Small bowel
`
`< Investigators of the
`Teduglutide 004 Study Group
`are listed in the online appendix.
`To view these files please visit
`the journal online (http://gut.
`bmj.com).
`1Department of
`Gastroenterology CA-2121,
`Rigshospitalet, Copenhagen,
`Denmark
`2Department of
`Gastroenterology, Kansas
`University Medical Center,
`Kansas City, Kansas, USA
`3Department of General Surgery
`and Clinical Nutrition, Medical
`University of Warsaw, Warsaw,
`Poland
`4Department of
`Gastroenterology, University of
`Toronto, Toronto, Ontario,
`Canada
`5Department of
`Gastroenterology and Nutrition
`support, Poˆle des Maladies de
`l’Appareil Digestif Hoˆpital
`Beaujon, Clichy la Garenne,
`France
`6Division of Gastroenterology,
`University of Pittsburgh,
`Pennsylvania, USA
`
`Correspondence to
`Palle Bekker Jeppesen,
`Department of Medicine
`CA-2121, Rigshospitalet,
`Blegdamsvej 9, DK-2100
`Copenhagen, Denmark;
`bekker@dadlnet.dk
`
`Revised 29 November 2010
`Accepted 5 December 2010
`Published Online First
`11 February 2011
`
`This paper is freely available
`online under the BMJ Journals
`unlocked scheme, see http://
`gut.bmj.com/site/about/
`unlocked.xhtml
`
`902
`
`Randomised placebo-controlled trial of teduglutide in
`reducing parenteral nutrition and/or intravenous fluid
`requirements in patients with short bowel syndrome
`P B Jeppesen,1 R Gilroy,2 M Pertkiewicz,3 J P Allard,4 B Messing,5 S J O’Keefe6
`
`ABSTRACT
`Background and aims Teduglutide, a GLP-2 analogue,
`may restore intestinal structural and functional integrity by
`promoting repair and growth of the mucosa and reducing
`gastric emptying and secretion, thereby increasing fluid
`and nutrient absorption in patients with short bowel
`syndrome (SBS). This 24-week placebo-controlled study
`evaluated the ability of teduglutide to reduce parenteral
`support in patients with SBS with intestinal failure.
`Methods In 83 patients randomised to receive
`subcutaneous teduglutide 0.10 mg/kg/day (n¼32),
`0.05 mg/kg/day (n¼35) or placebo (n¼16) once daily,
`parenteral fluids were reduced at 4-week intervals if
`intestinal fluid absorption (48 h urine volumes) increased
`$10%. Responders were subjects who demonstrated
`reductions of $20% in parenteral volumes from baseline
`at weeks 20 and 24. The primary efficacy end point,
`a graded response score (GRS), took into account higher
`levels and earlier onset of response, leading to longer
`duration of response. The intensity of the response was
`defined as a reduction from baseline in parenteral volume
`(from 20% to 100%), and the duration of the response
`was considered the response at weeks 16, 20 and 24.
`The results were tested according to a step-down
`procedure starting with the 0.10 mg/kg/day dose.
`Results Using the GRS criteria, teduglutide in a dose of
`0.10 mg/kg/day did not have a statistically significant
`effect compared with placebo (8/32 vs 1/16, p¼0.16),
`while teduglutide in a dose of 0.05 mg/kg/day had
`a significant effect (16/35, p¼0.007). Since parenteral
`volume reductions were equal (3536475 and
`3546334 ml/day), the trend towards higher baseline
`parenteral volume (181661008 vs 13746639 ml/day,
`p¼0.11) in the 0.10 mg/kg/day group compared with the
`0.05 mg/kg/day group may have accounted for this
`discrepancy. Three teduglutide-treated patients were
`completely weaned off parenteral support. Serious adverse
`events were distributed similarly between active treatment
`groups and placebo. Villus height, plasma citrulline
`concentration and lean body mass were significantly
`increased with teduglutide compared with placebo.
`Conclusions Teduglutide was safe, well tolerated,
`intestinotrophic and suggested pro-absorptive effects
`facilitating reductions in parenteral support in patients
`with SBS with intestinal failure.
`ClinicalTrials.gov number NCT00172185.
`
`INTRODUCTION
`Short bowel syndrome (SBS) is characterised by
`large heterogeneity where patients with intestinal
`insufficiency are able to compensate for their
`malabsorption
`of
`fluids,
`electrolytes,
`trace
`
`Significance of this study
`
`What is already known on this subject?
`< In an open-label non-placebo controlled 21-day
`phase 2 study, teduglutide has been shown to
`increase intestinal wet weight absorption in
`patients with short bowel syndrome using
`metabolic balance studies.
`
`What are the new findings?
`< This is the first long-term (24 weeks) rando-
`mised placebo-controlled study of teduglutide in
`patients with short bowel syndrome dependent
`on parenteral support.
`< Teduglutide was safe, well tolerated and led to
`restoration of intestinal functional and structural
`integrity through significant intestinotrophic and
`pro-absorptive effects.
`
`How might it impact on clinical practice in the
`foreseeable future?
`< Teduglutide has the potential
`to reduce the
`burden often seen with parenteral support in
`patients with short bowel syndrome with
`intestinal failure, and could add to the limited
`clinical
`treatment armamentarium in treating
`patients with short bowel syndrome.
`
`elements, vitamins or nutrients by increasing oral
`intake and adapt metabolically,1 2 whereas patients
`with intestinal failure depend on parenteral support
`(fluids, electrolytes or nutrients).3e5 A large part of
`this heterogeneity is explained by differences in
`the anatomy of the remnant bowel.6 7 Patients
`with mild intestinal failure with a jejunostomy
`or ileostomy need approximately 1000 ml of fluid
`and electrolytes taken over a few hours 3e7 times
`per week. Patients with SBS with jejunostomies or
`ileostomies frequently have complications such as
`dehydration and electrolyte deficiencies due to
`stomal losses. In severe cases, significant protein
`and energy malabsorption can occur and may
`require supplementary hypertonic nutrients and
`electrolyte infusions administered both daytime
`and nocturnally. Patients with SBS and intestinal
`failure who have a preserved colon in continuity
`often suffer from large amounts of rectal fluid loss,
`fear of
`incontinence and the consequences of
`colonic fermentation such as gaseous distension
`and flatulence, whereas fluid and electrolyte
`deficiencies are less prominent.7 Since some of
`
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`
`these patients do not imminently suffer from dehydration, days
`off parenteral nutrients are possible. However, on those nights
`when nutrient infusions are required, both the infusion and the
`accompanying excessive urine production may disturb the sleep
`pattern of the patients. In the most severe cases, nocturnal
`nutrients as well as daytime fluid and electrolytes are required.
`Although frequently life-saving in patients with SBS with
`intestinal failure, the parenteral administration of fluids, elec-
`trolytes, trace elements, vitamins and nutrients has been asso-
`ciated with potentially life-threatening complications. Poor
`catheter care technique,
`insertion site, tunnel and catheter-
`related blood stream infections may lead to bacteraemia and
`even septicaemia, and the presence of a central catheter may lead
`to central venous thrombosis and even embolism.5 In addition,
`parenteral constituents and chronic dehydration may contribute
`to progressive intestinal failure-associated liver and renal disease
`and eventually failure.8 9 Mutually, the symptoms of SBS with
`intestinal failure and the inconveniences and complications in
`relation to parenteral support may cause potential restrictions in
`the lifestyle of these patients and may lead to significant
`impairment of their quality of life.10 11
`In the past, the clinical care of patients with SBS has mainly
`focused on ‘making the most of what the SBS patient still had’
`by optimising remnant intestinal function through dietary
`interventions, oral rehydration solutions, antidiarrhoeal and
`antisecretory agents. Furthermore, anastomosis of excluded
`bowel has been advocated, when it is possible, and experimental
`surgical procedures have also been employed. Intestinal trans-
`plantation is currently only recommended in patients failing
`parenteral support due to recurrent life-threatening sepsis, loss
`of venous access and end stage intestinal failure-associated liver
`disease.5 Treatments focused on improving the structural and
`functional
`integrity of the remaining intestine by so-called
`intestinal rehabilitation which minimise or eliminate the need
`for parenteral support are therefore needed.
`In recent years hormonal stimulation to augment remnant
`bowel adaptation has been suggested, with glucagon-like peptide
`2 (GLP-2)da peptide which is secreted from the intestinal L-cells
`following ingestion of a mealdas a key factor. Repeated
`administration of GLP-2 promotes the expansion of the intes-
`tinal mucosa via the stimulation of crypt cell growth and the
`reduction of enterocyte apoptosis.12 Exogenous GLP-2 adminis-
`tration inhibits gastric acid secretion and gastric emptying,13 14
`stimulates intestinal blood flow,15 increases intestinal barrier
`function16 and enhances nutrient and fluid absorption in both
`preclinical and clinical models.17 In addition, GLP-2 may decrease
`bone resorption and it has been suggested as a potential therapy
`in osteoporosis.18
`Open uncontrolled clinical studies have suggested positive
`effects of exogenously administered GLP-2 and the di-peptidyl
`peptidase IV degradation resistant analogue, teduglutide,
`in
`patients with SBS.19e22 In an open-label 3-week study where the
`oral
`intake and parenteral support were intentionally kept
`constant during 72 h balances, teduglutide reduced faecal wet
`weight excretions by 7116734 g/day (p¼0.001) and increased
`wet weight absorption by 7436477 g/day causing increases in
`urine volumes of 5556485 g/day (p<0.001). In addition, faecal
`energy losses decreased by 80861453 kJ/day (p¼0.04) in relation
`to teduglutide treatment, but all effects reverted 3 weeks after
`treatment.22
`In the present study, the largest randomised placebo-controlled
`trial ever performed in patients with SBS with intestinal failure,
`the objective was to determine whether teduglutide could
`reduce the burden of parenteral nutrition and intravenous fluid
`
`Small bowel
`
`requirements. Secondary end points included the ability to obtain
`additional days off or eliminate the need for parenteral support
`in this SBS population with demonstrated intestinal failure. In
`detail, during 24 weeks of treatment with placebo or teduglutide,
`adjustments in the parenteral support were performed when
`the urine volume was increased to a certain threshold. This
`algorithm-based approach considered the changes in urine
`volumes to be based on changes in intestinal wet weight
`absorption. In addition to safety evaluations, DEXA scanning,
`histological evaluation of bowel morphology in biopsies, plasma
`citrulline and quality of life questionnaires described changes in
`body composition, structural intestinal adaptation and quality of
`life, respectively, in relation to placebo and teduglutide treatment.
`
`METHODS
`Patients, study design, efficacy and safety
`After receiving approval from local IRBs and medical ethics
`committees, centres screened patients of both sexes aged
`$18 years with a history of SBS due to intestinal resection and
`dependent on parenteral support (fluids, electrolytes or nutri-
`ents) at least three times per week for a period of at least
`12 months prior to the start of the study. Exclusion criteria are
`shown in box 1.
`The basic study design is presented in figure 1.
`
`Parenteral optimisation
`To establish that the patients minimally tolerated baseline
`parenteral support resulted in a urine output of 1.0e2.0 l/day,
`a period of optimisation was used. The patients were instructed
`how to perform home collections of their 48 h urine output and
`
`Box 1 Exclusion criteria
`
`< Pregnancy or lactation.
`< Body mass index <18 or >27 kg/m2.
`< Active Crohn’s disease as evaluated by standard procedures
`employed by the investigator.
`< Radiation enteritis, scleroderma, coeliac disease, refractory or
`tropical sprue, diabetes.
`< Alcohol or drug abuse within the last year.
`< Previous use of teduglutide or potential allergies to teduglutide
`or its constituents.
`< Inadequate hepatic function: ALT and AST both >2.03 upper
`limit of normal (ULN), total bilirubin >1.253 ULN or alkaline
`phosphatases >2.53 ULN.
`< Inadequate renal
`function: serum creatinine or blood urea
`nitrogen >1.53 ULN.
`< Urine sodium <20 mmol/day.
`< Any hospitalisation within 1 month before screening.
`< Use of infliximab, growth hormone or growth factors such as
`native GLP-2 or other biological therapy within the last 12
`weeks.
`< Use of systemic corticosteroids, methotrexate, cyclosporine,
`tacrolimus, sirolimus, octreotide, intravenous glutamine or any
`investigational drug within last 30 days.
`< The use of antimotility and antidiarrhoeal agents (loperamide,
`difenoxylate, codeine and other opiates), H2-receptor antag-
`onists, proton pump inhibitors, bile sequestering agents, oral
`glutamine, diuretics and oral
`rehydration solutions were
`required to be stable for $4 weeks prior
`to baseline
`evaluations and remain stable during the study.
`
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`
`Small bowel
`
`Figure 1 Basic study design. AE, adverse event.
`
`completed these 2 days before each visit. Although the osmo-
`larity and oral intake were not kept strictly controlled, study
`participants were asked to try to keep the timing, quantity and
`quality of beverages as constant as possible during the 48 h
`collection periods. The study subjects were seen in outpatient
`clinics at 2-week intervals. Adjustment to the study subjects’
`baseline parenteral volume was performed when urine volume
`fell below 1.0 l/day or exceeded 2.0 l/day. At all times, interim
`safety evaluations were performed within 1 week after adjusting
`parenteral volumes by repeating 48 h urine collections, again
`recording and keeping oral beverages the same as during previous
`balances. Blood samples were taken (including haematocrit,
`blood urea nitrogen and creatinine), urine sodium was measured
`and a clinical evaluation was performed to check for clinical signs
`of dehydration. If tolerated, the new parenteral volume was
`maintained stable until the next visit and, if not, the original
`parenteral volume was resumed. The patient was excluded from
`the study if parenteral optimisation was not achieved, defined as
`stable urine output volume of 1.0e2.0 l/day after 8 weeks.
`
`Parenteral stabilisation
`After optimisation, the patients were maintained for 4e8 weeks
`on the stabilised tolerated parenteral volume. If the patients still
`had a urine volume of 1.0e2.0 l/day while keeping oral beverages
`constant, the patients were eligible for randomisation.
`
`Randomisation
`Eligible patients were randomly assigned to one of three groups
`according to a computer-generated interactive response system
`(Fisher Automated Clinical Trial Services). Randomisation was
`
`stratified for the three groups and the parenteral volume at three
`levels of consumption: (1) parenteral volume consisting of
`intravenous fluids and electrolytes only (3e7 times weekly); (2)
`parenteral volume consisting of fluids and nutrients 3e5 times
`weekly; and (3) parenteral volume consisting of fluids and
`(6e7 times weekly). These patients with SBS,
`nutrients
`depending on their parenteral support (nutrients and/or fluids),
`were randomised to receive teduglutide (Cangene, Winnipeg,
`Manitoba, Canada) at doses of 0.05 or 0.10 mg/kg/day or
`placebo (2:2:1) given subcutaneously into one of the four
`quadrants of the abdomen or either thigh once daily in the
`morning for 24 weeks. The placebo consisted of a lyophilised
`powder containing L-histidine, mannitol, monobasic and dibasic
`sodium phosphate, which were also contained in the active
`treatment.
`
`Parenteral adjustments after randomisation
`A strict parenteral weaning algorithm was used in the protocol
`that allowed for no more than 10% reductions in parenteral
`volumes at 4-week intervals (figure 2). Weaning was performed
`if the 48 h urinary volumes exceeded the baseline values by more
`than 10%, regardless of the absolute amount. Comparisons for
`subsequent reductions were always made to baseline urinary
`volumes. Greater reductions were allowed if urinary volumes
`exceeded 2.0 l/day. A maximum of five reductions in parenteral
`support were allowed from baseline to week 24. The physician
`responsible for adjusting the parenteral support was expert in
`the management of intestinal failure and parenteral infusion
`weaning. The physicians were educated in the algorithm and
`instructed to follow it. This physician was required to be
`
`904
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`
`Small bowel
`
`Figure 2 Algorithm for parenteral volume adjustment during dosing.
`
`different from the person conducting the physical examinations
`and assessing safety because the observation of stomal swelling,
`known to occur in relation to GLP-2 and teduglutide treatment,
`may have unblinded the observer.22 The mode of parenteral
`adjustments, either by adjusting daily parenteral provisions or
`providing days off parenteral support, was entrusted to this
`person and was not specified in the protocol. As previously
`described, interim safety evaluations were performed within the
`week following adjustment to parenteral volumes. This was
`done by repeating 48 h urine collections, attaining weights and
`by reviewing the recorded oral fluid intakes as per the previous
`balance studies leading to a change in parenteral support in the
`algorithm. Blood samples were taken (including haematocrit,
`creatinine, blood urea nitrogen), urine sodium was measured and
`a clinical evaluation was performed checking for clinical signs of
`dehydration. Only if this assessment led to a conclusion that the
`new parenteral volume was tolerated would the weekly paren-
`teral support volume be maintained until the next visit.
`Otherwise, the original parenteral volume was resumed.
`The primary efficacy variable in the study was initially the
`responder ratedthat is, the percentage of patients who had
`a reduction from baseline in parenteral volume of $20% at week
`20 of treatment and again at week 24. A decrease of at least 20%
`in parenteral fluid was considered to result in a clinical benefit to
`
`Table 1 Criterion values for the graded response score
`
`the patients. After an independent review of the protocol by
`a statistical and regulatory panel prior to database lock, an
`expanded graded primary end point was introduced to compare
`the patients treated with teduglutide versus placebo with
`respect to a graded response score (GRS) criterion that accounted
`for both intensity and duration of a response at the end of the
`24-week period. The intensity of the response relied on a reduc-
`tion from baseline in weekly parenteral volume (from 20% to
`100%). The duration of the response considered the responses at
`weeks 16 and 20, as well as weeks 20 and 24. The analysis of this
`expanded end point took into account higher levels of response
`and earlier onset of response coupled with a longer duration of
`response as shown in table 1. Thus, the score arose from the
`concept that, optimally, a graded change could be seen at the
`earlier time point and still observed at the later time point.
`The statistical analysis of the GRS score compared the effects
`of placebo and teduglutide, starting with the 0.10 mg/kg/day
`dose according to a pre-specified step-down procedure.
`Secondary efficacy end points included the number and
`percentage of subjects who responded (defined as a parenteral
`volume reduction of $20% from baseline at week 20 and
`maintained at week 24); the absolute reduction from baseline in
`parenteral volume and parenteral kilojoules; achievement of at
`least one day reduction in weekly parenteral administration or
`
`Week 20 maintained at week 24
`<20% reduction
`20e39%
`in PV
`reduction in PV
`
`40e99%
`reduction in PV
`
`100% reduction
`in PV
`
`Week 16 maintained to week 20
`
`<20% reduction in PV
`20e39% reduction in PV
`>40% reduction in PV
`
`0
`0
`0
`
`1
`2
`3
`
`2
`3
`4
`
`3
`4
`5
`
`The criterion values relied on the timing and reduction from baseline in weekly parenteral volumes (PV). The protocol-defined reduction was set at a minimum of 20% and a maximum of 100%.
`The timing of onset and the duration of response incorporated the responses at week 16 maintained to week 20 and week 20 maintained at week 24.
`
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`Small bowel
`
`total weaning from parenteral support. Further exploratory end
`points included the change from baseline in oral fluid intake and
`urine production, body composition (evaluated by DEXA),22
`plasma citrulline (an amino acid produced by enterocytes as
`a biomarker of a reduced enterocyte mass),23 bowel morphology
`(histopathological evaluation and villus height and crypt
`depth morphometrics, optionally taken via stomas or by
`colonoscopy)22 and health-related quality of life questionnaires
`(SF-36,24 the EuroQol EQ-5D25 and the IBDQ26).
`Safety evaluations were conducted throughout the study,
`which included all reports of adverse events (AEs) and clinical
`laboratory tests. An independent data and safety monitoring
`committee oversaw the study.
`All patients completing the randomised 24-week placebo-
`controlled trial were offered active treatment in a 28-week
`extension trial. The results from this study will be presented in
`a separate publication.
`
`Statistical analysis
`Based on the previous findings in a phase 2 study,22 the
`prospective primary hypothesis was that subcutaneous injec-
`tions of teduglutide would result in a higher GRS than placebo
`in patients with SBS dependent on parenteral support. The
`statistical analysis plan specified a step-down procedure which
`required teduglutide at a dose of 0.10 mg/kg/day to be statisti-
`cally significantly greater than placebo before evaluation of
`the 0.05 mg/kg/day dose. Statistical analyses were performed on
`the intent-to-treat population. The analysis of AEs included all
`83 patients who received at least one dose of the assigned
`treatment. Results are expressed as mean6SD.
`All statistical tests were two-sided with an a level of 0.05. A
`sample size of 80 randomised subjects (32 subjects in each of the
`two teduglutide treatment groups and 16 subjects in the placebo
`group) was required to provide at least 90% power to detect an
`increase in the percentage of subjects who had the protocol-
`defined minimum response defined as a parenteral volume
`decrease of $20% for week 20 and maintained at week 24
`which, on average, was estimated to correspond to one day off
`parenteral support (from 5% in the placebo treatment group to
`50% in the teduglutide treatment groups in the study). The
`power calculations were based on two-sided tests of significance
`using the Fisher exact test.
`For the analysis of the primary efficacy end point (the GRS),
`pairwise treatment comparisons were made using a rank anal-
`ysis of covariance (an extension of the Wilcoxon rank sum test)
`with strata for the baseline parenteral consumption level used
`for the stratification of the randomisation and treatment groups,
`with the baseline weekly parenteral volume as a covariate and
`a step-down procedure for multiple comparisons. For the main
`secondary end point (responses maintained from week 20 and
`week 24 and defined as a $20% reduction from baseline in
`weekly parenteral volume), pairwise comparisons between
`treatment groups were made using the Fisher exact test.
`
`RESULTS
`Patients
`In the period from May 2004 to November 2007, 139 patients
`signed informed consent forms and were screened at 32 centres
`in the USA, Canada, Denmark, France, Poland, Germany, the
`Netherlands, the UK and Belgium. Eighty-four patients with
`SBS were randomised and 83 were dosed (figure 1). The study
`data were gathered by the investigators and by a contract
`research organisation, and the data were held and analysed by
`
`NPS Pharmaceuticals in collaboration with the principal inves-
`tigators on the writing team who had access to all data.
`There were no significant differences in the demographic
`characteristics and medications among the groups at baseline
`compared with the placebo group, although parenteral volume
`and energy infusions tended to be higher in the 0.10 mg/kg/day
`teduglutide group (table 2). The numbers of patients completing
`the 24-week study were 15 (94%), 29 (88%) and 27 (77%) in the
`placebo, 0.10 mg/kg/day teduglutide and 0.05 mg/kg/day tedu-
`glutide groups, respectively.
`
`Efficacy
`Primary efficacy end point: GRS
`The primary efficacy end point of the study, the GRS, was not
`significantly different from placebo in the teduglutide 0.10 mg/
`kg/day group (p¼0.16), although a greater frequency of higher
`category responses was seen (table 3).
`
`Ad hoc analysis of the primary efficacy end point
`The prespecified statistical analysis plan required the 0.10 mg/
`kg/day dose to be significantly greater than placebo before
`further analyses. To gain further understanding about the effect
`of teduglutide,
`it was decided to explore the effect of the
`0.05 mg/kg/day dose on the primary end point. These results
`showed a statistically significant improvement compared with
`placebo in the GRS for the 0.05 mg/kg/day teduglutide dose
`group (p¼0.007).
`
`Secondary and exploratory efficacy end points
`The binary response end point represented the proportion of
`patients that responded to treatment which was defined as the
`achievement of a $20% reduction from baseline in weekly
`parenteral volume at week 20 and maintained at week 24. The
`responder rate was not significantly different between the
`teduglutide 0.10 mg/kg/day dose group and the placebo group
`(25% (8/32) vs 6% (1/16), p¼0.17), but the responder rate was
`significantly higher in the teduglutide 0.05 mg/kg/day dose group
`compared with placebo (46% (16/35) vs 6% (1/16), p¼0.005).
`Three subjects were completely weaned from parenteral
`support; two patients in the 0.05 mg/kg/day teduglutide treat-
`ment group became completely independent of parenteral
`support after 25 and 6.5 years on this treatment, receiving 5.4 l
`and 3.5 l parenteral support per week at baseline, respectively.
`Another patient receiving the 0.10 mg/kg/day teduglutide dose,
`who had been receiving parenteral support for 3.7 years and
`received 4.5 l parenteral support at baseline, was also completely
`weaned from parenteral support at the end of treatment at week
`24. Neither active treatment arm resulted in a significant
`reduction in the number of days on parenteral support.
`As shown in figure 3, a minor but statistically significant
`reduction in parenteral volume was observed in patients in the
`placebo group at weeks 12 and 24 compared with baseline
`(1066167 ml/day, p¼0.02
`1286202 ml/day, p¼0.03,
`and
`respectively). No significant changes were seen in the oral fluid
`intake or urine volume in the placebo group.
`Despite not meeting the a priori end point of a minimum
`reduction of 20% in parenteral fluid volume at weeks 20 and 24,
`patients receiving the teduglutide 0.10 mg/kg/day dose reduced
`their oral fluid intake by 3426599, 2506624, 3656575,
`3076525, 3596638 and 3926647 ml/day at weeks 4, 8, 12, 16,
`20 and 24, respectively, compared with baseline (all p<0.05).
`Oral fluid intake was significantly lower than placebo at weeks
`12 and 20 (4476526 ml/day and 6676738 ml/day, p<0.05). Oral
`fluid intake in this group (teduglutide 0.10 mg/kg/day) initially
`
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`Table 2 Demographic characteristics and medication at baseline
`
`Age (years), mean (SD)
`N
`Range
`BMI (kg/m2), mean (SD)
`N
`Range
`Female sex, n (%)
`Cause of major intestinal resection, n (%)
`Crohn’s disease
`Vascular disease
`Injury
`Volvulus
`Other
`Patients in whom the intestinal anatomy
`or remnant small bowel length was
`unknown
`Jejunostomy/ileostomy, n
`Ileostomy
`Jejunostomy
`Colon in continuity, n (%)
`Overall remnant small bowel length, cm
`N
`Mean (SD)
`Median
`Range
`Remnant small bowel length in patients
`with jejunostomy/ileostomy, cm
`N
`Mean (SD)
`Median
`Range
`Remnant small bowel length in patients
`with colon in continuity, cm
`N
`Mean (SD)
`Median
`Range
`Remnant colon, n (%)
`>25e50% colon remnant
`>50e75% colon remnant
`>75e100% colon remnant
`Time on parenteral support, years
`N
`Mean (SD)
`Range
`Parenteral volume, ml/day
`N
`Mean (SD)
`Range
`Parenteral energy, kJ/day
`N
`Mean (SD)
`Range
`Number of patients in parenteral type
`stratification
`Type group 1, n (%)
`(No with 3/4/5/6/7 days PS/week)
`Type group 2, n (%)
`(No with 3/4/5/6/7 days PS/week)
`Type group 3, n (%)
`(No with 3/4/5/6/7 days PS/week)
`
`Placebo (n[16)
`
`49.4 (15.1)
`16
`(20e72)
`22.0 (2.9)
`16
`(17.4e28.4)
`9 (56.3%)
`
`7 (44%)
`3 (19%)
`1 (6%)
`2 (13%)
`3 (19%)
`0
`
`1
`4
`11 (69%)
`
`15
`77 (53)
`60
`(15e200)
`
`4
`144 (52)
`150
`(75e200)
`
`11
`53 (26)
`50
`(15e110)
`
`4 (36%)
`4 (36%)
`3 (27%)
`
`16
`7.9 (7.5)
`(1e23)
`
`16
`1531 (874)
`(742e3850)
`
`16
`3385 (2591)
`(0e9984)
`
`4 (25%)
`(1/0/0/2/1)
`8 (50%)
`(2/4/1/0/1)
`4 (25%)
`(0/0/0/0/4)
`
`Gut 2011;60:902e914. doi:10.1136/gut.2010.218271
`
`Small bowel
`
`Teduglutide
`0.10 mg/kg/day
`(n[32)
`
`Teduglutide
`0.05 mg/kg/day
`(n[35)
`
`Overall (n[83)
`
`p Value
`
`50.3 (14.0)
`32
`(19e79)
`21.7 (2.6)
`32
`(17.0e26.4)
`19 (59.4%)
`
`13 (41%)
`8 (25%)
`2 (6%)
`4 (13%)
`5 (16%)
`2
`
`7
`4
`19 (59%)
`
`27
`68 (43)
`60
`(10e200)
`
`8
`77 (60)
`52
`(30e200)
`
`17
`62 (27)
`60
`(10e120)
`
`8 (42%)
`4 (21%)
`7 (37%)
`
`32
`7.3 (5.9)
`(1e24)
`
`32
`1816 (1008)
`(470e4643)
`
`32
`5296 (2845)
`(0e13749)
`
`3 (9%)
`(0/0/1/0/2)
`18 (56%)
`(3/5/6/4/0)
`11 (34%)
`(0/0/0/2/9)
`
`47.1 (14.2)
`35
`(20e68)
`21.2 (3.0)
`35
`(15.6e26.7)
`18 (51.4%)
`
`10 (29%)
`14 (40%)
`3 (9%)
`5 (14%)
`3 (9%)
`1
`
`2
`6
`26 (74%)
`
`31
`58 (44)
`50
`(6e200)
`
`7
`105 (54)
`80
`(60e200)
`
`24
`45 (29)
`40
`(6e125)
`
`7 (27%)
`9 (35%)
`10 (39%)
`
`35
`6.6 (6.5)
`(1e24)
`
`34
`1374 (639)
`(333e2500)
`
`35
`3992 (2689)
`(0e11514)
`
`8 (23%)
`(1/2/0/1/4)
`19 (54%)
`(5/7/6/0/0)
`8 (23%)
`(0/0/0/0/8)
`
`48.8 (14.2)
`83
`(19e79)
`21.5 (2.8)
`83
`(15.6e28.4)
`46 (55.4%)
`
`30 (36%)
`25 (30%)
`6 (7%)
`11 (13%)
`11 (13%)
`3
`
`10
`14
`56 (68%)
`
`73
`66 (45)
`60
`(6e200)
`
`19
`101 (59)
`75
`(30e200)
`
`52
`52 (28)
`50
`(6e125)
`
`19 (34%)
`17 (30%)
`20 (36%)
`
`83
`7.1 (6.4)
`(1e24)
`
`82
`1577 (859)
`(333e4643)
`
`83
`4378 (2805)
`(0e13749)
`
`15 (18%)
`(2/2/1/3/7)
`45 (54%)
`(10/16/13/4/1)
`23 (28%)
`(0/0/0/2/21)
`
`0.64y
`
`0.60y
`
`0.81*
`0.81*
`
`0.22*
`
`0.40y
`
`0.19y
`
`0.15y
`
`0.76*
`
`0.79y
`
`0.11y
`
`0.046y
`
`0.52z
`
`Continued
`
`907
`
`PROTECTIVE ORDER MATERIAL
`
`Page 6
`
`

`
`Small bowel
`
`Table 2 Continued
`
`Placebo (n[16)
`
`Teduglutide
`0.10 mg/kg/day
`(n[32)
`
`Teduglutide
`0.05 mg/kg/day
`(n[35)
`
`Overall (n[83)
`
`p Value
`0.43z
`
`Number of patients in parenteral volume
`stratification
`Parenteral volume 0e7 l/week, n (%)
`(No with 3/4/5/6/7 days PS/week)
`Parenteral volume 7e14 l/week, n (%)
`(No with 3/4/5/6/7 days PS/week)
`Parenteral volume 14e21 l/week, n (%)
`(No with 3/4/5/6/7 days PS/week)
`Parenteral volume >21 l/week, n (%)
`(No with 3/4/5/6/7 days PS/week)
`Concomitant medication
`Antidiarrhoeal agents, n (%)
`8 (50%)
`Antisecretory agents, n (%)
`7 (44%)
`*p Value based on the c2contingency table using the exact method.
`yp Value calculated using the general linear model (GLM) method with corresponding variables as dependent variables and treatment group as the independent variable.
`zp Values for overall treatment comparisons based on the Fisher exact test for categorical variables and on a one-way ANOVA with effect for treatment for continuous variables.
`Parenteral type group 1: parenteral support consisting of intravenous fluids and electrolytes only (3e7 times weekly); parenteral type group 2: parenteral nutrition 3e5 times weekly; parenteral
`type group 3: parenteral nutrition 6e7 times weekly.
`PS, parenteral support.
`
`6 (38%)
`(2/3/0/1/0)
`6 (38%)
`(1/1/1/0/3)
`3 (19%)
`(0/0/0/1/2)
`1 (6%)
`(0/0/0/0/1)
`
`9 (28%)
`(3/5/0/1/0)
`13 (41%)
`(0/0/6/5/2)
`6 (19%)
`(0/0/1/0/5)
`4 (13%)
`(0/0/0/0/4)
`
`19 (59%)
`17 (53%)
`
`14 (40%)
`(5/6/0/0/2)
`11 (31%)
`(1/2/5/1/2)
`9 (26%)
`(0/1/1/0/7)
`0 (0%)
`(0/0/0/0/0)
`
`22 (63%)
`19 (54%)
`
`29 (35%)
`(10/14/0/2/3)
`30 (36%)
`(2/3/12/6/7)
`18 (22%)
`(0/1/2/1/14)
`5 (6%)
`(0/0/0/0/5)
`
`49 (59%)
`43 (52%)
`
`increased urine production by 2106537 ml/day at week 4
`compared with baseline (p¼0.04), but urine production subse-
`quently decreased to baseline levels. In addition, parenteral
`volume was gradually decreased by 1596342, 2426361,
`2756367, 3096431 and 3536475 ml/day at weeks 8, 12, 16, 20
`and 24, respectively (all p<0.05) compared with baseline. These
`parenteral volume reductions were not
`significant when
`compared with placebo (p¼0.08 at week 24).
`Demonstrating a consistent effect, patients receiving the
`teduglutide 0.05 mg/kg/day dose produced significantly more
`(2606521, 2076485, 2886477,
`urine at all
`time points
`2136261, 3066567 and 3676485 ml/day at weeks 4, 8, 12, 16,
`20 and 24, all p<0.05 vs baseline),
`in spite of maintaining
`a constant oral fluid intake and having parenteral volume
`significantly decreased by 1096230, 1936223, 2466277,
`3196295 and 3546334 ml/day at weeks 8, 12, 16, 20 and 24 (all
`p<0.05), respectively, compared with baseline (figure