| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 16.1 |
| 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 objective of this clinical study is to evaluate the pharmacokinetic (PK) profile, safety and tolerability, and pharmacodynamic effects of teduglutide compared with standard of care in pediatric subjects (aged 1 year through 17 years) with short bowel syndrome (SBS) who are dependent on parenteral support. |
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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 a parent or guardian or emancipated minor prior to any study-related procedures
2. When applicable, an informed assent by the subject prior to any study-related procedures (as deemed appropriate by the Ethics Committee/Institutional Review Board)
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis) for at least 12 months prior to screening
4. Short bowel syndrome that requires parenteral nutrition/intravenous (PN/IV) support that provides at least 30% of caloric and/or fluid/electrolyte needs
5. Stable PN/IV support for at least 3 months prior to enrollment based upon the opinion of the investigator and approval by the Sponsor’s Medical Monitor
6. Female subjects of child-bearing potential must use medically acceptable methods of birth control during and for 30 days after the treatment period. |
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| E.4 | Principal exclusion criteria |
1. Serial transverse enteroplasty or any other bowel lengthening procedure performed within the past 3 months
2. Evidence of untreated intestinal obstruction or active stenosis
3. Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known DNA abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
4. Radiographic or manometric evidence of pseudo-obstruction or severe known dysmotility syndrome, including gastroschisis-related motility disorders
5. Evidence of obstruction on upper gastrointestinal (GI) series done within 6 months prior to screening
6. Major gastrointestinal surgical intervention within 3 months prior to screening (insertion of feeding tube or endoscopic procedure is allowed)
7. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of subjects who had undergone ventricular or atrial septal defect repair
8. History of cancer or clinically significant lymphoproliferative disease within 5 years, not including resected cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically resected cancer
9. Pregnant or lactating female subjects
10. Participation in a clinical study using an experimental drug within 1 month or an experimental antibody treatment within 3 months prior to screening, or concurrent participation in any clinical study using an experimental drug that would affect the safety of teduglutide
11. Previous use of native glucagon-like peptide-2 (GLP-2) and glucagon-like peptide-1 analog or human growth hormone within 3 months prior to screening
12. Previous use of oral or IV glutamine, octreotide, or dipeptidyl peptidase IV (DPP-IV) inhibitors within 3 months prior to screening
13. Previous use of teduglutide
14. Subjects with active Crohn’s disease who had been treated with biological therapy (eg, antitumor necrosis factor [anti-TNF] or natalizumab) within the 6 months prior to screening
15. Subjects with inflammatory bowel disease (IBD) who required chronic systemic immunosuppressant therapy that had been introduced or changed during the last 3 months
16. More than 3 SBS-related or PN-related hospital admissions (eg, catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) within 3 months prior to screening visit
17. Hospital admission, other than scheduled, within 1 month prior to screening
18. Body weight < 5 percentile for age or < 10 kg
19. Signs of severe hepatic impairment:
a. Total bilirubin ≥ 2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥ 5 x ULN
c. Alanine aminotransferase (ALT) ≥ 5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥ 2 x ULN
20. Signs of or disturbed renal function:
a. Serum creatinine ≥ 2 x ULN
b. Creatinine clearance < 50 mL/min
21. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to the study visit schedule and other protocol requirements
22. Active or history of clinically significant pancreatic or biliary disease
23. Any condition or circumstance that in the investigator’s opinion puts the subject at any undue risk, prevented completion of the study, or interfered with analysis of the study results
24. Presence of any of the excluded disease states |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Pharmacokinetic parameters:
Study drug doses will be evaluated based on PK sampling and increased absorptive capacity as measured by PN/IV volume reduction. Samples for PK analysis will be collected pre-dose, at 1 and 6 hours post-dose at the start of treatment (SOT) and again at Week 4 predose, and 2 and 4 hours postdose for subjects in Cohorts 1, 2, and 3. If blood samples are not/cannot be collected at Week 4, the uncollected samples can be collected during any future visit while the subject is still on study drug.
The following parameters will be derived:
• Area under the plasma concentration–time curve (AUC) of zero to infinity (0–inf);
• AUC from zero to the last measurable concentration (AUC0–t);
• Maximum plasma concentration (Cmax);
• Time to Cmax (tmax);
• Terminal-phase half-life (t1/2λz);
• Apparent clearance (CL/F);
• Apparent volume of distribution (Vλz/F)
Safety and Tolerability
Safety and tolerability will be assessed by evaluations of:
• Adverse events, including GI symptoms
• Vital signs, including changes in body weight
• Electrocardiograms
• Laboratory safety data, including electrolyte balance
• Antibodies to teduglutide and Escherichia coli protein (ECP). Samples for antibody analysis will be drawn at SOT and at the end of treatment (EOT ) visit (prior to the administration of teduglutide and at least 14 hours after the previous dose). One sample will also be collected at the final visit 4 weeks after the EOT. It is planned to follow-up with any subjects testing positive for antibodies to teduglutide for up to 6 months after the last dose of study drug.
• Maintaining a trend consistent with 5 to 95 percentile growth chart, including weight, head circumference, and length
• Oral/enteral feeding tolerance
• Nutritional intake and urinary/fecal output (intake/output)
• Results of routine clinical evaluations including physical examination, and where appropriate, GI-specific testing including imaging (eg, colonoscopy, sigmoidoscopy) abdominal ultrasound, fecal occult blood testing)
Pharmacodynamic Parameters
The pharacodynamic parameter is parenteral support reduction at the end of 12 weeks (or EOT) compared to baseline. Analysis of this PD endpoint will examine:
• ≥10% reduction in PN/IV support
• ≥20% reduction in PN/IV support
• An increase in enteral nutritional tolerance (calories and volume)
• A decrease in parenteral support (calories and volume)
• Ostomy output/stool balance testing (at selected sites)
• Urine output
• Weight gain or stabilization (Z-scores), height (length)
• Changes in plasma citrulline from baseline to Weeks 12 (or EOT)
• Change in PN/IV support 4 weeks after EOT compared to baseline.
• Change in PN/IV support 3 and 6 months EOT compared to baseline for those who developed antibodies specific to teduglutide
• Change in hours per day or days per week of PN/IV as well as any subjects who are able to completely wean off PN/IV support |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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 | Yes |
| 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Observational cohort receiving Standard of Care |
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| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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 |
| Sweden |
| United Kingdom |
| United States |
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| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 11 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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