Short Bowel Syndrome
Conditions
Brief summary
This research study was done to see what the effects are of Teduglutide on people with short bowel syndrome (SBS). Teduglutide is a synthetic medication administered as an injection, which has shown to increase intestinal blood flow, inhibit gastric secretion, increase growth of intestinal cells and increase absorption of nutrients. Teduglutide has demonstrated to decrease Total Parenteral Nutrition (TPN) requirements by 20%. Teduglutide is approved by the Food and Drug Administration (FDA) for the treatment of adult patients with Short Bowel Syndrome (SBS) who are dependent on parenteral support. The primary hypotheses for this study were 1) that Teduglutide significantly increases the gastric emptying half time of solids when compared to placebo. 2) Teduglutide will significantly decrease the intestinal permeability and urinary excretion of lactulose when compared to placebo.
Detailed description
Short bowel syndrome (SBS) refers to the anatomical and/or functional decrease in small intestinal absorptive capacity, mostly caused by extensive intestinal resections. The decrease in intestinal absorptive capacity leads to malabsorption causing malnutrition, dehydration and weight loss, all of which severely impact patient's quality of life. In this study, qualifying participants were assigned to 2 different treatment arms consisting of placebo or Teduglutide 0.05 mg/kg subcutaneously daily for seven days. Subsequently, participants were switched over to the alternate treatment arm for seven days, after a washout period of at least seven days. In both arms, after six days of treatment or placebo, participants underwent a series of measurements during day 7 of treatment, including 8 hour GI transit, permeability measurements by using mannitol and lactulose (0-2h, 2-8h collections), and 8 hour urine and stool collections for measurement of volume. Throughout the study participants filled out a food diary and a stool diary (number, consistency, ease of passage) every day. On day 7 of each intervention period participants arrived in the clinical research unit after having fasted for at least 8 hours. Women of childbearing potential had a pregnancy test. Participants then received their seventh dose of placebo or Teduglutide (1 dose, 1 hour before breakfast). Technetium sestamibi (99mTc) pellets were ingested in a scrambled egg, toast, and milk meal (218 kcal) to facilitate measurement of gastric transit. All subjects received a standard 550 kcal meal at 4 hours (chicken meal) after the radiolabeled meal.
Interventions
DRUGTeduglutide
Participants will receive Teduglutide 0.05 mg/kg/d administered subcutaneously.
DRUGPlacebo
Participants will receive placebo matching study drug, administered subcutaneously.
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Short bowel syndrome * Dependent on parenteral nutrition
Exclusion criteria
* Pregnant, trying to become pregnant or lactating * Diabetes * Alcohol or drug abuse within the last year by history * Active Crohn's disease as evaluated by standard procedures employed by the investigator * History of radiation enteritis, scleroderma, celiac disease, tropical sprue, diabetes, chronic pseudo-obstruction or malignancies * Previous use of Teduglutide or potential allergies to Teduglutide or its constituents * Any hospitalization within 1 month before screening * Use of Octreotide, intravenous glutamine growth hormone or growth factors such as native Glucagon-like Peptide 2 (GLP-2) within the last 12 weeks * Infliximab or other biological agents, Azathioprine, Methotrexate, Cyclosporine, Tacrolimus, Sirolimus, should be stable for at least 8 weeks prior to baseline and remain stable during the study \- Any investigational drug within last 30 days * Diuretics and oral rehydration solutions will be required to be stable for ≥4 weeks prior to baseline evaluations and remain stable during the study * Change in dose of antimotility or secretory agents from 2 days prior to, and throughout the two phases and washout periods of the study * Use of tobacco products within the prior 1 month (since nicotine can affect permeability) * Use of NSAIDS or aspirin within the past week * Use of oral corticosteroids within the previous 6 weeks * Ingestion of artificial sweeteners such as Splenda (sucralose), Nutrasweet (aspartame), lactulose or mannitol 2 days each of the study measurement days, e.g., foods to be avoided are sugarless gums or mints and diet soda * History of pancreatitis * Primary renal impairment (estimated glomerular filtration rate (eGFR)) \<30 ml/min.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gastric Emptying Half-Time (T1/2) | approximately 2 hours after radiolabeled meal is ingested | The time for half of the ingested solids or liquids to leave the stomach. |
| Overall Gut Transit | baseline, approximately 6 hours after ingestion of radiolabeled meal | Given the variable extent of the residual length of the small intestine and colon, the proportion emptied from the body at 6 hours was assessed as an overall estimate of the whole gut transit. The 6-hour values for intra-abdominal counts were then compared with the 100% reference values of counts (at time zero, which is immediately after ingestion of the radiolabeled meal) to determine the percentage of isotope retained in the abdomen. 100% minus the percentage of retained isotope reflected the amount emptied from the GI tract. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Small Intestinal and Colonic Permeability as Measured by Lactulose/Mannitol Ratio at 2 Hours | baseline, approximately 2 hours after ingestion of radiolabeled meal | Permeability is measured through differential excretion of urine saccharides. A sugar solution (200 mg of mannitol and 1 g lactulose in 30 mL of water) was administered with the radiolabeled test meal at visits 1 and 2. Urine was collected during 0-2 and 2-8 hours. A baseline urine sample was also collected prior to ingestion of the sugars. Chemical analysis was preformed with high-speed liquid chromatography tandem mass spectrometry. |
| Change in Small Intestinal and Colonic Permeability as Measured by Urinary Excretion of Lactulose at 2 Hours | baseline, approximately 2 hours after ingestion of radiolabeled meal | Permeability is measured through differential excretion of urine saccharides. A sugar solution (200 mg of mannitol and 1 g lactulose in 30 mL of water) was administered with the radiolabeled test meal at visits 1 and 2. Urine was collected during 0-2 and 2-8 hours. A baseline urine sample was also collected prior to ingestion of the sugars. Chemical analysis was preformed with high-speed liquid chromatography tandem mass spectrometry. |
| Change in Small Intestinal and Colonic Permeability as Measured by Urinary Excretion of Mannitol | baseline, approximately 2 hours and 8 hours after ingestion of radiolabeled meal | Permeability is measured through differential excretion of urine saccharides. A sugar solution (200 mg of mannitol and 1 g lactulose in 30 mL of water) was administered with the radiolabeled test meal at visits 1 and 2. Urine was collected during 0-2 and 2-8 hours. A baseline urine sample was also collected prior to ingestion of the sugars. Chemical analysis was preformed with high-speed liquid chromatography tandem mass spectrometry. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Stool Weight at 8 Hours | approximately 8 hours after ingestion of radiolabeled meal | After an overnight fast, subjects received a single dose of placebo or Teduglutide 1 hour before breakfast, then consumed a radiolabeled meal. After 8 hours a stool collection was taken. |
| Urine Volume at 8 Hours | Start of the ingestion of the radiolabeled meal until 8 hours after the meal | After an overnight fast, subjects received a single dose of placebo or Teduglutide 1 hour before breakfast, then consumed a radiolabeled meal. Urine was collected twice: from the start of the ingestion of the meal to 2 hours, and 2-8 hours. The total volume of urine collected was the sum of these two collections. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the Mayo Clinic Home Parenteral Nutrition program in Rochester, Minnesota.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to receive placebo first and Teduglutide first. | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 54 years STANDARD_DEVIATION 13 |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 8 | 1 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
Gastric Emptying Half-Time (T1/2)
The time for half of the ingested solids or liquids to leave the stomach.
Time frame: approximately 2 hours after radiolabeled meal is ingested
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Teduglutide | Gastric Emptying Half-Time (T1/2) | 113 minutes | Standard Deviation 16 |
| Placebo | Gastric Emptying Half-Time (T1/2) | 106 minutes | Standard Deviation 20 |
Comparison: Level of significance = .05p-value: 0.74t-test, 2 sided
Primary
Overall Gut Transit
Given the variable extent of the residual length of the small intestine and colon, the proportion emptied from the body at 6 hours was assessed as an overall estimate of the whole gut transit. The 6-hour values for intra-abdominal counts were then compared with the 100% reference values of counts (at time zero, which is immediately after ingestion of the radiolabeled meal) to determine the percentage of isotope retained in the abdomen. 100% minus the percentage of retained isotope reflected the amount emptied from the GI tract.
Time frame: baseline, approximately 6 hours after ingestion of radiolabeled meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Teduglutide | Overall Gut Transit | 53.4 Percentage of isotope emptied | Standard Deviation 15 |
| Placebo | Overall Gut Transit | 62.4 Percentage of isotope emptied | Standard Deviation 15.2 |
Comparison: Level of significance = .05p-value: 0.075t-test, 2 sided
Secondary
Change in Small Intestinal and Colonic Permeability as Measured by Lactulose/Mannitol Ratio at 2 Hours
Permeability is measured through differential excretion of urine saccharides. A sugar solution (200 mg of mannitol and 1 g lactulose in 30 mL of water) was administered with the radiolabeled test meal at visits 1 and 2. Urine was collected during 0-2 and 2-8 hours. A baseline urine sample was also collected prior to ingestion of the sugars. Chemical analysis was preformed with high-speed liquid chromatography tandem mass spectrometry.
Time frame: baseline, approximately 2 hours after ingestion of radiolabeled meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Teduglutide | Change in Small Intestinal and Colonic Permeability as Measured by Lactulose/Mannitol Ratio at 2 Hours | 0.024 ratio | Standard Deviation 0.005 |
| Placebo | Change in Small Intestinal and Colonic Permeability as Measured by Lactulose/Mannitol Ratio at 2 Hours | 0.021 ratio | Standard Deviation 0.005 |
Secondary
Change in Small Intestinal and Colonic Permeability as Measured by Urinary Excretion of Lactulose at 2 Hours
Permeability is measured through differential excretion of urine saccharides. A sugar solution (200 mg of mannitol and 1 g lactulose in 30 mL of water) was administered with the radiolabeled test meal at visits 1 and 2. Urine was collected during 0-2 and 2-8 hours. A baseline urine sample was also collected prior to ingestion of the sugars. Chemical analysis was preformed with high-speed liquid chromatography tandem mass spectrometry.
Time frame: baseline, approximately 2 hours after ingestion of radiolabeled meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Teduglutide | Change in Small Intestinal and Colonic Permeability as Measured by Urinary Excretion of Lactulose at 2 Hours | 0.42 mg | Standard Deviation 0.14 |
| Placebo | Change in Small Intestinal and Colonic Permeability as Measured by Urinary Excretion of Lactulose at 2 Hours | 0.38 mg | Standard Deviation 0.14 |
Secondary
Change in Small Intestinal and Colonic Permeability as Measured by Urinary Excretion of Mannitol
Permeability is measured through differential excretion of urine saccharides. A sugar solution (200 mg of mannitol and 1 g lactulose in 30 mL of water) was administered with the radiolabeled test meal at visits 1 and 2. Urine was collected during 0-2 and 2-8 hours. A baseline urine sample was also collected prior to ingestion of the sugars. Chemical analysis was preformed with high-speed liquid chromatography tandem mass spectrometry.
Time frame: baseline, approximately 2 hours and 8 hours after ingestion of radiolabeled meal
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Teduglutide | Change in Small Intestinal and Colonic Permeability as Measured by Urinary Excretion of Mannitol | 0 - 2 hours | 16.2 mg | Standard Error 3.6 |
| Teduglutide | Change in Small Intestinal and Colonic Permeability as Measured by Urinary Excretion of Mannitol | 0 - 8 hours | 48.8 mg | Standard Error 8.9 |
| Placebo | Change in Small Intestinal and Colonic Permeability as Measured by Urinary Excretion of Mannitol | 0 - 2 hours | 11.3 mg | Standard Error 2.2 |
| Placebo | Change in Small Intestinal and Colonic Permeability as Measured by Urinary Excretion of Mannitol | 0 - 8 hours | 32.7 mg | Standard Error 5.9 |
Comparison: Comparison between the groups for change between 0- and 2-hours. Level of significance = .05p-value: 0.2t-test, 2 sided
Comparison: Comparison between the groups for change between 0- and 8-hours. Level of significance = .05p-value: 0.17t-test, 2 sided
Other Pre-specified
Stool Weight at 8 Hours
After an overnight fast, subjects received a single dose of placebo or Teduglutide 1 hour before breakfast, then consumed a radiolabeled meal. After 8 hours a stool collection was taken.
Time frame: approximately 8 hours after ingestion of radiolabeled meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Teduglutide | Stool Weight at 8 Hours | 77 g | Standard Deviation 18 |
| Placebo | Stool Weight at 8 Hours | 106 g | Standard Deviation 43 |
Comparison: Level of significance = .05p-value: 0.42t-test, 2 sided
Other Pre-specified
Urine Volume at 8 Hours
After an overnight fast, subjects received a single dose of placebo or Teduglutide 1 hour before breakfast, then consumed a radiolabeled meal. Urine was collected twice: from the start of the ingestion of the meal to 2 hours, and 2-8 hours. The total volume of urine collected was the sum of these two collections.
Time frame: Start of the ingestion of the radiolabeled meal until 8 hours after the meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Teduglutide | Urine Volume at 8 Hours | 408.9 mL | Standard Deviation 52.2 |
| Placebo | Urine Volume at 8 Hours | 365.7 mL | Standard Deviation 57.3 |
Comparison: Level of significance = .05p-value: 0.34t-test, 2 sided