| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Systemic sclerosis-associated interstitial lung disease (SSc-ILD) |
| sclerosi sistemica associata a malattia polmonare interstiziale (SSc ILD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Systemic sclerosis is a disease characterized by abnormal and excess fibrosis, a hardening of tissues and organs. |
La sclerosi sistemica è una malattia caratterizzata da
fibrosi anormale ed eccesso, un indurimento di tessuti e organi. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| 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 | 10025109 |
| E.1.2 | Term | Lung involvement in systemic sclerosis |
| E.1.2 | System Organ Class | 100000004855 |
|
| 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 |
| The primary objective of the trial is to demonstrate efficacy of abituzumab in improving lung function of subjects with SSc-ILD. |
L’obiettivo primario della sperimentazione è dimostrare l’efficacia di abituzumab nel migliorare la
funzionalità polmonare in soggetti affetti da sclerosi sistemica (SSc) associata a malattia polmonare interstiziale (SSc-ILD). |
|
| E.2.2 | Secondary objectives of the trial |
•To characterize further the effect of abituzumab on subjects with SSc-ILD who are treated with a stable mycophenolate regimen;
•To characterize the safety, tolerability, and immunogenicity of abituzumab in subjects with SSc-ILD who are treated with a stable mycophenolate regimen;
•To evaluate the effect of abituzumab on SSc skin disease in subjects with diffuse skin involvement who are treated with a stable mycophenolate regimen;
•To evaluate health-related quality of life (HRQoL) outcomes of abituzumab in subjects with SSc-ILD who are treated with a stable mycophenolate regimen;
•To evaluate pharmacokinetic (PK) parameters of abituzumab in subjects with SSc-ILD who are treated with a stable mycophenolate regimen.
|
•definire ulteriormente l’effetto di abituzumab in soggetti affetti da SSc-ILD in regime terapeutico
stabile con micofenolato;
•definire sicurezza, tollerabilità e immunogenicità di abituzumab in soggetti affetti da SSc-ILD in regime terapeutico stabile con
micofenolato;
•valutare l’effetto di abituzumab sulla sclerodermia sistemica in soggetti con interessamento cutaneo diffuso e in regime
terapeutico stabile con micofenolato;
•valutare gli esiti di abituzumab sulla qualità della vita correlata alla salute (health-related quality of life, HRQoL) in soggetti affetti
da SSc-ILD in regime terapeutico stabile con micofenolato;
•valutare i parametri farmacocinetici (pharmacokinetic, PK) di abituzumab in soggetti affetti da SSc-ILD in regime terapeutico
stabile con micofenolato. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects are eligible for this trial if they fulfill all of the following inclusion criteria:
1. Female or male subjects aged between 18 and 75 years of age who provide informed written consent.
2. Subjects fulfilling the 2013 ACR/European League Against Rheumatism criteria for classification of SSc.
3. Disease duration of <7 years from first non-Raynaud’s symptom.
4. According to central readings: DLCO ≥30% predicted, FVC 40% to 85% predicted, and ratio of FVC % predicted to DLCO % predicted <1.8. If these criteria are met, then HRCT of lungs will be performed, and must show at least 5% fibrosis for subjects to be eligible.
5. Use of mycophenolate for at least 6 months before the screening visit. The dose must be stable for at least 3 months prior to screening and be in the range as follows: MMF 1.5 to 3 g/day, MPS 1080 to 2160 mg/day.
6. For women who are not postmenopausal (≥ 12 months of non−therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use two effective methods of contraception, including at least one highly effective method that can achieve a failure rate of < 1% per year, when used consistently and correctly, and one other reliable method during the treatment period and for at least 90 days after the last dose of study treatment.
Examples of contraceptive methods with a failure rate of < 1% per year (highly effective contraceptive methods) include:
• combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
• progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
• intrauterine device (IUD)
• intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion
• vasectomized partner
• sexual abstinence |
I soggetti sono eleggibili per questo studio se soddisfano tutti i seguenti criteri di inclusione:
1. donne e uomini soggetti di età compresa tra i 18 ei 75 anni di età che forniscono il consenso informato scritto.
2. I soggetti che soddisfano i criteri di 2013 ACR / EULAR per la classificazione della SSC.
3. La durata della malattia di <7 anni dal sintomo del primo non-Raynaud.
4. Secondo le letture centrali: DLCO ≥30% del predetto, FVC 40% al 85% del predetto, e il rapporto di FVC% del predetto per
DLCO% del predetto <1.8. Se sono soddisfatti questi criteri, allora verrà eseguito HRCTdei polmoni , e deve dimostrare almeno il
5% di fibrosi per i soggetti per essere includibili.
5. L'utilizzo di micofenolato per almeno 6 mesi prima della visita di screening. La dose deve essere stabile per almeno 3 mesi
prima dello screening e deve essere nel range come di seguito indicato: MMF 1,5 a 3 g / die, MPS 1080-2160 mg / giorno.
6. Per le donne che non sono in post-menopausa (età ≥ 12 mesi di non-terapia indotta amenorrea) o chirurgicamente sterili
(assenza di ovaie e / o dell'utero): devono essere d'accordo a rimanere astinenti o utilizzare due metodi contraccettivi efficaci, di
cui almeno un metodo altamente efficace che può raggiungere un tasso di fallimento di <1% per anno, se usato in modo coerente
e corretto, e un altro metodo affidabile durante il periodo di trattamento e per almeno 90 giorni dopo l'ultima dose del trattamento
dello studio.
Esempi di metodi contraccettivi con un tasso di fallimento di <1% per anno (metodi contraccettivi altamente efficaci) includono:
• combinato (estrogeni e progesterone che contiene) contraccezione ormonale associata ad inibizione dell'ovulazione (orale,
intravaginale, transdermica)
• contraccezione ormonale del progesterone-solo associato con l'inibizione dell'ovulazione (orale, iniettabile, impiantabile)
• dispositivo intrauterino (IUD)
• intrauterino rilasciante sistema ormonale (IUS)
• occlusione tubarica bilaterale
• Partner vasectomizzato
• l'astinenza sessuale |
|
| E.4 | Principal exclusion criteria |
1. Any condition that in the Investigator's opinion constitutes an inappropriate risk or a contraindication for participation in the trial or that could interfere with the trial objectives, conduct, or evaluation.
2. Renal impairment (glomerular filtration rate [GFR] <45 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation) calculated by the central laboratory as follows:
GFR (mL/min per 1.73 m^2) = 175 x (standardized serum creatinine)^-1.154 x (age)^-0.203 x 1.212 (if black) x 0.742 (if female)
3. Urine dipstick with ≥3+ protein and urine protein:creatinine ratio >2 mg/mg. Urine protein:creatinine ratio will be determined only if urine dipstick indicates ≥3+ protein.
4. Known diagnosis of obstructive lung disease/emphysema as defined by forced expiratory volume in 1 second (FEV1)/FVC ratio <0.65 and/or significant emphysematous change on screening HRCT according to the central reader.
5. Other clinically significant abnormalities on HRCT not attributable to scleroderma or emphysema as defined above, which in the Investigator's opinion make enrollment in the trial inappropriate.
6. Known diagnosis of other significant respiratory disorders in the opinion of the Investigator.
7. Pulmonary hypertension that fulfills at least one of the following:
- Currently being treated with systemic therapy targeted to PAH or pulmonary hypertension;
- Considered by the Investigator to require initiation of systemic therapy;
- History of transthoracic echocardiography showing at least one of the following (unless right heart catheterization subsequent to these measures did not reveal pulmonary hypertension): tricuspid regurgitation jet >2.8 m/sec, right atrial enlargement (major dimension >53 mm), right ventricular enlargement (mid cavity dimension >35 mm), moderate to severe left ventricular dysfunction;
- At screening, N-terminal prohormone brain natriuretic peptide (NT pro-BNP) >3 x the upper limit of normal (ULN), unless, for example, right heart catheterization performed within 2 months did not reveal pulmonary hypertension.
8. Current clinical diagnosis of another inflammatory connective tissue disease (eg, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, or dermato/polymyositis); concomitant scleroderma-associated myopathy and fibromyalgia are allowed.
9. Clinical suspicion of or recent evidence of significant aspiration within the previous 6 months, such as chemical induced pneumonitis or aspiration pneumonia.
10. Active clinically significant viral, bacterial, or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks prior to screening or during the Screening Period, or completion of oral antiinfectives within 2 weeks before screening or use of oral anti-infectives during the Screening Period. Vaginal candidiasis, onychomycosis, and chronically suppressed oral herpes simplex virus would not be exclusionary.
11. History of or positive human immunodeficiency virus (HIV), hepatitis C antibody and/or polymerase chain reaction or hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (total and/or immunoglobulin M [IgM]) antibody at screening.
12. History of or current diagnosis of active tuberculosis (TB), or untreated latent TB infection (LTBI), determined by a TB skin test with purified protein derivative as evidenced by induration ≥5 mm or a positive QuantiFERON-TB or positive or borderline T-SPOT (Elispot) test performed locally, or centrally as needed, either at screening or documented with results within 3 months of the screening visit. Subjects who have previously completed appropriate and documented LTBI treatment or who are undergoing current treatment for LTBI will not be required to be tested. If the subject is undergoing current treatment for LTBI, they must have received at least 4 continuous weeks of an appropriate LTBI treatment prior to the screening visit (ie, start of trial treatment) without evidence of re-exposure. If on LTBI treatment at the screening visit, the subject will be expected to complete an appropriate LTBI treatment regimen to remain in the trial:
- Subjects with current household contacts with active TB will also be excluded unless treated and evidence of household contacts being treated;
- Indeterminate QuantiFERON-TB or T-SPOT tests may be repeated once, and will be considered positive if retest results are positive or indeterminate.
13. Presence of uncontrolled or New York Heart Association (NYHA) Class 3 or 4 congestive heart failure. |
1. Qualsiasi condizione che a giudizio dello sperimentatore costituisce un rischio inappropriato o una controindicazione per la
partecipazione al processo o che potrebbero interferire con gli obiettivi di prova, condotta o valutazione.
2. Insufficienza renale (velocità di filtrazione glomerulare [GFR] <45 mL / min / 1,73 m2 come calcolato dalla modifica di dieta in
Renal Disease equazione) calcolato dal laboratorio centrale come segue:
GFR (mL / min per 1,73 m ^ 2) = 175 x (standardizzato creatinina sierica) ^ - 1.154 x (età) ^ - 0.203 x 1.212 (se nero) x 0,742 (se
femmina)
3. astina urina con ≥3 + proteine e proteine nelle urine: creatinina Rapporto> 2 mg / mg. Urina proteine: creatinina sarà
determinata solo se l'urina di livello indica ≥3 + proteine.
4. diagnosi nota di ostruttiva malattia polmonare / enfisema come definito dal volume espiratorio forzato in 1 secondo (FEV1) / FVC
<0,65 e / o rilevante cambiamento enfisematosa sullo screening HRCT in base al lettore centrale.
5. Altre anomalie clinicamente significativi sulla HRCT non imputabili a sclerodermia o enfisema come sopra definito, che, a parere
dello sperimentatore rendono l'iscrizione nel processo inadeguato.
6. Conosciuto diagnosi di altri disturbi respiratori significativi secondo il parere dello sperimentatore.
7. L'ipertensione polmonare che soddisfa almeno una delle seguenti:
- Attualmente in trattamento con terapia sistemica mirata a PAH o ipertensione polmonare;
- Considerato da ricercatore a richiedere l'inizio della terapia sistemica;
- Storia di ecocardiografia transtoracica indicare almeno uno dei seguenti (a meno che il cateterismo cardiaco destro a seguito di
queste misure non hanno evidenziato ipertensione polmonare): tricuspide rigurgito jet> 2,8 m / sec, l'allargamento atriale destra
(maggiore dimensione> 53 millimetri), del ventricolo destro allargamento (metà cavità dimensione> 35 mm), da moderata a
grave disfunzione ventricolare sinistra;
- Allo screening, N-terminale natriuretico pro-ormone del cervello peptide (NT pro-BNP)> 3 volte il limite superiore della norma
(ULN), a meno che, per esempio, a destra cateterizzazione cardiaca eseguita entro 2 mesi non ha evidenziato ipertensione
polmonare.
8. attuale diagnosi clinica di un'altra malattia infiammatoria del tessuto connettivo (ad esempio, lupus eritematoso sistemico,
artrite reumatoide, spondilite anchilosante, o dermato / polimiosite); concomitante miopatia e fibromialgia sclerodermia associate
sono ammessi.
9. sospetto clinico di o recente evidenza di aspirazione significative nei 6 mesi precedenti, come ad esempio sostanze chimiche
indotte polmonite o polmonite da aspirazione.
10. clinicamente significativo Infezione attiva virali, batteriche, fungine o, o qualsiasi episodio di infezione che richiedono il
ricovero o il trattamento con parenterali antinfettivi entro 4 settimane prima dello screening o durante il periodo di screening, o il
completamento di antinfettivi orali entro 2 settimane prima dello screening o l'uso di anti-infettivi orali durante il periodo di
screening. candidosi vaginale, onicomicosi, e cronicamente soppresso simplex virus herpes orale non sarebbero di esclusione.
11. Storia di positivo o virus dell'immunodeficienza umana (HIV), anticorpi dell'epatite C e / o la reazione a catena della polimerasi
o di superficie dell'epatite B (HBsAg) e / o anticorpi nucleo dell'epatite B (totale e / o immunoglobuline M [IgM]) anticorpo a
selezione.
12. Storia di diagnosi o di corrente di tubercolosi attiva (TB), o non trattati infezione tubercolare latente (LTBI), determinata da un
test cutaneo TB con derivato proteico purificato come evidenziato da indurimento ≥5 mm o un positivo QuantiFERON-TB o positivo
o borderline T-SPOT (Elispot) prova eseguita localmente o centralmente, se necessario, sia a screening o documentati con risultati
entro 3 mesi dalla visita di screening. I soggetti che hanno già completato il trattamento LTBI adeguato e documentato o che sono
sottoposti a trattamento in corso per ITBL non saranno tenuti da testare. Se il soggetto è in fase di attuale trattamento per LTBI,
devono aver ricevuto almeno 4 settimane continue di un adeguato trattamento LTBI prima della visita di screening (cioè, inizio del
trattamento di prova) senza evidenza di ri-esposizione. Se il trattamento ITBL alla visita di screening, il soggetto sarà chiamato a
completare un appropriato regime di trattamento LTBI di rimanere nel processo:
- Saranno esclusi soggetti con contatti familiari attuali con tubercolosi attiva a meno che non trattata e la prova di contatti
domestici da trattare;
- Indeterminato QuantiFERON-TB o T-SPOT test possono essere ripetuti una volta, e saranno considerati positivi se i risultati del
nuovo test sono positivi o indeterminato.
13. La presenza di 3 o 4 insufficienza cardiaca congestizia non controllata o New York Heart Association (NYHA) Class. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Annual rate of absolute FVC change in volume (mL) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 52 or prematurely discontinued from the trial, whichever occur first. |
|
| E.5.2 | Secondary end point(s) |
a) Change in dyspnea from baseline as measured by the Mahler Transition Dyspnea Index (TDI)
b) Absolute change from baseline in St. George Respiratory Questionnaire (SGRQ) total score
c) Absolute change from baseline in Modified Rodnan skin score (mRSS) at Week 52 in subjects with diffuse cutaneous skin involvement at baseline
d) Absolute change from baseline in Quantitative lung fibrosis (QLF) in the region of highest severity
e) Overall survival
f) Proportion of subjects with clinically meaningful progression of Systemic sclerosis (SSc) by meeting Criterion 1 (Interstitial lung disease, ILD)
g) Proportion of subjects with clinically meaningful progression of SSc by meeting Criterion 2 (SSc progression other than ILD)
h) Proportion of subjects with clinically meaningful progression
i) Proportion of subjects with absolute decrease from baseline of FVC % predicted ≥10% on 2 or more consecutive occasions at least 4 weeks apart
j) Time to first clinically meaningful progression
k) Absolute change from baseline in FVC % predicted
l) Absolute change from baseline in Total lung capacity (TLC) % predicted
m) Absolute change from baseline in Diffusion capacity of the lung for carbon monoxide (DLCO) % predicted
n) Absolute change from baseline in transfer coefficient of the lung for carbon monoxide (KCO)
o) Absolute change from baseline in QLF in the region of highest severity
p) Absolute change from baseline in quantitative High-resolution computed tomography (HRCT) analyses of extent of total ILD |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) At Week 52
b) At Week 52
c) At Week 52
d) At Week 52
e) Time from date of randomization until death, assessed up to 5 years
f) By Week 52 and by Week 104
g) By Week 52 and by Week 104
h) By Week 52 and by Week 104
i) By Week 52 and by Week 104
j) not defined
k) Up to Week 104
l) Up to Week 104
m) Up to Week 104
n) At Week 104
o) At Week 104
p) Up to Week 104 |
|
| 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 | 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 | 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 | 3 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 | Information not present in EudraCT |
| 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 |
| Argentina |
| Australia |
| Canada |
| France |
| Israel |
| Italy |
| Poland |
| Singapore |
| Spain |
| Turkey |
| 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
|
A clinical trial protocol may not be considered closed as long as:
* Any subject is still receiving any IMP;
* Visits specified by the protocol are still taking place;
* Procedures or interventions according to the protocol are still being undertaken in any subject;
*The post-treatment safety follow up period, defined in the clinical trial protocol as being part of the trial, has not yet been completed for any subject.
The Survival follow up period will end with the end of trial. |
| Un protocollo di sperimentazione clinica non può essere considerato chiuso fintantoché:* Tutti i soggetti continuano a ricevere qualsiasi IMP;* Visite specificate dal protocollo sono ancora in corso;* Procedure o interventi in base al protocollo sono ancora in corso in qualsiasi argomento;* Il periodo di follow up di sicurezza post-trattamento non è stato ancora completato per qualsiasi soggetto. Il periodo di follow-up di sopravvivenza si concluderà con la fine del processo. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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