E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
idiopathic retroperitoneal fibrosis |
fibrosi retroperitoneale idiopatica |
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E.1.1.1 | Medical condition in easily understood language |
idiopathic retroperitoneal fibrosis |
fibrosi retroperitoneale idiopatica |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021244 |
E.1.2 | Term | Idiopathic retroperitoneal fibrosis |
E.1.2 | System Organ Class | 100000004856 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
to assess the rate of remission at the end of treatment (month 6). Remission denotes absence of disease-related symptoms, resolution or improvement of hydronephrosis (without indwelling stents), near-normalization (i.e. normalization or reduction to <30% of baseline values) of erythrocyte sedimentation rate and C-reactive protein levels, as previously described; prednisone dose must be =5 mg/die for the definition of remission
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valutare il tasso di remissione dei pazienti affetti da fibrosi retroperitoneale idiopatica al termine del trattamento (dopo 6 mesi di terapia). Per remissione si intende l’assenza di sintomi correlati alla malattia, miglioramento o completa risoluzione dell’idronefrosi (rimozione degli stents), normalizzazione o riduzione >30% rispetto ai valori basali degli indici aspecifici di flogosi. Il dosaggio massimo di prednisone consentito al momento della definizione di remissione sarà = a 5 mg/die.
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E.2.2 | Secondary objectives of the trial |
• to assess the rate of remission at the end of month 12 • to assess percentage reduction in IRF thickness on CT/MRI and of FDG uptake on PET scans • to assess treatment-related toxicity throughout the study period
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• valutare il tasso di remissione al termine del follow-up (12 mesi) • valutare la percentuale di riduzione delle massa valutata mediante TC o RMN e valutare la riduzione dell’ipercaptazione a livello della PET-TC • valutare la tossicità correlata al farmaco (tocilizumab)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Written signed Informed consent - patients with clinically active IRF, who have refractory disease: disease unresponsive to standard glucocorticoid therapy (initial dose 1 mg/kg/d) +/- conventional immunosuppressants (MTX, MMF). - patients with clinically active IRF who previously reported serious adverse events related to the use of standard-dose glucocorticoids with or without common immunosuppressive drugs -age 18-80 years - Men and women of reproductive potential must agree to use a highly efficient means of contraception during the study. Such means include: a) intrauterine device (IUD) b) hormonal methods (such methods were used for at least three months prior to study entry and that they are used with a condom in the male partner); c) Essure micro-insert system ; d)complete abstinence from intercourse of reproductive potential; e) for male patients with female partners of childbearing potential, use of condoms is required. Female partners of male study subjects are asked to select one of the above methods.
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• pazienti che hanno firmato il consenso informato • pazienti affetti da fibrosi retroperitoneale idiopatica in fase attiva che si sono dimostrati refrattari ai trattamenti immunosoppressivi convenzionali (glucocorticoidi al dosaggio di 1 mg/kg/die con o senza farmaci immunosoppressori (MTX, MMF) • pazienti affetti da fibrosi retroperitoneale idiopatica in fase attiva che presentino controindicazioni all’uso di dosi standard di glucocorticoidi o di altri trattamenti immunosoppressivi convenzionali • pazienti di età compresa tra 18 e 80 anni • soggetti in età fertile dovranno accettare l’uso di metodi contraccettivi ad elevata efficienza durante tutte la durata dello studio. Questi ultimi includono l’uso di dispositivi intrauterini (IUD), metodi ormonali (che dovranno essere usati nei tre mesi precedenti l’inizio dello studio ed utilizzati assieme a condom maschile), Essure micro-insert system, astinenza completa, uso di comdom.
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E.4 | Principal exclusion criteria |
-Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following enrolment. -secondary forms of retroperitoneal fibrosis -Treatment-naïve patients -Treatment with the investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening. -Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples include: CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20. -Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline. -Immunization with a live/attenuated vaccine within 4 weeks prior to baseline. -Previous treatment with TCZ (an exception to this criterion may be granted for single dose exposure). -Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, ulcerative colitis, or Crohn’s disease.) - Any history of recent serious bacterial, viral, fungal, or other opportunistic infections. -Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation. -Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial. - History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer. - Pregnant women or nursing (breast feeding) mothers. - Patients with reproductive potential not willing to use an effective method of contraception. - History of alcohol, drug or chemical abuse within 1 year prior to screening. - Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation. - Patients with lack of peripheral venous access.
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- interventi di chirurgia maggiore nelle 8 settimane precedenti lo screening o programmati nei 6 mesi successivi all’arruolamento - forme secondarie di fibrosi retroperitoneale idiopatica - pazienti naïve - trattamenti con farmaci sperimentali nelle 4 settimane precedenti lo screening - trattamenti precedenti con farmaci depletanti cellule (come ad esempio CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20) - trattamenti con immunoglobuline EV, plasmaferesi nei sei mesi precedenti il trattamento - immunizzazione con vaccini vivi/attenuati nelle 4 settimane precedenti il trattamento - precedente trattamento con Tocilizumab (eccetto che per una solo esposizione) - precedenti trattamenti con agenti alchilanti - storia di severa allergia o reazione anafilattica ad anticorpi monoclonali murini, umanizzati o umani - malattie concomitanti severe a carico di Sistema cardiovascolare, nervoso, polmonare, renale, epatico, endocrino, gastrointestinale - recenti infezioni batteriche, virali, fungine o di infezioni opportunistiche - storia di immunodeficienza primitiva o secondaria o malattia in fase attiva - qualsiasi condizione clinica o psicologica che posso interferire, a giudizio dell’investigatore, con il completamento del trial in tutta sicurezza - storia di neoplasia nei 5 anni precedenti lo screening, fatto salvo per carcinoma in situ della cervice, carcinoma della pelle non melanomatoso, cancro uterino Stadio I, trattati in maniera radicale - donne in gravidanza o allattamento - pazienti in età fertile che rifiutino di sottoporsi ad adeguata contraccezione - storia di abitudini voluttuarie (all’alcool, droghe o farmaci) circa un anno prima dello screening - pazienti senza accesso vascolare periferico - neuropatie o altre condizioni che possano interferire con la valutazione del dolore o della sintomatologia correlata alla malattia in oggetto - pazienti senza accessi vascolari periferici
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E.5 End points |
E.5.1 | Primary end point(s) |
- We will assess the remission rate at month 6, defined as the proportion of treated patients who achieve and maintain remission at the end of month 6 (=end of the treatment period). Remission is a composite end-point which includes absence of disease-related symptoms, resolution or improvement of hydronephrosis (without indwelling stents), near-normalization (i.e. normalization or reduction to <30% of basal values) of erythrocyte sedimentation rate and C-reactive protein levels, as described in a previous randomised controlled trial; prednisone dose must be =5 mg/die for the definition of remission. We expect that at least 60% of the treated patients will experience remission by the end of treatment |
-valutare il tasso di remissione al mese 6, definito come la percentuale di pazienti trattati che raggiungono e mantengono la remissione fino al termine del sesto mese di trattamento. Per remissione si intende l’assenza di sintomi correlati alla malattia, miglioramento o completa risoluzione dell’idronefrosi (rimozione degli stents), normalizzazione o riduzione >30% rispetto ai valori basali degli indici aspecifici di flogosi. Il dosaggio massimo di prednisone consentito al momento della definizione di remissione sarà = a 5 mg/die. Il tasso di remissione atteso è almeno del 60% dei pazienti trattati.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
6 months (stop treatment) |
6 mesi (fine del trattamento) |
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E.5.2 | Secondary end point(s) |
- We will assess the remission rate at month 12, defined as the proportion of treated patients who are in remission at the end of the 12th month of study (=6 months after the end of treatment). Remission is a composite end-point which includes absence of disease-related symptoms, resolution or improvement of hydronephrosis (without indwelling stents), near-normalization (i.e. normalization or reduction to <30% of basal values) of erythrocyte sedimentation rate and C-reactive protein levels, as described in a previous randomised controlled trial; prednisone dose must be =5 mg/die for the definition of remission. - Reduction in IRF thickness will be assessed as the percentage reduction in maximal peri-aortic or peri-iliac thickness of the retroperitoneal tissue (end of treatment vs baseline) on CT or MRI, as previously described - Reduction in FDG uptake will be assessed as percentage reduction in maximum standardized uptake value (SUVmax) on FDG-PET (end of treatment vs baseline) - In order to assess treatment-related toxicity or other types of adverse events, we will record all adverse events occurred during the study and divide them in two periods, the 6 months of treatment and the subsequent 6 months of follow-up.
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-Valutazione del tasso di remissione al mese 12, definito come percentuale di pazienti trattati che raggiungono e mantengono la remissione fino al termine del 12 mese (6 mesi dopo il termine del trattamento). Per remissione si intende l’assenza di sintomi correlati alla malattia, miglioramento o completa risoluzione dell’idronefrosi (rimozione degli stents), normalizzazione o riduzione >30% rispetto ai valori basali degli indici aspecifici di flogosi. Il dosaggio massimo di prednisone consentito al momento della definizione di remissione sarà = a 5 mg/die. -Riduzione dello spessore a livello periaortico e periiliaco del tessuto retroperitoneale (fine trattamento vs basale) misurato alla TC o RMN -riduzione dell’ipercaptazione del radiofarmaco valutato alla PET-TC in termini di SUV max (fine trattamento vs baseline) -gli eventi avversi riguardanti il trattamento verranno registrati durante tutto il period dello studio e suddivisi in avventi avversi relative al period di trattamento (primi 6 mesi) ed eventi avversi intercorsi nei successi 6 mesi di follow-up
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
12 months (rate remission ant drug toxicity), 6 months (reduction up-take of PET-TC) |
12 mesi (per tasso di remissione e tossicità relativa al trattamento), 6 mesi (per riduzione dell’up-take alla PET-TC) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 24 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 24 |
E.8.9.2 | In all countries concerned by the trial days | 0 |