| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Active Crohn's Disease |
| Morbo di Crohn in fase attiva |
|
| E.1.1.1 | Medical condition in easily understood language |
| Active Crohn's Disease |
| Morbo di Crohn in fase attiva |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| 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 | 10013099 |
| E.1.2 | Term | Disease Crohns |
| E.1.2 | System Organ Class | 100000004856 |
|
| 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 explore the mechanism of action of Mongersen (GED-0301) 160 mg once daily (QD)
in subjects with active CD |
| Esplorare il meccanismo d'azione di Mongersen (GED-0301) 160 mg una volta al giorno (QD) nei soggetti affetti da morbo di Crohn (CD) attivo |
|
| E.2.2 | Secondary objectives of the trial |
- To explore the effect of mongersen (GED-0301) 160 mg QD on inflammatory cytokines, and gene expression in the intestinal mucosa
- To explore the effect of mongersen (GED-0301) 160 mg QD on clinical activity, as measured by the Crohn’s Disease Activity Index (CDAI) in subjects with active CD.
- To explore the effect of mongersen (GED-0301) 160 mg QD on endoscopic outcomes, as measured by the Simple Endoscopic Score for Crohn's Disease (SES-CD) in subjects with active CD
- To evaluate the safety and tolerability of mongersen (GED-0301) 160 mg QD in subjects
with active CD |
- Esplorare l'effetto di mongersen (GED-0301) 160 mg QD sulle citochine infiammatorie e l'espressione genica della mucosa intestinale
- Esplorare l'effetto di mongersen (GED-0301) 160 mg QD sull'attività clinica, misurata in base all'Indice di attività del Morbo di Crohn (CDAI) nei soggetti affetti da CD attivo.
- Esplorare l'effetto di mongersen (GED-0301) 160 mg QD sui risultati endoscopici, misurati in base all'indice SES-CD (Simple Endoscopic Score for Crohn's Disease) nei soggetti affetti da CD attivo.
- Valutare la sicurezza e tollerabilità di mongersen (GED-0301) 160 mg QD nei soggetti affetti da CD attivo
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is a male or female ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments / procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
4. Subject must have a diagnosis of CD with a duration of at least 3 months prior to Screening Visit 1.
5. Subject must have a diagnosis of ileitis, ileocolitis or colitis, as determined by endoscopic, radiographic or any other imaging modality (eg, magnetic resonance imaging
[MRI], or computed tomography [CT] scan).
6. Subject must have active disease, defined as a CDAI score ≥ 220 and ≤ 450 at screening.
7. Subject must have a total SES-CD ≥ 6 at screening, or the ileum segmental SES-CD ≥ 4
at screening.
8. Subject must have failed or experienced intolerance to at least one of the following:
aminosalicylates; budesonide; systemic corticosteroids; immunosuppressants (eg,
azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]); or TNF-α blockers (eg, infliximab or adalimumab).
9. Subject must meet the following laboratory criteria: (One laboratory test repeat is allowed during the Screening Period after consultation with the medical monitor.)
- White blood cell (WBC) count ≥ 3000/mm3
(≥ 3.0 x 10*9/L)
- Platelet count ≥ 100,000/mm3 (≥ 100 x 10*9/L)
- Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L)
- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT),
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 x upper limit of normal (ULN)
-Total bilirubin ≤ 2 mg/dL (34 μmol/L), unless the subject has a confirmed diagnosis of Gilbert’s disease.
- Hemoglobin ≥ 8 g/dL (≥ 4.98 mmol/L)
- Activated partial thromboplastin time (APTT) ≤ 1.5 x ULN
10. Females of childbearing potential (FCBP) must have a negative pregnancy test at the
Screening and Baseline Visits. While on IP and for at least 28 days after taking the last dose of IP, FCBP who engage in activity in which conception is possible must use one of the approved contraceptive options described below:
Option 1: Any one of the following highly effective methods: hormonal contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or partner’s vasectomy
OR
Option 2: Male or female condom PLUS 1 additional barrier method: (a) diaphragm
with spermicide; (b) cervical cap with permicide; or (c) contraceptive sponge with spermicide
11. Male subjects (including those who have had a vasectomy) when engaging in sexual activity with females who are able to become pregnant must use barrier contraception (male latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while on IP and for at least 28 days after the last dose of IP. |
1.Soggetto di sesso maschile o femminile ≥ 18 anni di età al momento della firma del modulo di consenso informato (ICF).
2.Il soggetto deve comprendere e firmare volontariamente un ICF prima che sia effettuata qualsiasi valutazione/procedura correlata allo studio.
3.Il soggetto intende ed è in grado di attenersi al programma di visite dello studio e agli altri requisiti del protocollo.
4.I soggetti devono avere una diagnosi di CD con una durata di almeno 3 mesi prima della Visita 1 di Screening.
5.I soggetti devono avere una diagnosi di ileite, ileocolite o colite, determinata mediante endoscopia, radiografia o altra modalità di imaging (ad es. risonanza magnetica per immagini
[RMI], o tomografia computerizzata [TC]).
6.I soggetti devono avere una malattia attiva, definita da un punteggio CDAI ≥ 220 e ≤ 450 allo screening.
7.I soggetti devono avere un indice totale SES-CD ≥ 6 allo screening, o un indice SES-CD del segmento ileo≥ 4 allo screening.
8.Il soggetto deve aver ricevuto un trattamento fallimentare o aver manifestato un'intolleranza ad almeno uno dei seguenti componenti:
aminosalicilati; budesonide; corticosteroidi sistemici; immunosoppressori (ad es.
azatioprina [AZA], 6-mercaptopurina [6-MP] o metotrexato [MTX]); o bloccante TNF-a (ad es. infliximab o adalimumab).
9.Il soggetto deve soddisfare i seguenti criteri di laboratorio: (È consentita una ripetizione del test di laboratorio durante il Periodo di Screening dopo il consulto con il medical monitor).
- Conta dei globuli bianchi (WBC) ≥ 3000 /mm3 (≥ 3,0 X 10*9/L)
- Conta piastrinica ≥100.000/mm3 (≥100 x 10*9/L)
- Creatinina nel siero <1,5 mg/dL (< 132,6 μmol/L)
- Aspartato aminotransferasi (AST)/transaminasi sierica-glutammico ossaloacetica (SGOT), alanina aminotransferasi (ALT)/transaminasi sierica glutammico-piruvica (SGPT) < 2,5 volte il limite superiore della norma (ULN)
-Bilirubina totale < 2 mg/dL (34 μmol/L), a meno che il soggetto non abbia una diagnosi nota di malattia di Gilbert.
- Emoglobina > 8 g/dL (> 4,98 mmol/L)
- Tempo di tromboplastina parziale attivata (APTT) < 1,5 x ULN
10.I soggetti di sesso femminile in età fertile (FCBP), devono avere un test di gravidanza negativo
alle visite di Screening e Baseline. Durante la somministrazione del prodotto sperimentale e per almeno 28 giorni dopo aver assunto l'ultima dose, le donne in età fertile che hanno rapporti sessuali che potrebbero dare inizio ad una gravidanza devono utilizzare un metodo contraccettivo approvato tra i due descritti di seguito:
Opzione 1: Uno dei seguenti metodi di elevata efficacia: contraccezione ormonale (orale, iniezione, impianto, cerotto transdermico, anello vaginale); dispositivo intrauterino (IUD); legatura delle tube; o vasectomia del partner
OPPURE
Opzione 2: Profilattico maschile o femminile OLTRE A 1 metodo di barriera aggiuntivo: (a) diaframma
con spermicida; (b) cappuccio cervicale con spermicida; oppure (c) spugna contraccettiva con spermicida.
11.I soggetti di sesso maschile (compresi coloro che sono stati sottoposti a vasectomia) durante i rapporti sessuali con donne in età fertile devono utilizzare un metodo contraccettivo di barriera (profilattico in lattice o altro profilattico non in lattice che NON sia costituito da membrana [animale] naturale [ad esempio, in poliuretano]) nel periodo di assunzione del prodotto sperimentale e per almeno 28 giorni dopo l’assunzione dell’ultima dose di prodotto sperimentale.
|
|
| E.4 | Principal exclusion criteria |
1. Subject has CD involvement of the upper gastrointestinal tract.
2. Subject has a diagnosis of UC, indeterminate colitis, ischemic colitis, microscopic colitis, radiation colitis or diverticular disease-associated colitis.
3.Subject has local manifestations of CD such as strictures, abscesses, short bowel syndrome or other disease complications for which surgery might be indicated or could confound the evaluation of efficacy.
4.Subject had an intestinal resection within 6 months or any intra-abdominal surgery within3 months prior to Screening Visit1.
5.Subject has an ileostomy or a colostomy.
6. Subject had prior treatment with mycophenolic acid, tacrolimus, sirolimus, cyclosporine, thalidomide or apheresis (eg, Adacolumn®) within8weeks prior to Screening Visit1.
7. Subject has received intravenous (IV) corticosteroids within2weeks prior to Screening
Visit1.
8.Subject has initiated, changed or discontinued the dose of oral aminosalicylates within2weeks prior to Screening Visit1.
9. Subject has initiated, changed or discontinued the allowed dose of oral corticosteroids (prednisone ≤ 20 mg/day or equivalent, budesonide ≤ 9 mg/day) within3weeks prior to
Screening Visit1.
10. Subject has initiated immunosuppressants (eg, AZA, 6-MP, or MTX) within12weeks prior to Screening Visit1.
11. Subject has changed or discontinued the allowed dose of immunosuppressants (eg, AZA,
6-MP, or MTX) within8weeks prior to Screening Visit1.
12.Subject has received topical GI treatments, such as, 5-aminosalicylic acid (5-ASA) or
corticosteroid enemas or suppositories within 2weeks prior to Screening Visit 1.
13.Subject has received cholestyramine within 3weeks prior to Screening Visit 1.
14.Subject has received antibiotics for the treatment of CD within3weeks prior toScreening Visit1.
15.Subject had prior treatment with more than 2TNF-α blockers (eg, infliximab or adalimumab).
16.Subject had treatment with a TNF-α blocker within8 weeks prior to the Screening Visit 1.
17.Subject had prior treatment with any integrin antagonists (eg, natalizumab or vedolizumab).
18.Subject has received total parenteral nutrition (TPN) within4weeks prior to the Screening Visit1.
19. Subject is stool positive for any enteric pathogen or Clostridium difficile toxin at Screening Visit1.
20.Subject has a history of any clinically significant neurological, renal, hepatic,gastrointestinal, pulmonary, metabolic, cardiovascular, psychiatric, endocrine,
hematological disorder or disease, or any other medical condition that, in the Investigator's opinion, would prevent the subject from participating in the study.
21.Subject has any condition, including the presence of laboratory abnormalities, which
would place the subject at unacceptable risk if he/she were to participate in the study or would confound the ability to interpret data from the study.
22.Subject is pregnant or breastfeeding.
23.Subject has a history of any of the following cardiac conditions within 6 months prior to
Screening Visit1 and at any time during the Screening Period, up through the first dose
of IP: myocardial infarction, acute coronary syndrome, unstable angina, new onset atrial
fibrillation, new onset atrial flutter, second- or third-degree atrioventricular block, ventricular fibrillation, ventricular tachycardia, heart failure, cardiac surgery,interventional cardiac catheterization (with or without a stent acement), interventional electrophysiology procedure, or presence of implanted defibrillator.
24. Subject has a known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections(including but not limited to tuberculosis and atypical
mycobacterial disease and herpes zoster), human immunodeficiency virus, or any major episode of infection requiring hospitalization or treatment with IV or oral antibiotics within 4 weeks prior to Screening Visit1 and at any time during the Screening Period, up through the first dose of IP.
25.Subject has a history of congenital or acquired immunodeficiency(eg, common variable
immunodeficiency disease).
26.Subject has a history of colorectal cancer or colorectal dysplasia (with the exception of
adenomatous colonic polyps that have been completely resected).
27.Subject has a history of malignancy, except for: a. Treated (ie, cured) basal cell or squamous cell in situ skin carcinomas b. Treated (ie, cured) cervical intraepithelial neoplasia or carcinoma in situ of the cervix with no evidence of recurrence within the previous 5 years prior to Screening Visit1
28.Subject has received any investigational drug or device within 1 month prior to ScreeningVisit1.
29. Subject has a history of alcohol, drug, or chemical abuse within the 6 months prior to
Screening Visit1.
30. Subject has a known hypersensitivity to oligonucleotides or any ingredient in the IP.
31. Subject has received prior treatment with mongersen, or participation in aclinical study involving mongersen (GED-0301). |
1.Il soggetto ha un coinvolgimento CD del tratto gastrointestinale superiore.
2.Il soggetto presenta una diagnosi di colite ulcerosa, colite indeterminata, colite ischemica, colite microscopica, colite da radiazioni o colite associata a diverticoli.
3. Il soggetto ha manifestazioni locali di CD quali stenosi, ascessi, sindrome dell'intestino corto o altre complicazioni della patologia per le quali l'intervento chirurgico potrebbe essere indicato o potrebbe confondere la valutazione dell'efficacia.
4.Il soggetto è stato sottoposto a resezione intestinale negli ultimi 6 mesi o a un intervento intra-addominale nei 3 mesi precedenti la Visita 1 di Screening.
5.Il soggetto ha una ileostomia o una colostomia.
6.Il soggetto è stato sottoposto in precedenza a un trattamento con acido micofenolico, tacrolimo, sirolimo, ciclosporina, talidomide o aferesi (ad es. Adacolumn®) nelle 8 settimane precedenti la Visita 1 di Screening.
7.Il soggetto ha assunto corticosteroidi per via endovenosa (IV) nelle 2 settimane che precedono a Visita 1 di Screening.
8.Il soggetto ha iniziato, cambiato o interrotto l'assunzione di una dose di aminosalicilati orali nelle 2 settimane precedenti la Visita 1 di Screening.
9.Il soggetto ha iniziato, cambiato o interrotto la dose consentita di corticosteroidi per via orale (prednisone < 20 mg/giorno o equivalente, budesonide < 9 mg/giorno) nelle 3 settimane che precedono la Visita 1 di Screening.
10.Il soggetto ha iniziato l'assunzione di immunosoppressori (ad esempio AZA, 6-MP, o MTX) nelle 12 settimane precedenti la Visita di screening.
11.Il soggetto ha cambiato o interrotto l'assunzione della dose consentita di immunosoppressori (ad es. AZA, 6-MP o MTX) nelle 8 settimane precedenti la Visita 1 di Screening.
12.Il soggetto è stato sottoposto a trattamenti GI topici, come acido 5-aminosalicilico (5-ASA) o
clismi/supposte a base di corticosteroidi nelle 2 settimane precedenti la Visita 1 di Screening.
13.Il soggetto ha assunto la colestiramina nelle 3 settimane precedenti la Visita 1 di Screening.
14.Il soggetto ha assunto degli antibiotici per il trattamento del CD nelle 3 settimane precedenti la Visita 1 di Screening.
15.Il soggetto è stato sottoposto in precedenza a un trattamento con più di 2 bloccanti TNF-a (ad es. infliximab o adalimumab).
(elenco completo disponibile nel protocollo) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Change from baseline of Smad7 expression in the
intestinal mucosa at Week 12, from biopsy samples taken during ileocolonoscopy |
| Variazione rispetto alla baseline dell'espressione di Smad7 nella mucosa intestinale nella Settimana 12, dai campioni per la biopsia prelevati durante l'ileocolonoscopia |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
PD: Change from baseline in the messenger RNA (mRNA) expression of inflammatory cytokines such as, but not limited to, interleukin (IL)-10, IL-25, chemokine (C-Cmotif) ligand 20 (CCL20) and tumor necrosis factor alpha(TNF-α) in the intestinal mucosa at Week 12, from biopsy samples during ileocolonoscopy
Efficacy:
1)The proportion of subjects achieving clinical remission, defined as a Crohn’s Disease Activity Index (CDAI) score < 150, at Weeks 4, 8, and 12
2) Change from baseline in the Simple Endoscopic Score for Crohn’s Disease (SES-CD) at Week 12
3) The evaluation of safety and tolerability of mongersen (GED-0301), assessed by the type, frequency and severity of adverse events, and its relationship to investigational product (IP), discontinuation due to adverse events, and
clinically significant changes in lectrocardiograms
(ECGs), vital signs, and/or laboratory findings |
PD: Variazione rispetto alla baseline nell'espressione dell'RNA messaggero (mRNA) delle citochine infiammatorie come ad esempio, ma non esclusivamente, interleuchina (IL)-10, IL-25, chemochina (C-Cmotif) ligando 20 (CCL20) e fattore di necrosi tumorale alfa (TNF-a) nella mucosa intestinale nella Settimana 12, dai campioni della biopsia durante l'ileocolonoscopia
Efficacia:
1) La proporzione di soggetti che raggiungono la remissione clinica, definita come punteggio dell'indice di attività del Morbo di Crohn (CDAI) < 150, nelle Settimane 4, 8 e 12
2) Variazione dalla baseline nel punteggio dell'indiceSES-CD alla Settimana 12
3) La valutazione della sicurezza e della tollerabilità di mongersen (GED-0301), valutata mediante il tipo, la frequenza e la gravità degli eventi avversi, e per il suo rapporto con il prodotto sperimentale, con l'interruzione dovuta ad eventi avversi e le variazioni clinicamente significative negli elettrocardiogrammi (ECG), nelle funzioni vitali e/o risultati di laboratorio
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PD: Week 12
Efficacy: 1) Weeks 4, 8,12; 2)Week 12; 3) Through Week 52 and 4 weeks postdose |
PD: Settimana 12
Efficacia: 1) Settimane 4, 8,12; 2)Settimana 12; 3) Fino alla Settimana 52 e per 4 settimane dopo la dose
|
|
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 | 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
|
The End of Study is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol,
whichever is the later date. |
| La Conclusione dello Studio è definita come la data dell'ultima visita dell'ultimo soggetto che conclude il follow-up post-trattamento o la data di ricezione dell'ultimo dato dall'ultimo soggetto, dato necessario per un'analisi primaria, secondaria e/o esplorativa, come preliminarmente specificato nel protocollo |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 15 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 15 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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