| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| idiopathic recurrent pericarditis |
| pericardite ricorrente idiopatica |
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| E.1.1.1 | Medical condition in easily understood language |
| pericarditis without a known etiology that recurs |
| pericardite senza causa nota che recidiva |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Recent findings suggest that idiopathic recurrent pericarditis (RP) may be a previously unrecognized autoinflammatory disease. The pivotal pathogenic role of interleukin (IL)-1 in RP has been demonstrated by the achievement of complete responses after treatment with the recombinant IL-1–receptor antagonist, anakinra. Anakinra is the recombinant form of IL-1Ra. The proposed study is designed to demonstararte the efficacy of anakinra in idiopathic RP. |
| Recenti evidenze clinico-sperimentali fanno supporre che la pericardite ricorrente idiopatica possa essere una malattia autoinfiammatoria. Il ruolo patogenetico dell’IL-1 è rilevante in questo contesto così come la risposta all’antagonista recettoriale dell’IL1 anakinra. L’anakinra è la forma ricombinante dell’IL-1Ra. Lo studio proposto ha lo scopo di dimostrare l’efficacia dell’anakinra nella pericardite ricorrente idiopatica. |
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| E.2.2 | Secondary objectives of the trial |
| To assess CS and concurrent medication sparing effects of anakinra over 8 months |
| Valutare l’effetto di anakinra sul concomitante trattamento corticosteroideo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Patient’s written informed consent for ≥ 18 years of age before any assessment is performed. Parents’ or legal guardian’s written informed consent and child’s assent, if appropriate, are required before any assessment is performed for patients < 18 years of age.
2. Age > 2 years and <70 years at screening visit;
3. Recurrent pericarditis defined as a first episode of acute pericarditis followed by recurrences (Ann Intern Med. 2011;155:409-14) (at least two recurrences for this study). First episode of
pericarditis is diagnosed when at least two of the following criteria were present: pericarditic typical chest pain (sharp and pleuritic, improved by sitting up and leaning forward), pericardial friction rubs, widespread ST segment elevation or PR depressions not previously reported, and new or worsening pericardial effusion. Recurrence is diagnosed when chest pain recurs and one or more of the following signs is present: fever, pericardial friction rub, ECG changes, echocardiographic evidence of new or worsening pericardial effusion, and elevations in the white blood cell count, erythrocyte sedimentation rate or C-reactive protein. To be enrolled in this study, elevation of C-reactive protein is mandatory both in the first attack and in the following recurrences. We differentiate recurrences from incessant pericarditis, term used to define patients with continued activity of pericarditis (with a symptom-free interval of < 6 weeks) (Soler-Soler J, Sagristà-Sauleda J, Permanyer-Miralda G. Relapsing pericarditis. Heart. 2004;90:1364-8).
4. Specific etiologies excluded, including tuberculous, neoplastic or purulent etiologies, post-cardiac injury syndromes, systemic diseases including rheumatic autoimmune diseases and autoinflammatory diseases such as familial Mediterranean fever (FMF) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS).
5. Records to document the number of prior pericardial recurrences, the time interval between them as well as prior treatments must be made available from the medical charts.
6. Troponin values during at least one previous attack is recorded.
7. QuantiFERON (QFT-TB G In-Tube) test or positive Purified Protein Derivative (PPD) test has been previously made and recorded.
8. Patients will be enrolled at the time of a recurrent episode (at least the second recurrence, i.e. third episode) or “relapse” of pericarditis documented by the following criteria:
- recurrent pericardial pain (with a score of least 5 on the 21 circles VAS) AND
- increase in CRP >1 mg/dL (being normal value = 0 - 0.5 mg/dL ), AND
- one or more of the following signs: fever (≥ 37°C), pericardial friction rub, pertinent ECG changes, echocardiographic evidence of of new or worsening pericardial effusion (see definition above)
9. Continuous treatment with CS, the dose of which must not have been increased in the three days preceding enrolment
10. Women of child bearing potentials (WCBP), defined as pre-menarche females aged 8 years and above or all women physiologically capable of becoming pregnant, sexually active, must use an effective form of contraception. Medically approved contraception (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, and some intrauterine devices) could include total abstinence. Reliable contraception should be maintained throughout the study and for 3 months after anakinra discontinuation. Women are considered post-menopausal and not WCBP if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. appropriate age, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks prior to study entry. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment she considered a WCBP.
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1. Consenso informato per pazienti adulti (>18 anni) e consenso informato scritto firmato da un genitore o un tutore legale per i minori che devono dare il loro assenso;
2. Età > 2 anni e <70 anni alla visita di screening;
3. Episodio di pericardite ricorrente idiopatica (almeno 2 episodi). La recidiva verrà diagnosticata in presenza di ricorrenza di dolore toracico pericarditico ed almeno un evidenza oggettiva di malattia: febbre, sfregamenti pericardici, versamento pericardico, ed elevazione dei globuli bianchi e/o proteina C reattiva , VES. Dovrà essere presente un intervallo libero di malattia > 6 settimane dall’ultimo episodio di pericardite.
4. Esclusione di eziologie specifiche incluse la tubercolosi, le forme batteriche o purulente, le forme post-pericardiotomiche, malattie infiammatorie sistemiche, incluse le malattie reumatiche ed autoinfiammatorie (es. Febbre Familiare Mediterranea e tumour necrosis factor receptor-associated periodic syndrome (TRAPS).
5. Documentazione delle precedente recidive pericarditiche con i relativi trattamenti.
6. Valutazione dei livelli di troponina nei precedent episodi.
7. QuantiFERON (QFT-TB G In-Tube) test o Purified Protein Derivative (PPD) test disponibili e precedentemente eseguiti.
8. Pazienti con almeno 2 recidive di malattia documentata da:
- Dolore pericarditico ricorrente (score di almeno 5/21 su scala visuale) e
- Proteina C reattiva >1 mg/dL (v.n 0 - 0.5 mg/dL ), e
- Uno o più caratteristiche: febbre (≥ 37°C), sfregamenti pericardici, alterazioni ECG, versamento pericardico
9. Trattamento con corticosteroidi che non deve essere aumentato negli ultimi 3 giorni.
10. Donne in età fertile con adeguato trattamento anticoncezionale che andrà mantenuto per ulteriori 3 mesi dopo la sospensione dell’anakinra.
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| E.4 | Principal exclusion criteria |
Patients fulfilling any of the following criteria are not eligible for enrollment in this study:
1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
2. History of being immunocompromised, including a positive HIV at screening (ELISA and Western blot) test result.
3. Positive QuantiFERON (QFT-TB G In-Tube) test or positive Purified Protein Derivative (PPD) test (≥ 5 mm induration) performed after the first attack of pericarditis. Patients with a positive PPD test (≥ 5 mm induration) at screening may be enrolled only if they have either a negative chest X-ray or a negative QuantiFERON test.
4. Live vaccinations within three months prior to the start of the trial, during the trial, and up to three months following the last anakinra dose.
5. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
6. History of significant other medical conditions, which in the Investigator’s opinion would exclude the patient from participating in this trial including current pericarditis due to known diseases (e.g. tuberculosis, neoplastic or purulent causes, connective tissue diseases, acute rheumatic fever, etc.)
7. History of recurrent and/or evidence of active bacterial, fungal, or viral infection(s).
8. History of Type I hypersensitivity to anakinra.
9. History of poor compliance.
10. Use of any investigational drug (or biologic), or device within five half-lives of the drug prior to study entry or during the study.
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1. Donne gravide od in corso di allattamento
2. Storia di immunodepressione (incluso un test positive per HIV)
3. Test QuantiFERON (QFT-TB G In-Tube) o Purified Protein Derivative (PPD) test (≥ 5 mm) positivo al primo attacco di pericardite performed after the first attack of pericarditis. Pazienti con test PPD positivo (≥ 5 mm induration) possono essere arruolati solo se rx torace ed il test QuantiFERON sono negativi
4. Vaccinazione nei 3 precedenti la recidiva (il paziente dovrà evitare le vaccinazione anche nei 3 mesi seguenti la fine dello studio ed il trattamento con anakinra).
5. Anamnesi di neoplasie di qualunque tipo (eccetto un basalioma localizzato), trattate o non trattate negli ultimi 5 anni indipendentemente dallo stato attuale di attività della malattia neoplastica
6. Anamnesi di qualunque altra condizione clinica che a discrezione del Curante o Sperimentatore possa richiedere l’esclusione dallo studio, (es.. tbc, tumore, malattia infiammatoria sistemica.)
7. Anamnesi di attuale o ricorrente infezione batterica, fungina o virale.
8. Ipersensibilità all’anakinra.
9. Scarsa compliance
10. Utilizzo di qualsiasi farmaco sperimentale entro 5 emivite prima dell’ingresso nello studio.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time to flare in the anakinra and placebo arms in the withdrawal phase |
| Tempo intercorrente fino alla recidiva nel gruppo trattato con anakinra e placebo nelle fase di sospensione. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. To assess the responder status in the open label phase at Day 8 and 60 and at the end of the study with the following three criteria all to be met:
a) no or mild pericardial pain (a score ≤2.5 on a 21 circle VAS), AND
b) normal CRP levels (CRP ≤0.5 mg/dL), AND
c) absent or mild (≤10 mm) echocardiographic effusion.
2. To assess the change over time of the 3 outcome criteria, i.e. pericardial pain, CRP levels, and echocardiographic effusion;
3. To assess the time to response in the open label phase
4. To assess the percentage of patients who relapse in the withdrawal part in the two arms;
5. To assess the change over time in patient’s/parent’s global assessment of overall well being on a 21 circle VAS;
6. To assess the change over time in the global evaluation of disease activity by physicians on a 21 circle VAS
7. To assess the change over time in quality of life as assessed by the SF-36 scale in adults and by the CHQ in children
8. To assess the percentage off CS and any other concurrent medication at 6weeks
9. To assess the tolerability and safety of the treatment, i.e. monitoring and recording all adverse events (AEs), with attention to local tolerability to s.c. injection, and serious adverse events (SAEs), and the regularly scheduled monitoring of hematology, blood chemistry, physical examinations, and vital signs including blood pressure over 8 months.
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1. Valutare lo stato di responder nella fase in aperto dello studio al giorno 8, 60 e fine studio avendo I seguenti 3 criteri:
a) Assenza di dolore o dolore lieve (score ≤2.5 su scala visuale), e
b) Livelli di proteina C reattiva normali (CRP ≤0.5 mg/dL), e
c) Versamento pericardico lieve (≤10 mm) o assente.
2. Valutare nel tempo l’evoluzione dei 3 criteri
(dolore pericardico, proteina C reattiva e versamento pericardico);
3. Valutare il tempo di risposta alla terapia nella fase in aperto
4. Valutare la percentuale di pazienti che recidivano nella fase di sospensione del trattamento;
5. Valutare il cambiamento nel tempo dello stato di benessere su scala visuale;
6. Valutare il cambiamento nel tempo dell’attività della malattia su scala visuale;
7. Valutare il cambiamento nel tempo della qualità di vita misurata attraverso la scala SF-36 negli adulti e CHQ nei bambini.
8. Valutare la percentuale di sospensione dei corticosteroidi e degli altri trattamenti concomitanti anti-infiammatori a 6 settimane.
9. Valutare la tollerabilità e sicurezza del trattamento (es. Monitoraggio e registrazione di tutti gli eventi avversi e degli eventi avversi gravi negli 8 mesi di trattamento)
Le valutazioni vengono effettuate nei giorni 4, 8, 30 e mesi 2, 4, 6 ed 8 dello studio.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | No |
| E.8.7 | Trial 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 |
| ultima visita dell'ultimo soggetto arruolato |
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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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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