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 | 19.0 |
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 safety, tolerability, pharmacokinetics, and efficacy/pharmacodynamics of teduglutide in pediatric subjects (through 17 years) with 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 (as deemed appropriate by the Ethics Committee/Institutional Review Board) prior to any study-related procedures
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis)
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric and/or fluid/electrolyte needs prior to screening
5. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or advance in feeds) for at least 3 months prior to and during screening, as assessed by the investigator.
Transient instability for events such as interruption of central access or treatment for sepsis is allowed if the PN/IV support returns to within 10% of baseline prior to the event.
6. Sexually active female subjects of child-bearing potential (in the
teduglutide treatment arm only) must use medically acceptable methods
of birth control during and 4 weeks after the treatment period |
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E.4 | Principal exclusion criteria |
1. Subjects who are not expected to be able to advance oral or tube
feeding regimens
2. Serial transverse enteroplasty or any other bowel lengthening
procedure performed within 3 months of screening
3. Known clinically significant untreated intestinal obstruction
contributing to feeding intolerance and inability to reduce parenteral
support
4. Unstable absorption due to cystic fibrosis or known DNA abnormalities
(eg, Familial Adenomatous Polyposis, Fanconi-Bickel syndrome)
5. 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.
6. Evidence of clinically significant obstruction on upper gastrointestinal
(GI) series done within 6 months prior to screening
7. Major GI surgical intervention including significant intestinal resection
within 3 months prior to the screening visit (insertion of feeding tube,
anastomotic ulcer repair, minor intestinal resections ≤10 cm, or
endoscopic procedure is allowed)
8. Unstable cardiac disease, congenital heart disease or cyanotic disease,
with the exception of subjects who had undergone ventricular or atrial
septal defect repair, and patent ductus arteriosus (PDA) ligation
9. History of cancer or clinically significant lymphoproliferative disease,
not including resected cutaneous basal or squamous cell carcinoma, or in
situ non-aggressive and surgically resected cancer
10. Pregnant or lactating female subjects (in the teduglutide treatment
arm only)
11. Participation in a clinical study using an experimental drug (other
than glutamine or Omegaven) within 3 months or 5.5 half-lives of the
experimental drug, whichever is longer, prior to screening and for the
duration of the study
12. Previous use of teduglutide or native/synthetic glucagon-like
peptide-2 (GLP-2)
13. Previous use of glucagon-like peptide-1 analog or human growth
hormone within 3 months prior to screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4)
inhibitors within 3 months prior to screening
15. Subjects with active Crohn's disease who had been treated with
biological therapy (eg, antitumor necrosis factor [anti-TNF]) within the 6
months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic
systemic
immunosuppressant therapy that had been introduced or changed during
the 3 months prior to screening
17. More than 3 SBS-related or PN-related hospital admissions (eg,
documented
infection-related catheter sepsis, clots, bowel obstruction, severe water
electrolyte disturbances) within 3 months prior to the screening visit
18. Any major unscheduled hospital admission which affects parenteral
support requirements within 1 month prior to or during screening,
excluding uncomplicated treatment of bacteremia, central line
replacement/repair, or issues of similar magnitude in an otherwise
stable subject
19. Body weight <10 kg at screening and baseline visits
20. Signs of active, severe, or unstable clinically significant hepatic
impairment during the screening period, indicative by any of the
following laboratory test results:
a. Total bilirubin (TBL) ≥2x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7x ULN
c. Alanine aminotransferase (ALT) ≥7x ULN
For subjects with Gilbert's disease:
d. Indirect (unconjugated) bilirubin ≥2x ULN
21. Signs of known continuous active or unstable, clinically significant
renal dysfunction shown by results of an estimated glomerular filtration
rate (eGFR) below 50 mL/min/1.73 m2
22. 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
23. Unstable, clinically significant, active, untreated pancreatic or biliary
disease
24. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
A 20% reduction or greater (including complete weaning) from baseline in volume of PN/IV at the end of 24 weeks of treatment
The primary pharmacodynamic (PD) parameter is parenteral support reduction of 20% to 100% at 24 weeks (or EOT) compared to baseline. |
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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) |
provide further information on the safety, PK, and efficacy/PD profile of teduglutide in pediatric subjects treated for up to 24 weeks. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Additional PD endpoints include:
100% reduction in PN/IV volume (complete weaning of PN/IV
support) at week 24 (or EOT) compared to baseline
Changes (absolute and percent change) from baseline in PN/IV
support (volume and calories), citrulline and enteral nutritional support
(volume and calories), separately, at each clinic visit
Changes (absolute and percent change) from week 24 (or EOT) in
PN/IV support (volume and calories), citrulline, and enteral nutritional
support (volume and calories), separately, to week 28 (or EOS)
Change in hours per day and days per week of PN/IV support
≥20% reduction in PN/IV volume at each clinic visit
Pharmacokinetics: teduglutide treatment arm only blood collected on
day 0 predose and 1, 2, and 4 hours postdose. |
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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 | 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 | 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 | 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 |
separate standard of care cohort |
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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 | 2 |
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 | 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 |
Belgium |
Canada |
Finland |
France |
Germany |
Italy |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |