Short Bowel Syndrome
Conditions
Keywords
Short Bowel Syndrome, Parenteral Nutrition, SBS
Brief summary
The purpose of this study is to evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of teduglutide compared with placebo in subjects with parenteral nutrition (PN)-dependent short bowel syndrome (SBS).
Detailed description
Teduglutide is an analog of glucagon-like peptide 2 (GLP-2), a naturally occurring hormone that regulates the growth, proliferation, and maintenance of cells lining the gastrointestinal tract. Teduglutide has been shown in animal studies and previous human clinical trials to increase the size and number of these cells, thereby increasing the absorptive surface area of the intestines. The multicenter, double-blind, international Phase III trial will randomly assign approximately 80 patients to receive daily subcutaneous injections of 0.05 milligrams or 0.10 milligrams of teduglutide per kilogram of body weight, or a placebo. Dosing will continue for a period of six months. The primary endpoint in the study is a reduction in the use of intravenous feeding, which is often required to sustain life in patients with SBS.
Interventions
DRUGPlacebo
placebo injectable subcutaneously daily into thigh or abdomen
Teduglutide 0.05 mg/kg/d daily injectable subcutaneously into the thigh or abdomen
DRUGTeduglutide 0.1 mg/kg/d
Teduglutide 0.1 /g/kg/d daily injection subcutaneously into thigh or abdomen
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women, aged 18 years of age or older at the time of signing the informed consent form (ICF) * SBS as a result of major intestinal resection resulting in at least 12 months intravenous feeding * Body weight must be less than 90 kg * At baseline, subjects must require PN treatment to meet their caloric or electrolyte needs due to ongoing malabsorption at least 3 times weekly and to be on a stable PN regimen for 4 weeks before dosing * Body mass index (BMI) 18 to 27 kg/m2 * Adequate hepatic and renal function
Exclusion criteria
* History of cancer or clinically significant lymphoproliferative disease with fewer than 5 years documented disease-free state * History of alcohol or drug abuse (within previous year) * Participation in a clinical study within 30 days prior to signing the ICF, or concurrent participation in any clinical study * Clinically significant laboratory abnormalities at the time of randomization * Previous use of teduglutide (ALX-0600) * Prior use of native GLP-2 within 3 months of screening visit * Hospital admission within 1 month prior to screening visit * Pregnant or lactating women * Any condition or circumstance, which in the investigator's opinion would put the subject at any undue risk, prevent completion of the study, or interfere with analysis of the study results. * Presence of excluded disease: Radiation enteritis, Scleroderma, Celiac disease, Refractory/Tropical sprue, Pseudo-obstruction, Active inflammatory bowel disease (IBD), Pre-malignant/malignant change in colonoscopy biopsy or polypectomy, Surgery scheduled within the time frame of the study, Human immunodeficiency virus (HIV) positive test, Immunological disorders, Possible allergies to teduglutide or its constituents, Significant, active, uncontrolled, untreated systemic diseases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| A Graded Response Score in Parenteral Nutrition (PN) Reduction | 6 months | The intensity of the response relied on a reduction from Baseline in weekly parenteral nutrition (PN) volume (minimum reduction of 20% and a maximum of 100%). Duration of the response incorporated responses at Weeks(Wk) 16-20 and at Wk20-24. Zero (0 - lowest) assigned if \<20% reduction at Wk20-24 and reduction at Wk16-20 of \< 20%, 20-39%, or \>=40%. One (1) assigned if reduction of 20-39% at Wk20-24 but \< 20% at Wk16-20. Two(2) assigned if reductions of 40-99% at Wk20-24 AND \<20% at Wk16-20 OR 20-39% at Wk20-24 AND 20-39% at Wk16-20. Three (3) assigned if reductions of 100% at Wk20-24 AND \<20% at Wk16-20 OR 40-99% at Wk20-24 AND 20-39% at Wk16-20 OR 20-39% at Wk20-24 AND \>=40% at Wk16-20. Four (4) assigned if reductions of 100% at Wk20-24 AND 20-39% at Wk16-20 OR 40-99% at Wk20-24 AND \>=40% at Wk16-20. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Achieving Binary Response at Week 20, Maintained at Week 24 | 6 months of treatment | An efficacy responder was defined as achieving at least a 20% reduction from Baseline to Week 20 and maintained at Week 24 in weekly actual PN infusion volume. |
Countries
Belgium, Canada, Denmark, France, Germany, Netherlands, Poland, United Kingdom, United States
Participant flow
Recruitment details
First subject was screened 25May2004 and last subject evaluations were completed on 06Jul2007.
Pre-assignment details
Patients underwent stabilization period for parenteral nutrition prior to randomization
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo injected subcutaneously daily | 16 |
| Teduglutide 0.05 mg/kg/d teduglutide 0.05 mg/kg/d injected subcutaneously | 35 |
| Teduglutide 0.1 mg/kg/d teduglutide 0.1 mg/kg/d injected subcutaneously | 32 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 5 | 2 |
| Overall Study | Randomized but not dosed | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Teduglutide 0.05 mg/kg/d | Teduglutide 0.1 mg/kg/d | Total |
|---|---|---|---|---|
| Age, Continuous | 49.4 years STANDARD_DEVIATION 15.1 | 47.1 years STANDARD_DEVIATION 14.2 | 50.3 years STANDARD_DEVIATION 14 | 48.8 years STANDARD_DEVIATION 14.2 |
| Age, Customized 35-44 years | 2 Participants | 5 Participants | 4 Participants | 11 Participants |
| Age, Customized < 35 years | 3 Participants | 7 Participants | 5 Participants | 15 Participants |
| Age, Customized 45 - 54 years | 3 Participants | 12 Participants | 10 Participants | 25 Participants |
| Age, Customized > 55 years | 8 Participants | 11 Participants | 13 Participants | 32 Participants |
| Region of Enrollment Belgium | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Canada | 1 Participants | 2 Participants | 5 Participants | 8 Participants |
| Region of Enrollment Denmark | 2 Participants | 3 Participants | 3 Participants | 8 Participants |
| Region of Enrollment France | 2 Participants | 5 Participants | 2 Participants | 9 Participants |
| Region of Enrollment Germany | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Netherlands | 0 Participants | 4 Participants | 1 Participants | 5 Participants |
| Region of Enrollment Poland | 3 Participants | 6 Participants | 8 Participants | 17 Participants |
| Region of Enrollment United Kingdom | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Region of Enrollment United States | 7 Participants | 11 Participants | 10 Participants | 28 Participants |
| Sex: Female, Male Female | 9 Participants | 18 Participants | 19 Participants | 46 Participants |
| Sex: Female, Male Male | 7 Participants | 17 Participants | 13 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 16 | 33 / 35 | 31 / 32 |
| serious Total, serious adverse events | 5 / 16 | 13 / 35 | 11 / 32 |
Outcome results
Primary
A Graded Response Score in Parenteral Nutrition (PN) Reduction
The intensity of the response relied on a reduction from Baseline in weekly parenteral nutrition (PN) volume (minimum reduction of 20% and a maximum of 100%). Duration of the response incorporated responses at Weeks(Wk) 16-20 and at Wk20-24. Zero (0 - lowest) assigned if \<20% reduction at Wk20-24 and reduction at Wk16-20 of \< 20%, 20-39%, or \>=40%. One (1) assigned if reduction of 20-39% at Wk20-24 but \< 20% at Wk16-20. Two(2) assigned if reductions of 40-99% at Wk20-24 AND \<20% at Wk16-20 OR 20-39% at Wk20-24 AND 20-39% at Wk16-20. Three (3) assigned if reductions of 100% at Wk20-24 AND \<20% at Wk16-20 OR 40-99% at Wk20-24 AND 20-39% at Wk16-20 OR 20-39% at Wk20-24 AND \>=40% at Wk16-20. Four (4) assigned if reductions of 100% at Wk20-24 AND 20-39% at Wk16-20 OR 40-99% at Wk20-24 AND \>=40% at Wk16-20.
Time frame: 6 months
Population: Intent to Treat (ITT) analysis using a stepdown procedure that was stopped if the 0.10 mg/kg dose was not significantly better than placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 4 | 0 participants |
| Placebo | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 2 | 1 participants |
| Placebo | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 0 (No Response) | 15 participants |
| Placebo | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 1 | 0 participants |
| Placebo | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 5 (No longer need PN) | 0 participants |
| Teduglutide 0.05 mg/kg/d | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 2 | 6 participants |
| Teduglutide 0.05 mg/kg/d | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 0 (No Response) | 19 participants |
| Teduglutide 0.05 mg/kg/d | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 1 | 6 participants |
| Teduglutide 0.05 mg/kg/d | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 4 | 2 participants |
| Teduglutide 0.05 mg/kg/d | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 5 (No longer need PN) | 2 participants |
| Teduglutide 0.1 mg/kg/d | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 5 (No longer need PN) | 0 participants |
| Teduglutide 0.1 mg/kg/d | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 4 | 2 participants |
| Teduglutide 0.1 mg/kg/d | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 0 (No Response) | 24 participants |
| Teduglutide 0.1 mg/kg/d | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 2 | 4 participants |
| Teduglutide 0.1 mg/kg/d | A Graded Response Score in Parenteral Nutrition (PN) Reduction | 1 | 2 participants |
p-value: 0.007ANCOVA
Secondary
Number of Subjects Achieving Binary Response at Week 20, Maintained at Week 24
An efficacy responder was defined as achieving at least a 20% reduction from Baseline to Week 20 and maintained at Week 24 in weekly actual PN infusion volume.
Time frame: 6 months of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Subjects Achieving Binary Response at Week 20, Maintained at Week 24 | Responder | 1 participants |
| Placebo | Number of Subjects Achieving Binary Response at Week 20, Maintained at Week 24 | Non-Responder | 15 participants |
| Teduglutide 0.05 mg/kg/d | Number of Subjects Achieving Binary Response at Week 20, Maintained at Week 24 | Responder | 16 participants |
| Teduglutide 0.05 mg/kg/d | Number of Subjects Achieving Binary Response at Week 20, Maintained at Week 24 | Non-Responder | 19 participants |
| Teduglutide 0.1 mg/kg/d | Number of Subjects Achieving Binary Response at Week 20, Maintained at Week 24 | Responder | 8 participants |
| Teduglutide 0.1 mg/kg/d | Number of Subjects Achieving Binary Response at Week 20, Maintained at Week 24 | Non-Responder | 24 participants |
Comparison: An efficacy responder was defined as achieving at least a 20% reduction from Baseline to Week 20 and maintained at Week 24 in weekly actual PN infusion volume.p-value: 0.005ANCOVA