| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Sjogrens disease |
| Sindrome di Sjögren primaria |
|
| E.1.1.1 | Medical condition in easily understood language |
| Sjogren's Syndrome |
| Sindrome di Sjögren |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061664 |
| E.1.2 | Term | Autoimmune disorder |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| 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 |
| Safety and tolerability of anti-BLyS / anti-CD 20 coadministration therapy and anti-BLyS and anti-CD 20 monotherapies |
| Valutare la sicurezza e la tollerabilità della terapia di co-somministrazione anti-BLyS/anti-CD 20 e delle monoterapie a base di anti-BLyS e anti-CD 20. |
|
| E.2.2 | Secondary objectives of the trial |
- Clinical efficacy of anti-BLyS / anti-CD 20 co-administration therapy and anti-BLyS and anti-CD 20 monotherapies
- Assessment of anti-BLyS / anti-CD 20 co administration therapy and anti-BLyS and anti-CD 20 monotherapies on tissue B-cells. |
- Valutare l’efficacia clinica della terapia di co-somministrazione anti-BLyS/anti-CD 20 e delle monoterapie a base di anti-BLyS e anti-CD 20.
- Valutazione della terapia di co-somministrazione anti-BLyS/anti-CD 20 e delle monoterapie a base di anti-BLyS e anti-CD 20 sulle cellule B nei tessuti.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
AGE
1. Age =18 years, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Documented Primary Sjögren's Syndrome by American European Consensus Group criteria including:
- either SS-A or SS-B positive.
3. Baseline unstimulated salivary flow >0.0 mL/min or evidence of glandular reserve function (stimulated baseline salivary flow >0.05 mL/min).
4. Symptomatic oral dryness (=5/10 on subject completed Numeric Response Scale)
5. Systemically active disease, ESSDAI=5 points and with at least:
a) 1 extraglandular domain moderate,
OR
b) 2 extraglandular domains low.
SEX
6. Male and female subjects; females of child bearing potential are eligible if using effective contraception:Female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotropin (hCG) test), not lactating, and at least one of the following conditions applies:
a. Non-reproductive potential defined as:
-Pre-menopausal females with one of the following:
-Documented tubal ligation
-Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
-Hysterectomy
-Documented Bilateral Oophorectomy
- Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating
hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study; otherwise,
they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
b. Reproductive potential and agrees to follow one of the options listed below in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days prior to the first dose of study medication up to Week 68 after Day 0.
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to
be abstinent from penilevaginal intercourse on a long term and persistent basis.
-Contraceptive subdermal implant that meets the SOP effectiveness criteria including a <1% rate of failure per year, as stated in the product label
-Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a <1% rate of failure per year, as stated in the product label
-Oral Contraceptive, either combined or progestogen alone
-Injectable progestogen
-Contraceptive vaginal ring
-Percutaneous contraceptive patches
-Male partner sterilization with documentation of azoospermia prior to the female subject's entry into the study, and this male is the sole partner for that subject.
-Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository).
These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label.
The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. |
Età:
1. età =18 anni al momento della firma del consenso informato
Tipo di soggetto e diagnosi, inclusa la gravità della malattia:
2. Sindrome di Sjögren primaria documentata secondo i criteri dell'American European Consensus Group
o positività per SS-A o per SS-B)
3. Flusso salivare basale non stimolato >0,0 mL/min o evidenza di funzionalità ghiandolare residua (flusso salivare basale stimolato >0,05 mL/min)
4. Xerostomia sintomatica (¿5/10 su una scala di valutazione numerica compilata dal soggetto)
5. Malattia sistemica attiva, ESSDAI =5 punti
o OPPURE (SOLO PER I CENTRI IN ITALIA)
Malattia sistemica attiva, ESSDAI =5 punti e con almeno:
a) 1 dominio extraghiandolare con livello di attività moderato
Oppure
b) 2 domini extraghiandolari con livello di attività basso
Sesso:
6. soggetti di sesso maschile e femminile; le donne potenzialmente fertili sono considerate idonee se utilizzano metodi di contraccezione efficaci.
Le pazienti di sesso femminile sono idonee a partecipare allo studio se non sono in gravidanza (come confermato dal risultato negativo al test della gonadotropina corionica umana (hCG) nelle urine), non sono in allattamento e presentano una delle seguenti condizioni:
a) non sono potenzialmente fertili (vedi definizione nel protocollo)
b) sono potenzialmente fertili e concordano l’uso di un metodo altamente efficace per evitare la gravidanza previsto dalla lista GSK modificata definita nel protocollo nei 30 giorni precedenti la prima dose di farmaco in studio fino alla Settimana 68 dopo il Giorno 0.
Consenso informato:
7. soggetti in grado di comprendere e rispettare le procedure richieste dal protocollo, e di fornire il proprio consenso informato |
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of secondary Sjögren's syndrome.
2. Active life-threatening or organ-threatening complications of SS disease at the time of screening based on treating physician evaluation including but not restricted to (a) vasculitis with renal, digestive, cardiac, pulmonary or CNS involvement characterized as severe, (b) active CNS or PNS involvement requiring high dose steroids, (c) severe
renal involvement defined by objective measures, (d) lymphoma.
3. History of major organ transplant
4. History of malignancy within past 5 years [with the exception of adequately treated:
(a) cervical carcinoma Stage 1B or less, (b) non-invasive basal cell and squamous cell skin carcinoma].
5. History of infection requiring long term systemic therapy including:
(a) history of positive HIV serology, (b) positive serology for Hepatitis C (HCV), (c) positive
serology for Hepatitis B (HB), defined as: (i) HB surface antigen positive (HBsAg+) OR (ii) HB core antibody positive (HBcAb+).
6. Previous serious opportunistic or atypical infections or hospitalization for treatment of infection within 364 days of Day 0 or use of parenteral
(IV or IM) antibacterials, antivirals, anti-fungals, or anti-parasitic agents within 364 days of prior to Day 0.
7. Patients in a severely immunocompromised state.
8. History of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies.
9. History of significant medical illness which in the opinion of the investigator would interfere with the study procedures and / or assessments - including but not limited to IgG4 disease or prior head or
neck irradiation.
10. Severe heart failure or other severe, uncontrolled cardiac disease.
11. Tuberculosis (TB), defined as: (a) prior history of TB infection, (b) suspicion of TB infection or (c) current TB infection
12. At risk of suicide, as indicated by a lifetime history of attempted suicide or significant suicidal ideation over the 6 months prior to the
screening visit; or, if in the Investigator's judgment, the subject is at risk for a suicide attempt.
13. Neurological findings consistent with Progressive Multifocal Leukoencephalopathy (PML) - not otherwise explained - or confirmed PML.
14. Electrocardiogram (ECG) showing a clinically significant abnormality at Screening or showing an average QTcB or QTcF interval =450 msec over 3 consecutive ECGs
15. ALT >2xULN and bilirubin >1.5xULN
16. Current or chronic history of liver disease, or known hepatic or biliary abnormalities.
CONCOMITANT MEDICATIONS
17. Use of systemic immunosuppressive or immunomodulatory agents including
methotrexate, azathioprine, leflunomide, mycophenolate, mizoribine, calcineurin inhibitors, sirolimus, 6-mercaptopurine, or thalidomide)
within 60 days prior to Day 0.
18. Have received cyclophosphamide within 180 days prior to Day 0.
19. Have received anti-BLyS, anti-CD 20, anti-CD22 or anti-CD52 or any other B-cell depleting agent within 364 days prior to Day 0.
For the remaining exclusion criteria refer to the corresponding section in the protocol. |
1.Diagnosi di sindrome di Sjögren secondaria. 2.Complicanze attive della sindrome di Sjögren al momento dello screening, in base alla valutazione del medico, includendo, ma non solo, a) vasculite con interessamento di reni, apparato digerente, cuore, polmoni o coinvolgimento del SNC considerata grave; b) interessamento attivo del SNC o del SNP che richieda un trattamento con steroidi ad alto dosaggio; c) grave coinvolgimento renale confermato da misurazioni obiettive; d) linfoma. 3.Anamnesi positiva per trapianto d'organi maggiori 4.Anamnesi di neoplasia maligna nei 5 anni precedenti (ad eccezione di a) carcinoma cervicale di stadio 1B o inferiore, b) carcinoma basocellulare e squamocellulare della pelle non invasivo, se adeguatamente trattati). 5.Anamnesi di infezione con necessità di ricorso a una terapia sistemica a lungo termine, ivi compresa positività ai test sierologici a) per l'HIV, b) per l'epatite C (HCV) e c) per l'epatite B (HB), definita come (i) positività all'antigene di superficie dell'HB (HBsAg+), OPPURE (ii) positività all'anticorpo diretto contro l'antigene “core” dell'HB (HBcAb+). 6.Gravi infezioni opportunistiche o atipiche pregresse, ricovero ospedaliero per il trattamento di un'infezione nei 364 giorni precedenti il Giorno 0, oppure impiego di antibatterici, antivirali, antimicotici o antiparassitari per via parenterale (ev o im) nei 364 giorni precedenti il giorno 0. 7.Pazienti gravemente immunocompromessi. 8.Pregressa reazione anafilattica alla somministrazione parenterale di mezzi di contrasto, proteine umane o murine, o anticorpi monoclonali. 9.Episodi di malattia significativa (o interventi chirurgici maggiori pianificati) che, secondo l'opinione dello sperimentatore, possano interferire con le procedure e/o le valutazioni previste dallo studio, comprese, in via esemplificativa, malattia legata alle IgG4 o pregressa radioterapia della testa o del collo. 10.Insufficienza cardiaca grave (classe IV della New York Heart Association) o altra malattia cardiaca grave e non controllata. 11.TB, definita come a) anamnesi pregressa di infezione da TB, b) sospetto di infezione da TB o c) infezione da TB in corso. 12.Rischio di suicidio, definito come più tentativi di suicidio nell'arco della vita o come ideazione suicidaria significativa nei 6 mesi precedenti la visita di screening, oppure soggetti che, a giudizio dello sperimentatore, presentino un rischio di tentato suicidio. 13.Reperti neurologici coerenti con una diagnosi di leucoencefalopatia multifocale progressiva (LMP) non altrimenti specificata o di LMP conclamata
14.Elettrocardiogramma (ECG) indicante un'anomalia clinicamente significativa alla visita di screening, o riscontro di un intervallo QTcB o QTcF medio ¿450 ms (¿480 ms per i soggetti con blocco di branca) in 3 ECG successivi (vedi sezione 7.4.5 del Protocollo). 15.Valori di ALT >2 volte l'ULN e bilirubinemia >1,5 volte l'ULN (il riscontro isolato di valori di bilirubinemia >1,5 volte l'ULN è accettabile se la bilirubina è frazionata e la bilirubina diretta risulta <35%) 16.Anamnesi positiva per epatopatia in corso o cronica, o anomalie epatiche o biliari note 17.Impiego di agenti immunosoppressori o immunomodulatori, quali metotrexato, azatioprina, leflunomide, micofenolato, mizoribina, inibitori della calcineurina, sirolimus, 6-mercaptopurina o talidomide nei 60 giorni precedenti il giorno 0. 18.Trattamento con ciclofosfamide nei 180 giorni precedenti il Giorno 0.
19.Trattamento con agenti anti-BLyS, anti-CD 20, anti-CD 22 o anti-CD 52, o con qualsiasi altra molecola che induca una deplezione delle cellule B nei 364 giorni precedenti il Giorno 0.
Per i restanti criteri di escusione fare riferimento sezione corrispondente nel protocollo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety and tolerability |
| Sicurezza e tollerabilità |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Weeks 24 and 52 |
| Settimane 24 e 52 |
|
| E.5.2 | Secondary end point(s) |
| ESSDAI score; stimulated salivary flow; oral dryness numeric response scale; B cell quantification within the salivary gland |
| Punteggio ESSDAI nel tempo; flusso salivare stimolato nel tempo; scala di valutazione numerica della xerostomia nel tempo; quantificazione delle cellule B tramite biopsia delle ghiandole salivari alla settimana 24 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 24 and 52 |
| Settimane 24 e 52 |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Sponsor in cieco |
| Sponsor unblinded |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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