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A Phase 3, Open-label Safety Study of Teduglutide in Japanese Pediatric Patients with Short Bowel Syndrome who are Dependent on Parenteral Support, Aged 4 Months of Corrected Gestational Age or older, and Requiring the Dosing of 1.25 mg Formulation

A study of teduglutide in Japanese children with short bowel syndrome who are 4 months or older

3

The enrolled subjects were all Japanese. The mean (standard deviation [SD]) heights or lengths for age Z-score were -3.060 (1.1601). The mean (SD) weights for age Z-score were -3.017 (1.8048).

A total of 3 subjects were enrolled and completed this study. No subjects prematurely discontinued from any treatment period or from the study.

- A total of 26 TEAEs were reported in 3 subjects (100%) during the study. - Of the 26 TEAEs reported in the 3 subjects (100%), events reported in 2 subjects (66.7%) each were enterocolitis, COVID-19, device related infection, and respiratory syncytial virus infection. Most TEAEs were single events in single subjects. - A total of 12 treatment-emergent SAEs (TESAEs) were reported in 3 subjects (100%). Of these, 5 events of device related infection and 4 events of vascular device occlusion were reported in 2 subjects and 1 subject, respectively. Reported events of bacteraemia, catheter site pruritus, and device breakage were single events in single subjects. None of the TESAEs were considered related to the study drug. - There were no deaths, TEAEs leading to treatment discontinuation, or AESIs during the study. - There were no clinically meaningful changes in hematology and biochemistry measures during the study. No clinically meaningful high or low values were observed from coagulation measures. - No clinically meaningful changes in any parameters of vital signs, body weight, height (or length), and head circumference were noted. - No clinically meaningful changes in fecal and urine output were noted.

Efficacy Results: - The mean (SD) change in PS volume at EOT was -10.99 (27.093) mL/kg/day from baseline, corresponding to a mean percent change of -13.13 (37.259) % for the teduglutide treatment periods. - For number and percent of subjects achieving at least 20% reduction in PS volume, 1 of the 3 subjects (33.33%) achieved at least 20% reduction in PS volume at EOT, based on diary data during the teduglutide treatment periods. - None of the subjects were weaned off PS during the study. - No change from baseline in number of days per week of PS usage at EOT was observed during the teduglutide treatment periods and NTT periods. - The observed mean reductions of 13.13% in PS volume, along with at least a 20% reduction in PS volume in 1 out the 3 subjects, suggest clinically meaningful efficacy results in the use of teduglutide in this patient population. Safety Results: Refer to "Adverse events".

Based on the results from efficacy evaluations, clinically meaningful reductions in PS volume were observed in the use of teduglutide in this patient population. Based on the results from safety evaluations, no new clinically significant findings or safety signals were observed. The nature and frequency of the reported TEAEs in this study were generally consistent with the underlying disease and known adverse drug reactions reported in previous pediatric studies and previous experiences in adult subjects.

Mar. 21, 2024

No

De-identified individual participant data from this particular study will not be shared as there is a reasonable likelihood that individual patients could be re-identified (due to the limited number of study participants/study sites).

https://jrct.niph.go.jp/latest-detail/jRCT2021210035

Koumura Emiko

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka

smb.Japanclinicalstudydisclosure@takeda.com

Contact for Clinical Trial Information

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka

+81-6-6204-2111

smb.Japanclinicalstudydisclosure@takeda.com

Complete

Jan. 04, 2022

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Male or female pediatric patient of corrected gestational age 4 months or older.
2. Body weight at the time of screening and baseline visits of at least 5 kg and <10 kg for participants with normal renal function or mild renal impairment (estimated glomerular filtration rate >=50 mL/min/1.73 m^2), OR at least 10 kg and <20 kg for participants with moderate or greater renal impairment (estimated glomerular filtration rate <50 mL/min/1.73 m^2).
3. Diagnosis of short bowel syndrome (SBS) with intestinal failure, defined as dependence on parenteral support (PS) to provide at least 30% of fluid or caloric needs.
4. Participants to have stable PS for at least 1 month prior to screening as assessed by the investigator. Stable PS is defined as inability to significantly reduce parenteral nutrition/intravenous fluid (PN/IV) support, usually associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or advance in feeds), assessed by the investigator.

1. A parent/guardian who is not capable of understanding or not willing to adhere to the study visit schedule and other protocol requirements.
2. Clinically significant intestinal obstruction, active or recurrent pancreatic or biliary disease, or dysmotility that prevents the advancement of enteral intake.
3. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, etc.
4. 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 PS, prior to screening. Dysmotility is defined as severe if it is expected to limit the advancement of enteral feeding.
5. Major gastrointestinal (GI) surgical intervention including significant intestinal resection or bowel lengthening procedure within 3 months prior to screening (insertion of feeding tube, anastomotic ulcer repair, minor intestinal resections =<10 cm and endoscopic procedures are allowed).
6. Cardiac disease that makes the patient vulnerable to changes in fluid status.
7. History of cancer or known cancer predisposition syndrome, such as juvenile polyposis or Beckwith-Wiedemann syndrome, or first degree relative with early onset of GI cancer (including hepatobiliary and pancreatic cancer).
8. Concurrent treatment with glucagon-like peptide-2 (GLP-2), human growth hormone, or analogs of these hormones within 6 months prior to the screening visit, or concurrent treatment with octreotide, or GLP-1 analogs within 30 days prior to the screening visit.
9. Concurrent treatment with biological therapy (eg, anti-tumor necrosis factor [anti-TNF]) for active Crohn's disease within 6 months prior to the screening visit.
10. 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 the screening visit and for the duration of the study.
11. Known or suspected intolerance or hypersensitivity to the study drug, closely related compounds, or any of the stated ingredients.
12. Signs of active, severe, or unstable clinically significant hepatic impairment during the screening period as meeting at least 2 of any of the following parameters:
a. International normalized ratio >1.5 not corrected with parenteral vitamin K
b. Platelet count <100x10^3/mcrL due to portal hypertension
c. Presence of clinically significant gastric or esophageal varices
d. Cirrhosis
e. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 mcr mol/L) over a 2-week period during screening
f. Total bilirubin >=2x upper limit of normal (ULN)
g. Aspartate aminotransferase (AST) >=3x ULN
h. Alanine aminotransferase (ALT) >=3x ULN

Both

Short Bowel Syndrome

Teduglutide 0.05 milligram per kilogram (mg/kg)
Participants will receive teduglutide 0.05 mg/kg (0.025 mg/kg for participants with moderate or greater renal impairment) subcutaneous (SC) injection once daily in a 28-week treatment cycle consisting of a 24-week treatment period followed by a 4-week no treatment follow-up period for a maximum of 3 cycles.

1. Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Time Frame: From first dose of study drug until follow-up visit (4 weeks after end of treatment [EOT]/end of termination [ET] {up to 47.3-51.3 weeks})
An AE is defined as any untoward medical occurrence in a clinical investigation subject administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAEs were defined as any AEs whose onset occurred, severity worsened, or intensity increased after receiving the investigational product.

2. Number of Participants With Serious Adverse Events (SAEs)
Time Frame: From first dose of study drug until follow-up visit (4 weeks after EOT/ET [up to 47.3-51.3 weeks])
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An SAE is defined as any untoward medical occurrence that at any dose: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly /birth defect, is the other important medical event.

3. Number of Participants With Adverse Events of Special Interest (AESIs)
Time Frame: From first dose of study drug until follow-up visit (4 weeks after EOT/ET [up to 47.3-51.3 weeks])
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AESI, whether serious or non-serious, is one of scientific and medical concern specific to the compound or program, for which ongoing monitoring and rapid communication by the investigator to the sponsor may be appropriate.

4. Number of Participants With Clinically Significant Abnormalities in Vital Signs Reported as an Adverse Event
Time Frame: From first dose of study drug until follow-up visit (4 weeks after EOT/ET [up to 47.3-51.3 weeks])
Vital signs included systolic and diastolic blood pressure, heart rate and body temperature.

5. Change From Baseline in Z-Score of Body Weight at EOT
Time Frame: Baseline, EOT (up to 47.3-51.3 weeks)
A z-score is the deviation of the value for an individual from the mean value of the reference population divided by the standard deviation for the reference population.

6. Change From Baseline in Z-Score of Height at EOT
Time Frame: Baseline, EOT (up to 47.3-51.3 weeks)
A z-score is the deviation of the value for an individual from the mean value of the reference population divided by the standard deviation for the reference population.

7. Change From Baseline in Z-Score of Head Circumference at EOT
Time Frame: Baseline, EOT (up to 47.3-51.3 weeks)
A z-score is the deviation of the value for an individual from the mean value of the reference population divided by the standard deviation for the reference population.

8. Change From Baseline in Z-Score of Weight-for-Length at EOT
Time Frame: Baseline, EOT (up to 47.3-51.3 weeks)
A z-score is the deviation of the value for an individual from the mean value of the reference population divided by the standard deviation for the reference population.

9. Number of Participants With Any Laboratory Safety Finding Reported as an Adverse Event
Time Frame: From first dose of study drug until follow-up visit (4 weeks after EOT/ET [up to 47.3-51.3 weeks])
Laboratory safety parameters included biochemistry, hematology and urinalysis.

10. Number of Participants With a Significant Change in Urine Output Reported as an Adverse Event
Time Frame: From first dose of study drug until follow-up visit (4 weeks after EOT/ET [up to 47.3-51.3 weeks])
Urine and stool output was recorded and calculated in the output diary over a 48-hour period of parenteral support (PS) and enteral nutrition (EN) stability before every site visit and within 1 week of implementing a change in the PS prescription.

11. Number of Participants With a Significant Change in Stool Output Reported as an Adverse Event
Time Frame: From first dose of study drug until follow-up visit (4 weeks after EOT/ET [up to 47.3-51.3 weeks])
Urine and stool output was recorded and calculated in the output diary over a 48-hour period of PS and EN stability before every site visit and within 1 week of implementing a change in the PS prescription.

1. Change From Baseline in PS Volume
Time Frame: Baseline, Cycle 1 = Week 1, 2, 4, 8, 12, 16, 20, 24, and EOT, Cycle 2 = Week 0, 1, 2, 4, 8, 12, 16, 20, 24, and EOT, Cycle 3 = Week 0, 1, 2, and EOT and overall EOT (for up to 47.3-51.3 weeks) [cycle length=28 weeks]
PS (parenteral nutrition or intravenous fluids) was considered for managing nutritional support in terms of volume and calories during the treatment period. An end of treatment (EOT) was defined as the last determination of endpoint of the last cycle.

2. Percent Change From Baseline in PS Volume
Time Frame: Baseline, Cycle 1 = Week 1, 2, 4, 8, 12, 16, 20, 24, and EOT, Cycle 2 = Week 0, 1, 2, 4, 8, 12, 16, 20, 24, and EOT, Cycle 3 = Week 0, 1, 2, and EOT and overall EOT (for up to 47.3-51.3 weeks) [cycle length=28 weeks]
Percent change from baseline in PS volume was calculated as follows; (PS volume at each point [Week 1, 2, 4, 8, 12, 16, 20, 24, and EOT] - PS volume at baseline)/ PS volume at baseline *100 (percent). PS (parenteral nutrition or intravenous fluids) was considered for managing nutritional support in terms of volume and calories during the treatment period. An EOT was defined as the last determination of endpoint of the last cycle.

3. Number of Participants who Demonstrate at least 20 Percent (%) Reduction From Baseline in PS Volume
Time Frame: Baseline, Cycle 1 = Week 1, 2, 4, 8, 12, 16, 20, 24, and EOT, Cycle 2 = Week 0, 1, 2, 4, 8, 12, 16, 20, 24, and EOT, Cycle 3 = Week 0, 1, 2, and EOT, and overall EOT (for up to 47.3-51.3 weeks) [cycle length=28 weeks]
PS (parenteral nutrition or intravenous fluids) was considered for managing nutritional support in terms of volume and calories during the treatment period. An EOT was defined as the last determination of endpoint of the last cycle.

4. Number of Participants who Achieved Enteral Autonomy
Time Frame: Cycle 1 = Week 1, 2, 4, 8, 12, 16, 20, 24, and EOT, Cycle 2 = Week 0, 1, 2, 4, 8, 12, 16, 20, 24, and EOT, Cycle 3 = Week 0, 1, 2, and EOT, and overall EOT (for up to 47.3-51.3 weeks) [cycle length=28 weeks]
Achieving enteral autonomy is defined as complete weaning off PS. PS (parenteral nutrition or intravenous fluids) was considered for managing nutritional support in terms of volume and calories during the treatment period.

5. Change From Baseline in Number of Days per Week of PS Usage at EOT
Time Frame: Baseline, Cycle 1 = Week 1, 2, 4, 8, 12, 16, 20, 24, and EOT, Cycle 2 = Week 0, 1, 2, 4, 8, 12, 16, 20, 24, and EOT, Cycle 3 = Week 0, 1, 2, and EOT, and overall EOT (for up to 47.3-51.3 weeks) [cycle length=28 weeks]
PS (parenteral nutrition or intravenous fluids) was considered for managing nutritional support in terms of volume and calories during the treatment period.

+81-22-717-7056

Aug. 23, 2021

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