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A Randomized Controlled Clinical Trial of the Serotonin Type 3 Receptor Antagonist Alosetron in Women With Diarrhea-Predominant Irritable Bowel Syndrome
Michael Camilleri, MD;
William Y. Chey, MD, DSci;
Emeran A. Mayer, MD;
Allison R. Northcutt, MS;
Amy Heath, MS;
George E. Dukes, PharmD;
David McSorley, MPH;
Allen M. Mangel, MD, PhD
Arch Intern Med. 2001;161:1733-1740.
ABSTRACT
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Background Irritable bowel syndrome (IBS) is a common gastrointestinal disorder
seen in primary care practice. The symptoms of IBS, including abdominal pain,
discomfort, and abnormal bowel function, may be modulated by activity of the
serotonin type 3 receptor (5-HT3). The efficacy and tolerability
of the 5-HT3 receptor antagonist alosetron hydrochloride in nonconstipated
female patients with IBS were evaluated in a double-blind, randomized, placebo-controlled
trial.
Methods Patients received either 1 mg of alosetron hydrochloride (n = 309) or
placebo (n = 317) twice daily for 12 weeks, followed by a 4-week posttreatment
period. Adequate relief of IBS pain and discomfort was the primary end point.
Secondary end points included improvements in urgency, stool frequency, stool
consistency, incomplete evacuation, and bloating.
Results Seventy-one percent of patients were classified as having diarrhea-predominant
IBS. Forty-three percent of alosetron-treated patients with diarrhea-predominant
IBS reported adequate relief for all 3 months compared with 26% of placebo-treated
patients (P<.001; percentage point difference
= 17; 95% confidence interval, 8.0-25.4). Improvement with alosetron compared
with placebo was observed by the end of the fourth week of treatment and persisted
throughout the remainder of treatment. Alosetron significantly decreased urgency
and stool frequency and caused firmer stools within 1 week of starting treatment.
Effects were sustained throughout treatment and symptoms returned following
treatment cessation. No significant improvement in the percentage of days
with sense of incomplete evacuation or bloating was observed compared with
placebo during the first month of treatment. Constipation was the most commonly
reported adverse event.
Conclusion Alosetron hydrochloride, 1 mg twice daily for 12 weeks, is effective
in relieving pain and some bowel-related symptoms in diarrhea-predominant
female patients with IBS.
INTRODUCTION
IRRITABLE BOWEL syndrome (IBS) is one of the most common functional
gastrointestinal disorders seen in primary care and gastroenterology practices.1-2 Irritable bowel syndrome primarily
affects women,3 with prevalence estimates of
14% to 24% of women in the United States and Great Britain.4
It negatively affects patients' daily activities and quality of life5-7 and contributes to significant
increases in health care resource utilization.5, 8
The primary symptoms of IBS are recurrent abdominal pain and discomfort.9 Patients with IBS also experience abnormal bowel function,
which presents primarily as diarrhea (diarrhea-predominant subtype), constipation
(constipation-predominant subtype), or alternation between the 2 (alternating
subtype). In addition, increased sense of urgency, bloating, and incomplete
evacuation may be present.
The serotonin type 3 (5-HT3) receptor antagonists represent
valuable therapeutic compounds for the treatment of IBS. The 5-HT3
receptors have been identified on sensory neurons of the gut and mediate reflexes
that control gastrointestinal motility and secretion, bowel function, and
perception of pain.10 In patients with IBS,
5-HT3 receptor antagonists increase colonic compliance, slow colonic
transit, and improve stool consistency.11-15
Previous studies16-17 with the
5-HT3 receptor antagonist alosetron have shown that 1 mg twice
daily is the most effective dose in female patients with IBS for improving
IBS abdominal pain and discomfort and urgency. A comparison study with the
smooth muscle relaxant mebeverine hydrochloride showed that alosetron provided
greater relief of pain and some IBS bowel abnormalities.18
The efficacy of a 1-mg, twice-daily dose of alosetron hydrochloride in the
treatment of IBS has recently been confirmed.19
Because of the range of symptoms associated with IBS, evaluating efficacy
of treatments can be challenging.20-21
In previous studies with IBS patients, we have introduced and validated the
end point of adequate relief of IBS pain and discomfort.22-23
Changes in adequate relief correlate with changes in measures that are meaningful
to diarrhea-predominant patients with IBS: improved pain severity scores,
a greater percentage of pain-free days, fewer days with urgency, and fewer
and firmer stools.22-23 Furthermore,
the adequate relief end point is responsive to treatment and the responses
are reproducible. Thus, adequate relief is a valid end point for measuring
improvement in multiple IBS-relevant dimensions.
This randomized, placebo-controlled clinical trial evaluated the efficacy
and tolerability of alosetron in nonconstipated women with IBS. The primary
efficacy measure was adequate relief of IBS pain and discomfort, with secondary
efficacy measures of improved urgency, stool frequency, stool consistency,
bloating, and incomplete evacuation. We have also assessed efficacy in the
subset of patients with diarrhea-predominant IBS. This subset comprised 71%
of the study population.
PATIENTS AND METHODS
PATIENTS
Female patients with IBS aged 18 years or older were eligible for enrollment
if their symptoms fulfilled the Rome I criteria for IBS for at least 6 months.24 Patients underwent a 2-week screening evaluation
to confirm sufficient level of pain and stool consistency before randomization.
Institutional review boards at all sites approved the protocol, and all patients
provided written informed consent.
Patients with IBS and a diarrhea-predominant bowel pattern or a bowel
pattern that alternated between diarrhea and constipation (ie, alternators)
were enrolled in this study. Since no objective criteria exist for subgrouping
of IBS patients,9 physicians were asked to
assess patients according to predominant pattern of bowel function based on
the patient's disease history. Physicians were provided with a guideline based
on the percentage of time the patient had experienced diarrhea or constipation
(if diarrhea or constipation was present for  75% of the time, a patient's
IBS was active, then the patient was classified as being diarrhea predominant
or constipation predominant, respectively; otherwise the patient was classified
as an alternator). Patients with constipation-predominant IBS were excluded
from the study.
Patients were excluded if they were pregnant, breastfeeding, or not
using approved methods of contraception (if of child-bearing potential); if
an unstable medical or other gastrointestinal condition existed; if there
was a major psychiatric disorder or substance abuse within the previous 2
years; if an investigational drug was used within 30 days of the screening
phase; or if a prohibited concurrent medication (likely to interfere with
gastrointestinal tract function or analgesia) was used within 7 days before
entering the screening phase.
STUDY DESIGN
Patients were randomized 1:1 to receive 12 weeks of oral treatment with
either matched (appearance and taste) placebo or alosetron hydrochloride,
1-mg tablets twice daily taken before meals. Treatments were randomly assigned
with equal allocation to alosetron and placebo using a blocked (block size
of 4) randomization schedule generated from Glaxo Wellcome's Random Codes
System. The treatment phase was followed by a 4-week follow-up period. Laboratory
evaluations, menstrual records, and assessments of fiber intake were collected
at the 4- and 8-week treatment visits and at the 12-week (or final treatment)
visit.
DATA COLLECTION
During the screening, treatment, and follow-up periods, daily and weekly
symptom data were collected using an interactive telephone-based system previously
described.25
Pain and bowel function data were collected during the screening phase
to ensure that patients had a suitable symptom level at study entry. Severity
of pain and discomfort was assessed daily on a 5-point scale (0, none; 1,
mild; 2, moderate; 3, intense; and 4, severe). Average daily baseline pain
and discomfort scores during the 2-week screening period were required to
be between 1.0 and 3.3 (inclusive) for patients to enter the treatment phase.
Stool consistency data were monitored daily and scored as follows: 1, very
hard; 2, hard; 3, formed; 4, loose; and 5, watery. Absence of stool was assigned
a value of 0. During the screening period, average daily stool consistency
scores of 2.5 or higher were required to exclude patients with hard stools
and enroll patients whose predominant bowel abnormality was diarrhea. Routine
laxative treatment was not permitted during the screening, treatment, or follow-up
periods.
During the treatment and follow-up phases, patients were asked once
every 7 days if they had obtained adequate relief of their IBS pain and discomfort
during the previous 7 days.22-23
Patients also recorded their IBS symptoms (pain severity, urgency, stool consistency,
stool frequency, bloating, and sense of incomplete evacuation) daily during
the treatment and follow-up phases.
Patients who experienced no bowel movements for 4 consecutive days were
required to stop treatment for up to 4 days. Patients were able to remain
in the study and resume treatment only if bowel movements returned within
the 4-day drug holiday.
STATISTICAL ANALYSIS
The primary efficacy end point was the proportion of patients with adequate
relief of IBS pain and discomfort on at least 2 weeks per month (defined as
a monthly responder). The sample size was chosen with 90% power at the 
= .05 significance level to detect a 15–percentage point difference
between treatment groups for the proportion of patients with adequate relief
on at least 2 weeks per month, assuming a 40% response in patients receiving
placebo and a 55% response for patients receiving alosetron hydrochloride,
1 mg twice daily. Two hundred forty-four patients per treatment group were
necessary to detect such a difference. Therefore, a target sample size of
300 patients per treatment group (total target of 600 patients) was chosen
to allow for a 20% dropout rate.
Efficacy analyses were by intention to treat and included all patients
randomized to study treatment; safety analyses included all patients randomized
to treatment except those who did not take at least 1 dose of study treatment.
The handling of missing data was managed according to the last observation
carried forward (LOCF) principle, whereby missing values were replaced with
the last previous nonmissing value. The impact of this imputation scheme on
treatment differences for adequate relief was assessed.
The proportion of patients with adequate relief was compared between
treatment groups using a Mantel-Haenszel test stratified by clusters of centers.26 Centers were prospectively grouped into 5 geographic
"clusters" to avoid the loss of centers with small numbers of subjects in
tests stratified by center or tests of treatment-by-center interaction. Therefore,
treatment-by-cluster interaction was assessed (using cluster as a surrogate
for center) via ordinal logistic regression using the total number of months
a patient was a monthly responder as the dependent variable and treatment,
cluster, and treatment-by-cluster interaction terms as independent predictors
in the model.
Daily stool consistency scores and daily number of bowel movements were
averaged at baseline (for the 2-week screening period) and for each week of
the treatment and follow-up phases. In addition, the percentage of days that
patients experienced a sense of urgency, incomplete evacuation, and bloating
was calculated at baseline and for the same weekly intervals. Changes from
baseline in the 2 treatment groups were compared using the van Elteren test
stratified by clusters of centers.27
Closed testing procedures were used to address multiple significance
testing in the analysis.28-29
RESULTS
STUDY POPULATION AND DEMOGRAPHICS
Six hundred twenty-six of 1417 patients screened were randomized from
104 sites within the United States. Site enrollment ranged from 1 to 19 patients
per site and averaged 6 patients per site. Seventy-one percent of patients
randomized were classified as having the diarrhea-predominant form of IBS.
A flowchart of patients' progression through the study is presented in Figure 1. Screening failures resulted primarily
from failure to meet the entry criteria for pain and stool consistency. Two
hundred eighty patients had harder stools than allowed, 175 patients had pain
below the severity criterion, and only 20 patients had pain exceeding the
severity criterion.
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Figure 1. Flowchart of patient progression
through the study. Reasons for screening failures and discontinuation from
the study are indicated. One patient in the placebo group withdrew from the
study before receiving the first dose and was not included in the safety analysis.
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A total of 237 (77%) of 309 and 247 (78%) of 317 randomized patients
in the alosetron and placebo groups, respectively, completed the study. Seventy-two
patients prematurely discontinued treatment in the alosetron group and 71
in the placebo-treated group. Reasons for premature discontinuation from the
study are indicated in Figure 1.
General and IBS-specific characteristics for randomized patients were
similar between treatment groups (Table
1). Patients were predominantly white and in their mid-40s.
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Table 1. Demographic and Baseline Characteristics of Study Patients
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ADEQUATE RELIEF OF PAIN AND DISCOMFORT
Forty-one percent of alosetron-treated patients in the intention-to-treat
population reported at least 2 weeks per month with adequate relief (monthly
responders) for all 3 months compared with 26% of placebo-treated patients,
a percentage point difference of 15 (P<.001; 95%
confidence interval [CI], 7.8-22.5). Analysis of the impact of the LOCF imputation
scheme showed that less than 1.4% of the treatment difference for adequate
relief was attributable to the LOCF approach.
There were no significant differences in alosetron efficacy between
diarrhea-predominant patients and alternators; however, the magnitude of efficacy
was numerically greater in diarrhea-predominant patients. Since diarrhea-predominant
patients represented 71% of the study population, efficacy, hereafter, will
be described for diarrhea-predominant patients only.
Forty-three percent of alosetron-treated diarrhea-predominant patients
and 26% of placebo-treated patients were monthly responders for all 3 months
of treatment (treatment difference of 17 percentage points; P<.001; 95% CI, 8.0-25.4). The proportion of monthly responders
at each month was also significantly greater in the alosetron group compared
with the placebo group for diarrhea-predominant patients (percentage point
differences of 11, 15, and 19 for months 1, 2, and 3, respectively; Table 2). There was no evidence of differential
treatment effects among clusters of centers.
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Table 2. Proportion of Diarrhea-Predominant Patients With Adequate
Relief During the 3 Months of Treatment
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We further assessed weekly response rates to evaluate onset and sustainability
of the response. The percentage of diarrhea-predominant patients in the alosetron
and placebo groups with adequate relief of pain and discomfort reported each
week is shown in Figure 2. Alosetron
provided significantly greater adequate relief of pain and discomfort than
placebo. Significant benefit was achieved by the fourth week of treatment
(P<.001) and was maintained throughout the remainder
of treatment. Symptoms rapidly returned following cessation of treatment.
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Figure 2. Percentage of diarrhea-predominant
patients with adequate relief of irritable bowel syndrome pain and discomfort
on a weekly basis during treatment with alosetron hydrochloride, 1 mg, or
placebo twice daily. Asterisk indicates P<.05
compared with placebo; dagger, P<.001 compared
with placebo.
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BOWEL FUNCTION
Alosetron also significantly decreased the percentage of days with urgency
and number of stools per day and caused firmer stools compared with placebo. Figure 3, Figure 4, and Figure 5 show the effects of alosetron and placebo on urgency, stool frequency, and
stool consistency for diarrhea-predominant patients, respectively. For each
symptom, significant improvement with alosetron compared with placebo occurred
during the first week of treatment and was sustained throughout the 12 weeks
of treatment. At week 12, days with urgency was decreased by 12.6 percentage
points (95% CI, 6.1-19.1), stool frequency was decreased by 0.5 stool per
day (95% CI, 0.3-0.7), and stool firmness was increased by 0.6 point (95%
CI, 0.4-0.7; see the "Patients and Methods" section for scale) relative to
placebo. Alosetron had no significant effect on the percentage of days diarrhea-predominant
patients experienced a sense of incomplete evacuation in the first month of
treatment, but did improve the percentage of days patients experienced this
symptom in months 2 (46.4% in the alosetron group vs 56.4% in the placebo
group; P = .02) and 3 (45.0% vs 57.1%; P = .009). Alosetron did not significantly improve bloating at any
time compared with placebo (data not shown).
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Figure 3. Percentage of days with urgency
in diarrhea-predominant patients with irritable bowel syndrome during treatment
with alosetron hydrochloride, 1 mg, or placebo twice daily or during posttreatment
follow-up. Asterisk indicates P<.01 compared with
placebo; dagger, P<.001 compared with placebo.
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Figure 4. Stool frequency in diarrhea-predominant
patients with irritable bowel syndrome during treatment with alosetron hydrochloride,
1 mg, or placebo daily during posttreatment follow-up. Asterisk indicates P<.001 compared with placebo.
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Figure 5. Stool consistency in diarrhea-predominant
patients with irritable bowel syndrome during treatment with alosetron hydrochloride,
1 mg, or placebo daily during posttreatment follow-up: 1, very hard; 2, hard;
3, formed; 4, loose; and 5, watery. Asterisk indicates P<.001 compared with placebo.
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SAFETY
Safety data were collected for all patients in the intention-to-treat
population who took at least 1 treatment dose. One hundred eighteen (38%)
of 309 patients in the alosetron group and 62 (20%) of 316 patients in the
placebo group had drug-related adverse events as assessed by the study physicians
(P<.001). Constipation was the most commonly reported
drug-related adverse event in the alosetron-treated group and occurred in
77 (25%) of 309 patients in the alosetron group compared with 15 (5%) of 316
patients in the placebo group. However, the percentage of alosetron-treated
patients who reported adequate relief at each week was similar whether or
not constipation was also reported. Constipation tended to occur within the
first month of therapy (median onset of 10 days following initiation of treatment
and duration of 6 days). Of patients reporting constipation, 76% reported
only a single episode (laxatives were not permitted by protocol). No other
drug-related adverse event was reported with a frequency greater than 5%,
and, with the exception of constipation, adverse event profiles between the
alosetron-treated and placebo groups were similar. Incidence of serious adverse
events were the same (2%) in the alosetron and placebo groups.
Forty-eight patients (16%) in the alosetron treatment group and 21 patients
(7%) in the placebo group withdrew from the study because of adverse events.
The adverse event associated with most of these withdrawals was constipation
in alosetron-treated patients (32 [10%] of 309 of alosetron-treated patients
withdrew because of constipation compared with 5 [2%] of 326 patients in the
placebo group). Most patients (45/77) who developed constipation remained
in the study.
Laboratory values were not significantly affected by alosetron treatment.
No drug-related serious adverse events or deaths were reported during treatment.
COMMENT
In this multicenter, randomized, double-blind, placebo-controlled study,
treatment with alosetron significantly relieved abdominal pain and discomfort,
decreased the percentage of days with urgency, decreased stool frequency,
and produced firmer stools compared with placebo in women with diarrhea-predominant
IBS. Beneficial effects of alosetron on percentage of days with incomplete
evacuation were noted during the second and third months of treatment. Alosetron
exerted no effect on bloating, and bloating may be of greater significance
to constipation-predominant patients.30 These
results confirm those of a previous study,19
which showed that alosetron improved pain, urgency, stool frequency, and stool
consistency after 1 to 2 weeks of therapy in diarrhea-predominant women with
IBS.
Most patients with IBS who present to physicians in Western countries
are women,4 and a number of chronic visceral
pain syndromes are more prevalent in women compared with men.31
The present study evaluated only women with IBS, because preferential efficacy
with alosetron has been reported in these patients.17
Although the reasons for sex-dependent responses are unknown, sex-based differences
in blood-brain perfusion patterns during colorectal distension have been noted
in IBS patients,32 and sex-based differences
in motility and sensitivity to luminal distension have been observed in healthy
volunteers.33-35
Preliminary studies also show that the effect of alosetron on colonic transit
is significantly greater in women with diarrhea-predominant IBS than in men.36
Evaluating the therapeutic potential of new drugs in IBS and other functional
gastrointestinal disorders is challenging because of the range and multiplicity
of symptoms and the variable and often high placebo response rates.20 Patients with IBS report that their lives are most
directly affected by IBS pain, discomfort, and altered bowel function,37 although IBS affects a range of patient's psychological
and social functioning.38-39 In
a recent survey of nonconstipated, female patients with IBS who participated
in the present and previous phase 3 study,19
the most bothersome symptoms reported were abdominal pain and discomfort,
urgency, and increased stool frequency.40 As
shown in the present study, alosetron treatment significantly improved all
3 of these symptoms but had no impact on bloating.
Assessing multiple symptoms and prospectively choosing a primary outcome
measure that allows clinical efficacy to be based on patients' integration
of their symptoms were recently endorsed by the Rome II working group guidelines
on functional gastrointestinal disorders.41
Use of adequate relief of abdominal pain and discomfort as the primary outcome
measure in the present study follows the Rome II guidelines, since it provides
a meaningful, patient-evaluated measurement of clinical improvement in multiple
symptoms of IBS.
Assessment of the clinical relevance of the alosetron treatment effect
is complicated by the fact that there is no "gold standard" to define "clinically
important." Alosetron was observed to produce significant improvement in adequate
relief of pain and discomfort, urgency, frequency, and stool consistency.
The magnitude of improvement on each end point was similar and showed an advantage
over placebo comparable to that observed for other drugs acting in the gastrointestinal
tract, such as histamine receptor antagonists for gastric ulcer.42
The specific mode of action by which alosetron modulates IBS symptoms
is not yet fully understood. Antagonists to the 5-HT3 receptor
have been reported to slow colonic transit, increase colonic compliance, and
increase pain thresholds during colorectal distension.11-13,15, 43-46
Using an intracolonic barostatically controlled balloon, alosetron was found
to increase colonic compliance in diarrhea-predominant patients with IBS without
changing the pressure perception threshold.12
Increases in compliance would be anticipated to allow distension of the lumen
during passage of a gas bolus without increased wall tension, thus attenuating
afferent impulse activation and reducing the perception of visceral pain.
Receptors for 5-HT3 are present in both the peripheral and
the central nervous system. Specifically, they have been reported on the spinal
and vagal innervation of the gut, the spinal cord, and multiple areas in the
brain, with highest binding in the amygdala and hippocampus. The amygdala
and hippocampus are involved in sensation and emotional or affective responses.
Blockade of 5-HT3 receptors by alosetron may, therefore, modulate
visceral sensation and autonomic responses in IBS by altering the encoding,
transmission, and processing of sensory information at different levels of
the brain-gut axis.10
As with any study, there are limitations in the present trial. Only
female patients were evaluated in the present study, based on female preferential
efficacy in an earlier report.17 Although patients
with continuous severe pain were excluded from enrollment by imposition of
an upper pain cutoff of 3.3 (between intense and severe) during the 2-week
screening period, only 20 (1.4%) of 1417 patients were excluded from the study
because of this criterion. Patients who had severe pain on several days during
the screening period were not excluded by this criterion. Many more patients
(175 [12%] of 1417) were excluded because of insufficient (ie, less than mild)
pain, and thus the randomized population generally was representative of patients
with moderate to severe IBS. As a screening requirement, achieving a minimum
stool consistency score, rather than both a consistency and frequency score,
was required. Because there are no formal objective criteria for constipation,
imposition of entry criteria for both stool frequency and consistency would
have been advantageous for excluding constipated patients during the screening
period.
Constipation was the most frequent drug-related adverse event during
alosetron treatment. Based on the increased colonic transit time observed
after treatment with 5-HT3 receptor antagonists,11, 43, 47
constipation is not an unexpected consequence of alosetron treatment, especially
since laxative use was not routinely permitted in the present study. However,
the percentage of alosetron-treated patients who reported adequate relief
at each week was similar whether or not constipation was also reported.
In summary, treatment with alosetron produced relief of abdominal pain
and discomfort, as well as improvements in some IBS-associated bowel function
disturbances, in women with diarrhea-predominant IBS.
AUTHOR INFORMATION
Accepted for publication December 5, 2000.
Glaxo Wellcome Research and Development provided support for this study.
Presented as an abstract at the 1999 American College of Gastroenterology
meeting, Phoenix, Ariz, November 16, 1999.
We thank the the investigators who participated in the study, whose
names are listed in a box on page 1738, and Patrice C. Ferriola, PhD, Glaxo
Wellcome Inc, for writing and editing assistance.
| Participating Investigators
Hector Allende, MD, Sun Research Institute, San Antonio, Tex; Matthew
Astroff, MD, Paoli Memorial Medical, Paoli, Pa; Charles F. Barish, MD, Wake
Research Associates, Raleigh, NC; Gary M. Barton, MD, Arkansas Gastroenterology,
North Little Rock; John W. Beckman, MD, Internal Medical Group, Cheyenne,
Wyo; Thomas D. Bianchi, MD, Community Medical Arts Center, Tallassee, Ala;
Philip Bird, MD, Research Association of Norman, Norman, Okla; Mark H. Bowles,
MD, Research Institute of Kansas, Wichita; Jeffrey R. Breiter, MD, Manchester
Memorial Hospital, Manchester, Conn; Robert Burakoff, MD, Winthrop University
Hospital, Mineola, NY; David R. Cave, MD, St Elizabeth's Medical Center, Brighton,
Mass; Lin Chang, MD, UCLA/WLA VAMC, Los Angeles, Calif; Fabio Cominelli, MD,
University of Virginia, Charlottesville; James N. Cooper, MD, Inova Fairfax
Hospital, Falls Church, Va; John Kelly DiBaise, MD, University of Nebraska
Medical Center, Omaha; Jack A. DiPalma, MD, University of South Alabama, Mobile;
Michael T. Draelos, MD, Corner Stone Research Care, High Point, NC; Sudhir
K. Dutta, MD, Sinai Hospital-Baltimore, Baltimore, Md; Mark S. Eisner, MD,
Florida Medical Clinic, Zephyrhills; M. Brian Fennerty, MD, Oregon Health
Science University, Portland; Robert M. Finlaw, MD, Southern Colorado Clinic,
Pueblo; Richard Fisher, MD, Gould Medical Foundation, Modesto, Calif; Ronald
Fogel, MD, Henry Ford Hospital, Detroit, Mich; Robert L. Frachtman, MD, Center
for Clinical Research, Austin, Tex; Gregory Fusilier, MD, Gastroenterology
Associates, Baton Rouge, La; Syam P. Gaddam, MD, Garden Grove, Calif; Oliver
Gilliam, MD, Health Advance Institute, South Bend, Ind; Jay Goldstein, MD,
University of Illinois at Chicago Medical Center; Alan Graff, MD, Fort Lauderdale,
Fla; Russell Graham, MD, Genesis Research Group, Altamonte Springs, Fla; Stephen
L. Green, MD, Hampton Roads Medical Specialists, Hampton, Va; Michael R. Grossman,
MD, Lynn Institute for Healthcare Research, Oklahoma City, Okla; Peter J.
Gulden, MD, Southeastern Clinical, Maitland, Fla; M. Scott Harris, MD, Digestive
Disease Specialists, Milwaukee, Wis; Keith P. Hussey, MD, Pharmacology Investigations,
Naples, Fla; John M. Inadomi, MD, VA Affairs Medical Center, Albuquerque,
NM; Adesh J. Jain, MD, Medical Research Institute, Slidell, La; Mario Kamionkowski,
MD, Gastroenterology, Lyndhurst, Ohio; Rashid A. Khairi, MD, Physicians Research
Group, Indianapolis, Ind; Donald Kirby, MD, Medical College of Virginia, Richmond;
Terry D. Klein, MD, Heartland Research Associates, Wichita, Kan; Ronica Kluge,
MD, Clinical Physiology Associates, Fort Myers, Fla; David G. Kogut, MD, Piedmont,
Statesville, NC; Ross Kommor, MD, Association of Medical Research, Marietta,
Ga; Richard A. Krause, MD, ClinSearch, Chattanooga, Tenn; Steven Krumholz,
MD, Gastroenterology Group of Palm Beach, West Palm Beach, Fla; Daniel M.
Kruss, MD, Digestive Disease Center, Oak Park, Ill; Mark Lamet, MD, Center
for Gastroenterology Disorders, Hollywood, Fla; Thomas F. Lansdale III, MD,
Greater Baltimore Medical Center, Baltimore, Md; Robert B. Lasser, MD, Minnesota
Clinical Research Center, St Paul; Michael Lawson, MD, Sacramento, Calif;
Paul J. Lebovitz, MD, Allegheny General Hospital, Pittsburgh, Pa; Robert S.
Lipetz, DO, Spring Valley, Calif; Bruce A. Luxon, MD, PhD, St Louis University,
St Louis, Mo; Richard Lynn, MD, Thomas Jefferson University, Philadelphia,
Pa; David G. Mangels, MD, TQM Research Center, Cincinnati, Ohio; Antoinette
Mangione, MD, Hill Top Research, Inc, Philadelphia, Pa; Oscar J. Martinez,
MD, Health Core Inc, Newark, Del; James M. McGill, MD, Indiana University
Medical Center, Indianapolis; S. David Miller, MD, New England Clinical Studies,
North Dartmouth, Mass; Philip B. Miner, Jr, MD, Oklahoma Foundation of Digestive
Research, Oklahoma City; William S. Mullican, MD, MediSphere Medical Research
Center, Evansville, Ind; Zev M. Munk, MD, Clinical Research Center, Houston,
Tex; William G. Murchison, MD, Colorado Springs Medical Center, Colorado Springs,
Colo; Mark E. Murphy, MD, The Savannah Center, Savannah, Ga; Joseph L. Nelson
III, MD, Valley Gastroenterology of South West Virginia, Salem; Oscar C. Oandasan,
MD, R&D Clinical Research, Lake Jackson, Tex; Frederick Opper, MD, Hanover
Medical Specialties, PA, Wilmington, NC; Daniel J. Pambianco, MD, Charlottesville
Gastroenterology Associates, Charlottesville, Va; Peter Pardoll, MD, Center
of Digestive Diseases, St Petersburg, Fla; John L. Petrini, MD, Sansum Medical
Clinic, Santa Barbara, Calif; Clinton D. Polhamus, MD, Lewis-Gale Clinic Inc,
Salem, Va; Ronald E. Pruitt, MD, Nashville Medical Research Institute, Nashville,
Tenn; Eamonn Quigley, MD, University of Nebraska Medical Center, Omaha; Adisesha
B. Reddy, MD, Tuscaloosa Endoscopy Center, Tuscaloosa, Ala; Peter M. Ripley,
MD, Clinical Studies Cape Cod, South Yarmouth, Mass; Herbert Rubin, MD, Digestive
Disease Foundation, Beverly Hills, Calif; Gary E. Ruoff, MD, Westside Family
Medical Center, Kalamazoo, Mich; Shahriar S. Safavi, MD, Irving, Tex; Michael
A. Safdi, MD, Consultants for Clinical Research Inc, Cincinnati, Ohio; David
G. Scholz, MD, Presbyterian Hospital, Charlotte, NC; Ronald P. Schwarz, MD,
Multi-Specialty Research Associates of North Carolina, Raleigh, NC; Bavikatte
N. Shivakumar, MD, Gastrointestinal Clinic, Davenport, Iowa; Howard Siegel,
MD, Eastside Comprehensive Medical Services, New York, NY; Thomas J. Sobieski,
MD, McGuire Medical Group, Richmond, Va; Eugene J. Spiotta, Jr, MD, Memphis,
Tenn; David Stanton, MD, Clinical Interventions Research Institute, Mission
Viejo, Calif; Lewis R. Strong, MD, Aspen Medical Center PC, Loveland, Colo;
Robert E. Tepper, MD, Great Neck, NY; Keith Tolman, MD, University of Utah
School of Medicine, Salt Lake City; Arnold Wald, MD, University of Pittsburgh
Gastroenterology & Hepatology, Pittsburgh, Pa; Richard H. White, MD, UCDMC,
Sacramento, Calif; Mel Wilcox, MD, University of Alabama at Birmingham; Salam
F. Zakko, MD, University of Connecticut Health Center, Farmington; Marc J.
Zuckerman, MD, Texas Tech University, El Paso.
|
|
Corresponding author and reprints: Allen M. Mangel, MD, PhD, Glaxo
Wellcome Inc, 5 Moore Dr, Research Triangle Park, NC 27709.
From the Gastroenterology Research Unit, Mayo Clinic, Rochester, Minn
(Dr Camilleri); Rochester Institute for Digestive Diseases and Science Inc,
Rochester, NY (Dr Chey); Division of Gastroenterology, University of California
at Los Angeles Medical Center (Dr Mayer); and Departments of Gastroenterology
Clinical Development (Ms Northcutt and Drs Dukes and Mangel) and Clinical
Statistics (Ms Heath and Mr McSorley), Glaxo Wellcome Inc, Research Triangle
Park, NC. Dr Camilleri has performed research that has been supported in part
by Glaxo Wellcome Inc, has served as a consultant to Glaxo Wellcome Inc, received
honoraria, and testified before the Food and Drug Advisory Committee on the
mechanism of action of alosteron. Drs Chey and Mayer have served as consultants
to Glaxo Wellcome Inc and have performed research that has been supported
in part by Glaxo Wellcome Inc. Drs Dukes and Mangel, Mss Northcutt and Heath,
and Mr McSorley are employees of Glaxo Wellcome Inc.
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