| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Systemic Lupus Erythematosus |
| Lupus eritematoso sistemico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Systemic Lupus Erythematosus |
| Lupus eritematoso sistemico |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10042945 |
| E.1.2 | Term | Systemic lupus erythematosus |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue 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 |
| The primary objective of this study is to evaluate the efficacy of sifalimumab compared to placebo in subjects with chronic, moderatelyto- severely active SLE with an inadequate response to SOC SLE at Day 365 (Week 52). |
| L’obiettivo primario dello studio e' quello di valutare l’efficacia di Sifalimumab al giorno 365 (settimana 52) in confronto al placebo, in pazienti con Lupus Eritematoso Sistemico (LES) cronico attivo, da moderato a severo, con un’inadeguata risposta al trattamento standard per il Lupus Eritematoso Sistemico. |
|
| E.2.2 | Secondary objectives of the trial |
| 1) To evaluate the effect of sifalimumab compared to placebo in reducing background oral corticosteroids dosage. 2) To evaluate the effect of sifalimumab compared to placebo in improving inflammatory cutaneous lupus lesions. 3) To evaluate the effect of sifalimumab compared to placebo in improving fatigue. 4) To evaluate the safety profile of sifalimumab. |
| 1) Valutare l’effetto di sifalimumab in confronto al placebo nella riduzione del dosaggio di background dei corticosteroidi orali 2) Valutare l’effetto di sifalimumab in confronto al placebo nel miglioramento delle lesioni infiammatorie cutanee causate dal lupus 3) Valutare l’effetto di sifalimumab in confronto al placebo nel miglioramento dell’affaticamento 4) Valutare il profilo di sicurezza di sifalimumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1) Able to comprehend and complete the informed consent, and all protocol-related subject assessments. 2) Age 18-75 years. 3) Written informed consent. 4) Fulfils at least 4 of the 11 American College of Rheumatology (ACR) classification criteria for SLE, one of which must be: a) Significantly positive antinuclear antibody (ANA) test at screening by immunofluorescent assay (IFA) at central lab; OR b) Elevated antidsDNA or Sm antibody at screening as determined by central lab 5) Weight ≥ 40.0 kg. 6) Diagnosis of pediatric or adult SLE with chronic disease activity requiring ongoing treatment or observation for ≥ 24 weeks prior to screening. 7) Receiving at least one of the following (at stable doses) prior to signing ICF through Day 1: a) prednisone (or equivalent) ≤ 20 mg/day for at least 2 weeks; b) one of the following for at least 8 weeks: azathioprine, an antimalarial, mycophenolate mofetil/ mycophenolic acid, weekly administrations of oral or SC methotrexate. 8) External Adjudication Group confirmation of both: a) SLEDAI-2K score ≥ 6 points or `Clinical` SLEDAI-2K score ≥ 6 points; b) At least one of the following: i) BILAG-2004 Index level A disease in ≥ 1 body/organ system ii) BILAG-2004 Index level B disease in ≥ 2 body/organ systems. 9) Day 1 `Clinical` SLEDAI-2K score ≥ screening `Clinical` SLEDAI-2K score. 10) Physicians Global assessment (MDGA) ≥ 1.0 on a 0-3 scale at screening. 11) Females of childbearing potential must use 2 effective methods of avoiding pregnancy from screening through 90 days after the final dose of investigational product unless surgically sterile, has a sterile male partner, is 1 year postmenopausal, or practices abstinence. 12) Non-sterilized males must practice two effective contraceptive measures with a female of childbearing potential from Day 1 through at least 90 days after the last dose of investigational product has been administered. 13) Females with an intact cervix must have documentation of a Pap smear with no documented malignancy within 24 weeks prior to Day 1. 14) Willing to forego other forms of experimental treatment for SLE during the study. 15) Meets various criteria for freedom from tuberculosis. 16) Adequate peripheral venous access. |
| 1)In grado di comprendere e completare il consenso informato e tutte le valutazioni relative al protocollo soggetto. 2)Eta' compresa tra 18-75 anni 3)Firma Consenso informato 4) soddisfare almeno 4 degli 11 criteri della classificazione LES della American College of Rheumatology (ACR), uno di qesti criteri deve essere: a) anticorpi antinucleari (ANA) positivo allo screening eseguiti conmetodo ad immunofluorescenza dal laboratorio centralizzato O b) elevati valori di anticorpi dsDNA o anticorpi Sm allo screening determinati da laboratorio centrale 5) peso ≥ 40 Kg, 6) diagnosi di LES pediatrico o adulto con attivita' di malattia cronica che richiede un trattamento in corso o di osservazione per ≥ 24 settimane precedenti allo screening, 7) aver ricevuto almeno uno dei seguenti farmaci (a dose stabile) prima della firma del consenso al giorno 1: - prednisone (o equivalente) ≤ 20 mg/giorno per almeno 2 settimane. - uno dei seguenti per almeno 8 settimane: azathioprina, un antimalarico, micofenolato mofetile/acido micofenolico, somministrazioni settimanali per os o SC di metotressato, 8) Conferma da parte di un gruppo esterno (External Adjudication Group) di entrambi i seguenti criteri: a)punteggio SLEDAI-2K ≥ 6 O punteggio ‘Clinical’ SLEDAI-2K ≥ 6; b) almeno uno dei seguenti: i) indice BILAG-2004 level A ≥ 1 organo o sistema ii) Indice BILAG-2004 level B n ≥ 2 organi o sistemi, 9)Al giorno 1 punteggio della `Clinical` SLEDAI-2K ≥ al punteggio allo screening della `Clinical` SLEDAI-2K, 10) Allo screening un Physicians Global assessment (MDGA) ≥ 1.0 su una scala da 0 a 3, 11) Donne in eta' fertile devono utilizzare due metodi efficaci per evitare la gravidanza dal momento dello screening fino a 90 giorni dopo la dose finale del prodotto in sperimentazione a meno che non siano chirurgicamente sterili, non abbaino un partner maschio sterile, non siano in menopausa da 1 anno, o non pratichino l`astinenza sessuale. 12) Uomini non sterilizzati con una partner in eta' fertile devono adottare 2 metodi contraccettivi efficaci dal giorno dello screening fino a 90 giorni dopo l`ultima dose di prodotto in sperimentazione. 13) Donne con cervice intatta deveno documentare con Pap l` assenza di malignita' nelle entro 24 settimane prima del 1 ° giorno, 14) Disponibilita' a rinunciare ad altre forme di trattamento sperimentale per il LES durante lo studio. 15)libero da tubercolosi 16)Adeguato accesso venoso periferico. |
|
| E.4 | Principal exclusion criteria |
| 1) Any condition that would interfere with evaluation of the IMP or interpretation of subject safety or study results. 2) Concurrent enrollment in any other study with an IMP within 4 weeks prior to Day 1 or within 5 half-lives of the IMP used in that study, whichever is longer. 3) Employees of the study site or any other individuals involved with the study or immediate family members. 4) Receipt of any of: a) any new oral prednisone therapy (or equivalent) or any change in current oral prednisone dose (or equivalent) from 2 weeks prior to signing of the ICF through Day 1; b) any new dose or change in current dose of any of the following anytime in the 8 weeks prior to signing of the ICF through Day 1: azathioprine; any antimalarial; mycophenolate mofetil/mycophenolic acid; oral methotrexate; or SC methotrexate. 5) Receipt of any of the following: a) azathioprine > 150 mg/day; b) mycophenolate mofetil/mycophenolic acid > 3.0 grams/day; c) oral or SC methotrexate > 20 mg/week; d) any change in route of administration of oral or SC methotrexate anytime within the 8 weeks prior to signing of the ICF. 6) Receipt of more than one dose of sifalimumab prior to screening. 7) Receipt of a biologic agent within 5 half-lives or prior to loss of PD and/or clinical effect, whichever is longer, prior to signing of the ICF. 8) A known history of allergy or reaction to any component of the IMP formulation or history of anaphylaxis to any human gamma globulin therapy. 9) Receipt of more than one prescribed NSAID at an anti-inflammatory dose within 2 weeks (14 days) prior to Day 1; OR receipt of fluctuating doses of a prescribed NSAID within 2 weeks (14 days) prior to Day 1;. 10) Receipt of any of the following: a) any live vaccine within 4 weeks prior to signing the ICF; b) oral anti-infectives (including antivirals) for active infection within 2 weeks prior to Day 1; c) BCG vaccine within 1 year of signing the ICF; d) any restricted medication (as listed in Appendix 3 of the protocol). 11) Receipt of any of the following: a) etanercept ≤ 4 weeks prior to signing the ICF; b) adalimumab, infliximab, or golimumab ≤ 12 weeks prior to signing the ICF; c) rituximab or belimumab < 24 weeks prior to signing the ICF. 12) Any fluctuation in hormone replacement therapy dose within 8 weeks of signing the ICF. 13) Active severe or unstable neuropsychiatric SLE that would make the subject unsuitable for the study or unable to fully understand the ICF. 14) Within 8 weeks prior to screening, active severe SLE-driven renal disease or unstable renal disease. 15) A diagnosis (within 1 year) of mixed connective tissue disease or any history of overlap syndromes of SLE with rheumatoid arthritis, erosive arthritis, or scleroderma. 16) History of, or current, inflammatory joint or skin disease other than SLE that could interfere with the inflammatory arthritis or skin assessments and confound the disease activity assessments. 17) History of asthma that has required treatment with oral or parenteral corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to randomization. 18) Known history of a primary immunodeficiency or an underlying condition such as HIV infection or splenectomy that predisposes to infection. for other, refer to CSP |
| 1.Qualunque condizione che possa interferire con la valutazione del farmaco di studio o con l’interpretazione della sicurezza del soggetto o dei risultati dello studio. 2.Contemporaneo arruolamento in altri studi che prevedono la somministrazione del farmaco di studio o nelle 4 settimane precedenti il giorno 1 o in un periodo di tempo pari a 5 emivite del farmaco di studio; fare riferimento al periodo di tempo piu' lungo. 3. Impiegati del centro in cui viene svolto lo studio o individui coinvolti nello studio o membri della loro famiglia. 4. Assunzione di: a) nuova terapia con prednisone (o farmaco equivalente) per via orale o qualunque cambio nella dose abituale di prednisone (o farmaco equivalente) per via orale nelle 2 settimane precedenti la firma del consenso fino al giorno 1; b) nuova dose o cambio nella dose abituale di uno dei seguenti farmaci nelle 8 settimane precedenti la firma dell consenso fino al giorno 1: azatioprina; farmaci antimalarici; micofenolato mofetil/ acido micofenolico; metotrexate per via orale; metotrexate per via sottocutanea. 5. Assunzione di uno dei seguenti farmaci: a) azatioprina in dose > 150 mg al giorno; b) micofenolato mofetil/ acido micofenolico in dose > 3.0 g al giorno; c) metotrexate per via orale o per via sottocutanea in dose > 20 mg al giorno; d) cambio della via di somministrazione di metotrexate per via orale o sottocutanea nelle 8 settimane precedenti la firma del consenso. 6. Assunzione di piu' di una dose di sifalimumab prima dello screening. 7. Assunzione di un farmaco biologico in un periodo di tempo o pari a 5 emivite del farmaco o che abbia esaurito ogni effetto farmacodinamico e/o clinico precedente la firma dell’ICF. Fare riferimento al periodo di tempo piu' lungo. 8. Storia conosciuta di allergia o reazione a una delle componenti del farmaco di studio una storia di anafilassi per una terapia con globuline gamma umane. 9. Assunzione di uno o piu' FANS ad una dose antiinfiammatoria entro 2 settimane (14 giorni) dal giorno 1; o assunzione di una dose fluttuante di FANS entro 2 settimane (14 giorni) dal giorno 1. 10. Assunzione di una delle seguenti terapie: a) ogni vaccino vivo entro le 4 settimane dalla firma del consenso; b) antiinfettivi orali ( inclusi antivirali) per infezioni attive entro le 2 settimane dal giorno 1; c) vaccino BCG entro 1 anno dalla firma dell’ICF; d) ogni altro farmaco non consentito (vedi Appendice 3 del Protocollo). 11. Assunzione di uno dei seguenti farmaci: a) etanercept ≤ 4 settimane prima della firma del consenso; b) adalimumab, infliximab o golimumab ≤ 12 settimane dalla firma del consenso; c) rituximab o belimumab < 24 settimane dalla firma del consenso; d) ogni altro farmaco non consentito (vedi appendice 3 del protocollo) 12. Ogni cambiamento di dose alla terapia ormonale sostitutiva nelle 8 settimane prima della firma del consenso 13. LES neuropsichiatrico attivo severo o instabile che rende il paziente non adatto allo studio e non in grado di firmare il consenso informato 14. LES attivo severo con implicazione renale o malattia renale instabile da 8 settimane prima dello screening 15. Una diagnosi (durante l’ultimo anno) di malattia mista del tessuto connettivo o una storia di sovrapposizione della sindrome del LES con artrite reumatoide, artrite erosiva o scleroderma 16. Una storia passata o presente di malattia infiammatoria delle articolazioni o della pelle oltre a quella del LES che potrebbe interferire con l’artrite infiammatoria o le valutazioni della pelle e confondere le valutazioni fatte sull’attivita' della malattia 17. Una storia di asma che ha richiesto un trattamento con corticosteroidi orali o parenterali per un totale di piu' di 2 settimane durante le 24 settimane prima della randomizzazione. 18. Una storia provata di immunodeficienza primaria o una condizione come una infezione da HIV o una splenectomia c |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint for this study is the proportion of subjects achieving a response in an SLE responder index [SRI (4)] at Day 365 in subjects with chronic moderately-to-severely active SLE. An SRI(4) Responder is defined as 1) a reduction in baseline SLEDAI-2K disease activity score of ≥ 4 points; and 2) no worsening of disease from baseline as measured by the MDGA (defined as an increase of ≥ 10% on a 0-3.0 VAS); and 3) no new BILAG-2004 Index A organ system score and no more than one new or worsening BILAG-2004 Index B organ system scores. There will be 6 primary comparisons for the primary endpoint. Sifalimumab 200 mg versus placebo, sifalimumab 600 mg versus placebo, and sifalimumab 1200 mg versus placebo will be compared for the overall population. The same 3 dose comparisons will also be performed for the subpopulation of subjects with a positive diagnostic test result for type I IFN signature at screening. The primary endpoint will be analyzed using a logistic regression model. The independent variables in the model will include treatment groups and stratification factors. The multiplicity adjustment for 3 dose comparisons within each of the 2 study populations, the overall population and the baseline gene signature positive subpopulation, will be done by performing a global test of all treatments prior to performing pairwise comparisons. No multiplicity adjustment for the 2 study populations is planned. An additional analysis with a more rigorous multiplicity adjustment approach may also be performed. The details of the multiplicity adjustments will be documented in the SAP that will be finalized prior to unblinding. Unless otherwise specified, the stratification factors will include geographic region (Latin America, Eastern Europe, and Asia vs. North America, Western Europe, and South Africa), SLEDAI-2K score at screening (< 10 points vs. ≥ 10 points), and the results of a diagnostic test for type I IFN signature in whole blood at screening using a 4-gene diagnostic test (positive vs. negative) for the overall population, and include geographic region and SLEDAI-2K score at screening only for subpopulation of subjects with a positive diagnostic test result for type I IFN signature at screening. The primary endpoint analysis will be conducted using the mITT Population. This analysis will also be conducted on the PP population as a sensitivity analysis. The dose-response trend based on SRI (4) at Day 365 will be tested using a Cochran-Armitage trend test. Other dose-response models may be evaluated. The details of the dose-response analysis will be described in the SAP. |
| In questo studio l’endpoint di efficacia primaria e' la proporzione di pazienti con Lupus Eritematoso Sistemico cronico attivo, da moderato a severo, che rispondono al trattamento al giorno 365 (settimana 52) secondo la scala di indice di risposta del LES. [SRI (4)]. L’endpoint primario verra' analizzato utilizzando un modello di regressione logistica. I seguenti endpoints secondari di efficacia saranno valutati nella popolazione totale con LES cronico, da moderato a severo ed in una sottopopolazione di pazienti con test diagnostico positivo per “IFN tipo I signature” allo screening. · La proporzione di pazienti in trattamento al baseline con una dose di prednisolone orale (o equivalente) ≥10 mg in grado di diminuire il dosaggio fino a 7.5 mg al giorno, al giorno 365 saranno confrontati tra i gruppi di trattamento utilizzando un modello di regressione logistica. · La proporzione di pazienti con un indice cutaneo di attivita' e severita' del lupus eritematoso sistemico ≥10 al baseline che raggiungeranno una riduzione ≥ 4 punti al giorno 365 saranno confrontati tra gruppi di trattamento utilizzando un modello di regressione logistica. · La proporzione di pazienti che raggiungeranno una riduzione superiore a 3 punti nella scala della Functional Assessment of Chronic Illness Therapy - Fatigue Scale al giorno 365 saranno confrontati tra gruppi di trattamento utilizzando un modello di regressione logistica. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| The following secondary efficacy endpoints will be evaluated in the overall population of subjects with chronic, moderately-to-severely active SLE; and a subpopulation of subjects with a positive diagnostic test for type I IFN signature at screening. 1) The proportion of subjects on ≥ 10 mg oral prednisone (or equivalent) at baseline who are able to taper ≤ 7.5mg/ day at Day 365 will be compared between treatment groups using logistic regression model. 2) The proportion of subjects with an active CLASI score ≥ 10 at baseline who achieve a ≥ 4-point reduction at Day 365 will be compared between treatment groups using logistic regression model. 3) The proportion of subjects who achieve a > 3-point reduction in the FACIT-FATIGUE Scale at Day 365 will be compared between treatment groups using logistic regression model. |
| The following secondary efficacy endpoints will be evaluated in the overall population of subjects with chronic, moderately-to-severely active SLE; and a subpopulation of subjects with a positive diagnostic test for type I IFN signature at screening. 1) The proportion of subjects on ≥ 10 mg oral prednisone (or equivalent) at baseline who are able to taper ≤ 7.5mg/ day at Day 365 will be compared between treatment groups using logistic regression model. 2) The proportion of subjects with an active CLASI score ≥ 10 at baseline who achieve a ≥ 4-point reduction at Day 365 will be compared between treatment groups using logistic regression model. 3) The proportion of subjects who achieve a > 3-point reduction in the FACIT-FATIGUE Scale at Day 365 will be compared between treatment groups using logistic regression model. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 | No |
| 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 |
| Brazil |
| Canada |
| Chile |
| India |
| Mexico |
| Peru |
| Philippines |
| South Africa |
| Thailand |
| United States |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 28 |
| 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 | 34 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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