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`
`Abstracts
`
`S487
`
`[1320]
`
` Symptom / scale
`
` Total GCSI
`
` Nausea
`
` Stomach fullness
`
` Early satiety
`
` Postprandial fullness
`
` Stomach visibly large
`
` Upper abdominal
`pain / Discomfort
`
` Lower abdominal
`pain / discomfort
`
` Mean (SD) change from baseline at day 28
` 20mg TZP-102
` Placebo
`( n =21)
`( n =23)
`
` P value
`
` Mean (SD) change from baseline average of D8, D15 & D28
` 20mg TZP-102
` Placebo
`( n =21)
`( n =23)
`
` − 1.4 (1.07)
`
` − 1.5 (1.69)
`
` − 1.6 (1.50)
`
` − 1.4 (1.57)
`
` − 1.8 (1.37)
`
` − 1.5 (1.47)
`
` − 1.2 (1.23)
`
` − 0.7 (0.99)
`
` − 0.5 (1.44)
`
` − 0.6 (1.31)
`
` − 0.3 (1.19)
`
` − 0.9 (1.32)
`
` − 0.7 (1.37)
`
` − 0.5 (1.53)
`
` − 1.0 (1.60)
`
` − 0.2 (1.20)
`
` 0.029
`
` 0.050
`
` 0.005
`
` 0.003
`
` 0.033
`
` 0.040
`
` 0.046
`
` 0.025
`
` − 1.0 (0.86)
`
` − 1.3 (1.48)
`
` − 1.1 (1.26)
`
` − 1.0 (1.26)
`
` − − 1.3 (1.11)
`
` − 1.0 (1.06)
`
` − 0.9 (0.97)
`
` − 0.9 (1.43)
`
` − 0.5 (0.74)
`
` − 0.3 (1.21)
`
` − 0.5 (1.19)
`
` − 0.3 (0.85)
`
` − 0.6 (1.08)
`
` − 0.6 (1.05)
`
` − 0.4 (1.04)
`
` − 0.4 (0.91)
`
` P value
`
` 0.029
`
` 0.025
`
` 0.035
`
` 0.010
`
` 0.025
`
` 0.159
`
` 0.058
`
` 0.053
`
`R Malik - Grant/Research Support: Tranyzme, Inc.; P Hellstöm - Grant/Research
`Support: Tranyzme, Inc.; L Shaughnessy - Employee: Tranyzme, Inc.; P Charlton -
`Employee: Tranyzme, Inc.; G Kosutić - Employee: Tranyzme, Inc.; N Ejskjaer -
`Consultant: Tranzyme, Inc., Grant/Research Support: Tranyzme, Inc.
`Th is research was supported by an industry grant from Tranzyme, Inc.
`
`1321
`Alosetron Treatment Led to Fewer Physician Contacts and Fewer Days of
`Lost Work Productivity Compared to Treatment with Traditional Th erapy
`for Diarrhea-Predominant IBS (IBS-D)
`Kevin Olden, MD,1 Reshma Shringarpure, PhD,2 Jean Paul Nicandro, PharmD,2
`Emil Chuang, MD2. 1. Washington Hospital Center, Washington, DC;
`2. Prometheus Laboratories Inc, San Diego, CA.
`Purpose: To compare the impact of alosetron treatment with that of tradi-
`tional therapy for IBS-D on healthcare resource use, productivity, and quality
`of life (QoL).
`Methods: Female patients with IBS-D were enrolled in a randomized, open-
`label study to evaluate health care resource use, QoL, and productivity fol-
`lowing treatment with alosetron (1 mg BID) versus traditional therapy for
`24 weeks. Healthcare resource use was primarily measured as number of phy-
`sician contacts and number of medications used during the treatment period.
`Improvement in IBS symptoms was assessed using the Global Improvement
`Scale (GIS) and QoL was assessed using the IBS-related QoL instrument. Total
`Lost Work Productivity was computed as: Days missed due to IBS + (Total days
`with IBS symptoms * (1 - % Eff ectiveness)).
`Results: Of 2,456 patients enrolled, 2,256 were evaluable with a mean age of
`48.8 yrs and mean duration of 12.2 yrs for IBS. Relative to traditional ther-
`apy, alosetron-treated patients reported signifi cantly fewer physician contacts
`(P=0.032) for any health problem. Although the diff erence in total number
`of medications used during the treatment period was not statistically signifi -
`cant between groups, the alosetron group used fewer medications on average
`compared to the traditional therapy group (9.1 vs. 9.5). Compared to patients
`treated with traditional therapy, alosetron-treated patients reported signifi -
`cantly greater improvement in all 9 domains of the IBSQoL (P<0.001), and
`a signifi cantly greater proportion of alosetron-treated patients were respond-
`ers on the GIS (P<0.001). In both cases, benefi t was evident at 4 weeks and
`sustained throughout the 6-month treatment period. Th e majority of patients
`(>70%) on traditional therapy were non-responders at the end of the study.
`Moreover, patients treated with traditional therapy missed more days from
`work (3.0 vs. 1.9 days; P<0.001) and lost more days of work productivity (5.0 vs.
`3.2 days, P<0.001), compared to alosetron-treated patients. Alosetron-treated
`patients also reported signifi cantly less restrictions on outdoor activities and
`attendance at social gatherings compared to patients on traditional therapy
`(P<0.001). With the exception of GI adverse events (AEs) of constipation and
`GI pain and discomfort, the incidence of other AEs was similar in both groups,
`and most of the AEs were mild or moderate.
`
`Conclusion: Alosetron therapy led to signifi cantly greater improvements in
`IBS symptoms and QoL compared to traditional therapy. Subjects treated with
`traditional therapy used more healthcare resources in terms of physician time,
`missed more days of work, and reported signifi cantly greater lost productivity
`time compared to alosetron-treated patients.
`Disclosure: Th e manufacturer / provider for Alosetron is Prometheus Laborato-
`ries Inc. Dr Olden - Consultant and Speakers Bureau: Prometheus Laboratories
`Inc. Dr Shringarpure, Dr Nicandro and Dr Chuang - Employees and stockhold-
`ers: Prometheus Laboratories Inc.
`
`1322
`Phase II Clinical Evaluation of SP-304, a Guanylate Cyclase-C Agonist, for
`Treatment of Chronic Constipation
`Kunwar Shailubhai, PhD, MBA,2 Craig Talluto, PhD,1 Stephen Comiskey, PhD,2
`John Foss, PhD,2 Alan Joslyn, PhD,1 Gary Jacob, PhD1. 1. Synergy Pharmaceuticals,
`Inc, New York, NY; 2. Synergy Pharmaceuticals, Doylestown, PA.
`Purpose: Uroguanylin (UG) and guanylin (GN) are physiological agonists of
`guanylate cyclase-C (GC-C) receptors. Activation of GC-C receptor promotes
`intracellular synthesis of cGMP and subsequent activation of the cystic fi brosis
`transmembrane conductance regulator (CFTR), resulting in fl uid and bicar-
`bonate secretion into the intestinal lumen. Optimum volume of fl uid secre-
`tion in the proximal intestine is critical for normal bowel movement and for
`complete defecation. Th us, oral treatment with a GC-C agonist is expected to
`promote spontaneous bowel movement (SBM) and to reduce abdominal pain
`and bloating. SP-304 is a superior analog of UG that appears to mimic physi-
`ological functions of UG in the GI tract. In T84 cell assays, SP-304 exhibits an
`8-fold higher binding affi nity to GC-C receptors than UG. Th e present trial is
`designed to evaluate effi cacy and safety in chronic constipation (CC) patients.
`Methods: Th is phase II clinical study (double-blind, placebo-controlled, ran-
`domized with cohorts of 0.3, 1, 3 and 9 mg repeated daily dose for 14-days) in
`CC patients has completed enrollment and dosing of the fi rst 2 of 4 cohorts. CC
`patients are being evaluated primarily for safety and effi cacy of SP-304. Bowel
`habits (stool frequency, consistency, straining, time to fi rst BM and complete-
`ness of evacuation) and degree of abdominal discomfort were monitored daily
`using patient diary. Patient reported outcomes of severity of constipation and
`overall relief were evaluated weekly.
`Results: A total of 14 sites open in the U.S. are presently evaluating SP-304 in
`CC patients. Total enrollment for the study is 80 patients. At present, 40 patients
`have been dosed, and the 1.0 mg and 3.0 mg dosage arms have been completed.
`Patients are currently being dosed at 9 mg. We recently added a fourth dos-
`age arm of 0.3 mg to the study. To date, no unexpected safety issues have been
`reported and based on the blinded review some patients in each cohort are expe-
`riencing improvements in bowel function. Phase II clinical data will be discussed
`to highlight pharmacodynamic and safety profi le of SP-304 in CC patients.
`Conclusion: GC-C agonists are rapidly emerging as a new class of drug can-
`didates to treat GI disorders. UG and Escherichia coli heat-stable (ST) toxins
`
`© 2010 by the American College of Gastroenterology
`
`The American Journal of GASTROENTEROLOGY
`
`MYLAN - EXHIBIT 1013
`
`

`

`S488
`
`Abstracts
`
`bind to a common GC-C receptor to stimulate fl uid secretion in the gut. Th e
`present study demonstrates that SP-304 possesses a similar clinical profi le as
`other GC-C agonists, based on the early clinical observations. Complete phase
`II clinical data on safety & effi cacy in CC patients will be discussed.
`Disclosure: Dr Shailubhai-Employee Dr Talluto-Employee Dr Steve Comiskey-
`Employee Dr John Foss-Employee Dr Alan Joslyn-consultant Dr Gary Jacob-
`Employee.
`
`1323
`High Resolution Anorectal Manometry in Healthy Egyptian Population:
`Age, Gender, and Parity Infl uence
`Hala Imam, MD, PhD, Essam Abdelmohsen, MD, PhD. Assiut University
`Hospital, Assiut, Egypt.
`Purpose: Th e aim was to study High Resolution Anorectal Manometry
`(HRAM) in Egyptian population and the infl uence of age, gender and parity
`on manometric parameters.
`Methods: We studied 22 healthy volunteers 10 males and 12 females with
`median age 42 y (range: 18-61 y) by using solid state probe with 8 transducers
`1 cm spaced with a rectal balloon mounted at the tip. Th e system is plotting
`graphs with high resolution topography and conventional pressure waves trac-
`ing as well (Solar GI MMS). Probe was introduced through the anal verge so
`the balloon is located at the rectum and the sensors at the rectum and anal
`
`[1323] High resolution topography of maximum anal squeeze.
`
`[1323] High resolution topography of RAIR.
`
` [1323] Table 1 . Correlation between age and manometry
`
`canal. External EMG electrodes were applied on either sides of anus. Subjects
`were asked to relax, squeeze the anal sphincter, bear down, and cough to meas-
`ure anal pressures at these situations. Rectal sensation and recto-anal inhibi-
`tory refl ex (RAIR) were evaluated by stepwise intermittent (10 ml) balloon
`distention. Finally balloon expulsion test was done.
`Results: Anal resting and maximum squeeze pressure were signifi cantly higher in
`males than females (median; range: 61; 45-71 and 140.0; 67-224 vs. 42; 32-67 and
`117; 58-220 respectively, P<0.05), while squeeze time, pressure increase to cough,
`push relaxation, RAIR, rectal sensation, and EMG were comparable in males and
`females. Age negatively correlated with some anorectal parameters (table 1), simi-
`larly parity negatively correlated with anal resting (r=-0.52, p <0.05) and squeeze
`pressure (r=-0.56, p<0.05). All subjects were able to expel the balloon.
`Conclusion: HRAM helps understanding anorectal physiology. It is infl uenced
`by age, gender, and parity. Th is study can aid in diagnosis anorectal dysfunc-
`tion in Egyptian population.
`
`1324
`Is Th ere a Unifying Pathophysiology of Medically Unexplained Symptoms
`in GW Veterans?
`
`2010 Presidential Poster
`Ashok Tuteja, MD, MPH.,1 Nicholas Talley, MD, PhD,2 Gregory Stoddard, MS,3
`Matthew Samore, MD,1 G. Nicholas Verne, MD4. 1. V.A. Medical Center, Salt
`Lake City, UT; 2. University of Newcastle, Callaghan, NSW, Australia;
`3. University of Utah, Salt Lake City, UT; 4. Ohio State University, Columbus, OH.
`Purpose: Th e prevalence of irritable bowel syndrome (IBS), dyspepsia, chronic
`fatigue syndrome (CFS) and other medically unexplained symptoms (MUS)
`in Gulf War (GW) veterans is high. It has been suggested that these problems
`are diff erent manifestations of a common disorder. Th e aim of this study was
`to determine whether these independent symptoms based subgroups exist in
`GW veterans.
`Methods: GW veterans (1990-1991) registered in two registries at two major
`Medical Centers were mailed the validated Bowel Disease Questionnaire
`inquiring about their bowel habits and somatic symptoms specifi cally inquir-
`ing about symptoms of CFS (fatigue, joint pain, general stiff ness, headache,
`insomnia) and MUS (including backache, shortness of breath, palpitation, eye
`pain, dizziness, hot and cold spells, anxiety, and nervousness). Defi nition of
`IBS and dyspepsia were based on Rome III criteria. Data was analyzed using
`Hierarchical cluster analysis with average linkage using symptoms of IBS, dys-
`pepsia, CFS, and other MUS.
`Results: Data from 433 GW veterans registered at the two VA Medical Centers
`were analyzed. Th is population consisted of predominantly men (86%) with
`a median age 48 years (range 34-76). Th e prevalence of IBS, dyspepsia, and
`symptom components of CFS, and MUS is described in Table 1. Th ere was sig-
`nifi cant overlap among all three disorders. Almost half (49.1%) of GW veterans
`with dyspepsia had IBS and 74% with IBS had dyspepsia. Forty-eight percent
`of GW veterans with IBS and 39% with dyspepsia also reported symptoms of
`CFS. Th e simultaneous presence of IBS, dyspepsia and CFS were reported by
`12% of GW veterans. Cluster analysis suggests the presence of four clusters.
`IBS and dyspepsia form two separate clusters, third consists of CFS, and the
`fourth consists of other MUS (Figure).
`Conclusion: MUS is common in GW veterans. Although IBS, dyspepsia, CFS,
`and MUS commonly co-exist, they form separate clusters. Th is would suggest
`that the pathophysiology of MUS in GW veterans cannot be explained by one
`unifying hypothesis and a single treatment is unlikely to be helpful.
`
`
`
`
` r
`
` P value
`
` Resting
`
` − 0.44
`
` .039
`
` Anal pressure
` Max squeeze
`
` − 0.49
`
` .027
`
` Cough increase
`
` 1st sensation
`
` Rectal sensation
` 1st urge
` Intense urge
`
` − 0.371
`
` .051
`
` − 0.553
`
`.008
`
` − 0.420
`
` .05
`
` − 0.508
`
` .016
`
` Max tolerable
`
` − 0.380
`
` 0.061
`
`The American Journal of GASTROENTEROLOGY
`
`VOLUME 105 | SUPPLEMENT 1 | OCTOBER 2010 www.amjgastro.com
`
`