Study in Japanese Pediatric Subjects With Short Bowel Syndrome (SBS) Who Are Dependent on Parenteral Support

Short Bowel Syndrome Clinical Trial

Official title:

A 24-week Safety, Efficacy, Pharmacodynamic, and Pharmacokinetic Study of Teduglutide in Japanese Pediatric Subjects, Aged 4 Months Through 15 Years, With Short Bowel Syndrome Who Are Dependent on Parenteral Support

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02980666
• Other study ID #: SHP633-302
• Secondary ID: 2020-005791-35
• Status: Completed
• Phase: Phase 3
• Start date: January 13, 2017
• Est. completion date: January 21, 2020

Study information

• Verified date: January 2021
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine if an investigational treatment (teduglutide) is safe and effective in Japanese children (age 4 months through 15 years of age) with SBS who are dependent on parenteral support. This study will also evaluate how teduglutide moves through the body (pharmacokinetics) and how it affects the body (pharmacodynamics).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: January 21, 2020
• Est. primary completion date: January 21, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Months to 15 Years

Eligibility

Inclusion Criteria:

• Informed consent by a parent or guardian prior to any study-related procedures
• When applicable, informed assent (as deemed appropriate by the Institutional Review Board) by the participant prior to any study-related procedures
• Male or female infant 4 to <12 months corrected gestational age or child or adolescent aged 1 year through 15 years
• Current history of SBS as a result of major intestinal resection (eg, due to necrotizing enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis)
• Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric and/or fluid/electrolyte needs
• Stable PN/IV support, defined as:

For infants 4 to <12 months corrected gestational age: 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 1 month prior to and during screening, as assessed by the investigator. For children 1 to 15 years of age: 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 of sepsis is allowed if the PN/IV support returns to within 10% of baseline prior to the event.

• Sexually active female participants of childbearing potential must use medically acceptable methods of birth control during and for 4 weeks following the last dose of investigational product.

Exclusion Criteria:

• Participants who are not expected to be able to advance oral or tube feeding regimens
• Serial transverse enteroplasty or any other bowel lengthening procedure performed within 3 months of screening
• Known clinically significant untreated intestinal obstruction contributing to feeding intolerance and inability to reduce parenteral support
• Unstable absorption due to cystic fibrosis or other known DNA abnormalities (eg, Familial Adenomatous Polyposis, Fanconi-Bickel syndrome)
• 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.
• Evidence of clinically significant obstruction on the most recent upper GI series done within 6 months prior to screening.
• Major GI surgical intervention including significant intestinal resection within 3 months prior to screening (insertion of feeding tube, anastomotic ulcer repair, minor intestinal resections <=10 centimeter (cm), or endoscopic procedure is allowed)
• Unstable cardiac disease or congenital heart disease or cyanotic disease, with the exception of participants who had undergone ventricular or atrial septal defect repair, and patent ductus arteriosus (PDA) ligation
• History of cancer or clinically significant lymphoproliferative disease, not including resected cutaneous basal or squamous cell carcinoma, or in situ nonaggressive and surgically resected cancer. Participants with 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) will also be excluded.
• Pregnant or lactating female participants
• 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
• Previous use of teduglutide or native/synthetic GLP-2
• Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months prior to screening
• Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior to screening
• Participants 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
• Participants with inflammatory bowel disease (IBD) who require chronic systemic immunosuppressant therapy that had been introduced or changed during the 3 months prior to screening
• More than 3 serious complications of SBS (eg, documented infection-related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) within 3 months prior to the screening visit
• A serious complication that 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 participant
• Body weight < 5 kilogram (kg) at screening and baseline visits
• Signs of active, severe, or unstable clinically significant hepatic impairment during the screening period: For infants 4 to <12 months corrected gestational age at least 2 of any of the following

parameters:

1. International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K

2. Platelet count <100×10^3/ (microliters)mcL due to portal hypertension

3. Presence of clinically significant gastric or esophageal varices

4. Documented cirrhosis

5. Persistent cholestasis defined as conjugated bilirubin >4 milligram per deciliter (mg/dL) (>68 micromoles per liter [mcmol/L]) over a 2 week period

For children 1 to 15 years of age:

1. Total bilirubin >= 2x upper limit of normal (ULN)

2. Aspartate aminotransferase (AST) >= 7x ULN

3. Alanine aminotransferase (ALT) >= 7x ULN

• Signs of known continuous active or unstable, clinically significant renal dysfunction shown by results of an estimated glomerular filtration rate below 50 milliliter per minute (mL/min)/1.73 meter (m)^2
• Parent(s)/guardian(s) and/or participants who are not capable of understanding or not willing to adhere to the study visit schedule and other protocol requirements
• Unstable, clinically significant, active, untreated pancreatic or biliary disease
• Any condition, disease, illness, or circumstance that in the investigator's opinion puts the participant at any undue risk, prevents completion of the study, or interferes with analysis of the study results.

Related Conditions & MeSH terms

• Short Bowel Syndrome
• Syndrome

Intervention

Drug:
• Teduglutide
0.05 mg/kg/day SC injection once daily for 24 weeks.

Locations

Country	Name	City	State
Japan	Kyushu University Hospital	Fukuoka-shi	Fukuoka-ken
Japan	Kagoshima University	Kagoshima-shi	Kagoshima-Ken
Japan	Tohoku University Hospital	Sendai-shi	Miyagi-Ken
Japan	Showa University	Shinagawa-ku	Tokyo-To
Japan	Tsukuba University Hospital	Tsukuba	Ibaraki-Ken

Sponsors (1)

Lead Sponsor	Collaborator
Shire

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Absolute Change From Baseline in Parenteral Support (PS) Volume at End of Treatment (EOT) Based on Dairy Data	Absolute change from baseline in PS volume at EOT (up to Week 24) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period. Here, milliliter per kilogram per day is abbreviated as mL/kg/day.	Baseline, EOT (up to Week 24)
Primary	Percent Change From Baseline in Parenteral Support (PS) Volume at End of Treatment (EOT) Based on Dairy Data	Percent change from baseline in PS volume at EOT (up to Week 24) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	Baseline, EOT (up to Week 24)
Primary	Absolute Change From Baseline in Parenteral Support (PS) Caloric Intake at End of Treatment (EOT) Based on Dairy Data	Absolute change from baseline in PS caloric intake at EOT (up to Week 24) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period. Here, kilo-calories per kilogram per day was abbreviated as (kcal/kg/day).	Baseline, EOT (up to Week 24)
Primary	Percent Change From Baseline in Parenteral Support (PS) Caloric Intake at End of Treatment (EOT) Based on Dairy Data	Percent change from baseline in PS caloric intake at EOT (up to Week 24) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	Baseline, EOT (up to Week 24)
Primary	Absolute Change From Baseline in Plasma Citrulline at End of Treatment (EOT)	Absolute change from baseline in plasma citrulline at EOT (up to Week 24) was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	Baseline, EOT (up to Week 24)
Primary	Percent Change From Baseline in Plasma Citrulline at End of Treatment (EOT)	Percent change from baseline in plasma citrulline at EOT (up to Week 24) was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	Baseline, EOT (up to Week 24)
Primary	Absolute Change From Baseline in Enteral Nutritional (EN) Volume at End of Treatment (EOT) Based on Dairy Data	Absolute change from baseline in EN volume at EOT (up to Week 24) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	Baseline, EOT (up to Week 24)
Primary	Percent Change From Baseline in Enteral Nutritional (EN) Volume at End of Treatment (EOT) Based on Dairy Data	Percent change from baseline in EN volume at EOT (up to Week 24) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	Baseline, EOT (up to Week 24)
Primary	Absolute Change From Baseline in Enteral Nutritional (EN) Caloric Intake at End of Treatment (EOT) Based on Dairy Data	Absolute change from baseline in EN caloric intake at EOT (up to Week 24) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	Baseline, EOT (up to Week 24)
Primary	Percent Change From Baseline in Enteral Nutritional (EN) Caloric Intake at End of Treatment (EOT) Based on Dairy Data	Percent change from baseline in EN caloric intake at EOT (up to Week 24) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	Baseline, EOT (up to Week 24)
Primary	Number of Participants Who Achieved At Least 20 Percent (%) Reduction in Parenteral Support (PS) Volume at Week 24	Number of participants who achieved at least 20% reduction in PS volume at Week 24 was reported.	Week 24
Primary	Number of Participants Who Achieved At Least 20 Percent (%) Reduction in Parenteral Support (PS) Volume at End of Treatment (EOT)	Number of participants who achieved at least 20% reduction in PS volume at EOT (up to Week 24) was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	EOT (up to Week 24)
Primary	Number of Participants Who Achieved 100 Percent (%) Reduction in Complete Weaning of Parenteral Support (PS) Volume at End of Treatment (EOT)	Number of participants who achieved at least 100% reduction in complete weaning of PS volume at EOT (up to Week 24) was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	EOT (up to Week 24)
Primary	Number of Participants Who Achieved Greater Than or Equal to (>=) 20 Percent (%) Reduction in Parenteral Support (PS) Volume at Week 28	Number of participants who achieved >= 20% reduction in PS volume at Week 28 was reported.	Week 28
Primary	Absolute Change From End of Treatment (EOT) in Parenteral Support (PS) Volume at End of Study (EOS) Based on Dairy Data	Absolute change from EOT (up to Week 24) in PS volume at EOS (up to Week 28) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	EOT (up to Week 24), EOS (up to Week 28)
Primary	Percent Change From End of Treatment (EOT) in Parenteral Support (PS) Volume at End of Study (EOS) Based on Dairy Data	Percent change from EOT (up to Week 24) in PS volume at EOS (up to Week 28) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	EOT (up to Week 24), EOS (up to Week 28)
Primary	Absolute Change From End of Treatment (EOT) in Parenteral Support (PS) Caloric Intake at End of Study (EOS) Based on Dairy Data	Absolute change from EOT (up to Week 24) in PS caloric intake at EOS (up to Week 28) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	EOT (up to Week 24), EOS (up to Week 28)
Primary	Percent Change From End of Treatment (EOT) in Parenteral Support (PS) Caloric Intake at End of Study (EOS) Based on Dairy Data	Percent change from EOT (up to Week 24) in PS caloric intake at EOS (up to Week 28) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	EOT (up to Week 24), EOS (up to Week 28)
Primary	Absolute Change From End of Treatment (EOT) in Plasma Citrulline at End of Study (EOS)	Absolute change from EOT (up to Week 24) in plasma citrulline at EOS (up to Week 28) was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	EOT (up to Week 24), EOS (up to Week 28)
Primary	Percent Change From End of Treatment (EOT) in Plasma Citrulline at End of Study (EOS)	Percent change from EOT (up to Week 24) in plasma citrulline at EOS (up to Week 28) was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	EOT (up to Week 24), EOS (up to Week 28)
Primary	Absolute Change From End of Treatment (EOT) in Enteral Nutritional (EN) Volume at End of Study (EOS) Based on Dairy Data	Absolute change from EOT (up to Week 24) in EN volume at EOS (up to Week 28) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	EOT (up to Week 24), EOS (up to Week 28)
Primary	Percent Change From End of Treatment (EOT) in Enteral Nutritional (EN) Volume at End of Study (EOS) Based on Dairy Data	Percent change from EOT (up to Week 24) in EN volume at EOS (up to Week 28) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	EOT (up to Week 24), EOS (up to Week 28)
Primary	Absolute Change From End of Treatment (EOT) in Enteral Nutritional (EN) Caloric Intake at End of Study (EOS) Based on Dairy Data	Absolute change from EOT (up to Week 24) in EN caloric intake at EOS (up to Week 28) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	EOT (up to Week 24), EOS (up to Week 28)
Primary	Percent Change From End of Treatment (EOT) in Enteral Nutritional (EN) Caloric Intake at End of Study (EOS) Based on Dairy Data	Percent change from EOT (up to Week 24) in EN caloric intake at EOS (up to Week 28) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	EOT (up to Week 24), EOS (up to Week 28)
Primary	Absolute Change From Baseline in Number of Hours Per Day of Parenteral Support (PS) Usage at End of Treatment (EOT) Based on Dairy Data	Absolute change from baseline in number of hours per day of PS Usage at EOT (up to Week 24) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	Baseline, EOT (up to Week 24)
Primary	Absolute Change From Baseline in Number of Days Per Week of Parenteral Support (PS) Usage at End of Treatment (EOT) Based on Dairy Data	Absolute change from baseline in number of days per Week of PS usage at EOT (up to Week 24) based on dairy data was reported. EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period.	Baseline, EOT (up to Week 24)
Primary	Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An Adverse Event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily 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.	From start of study drug administration up to EOS (up to Week 28)
Primary	Change From Baseline in Body Weight for Age Z-score at Week 28	Body weight was measured using age Z-score. A Z-score was defined as 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. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean. Change from baseline in body weight for age Z-score at Week 28 was reported.	Baseline, Week 28
Primary	Change From Baseline in Height for Age Z-score at Week 28	Height was measured using age Z-score. A Z-score was defined as 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. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean. Change from baseline in height for age Z-score at Week 28 was reported.	Baseline, Week 28
Primary	Change From Baseline in Head Circumference for Age Z-score at Week 28	Head circumference was measured using age Z-score. A Z-score was defined as 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. A negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean. Change from baseline in head circumference for age Z-score at Week 28 was reported.	Baseline, Week 28
Primary	Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Emergent Adverse Events (TEAEs)	Vital sign assessments included pulse rate, blood pressure, or body temperature. Number of participants with clinically significant changes in vital signs by the investigator were recorded as TEAEs.	From start of study drug administration up to EOS (up to Week 28)
Primary	Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Reported as Treatment Emergent Adverse Events (TEAEs)	12-lead ECG was performed. Any change in ECG assessments which were deemed to be clinically significant changes were recorded as TEAEs.	From start of study drug administration up to EOS (up to Week 28)
Primary	Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)	Clinical laboratory assessments included biochemistry, hematology, coagulation, urinalysis. The number of participants with clinically significant laboratory abnormalities were reported as TEAEs.	From start of study drug administration up to EOS (up to Week 28)
Primary	Change From Baseline in the Average Urine Output at Week 28	Average urine output was recorded in measured volume at Week 28 was recorded.	Baseline, Week 28
Primary	Change From Baseline in the Fecal Output at Week 28	Change from baseline in the fecal output (Average number of stools per day) at Week 28 was recorded.	Baseline, Week 28
Primary	Number of Participants With Positive Specific Antibodies to Teduglutide	Number of participants with positive specific antibodies to teduglutide were used to summarize the presence of antibodies.	From start of study drug administration up to EOS (up to Week 28)
Primary	Number of Participants With Clinically Significant Abnormal Findings in Gastrointestinal (GI) Specific Testing	GI specific testing included colonoscopy or sigmoidoscopy, abdominal ultrasound, fecal occult blood testing, upper GI series with small bowel follow-through (UGI/SBFT). EOT was defined as the last available measurement after the date of first dose during the 24-week treatment period. Number of participants with clinically significant abnormal findings in gastrointestinal specific testing were reported.	Baseline, EOT (up to Week 24)
Primary	Area Under the Concentration-time Curve at Steady State (AUCtau,ss) of Teduglutide in Plasma	Since only 2 sparse pharmacokinetics (PK) samples were collected during the study, PK parameters were not estimated and analyzed using this study samples. Therefore, no PK parameters were reported in this study.	Baseline: Pre-dose, 1, 6 hours post-dose; Week 4: Pre-dose, 2, 4 hours post-dose
Primary	Maximum Plasma Concentration at Steady-state (Cmax,ss) of Teduglutide in Plasma	Since only 2 sparse PK samples were collected during the study, PK parameters were not estimated and analyzed using this study samples. Therefore, no PK parameters were reported in this study.	Baseline: Pre-dose, 1, 6 hours post-dose; Week 4: Pre-dose, 2, 4 hours post-dose
Primary	Minimum Plasma Concentration at Steady-state (Cmin.ss) of Teduglutide in Plasma	Since only 2 sparse PK samples were collected during the study, PK parameters were not estimated and analyzed using this study samples. Therefore, no PK parameters were reported in this study.	Baseline: Pre-dose, 1, 6 hours post-dose; Week 4: Pre-dose, 2, 4 hours post-dose
Primary	Time to Reach Maximum Observed Drug Concentration (Tmax) of Teduglutide in Plasma	Since only 2 sparse PK samples were collected during the study, PK parameters were not estimated and analyzed using this study samples. Therefore, no PK parameters were reported in this study.	Baseline: Pre-dose, 1, 6 hours post-dose; Week 4: Pre-dose, 2, 4 hours post-dose
Primary	Terminal-Phase Half-life (t1/2) of Teduglutide in Plasma	Since only 2 sparse PK samples were collected during the study, PK parameters were not estimated and analyzed using this study samples. Therefore, no PK parameters were reported in this study.	Baseline: Pre-dose, 1, 6 hours post-dose; Week 4: Pre-dose, 2, 4 hours post-dose
Primary	Apparent Clearance (CL/F) of Teduglutide	Since only 2 sparse PK samples were collected during the study, PK parameters were not estimated and analyzed using this study samples. Therefore, no PK parameters were reported in this study.	Baseline: Pre-dose, 1, 6 hours post-dose; Week 4: Pre-dose, 2, 4 hours post-dose
Primary	Apparent Volume of Distribution (V[Lambda z]/F) of Teduglutide	Since only 2 sparse PK samples were collected during the study, PK parameters were not estimated and analyzed using this study samples. Therefore, no PK parameters were reported in this study.	Baseline: Pre-dose, 1, 6 hours post-dose; Week 4: Pre-dose, 2, 4 hours post-dose