| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Scleroderma is a rare, chronic disease of the immune system, blood vessels and connective tissue. It is an autoimmune condition, meaning that the immune system becomes overactive and attacks healthy tissue within the body. Hardening of the skin can be one of the first noticeable symptoms, as the body produces too much collagen. This excess of collagen can affect the skin, joints, tendons and internal organs. It causes scarring and stops the affected parts of the body from functioning normally. |
| La sclerodermia è una malattia rara e cronica del sistema immunitario, dei vasi sanguigni e del tessuto connettivo. È una condizione autoimmune, il che significa che il sistema immunitario diventa iperattivo e attacca i tessuti sani all'interno del corpo. L'indurimento della pelle può essere uno dei primi sintomi evidenti, poiché il corpo produce troppo collagene. Questo eccesso di collagene può colpire la pelle, le articolazioni, i tendini e gli organi interni. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Diffuse cutaneous systemic sclerosis is likely to affect the whole body, and there can be potentially serious complications involving the heart, lungs and kidneys. |
| La sclerosi sistemica diffusa spesso causa danni cutanei che si diffondono a tutto il corpo, progredisce rapidamente. Le principali complicanze sono polmonare interstiziale e insufficienza renale. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| 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 determine the optimal treatment strategy in early diffuse cutaneous systemic sclerosis (dcSSc): the effect of HSCT as upfront therapy compared with that of immunosuppressive medication in early dcSSc, with respect to survival and prevention of major organ failure (referred to as ‘event-free survival’ which is considered as primary endpoint), safety and the impact on skin thickening, visceral involvement, functional status, and quality of life |
| Determinare la strategia di trattamento ottimale per il dcSSc precoce: l'effetto dell'HSCT come terapia iniziale rispetto ai farmaci immunosoppressivi nel dcSSc precoce in termini di sopravvivenza e di prevenzione dell'insufficienza d'organo grave (indicata come "sopravvivenza libera da eventi", che è considerata l'endpoint primario), sicurezza e impatto sull'ispessimento della pelle, coinvolgimento viscerale, stato funzionale e qualità della vita. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
• Safety
• Impact on skin thickening, visceral involvement, functional status, sexual functioning and quality of life
• To determine cost-effectiveness of HSCT as upfront therapy compared to immunosuppressive medication and rescue HSCT
• Biomarker substudies: To identify factors associated with response to treatment (including nailfold microscopy and skin biopsy characteristics, immune cell subsets). |
Gli obiettivi secondari sono di valutare:
• Sicurezza
• Impatto sull'ispessimento cutaneo, coinvolgimento viscerale, stato funzionale, funzionamento sessuale e qualità della vita
• Determinare il rapporto costo-efficacia del trapianto come terapia iniziale rispetto ai farmaci immunosoppressivi e al trapianto di emergenza
• Sottostudi sui biomarcatori: per identificare i fattori associati alla risposta al trattamento (compresi la microscopia delle pieghe ungueali e le caratteristiche della biopsia cutanea, sottogruppi di cellule immunitarie). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Life quality
Version: v2.1
Date: 13/05/2021
Title: Quality of Life UPSIDE substudy
Objectives: assess changes in quality of life after treatment
Other types of substudies
Specify title, date and version of each substudy with relative objectives: Biomarker substudies, v2.1, date 13.05.2021
- Immunoreconstitution, ATG levels and autoantibodies
- Eicosanoids in systemic sclerosis
- Inflammatory and fibrotic characteristics of the skin
- Hand mobility
- Microvascular changes
- Cardiac scleroderma
- Quality of Life
|
Qualita' della vita
Versione: v2.1
Data: 13/05/2021
Titolo: Qualità della vita Sottostudio UPSIDE
Obiettivi: valutare i cambiamenti nella qualità della vita dopo il trattamento
Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Sottostudi sui biomarcatori, v2.1, data 13.05.2021
- Immunoricostituzione, livelli di ATG e autoanticorpi
- Eicosanoidi nella sclerosi sistemica
- Caratteristiche infiammatorie e fibrotiche della pelle
- Mobilità della mano
- Cambiamenti microvascolari
- Sclerodermia cardiaca
- Qualità della vita
|
|
| E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must be eligible for HSCT treatment and therefore meet all of the following criteria:
1. Age between 18 and 65 years.
2. Fulfilling the 2013 ACR-EULAR classification criteria for SSc
3. Disease duration = 2 years (from onset of first non-Raynaud’s symptoms) and diffuse cutaneous disease with
- mRSS = 15 and/or
- clinically significant organ involvement as defined by either:
a) respiratory involvement = i. DLCO and/or (F)VC = 85% (of predicted) and evidence of interstitial lung disease on HR-CT scan with clinically relevant obstructive disease and emphysema excluded. ii. Patients with a DCLO and/or FVC > 85%, but with a progressive course of lung disease: defined as relative decline of >10% in FVC predicted and/or TLC predicted, or >15% in DLCO predicted and evidence of interstitial lung disease on HR-CT scan with clinically relevant obstructive disease and emphysema excluded, within 12 months. Intercurrent infections excluded.
b) renal involvement = any of the following criteria: hypertension (two successive BP readings of either systolic = 160 mm Hg or diastolic > 110 mm Hg, at least 12 hours apart), persistent urinalysis abnormalities (proteinuria, haematuria, casts), microangiopathic haemolytic anaemia, new renal insufficiency (serum creatinine > upper limit of normal); non-scleroderma related causes (e.g. medication, infection etc.) must be reasonably excluded.
c) cardiac involvement = any of the following criteria: reversible congestive heart failure, atrial or ventricular rhythm disturbances such as atrial fibrillation or flutter, atrial paroxysmal tachycardia or ventricu-lar tachycardia, 2nd or 3rd degree AV block, pericardial effusion (not leading to hemodynamic problems), myo-carditis; non-scleroderma related causes must have been reasonably excluded.
4. Written Informed consent |
| Pazienti di età compresa tra 18 e 65 anni con una diagnosi stabilita di dcSSc secondo i criteri ACR/EULAR. La durata della malattia dei pazienti (senza sintomi di Raynaud) deve essere = 2 anni e avere un mRSS = 15 (aspetto cutaneo diffuso) e/o un coinvolgimento d'organo clinicamente significativo (cardiaco e polmonare). |
|
| E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study:
1. Pregnancy (confirmed by positive pregnancy test) or unwillingness to use adequate contraception during study
2. Concomitant severe disease =
a) respiratory:
- pulmonary hypertension: a resting mean pulmonary artery pressure (mPAP) > 25 mmHg (byright heart
catheterisation),
- DLCO < 40% predicted or
- respiratory failure as defined by the primary endpoint (see 8.1)
b) renal: creatinine clearance < 40 ml/min (measured or estimated)
c) cardiac: clinical evidence of refractory congestive heart failure; LVEF < 45% by cardiac echo or cardiac
MR; chronic atrial fibrillation necessitating oral anticoagulation; uncontrolled ventricular
arrhythmia; pericardial effusion with hemodynamic consequences (10)
d) liver failure as defined by a sustained 3-fold increase in serum transaminase or bilirubin, or a Child-
Pugh score C
e) psychiatric disorders including active drug or alcohol abuse
f) concurrent neoplasms or myelodysplasia, leading to exclusion of cyclo-
phosphamide, mycophenolate mofetil or autologous stem cell transplantation in routine clinical practice.
g) bone marrow insufficiency defined as leukocytopenia < 4.0 x 109/L, thrombocytopenia < 50
x 109/L, anaemia < 8 gr/dL, CD4+ T lymphopenia < 200 x 106/L
h) uncontrolled hypertension (systolic blood pressure >150mmHg despite medication)
Blood pressure needs to be controlled prior to inclusion
i) uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity, leading to exclusion of cyclo-
phosphamide, mycophenolate mofetil or autologous stem cell transplantation in routine clinical practice.
Infection needs to be treated/controlled prior to inclusion.
j) ZUBROD-ECOG-WHO Performance Status Scale > 2 (Appendix C)
k) Known hypersensitivity to any of the study drug constituents
3. Previous treatments with immunosuppressants > 6 months including MMF, methotrexate, azathioprine, rituxi-mab, tocilizumab, glucocorticosteroids.
4. Previous treatments with TLI, TBI or alkylating agents including CYC.
5. Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica;
6. eosinophilic myalgia syndrome; eosinophilic fasciitis.
7. Poor compliance of the patient as assessed by the referring physicians. |
Un potenziale soggetto che soddisfi uno qualsiasi dei seguenti criteri sarà escluso dalla partecipazione a questo studio:
1. Gravidanza (confermata da test di gravidanza positivo) o riluttanza a usare un'adeguata contraccezione durante lo studio
2. Malattia grave concomitante =
a) respiratorio:
- ipertensione polmonare: una pressione arteriosa polmonare media a riposo (mPAP) > 25 mmHg (byright heart
cateterizzazione),
- DLCO < 40% previsto o
- insufficienza respiratoria definita dall'endpoint primario (vedere 8.1)
b) renale: clearance della creatinina < 40 ml/min (misurata o stimata)
c) cardiaco: evidenza clinica di insufficienza cardiaca congestizia refrattaria; LVEF < 45% per eco cardiaco o cardiaco
SIG; fibrillazione atriale cronica che richiede anticoagulante orale; ventricolare incontrollato
aritmia; versamento pericardico con conseguenze emodinamiche (10)
d) insufficienza epatica come definita da un aumento sostenuto di 3 volte delle transaminasi o della bilirubina sieriche, o un
Pug punteggio C
e) disturbi psichiatrici compreso l'abuso di droghe attive o alcol
f) neoplasie o mielodisplasia concomitanti, che portano all'esclusione del ciclo-
fosfamide, micofenolato mofetile o trapianto autologo di cellule staminali nella pratica clinica di routine.
g) insufficienza midollare definita come leucocitopenia < 4,0 x 109/l, trombocitopenia < 50
x 109/l, anemia < 8 gr/dl, linfopenia T CD4+ < 200 x 106/l
h) ipertensione non controllata (pressione sistolica >150 mmHg nonostante i farmaci)
La pressione sanguigna deve essere controllata prima dell'inclusione
i) infezione acuta o cronica non controllata, inclusa la positività all'HIV, HTLV-1,2, che porta all'esclusione del ciclo-
fosfamide, micofenolato mofetile o trapianto autologo di cellule staminali nella pratica clinica di routine.
L'infezione deve essere trattata/controllata prima dell'inclusione.
j) ZUBROD-ECOG-WHO Scala dello stato di prestazione > 2 (Appendice C)
k) Ipersensibilità nota a uno qualsiasi dei componenti del farmaco in studio
3. Precedenti trattamenti con immunosoppressori > 6 mesi inclusi MMF, metotrexato, azatioprina, rituximab, tocilizumab, glucocorticosteroidi.
4. Trattamenti precedenti con TLI, TBI o agenti alchilanti incluso CYC.
5. Esposizione significativa a bleomicina, olio di colza contaminato, cloruro di vinile, tricloroetilene o silice;
6. sindrome mialgica eosinofila; fascite eosinofila.
7. Scarsa compliance del paziente valutata dai medici di riferimento. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The main study parameter is event-free survival 2 year after randomisation |
| Il principale parametro dello studio è la sopravvivenza libera da eventi a 2 anni dopo la randomizzazione/inizio del trattamento. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| In the first 2 years 3-monthly, year 2-5 annually. |
| Nei primi 2 anni trimestrale, anno 2-5 annuale. |
|
| E.5.2 | Secondary end point(s) |
| Overall survival (OS), progression-free survival, number of participants who required rescue therapy (i.e. alternative treatment) due to treatment failure. Treatment-related mortality, treatment toxicity, and changes in mRSS, FVC, TLC and Dlco, nail fold microscopy, and cardiac MRI. The CRISS at 12 months. Safety and tolerability outcomes according to CTC criteria (CTCAE v5.0) and BMT-CTN classification (viral infections). |
| Sopravvivenza globale (OS), sopravvivenza libera da progressione, numero di partecipanti che hanno richiesto una terapia di salvataggio (cioè il trattamento alternativo) a causa del fallimento del trattamento. Mortalità legata al trattamento, tossicità del trattamento e cambiamenti in mRSS, FVC, TLC e DLCO, microscopia delle pieghe delle unghie e RM cardiaca. Il CRISS a 12 mesi. Esiti di sicurezza e tollerabilità secondo i criteri CTC (CTCAE v5.0) e la classificazione BMT-CTN (infezioni virali). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All abovementioned time points are measured at 6,12,18,21,24, 36, 48, 60m. |
| Tutti i suddetti punti temporali sono misurati a 6,12,18,21,24, 36, 48, 60m. |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| optimal timing of different treatment strategies |
| treatment strategy |
|
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 |
| after completion of the last visit of the last included patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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