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Management of Short Bowel Syndrome in the Era of Teduglutide
Charlene Compher, PhD, RD
University of Pennsylvania
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Disclosures
• Research funding for clinical trials by NPS Pharmaceuticals 2003-2012
• Investigator-initiated protocol funding by NPS Pharmaceuticals 2009-2011
• No current conflicts to report
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Overview
• Review of short bowel syndrome
• Home parenteral nutrition risks
• Gut adaptation
• Established dietary strategies
• Human growth hormone
• Teduglutide
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What is Short Bowel Syndrome (SBS)?
• SBS exists when a patient’s remaining intestinal function cannot meet nutrient needs for survival, growth (children), hydration, electrolyte balance
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What Causes SBS in Adults?
• Surgical response to
– Blood clots in the artery or vein that feeds the bowel
– Malrotation (volvulus)
– Crohn’s disease resections
– Abdominal trauma
– Adhesions that cause bowel obstruction
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What Causes SBS in Children?
• Surgical response to – Congenital anomalies
• Atresias (20%) – Narrowing or absence of a segment of bowel
• Gastroschisis (12.5%) – Bowel outside the abdominal wall at birth
• Aganglionosis (6%) – Nerves that control the bowel do not develop in utero
– Necrotizing enterocolitis in very low birth weight neonates (35%)
– Malrotation (10%)
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Short Bowel Syndrome Anatomy
www.shortbowelsupport.com
Jejunocolic Anastomosis Jejunoileal Anastomosis
End Jejunostomy
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SBS and HPN
• HPN is needed – When the bowel is very short
• <100 cm or 40 inches in adults • <40cm in children
– When much ileum is gone – When remaining bowel is diseased
• Active Crohn’s disease • Radiation damage • When bowel just doesn’t work
– Early after the bowel resection • Some patients don’t need HPN for a long time • Others do
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Patient-identified Risks of HPN
• These factors are most important to patients
– Line infections
– Survival
– Quality of life
• Education about HPN
• Rapport with HPN team
• Psychological support
• Maximal HPN-free days – Dreesen, JPEN June 10 2014
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Clinician-identified HPN Risks
• Catheter-related bloodstream infections – 61% of PN complications
• Van Gossum, Clin Nutr 2001; 20:205
– 50% of PN-associated deaths • Jeppesen, Scand J Gastro
1998; 338:839 • Am Gastro Assoc Position,
Gastro 2003; 124:1107
– Correlated with liver disease risk
• Kaufman, Pediatr Transpl 2002; 6:37
• Bouza, Clin Micro Infect 2002; 8:265
• PN-associated liver disease – 15% to 50%, depending on
definitions • Chan, 1999 • Cavicchi, Ann Intern Med
2000; 132:525
• Metabolic bone disease – 41% osteoporosis
• Pironi, Clin Nutr 2002; 21:289
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Management Goals of PN-dependent SBS
• In adults
– Wean HPN as gut adaptation proceeds
– Push oral diet as key approach
• In children
– Achieve enteral autonomy
– Push enteral tube feedings and diet as approach to reduce PN dependence
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Gut Adaptation
• Normal process by which the intestine steps up to do the work (absorbing nutrition from food) of bowel that’s gone
– Intestine tissue grows in number of cells
– Takes 1-2 years at least in adults, may be shorter in children
– Eating food is important
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Gut Adaptation
• Spontaneous adaptation (SA)
• Hyper adaptation (HA) > SA
• Accelerated adaptation (AA), faster than SA
• Accelerated hyperadaptation (AHA)
• Goal of growth factors is to enhance adaptation
Jeppesen, Gastroenterol 2006; 130:S127-S131
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Diet to Support Adaptation
• Grazing eating style
• Good quality protein foods, simply prepared
• Complex carbohydrates
• Salty foods
• Sip salty fluids
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Somatropin
• Growth hormone (Zorbtive®)
• Approved by FDA for use in adult SBS
• Course is 4 weeks, dose 0.14 mg/kg/d
• Intestinotrophic
• Not advised for patients with history of cancer
• Common adverse drug effects are musculoskeletal pain, peripheral edema
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Somatropin
• 41 adult HPN patients with SBS
• 4 wk treatment arms – 0.1 mg/kg/d GH vs – 0.1 mg/kg/d GH+ 30 g/d
oral glutamine vs – 30 g/d oral glutamine
• Byrne, Ann Surg 2005; 242:655
• Somatropin permitted significantly more HPN weaning than oral glutamine
• Only somatropin + glutamine + diet maintained reduction for 12 weeks
• AE – 94% w peripheral edema,
44% musculoskeletal complaints
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Somatropin
HPN Volume (Liters/week) Infusions (Days/week)
* * *
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Weight Change
• No significant change in weight during study
• Weight change after study end attributed to fluid shifts
– Byrne, Ann Surg 2005; 242:655
-4
-3
-2
-1
0
1
2
3
4
End Follow-up
Ch
an
ge f
rom
Baseli
ne (
kg
)
Weeks
Gln GH Gln + GH
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Human Growth Hormone in Children
• N=14 children – Age 8-10 years – HPN dependent 8 years – 33 cm small bowel
• 0.14 mg/kg/day growth hormone for 4 months (N=7) vs no treatment (N=7)
• No difference in weaning from HPN
• No effect at 6 months off drug – Peretti JPEN 2011; 35:723
• N=8 children – Age 3-12 years – HPN dependent 4-12 years – 5-38 cm small bowel
• Gave 0.12 mg/kg/day for 3 months
• 6 of 8 children weaned off HPN
• At 12 months only 2 of 8 still off HPN – Goulet JPEN 2010; 34:513
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Summary Somatropin
• In adults, usually 1 month treatment
• In children, 3-4 months
• Most studies show reduced benefit when drug stopped
• Side-effects improve with lower doses
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Glucagon Like Peptide 2 (GLP2)
• Intestinotrophic
• Antisecretory
• ↑ blood flow to the bowel
– Brenholm, Scand J Gastro 2008
• Increases absorption of fluid, energy, nutrients
– Jeppesen JPEN J Parenter Enteral Nutr 2014 38: 45S
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Teduglutide Clinical Trials
Inclusion
• Adults • 1 year HPN dependent
SBS • HPN 3 infusions/week • Urinary output > 1 L/d • Urine sodium >20 mmol/d • Serum Cr, BUN <1.5 ULN • LFTs < 2 ULN
Exclusion
• Pregnancy, lactation
• Cancer
• Clinical trial within 30 d
• GLP2 in past 3 m
Primary Outcome
• ≥20% reduction in HPN Volume
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Teduglutide RCT Flow Chart
O’Keefe, Clin Gastroenterol Hepatol 2013; 11:815-823
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HPN Reduction after 12 months, N=52
O’Keefe, Clin Gastroenterol Hepatol 2013; 11:815-823
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Adverse Events
AE 0.05 mg/kg/d (N=25) 0.10 mg/kg/d (N=27)
Cardiac 3(12%) 2 (7%)
GI 17 (68%) 17 (63%)
• Abd distension 4 (16%) 4 (15%)
• Abd pain 7 (28%) 6 (22%)
• Nausea 5(20%) 11 (41%)
Musculoskeletal 9(36%) 11 (41%)
Headache 7 (29%) 11 (41%)
Stoma complication 3 (12%) 3 (11%)
Catheter sepsis 5 (20%) 4 (15%)
Injection site disorders 13 (52%) 19 (70%)
O’Keefe, Clin Gastroenterol Hepatol 2013; 11:815-823
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SBS-QOL in Teduglutide Patients
Significantly improved • Diarrhea/ostomy output • GI s/s • Sleep • Daily activities • Skeletal muscle s/s • Social life • Physical health • Fatigue
• But not significantly better
than placebo (N=35 each group)
• >20% HPN volume reductions associated with improved QOL scores
• Patients with > 100 cm SB had more GI s/s • Jeppesen, Clinical Nutrition 32
(2013) 713e721
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What happens to adults after stopping teduglutide?
• Subjects had received the drug ≥ 28 wk (N=37)
• Subset of drug responders, defined as ≥ 20% reduction in PN volume in response to drug (N=25)
Hypothesis:
• Most subjects would require increase in PN back to baseline levels
– Compher, JPEN J Parenter Enteral Nutr published online 8 August 2011
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Intestinal Anatomy
30
60 67
59
91 91
Small Bowel(cm)
Colon(cm)
Colon inContinuity
(%)
INCREASE PN (n=15)
NO CHANGE/DECREASE PN (n=22)
* *
• No difference – Age
– Gender
– Time since GI surgery
– Pre-drug citrulline
– Drug dose
– Drug duration
– Change in citrulline on-drug
• 3 patients came off, stayed off PN – JPEN J Parenter Enteral Nutr
published online 8 August 2011
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INC NEUT/DEC-6-4
-20
2
kg
/m2
0 1
Entire Sample
BMI Change After Stopping Teduglutide
BMI_Chg_3M BMI_Chg_6M
BMI_Chg_12M
Median, IQR error bars. BMI ↓in INC, p<0.001; no change in NEUT/DEC subjects
BMI Change and Complications
Complication Incidence
Increase PN
Decrease/ No Change PN
All, N=25 14 in 3/15 subjects
11 in 7/22 subjects
Drug responders, N=18
13 in 3/12 subjects; 1.5/person year*
5 in 3/13 subjects 0.38/ person year*
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Regression Models Predict Change in BMI off-drug
Entire Sample adj R2=0.71
Variable Beta P
Colon(cm) 0.010 <0.001
SB (cm) 0.010 0.002
BMI off-drug (kg/m2)
-0.155 0.001
On-drug Reduction in PN vol (L/wk)
0.150 0.001
Drug Responders, adj R2=0.74
Beta P
0.012 <0.001
0.010 0.007
-0.120
0.037
0.198
0.012
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Summary Teduglutide
• Teduglutide (Gattex®) – Safe for at least 12 months
• Adverse events not > placebo
– Effective • > 65% patients had > 20% ↓ in HPN volume over 12 months • 5/82 patients came off HPN
• Drug approved by FDA in December 2012 • Not if history of intestinal cancer • Require colonoscopy within 6 months of drug start • Insurance coverage • Not approved for children
• Outcomes after stopping drug less clear • No data on reduced doses
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Pediatric Teduglutide Study
• Safety study
– Measure adverse effects after 3 months drug therapy
• 3 doses of Teduglutide, 1 placebo
– 36 children age 1-17 years
– Excluded if
• STEP in past 3 months
• Bowel obstruction
• Major intestinal surgery in past 3 months
• Untreated intestinal disease
– www.clinicaltrials.gov
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Neonatal Piglets Treated with GLP2 5 days after SBS
Vegge A et al. Am J Physiol Gastrointest Liver Physiol
2013;305:G277-G285
©2013 by American Physiological Society
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Neonatal Piglet Jejunostomy Model, Teduglutide + PN for 7 days
Enhanced early trophicity No early effect on function
Twymann, JPGN 2014; 58: 694
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Neonatal Piglets with HPN +/- Teduglutide 17 days
Improved Liver Histology Improved Bile Flow
HPN w saline, cholestasis
HPN w Teduglutide, less cholestasis
Non-HPN oral diet control, normal
Turner, JPEN epub 2014; Oct 3.
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Summary
• At present, we use best available approaches to improve the quality of life and reduce HPN dependence for patients with SBS – Diet strategies – Teduglutide in some adults
• Data not yet available in – Early adaptation window – Children – Dose reduction or alternate day dosing – Long-term outcomes – Data on outcomes after stopping drug
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