E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Systemic Sclerosis and associated Interstitial Lung Disease |
Pacientes con esclerosis sistémica y enfermedad pulmonar intersticial asociada |
|
E.1.1.1 | Medical condition in easily understood language |
Systemic Sclerosis (SSc) is a disease of unknown etiology. Patients suffer from multiple organ fibrosis whereas lung fibrosis is one of the main driver for mortality. |
La esclerosis sistémica(SSc)es una enfermedad de etiología desconocida.Los pacientes sufren fibrosis orgánica múltiple aunque la fibrosis pulmonar es uno de los principales causantes de la mortalidad. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012977 |
E.1.2 | Term | Diffuse systemic sclerosis |
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 | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036814 |
E.1.2 | Term | Progressive systemic sclerosis |
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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042954 |
E.1.2 | Term | Systemic sclerosis pulmonary |
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 | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025109 |
E.1.2 | Term | Lung involvement in systemic sclerosis |
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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042953 |
E.1.2 | Term | Systemic sclerosis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate a reduction in the annual rate of decline in FVC in mL over 52 weeks |
Demostrar una reducción en la tasa anual de deterioro de la FVC en ml durante 52 semanas. |
|
E.2.2 | Secondary objectives of the trial |
To demonstrate efficacy in regard to skin fibrosis at week 52 and to demonstrate an improvement of patient's symptoms at week 52 |
Demostrar eficacia en relación a la fibrosis cutánea en la semana 52 y demostar una mejora en los síntomas de los pacientes en la semana 52. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >= 18 years
- 2013 ACR / EULAR classification criteria for SSc fulfilled
- SSc disease onset (defined by first non-Raynaud symptom) within 5 years
- SSc related Interstitial Lung Disease confirmed by HRCT; Extent of fibrotic disease in the lung >= 10%
- FVC >= 40% of predicted normal
- DLCO 30% to 89% of predicted normal |
- Edad >= 18 años
- Se cumplen los criterios de clasificación de ACR / EULAR 2013 para la SSc
- El comienzo de la SSc (definido como el primer síntoma que no corresponde al síndrome de Raynaud) debe haberse producido en el plazo de 5 años
-Patrón de la enfermedad pulmonar intersticial relacionada con la SSc confirmado mediante HRCT; el grado de enfermedad fibrótica en el pulmón debe ser >= 10%
- FVC >= 40% del valor normal teórico
- DLCO del 30% al 89% del valor teórico |
|
E.4 | Principal exclusion criteria |
- AST, ALT >1.5 x ULN
- Bilirubin >1.5 x ULN
- Creatinine clearance <30 mL/min
- Airway obstruction (pre-bronchodilator FEV1/FVC <0.7)
- Other clinically significant pulmonary abnormalities
- Significant pulmonary hypertension
- Cardiovascular diseases
- More than 3 digital fingertip ulcers
- Bleeding risk (such as predisposition to bleeding, fibrinolysis, full-dose anticoagulation, high dose antiplatelet therapy, history of hemorrhagic central nervous system (CNS) event within last year
- international normalised ratio (INR) >2, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT) by >1.5 x ULN)
- History of thrombotic event within last year
- Clinical signs of malabsorption or needing parenteral nutrition
- Previous treatment with nintedanib or pirfenidone
- Treatment with prednisone >10 mg/day, azathioprine, hydroxychloroquine, colchizine, D-penicillamine, sulfasalazine, cyclophosphamide, rituximab, tocilizumab, abatacept, leflunomide, tacrolimus, newer anti-arthritic treatments like tofacitinib and ciclosporine A, potassium para-aminobenzoate
- Unstable background therapy with either mycophenolate mofetil or methotrexate
- Previous or planned hematopoietic stem cell transplantation |
- AST, ALT >1.5 x ULN
- Bilirubin >1.5 x ULN
- Aclaramiento de creatinina <30 mL/min
- Obstrucción de las vías respiratorias (FEV1/FVC <0.7 antes de la broncodilatación)
- Otras anomalías pulmonares clínicamente significativas
- Hipertensión pulmonar significativa
- Enfermedades cardiovasculares
- Más de 3 úlceras digitales en la yema del dedo.
- Riesgo de hemorragia (como predisposición a la hemorragia, fibrinólisis, dosis completa de tratamiento anticaogulante, tratamiento antiagregante plaquetario a dosis elevadas, antecedentes de un episodio hemorrágico del sistema nervioso central (SNC) en el último año
- cociente internacional normalizado (INR) >2, prolongación en el tiempo de protrombina (PT) y tiempo de tromboplastina parcial (PTT) >1.5 x ULN)
- Antecedentes de episodio trombótico en el último año
- Signos clínicos de mala absorción o que necesiten nutrición parenteral.
- Tratamiento previo con nintedanib o pirfenidona
- Tratamiento con prednisona >10 mg/día, azatioprina, hidroxicloroquina, colchicina, D-penicilamina, sulfasalazina, ciclofosfamida, rituximab, tocilizumab, abatacept, leflunomida, tacrolimus, tratamientos de nueva generación para la artosis como tofacitinib y ciclosporina A, paraaminobenzoato de potasio
- Tratamiento de base inestable con micofenolato mofetilo o metotrexato
- Trasplante previo o programado de células madre hematopoyéticas |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1: Annual rate of decline in FVC in mL |
1: Tasa anual de deterioro de la FVC en ml |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1: 52 weeks |
1: 52 semanas |
|
E.5.2 | Secondary end point(s) |
1: Absolute change from baseline in the mRSS
2: Absolute change from baseline in SGRQ total score
3: Annual rate of decline in FVC in percent predicted
4: Absolute change from baseline in FVC in mL
5: Relative change from baseline (%) of mRSS
6: Time to all-cause mortality
7: Absolute change from baseline in DLCO in percent predicted
8: Absolute change from baseline in digital ulcer net burden
9: Absolute change from baseline in SHAQ total score
10: Absolute change from baseline in FACIT dyspnoea score |
1: Cambio absoluto respecto al periodo basal en el Índice cutáneo de Rodnan modificado(mRSS)
2: Cambio absoluto respecto al periodo basal en la puntuación total del cuestionario SGRQ
3: Tasa anual de deterioro de la FVC expresada en porcentaje teórico de referencia
4: Cambio absoluto respecto al periodo basal en la FVC en mL
5: Cambio relativo respecto al periodo basal (%) en el índice mRSS
6: Tiempo trnascurrido hasta la mortalidad por cualquier causa
7: Cambio absoluto respecto al periodo basal en la DLCO en porcentaje teórico de referencia
8: Cambio absoluto respecto al periodo basal en la carga neta de las úlceras digitales
9: Cambio absoluto respecto al periodo basal en la puntuación total del cuestionario SHAQ
10: Cambio absoluto respecto al periodo basal en la puntuación de disnea del cuestionario FACIT |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1: 52 weeks
2: 52 weeks
3: 52 weeks
4: 52 weeks
5: 52 weeks
6: 52 weeks
7: 52 weeks
8: 52 weeks
9: 52 weeks
10: 52 weeks |
1: 52 semanas
2: 52semanas
3: 52 semanas
4: 52 semanas
5: 52 semanas
6: 52 semanas
7: 52 semanas
8: 52 semanas
9: 52 semanas
10: 52 semanas |
|
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 | 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 | 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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 83 |
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 |
Australia |
Belgium |
Canada |
China |
Denmark |
France |
Germany |
Greece |
India |
Ireland |
Israel |
Italy |
Japan |
Netherlands |
Poland |
Portugal |
Spain |
Switzerland |
United Kingdom |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 15 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 27 |