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 |
Patients atteints de sclérodermie systémique avec atteinte interstitielle pulmonaire |
|
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 sclérodermie systémique est une maladie dont l'étiologie reste inconnue. Les patients peuvent avoir plusieurs atteintes d'organes mais l'atteinte pulmonaire reste la première cause de mortalité. |
|
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 | 18.1 |
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 | 18.1 |
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 | 18.1 |
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 | 18.1 |
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 | 18.1 |
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 |
Démontrer une réduction du taux annuel de déclin de la capacité vitale forcée (CVF) en mL sur 52 semaines |
|
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 |
Démontrer l’efficacité sur la fibrose cutanée à la semaine 52 et démontrer une amélioration des symptômes à la semaine 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
|
- Age >= 18 ans
- classification selon les critères 2013 ACR / EULAR pour la SSc
- Survenue de la SSc (définie par le premier symptôme non-Raynaud) au cours des 5 années
- SSc-ILD confirmée par HRCT; L’étendue des lésions fibrotiques pulmonaires doit être d’au moins 10 % sur l’HRCT
- FVC >= 40% de la valeur théorique
- DLCO entre 30% et 89% de la valeur théorique
|
|
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
- Bilirubine >1.5 x ULN
- Clairance de la créatinine <30 mL/min
- Obstruction bronchique (VEMS/CVF < 0,7 avant prise de bronchodilatateur)
- Autres anomalies pulmonaires cliniquement significatives
- Hypertension pulmonaire significative
- Maladies cardiovasculaires
- Plus de 3 ulcères affectant la pulpe des doigts
- facteurs de risque hémorragique (Prédisposition génétique connue aux saignements. Patient qui nécessite : Fibrinolyse ou traitement anticoagulant à pleine dose (par exemple anti-vitamine K, inhibiteur direct de la thrombine, héparine, hirudine) ou Traitement antiagrégant plaquettaire à forte dose). Antécédents d’hémorragie du système nerveux central (SNC) au cours de la dernière année
- Paramètres de la coagulation : International normalized ratio (INR) >2, temps de prothrombine (TP) et temps de céphaline avec activateur (TCA) > 1,5 x LSN
- Antécédents d’accident thrombotique au cours de la dernière année
- Patient présentant des signes cliniques de malabsorption ou nécessitant une nutrition parentérale
- Antécédents de traitement par Nintedanib ou Pirfénidone
- Traitement par prednisone >10 mg/jour, azathioprine, hydroxychloroquine, colchizine, D-penicillamine, sulfasalazine, cyclophosphamide, rituximab, tocilizumab, abatacept, leflunomide, tacrolimus, nouveaux agents antirhumatismaux comme tofacitinib and ciclosporine A, potassium para-aminobenzoate
- Traitement de fond à dose non stable par mycophénolate mofétil ou méthotrexate
- Antécédents de greffe de cellules souches hématopoïétiques |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1: Annual rate of decline in FVC in mL
|
1 : taux déclin annuel de la CVF en mL |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1: 52 weeks
|
1 : 52 semaines |
|
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: Modification absolue du score mRSS
2: Modification absolue du score SGRQ total
3: Taux annuel de déclin de la CVF en pourcentage de la valeur théorique
4: Modification absolue de la CVF en ml
5: Modification relative (%) du score mRSS
6: Temps écoulé jusqu’au décès toutes causes confondues
7: Modification absolue du DLCO (pourcentage de la valeur théorique)
8: Modification absolue de la charge lésionnelle nette liée aux ulcères digitaux
9: Modification absolue du score SHAQ total
10: Modification absolue du score de dyspnée 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 semaines
2: 52 semaines
3: 52 semaines
4: 52 semaines
5: 52 semaines
6: 52 semaines
7: 52 semaines
8: 52 semaines
9: 52 semaines
10: 52 semaines
|
|
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 | 14 |
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
|
LVLS |
Dernière visite du dernier patient de l'étude |
|
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 | 6 |
E.8.9.1 | In the Member State concerned days | 27 |
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 |