GASTROENTEROLOGY 2012;143:1473–1481

CLINICAL—ALIMENTARY TRACT

Teduglutide Reduces Need for Parenteral Support Among Patients With

Short Bowel Syndrome With Intestinal Failure

CLINICAL AT
PALLE B. JEPPESEN,* MAREK PERTKIEWICZ,‡ BERNARD MESSING,§ KISHORE IYER,储 DOUGLAS L. SEIDNER,¶
STEPHEN J. D. O’KEEFE,# ALASTAIR FORBES,** HARTMUT HEINZE,‡‡ and BO JOELSSON§§
*Department of Medical Gastroenterology, Rigshospitalet, Copenhagen, Denmark; ‡Department of General Surgery and Clinical Nutrition, Warszawa, Poland; §Hopital
Beaujon Service de Gastroenterologie et Assistance Nutritive, Clichy, France; 储Mount Sinai Medical Center, New York, New York; ¶Vanderbilt University Medical
Center, Nashville, Tennessee; #University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; **University College London, London, UK; ‡‡Nycomed, a Takeda
Company, Nycomed GmbH, Konstanz, Germany; and §§NPS Pharmaceuticals, Bedminster, New Jersey

Keywords: Clinical Trial; Glucagon-Like Peptide 2; Gastro-

See Covering the Cover synopsis on page intestinal Disorder; Therapy.
1403; see editorial on page 1416.

BACKGROUND & AIMS: Teduglutide, a glucagon-like

peptide 2 analogue, might restore intestinal structural
and functional integrity by promoting growth of the mu-
cosa and reducing gastric emptying and secretion. These
factors could increase fluid and nutrient absorption in
patients with short bowel syndrome with intestinal failure
(SBS-IF). We performed a prospective study to determine
whether teduglutide reduces parenteral support in pa-
tients with SBS-IF. METHODS: We performed a 24-week
study of patients with SBS-IF who were given subcutane-
S hort bowel syndrome (SBS) results from surgical re-
section, congenital defect, or disease associated loss of
absorption. The concomitant malabsorptive spectrum of
ous teduglutide (0.05 mg/kg/d; n ⫽ 43) or placebo (n ⫽ SBS is wide, and patients with SBS are heterogeneous
43) once daily. Parenteral support was reduced if 48-hour because of large variations in remnant bowel anatomy and
urine volumes exceeded baseline values by ⱖ10%. The function. Patients with intestinal insufficiency are able to
primary efficacy end point was number of responders compensate for their malabsorption by physiologic or
(patients with ⬎20% reduction in parenteral support vol- pharmacologic adaptation,1,2 whereas supplemental par-
ume from baseline at weeks 20 and 24). RESULTS: There enteral support (PS; parenteral nutrition and/or intrave-
were significantly more responders in the teduglutide nous [PN/IV] fluids) is required to maintain fluid, elec-
group (27/43 [63%]) than the placebo group (13/43 [30%]; trolytes, trace elements, vitamins, and nutrient balances in
P ⫽ .002). At week 24, the mean reduction in parenteral patients with SBS with intestinal failure (SBS-IF).3,4 Treat-
support volume in the teduglutide group was 4.4 ⫾ 3.8 ments aim to maximize remnant intestinal absorptive
L/wk (baseline 12.9 ⫾ 7.8 L/wk) compared with 2.3 ⫾ 2.7 capacity; to minimize the symptoms of malabsorption;
L/wk (baseline 13.2 ⫾ 7.4 L/wk) in the placebo group and to avoid, minimize, or eliminate the need for PS,
(P ⬍ .001). The percentage of patients with a 1-day or thereby alleviating the daily burden of this debilitating
more reduction in the weekly need for parenteral support condition. Hormonal therapies focusing on enhancing
was greater in the teduglutide group (21/39 [54%]) than in the structural and functional integrity of the remaining
the placebo group (9/39 [23%]; P ⫽ .005). Teduglutide intestine are emerging. Glucagon-like peptide 2 (GLP-2), a
increased plasma concentrations of citrulline, a biomarker peptide secreted from the intestinal L cells after food
of mucosal mass. The distribution of treatment-emergent ingestion, ameliorates the pathophysiologic consequences
adverse events that led to study discontinuation was sim- of SBS. GLP-2 administration inhibits gastric acid secre-
ilar between patients given teduglutide (n ⫽ 2) and pla-
cebo (n ⫽ 3). CONCLUSIONS: Twenty-four weeks of Abbreviations used in this paper: AE, adverse event; FCE, fluid com-
teduglutide treatment was generally well tolerated in posite effect; GLP-2, glucagon-like peptide 2; IF, intestinal failure;
patients with SBS-IF. Treatment with teduglutide re- PN/IV, parenteral nutrition and/or intravenous; PS, parenteral support;
SBS, short bowel syndrome; TEAE, treatment-emergent adverse event.
duced volumes and numbers of days of parenteral © 2012 by the AGA Institute
support for patients with SBS-IF; [Link] 0016-5085/$36.00
Number, NCT00798967. [Link]
 1474 JEPPESEN ET AL GASTROENTEROLOGY Vol. 143, No. 6

Table 1. Key Inclusion and Exclusion Criteria

Inclusion criteria Exclusion criteria
SBS resulting from intestinal failure caused by a major intestinal Cancer within last 5 y
resection (eg, injury, cancer, Crohn’s disease, vascular disease, Body mass index ⬍15 kg/m2
volvulus) Inflammatory bowel disease on immunosuppressant therapy that
At least 12 continuous months of PS dependency (PN and/or IV fluids) has been introduced or changed within last 3 mo or treatment
before signing informed consent with biologics within last 6 mo
PS required ⱖ3 times weekly to meet caloric, fluid, or electrolyte needs Previous use of teduglutide
Patients with Crohn’s disease had to be in clinical remission for ⱖ12 Previous use of native GLP-2 or human growth hormone within 6
CLINICAL AT

wk before dosing mo before screening

⬎4 SBS-related hospital admissions within 12 mo or hospital
admission within 30 d before screening

tion and motility,5,6 stimulates intestinal blood flow,7 col did not specify whether previous attempts at weaning had to
increases intestinal barrier function,8 and enhances nutri- be made.
ent and fluid absorption in preclinical and clinical mod- Inclusion and exclusion criteria are listed in Table 1. Al-
els.9-12 though patients with neoplasms could be included in the study,
patients with ongoing radiation enteritis or the presence of
Teduglutide, a dipeptidyl-peptidase degradation-resis-
damaged enteral tissue due to radiation enteritis were excluded,
tant GLP-2 analogue, has been demonstrated to enhance along with any condition or circumstance that, in the investiga-
structural and functional integrity of the remaining intes- tor’s opinion, put the patient at undue risk or jeopardized the
tine in SBS. Open-label, uncontrolled studies in adult integrity of the study results, including the presence of any of
patients with SBS have suggested clinically meaningful the excluded disease states described in the Supplementary Ma-
reductions of fecal excretions of wet weight (⬃700 to terials (Supplementary Table 1).
1000 g/d) and energy (⬃1 MJ/d) after treatment with Patients were not categorized by whether they were receiving
GLP-2 and teduglutide.10,11,13,14 A recently published, ran- parenteral nutrition vs intravenous fluids alone. Throughout the
domized, placebo-controlled phase 3 study investigated study, patients were requested to maintain habitual diet and
whether teduglutide, by increasing intestinal absorption, fluids, and no new medications were started or ongoing treat-
could facilitate PS reductions in patients with SBS-IF.12 ments changed during the stabilization period or throughout
the 24-week treatment period unless deemed medically neces-
Contrary to the expectations of a dose response, a 0.10-
sary. Patients who completed the 24-week treatment period were
mg/kg/d dosage did not meet the primary end point of PS offered entry into an open-label extension study, the results of
reduction, but significant findings from the ad hoc anal- which will be the subject of a separate report.
ysis of a 0.05-mg/kg/d dosage in that study suggested that
these differences could be explained by the limitation of Study Design
PS volume reductions to no more than 10% of baseline In this multinational, multicenter, randomized, double-
levels, beginning only at the fourth week of dosing, along blind, placebo-controlled, parallel-group, 2-stage, phase 3 study
with a trend toward larger baseline PS volume require- (Figure 1), patients were recruited from 27 sites in 10 countries
ments in the 0.10-mg/kg/d group. Therefore, the primary across Europe and North America. Stage 1 consisted of a screen-
objective of this study, the largest double-blind, random- ing visit and optimization and stabilization periods. After
ized, placebo-controlled trial performed in patients with screening, eligible patients underwent a PS optimization period,
if needed, of up to 8 weeks to achieve a stable target urine output
SBS-IF, was to evaluate whether teduglutide at the 0.05-
of 1.0 to 2.0 L/d. This range, at the higher end of normal output
mg/kg/d dosage and with a protocol allowing for earlier
(⬃1.5 L/d), was considered to minimize the risk for dehydration-
(ie, at second week of dosing) and more aggressive PS related complications (eg, renal calculi) without provoking hy-
reductions of 10% to 30% of baseline levels of PN/IV fluid perhydration in a population that is prone to diarrhea and
could reduce PS volume in these patients.

Materials and Methods

All authors had access to the study data and have re-
viewed and approved the final manuscript.

Patients
After receiving approval from local institutional review
boards or medical ethics committees, centers screened patients
of both sexes who were 18 years of age or older and who had a
history of SBS that resulted in a dependency on PS for a period
of at least 12 months before the start of the study. PS depen-
dency was defined as at least 12 continuous months of PS
required at least 3 times weekly to meet their caloric, fluid, or
electrolyte needs because of ongoing malabsorption. The proto- Figure 1. Study design.
December 2012 TEDUGLUTIDE AND SBS 1475

Table 2. PN/IV Adjustments Based on 48-Hour Urinary Output

Urine outputa PN/IV action
⬍1.0 L/d or target based on stabilized urine output Increase PN/IV by ⱖ10% (wk 2) or to previous level
ⱖ1.0 L/d but less than baseline If patient is dehydrated or inadequately nourished, increase PS; if not, maintain PS
0% to ⬍10% increase over baseline Maintain PS
ⱖ10% increase over baseline Reduce PS by ⱖ10% of stabilized baseline level up to a clinically appropriate
amount (maximum of 30%)
aBaseline urine output is the urine volume obtained during the stabilization period before initiating treatment.

CLINICAL AT
dehydration. All patients then underwent a 4- to 8-week stabi- Efficacy and Safety
lization period during which PS usage was to match prescribed
During the treatment period, PS adjustments were
PS, and oral fluid intake and urine volume could not deviate
targeted to be ⱖ10% but ⬍30% of stabilized PS level. Patients
⬎25% from the optimized levels. Although the osmolarity and
were required to remain compliant with the prescribed PS
oral intake were not strictly controlled, patients were asked to
throughout the study, with all adjustments based on the
keep intake as constant as possible. Patients who were not stable
actual PS volume infused. Patients were assessed at planned
could repeat stage 1 once.
intervals (baseline and weeks 2, 4, 8, 12, 16, and 20) for
Stage 2 began when the patients demonstrated PS volume
hydration and nutrition. Before all scheduled visits, 48-hour
stability. Eighty-six patients were randomized in a 1:1 ratio to
oral fluid intake and urinary output measurements were
placebo or teduglutide 0.05 mg/kg/d (administered once daily
taken and included 1 day on and 1 day off PS, unless the PS
subcutaneously into the abdomen, thigh, or arm, at approxi-
was infused daily.
mately the same time each day) for 24 weeks (Figure 1). Ran-
Reductions in PS volumes by 10% to 30% of baseline PS levels
domization was performed according to a computer-generated
were allowed if the 48-hour urinary volumes exceeded the base-
interactive response system and was stratified at 2 levels of
line values by ⬎10%. Oral intake during these 48-hour balances
baseline PS volume (ⱕ6 or ⬎6 L/wk). The postrandomization
study evaluations and visits were scheduled at weeks 1, 2, 4, 8, was to be constant. Determination of the amount of PS volume
12, 16, 20, and 24. reduction was based on 48-hour urinary output, according to
All patients were required to record PS volume, 48-hour oral the algorithm described in Table 2. The decision of whether to
fluid intake and urinary output, and study drug dosing infor- stop a day of PS, reduce the percentage volume of all days that
mation in an electronic diary. PS volume was recorded daily and PS was administered, or change the relative PN/IV constituents
48-hour oral fluid intake and urinary output was recorded dur- of the PS or whether total PS weaning was possible was based on
ing the optimization and stabilization periods and at weeks 2, 4, the investigator’s clinical judgment and the personal preference
8, 12, 16, 20, and 24 during the treatment period. If there was a of the patient.
change in oral intake, the clinician considered whether to adjust Interim safety evaluations 1 week after PS reductions ensured
PS volume. Attempts to reduce PS volume were made at every that PS reductions were well tolerated. This assessment of nour-
visit before week 24. ishment and hydrational status was based on repeated 48-hour
urine collections and a clinical evaluation that included clinical
Optimization and Stabilization signs and symptoms of dehydration, change in body weight,
During the optimization period, patients were assessed reviews of the recorded oral fluid intake, blood samples (hemat-
at planned intervals (weeks 2, 4, 6, and 8, ⫾3 days) for hydration ocrit, creatinine, blood urea nitrogen), and urine sodium. Be-
and nutrition. PS was adjusted in targeted increments of ⱖ10% cause the injection site reactions or stomal changes that are
of the volume at the previous visit. Immediately before each known to occur with GLP-2 and teduglutide might have un-
scheduled visit, 48-hour oral fluid intake and urine output were blinded the observer, the clinician assessing and adjusting PS
measured. The measurement included 1 day on and 1 day off PS, volume was required to be different from the one conducting
unless the PS was infused daily. Blood and urine samples were the physical examination and assessing safety. If the reduced PS
collected at each visit to evaluate hydration and nutrition. A volume was well tolerated, the new weekly PS volume was main-
targeted urine output of 1.0 to 2.0 L/d was used to determine if tained until the next visit; if not, the previously tolerated PS
patients required optimization or could enter the stabilization volume was resumed. Patients could be rechallenged at the next
period. visit if adequate hydration and nutrition requirements were met.
Stability was defined as actual PS usage matching the pre- The primary efficacy end point was the percentage of patients
scribed PS, baseline 48-hour oral fluid intake and urine output who demonstrated a response at week 20 and maintained that
volumes within ⫾25% of the respective 48-hour volumes, and response at week 24 (responder). A response at a given visit was
urine output volume of 2 to 4 L per 48 hours. No further PS defined as the achievement of a 20% to 100% reduction from
adjustments were permitted during the stabilization period. baseline in weekly PS volume. The secondary efficacy end points
The purpose of the PS optimization period was to ensure that included the percentage and absolute change in PS and the
all patients received and tolerated a stable minimal level of PS number of patients who stopped PS and their time of discon-
before treatment, with adequate hydration as indicated by urine tinuation.12
output. Patients who failed to remain stable for at least 4 Exploratory end points included response by visit, reduction
consecutive weeks immediately before randomization were to in days on PS, change from baseline in plasma concentrations of
start the optimization period again. Those patients who failed to citrulline (an amino acid produced by enterocytes and used here
stabilize after 2 attempts could not proceed and were not ran- as a biomarker of remnant enterocyte mass),15 and change in the
domized. fluid composite effect (FCE).12 The FCE is a putative measure of
 1476 JEPPESEN ET AL GASTROENTEROLOGY Vol. 143, No. 6

the combined effects of teduglutide on intestinal fluid absorp- Efficacy

tion, that is, not only on PS volume reduction, but also on the
Primary efficacy end point. The primary efficacy
ability to reduce oral fluid intake and increase urine output
volume. The FCE was a summation of the increase in urine end point was the responder rate. There were 27/43 (63%)
production, reduction in PN/IV volume, and reduction in oral responders in the teduglutide group and 13/43 (30%) in
fluid intake (L/wk), calculated as a baseline measurement of the the placebo group (P ⫽ .002). Small bowel length did not
individual components. The FCE was also calculated for each appear to be a predictor of response. Responder rate was
scheduled postbaseline visit using the following equation: reduc- higher for patients without colon in continuity (com-
tion in PS volume (L/wk) ⫹ reduction in oral fluid intake pared with patients with colon in continuity); however,
volume (L/wk) ⫹ increase in urine output volume (L/wk).
CLINICAL AT

findings did not achieve statistical significance.

Clinical evaluations (vital signs, physical examinations, and
Secondary end points. At all visits, change from
electrocardiograms), adverse event (AE) monitoring, and labora-
tory tests (hematology, serum chemistries, and urinalysis) were baseline in actual PS volume was greater in the teduglu-
assessed. Safety assessments also included body weight, 48-hour tide group than in the placebo group (Figure 2). At Week
urine output, antibodies to teduglutide, and any required endo- 24, the mean ⫾ SD PS volume reduction in the teduglu-
scopic evaluations. In patients with colon, a baseline colonos- tide group was 4.4 ⫾ 3.8 L/wk from a baseline of 12.9 ⫾
copy was required for inclusion to rule out the presence of 7.8 L/wk vs 2.3 ⫾ 2.7 L/wk from a baseline of 13.2 ⫾ 7.4
polyps or active intestinal disease. L/wk in the placebo group. The difference in absolute
Statistical Analysis change between the treatment groups was statistically
Eighty-six patients were randomized in a 1:1 ratio to significant at week 8 (P ⫽ .011) and remained significant
detect differences in responder rates between teduglutide 0.05 through week 24 (P ⬍ .001). The percentage reduction in
mg/kg/d and placebo groups of 35% vs 6%, respectively, based on actual PS volume at week 24 was 32% ⫾ 19% in the
the response rates reported in the earlier phase 3 study12 (␣ ⫽ teduglutide group vs 21% ⫾ 25% in the placebo group.
.05, 2-sided test and power ⫽ 90%). Grounded on these assump- The difference in percentage change between the treat-
tions, nQuery Advisor (version 6.0, Statistical Solutions, Saugus, ment groups was significant at week 12 (P ⫽ .028) and
MS) based on Fisher exact test was used to calculate the power. remained significant through week 24 (P ⫽ .030). No
The number and percentage of responders are presented here
patients were completely weaned from PS at week 24.
by treatment group. The intent-to-treat analysis compared the
event rates for the 2 treatment groups using the Cochran- Selected exploratory end points. The percentage
Mantel-Haenszel test statistics adjusted for the randomization of patients with response (20%⫺100% PS reduction vs
stratification variable (ⱕ6 or ⬎6 L/wk of PS volume at baseline). baseline) was higher in the teduglutide group than in the
The percentage and absolute change in PS volume from baseline placebo group at all visits. At week 24, 30/39 teduglutide
to the last dosing visit as well as all scheduled visits starting at patients (77%) demonstrated response vs 18/39 placebo
week 4 are presented by treatment group using descriptive sta- patients (46%; P ⫽ .01). The percentage of patients with a
tistics. Treatment group differences were compared using an 1-day or more reduction in weekly actual PS use at week
analysis of covariance model with effects for treatment and
24 was higher in the teduglutide group (54%, n ⫽ 21/39
baseline PS volume, with the potential for the interaction of the
2 variables also included as an effect. Safety analyses were de- [13 with 1 day off; 8 with ⱖ2 days off]) than in the
scriptive. placebo group (23%, n ⫽ 9/39; [6 with 1 day off; 3 with ⱖ2
days off]; P ⫽ .005).
Results Oral fluid intake was significantly higher in patients
Patients receiving placebo compared with those receiving teduglu-
tide at weeks 12, 20, and 24 (Figure 3). At all visits, greater
From November 2008 to January 2011, one hun-
reduction in FCE was seen in the teduglutide group than
dred and thirty-two patients who signed informed con-
in the placebo group. At week 24, the mean ⫾ SD reduc-
sent forms were screened, 86 were randomized, and 78
tion in the teduglutide group was 5.4 ⫾ 6.0 L/wk vs 1.1 ⫾
completed the dosing period (Supplementary Figure 1).
There were no significant differences between treatment 4.3 L/wk in the placebo group (P ⬍ .0006).
groups regarding demographic characteristics and medi- Teduglutide resulted in a significant increase in plasma
cations at baseline (Table 3). A total of 39 patients (17 in citrulline concentration from baseline levels. At baseline,
the teduglutide group and 22 in the placebo group) re- mean ⫾ SD plasma citrulline concentration values were
quired optimization of PN/IV volume before entering the 18.4 ⫾ 9.5 0 ␮mol/L and 17.5 ⫾ 9.0 ␮mol/L in the
stabilization period; 26 patients in the teduglutide group teduglutide and placebo groups, respectively. At 24 weeks,
and 21 in the placebo group went directly from screening the mean ⫾ SD increase over baseline in plasma citrulline
to stabilization. However, 12 of these (6 in each group) concentration was 20.6 ⫾ 17.5 ␮mol/L in the teduglutide
failed to remain stable for a full 4-week period and re- group vs 0.7 ⫾ 6.3 ␮mol/L in the placebo group (P ⱕ
quired a return to the optimization period. Overall, mean .0001). Over 24 weeks, patients receiving teduglutide had
time spent in the optimization stage was 19 ⫾ 23 days for a nonsignificant increase in body weight of 1.0 ⫾ 3.7 kg
the teduglutide group and 23 ⫾ 24 days for the placebo compared with baseline (P ⫽ .10), whereas patients receiv-
group. No patients were weaned off PS during the opti- ing placebo had a decrease in body weight of ⫺0.6 ⫾ 2.8
mization period. kg (P ⫽ .20).
December 2012 TEDUGLUTIDE AND SBS 1477

Table 3. Demographic Characteristics and Medication at Baseline

Teduglutide, 0.05
Placebo (n ⫽ 43) mg/kg/d (n ⫽ 43) Overall (N ⫽ 86) P value
Age, mean (SD), y 49.7 (15.6) 50.9 (12.6) 50.3 (14.1) .694a
Range 18–82 22–78 18–82
BMI, mean (SD), kg/m2 22.3 (3.1) 22.5 (3.2) 22.4 (3.1) .759a
n 43 42 85
Range 17.5–28.6 17.6–9.8 17.5–29.8
Women, n (%) 24 (56) 22 (51) 46 (54) .829b

CLINICAL AT
Cause of major intestinal resection, n (%)
Vascular disease 16 (37) 13 (30) 29 (34)
Crohn’s disease 8 (19) 10 (23) 18 (21) .694b
Volvulus 6 (14) 3 (7) 9 (11)
Injury 4 (9) 4 (9) 8 (9)
Cancer 2 (5) 1 (2) 3 (4)
Other 7 (16) 12 (28) 19 (22)
Intestinal anatomy or remnant small bowel 3 3 6
length unknown, n
Patients with stoma, n 17 21 38
Types of stoma, n (%) .100b
Jejunostomy 5 (29) 11 (52) 16 (42)
Ileostomy 9 (53) 6 (29) 15 (40)
Colostomy 1 (6) 4 (19) 5 (13)
Other (duodenostomy; jejunostomy ⫹ 2 (12) 0 (0) 2 (5)
ileostomy)
Colon in continuity, n (%) 23 (54) 26 (61) 49 (57)
Overall remnant small bowel length, mean 68.7 (63.9) 84.4 (64.6) 76.5 (64.4) .277a
(SD), cm
n 40 40 80
Median 48.0 70.0 57.5
Range 5–343 15–250 5–343
Remnant small bowel length in patients with 122.8 (81.6) 137.7 (70.9) 130.8 (75.0) .608a
jejunostomy/ileostomy, mean (SD), cm
n 13 15 28
Median 130 120 125
Range 40–343 45–250 40–343
Remnant small bowel length in patients with 43.3 (31.5) 52.4 (31.8) 48.1 (31.6) .332a
colon in continuity, mean (SD), cm
n 22 25 47
Median 32.5 50 38
Range 5–100 15–140 5–140
Remnant colon, n (%) .019b
⬎25%⫺50% 5 (12) 14 (33) 19 (22)
⬎50%⫺75% 8 (19) 6 (14) 14 (16)
⬎75%⫺100% 10 (23) 3 (7) 13 (15)
Time since last small bowel resection, mean, y 7.9 6.9 7.4
n 43 42 85
⬍1 0 1 1
ⱖ1 to ⬍2 6 7 13
ⱖ2 to ⬍5 17 15 32
ⱖ5 20 19 39
Time receiving PS, mean (SD), y 5.9 (5.7) 6.8 (6.3) 6.3 (6.0) .504a
Median 3.9 3.6 3.9
Range 1.0–25.8 1.0–24.7 1.0–25.8
Parenteral volume, mean (SD), mL/d 1929 (1026) 1844 (1057) 1887 (1036) .707a
Median 1771 1714 1764
Range 514–5000 124–4714 124–5000
Time receiving PS, mean (SD) d/wk 5.9 (1.5) 5.6 (1.7) 5.8 (1.6) .388a
Median 7.0 7.0 7.0
Range 3.0–7.0 3.0–7.0 3.0–7.0
Parenteral volume stratification 1.000c
Parenteral volume ⱕ6 L/wk, n (%) 7 (16) 8 (19) 15
Receiving PS 3/4/5/6/7 d/wk, n 4,1,0,1,1 7,0,1,0,0 11,1,1,1,1
Parenteral volume ⬎6 L/wk, n (%) 36 (84) 35 (81) 71
Receiving PS 3/4/5/6/7 d/wk, n 2,2,2,6,24 3,4,2,4,22 5,6,4,10,46
 1478 JEPPESEN ET AL GASTROENTEROLOGY Vol. 143, No. 6

Table 3. Continued
Teduglutide, 0.05
Placebo (n ⫽ 43) mg/kg/d (n ⫽ 43) Overall (N ⫽ 86) P value
Concomitant medication
Antidiarrheals, n (%) 16 (37) 22 (51) 38 (44)
Antisecretory agents, n (%) 22 (51) 25 (58) 47 (55)

BMI, body mass index.

aP value is calculated using the general linear model method, with corresponding variables as dependent variables and treatment group as the
CLINICAL AT

independent variable.
bP value is based on the ␹2 contingency table using the exact method.
cP values for overall treatment comparisons are base on the Fisher exact test for categorical variables and on a 1-way analysis of variance with

effect for treatment for continuous variable.

Safety and Tolerability tibodies were non-neutralizing and without evidence of

The safety population consisted of 85 patients who decreased effect on PS volume reduction or evidence of
received ⱖ1 doses of study drug. Total exposure to study systemic hypersensitivity or other clinically significant se-
drug was similar in the 2 study groups. There were no quelae.
deaths during the study. The number of patients with
AEs, serious AEs, treatment-emergent AEs (TEAEs), or Discussion
discontinuations due to treatment-emergent serious AEs
In this phase 3 study, teduglutide met the primary
was comparable between treatment groups. Treatment-
efficacy end point, defined as the percentage of patients
emergent serious AEs were reported by 27 patients (15/42
who achieved a 20% to 100% reduction in weekly PS
patients [36%] vs 12/43 patients [28%] in the teduglutide
volume at weeks 20 and 24 compared with baseline. There
group vs placebo group, respectively). Sixty-nine patients
were 27/43 (63%) responders in the teduglutide group and
were reported to have ⱖ1 TEAEs during the study (35/42
13/43 (30%) in the placebo group (P ⫽ .002). When
[83%] vs 34/43 [79%]). Five patients were reported to have
addressing the proabsorptive effects of teduglutide, im-
experienced TEAEs leading to discontinuation during the
provements in intestinal fluid absorption under ideal cir-
study (2/42 [5%] vs 3/43 [7%]); none were serious.
cumstances should be counterbalanced by equivalent
The most frequently reported TEAEs in the teduglutide
PN/IV volume reductions.
group were of gastrointestinal origin, such as abdominal
One of the observations in the previous phase 3 study
pain, nausea, gastrointestinal stoma complication, or ab-
was that, in addition to significant reductions in PS vol-
dominal distension (Supplementary Table 2). Two treat-
ume in patients assigned to teduglutide 0.05 mg/kg/d
ment-emergent serious AEs reported in the teduglutide
(and nonsignificant reductions in those receiving the 0.10-
group were deemed related to the study treatment (acute
mg/kg/d dosage), there were also small decreases in PS
cholecystitis and small intestinal stenosis); both resolved.
volume in patients randomized to placebo.12 This sug-
No major findings were reported in the laboratory/
gests that appropriate day-to-day fluid management with
chemistry or hematology tests of the teduglutide-treated
strict adherence to the weaning algorithm can have an
vs placebo patients. Six patients from the teduglutide
intrinsic benefit and that treatment with teduglutide 0.05
group and none from the placebo group developed anti-
mg/kg/d provides an important additional benefit.
teduglutide antibodies after the start of study drug. An-
Compared with the previous phase 3 study, this study
protocol allowed earlier (after 2 weeks vs 4 weeks) and
more aggressive (10%⫺30% vs 10%) PS volume reduc-
tions.12 This was intended to minimize fluid accumula-
tion (edema), reductions in oral intake, and increases in
urine production encountered in the previous phase 3
study in relation to treatment with teduglutide 0.10 and
0.05 mg/kg/d, which negatively affected the primary study
end point.12
At week 24, after these protocol adjustments, a larger
mean PS volume reduction, of 4.4 ⫾ 3.8 L/wk (32%
change from baseline mean of 12.5 L/wk) was observed
compared with a reduction of 2.5 ⫾ 2.3 L/wk (27% change
from baseline mean of 9.6 L/wk) in the teduglutide
0.05-mg treatment group in the previous study, which
might explain this study’s higher responder rate. In this
study, the effects of teduglutide on PS volume reduction
Figure 2. Mean (SE) absolute reduction in parenteral support. more closely reflected the FCE (5.4 ⫾ 6.0 L/wk). The FCE
December 2012 TEDUGLUTIDE AND SBS 1479

CLINICAL AT
Figure 3. Summary of changes
in (upper left panel) oral fluid in-
take, from baseline mean, 1888
(SD 883) mL/d for teduglutide,
1637 (603) mL/d for placebo; (up-
per right panel) urine volume, from
baseline mean 1350 (216) mL/d
for teduglutide, 1372 (269) mL/d
for placebo; (lower left panel) par-
enteral volume, from baseline
mean 1777 (1096) mL/d for te-
duglutide, 1899 (1077) mL/d for
placebo; and (lower right panel)
fluid composite effect, from base-
line mean 2317 (1651) mL/d for te-
duglutide, 2176 (1270) mL/d for
placebo. Mean (SE) values for
changes are shown.

at week 24 was in the same magnitude in both studies in the 3-week, phase 2, metabolic balance study in pa-
(4.4 ⫾ 7.3 L/wk). tients with SBS, in which fecal wet weight excretion was
The high placebo response in this study (30% vs 5% in reduced from baseline by 711 ⫾ 734 g/d (P ⫽ .001) and
the previous study) might be explained by addressing the intestinal wet weight absorption was increased by 743 ⫾
components of the FCE (Figure 3). In the previous study, 477 g/d (P ⬍ .001).11 Although FCE is not a standard
at week 24, patients receiving placebo had no significant measure, it can be of value in the clinical assessment of
changes in the oral fluid intake or urine output volume patients with SBS as another potential indicator, along
during 48-hour measurements. Therefore, the PS volume with urine output alone or determination of enteral bal-
reduction (0.9 ⫾ 1.4 L/wk) was in the same magnitude as ance (ie, oral fluid intake minus stool volume) when
the FCE (0.8 ⫾ 6.2 L/wk) in the previous study. In the making weaning decisions.
current study, where protocol modifications encouraged The PS volume reductions from baseline of 32% ⫾ 19%
earlier and more aggressive PS reductions, significantly
(4.4 ⫾ 3.8 L/wk) demonstrated in this study provide
larger PS reductions were also achieved in patients receiv-
correspondingly less time connected to the central line, if
ing placebo (2.3 ⫾ 2.7 L/wk), but subsequently these
the infusion rate is the same. Because patients with SBS
patients had to increase their oral fluid intake signifi-
cantly (1.6 ⫾ 3.6 L/wk; P ⫽ .009) to maintain urine can spend up to 16 hours per day connected to the central
production and hydration constant (Figure 3). line, this will liberate considerable time for unhindered
At week 24, the FCE was 1.1 ⫾ 4.3 L/wk in this study in daytime activities or undisturbed sleep.16 It is appealing
the patients receiving placebo, which closely reflected that significantly more patients treated with teduglutide
findings in the first phase 3 study. In addition, because had at least 1 day off PS compared with patients treated
the oral fluid intake and urine output were not constant with placebo (54% vs 23%; P ⫽ .005). Although an assess-
over time, the observed effects of teduglutide on absolute ment of quality-of-life measures was beyond the scope of
and relative PS volume reduction might imprecisely esti- this study, PS therapy might negatively impact a variety
mate the true effect of teduglutide on intestinal fluid of physical and psychosocial factors, including restriction
absorption. Therefore, the FCE might better illustrate the of daily activities and the potential for sleep alteration.
summarized effects of teduglutide as also demonstrated Because SBS-IF is a complex disease, PS reduction alone
 1480 JEPPESEN ET AL GASTROENTEROLOGY Vol. 143, No. 6

might not capture all the factors that affect quality of life cer surveillance colonoscopies are relevant in patients with
in these patients. a preserved colon.
When introducing teduglutide in current treatment This study did not include any follow-up to assess the
practice, the clinical meaningfulness and implications of duration of effect of teduglutide after discontinuation.
the observed effects should be balanced against treat- However, there is evidence that some patients experience
ment-related AEs and possible unfavorable effects of long- nearly immediate increases in their need for PS when
term treatment. In this study, teduglutide was well toler- teduglutide is discontinued, and that others maintain PS
ated. Only 2/42 (5%) patients in the teduglutide group vs reductions for up to 1 year. These observations under-
3/43 (7%) in the placebo group experienced TEAEs leading score the importance of individualized treatment in this
CLINICAL AT

to discontinuation within the 24 weeks of treatment (see heterogenous population.

Supplementary Materials for details on patients with- It is noteworthy that even in dedicated centers manag-
drawn because of AEs considered related to treatment). In ing to recruit patients for this study, the numbers of
general, the tolerability profile resembles findings from patients receiving adequate conventional antidiarrheal
the previous phase 3 study.12 The presence of antibodies and antisecretory medication seems low (Table 3). In gen-
to teduglutide did not appear to have any clinical signif- eral, it is prudent to use these conventional therapies
icance, and there were no differences in efficacy parame- before additional therapies are considered. This study also
ters in patients with or without anti-teduglutide antibod- does not answer the question of whether there might be a
ies; importantly, no neutralizing antibodies were detected benefit to initiating teduglutide therapy earlier in the
(see Supplementary Materials for additional discussion of course of SBS, for example, immediately after resection or
antibody assays). concurrent with the beginning of enteral or oral feeding
The preponderance of gastrointestinal effects is not when enteral GLP-2 receptors are up-regulated.18,19 Limi-
surprising in view of the effects of teduglutide. Adverse tations of the study design are addressed in further detail
effects are mainly related to either the proabsorptive and in the Supplementary Materials.
intestinotrophic effects of teduglutide or insufficient PS In conclusion, in a 24-week study, teduglutide was safe
weaning. In patients with SBS, symptoms such as abdom- and well tolerated, facilitated reduction in PS volume, and
inal pain, nausea, vomiting, and abdominal distension are provided days off PS in patients with SBS-IF. In this
also known to arise when reducing diarrhea with antidi- relatively rare and heterogeneous condition, teduglutide
arrheal medications. Intestinal epithelial hyperplasia can can reduce malabsorption-related consequences (eg, diar-
lead to small intestinal obstruction; it is possible that the rhea, large stomal output, stomal problems, fecal incon-
AE of small intestinal stenosis observed in this study tinence, meteorism, abdominal pain), PS-related inconve-
might have developed as a consequence of underlying niences (eg, time spent connected to PS, social isolation,
luminal compromise that the investigator was unaware of disturbed sleep, altered body image), and potentially life-
before the patient’s entry into the study. Patients with threatening complications (eg, catheter-related sepsis,
signs and symptoms of small bowel obstruction would central venous thrombosis, and IF-associated liver dis-
need to be further evaluated before initiating treatment ease). Based on the findings of this study, teduglutide
with teduglutide. could positively add to the limited treatment armamen-
Ten patients in the teduglutide group experienced sto- tarium.
mal changes; however, enlargement of the stoma nipple
size is an expected effect of teduglutide.11 With proper
patient information and guidance to adjust and enlarge Appendix
the hole in the stoma pad, discomfort in relation to the The participating investigators for this study were
protruding stoma nipple can be reduced. Decreased fluid as follows: C. Compher, University of Pennsylvania School
output from a stoma could result in less peristomal skin of Nursing, Philadelphia, PA; D. Kirby, Cleveland Clinic,
breakdown. However, this was not investigated in this Cleveland, OH; T. Ziegler, Atlanta Clinical and Transla-
study. tional Science Institute, Atlanta, GA; K. Fujioka, Scripps
Increased intestinal fluid absorption, which is desirable Clinical Research Services, LaJolla, CA; K. Olden, Wash-
in the majority of patients with SBS, could cause concern ington Hospital Center, Washington, DC; J. Allard, To-
in patients with latent or overt cardiac decompensation, if ronto General Hospital, University Health Network, To-
PS is not weaned accordingly. The presence of edema and ronto, ON, Canada; K. Jeejeebhoy, Polyclinic Family and
dyspnea can be signs of insufficient PS weaning; however, Specialty Medicine Facility, North York, ON, Canada; D.
PS reduction that is too aggressive can cause signs of Armstrong, Hamilton Health Sciences Corporation, Ham-
dehydration, such as headache, decreased weight, and ilton, ON, Canada; L. Gramlich, GI Research, Edmonton,
muscle spasms. AB, Canada; S. Rudzki, Samodzielny Publiczny Szpital,
Considering the intestinotrophic effect of teduglutide Lubin, Poland; K. T. Urbanowicz, Wojewódzki Szpital
reflected in increases in plasma citrulline concentration Specjalistyczny, Olsztyn, Poland; M. Kunecki, Wojewǒdzki
and based on preclinical findings, it cannot be excluded Specjalistyczny Szpital, LǒdŸ, Poland; S. Schneider, Hôpi-
that long-term treatment with teduglutide can promote tal de l’Archet, Nice, France; H. G. Lamprecht, Medizinis-
growth of existing tumors in patients with SBS-IF.17 Can- che Klinik, Universitätsklinikum Tübingen, Tübingen,
December 2012 TEDUGLUTIDE AND SBS 1481

Germany; U. F. Pape, Charité, Universitätsmedizin, Berlin, and/or intravenous fluid requirements in patients with short bowel
Germany; L. Pironi, Università di Bologna, Bologna, Italy; syndrome. Gut 2011;60:902–914.
13. Jeppesen PB, Lund P, Gottschalck IB, et al. Short bowel patients
F. Contaldo, Università Federico II di Napoli, Naples, treated for two years with glucagon-like peptide 2 (GLP-2): com-
Italy; D. Boggio Bertinet, Azienda Ospedaliera Unisersita- pliance, safety, and effects on quality of life. Gastroenterol Res
ria S. Giovanni Battista-Molinette di Torino, Turin, Italy; Pract 2009;2009:425759.
S. M. Gabe, St. Mark’s Hospital, Harrow, UK; J. M. 14. Jeppesen PB, Lund P, Gottschalck IB, et al. Short bowel patients
Moreno Villares, Hospital Universitario 12 de Octubre, treated for two years with glucagon-like peptide 2: effects on
intestinal morphology and absorption, renal function, bone and
Madrid, Spain; M. N. Virgili Casas, Hospital Universitari body composition, and muscle function. Gastroenterol Res Pract

CLINICAL AT
de Bellvitge, Barcelona, Spain; G. Wanten, Radboud Uni- 2009;2009:616054.
versity Nijmegen, Medical Centre, Nijmegen, Netherlands. 15. Crenn P, Coudray-Lucas C, Thuillier F, et al. Postabsorptive
plasma citrulline concentration is a marker of absorptive entero-
cyte mass and intestinal failure in humans. Gastroenterology
Supplementary Material 2000;119:1496 –1505.
Note: To access the supplementary material 16. Scolapio JS, Savoy AD, Kaplan J, et al. Sleep patterns of cyclic
accompanying this article, visit the online version of parenteral nutrition, a pilot study: are there sleepless nights?
JPEN J Parenter Enteral Nutr 2002;26:214 –217.
Gastroenterology at [Link], and at http:// 17. Thulesen J, Hartmann B, Hare KJ, et al. Glucagon-like peptide 2
[Link]/10.1053/[Link].2012.09.007. (GLP-2) accelerates the growth of colonic neoplasms in mice. Gut
2004;53:1145–1150.
References 18. Compher C, Gilroy R, Pertkiewicz M, et al. Maintenance of paren-
teral nutrition volume reduction, without weight loss, after stop-
1. Jeppesen PB, Mortensen PB. Intestinal failure defined by mea-
ping teduglutide in a subset of patients with short bowel syn-
surements of intestinal energy and wet weight absorption. Gut
drome. JPEN J Parenter Enteral Nutr 2011;35:603– 609.
2000;46:701–706.
19. Garrison AP, Dekaney CM, von Allmen DC, et al. Early but not late
2. Messing B, Pigot F, Rongier M, et al. Intestinal absorption of free
administration of glucagon-like peptide-2 following ileo-cecal re-
oral hyperalimentation in the very short bowel syndrome. Gastro-
section augments putative intestinal stem cell expansion. Am J
enterology 1991;100:1502–1508.
Physiol Gastrointest Liver Physiol 2009;296:G643–G650.
3. O’Keefe SJ, Buchman AL, Fishbein TM, et al. Short bowel syn-
drome and intestinal failure: consensus definitions and overview.
Clin Gastroenterol Hepatol 2006;4:6 –10. Received March 27, 2012. Accepted September 7, 2012.
4. Buchman AL, Scolapio J, Fryer J. AGA technical review on short
bowel syndrome and intestinal transplantation. Gastroenterology Reprint requests
2003;124:1111–1134. Address requests for reprints to: Palle B. Jeppesen, MD, PhD,
5. Wojdemann M, Wettergren A, Hartmann B, et al. Glucagon-like Department of Medical Gastroenterology CA-2121, Rigshospitalet,
peptide-2 inhibits centrally induced antral motility in pigs. Scand J Blegdamsvej 9, DK-2100 Copenhagen, Denmark; e-mail:
Gastroenterol 1998;33:828 – 832. Bekker@[Link]; fax: ⴙ45 35452913.
6. Wojdemann M, Wettergren A, Hartmann B, et al. Inhibition of sham
feeding-stimulated human gastric acid secretion by glucagon-like Acknowledgments
peptide-2. J Clin Endocrinol Metab 1999;84:2513–2517. The authors thank the Investigators in the Teduglutide 020 Study
7. Bremholm L, Hornum M, Andersen UB, et al. The effect of gluca- Group (Appendix) and Professor Augusta Palmo of the
gon-like peptide-2 on mesenteric blood flow and cardiac parame- Physiopathology Department, University of Turin, and Professor Peter
ters in end-jejunostomy short bowel patients. Regul Pept 2011; Layer of the Israelitischen Krankenhauses in Hamburg for their
168:32–38. contributions to the study design, and Benjamin Li and Henry Chu of
8. Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut NPS Pharmaceuticals (Bedminster, NJ) for their statistical analyses.
microbiota control inflammation in obese mice through a mecha- Editorial assistance was provided by Peter A. Rittenhouse, PhD
nism involving GLP-2-driven improvement of gut permeability. Gut and Maryann Travaglini, PharmD, of Complete Healthcare
2009;58:1091–1103. Communications, Inc. (Chadds Ford, PA), who assisted the authors in
9. Brubaker PL, Izzo A, Hill M, et al. Intestinal function in mice with editing the manuscript; the manuscript was written by the authors.
small bowel growth induced by glucagon-like peptide-2. Am J
Physiol 1997;272:E1050 –E1058. Conflicts of interest
10. Jeppesen PB, Hartmann B, Thulesen J, et al. Glucagon-like pep- The authors disclose the following: Palle B. Jeppesen, Marek
tide 2 improves nutrient absorption and nutritional status in short- Pertkiewicz, Bernard Messing, Kishore Iyer, Douglas L. Seidner,
bowel patients with no colon. Gastroenterology 2001;120:806 – Stephen J. D. O’Keefe, and Alastair Forbes have served on the
815. advisory board of and as consultants for NPS Pharmaceuticals.
11. Jeppesen PB, Sanguinetti EL, Buchman A, et al. Teduglutide (ALX- Hartmut Heinze is an employee at Nycomed GmbH and Bo Joelsson
0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 is an employee at NPS Pharmaceuticals.
analogue, improves intestinal function in short bowel syndrome
patients. Gut 2005;54:1224 –1231. Funding
12. Jeppesen PB, Gilroy R, Pertkiewicz M, et al. Randomised placebo- This research was funded by NPS Pharmaceuticals and Nycomed,
controlled trial of teduglutide in reducing parenteral nutrition a Takeda company.
1481.e1 JEPPESEN ET AL GASTROENTEROLOGY Vol. 143, No. 6

Narratives of Patients Discontinuing Study drug product or its process impurities in treated patients.
Because of an Adverse Event Considered Immunogenicity antibody binding assays were developed
Related to Treatment and validated in accordance with current literature rec-
Patient 1. This patient was a 60-year-old white ommendations and “guidance for industry” documents,
woman whose SBS resulted from a major intestinal re- that is, the Food and Drug Administration’s Draft Guid-
section 10 years earlier due to radiation enteritis. Four ance for Industry Assay Development for Immunogenicity Test-
hours after her first dose of teduglutide 0.05 mg/kg/d, ing of Therapeutic Proteins (December 2009) and the Euro-
she experienced intermittent abdominal pain and nausea. pean Medicines Agency’s Guideline on Immunogenicity
Both events were deemed mild in severity and related to Assessment of Biotechnology-Derived Therapeutic Proteins (Jan-
the study drug, which was continued. After 12 days on uary 2007).
teduglutide, the patient experienced abdominal disten- The Meso Scale Discovery method was used for the
sion, which became severe 9 days later; this event also was detection of anti-teduglutide antibodies. The neutraliz-
deemed related to study drug. One week later, after a ing antibody assay was based on a functional adenosine
month of treatment, the study drug was permanently 3=,5=-cyclic monophosphate accumulation assay, which is
discontinued. All events resolved within 3 days of consistent with the known activation of the GLP-2 recep-
discontinuation. tor to GLP-2 and its analogues. Antibody assays were
Patient 2. This patient was a 37-year-old white conducted at baseline, week 12, and week 24 or end of
man whose SBS resulted from major intestinal resection treatment; the 6 positive results were detected at week 24.
10 years earlier due to Crohn’s disease. He was random- No factors predisposing patients to the development
ized to 0.05 mg/kg/d teduglutide and, after 3 days of of antibodies have been identified.
taking the study drug, he experienced intermittent ab-
dominal pain deemed severe in intensity and related to References
teduglutide use. Administration of teduglutide was dis- 1. Tavares W, Drucker DJ, Brubaker PL. Enzymatic- and renal-depen-
continued, and the event resolved within 3 days. The dent catabolism of the intestinotropic hormone glucagon-like pep-
patient was withdrawn from the study. tide-2 in rats. Am J Physiol Endocrinol Metab 2000;278:E134 –
E139.
Weaning Failure 2. Jeppeson PB, Sanguinetti EL, Buchman A, et al. Teduglutide (ALX-
0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2
Of 13/86 patients (15%) who failed an attempt at analogue, improves intestinal function in short bowel syndrome
weaning, only 1 (randomized to placebo) also failed a patients. Gut 2005;54:1224 –1231.
second attempt. This patient’s baseline PS volume was
24.5 L/wk, and the first attempt was to reduce the vol- Limitations of the Study Design
ume by 3.5 L/wk to 21 L/wk (ie, 14.28% of the PS volume, Due to the rare nature of the condition and chal-
consistent with the per-protocol targeted reductions of lenges in conducting a clinical trial of this nature in an
ⱖ10% of PS volume at previous visit). The patient was outpatient setting, certain questions about the optimal
not able to tolerate this reduction and the initial PS use of teduglutide in patients with SBS remain unan-
volume of 24.5 L/wk was resumed. A second attempt was swered by this study.
then made (at the next visit) to reduce the prescribed PS One limitation is that the study was not designed to
volume by 2.45 L/wk (ie, 10% reduction from the current stratify patients according to whether they were receiving
prescribed volume) to 22.05 L/wk. This reduction was intravenous fluids and electrolytes alone. Because these
also not tolerated and the patient remained at the initial data were not collected, it is not known whether such
prescribed PS volume of 24.5 L/wk for the duration of patients might have a different response to teduglutide
the study. therapy than patients who require PN. Although some
patients were receiving PN only and others receiving IV
Antibody Assay Strategy only at baseline, the investigators had the option to
Teduglutide is an analogue of native human change the constituents of PS throughout the study,
GLP-2 produced by recombinant DNA technology that according to individual patients’ clinical needs. The study
differs from the native 33-amino acid GLP-2 only by the also did not require patients to document details of
substitution of the amino acid glycine for alanine at dietary intake, such as use of oral rehydration solutions,
position 2.1,2 Consequently, the likelihood for cross reac- so it is not possible to determine whether this might have
tivity with native GLP-2 can be high. (As noted in the resulted in any differences in response.
inclusion/exclusion criteria, all patients participating in This study also did not elucidate whether the timing of
this study were required to be treatment-naïve to tedug- teduglutide dosing (ie, pre- or postprandial) had an im-
lutide.) pact on efficacy. Given that native GLP-2 inhibits gastric
The immunogenicity assay strategy used in the tedug- motility,1 it is possible that teduglutide might elicit early
lutide clinical development program was designed to satiety. In that case, the beneficial effect on absorption of
examine the risk of immunogenicity to either teduglutide nutrients and/or fluids could, hypothetically, be slightly
December 2012 TEDUGLUTIDE AND SBS 1481.e2

diminished by a subsequent decline in oral intake. In this SBS-IF, or to assess the impact of discontinuation on
study, although instructions to the investigators in- patients’ clinical status. Additional studies are warranted
cluded the suggestion that the dose be administered at to explore these questions, as well as to determine
approximately the same time each day, there was no require- whether there is a need for retreatment or maintenance
ment regarding timing relative to meals. Thus, it was not therapy and, if so, what the optimal dose and timing of
possible to analyze the data to determine if there was any such treatment would be.
difference in response relative to timing of the dose.
As noted in the Discussion of our primary report, this Reference
study also was not designed to evaluate the impact of 1. Jeppesen PB. Clinical significance of GLP-2 in short-bowel syn-
administering teduglutide earlier or later in the course of drome. J Nutr 2003;133:3271–3724.
1481.e3 JEPPESEN ET AL GASTROENTEROLOGY Vol. 143, No. 6

Supplementary Figure 1. Patient disposition.

Supplementary Table 1. Excluded Diseases and Illnesses

Body system Conditions excluded
Related to SBS Ongoing radiation enteritis or the presence of damaged enteral tissue due to radiation
enteritis; celiac disease; refractory or tropical sprue; pseudo-obstruction
Gastrointestinal Active IBD that required chronic systemic immunosuppressant therapy that had been
introduced or changed during the last 3 months; IBD that required chronic systemic
immunosuppressant therapy for symptom control; untreated premalignant or malignant
change in colonoscopy biopsy or polypectomy; intestinal or other major surgery scheduled
within the time frame of the study; chronic pancreatitis or cholecystitis
Immune Compromised immune system (eg, AIDS, severe combined immunodeficiency); hypersensitivity
or allergies to teduglutide or its constituents or GLP-2
Psychiatric Alcohol or drug addiction within the previous year; major uncontrolled psychiatric illness
General Significant active, uncontrolled, untreated systemic diseases (eg, cardiovascular, respiratory,
renal, infectious, endocrine, hepatic, or central nervous system)

AIDS, acquired immunodeficiency syndrome; GLP-2, glucagon-like peptide 2; IBD, irritable bowel disease.

Supplementary Table 2. Treatment-Emergent Adverse Events Reported in ⬎5% of Teduglutide-Treated Patients in Safety
Populationa
Patients, n (%)

Adverse event Teduglutide (n ⫽ 42) Placebo (n ⫽ 43)

All TEAEs 35 (83) 34 (79)
Abdominal pain 13 (31) 10 (23)
Nausea 12 (29) 8 (19)
Gastrointestinal stoma changeb 10 (24) 3 (7)
Abdominal distension 9 (21) 1 (2)
Central line systemic infectionsc 7 (17) 7 (16)
Peripheral edema 7 (17) 2 (5)
Urinary tract infection 6 (14) 4 (9)
Flatulence 5 (12) 3 (7)
Vomiting 5 (12) 4 (9)
Fatigue 4 (10) 3 (7)
Pyrexia 4 (10) 4 (9)
Diarrhea 3 (7) 5 (12)
Weight increase 3 (7) 3 (7)
Dyspnea 3 (7) 0 (0)
Nasopharyngitis 3 (7) 0 (0)

TEAEs, treatment-emergent adverse events.

aAdverse events were spontaneously reported, obtained through nonleading questioning, or noted during examination of a patient.
bStomal changes are complications defined as reports of swelling, growth, hypertrophy, enlargement, or increased size of stoma or stoma nipple;

stomal mucosal excoriation; peristomal polyps; peristomal rash; peristomal inflammatory lesion.
cIncludes catheter-related infection, central line infection, catheter sepsis, infective thrombosis, and bacteremia.