E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Short Bowel Syndrome (SBS) |
sindrome dell’intestino corto |
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E.1.1.1 | Medical condition in easily understood language |
Short Bowel Syndrome (SBS) |
sindrome dell’intestino corto |
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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 | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10049416 |
E.1.2 | Term | Short-bowel syndrome |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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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 |
the objectives of this trial are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics (PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support. |
Gli obiettivi di questo studio clinico sono quelli di valutare la sicurezza, l’efficacia/la farmacodinamica e la farmacocinetica (PK) del trattamento con teduglutide in neonati affetti da sindrome dell’intestino corto (SIC) dipendenti da supporto parenterale. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Informed consent by the parent or legal guardian.
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric needs.
5. Stable Parenteral Nutrition (PN) requirements for at least 1 month prior to screening, defined as a ≤10% change in the weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, notwithstanding transient instability for events such as sepsis or interruption of
central venous access.
6. Lack of terminal ileum and ileocecal valve.
7. Parent or legal guardian understands and is willing and able to fully adhere to study requirements as defined in this protocol. |
1. Consenso informato rilasciato dal genitore o dal tutore legale.
2. Neonato di sesso maschile o femminile di età gestazionale compresa tra i 4 e i 12 mesi corretta allo screening.
3. Peso di almeno 5 kg e punteggio Z del rapporto peso/altezza superiore a -2 allo screening e al basale.
4. Sindrome dell’intestino corto con dipendenza da supporto parenterale per l’apporto di almeno il 50% del fabbisogno di liquidi o di quello calorico.
5. Fabbisogno di NP stabile per almeno 1 mese prima dello screening, definito come una variazione ≤10% dell’apporto totale di liquidi e di calorie per via parenterale a peso normalizzato, nonostante i tentativi di cessare gradualmente la NP, malgrado l’instabilità transitoria di eventi come la sepsi o l’interruzione a carico di un accesso venoso centrale.
6. Mancanza di ileo terminale e valvola ileocecale
7. Il genitore o il tutore legale comprende i requisiti dello studio definiti nel presente protocollo e sono disposti ed in grado di aderirvi pienamente.
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E.4 | Principal exclusion criteria |
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal resection or anastomosis, within 3 months prior to screening or planned during the study period.
7. Unstable cardiac disease.
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9. Biliary obstruction, stenosis, or malformation.
10. Clinically significant pancreatic disease.
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a. International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/μL due to portal hypertension
c. Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 μmol/L) over a 2 week period.
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream infections, interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer (including hepatobiliary and pancreatic cancers).
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or glutamine.
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any undue risk, prevents completion of the study, or interferes with analysis of the study results. |
1. Precedente trattamento con teduglutide.
2. Malassorbimento intestinale a causa di una condizione di natura genetica, come la fibrosi cistica, la malattia da inclusione dei microvilli, ecc.
3. Grave sindrome da dismotilità nota, come pseudo-occlusione o dismotilità correlata a gastroschisi persistente, grave, attiva, che costituisca il fattore principale concorrente all’intolleranza all’alimentazione e all’impossibilità di ridurre il supporto parentale, prima dello screening. La dismotilità è definita grave se si prevede che limiti i progressi nell’alimentazione enterale.
4. Incapacità di progredire con l’alimentazione orale o enterale a causa della mancanza di accesso all’intestino, come l’avversione orale in assenza di un tubo di alimentazione.
5. Ostruzione intestinale o stenosi intestinale clinicamente significativa.
6. Intervento chirurgico gastrointestinale maggiore, come l’enteroplastica trasversale seriale o la resezione intestinale maggiore o l’anastomosi, nei 3 mesi precedenti allo screening o programmato durante il periodo dello studio.
7. Malattia cardiaca instabile.
8. Disfunzione renale, definita come velocità di filtrazione glomerulare stimata < 50 ml/min/1,73 m2.
9. Ostruzione, stenosi o malformazione biliari.
10. Malattia del pancreas clinicamente significativa.
11. Grave disfunzione epatica o ipertensione portale, definite da almeno 2 dei seguenti parametri:
a. rapporto normalizzato internazionale (RNI) > 1,5 non corretto con vitamina K per via parenterale
b. conta piastrinica < 100×10^3/µl dovuta a ipertensione portale
c. presenza di varici gastriche o esofagee clinicamente significative
d. cirrosi documentata
12. Colestasi persistente definita come bilirubina coniugata > 4 mg/dl (> 68 µmol/l) nell’arco di un periodo di 2 settimane.
13. Presenza di più di 3 gravi complicanze dell’insufficienza intestinale (ad es., infezioni del circolo sanguigno associate al catetere, interruzione della nutrizione per intolleranza alimentare, trombosi associata all’uso del catetere, gravi squilibri dei liquidi o degli elettroliti) nel mese precedente lo screening o durante lo screening.
14. Anamnesi di tumore o nota sindrome di predisposizione a tumore, come la poliposi giovanile o la sindrome di Beckwith-Wiedemann oppure presenza di un parente di primo grado con insorgenza precoce di tumore gastrointestinale (come tumori epatobiliari e pancreatici).
15. Trattamento concomitante con il peptide-1 glucagone-simile (GLP-1), peptide-2 glucagone-simile (GLP-2), fattore di crescita insulino-simile di tipo 1 (IGF-1), ormone della crescita, somatostatina o analoghi di questi ormoni; oppure, glutamina.
16. Partecipazione a uno studio clinico in cui è impiegato un farmaco sperimentale nei 3 mesi o in un periodo pari a 5,5 emivite del farmaco sperimentale, a seconda di quale sia il periodo più lungo.
17. Intolleranza o ipersensibilità nota o sospetta al prodotto sperimentale, ai composti strettamente correlati o a qualsiasi ingrediente specificato.
18. Qualsiasi condizione, disturbo, malattia o circostanza che, secondo il parere dello sperimentatore, esponga il soggetto a un rischio ingiustificato, impedisca il completamento dello studio o interferisca con l’analisi dei risultati dello studio.
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E.5 End points |
E.5.1 | Primary end point(s) |
Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT (end of treatment) |
• riduzione di almeno il 20% rispetto al basale del volume di liquidi somministrato con la NP a peso normalizzato alla Settimana 24/all’EOT |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
week 24/EoT |
Settimana 24/all’EOT |
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E.5.2 | Secondary end point(s) |
- Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT
- Achievement of enteral autonomy by week 24
- Change in weight-normalized parenteral fluid volume from baseline to each visit
- Change in weight-normalized parenteral calories from baseline to each visit
- Change in weight-normalized enteral fluid volume from baseline to each visit
- Change in weight-normalized enteral caloric intake from baseline to each visit
- Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT
- Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:
- Adverse events (AEs)
- Physical examinations
- Vital signs
- Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)
- Laboratory safety data (biochemistry and haematology)
- Urine output
- Stool (including mixed) output
- Antibodies to teduglutide
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:
- Cumulative number of hospitalization days during the study |
• riduzione di almeno il 20% rispetto al basale delle calorie somministrate per via parenterale a peso normalizzato alla Settimana 24/all’EOT
• raggiungimento dell’autonomia enterale entro la settimana 24
• variazione rispetto al basale del volume di liquidi somministrato per via parenterale a peso normalizzato a ogni visita
• variazione rispetto al basale delle calorie somministrate per via parenterale a peso normalizzato a ogni visita
• variazione rispetto al basale del volume di liquidi assunto per via enterale a peso normalizzato a ogni visita
• variazione rispetto al basale delle calorie assunte per via enterale a peso normalizzato a ogni visita
• aumento di almeno il 20% rispetto al basale dei liquidi assunti per via enterale a peso normalizzato alla Settimana 24/all’EOT
• aumento di almeno il 20% rispetto al basale delle calorie assunte per via enterale a peso normalizzato alla Settimana 24/all’EOT
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
each visit and week 24/EoT |
Ogni visita e alla Settimana 24/all’EOT |
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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 | Yes |
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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
1 braccio in SOC e 1 braccio con teduglutide |
1 arm standard of care and 1 arm on teduglutide |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |