Use of tegaserod along with polyethylene glycol electrolyte solution for colonoscopy bowel preparation: a prospective, randomized, double-blind, placebo-controlled study.

Abstract

Polyethylene glycol electrolyte solution (PEG-EL) used for colonoscopy preparation is not well tolerated by several patients. A significant number of patients have inadequate bowel preparation despite taking PEG-EL.
To determine the effect of prokinetic agent, tegaserod when given in addition to PEG-EL on patient tolerance, quality of colonic preparation and adverse side effects experienced.
In this prospective, randomized, placebo-controlled, double-blind study, a total of 130 patients scheduled for colonoscopy were enrolled. They were instructed to take three pills of either tegaserod 6 mg each or placebo (one pill twice on the day prior to and third pill in the morning on the day of colonoscopy) in addition to standard 4L of PEG-EL in the evening prior to the day of colonoscopy. Patient tolerance of preparation, quality of bowel preparation, overall satisfaction and adverse side effects were compared between the two groups.
Fifty-five patients in placebo group and 58 patients in tegaserod group completed the study. There was no difference between the two groups in the tolerance of preparation, quality of bowel preparation, overall satisfaction and the side effects.
Addition of tegaserod to polyethylene glycol electrolyte solution during colonoscopy preparation does not improve patient tolerance, quality of colonic preparation or the adverse side effects.

Full text

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Use of tegaserod along with polyethylene glycol electrolyte
solution for colonoscopy bowel preparation: a prospective,
randomized, double-blind, placebo-controlled study
M. R. SANAKA, D. M. SUPER, K. D. MULLEN, D. R. FERGUSON & A. J. McCULLOUGH
Division of Gastroenterology, Metro-
Health Medical Center/CaseWestern
Reserve University, Cleveland, OH,
USA
Correspondence to:
Dr M. R. Sanaka, Division of
Gastroenterology, MetroHealth
Medical Center/CaseWestern Reserve
University, 2500 MetroHealth Drive,
Cleveland, OH 44109, USA.
E-mail: msanaka@gmail.com
Publication data
Submitted 17 November 2005
First decision 23 November 2005
Resubmitted 5 December 2005
Accepted 5 December 2005
SUMMARY
Background
Polyethylene glycol electrolyte solution (PEG-EL) used for colonoscopy
preparation is not well tolerated by several patients. A significant num-
ber of patients have inadequate bowel preparation despite taking
PEG-EL.
Aims
To determine the effect of prokinetic agent, tegaserod when given in
addition to PEG-EL on patient tolerance, quality of colonic preparation
and adverse side effects experienced.
Methods
In this prospective, randomized, placebo-controlled, double-blind study,
a total of 130 patients scheduled for colonoscopy were enrolled. They
were instructed to take three pills of either tegaserod 6 mg each or pla-
cebo (one pill twice on the day prior to and third pill in the morning on
the day of colonoscopy) in addition to standard 4L of PEG-EL in the even-
ing prior to the day of colonoscopy. Patient tolerance of preparation,
quality of bowel preparation, overall satisfaction and adverse side effects
were compared between the two groups.
Results
Fifty-five patients in placebo group and 58 patients in tegaserod group
completed the study. There was no difference between the two groups
in the tolerance of preparation, quality of bowel preparation, overall
satisfaction and the side effects.
Conclusion
Addition of tegaserod to polyethylene glycol electrolyte solution during
colonoscopy preparation does not improve patient tolerance, quality of
colonic preparation or the adverse side effects.
Aliment Pharmacol Ther 23, 669–674
Alimentary Pharmacology & Therapeutics
ª 2006 The Authors
Journal compilation ª 2006 Blackwell Publishing Ltd
doi:10.1111/j.1365-2036.2006.02790.x
669

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INTRODUCTION
The polyethylene glycol-electrolyte lavage (PEG-EL)
solution has been the standard for colonoscopy bowel
preparation since 1980.1Although this preparation is
effective, the need to drink large volumes and the poor
taste of PEG-EL are limiting factors that affect patient
compliance.2–13Hence alternative low volume bowel
preparations like sodium phosphate solution (NAP)
have been developed. NAP has been shown to be bet-
ter tolerated than PEG-EL.2–15However, comparative
studies of NAP and PEG-EL have yielded conflicting
results regarding the quality of bowel preparation2–14
with some studies showing unsatisfactory preparation
with NAP.6–14
The prokinetic agent, cisapride has been co-adminis-
tered with PEG-EL to improve the tolerance and qual-
ity of preparation. But the combination of cisapride
with PEG-EL has shown conflicting results on efficacy
and tolerance.16–20The use of cisapride is currently
restricted worldwide because of the concern of induc-
tion of possible cardiac dysrhythmias. Tegaserod is a
partial 5-hydroxy tryptamine-4 (5HT4) agonist and sti-
mulates the peristaltic reflex and intestinal secretion,
as well as inhibiting visceral sensitivity. Both pre-cli-
nical and clinical investigations have shown that
tegaserod can stimulate motility throughout the gas-
trointestinal tract.21–23Long-term safety of tegaserod
has been established and it is devoid of cardiac dys-
rhythmias.24–26
We hypothesized that the combined actions of
tegaserod on the gastrointestinal tract would make it a
favourable adjunct to PEG-EL for colonoscopy bowel
preparation. The aims of our study are to evaluate the
efficacy of tegaserod when given in conjunction with
PEG-EL in improving patient tolerance of the prepar-
ation and quality of bowel preparation.
METHODS
This was a prospective, randomized, double-blind, pla-
cebo-controlled trial. The study was conducted at Met-
roHealth Medical Center (MHMC), a tertiary care,
academic medical center, Cleveland, OH, USA. MHMC
has a gastroenterology fellowship-training program
with seven fellows in training and 10 attending physi-
cians. The protocol was approved by the Institutional
Review Board at MHMC.
Inclusion criteria were that the patient must be an
out-patient scheduled for routine colonoscopy, over
18 years of age and willing to sign the informed con-
sent. Exclusion criteria included mainly contraindica-
tions to take tegaserod, i.e. severe renal impairment
(serum creatinine over 2 mg/dL), moderate to severe
hepatic impairment (cirrhosis of liver with Child–Pugh
scores of B and C), history of bowel obstruction in the
past, symptomatic gall bladder disease, suspected
sphincter of Oddi dysfunction or abdominal adhesions
and known hypersensitivity to the drug. Patients who
were taking prokinetic agents and stimulant laxatives
were also excluded.
Precolonoscopy preparation
Each patient received oral and written instructions
from a trained Registered Nurse (RN) in the clinic
regarding the diet, taking the study medication and
drinking of PEG-EL. Opaque numbered envelopes con-
taining three pills of identical appearance, each of
either placebo or tegaserod 6 mg, were distributed to
the patients while instructing them. Both the RN and
the patients were blinded to the kind of study medica-
tion contained in the envelope. A questionnaire for
assessing the baseline gastrointestinal symptoms of
patients was completed by all patients at the time of
enrollment. They were asked if they had constipation,
diarrhoea, abdominal pain, nausea or vomiting.
No solid foods were allowed during the day of prepar-
ation i.e. the day prior to scheduled colonoscopy. Clear
liquids were allowed ad libitum throughout the day until
midnight. On the day of preparation, patients were
instructed to take one pill in the morning and the sec-
ond pill at 3.30 PM. They were instructed to begin con-
suming the PEG-EL at 4.00 PM and complete ingestion
of 4 L before 8 PM. Patients were allowed to take any
flavoured PEG-EL of their choice and the type of flavour
was not recorded. Patients were instructed to take the
third pill in the morning on the day of colonoscopy.
Patient tolerance and symptoms during
preparation
A questionnaire for assessing the patient symptoms
experienced during the preparation was completed by
all patients on their arrival to endoscopy unit before the
colonoscopy. Using a 4-point scale (1 ¼ absent, 2 ¼
670 M. R. SANAKA et al.
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mild, 3 ¼ moderate and 4 ¼ severe), patients were
asked to grade the severity of five symptoms during pre-
paration (nausea and vomiting, abdominal pain or
cramps, bloating and anal irritation). Patients were
asked to evaluate the overall tolerance of bowel prepar-
ation on a 5-point scale (1 ¼ not at all distressing,
2 ¼ mildly
4 ¼ severely distressing and 5 ¼ unable to finish). A
score of 3 and less was considered as acceptable toler-
ance and a score 4 or 5 were considered as unacceptable
tolerance. Finally, patients were asked to state their will-
ingness to repeat the assigned preparation and whether
they would prefer another preparation.
distressing,3 ¼ moderately distressing,
Colonoscopy and quality of bowel preparation
All colonoscopies were performed by either a senior fel-
low (individual experience of performing at least 300
colonoscopies) under the direct supervision of an
attending physician or by the attenders themselves. All
the endoscopists were blinded to the kind of study medi-
cation received by the patient. The endoscopist scored
the quality of preparation on both the right and left
colon (right-proximal to splenic flexure; left-distal to
splenic flexure) with a 5-point scale as follows: 1 ¼ no
retained fluid or stool; 2 ¼ clear liquid; 3 ¼ liquid
stool; 4 ¼ semi-solid stool; and 5 ¼ solid stool. Scores
of 1and 2 were considered excellent preparation, score 3
indicated satisfactory preparation, and scores 4 and 5 as
an unsatisfactory preparation. The quality of prepar-
ation is defined as adequate if the score is 3 or less, and
inadequate if the score was 4 and above. All colonos-
copies are performed under conscious sedation by giv-
ing a combination of narcotic, meperidine along with a
benzodiazepine, midazolam.
Statistical analysis
Intent to treat per protocol analyses was performed. The
differences between the two groups were analysed by
t-test family for parametric interval data (i.e. patient
age, amount of medication used for sedation); Mann–
Whitney U-test for ordinal or non-parametric interval
data (i.e. patient symptom scores) and Chi-Square test
for categorical variables (i.e. successful cleanout). A P-
value of <0.05 (two tail) was considered as statistically
significant. Assuming that 65% in placebo group and
90% in tegaserod group will have acceptable tolerance
to bowel preparation, a sample size of 56 per group will
be required for detecting the difference with a power of
90% and a Type I error of 0.05. This improved difference
in patient acceptance (25%) was regarded as clinically
relevant as was proposed in the previous studies.20
RESULTS
Seventeen of 130 patients randomized were excluded
from the final analysis (12 patients failed to keep their
appointment for colonoscopy and five patients opted
out of the study). Hence a total of 113 patients (55 in
placebo group and 58 in tegaserod group) were ana-
lysed. Both groups were comparable with regards to
patient demographics and baseline gastrointestinal
symptoms (Table1). No
occurred in either of the groups. There were two
patients in the Placebo group and one in the tegaserod
group that took only two of the three pills given.
seriousadverse events
Side effects and patient tolerance
There was no difference in adverse side effects experi-
enced by patients during bowel preparation between
the two groups (Table 2). Tolerance of preparation was
similar in both groups. Also abdominal pain and
bloating associated with colonoscopy procedure were
similar in the two groups.
Efficacy of colon cleansing and colonoscopic
Characteristics
There was no difference found between the Placebo
and tegaserod groups, findings are summarized in
Table 3. Amount of sedation required for colonoscopy
was also similar in both the groups.
Overall satisfaction and willingness to repeat
the preparation
There was no difference in overall satisfaction with
preparation between the placebo and tegaserod groups
[mean score of 7.24 (S.E.M., 2.88) vs. 7.24 (S.E.M.,
2.82), P-value 0.98]. Also the willingness to repeat the
assigned preparation in future was similar between
the placebo and tegaserod groups, 76.4% vs. 77.6%
(P-value 0.88).
DISCUSSION
The key finding of this prospective randomized-con-
trolled study was that the addition of tegaserod to
TEGASEROD FOR COLONOSCOPY PREPARATION
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standard PEG-EL for colonoscopy bowel preparation
does not help in improving patient tolerance of taking
preparation or the quality of bowel preparation.
This is the first study, to our knowledge, that has
evaluated the effect of tegaserod when used in con-
junction with standard PEG-EL for precolonoscopy
bowel preparation. The combined effects of tegaserod
on the gastrointestinal tract, i.e. increasing motility
throughout the gut and decreasing visceral sensitivity
and flatulence, prompted us to conduct this study.
After extreme restrictions on the use of cisapride
worldwide because of the risk of cardiac dysrhythmias,
tegaserod is the only available drug that promotes
pangastrointestinal motility. Adult dosage for tegas-
erod is 6 mg twice a day for constipation and consti-
pation predominant irritable bowel syndrome,22,
hence we chose to give 6 mg twice a day dosage on
the colonoscopy preparation day. A third dose in the
morning of the day of procedure is given to help
decrease the abdominal discomfort and flatulence
during and in the post-procedure period. The peak
plasma concentration of tegaserod is reached approxi-
mately 1 h after oral dosing and has an estimated
half-life of 11 ? 5 h.
27
Table 1. Demographics of patients
Placebo group (n ¼ 55)Tegaserod group (n ¼ 58)P-value
Mean age in years (s.d.)
Gender
Female
Race
White
Baseline symptoms
Abdominal pain
Constipation
Diarrhoea
Nausea
Vomiting
Patients who had colonoscopy in past
Patients who had abdominal/pelvic surgery in past
Patients with diabetes mellitus
51.9 (11.0) 52.5 (13.9)0.82
34 (61.8%)37 (63.8%)0.83
31 (56.4%) 35 (60.3%)0.55
17 (30.9%)
13 (23.6%)
13 (23.6%)
11 (20%)
4 (7.3%)
17 (30.9%)
19 (34.5%)
9 (16.4%)
24 (41.4%)
15 (25.9%)
21 (36.2%)
10 (17.2%)
1 (1.7%)
20 (34.5%)
26 (44.8%)
10 (17.3%)
0.29
0.78
0.15
0.71
0.15
0.69
0.26
0.90
Table 2. Side effects reported by patients during colonoscopy preparation, colonoscopy procedure and post-procedure
(Scale 1–5; lower scores indicate lesser symptoms)
Placebo group (n ¼ 55) Tegaserod group (n ¼ 58) P-value
Nausea/vomiting
Abdominal discomfort/cramps
Bloating
Anal irritation
Tolerance of preparation
Mean score
No. of patients with acceptable tolerance* (score of 3 and less)
Abdominal discomfort during colonoscopy
Symptoms 1 h after colonoscopy
Abdominal discomfort
Bloating
Symptoms one day after colonoscopy
Abdominal discomfort
Bloating
1.40 (0.87)
1.40 (0.74)
1.60 (0.74)
1.38 (0.68)
1.48 (0.90)
1.45 (0.65)
1.74 (0.83)
1.41 (0.70)
0.54
0.41
0.39
0.69
2.04 (1.20)
47 (85.5%)
1.76 (0.84)
2.14 (0.96)
53 (91.4%)
1.81 (0.85)
0.27
0.32
0.79
1.44 (0.74)
1.62 (0.87)
1.40 (0.70)
1.53 (0.63)
0.86
0.96
1.24 (0.43)
1.18 (0.43)
1.23 (0.42)
1.25 (0.54)
0.92
0.64
* Data expressed as mean (s.d.) and percentages.
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In our study, there was no difference in any of the
parameters compared between the tegaserod and pla-
cebo groups. Based on the acceptable tolerance rates
in previous studies,14, 18we assumed that 65% of the
patients in placebo group would have acceptable toler-
ance of bowel preparation. The acceptable tolerance of
standard PEG-EL without the addition of tegaserod
was high (85%) in our study. This may have been rela-
ted to unrestricted use of flavoured PEG-EL, which are
known to be better tolerated than plain PEG-EL.28
Even though the acceptable tolerance in tegaserod
group was 91.4%, the difference between the groups
was not statistically significant. Negative result of this
study may be due to inadequate power, as our study
was designed to be able to detect a major effect (25%)
of tegaserod in improving patient tolerance of prepar-
ation. Because of the high tolerance rate of PEG-EL
alone, further improvement with the addition of tegas-
erod might be difficult to demonstrate.
Tegaserod has been shown to improve motility
throughout the gastrointestinal tract.21–23This prop-
erty might make it a favourable adjunct to standard
PEG-EL especially in certain patient groups such as
those with gastroparesis, constipation and slow transit.
Drinking a large volume i.e. 4L of standard PEG-EL
might be a difficult task because of adverse side
effects in these patients. Hence, baseline tolerance of
standard PEG-EL is expected to be low in these patient
groups and addition of tegaserod may show a signifi-
cant improvement in patient tolerance, adverse side
effects and the quality of bowel preparation.
There are some limitations in our study. The symp-
toms reported by patients in our study were subjective
and there was no objective scoring used to confirm
these. Multiple endoscopists performed the colonos-
copies and rated the quality of preparation, hence
there may be no concordance between the different
endoscopists. The strengths of our study include the
study design: a prospective, randomized, placebo-con-
trolled, double-blinded study and the intent to treat
analysis used for analyzing the data.
In conclusion, tegaserod when given in conjunction
with PEG-EL does not improve the patient tolerance or
the quality of bowel preparation. Further studies are
required to evaluate the efficacy of tegaserod in con-
junction with PEG-EL in subgroups of patients with
gastroparesis, constipation and slow transit.
ACKNOWLEDGEMENTS
This study was presented as an abstract in American
College of Gastroenterology 70th Annual Scientific
Meeting, 28 October to 2 November 2005, Honolulu,
HI, USA.
This study was supported in part through the Gen-
eral Clinical Reseach Center at Case Western Reserve
University,Cleveland, OH,
RR00080).
USA(NIH no. MO1
Table 3. Quality of bowel preparation and colonoscopic characterisitics
Placebo group (n ¼ 55)
Tegaserod group
(n ¼ 58)P-value
Quality of bowel preparation (Scale 1–5, lower scores indicate better preparation)
Left side of colon
Right side of colon
No. of patients with adequate preparation on left side
No. of patients with adequate preparation on right side
No. of patients with excellent preparation on left side
No. of patients with excellent preparation on right side
Insertion time to cecum in minutes
Colonoscopy completion rate
Technical difficulty (Scale 1–10, lower scores indicate less difficulty)
Amount of sedation required
Meperidine (mg)
Midazolam
Diverticulosis seen*
2.28 (1.10)
2.65 (0.96)
49/54 (90.7%)
47/54 (87%)
27/54 (50%)
18/54 (33.3%)
12.9 (7.23)
54/55 (98.2%)
4.67 (2.16)
2.19 (1.03)
2.45 (1.13)
51/57 (89.5%)
46/56 (82.1%)
33/57 (57.9%)
26/56 (46.4%)
11.8 (8.01)
56/58 (95.6%)
4.58 (2.29)
0.64
0.34
0.82
0.48
0.40
0.16
0.47
0.50
0.81
77.4 (38.4)
4.76 (1.4)
15 (27.3%)
73.6 (40.9)
4.9 (1.7)
19 (32.3%)
0.33
0.52
0.53
* Data expressed as mean (s.d.) and percentages.
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