| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Active Systemic Lupus Erythematosus |
| lupus eritematoso sistémico (LES) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Systemic Lupus Erythematosus |
| lupus eritematoso sistémico |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025139 |
| E.1.2 | Term | Lupus erythematosus systemic |
| E.1.2 | System Organ Class | 100000004859 |
|
| 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 |
| Evaluate the efficacy of efavaleukin alfa at week 52, as measured by the SRI-4 response |
| -Evaluar la eficacia de efavaleucina alfa en la semana 52, determinada según la respuesta del SRI-4. |
|
| E.2.2 | Secondary objectives of the trial |
- Evaluate the efficacy of efavaleukin alfa at week 52, as measured by the BICLA index responses
- Evaluate the efficacy of efavaleukin alfa at week 52, as measured by LLDAS response
- Evaluate the efficacy of efavaleukin alfa at week 52, as measured by OCS tapering
- Evaluate the efficacy of efavaleukin alfa at week 24, as measured by SRI-4 response
- Evaluate the efficacy of efavaleukin alfa at week 24, as measured by the BICLA index responses
- Evaluate the efficacy of efavaleukin alfa at weeks 24 and 52, as measured by hSLEDAI
- Evaluate the efficacy of efavaleukin alfa on joints and skin
- Evaluate the efficacy of efavaleukin alfa using BILAG score
- Evaluate the efficacy of efavaleukin alfa using patient reported outcomes
- Characterize the safety of efavaleukin alfa
- Characterize the PK of efavaleukin alfa |
-Evaluar la eficacia de efavaleucina alfa en la semana 52, determinada por las respuestas del índice BICLA
-Evaluar la eficacia de efavaleucina alfa en la semana 52, determinada por la respuesta del LLDAS.
-Evaluar la eficacia de efavaleucina alfa en la semana 52, determinada por la reducción gradual de la dosis de CSO.
-Evaluar la eficacia de efavaleucina alfa en la semana 24, determinada por la respuesta del SRI-4.
-Evaluar la eficacia de efavaleucina alfa en la semana 24, determinada por las respuestas del índice BICLA.
-Evaluar la eficacia de efavaleucina alfa en las semanas 24 y 52, determinada por el hSLEDAI.
-Evaluar la eficacia de efavaleucina alfa en las articulaciones y la piel.
-Evaluar la eficacia de efavaleucina alfa mediante la puntuación del BILAG.
-Evaluar la eficacia de efavaleucina alfa según los resultados notificados por los pacientes. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria - Screening Visit
101 Subject has provided informed consent prior to initiation of any study specific activities/procedures.
102 Age ≥ 18 years to 75 years at screening.
103 Fulfills classification criteria for SLE according to the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE (Aringer et al, 2019), with antinuclear antibody ≥ 1:80 by immunofluorescence on Hep-2 cells being present at screening. AntidsDNA results based on the Phadia method will be used for SLE classification criteria and for the purposes of hSLEDAI scoring during screening and throughout the study.
104 Hybrid SLEDAI score ≥ 6 points with a "Clinical" hSLEDAI score ≥ 4 points. The "Clinical" hSLEDAI is the hSLEDAI assessment score without the inclusion of points attributable to laboratory results, including urine and immunologic parameters. Including the following protocol specific rules: - Arthritis: for hSLEDAI scoring purposes, arthritis must involve small joints in the hands or wrists. - Alopecia: subjects should have hair loss without scarring; should neither have alopecia areata nor androgenic alopecia; and should have a CLASI activity score for alopecia ≥ 2. - Oral ulcers: ulcers location and appearance must be documented by the investigator. - Scleritis and episcleritis: the presence of stable SLE-related scleritis and episcleritis (ie, that will likely not require initiation/increase in immunosuppressants/immunomodulators as outlined in the inclusion/exclusion criteria) must be documented by an ophthalmologist and other causes excluded. - Renal: subjects with urine protein/creatinine ratio < 3000 mg/g (or equivalent) in a clean catch spot urine sample can enroll and be scored in the hSLEDAI, provided the subject has a clinical hSLEDAI ≥ 4. - Pleurisy and Pericarditis: symptoms of pleurisy and pericarditis must be accompanied by objective findings to be scored in the hSLEDAI.
105 BILAG index score (BILAG 2004) of ≥ 1 A item or ≥ 2 B items.
106 Must be taking ≥ 1 of the following SLE treatments (or regional equivalent): hydroxychloroquine, chloroquine, quinacrine, mycophenolate mofetil, azathioprine, methotrexate, dapsone, or oral calcineurin inhibitors, or OCS. A subject may enter the study on OCS alone (prednisone 10 mg/day or equivalent) only if the subject has previously documented trial of anti-malarial or immunosuppressant treatment for SLE. Subjects must be on a stable dose for ≥ 8 weeks prior to screening for all antimalarials and immunosuppressants, with the exception of OCS doses which must be stable for ≥ 2 weeks prior to screening.
107 For subjects taking OCS, the dose must be ≥ 20 mg/day of prednisone or OCS equivalent, and the dose must be stable for ≥ 2 weeks prior to screening visit.
Inclusion Criteria - Day 1 (Baseline)
The baseline/day 1 visit should occur after confirmation of eligibility by the Central Review Team within 33 days after the screening visit. At the baseline/day 1 visit, the following 2 criteria should be assessed prior to randomization:
108 Stability of SLE treatments: OCS and other immunosuppressants/ immunomodulators doses must be stable since screening visit, by reviewing subject’s medication history.
109 Disease activity: active disease as indicated by clinical hSLEDAI score ≥ 4 must be observed |
-Los sujetos elegibles deben tener entre 18 y 75 años, ambos incluidos, y poder proporcionar el consentimiento informado.
-Para obtener una lista completa de los criterios de inclusión, consulte el protocolo
-Los sujetos deben cumplir los criterios de clasificación establecidos en 2019 por la Liga Europea contra el Reumatismo (EULAR) y el Colegio Americano de Reumatología (ACR) para el LES, con una presencia de anticuerpos antinucleares en una proporción 1:80 mediante inmunofluorescencia en las células HEp-2 presentes en la selección. Además, en la selección, los sujetos deben presentar un hSLEDAI ≥ 6 puntos y un hSLEDAI clínico 4 puntos.
-Los sujetos deben estar tomando 1 de los siguientes tratamientos para el LES (o un tratamiento regional equivalente): micofenolato de mofetilo, azatioprina, metotrexato, hidroxicloroquina, cloroquina, dapsona, quinacrina, inhibidores orales de la calcineurina o CSO. Un sujeto tratado con CSO en monoterapia (prednisona 10 mg/día o equivalente) puede entrar en el estudio solo si ha participado en un ensayo previamente documentado de un tratamiento antimalárico o inmunosupresor para el LES.
-Los sujetos deben recibir una dosis estable de todos los antimaláricos e inmunosupresores durante ≥ 8 semanas antes de la selección, con la excepción de las dosis de CSO, que deben permanecer estables durante 2 semanas antes de la selección. |
|
| E.4 | Principal exclusion criteria |
Subjects are excluded from the study if any of the following criteria apply:
201 Lupus nephritis with urine protein creatinine ratio 3000 mg/g at screening or having required induction therapy within 1 year prior to screening.
202 Active CNS lupus within 1 year prior to screening including, but not limited to, aseptic meningitis, ataxia, CNS vasculitis, cranial neuropathy, demyelinating syndrome, optic neuritis, psychosis, seizures, or transverse myelitis.
Other Medical Conditions
203 Currently present or within 1 year prior to screening a diagnosis of any inflammatory joint or skin disease other than SLE which would interfere with SLE disease assessment based on investigator judgement.
204 History of any disease other than SLE that has required treatment with oral or parenteral corticosteroids for > 2 weeks within 4 months prior to screening.
205 Active infection for which anti-infectives were indicated within 4 weeks prior to screening visit OR presence of serious infection, defined as requiring hospitalization or intravenous anti-infectives within 8 weeks prior to screening visit.
206 Active tuberculosis or latent tuberculosis with no documented past history of adequate treatment per local standard of care.
207 Positive test for tuberculosis during screening defined as: either a positive or indeterminate QuantiFERON®-TB or T-spot test OR positive purified protein derivative (PPD).
208 Positive for hepatitis B surface antigen (HBsAg); or positive for hepatitis B core antibody (HBcAb) in the presence of detectable viral DNA in peripheral blood
209 Positive for hepatitis C antibody in the presence of detectable viral RNA in peripheral blood
210 Known history of HIV or positive HIV test at screening.
211 Presence of 1 or more significant concurrent medical conditions per investigator judgment
212 Any history of malignancy
213 Currently receiving or had treatment with: cyclophosphamide, chlorambucil, nitrogen mustard, or any other alkylating agent within 6 months prior to screening or sirolimus within 4 weeks prior to screening.
214 Currently receiving or had treatment with a JAK inhibitor within 3 months or less than 5 drug half-lives prior to screening.
215 Currently receiving or had treatment with an immune checkpoint inhibitor
216 Currently receiving or had treatment within 12 months prior to screening with T-cell depleting agents.
217 Currently receiving or had treatment with recombinant IL-2.
218 Current or previous treatment with a biologic agent
219 Subjects who have received intraarticular, intralesional, or intramuscular corticosteroids within 2 weeks prior to screening or intravenous corticosteroids within 6 weeks prior to screening.
220 Subjects who have received live vaccines within 5 weeks prior to screening, or plan to receive live vaccines during the treatment period and up to 6 weeks after the end of treatment period in the study.
221 Currently receiving treatment in another investigational device or drug study.
222 Ending a treatment with an investigational drug or investigational device less than 3 months or 5 half-lives from the last dose of the investigational drug at screening.
223 Presence of laboratory abnormalities at screening
224 Any other laboratory abnormality, which in the opinion of the investigator or Central Review Team, poses a safety risk, will prevent the subject from completing the study or will interfere with the interpretation of the study results, or might cause the study to be detrimental to the subject. Other Exclusions
225 Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during the study and for an additional 6 weeks after the last dose of investigational product.
226 Female of childbearing potential with a positive pregnancy test.
227 Female subject of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 6 weeks after the last dose of investigational product.
228 Subject has known sensitivity to any products to be administered during dosing.
229 Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge.
230 History or evidence of any other clinically significant disorder, condition or disease that, in the opinion of the investigator or Central Review Team would pose a risk to subject safety or interfere with the study evaluation, procedures or completion. |
-Los sujetos que hayan requerido tratamiento de inducción para la nefritis lúpica durante el año anterior a la selección o para el lupus del sistema nervioso central (SNC) durante el último año no son elegibles para la inclusión.
-Los sujetos con cualquier otra enfermedad aparte del LES que hayan requerido tratamiento con corticosteroides orales o parenterales durante 2 semanas en los 4 meses previos a la visita de selección o con cualquier enfermedad concurrente clínicamente significativa y/o anomalía analítica significativa.
-Las mujeres participantes no deben estar embarazadas ni en período de lactancia ni tener previsto quedarse embarazadas durante el tratamiento ni durante las 6 semanas posteriores a la última dosis del producto en investigación.
-Para obtener una lista completa de los criterios de exclusión, consulte el protocolo |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - SRI-4 response at week 52 |
| -Respuesta del SRI-4 en la semana 52. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- BICLA response at week 52
- LLDAS response at week 52
- Reduction of OCS to ≤ 7.5 mg/day by week 44 and sustained through
week 52 in subjects with a baseline OCS dose ≥ 10 mg/day
- SRI-4 response at week 24
- BICLA response at week 24
- hSLEDAI response (ie, reduction ≥ 4 points from baseline) at
week 24
hSLEDAI response (ie, reduction ≥ 4 points from baseline) at
week 52
- Improvement from baseline in tender and swollen joint count
≥ 50% at weeks 8, 12, 24, 36, and 52 in subjects with ≥ 6 tender and
swollen joints involving hands and wrists at baseline
- Improvement from baseline in CLASI activity score ≥ 50% at
week 8, 12, 24, 36, and 52 in subjects with a CLASI activity
score ≥ 8 at baseline
- Annualized flare rate (as measured by BILAG score designation of “worse” or “new” resulting in a B score in ≥ 2 organs or an A score in ≥ 1 organ) over 52 weeks
- Change from baseline in fatigue standardized score using the PROMIS Fatigue SF 7a at week 12, 24, 36, and 52
- Change from baseline in the physical component score, mental
component score and individual domains of the SF 36 v2 at week
12, 24, 36, and 52
- Change from baseline in the domain scores on the Lupus QoL
at weeks 12, 24, 36, and 52
- Treatment-emergent adverse events
- Serious adverse events
- Clinically significant changes in laboratory values and vital signs
- Trough and sparse post-dose serum concentrations of efavaleukin alfa |
-Respuesta del BICLA en la semana 52.
-Respuesta del LLDAS en la semana 52.
-Reducción de la dosis de CSO a ≤ 7,5 mg/día en la semana 44 y mantenimiento de la dosis hasta la semana 52 en sujetos con una dosis basal de CSO ≥ 10 mg/día.
-Respuesta del SRI-4 en la semana 24.
-Respuesta del BICLA en la semana 24.
-Respuesta del hSLEDAI (es decir, reducción ≥ 4 puntos respecto al valor basal) en la semana 24.
-Respuesta del hSLEDAI (es decir, reducción ≥ 4 puntos respecto al valor basal) en la semana 52.
-Mejora ≥ 50% en el recuento de articulaciones dolorosas e inflamadas respecto al valor basal en las semanas 8, 12, 24, 36 y 52 en sujetos con ≥ 6 articulaciones dolorosas e inflamadas, incluidas las manos y las muñecas, en el momento basal.
-Mejora ≥ 50% en la puntuación de la actividad del CLASI respecto al valor basal en las semanas 8, 12, 24, 36 y 52 en sujetos con una puntuación de actividad del CLASI 8 en el momento basal.
-Tasa anualizada de brotes (determinada según la designación de «peor» o «nuevo» de la puntuación del BILAG con resultado de una puntuación B en ≥ 2 órganos o una puntuación A en ≥ 1 órgano) durante 52 semanas.
-Cambio respecto al valor basal en la puntuación estandarizada de la fatiga mediante el formulario PROMIS-Fatigue SF7A en las semanas 12, 24, 36 y 52.
-Cambio respecto al valor basal en la puntuación del componente físico, la puntuación del componente mental y los dominios individuales del SF-36v2 en las semanas 12, 24, 36 y 52.
-Cambio respecto al valor basal en las puntuaciones de los dominios del cuestionario sobre CdV del lupus en las semanas 12, 24, 36 y 52. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 8, 12, 24, 36, and 52 |
| Semanas 8, 12, 24, 36 y 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 | 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 | 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Canada |
| Chile |
| Colombia |
| Hong Kong |
| Japan |
| Mexico |
| Russian Federation |
| Taiwan |
| Turkey |
| United States |
| Austria |
| Bulgaria |
| France |
| Greece |
| Italy |
| Poland |
| Switzerland |
|
| 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
|
| Completion of follow-up |
| finalización del seguimiento |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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