid or with mild hypo- or hyperthyroidism defined as free thyroxine (FT4) and free triiodothyronine (FT3) levels less than 50% above or below the normal limits. Every effort should be made to correct the mild hypo- or hyperthyroidism promptly.
    6. Not requiring immediate surgical ophthalmological intervention.
    7. ALT/AST ≤ 3 x the upper limit of normal (ULN) for the reference laboratory; serum creatinine < 1.5 x ULN according to age.
    8. Diabetic patients must have a well controlled disease, demonstrated by no change in the diabetes medication (oral or insulin) greater than 10% for the past 60 days
    9. Women of child bearing potential, including women with an onset of menopause within the past 2 years (women who have not had at least 12 months of non-therapy-induced amenorrhea or who are not surgically sterile (absence of ovaries and/or uterus), will require a negative pregnancy test at baseline and at all treatment visits up to follow up visit 2 (month 9) post randomization and must be willing and able to use two different methods of contraceptive, one of which must be an oral contraceptive. Male patients must be surgically sterile or must agree to use a barrier contraceptive method. Contraception must be continued for 3 months after the last dose of study drug.
    1. Età compresa tra 18 e 75 anni (inclusi);
    2. Diagnosi clinica della malattia di Graves associata a OB attiva da moderata a grave secondo il Clinical Severity Score (CSS), con un punteggio di attività clinica (clinical activity score, CAS) ≥ 4 (su una scala di 7 punti) per l’occhio più gravemente colpito;
    3. OB comparsa da meno di 9 mesi, come confermato dalle cartelle cliniche dei pazienti;
    4. Nessuna terapia medica o chirurgica precedente per la OB, ad eccezione delle misure di supporto locali e degli steroidi orali, purché la dose massima cumulativa sia inferiore a 1000 mg di metilprednisolone o equivalente. Tra l’ultima somministrazione di steroidi e la randomizzazione dello studio devono essere trascorse almeno 6 settimane;
    5. I pazienti devono essere eutiroidei o presentare ipo/ipertiroidismo lieve, definito come livelli di tiroxina libera (free thyroxine, FT4) e triiodotironina libera (free triiodothyronine, FT3) con percentuali di inferiorità o superiorità al di sotto del 50% rispetto ai limiti normali. Occorre adottare ogni misura possibile per correggere tempestivamente l’ipo/ipertiroidismo lieve;
    6. Non è necessario un intervento chirurgico oculistico immediato;
    7. ALT/AST ≤ 3 x il limite superiore della norma (upper limit of normal, ULN) del laboratorio di riferimento; creatinina sierica < 1,5 x ULN in base all’età;
    8. I pazienti diabetici possono essere arruolati qualora la patologia sia adeguatamente controllata, ovvero qualora negli ultimi 60 giorni non sia stata apportata alla dose di farmaco antidiabetico (orale o insulina) una modifica superiore al 10%;
    9. Le donne in età fertile, comprese le donne in menopausa da meno di 2 anni (donne che non hanno avuto almeno 12 mesi di amenorrea non indotta da terapia o che non sono chirurgicamente sterili (assenza di ovaie e/o utero), dovranno presentare un test di gravidanza negativo al basale e in occasione di tutte le visite del trattamento dopo la randomizzazione, fino alla seconda visita di follow-up (mese 9); dovranno altresì essere disposte ad impiegare ed essere in grado di utilizzare due diversi metodi anticoncezionali, uno dei quali deve essere un contraccettivo orale. I pazienti di sesso maschile devono essere chirurgicamente sterili o devono accettare di utilizzare un metodo contraccettivo di barriera. La contraccezione deve essere continuata fino a 3 mesi dopo l'ultima dose del farmaco in studio.
    E.4Principal exclusion criteria
    1. Decreased best corrected visual acuity due to optic neuropathy as defined by a decrease in vision within the last 6 months of two lines of Snellen chart, new visual field defect or color defect secondary to optic nerve involvement.
    2. Corneal decompensation unresponsive to medical management.
    3. Improvement in CAS of ≥ 2 points between screening and baseline.
    4. Treatment with oral or intravenous (IV) steroids within the previous 3 months except oral steroids for the treatment of TED with a cumulative dose less than 1000 mg methylprednisolone or equivalent providing there is a 6 week washout prior to study randomization. Administration of any other immunosuppressive agent for any indication in the previous 3 months. Topical steroids for dermatological conditions are not excluded.
    5. Any treatment with any investigational agent for any condition in the past 60 days, or treatment with an investigational agent for any condition during the trial.
    6. Any previous treatment with Rituximab (Rituxan or MabThera)
    7. Previous orbital irradiation.
    8. Identified preexisting ophthalmic disease which, in the judgment of the investigator, would preclude study participation or complicate interpretation of study results.
    9. Platelet count < 100 x 109/L at screening or baseline. Patients with platelet count < 35 x 109/L following dosing will be withdrawn.
    10. Bleeding diathesis.
    11. Hemoglobin concentration > 2 gr/dL below the lower limit of the local laboratory reference range.
    12. Malignant condition in the past 12 months (with the exception of successfully treated basal cell carcinoma of the skin).
    13. Pregnant or lactating women.
    14. Drug or alcohol abuse.
    15. Poorly controlled diabetes.
    16. Known hypersensitivity to any of the components of RV 001 or prior hypersensitivity reactions to monoclonal antibodies.
    17. Any other condition which, in the opinion of the investigator, would preclude inclusion in the study.
    18. Patients who have already been randomized and received treatment under this protocol. Under no circumstances are patients who enroll in this study permitted to be re-randomized to this study and enrolled for a second course of treatment.
    1. Riduzione della migliore acuità visiva corretta a causa della neuropatia ottica, definita come la diminuzione della visione negli ultimi 6 mesi di due righe della tabella di Snellen, insorgenza di un nuovo difetto del campo visivo o comparsa di un’alterazione nella percezione dei colori secondaria al coinvolgimento del nervo ottico;
    2. Scompenso corneale che non risponde alla terapia medica;
    3. Miglioramento del CAS di ≥ 2 punti tra lo screening e il basale;
    4. Trattamento con steroidi per via orale o endovenosa nei 3 mesi precedenti, ad eccezione degli steroidi orali per il trattamento della OB con una dose cumulativa inferiore a 1000 mg di metilprednisolone o equivalente, purché siano trascorse 6 settimane tra l’ultima somministrazione del farmaco e la randomizzazione dello studio. Somministrazione di qualsiasi altro agente immunosoppressivo per qualunque indicazione nei 3 mesi precedenti. Non sono esclusi gli steroidi topici per il trattamento di condizioni dermatologiche;
    5. Qualsiasi trattamento con un farmaco sperimentale per una qualunque condizione negli ultimi 60 giorni, oppure trattamento con un farmaco sperimentale per una qualsiasi condizione durante la sperimentazione;
    6. Qualsiasi trattamento pregresso con rituximab (Rituxan or MabThera)
    7. Precedente irradiazione dell’orbita;
    8. Identificazione di una patologia oftalmica preesistente che, a giudizio dello sperimentatore, precluderebbe la partecipazione allo studio del soggetto o complicherebbe l’interpretazione dei risultati della sperimentazione;
    9. Conta piastrinica < 100 x 109/l allo screening o al basale. I pazienti con conta piastrinica < 35 x 109/l a seguito della somministrazione del farmaco dovranno abbandonare lo studio;
    10. Diatesi emorragica;
    11. Concentrazione di emoglobina >2 g/dl al di sotto del limite inferiore dell’intervallo di riferimento del laboratorio locale;
    12. Malignità negli ultimi 12 mesi (con l'eccezione del carcinoma basocellulare della pelle trattato con successo);
    13. Pazienti di sesso femminile in gravidanza o allattamento;
    14. Abuso di sostanze o alcool;
    15. Diabete non adeguatamente controllato;
    16. Ipersensibilità nota a uno qualsiasi dei componenti di RV 001 o precedenti reazioni di ipersensibilità agli anticorpi monoclonali;
    17. Qualsiasi altra condizione che, a giudizio dello sperimentatore, precluderebbe l’inclusione nello studio;
    18. Pazienti che sono già stati randomizzati e sottoposti al trattamento in conformità al presente protocollo. I pazienti che sono già stati arruolati per questo studio non potranno in nessun caso essere nuovamente randomizzati nella sperimentazione e ricevere un secondo ciclo di trattamento.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the assessment of whether the patient is a responder or not (yes or no) at the end of the 6 month treatment phase (week 24). A responder is defined as a patient with a decrease in overall CAS ≥ 2 points, OR an improvement in ductions of ≥ 10 degrees, OR a reduction in proptosis ≥ 2 mm. All responses must be observed in the study eye without deterioration of CAS in the fellow eye (i.e. increase in CAS ≥ 2 points).
    L’obiettivo primario dello studio è quello di valutare se il paziente risulta o meno responsivo alla fine dei 6 mesi di trattamento (settimana 24).
    Un paziente sarà considerato responder se il suo CAS complessivo è sceso di 2 o più punti dalla misurazione del basale, OPPURE se si è verificato un miglioramento delle duzioni ≥ 10 gradi, OPPURE se la proptosi ha subito una riduzione ≥ 2 mm. Le misurazioni della risposta devono essere osservate nell’occhio in studio e non deve esservi alcun deterioramento del CAS nell’altro occhio (ovvero, un aumento del CAS ≥ 2 punti).
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of the 6 month treatment phase.
    Fine dei 6 mesi di trattamento
    E.5.2Secondary end point(s)
    Secondary endpoints include: CAS, motility, proptosis, clinical measures of severity, time to response, and GO-QOL.
    Gli endpoint secondari includono: CAS, proptosi, limitazione della motilità, CSS, tempo alla risposta e GO-QOL.
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of the 6 month treatment phase.
    Fine dei 6 mesi di 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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    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 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 trial2
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Germany
    Italy
    Netherlands
    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
    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 months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months2
    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: 78
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 84
    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 Decision2014-11-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-02-22
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