E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic lupus erythematosus (SLE) |
Lupus eritematoso sistémico |
|
E.1.1.1 | Medical condition in easily understood language |
Systemic Lupus |
lupus sistémico |
|
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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042946 |
E.1.2 | Term | Systemic lupus erythematosus rash |
E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042948 |
E.1.2 | Term | Systemic lupus erythematosus syndrome aggravated |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
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 | 10042947 |
E.1.2 | Term | Systemic lupus erythematosus synd |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029142 |
E.1.2 | Term | Nephritis systemic lupus erythematosus |
E.1.2 | System Organ Class | 100000004857 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067657 |
E.1.2 | Term | Systemic lupus erythematosus disease activity index increased |
E.1.2 | System Organ Class | 10022891 - Investigations |
|
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 | 10067658 |
E.1.2 | Term | Systemic lupus erythematosus disease activity index decreased |
E.1.2 | System Organ Class | 10022891 - Investigations |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067659 |
E.1.2 | Term | Systemic lupus erythematosus disease activity index abnormal |
E.1.2 | System Organ Class | 10022891 - Investigations |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10080670 |
E.1.2 | Term | Systemic lupus erythematosus reactivation |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
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 | 10073694 |
E.1.2 | Term | Lupus pleurisy |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040968 |
E.1.2 | Term | SLE arthritis |
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 |
To evaluate the safety and tolerability of ALPN-101 compared to placebo in subjects with moderate to severe active SLE |
Evaluar la seguridad y tolerabilidad de ALPN-101 en comparación con placebo en sujetos con SLE activo de moderado a grave |
|
E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of ALPN-101 in subjects with active SLE • To assess the pharmacokinetics (PK) of ALPN-101 in active SLE • To assess the incidence of anti-drug antibodies (ADA) against ALPN-101 |
• Evaluar la eficacia de ALPN-101 en sujetos con SLE activo • Evaluar la farmacocinética (PK) de ALPN-101 en el SLE activo • Evaluar la incidencia de anticuerpos antimedicamento (ADA) contra ALPN-101 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Written informed consent •Age 18 to 65 •Diagnosis of lupus for ≥ 6 months prior to Screening •Positive ANA and/or elevated anti-dsDNA and/or elevated anti-Smith antibody test at Screening •Active lupus at Screening and Baseline, as defined per-protocol and confirmed by the study's medical monitor •Standard lupus medications must be stable prior to Screening •Women must have a PAP smear and known HPV status within 12 months of Day 1 •All participants must use highly effective birth control if they/their partner are capable of becoming pregnant |
• Consentimiento informado por escrito • De 18 a 65 años • Diagnóstico de SLE en los ≥ 6 meses anteriores a la selección • Prueba de anticuerpos antinucleares (antinuclear antibody, ANA) positiva y/o elevación de anticuerpos anti-DNA y/o elevación de anticuerpos anti-Smith en la selección • SLE activo en la selección, confirmado por el el monitor médico del estudio y en el momento basal • Tratamiento habitual estable y apropiado para el SLE previo a la selección • Mujeres con el útero intacto: prueba de Papanicolaou con estado del virus del papilomavirus humano (human papillomavirus, HPV) <=12 meses antes del momento basal (día 1) • Todos los participantes deberán utilizar métodos anticonceptivos altamente efectivos si ellas/sus parejas pueden quedarse embarazadas |
|
E.4 | Principal exclusion criteria |
•Life-threatening or organ system-threatening lupus activity that is anticipated to require increased treatment during the study •Proteinuria consistent with nephrotic syndrome •Active lupus-related neuropsychiatric disease •Drug-induced lupus •Any serious health condition that would place the subject at undue risk from the study or would confound interpretation of safety or efficacy outcomes •Recent or serious ongoing infection; risk or history of serious infection •Receipt of live vaccination within 8 weeks of Day 1, or expected to require live vaccination during the study •Unacceptable Screening laboratory results •History of new, ongoing, or recurrent malignancy <= 5 years prior to Day 1, with some exceptions per-protocol •Pregnant or breastfeeding at the time of screening, or plans to become pregnant <= 3 months following the last dose of study drug •Prior diagnosis of, or fulfills diagnostic criteria for, another rheumatic disease that overlaps with lupus or another autoimmune or inflammatory disease that may confound clinical assessments or increase subject risk in the study •Diagnosis of, or fulfills diagnostic criteria for, fibromyalgia •Functional class IV lupus •Does not meet protocol washout periods for concomitant medications •Serious lupus disease activity, which warrants immediate immunosuppressive therapy not appropriate for the study or which makes the possibility of receiving placebo or investigational agent an inappropriate risk •Ongoing participation in another therapeutic clinical trial •Known hypersensitivity to ALPN-101, components thereof, or excipients contained in the drug formulation |
• Actividad del SLE que ponga en peligro la vida o afecte gravemente a órganos y sistemas y que sea lo suficientemente activo como para que se espere que requiera un aumento del tratamiento durante el estudio • Proteinuria compatible con síndrome nefrótico3. • Enfermedad neuropsiquiátrica activa relacionada con el lupus • Lupus inducido por medicamentos • Cualquier enfermedad o trastorno grave que pudiera poner al sujeto en un riesgo excesivo por el estudio o pudiera confundir la interpretación de los resultados de seguridad o eficacia • Infección grave reciente o en curso; riesgo o antecedentes de infección grave • Administración de vacunas con gérmenes vivos ≤8 semanas antes del momento basal (es decir, el día 1 antes de la aleatorización) o previsión de que requieran vacunas con gérmenes vivos durante el estudio • Resultados de laboratorio de la selección no aceptables • Antecedentes de neoplasias malignas nuevas, en curso o recurrentes de <=5 años antes de la administración de la primera dosis del medicamento del estudio, con ciertas excepciones señaladas en el protocolo • Embarazo o lactancia en la selección, o planificación de embarazo <=3 meses después de la última dosis del medicamento del estudio • Cumplimiento de los criterios diagnósticos de otra enfermedad reumática que se solape con el SLE y pueda confundir las evaluaciones clínicas en el estudio • Diagnóstico previo o cumplimiento de los criterios diagnósticos de fibromialgia • SLE de clase funcional IV • No cumplir los periodos de lavado de los medicamentos concomitantes señalados por el protocolo • Actividad grave del SLE que, en opinión del investigador, justifique un tratamiento inmunosupresor inmediato no apropiado para el estudio o que haga que la posibilidad de recibir placebo o un medicamento en investigación suponga un riesgo inadecuado • Participación en curso en otro ensayo clínico terapéutico • Hipersensibilidad conocida al ALPN-101, a sus componentes o a los excipientes contenidos en la formulación del medicamento |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability will be assessed by evaluating the type, frequency, severity, and seriousness of adverse events, including clinically significant changes in symptoms, physical exam findings, vital signs, laboratory tests (hematology, serum chemistries and coagulation, urinalysis), and electrocardiograms. |
La seguridad y la tolerabilidad se evaluarán a partir del tipo, la frecuencia, la severidad y la gravedad de los acontecimientos adversos, incluidos los cambios clínicamente significativos en los síntomas, los resultados de la exploración física, las constantes vitales, las pruebas de laboratorio (hematología, bioquímica sérica y coagulación, análisis de orina) y los electrocardiogramas. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
According to protocol |
De acuerdo con el protocolo |
|
E.5.2 | Secondary end point(s) |
Efficacy Endpoints: Efficacy endpoints will be assessed by evaluating disease activity relative to baseline and across treatment groups using the tools and assessments listed below, and derivatives calculated from them (e.g. SLE Responder Index [SRI] -4, -5, -6 response; time to and proportion with flare of SLE; others). -Global disease Activity Assessment Tools: • BILAG 2004 • SLEDAI-2K; SLEDAI-2K 30 • Physician’s Global Assessment of SLE Disease Activity (PhGA) -Organ-Specific Disease Activity Assessment Tools: • Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), with photography when appropriate • Swollen joints based on assessment of 28 joints (SJC-28) • Tender joints based on assessment of 28 joints (TJC-28) • Estimated glomerular filtration rate (eGFR) • Proteinuria assessed as urine protein to creatinine ratio (UPCR), • Urinary sediment analysis for hematuria, pyuria, and red cell casts -Patient Reported Outcomes and Quality of Life (QoL) Assessment tools: • Patient’s Global Assessment of Disease Activity (PtGA) • Short Form Health Survey-36 (SF-36) • Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) (13-Item) -Clinical Biomarkers of SLE Activity: • High-sensitivity C-reactive protein (hsCRP) • Complement levels: C3, C4, CH50 • Anti-dsDNA antibodies -Corticosteroids: • Dose of oral and parenteral corticosteroids
Pharmacokinetic Endpoints: Serum concentrations of ALPN-101 will be measured. Pharmacokinetic endpoints include estimates of maximum observed concentration (Cmax), area under the concentration-time curve (AUC), and trough concentration at the end of dosing intervals (Ctrough).
Immunogenicity Endpoints: The presence and titer of ADA against ALPN-101 will be assessed at Baseline (prior to study drug administration on Day 1) and at intervals throughout the study. Samples confirmed positive for ADA may be explored for neutralizing (NAb) capacity. The relationship between ADA and PK will be analyzed; relationship between ADA and clinical outcomes may be explored.
Pharmacodynamic Endpoints: Blood and urine will be collected at intervals; target saturation by ALPN-101 on circulating lymphocytes will be assessed; plasma, sera and peripheral blood mononuclear cells (PBMCs) will be prepared and may be assessed for biomarkers. |
Criterios de valoración de la eficacia: Los criterios de valoración de la eficacia se basarán en la actividad de la enfermedad en relación con el valor basal y en todos los grupos de tratamiento, utilizando los instrumentos y valoraciones que se indican a continuación, y las derivadas calculadas a partir de ellos (por ejemplo, respuesta 4, 5 o 6 en el índice de respondedores del SLE [SLE Responder Index, SRI]; el tiempo transcurrido hasta la aparición de un brote de SLE y el porcentaje de estos; otros). Instrumentos de valoración global de la actividad de la enfermedad: • Índice BILAG 2004 (British Isles Lupus Assessment Group) • Índices de actividad del lupus eritematoso sistémico (SLEDAI-2K y SLEDAI-2K 30) • Evaluación global de la actividad del SLE por parte del médico (Physician’s Global Assessment, PhGA) Instrumentos de valoración de la actividad de la enfermedad específicos de órgano: • CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index), con fotografía cuando corresponda • Recuento de articulaciones tumefactas, basándose en la evaluación de 28 articulaciones (swollen joint count based on assessment of 28 joints, SJC-28) • Recuento de articulaciones dolorosas a la palpación, basándose en la evaluación de 28 articulaciones (tender joint count based on assessment of 28 joints, TJC-28) • Tasa de filtración glomerular estimada (estimated glomerular filtration rate, eGFR) • Proteinuria como relación proteína/creatinina en orina (urine protein to creatinine ratio, UPCR) • Análisis del sedimento urinario para detectar hematuria, piuria y cilindros de hematíes Resultados comunicados por el paciente e instrumentos de evaluación de la calidad de vida (quality of life, QoL): • Evaluación global de la actividad de la enfermedad por parte del paciente (Patient’s Global Assessment, PtGA) • Encuesta breve de salud-36 (SF-36, short form-36) • Evaluación funcional del tratamiento en enfermedades crónicas – fatiga (13 ítems) (FACITīF, Functional Assessment of Chronic Illness Therapy-Fatigue, 13 items) Biomarcadores clínicos de la actividad del SLE: • Prueba de proteína C reactiva de alta sensibilidad (high-sensitivity C-reactive protein, hsCRP) • Nivel de complementos: C3, C4, CH50 • Anticuerpos anti-dsDNA Corticoides: • Dosis de corticoides orales y parenterales
Criterios de valoración de la farmacodinámica: Se medirán las concentraciones séricas de ALPN-101. Los criterios de valoración farmacocinética incluyen estimaciones de la concentración máxima observada (Cmax), el área bajo la curva de concentración-tiempo (area under the curve, AUC) y la concentración valle o concentración al final de los intervalos de administración (trough concentration, Ctrough).
Criterios de valoración de la inmunogenicidad La presencia y el título de ADA contra ALPN-101 se evaluarán en el momento basal (antes de la administración del medicamento del estudio el día 1) y a intervalos en el transcurso del estudio. Las muestras que den positivo en ADA se explorarán para determinar la capacidad neutralizante (neutralizing antibodies, Nab). Se analizará la relación entre los ADA y la PK; se podrá explorar la relación entre los ADA y los resultados clínicos.
Criterios de valoración de la farmacodinámica Se recogerán muestras de sangre y orina a intervalos; se evaluará el objetivo de saturación de ALPN-101 en los linfocitos circulantes; se preparará plasma, suero y células mononucleares de sangre periférica (peripheral blood mononuclear cells, PBMC) para evaluar la presencia de biomarcadores. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
According to protocol |
De acuerdo con el protocolo |
|
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity |
Inmunogenicidad |
|
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 | 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 |
Korea, Republic of |
Russian Federation |
United States |
France |
Germany |
Poland |
Spain |
|
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
|
LVLS |
Última Visita del Último Paciente (Last Patient Last Visit) |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 16 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |