Zelmac (tegaserod) Advisory Committee

Briefing Document

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| #####          | May 24, 2000                                        |
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> Table of contents

1 Introduction/Background [4](#introductionbackground)

2 Pharmacological Class [6](#pharmacological-class)

3 Preclinical Study Program [7](#preclinical-study-program)

3.1.1 Pharmacodynamics [7](#pharmacodynamics)

3.1.2 Pharmacokinetics [8](#pharmacokinetics)

3.1.3 Safety/toxicology [8](#safetytoxicology)

4 Rationale for the Use of Tegaserod in the Treatment of C-IBS
[10](#rationale-for-the-use-of-tegaserod-in-the-treatment-of-c-ibs)

5 Clinical Pharmacology [11](#clinical-pharmacology)

6 Clinical Program Development [14](#clinical-program-development)

6.1 IBS Trial Methodology [14](#ibs-trial-methodology)

6.2 Tegaserod Phase 2 Program [14](#tegaserod-phase-2-program)

6.3 Tegaserod clinical program, regulatory guidelines and agreements
[16](#tegaserod-clinical-program-regulatory-guidelines-and-agreements)

6.3.1 Modification of analysis plan [17](#modification-of-analysis-plan)

6.4 Tegaserod Phase 3 program study design
[17](#tegaserod-phase-3-program-study-design)

6.5 Phase 3 outcome measures and statistical methodology
[18](#phase-3-outcome-measures-and-statistical-methodology)

6.5.1 Outcome measures evaluation in adequate and well-controlled
studies
[18](#outcome-measures-evaluation-in-adequate-and-well-controlled-studies)

6.5.2 Primary efficacy variable(s) [19](#primary-efficacy-variables)

6.5.3 Secondary efficacy variables [22](#secondary-efficacy-variables)

6.5.4 Statistical methodology in adequate and well-controlled trials
[22](#statistical-methodology-in-adequate-and-well-controlled-trials)

7 Phase 3 efficacy analysis [25](#phase-3-efficacy-analysis)

7.1 Phase 3 individual study results
[25](#phase-3-individual-study-results)

7.1.1 Study B351 Results [27](#study-b351-results)

7.1.2 Study B301 Results [37](#study-b301-results)

7.1.3 Study B307 Results [47](#study-b307-results)

7.2 Sensitivity Analyses [56](#sensitivity-analyses)

7.3 Phase 3 studies comparative efficacy
[59](#phase-3-studies-comparative-efficacy)

7.3.1 Primary efficacy variable-SGA of relief
[59](#primary-efficacy-variable-sga-of-relief)

7.3.2 Secondary efficacy variables [61](#secondary-efficacy-variables-1)

7.3.3 Efficacy variables summary [65](#efficacy-variables-summary)

7.4 Post-hoc analyses [66](#post-hoc-analyses)

7.4.1 Pooled analyses [66](#pooled-analyses)

7.4.2 Supportive Analyses [67](#supportive-analyses)

7.5 Responses in population subgroups
[69](#responses-in-population-subgroups)

7.6 Efficacy Discussion/Conclusions
[71](#efficacy-discussionconclusions)

8 Safety Analysis [73](#safety-analysis)

8.1 Demographics, disposition and exposure
[73](#demographics-disposition-and-exposure)

8.1.1 Safety population demographics
[73](#safety-population-demographics)

8.1.2 Extent of exposure [74](#extent-of-exposure)

8.1.3 Disposition of patients [75](#disposition-of-patients)

8.2 Adverse events [76](#adverse-events)

8.2.1 Methodology [76](#methodology)

8.2.2 Most commonly reported AEs [76](#most-commonly-reported-aes)

8.3 Discontinuations due to AEs [77](#discontinuations-due-to-aes)

8.4 Deaths/Serious adverse events [78](#deathsserious-adverse-events)

8.4.1 Deaths [78](#deaths)

8.4.2 Serious adverse events [79](#serious-adverse-events)

8.4.3 Pregnancies [81](#pregnancies)

8.5 Clinical laboratory data [81](#clinical-laboratory-data)

8.6 Other Safety Assessments [82](#other-safety-assessments)

8.6.1 Blood Pressure [82](#blood-pressure)

8.7 Long-term safety (study B209) [83](#long-term-safety-study-b209)

8.8 Notable safety issues [85](#notable-safety-issues)

8.8.1 Electrocardiography [85](#electrocardiography)

8.8.2 Ovarian cysts [87](#ovarian-cysts)

8.9 Safety summary and conclusions [88](#safety-summary-and-conclusions)

9 Benefits/Risk Assessment [90](#benefitsrisk-assessment)

10
References.................................................................................................91

> Appendix 1: Rome Diagnostic Criteria for IBS

# Introduction/Background

Novartis Pharmaceuticals Corporation (the sponsor) submitted a New Drug
Application (NDA) on February 11, 2000, for Zelmac(tegaserod) tablets
for the symptomatic treatment of irritable bowel syndrome (IBS) in
patients who identify abdominal pain and discomfort and constipation as
their predominant symptoms.

The purpose of this briefing document is to provide an overview of the
tegaserod clinical program as contained in the dossier submitted to the
Food and Drug Administration (FDA). The tegaserod clinical program for
the treatment of constipation-predominant irritable bowel syndrome
(C-IBS) included 48 studies, five of which were controlled clinical
studies. At the core of the clinical program are three adequate and
well-controlled studies, B351, B301 and B307, evaluating the safety and
efficacy of tegaserod compared to placebo. The totality of the efficacy
data across all studies provides strong evidence that tegaserod at a
dose of 12 mg/ day produces clinically meaningful and statistically
significant results on abdominal pain and discomfort, and altered bowel
function in patients with C-IBS. Overall, tegaserod has an excellent
benefit to risk ratio profile for treatment of this IBS population.

#### Irritable bowel syndrome {#irritable-bowel-syndrome .unnumbered}

Irritable bowel syndrome (IBS) is a common functional gastrointestinal
(GI) disorder characterized by chronic or recurrent abdominal pain or
discomfort and disturbed defecation. The disorder has a broad range of
severity, ranging from mild symptoms to severe and intractable symptoms.
Although the pathophysiology of IBS is not fully understood, symptoms
appear to be due to disturbances in GI motility and enhanced visceral
sensitivity.[^1] Psychosocial factors may also contribute to overall
symptom expression.

IBS is highly prevalent in the general population and is associated with
significant disability and health care costs. Prevalence estimates from
surveys in the United States and Great Britain indicate that IBS affects
14-24% of women and 5-19% of men.[^2] The Rome diagnostic criteria for
IBS requires the presence for at least 3 months of continuous or
recurrent symptoms of abdominal pain or discomfort relieved with
defecation, or associated with a change in frequency or consistency of
stool. Subgroups of IBS exist with clearly varying responses to
particular forms of therapy. The most common subdivision is based on
altered bowel habit, with classification into constipation-predominant
IBS (C-IBS), diarrhea-predominant IBS (D-IBS) and alternating IBS.
Physiological differences between patients with C-IBS and D-IBS have
been demonstrated.[^3]

Currently, there is no drug that is effective for treatment of all forms
and all symptoms of IBS. Treatment is based on the physician's
understanding of the individual patient's symptom pattern and associated
psychosocial factors.[^4] Current recommendations include:
anticholinergics for acute episodes of pain; supplemental dietary fiber
for constipation; opiates for diarrhea; and, in patients with sustained
pain or bloating, low doses of antidepressants such as tricyclic agents
and selective serotonin reuptake inhibitors (SSRIs). ^2^ Recently, a
5-HT~3~ receptor antagonist has been approved for treatment of female
patients with D-IBS.

Treatment of patients with C-IBS is usually based on increased dietary
fiber and bulking agents, exercise, habit training, and psychological
intervention. However, often only partial relief is obtained, and the
majority of patients use non-bulking laxatives on a regular basis
without medical supervision. Side effects of frequent use of laxatives
include dependency and progressive tolerance, electrolyte imbalance, and
for the anthraquinones, melanosis coli. Chronic use of non-bulking
laxatives is very unsatisfactory therapy, and additional therapeutic
measures are needed.

There is growing interest in and knowledge of the enteric nervous system
as playing a pivotal role in the altered motility and visceral
hypersensitivity of IBS. Rational pharmacotherapy for IBS may,
therefore, be directed towards restoring normal motor activity and
signal processing within the enteric nervous system.

Several neurotransmitters, including substance P, calcitonin
gene-related peptide (CGRP) and serotonin (5-hydroxytryptamine, 5-HT)
have been reported to be involved in the regulation of gut motility and
visceral pain. The presence of 5-HT receptors throughout the human GI
tract and the high amounts of serotonin in enterochromaffin cells, and
also its presence in enteric nerves, suggest that 5-HT plays an
important role in several physiological functions.[^5] Recent
investigations demonstrate the involvement of serotonin type-4
(5‑HT~4~)-receptors in gut motility, intestinal secretion, as well as
visceral sensitivity.[^6]^,^[^7]

# Pharmacological Class

Tegaserod is a potent partial agonist of serotonin type-4
(5‑HT~4~) receptors located in the GI tract.

Chemically designated as
3-(5-methoxy-1H-indol-3-ylmethylene)-N-pentyl-carbazimidamide, tegaserod
is an aminoguanidine-indole derivative structurally similar to
serotonin, as depicted below:

![](media/image1.wmf)• C~4~H~4~O~4~

Tegaserod Serotonin (5-hydroxytryptamine)

It is structurally different from substituted benzamides, such as
cisapride or metoclopramide. [^8]^,^[^9]

It also lacks relevant 5‑HT~3~ receptor and dopamine D~2~ receptor
blocking properties[^10], as well as QT prolongation properties[^11]
typical of many substituted benzamide derivatives. Tegaserod binds with
high affinity at human 5-HT~4~ receptors.[^12]

# Preclinical Study Program

An extensive preclinical program consisting of pharmacodynamic,
pharmacokinetic and safety/toxicological studies was completed for
tegaserod.

### Pharmacodynamics

The pharmacodynamic investigations in the GI tract demonstrated that
tegaserod is a potent 5-HT~4~ receptor partial agonist that exerts the
following activities:

-   modulation of both normal and altered motility throughout the GI
    tract

-   modulation of intestinal secretion

-   inhibition of visceral afferent responses upon colorectal
    distention.

#### Motility {#motility .unnumbered}

Propulsion studies using isolated segments from Guinea pig colon
demonstrated the promotile activity of tegaserod.[^13] The compound
potently and efficiently increased the propulsion velocity of artificial
fecal pellets.

*In vivo* studies revealed tegaserod to exert promotile activity
throughout the GI tract. It stimulated the gastric emptying rate in rats
and dogs under normal and impaired conditions Error: Reference source
not found^,^ [^14]^,^ [^15]. Mechanistic investigations confirmed the
crucial involvement of 5‑HT~4~ receptors, consistent with its mode of
action. Tegaserod stimulated small and large intestinal postprandial
motility in a dose-dependent manner in dogs. Radioscintigraphy studies
demonstrated a signifi­cant acceleration of colonic transit. Effects on
impaired colonic motor activity and transit were examined in mice
treated with the ~2~ receptor agonist, lidamidine. Treatment with
tegaserod offset the inhibitory effects of lidamidine.

#### Intestinal secretion {#intestinal-secretion .unnumbered}

Tegaserod increased cyclic AMP (cAMP) and stimulated chloride and water
secretion in crypt cells from rat distal colon at low nanomolar
concentrations by activation of 5‑HT~4~ receptors.[^16] These findings
suggest a modulatory effect on intestinal secretion *in vivo*.

#### Visceral sensitivity {#visceral-sensitivity .unnumbered}

A study using decerebrate cats was performed to assess whether or not
tegaserod, besides modulating intrinsic primary afferent neurons, had
any effects on extrinsic afferents. The compound dose-dependently
inhibited the firing rate of rectal afferents following rectal
distensionError: Reference source not found. The effects were reversed
by administration of a selective 5‑HT~4~ receptor antagonist,
SB 203186*.* Tegaserod did not modify the pressure-volume relationship
during rectal distension (barostat system). These data suggest a role of
5‑HT~4~ receptors in modulating visceral sensitivity without affecting
compliance of the rectal wall. Data obtained in conscious rats
(colorectal distension using a barostat system) confirmed the findings
in decerebrate cats suggesting that tegaserod can exert antinociceptive
activity during colorectal distension .[^17]

### Pharmacokinetics

The pharmacokinetics and metabolism of tegaserod were investigated in
animal (rat, mouse, rabbit and dog) models and in vitro using human
liver and intestinal slices as well as rat and human liver microsomes.
In the rat, no major accumulation of tegaserod or its metabolites in
organs was observed, with the possible exception of melanin-containing
ocular membranes. This, however, does not seem to be of toxicological
relevance as there were no toxicological findings in the pigmented dog
eye. Furthermore, many drugs bind to eye melanin without being
predictive of ocular toxicity. Brain penetration of both tegaserod and
its metabolites was negligible in the rat. Oral treatment of pregnant
rats and rabbits with tegaserod resulted in a low but measurable
exposure of the embryos/fetuses to the parent drug (and metabolites, at
least in rat). *In vitro* studies with human liver microsomes indicated
a low potential of tegaserod to inhibit CYP2C8, CYP2C9, CYP2C19, CYP2E1
and CYP3A4. More potent effects were found for CYP1A2 and CYP2D6. These
isoenzymes were further investigated in clinical studies, which however
did not reveal clinically relevant drug-drug interactions (see page 12).
The major circulating human metabolite, 5-methoxy-indole-3-carboxylic
acid glucuronide, did not show any potential for inhibition of
cytochrome P450 isoenzymes *in vitro.*

### Safety/toxicology

The toxicological test species (mouse, rat, rabbit and dog) were
systemically exposed to tegaserod to a much higher extent at their
respective no observed adverse-effect level (NOAELs) than humans at the
recommended therapeutic dose. The major human metabolites were observed
in at least one of the test species. These data support the
extrapolation of the animal toxicity data to humans.

In repeated dose toxicity studies, exaggerated pharmacological effects
of tegaserod on the GI tract were observed in mice, rats and dogs
without relevant target organ toxicity. The main metabolite has
negligible affinity for 5-HT~4~ receptors and is devoid of promotile
activity in the dog. There was no evidence for effects on the immune
system and therefore no specific immunotoxicity studies were performed.
General toxicity, reproductive and carcinogenicity studies did not
identify changes related to hormonal modifications.

There were no relevant effects on reproductive function, or embryofetal
and neonatal development. However, tegaserod was detected in low amounts
in fetuses and to a significant extent in milk. Therefore, caution
should be taken when administered to a nursing woman.

Thorough *in vitro* and *in vivo* testing showed that tegaserod had no
mutagenic and clastogenic potential, and did not induce DNA damage.

Doses used in the rat and mouse carcinogenicity studies satisfied (and
exceeded) both maximum tolerated dose and exposure criteria as described
in the ICH guidelines. The rat carcinogenicity study did not identify
any carcinogenic potential. In mice, mucosal hyperplasia and
adenocarcinoma were observed in the small intestine in respectively 12%
and 7% of animals at the very high dose of 600 mg/kg p.o., which
represents about 1800 times the human therapeutic dose (\~ 70 times
AUC). These effects were not observed at lower doses (60 and 200 mg/kg).
The intestinal neoplastic changes are considered to be a result of an
epigenetic effect. Tegaserod was shown to stimulate mucosal cell
proliferation, possibly via an increase in polyamine levels triggered by
an inhibition of diamine oxydase activity by pentylaminoguanidine (PAG),
a degradation product of tegaserod formed in the stomach. The
adenocarcinomas appear thus as the consequence of an exaggerated and
sustained effect on polyamine metabolism, with a clear threshold
relationship. From the large margin of safety and from the postulated
epigenetic pathogenesis, it can be concluded that adenocarcinomas
observed in mice do not represent a relevant risk to human health.

Safety pharmacology studies indicated that tegaserod lacks relevant
cardiovascular, renal, respiratory, central nervous system (CNS) and
endocrine effects.

Together with the good clinical tolerance and efficacy, the data support
the administration of tegaserod in patients with IBS, at the intended
therapeutic dosage.

# Rationale for the Use of Tegaserod in the Treatment of C-IBS

Due to limitations of currently available therapies, a significant
clinical need remains for a safe, well-tolerated and effective drug to
manage the abdominal pain and discomfort, bloating and constipation
associated with C-IBS.

The mechanism of action of tegaserod is reflected in its stimulation of
the peristaltic reflex Error: Reference source not found^,^ [^18]
intestinal secretionError: Reference source not found, as well as
inhibition of visceral sensitivityError: Reference source not
found^,Error:\ Reference\ source\ not\ found^ via activation of 5-HT~4~
receptors in the gastrointestinal tract. Tegaserod acts as a partial
agonist at neuronal 5-HT~4~ receptorsError: Reference source not found
triggering the release of further neurotransmitters such as calcitonin
gene-related peptide from sensory neurons. In vivo studies showed that
tegaserod enhanced basal motor activity and normalized impaired motility
throughout the gastrointestinal tract.Error: Reference source not
found^,Error:\ Reference\ source\ not\ found^ In addition, studies
demonstrated that tegaserod moderates visceral sensitivity during
colorectal distention in animals.Error: Reference source not found^,17^

Based upon its pharmacodynamic activities exerted throughout the GI
tract, tegaserod was selected for study in patients with C-IBS. It was
hypothesized that by restoring and propagating motor activity, and
moderating visceral sensitivity, tegaserod would be effective in
relieving symptoms of IBS. Tegaserod was expected to have a dual effect
in improving the altered bowel function and abdominal discomfort and
pain that characterize C-IBS.

# Clinical Pharmacology

The clinical pharmacology program for tegaserod included 25 studies,
involving more than 540 healthy subjects, 13 patients with hepatic
impairment and 11 patients with renal impairment. Studies were conducted
to elucidate the dose-tolerability, absorption, distribution, metabolism
and elimination, the effects of food and demography on the
pharmacokinetics (PK) of tegaserod, the effects of possible
co-administration with other drugs, and the PK of tegaserod in subjects
with hepatic or renal impairment.

The final market formulation tablet was used in the Phase 3 efficacy
trials. A similar tablet was used in late Phase 2 Clinical Pharmacology
studies and two capsule formulations were used in Phase 1 and 2. The two
tablet formulations are similar in terms of relative bioavailability and
exceeded that of the Phase 1 and Phase 2 capsules by about 60% and 30%,
respectively.

#### Pharmacokinetics {#pharmacokinetics-1 .unnumbered}

Tegaserod is rapidly absorbed following oral administration; peak plasma
concentrations are reached after approximately 1 hour. The solubility of
tegaserod is pH dependent. It is about 10-fold lower at pH 7.5 compared
to pH 1 with a minimum solubility at pH 4.5 Below pH 3, tegaserod is
rapidly degraded through hydrolytic breakdown. Absolute bioavailability
is about 10 % under fasted conditions. Food reduced the systemic
exposure to tegaserod by 40‑65 % and C~max~ by approximately 20‑40 %.
Although there is a food effect on the PK of tegaserod, the relative
timing of drug intake within 30 minutes before a meal is not critical.
It is recommended to take tegaserod orally before a meal. Tegaserod is
approximately 98 % bound to plasma proteins, primarily to ~1~-acid
glycoprotein. It is extensively distributed into tissues following
intravenous administration with a volume of distribution at steady state
of 368  223 L. Tegaserod is metabolized mainly via two pathways. The
first is a presystemic acid-catalyzed hydrolysis in the stomach followed
by oxidation and conjugation, which produces the main metabolite of
tegaserod, 5‑methoxy‑indole‑3‑carboxylic acid glucuronide. The main
metabolite has negligible affinity for human 5‑HT~4~ receptors and is
devoid of promotile activity in the dog. In man, systemic exposure to
tegaserod was not statistically significantly altered at neutral gastric
pH values. The second metabolic pathway of tegaserod degradation is
direct glucuronidation, which leads to generation of three isomeric
N‑glucuronides. The plasma clearance of tegaserod is 77 15 L/h, with an
estimated terminal half‑life (t~1/2~) of 11  5 h following intravenous
administration. Approximately two‑thirds of the orally administered dose
of tegaserod is excreted unchanged in the feces, with the remaining one
third excreted in the urine, primarily as the main metabolite.

The PK of tegaserod are dose proportional over the range 2 to 12 mg
given twice daily for five days, with no relevant accumulation of
tegaserod. The PK of tegaserod in IBS patients are comparable to those
in healthy subjects. Inter-patient coefficients of variation in the PK
parameters of tegaserod were comparable in C-IBS and D-IBS patients
(40-50%) and healthy subjects.

Based on an analysis across several PK studies in healthy subjects (12
mg single dose, n=134), there is no effect of gender, age and ethnic
origin on the PK of tegaserod when allowing for body weight as a
covariate. Systemic concentrations of tegaserod are lower with higher
body weight. Given the variability in tegaserod PK and its wide safety
margin, the data suggest that dose adjustment based on individual body
weight is not needed.

#### Pharmacokinetics in special and other patient populations {#pharmacokinetics-in-special-and-other-patient-populations .unnumbered}

##### Gender {#gender .unnumbered}

Based on a special age/gender PK study, gender does not effect the PK of
tegaserod in either the young or elderly population matched for height,
weight, and gender. Then mean AUC~0-∞~ and C~max~ were 5% lower and 8%
greater in young females compared to young malesl; for the elderly, in
females mean AUC~0-∞~ and C~max~ were 2% and 30% greater than in males
(for the latter see the effect of age below). Supportive information for
no gender effect on the PK of tegaserod further is provided by pooled
data from healthy subjects (12 mg dose, n=134) as discussed above.

##### Elderly {#elderly .unnumbered}

The PK of tegaserod are similar in elderly and young males, whereas the
mean AUC~0-∞~ and C~max~ are 40 % and 22 % greater in elderly females
than young females; young and elderly were matched for height, weight,
and gender. No dosage adjustment is required in elderly patients.

##### Hepatic impairment {#hepatic-impairment .unnumbered}

In subjects with mild (n=11) to moderate (n=1) hepatic impairment (liver
cirrhosis, matched for age, gender, and weight withhealthy control
subjects), mean AUC~0-∞~ was 43 % higher and C~max~ 18 % higher (not
statistically significant). Both parameters showed positive correlations
with dihydroxy bile acid concentrations. Given the variability in
pharmacokinetic parameters in healthy subjects, and the wide safety
margin of tegaserod, the data suggest that dose adjustment is not
necessary in subjects with mild to moderate hepatic impairment. However,
caution should be used in subjects with severe hepatic impairment.

##### Renal impairment {#renal-impairment .unnumbered}

No change in the PK of tegaserod was observed in subjects with severe
renal impairment requiring hemodialysis (matched for age, gender, and
weight with healthy control subjects). No dosage adjustment is required
in patients with any degree of renal impairment.

#### Drug-drug interactions {#drug-drug-interactions .unnumbered}

No clinically relevant drug-drug interactions have been identified in
specific drug-drug interaction studies, or in concomitant use, during
the clinical development of tegaserod. In vivo drug-drug interaction
studies with theophylline (CYP1A2 prototype substrate), dextromethorphan
(CYP2D6 prototype substrate), digoxin, warfarin, and oral contraceptives
indicate no clinically relevant interactions. No dosage adjustment is
required for either drug when tegaserod is co-administered with drugs
metabolized by CYP1A2 (e.g. omeprazole, oestradiol, fluvoxamine) and
CYP2D6 (e.g. fluoxetine, captopril, omeprazole), digoxin, warfarin, or
oral contraceptives. Tegaserod is a substrate of P glycoprotein (Pgp),
but its potential to inhibit Pgp is low. It could theoretically interact
with other Pgp substrates/inhibitors by competing for this transport
protein. However, because of the relatively wide safety margin, the
shallow dose-response relationship, and other factors limiting the
maximum possible increase in systemic exposure to tegaserod, potential
interactions with Pgp substrates/inhibitors are unlikely to have any
clinically relevant effects. Although a substrate of Pgp, effects of
tegaserod on systemic exposure to other substrates/inhibitors of this
transport protein are unlikely because tegaserod is a weak inhibitor.

#### Pharmacodynamics in healthy subjects {#pharmacodynamics-in-healthy-subjects .unnumbered}

Pharmacodynamic data in healthy subjects indicate that tegaserod has a
maximum well-tolerated oral dose of 58 mg/day of the market formulation
(tablet) and that higher doses may produce GI symptoms compatible with
an exaggerated pharmacodynamic action. Furthermore the promotile action
on the GI tract has been demonstrated at an oral dose of 6 mg b.i.d. and
an i.v. dose of 0.6 mg b.i.d. Gastric emptying, small bowel transit, and
colonic transit were enhanced to a clinically and statistically
significant extent as compared to placebo. These effects were not
statistically significant between the two tegaserod treatments. The
effects on both stool consistency and frequency were more pronounced
after the initial dose with the oral than i.v. route of administration.

#### Pharmacodynamics in patients {#pharmacodynamics-in-patients .unnumbered}

The PD properties of tegaserod have been evaluated primarily with
respect to the effects on lower esophageal sphincter pressure (LESp),
esophageal pH, rectal sensitivity and compliance, gastric emptying,
small bowel transit, and colonic transit.

Study B252 explored the effects of tegaserod in patients with mild to
moderate gastroesophageal reflux disorder. In this pilot study,
tegaserod 1 mg/day and 4 mg/day decreased the post-prandial percentage
of time that esophageal pH was \<4 and the number of reflux episodes.
The effects on esophageal acid exposure were not due to an increase in
LESp, however a trend towards a decrease in lower esophageal sphincter
relaxations was seen.

Study B304 was conducted to investigate the effect of tegaserod in
comparison to placebo on rectal sensitivity measured by Barostat
methodology inpatients with C-IBS. In this study, tegaserod at a dose of
4 mg/day did not have a significant effect on the perception of rectal
distention in IBS patients with rectal hypersensitivity.

Study B357 was carried out to assess the effects of tegaserod on GI
transit (gastric emptying, small bowel transit , colonic transit) in
patients with C-IBS. Tegaserod 4 mg/day significantly accelerated small
bowel transit without altering gastric emptying in patients with C-IBS.
Results also suggested that tegaserod facilitates colonic transit.

#  Clinical Program Development

## IBS Trial Methodology

Trial methodology for studies in functional GI disorders, and in
particular IBS, has been extensively discussed in recent years in the
scientific community. Nonetheless, to our knowledge, there are no
regulatory guidelines available for clinical development of drugs in
IBS. For this reason, the clinical development of tegaserod required
numerous consultations with regulatory authorities and academia. Most of
the scientific interactions with health authorities were initiated at
the request of the sponsor to discuss methodological issues, especially
related to the efficacy assessment.

A significant issue in designing and conducting clinical trials in IBS
is the lack of consensus in the medical/scientific community on outcome
measures. This relates both to the measurement of outcomes (i.e., how to
define and record parameters that accurately assess patient's symptoms)
as well as the specific symptom(s) to be assessed. At present, there is
no outcome measure sufficiently well validated to be recommended for
treatment trials in IBS.[^19]

Outcomes for IBS trials have been assessed using ordinal scales (usually
5 or 7 items), visual analogue scales (VAS), and most recently, a binary
scale (yes/no). At the September 1998 Vienna symposium on the Definition
of a Responder in Clinical Trials for Functional Gastrointestinal
Disorders, either a global assessment which integrates the patient's
symptoms or a specific symptom measure (e.g., abdominal pain) were
recommended as primary outcome measures.[^20] No clear recommendations
on measurement scales were given, although the difficulty of defining
response on a VAS was noted. The most recent recommendation of the Rome
Committee on the Design of Treatment Trials of Functional
Gastrointestinal Disorders (Rome II) is that the primary outcome measure
should "integrate" the symptoms of the disease. Because the symptoms
that result in a diagnosis of IBS are varied and interact in complex
ways, it was felt most appropriate that the primary outcome measure
should allow the patient to "integrate the contribution of a disparate
group of symptoms into a single global clinical rating."Error: Reference
source not found In addition, it was recommended that a responder
approach be used to assess outcome and that efficacy assessments should
be made by the patient.

## Tegaserod Phase 2 Program

Two double-blind Phase 2 studies (B251 and B202) evaluated four doses of
tegaserod and placebo. A total of 894 patients were enrolled and a total
of 670 patients with C-IBS were randomized in the two studies. Study
B251 randomized 547 patients at 45 study sites in North America and
Europe. Study B202 randomized 123 patients at 16 sites in Europe and
Canada.

Study B251 was a dose-ranging study in which patients received one of
four doses of tegaserod or placebo for 12 weeks. Study 202 utilized a
dose-escalation design in which patients were randomized to receive
tegaserod or placebo, and underwent dose-titration depending on efficacy
response and tolerability.

A summary of the main features of the Phase 2 studies is given in Table
6-1.

###### Table 6-1. Main features of dose-finding studies {#table-6-1.-main-features-of-dose-finding-studies .unnumbered}

  --------------------------------------------------------------------------------------------
  **Study\   **Objective**    **Patients**   **Treatment   **Tegaserod        **Population**
  No.**                                      Duration**    dose/day**         
  ---------- ---------------- -------------- ------------- ------------------ ----------------
  B251       Dose-ranging     547            12 weeks      1, 4, 12, 24 mg/d, C-IBS
                                                           Placebo            

  B202       Dose-titration   123            20 weeks      1, 4, 12, 24 mg/d, C-IBS
                                                           Placebo            
  --------------------------------------------------------------------------------------------

The Subject's Global Assessment (SGA) of overall GI symptoms was the
primary efficacy assessment in both studies and was assessed by monthly
patient interview:

Patients responded to the following question:

*\"Compared to the way you usually felt during the 3 months before you
entered the study, are your overall GI symptoms over the past 4 weeks:
completely relieved, considerably relieved, somewhat relieved, unchanged
or worse?"*

Patients also responded to similar questions regarding abdominal
discomfort/pain (SGA of abdominal discomfort/pain) and constipation (SGA
of constipation). A patient with a score of "considerable" or "complete"
relief at the study endpoint (the last month of treatment) was
considered a responder.

In study B251, response rates on the SGA of overall GI symptoms were
consistently higher in the tegaserod 4 mg/day, 12 mg/day and 24 mg/day
treatment groups compared with placebo (Figure 6-1). Response rates on
the SGA of abdominal/discomfort and SGA of constipation showed a similar
pattern of response.

####### Figure 6-1. Study B251: Responder rate for SGA of overall GI symptoms by monthly interval and at endpoint {#figure-6-1.-study-b251-responder-rate-for-sga-of-overall-gi-symptoms-by-monthly-interval-and-at-endpoint .unnumbered}

![](media/image3.wmf)

In the dose-titration study B202 (n=123), for all three SGA variables,
there was a placebo response of approximately 30% which was sustained
throughout the treatment period. After month 2 (optional dose-titration
to 12 mg/day) and at endpoint, responder rates for tegaserod exceeded
those of placebo by 10-17%.

Results of the dose-ranging study B251 indicated that tegaserod 4 mg/day
was the most effective dose, while tegaserod 1 mg/day was similar to
placebo. The dose-response was, however, relatively flat over the dose
range 4 mg/day -- 24 mg/day. Although not designed as a dose-response
study, it was interesting to note that in study B202 the increase in
response rates in the tegaserod group occurred during dose-titration
from 4 mg/day to 12 mg/day.

Based on these results, tegaserod doses of 4 mg/day and 12 mg/day were
chosen for further investigation in the Phase 3 program.

## Tegaserod clinical program, regulatory guidelines and agreements

An End-of-Phase 2 meeting was held with representatives from the FDA.
Results of two Phase 2 studies were reviewed, and proposed Phase 3
protocols were presented and discussed. Subsequent meetings were held
primarily to discuss efficacy outcome measures. The design of the Phase
3 program was based on the results of these meetings and input received
from expert consultants.

The primary efficacy measure used in the tegaserod Phase 2 trials was a
5-point ordinal scale, which captured the patient's relief of "overall
GI symptoms." At the End-of-Phase-2 meeting, FDA recommended that
abdominal pain should be the specific symptom assessment used as the
primary efficacy variable, and suggested that improvement of 2 levels on
a 5 level ordinal assessment scale define a responder for the Phase 3
program. Subsequently, an advisory panel of academic experts recommended
that the sponsor use a VAS for the tegaserod trials. At a follow-up
pre-Phase 3 meeting with the Agency to discuss clinically meaningful
changes based on the VAS, FDA recommended use of a primary outcome
measure that encompasses overall well-being, abdominal discomfort/pain,
and altered bowel habit, and discouraged use of a VAS as a measurement
tool for the primary outcome measure.

Faced with these disparate recommendations, the sponsor elected to adopt
two primary outcome measures (see Section 6.5.2) for the Phase 3
clinical program:

-   the Subject's Global Assessment (SGA) of relief, which encompassed
    overall well-being, abdominal pain/discomfort and altered bowel
    habit, measured with a 5-point ordinal scale (completely relieved,
    considerably relieved, somewhat relieved, unchanged, worse),

-   the Subject's Global Assessment (SGA) of abdominal discomfort/pain,
    measured by a 100 mm VAS with verbal descriptors.

Although the same 5-point ordinal scale had been used in the Phase 2
trials to measure relief of overall GI symptoms, there were several
important differences between the Phase 2 and Phase 3 relief efficacy
variable. Unlike the Phase 2 relief efficacy variable, which focused on
overall GI symptoms and was administered by monthly investigator
interview of the patient, the Phase 3 SGA of relief efficacy variable
included a component of overall well-being and was self-administered
weekly in a patient diary.

Three Phase 3 trials, B351, B301 and B307, were planned using two
primary efficacy variables, the SGA of relief and the SGA of abdominal
discomfort/pain, to determine the efficacy of tegaserod in the treatment
of patients with C-IBS.

### Modification of analysis plan

Due to differing patient recruitment rates, results of study B351 became
available before those of the other two trials. As a consequence of the
findings in study B351, the sponsor, with FDA agreement, revised the
definition of response and statistical analysis for the primary outcome
measures in the remaining, rigorously blinded Phase 3 trials B301 and
B307. Subsequently, prior to database lock, protocol amendments were
submitted for the two studies. The rationale for the modification of the
analysis plan is provided below in section 6.5.2.1.

## Tegaserod Phase 3 program study design 

Three large, multinational, parallel group, double-blind,
placebo-controlled Phase 3 studies were conducted to evaluate the
efficacy and safety of two doses of tegaserod. Each study consisted of a
4-week baseline period (with no placebo medication) and a 12-week
double-blind treatment period. An overview of the major features of the
adequate and well-controlled Phase 3 trials is given in Table 6-2.

###### Table 6-2. Summary of adequate and well-controlled trials {#table-6-2.-summary-of-adequate-and-well-controlled-trials .unnumbered}

  --------------------------------------------------------------------------------------
  Study    Location     Design                N        Study         Treatment groups
  No.                                                  duration      
  -------- ------------ --------------------- -------- ------------- -------------------
  B351     North        placebo-controlled,   799      4-week        tegaserod 4 mg/d;
           America^1^   double-blind,                  baseline;     tegaserod 12 mg/d;
                        parallel group                 12-week       placebo
                                                       treatment     

  B301     Europe, S    placebo-controlled,   881      4-week        tegaserod 4 mg/d;
           Africa,      double-blind,                  baseline;     tegaserod 12 mg/d;
           US^2^        parallel group                 12-week       placebo
                                                       treatment     

  B307     North        placebo-controlled,   841^4^   4-week        tegaserod 4 mg/d;
           America,     double-blind,                  baseline;     tegaserod 4 to 12
           Europe^3^    parallel group,                12-week       mg/d (optional
                        dose-titration                 treatment     dose-titration);
                                                                     placebo
  --------------------------------------------------------------------------------------

^1^ 49 centers in US (47) and Canada (2); 97% of patients randomized
from US.

^2^ 92 centers in UK(18), Germany(15), Netherlands(12), Switzerland(9),
US(9), Italy(7), Turkey(6), South Africa(6), Finland(4), Austria(3),
Spain(2), Portugal(1); 90% of patients randomized from Europe.

^3^ 67 centers in US (37), UK (10), France (8), Germany (5), Belgium
(3), Canada (3), Spain (1); 66% of patients randomized from US.

^4^ Excludes 4 randomized patients at one study center, which was
terminated early due to concern with possible noncompliance with Good
Clinical Practices.

A total of 3378 patients were enrolled and a total of 2521 patients with
C-IBS were randomized in these studies.

Studies B351 and B301 had identical study designs: following the
baseline period, eligible patients were randomized to receive either a
fixed dose of tegaserod or placebo for 12 weeks.

Study B307 included a dose-titration in which patients were randomized
to receive either a fixed dose of tegaserod 4 mg/day, a dose-titration
regimen or placebo. Those patients randomized to dose-titration received
tegaserod 4 mg/day and underwent dose titration at week 4 to 12 mg/day
if the response on the SGA of relief was complete or considerable relief
\<50% of the time.

Selection criteria were similar for the 3 studies. Men and women
[\>]{.underline}18 years ([\>]{.underline}12 years in Study B351) who
satisfied Rome I criteria (abdominal discomfort/pain for at least 3
months relieved with a bowel movement or associated with a change in
frequency or consistency of stool) for IBS were eligible to
participate.[^21]

In addition, patients were required to have at least 2 of 3 constipation
symptoms (\<3 bowel movements (BM)/week, hard/lumpy stools, straining
with a BM, 25% of the time).

Patients underwent appropriate endoscopic or radiologic examinations to
rule out other causes for the GI symptoms. Patients with significant
diarrhea (loose stools and/or \>3 BM/day with urgency, 25% of the time),
diseases or conditions that affect bowel transit or other clinical
evidence of significant disease, those using medications that interfere
with the evaluations (i.e. narcotics analgesics, motility agents), and
fertile women not using approved methods of contraception were excluded.

Following the 4-week baseline period in which patients recorded symptoms
in a paper diary, patients who had at least mild abdominal
discomfort/pain (as determined by a mean score [\>]{.underline} 35 mm on
a 100 mm VAS during the 4-week baseline period) were randomized. Given
the fluctuation in the disease, patients were not required to meet
specific bowel habit criteria during the baseline period and were not
excluded based on their 4-week baseline bowel habit diary data.

Concomitant laxative use was not allowed during the study, unless
requirements for rescue use were met (ie, no bowel movement for 4
consecutive days associated with bothersome abdominal discomfort/pain or
bloating). Bulk-forming agents and use of tricyclic antidepressants and
SSRIs were allowed if used in constant doses for at least one month
prior to study entry and were to be taken in constant doses throughout
the study.

Study medication was administered on a b.i.d. regimen and was to be
taken within 30 minutes prior to meals. A double-dummy technique was
used and patients took two tablets twice a day throughout the 12 week
treatment period, including all 12 treatment weeks in study B307 (ie,
patients took the same number of tablets before and after dose titration
in study B307).

## Phase 3 outcome measures and statistical methodology 

### Outcome measures evaluation in adequate and well-controlled studies

No outcome measure has been sufficiently validated to be recommended as
the standard for treatment trials in IBS. At the time the Phase 3
tegaserod studies were initiated, both an overall integrative measure of
symptoms and a specific measure of abdominal pain or discomfort were
proposed as appropriate outcome measures. More recently, a consensus
committee has recommended that the primary outcome measure should
"integrate" the symptoms of the disease. Because the symptoms that
result in a diagnosis of IBS are varied and interact in complex ways, it
was felt most appropriate that the primary outcome measure should allow
the patient to "integrate the contribution of a disparate group of
symptoms into a global clinical
rating".^Error:\ Reference\ source\ not\ found^

All efficacy assessments in the Phase 3 studies were recorded by the
patients in paper diaries. The diaries were collected at the monthly
visits. Three weekly self-assessments (SGA of relief, SGA of abdominal
discomfort/pain, SGA of bowel habits) and 4 daily self-assessments
(intensity of abdominal pain/discomfort, intensity of bloating,
frequency of bowel movements and average stool consistency) were made by
the patient throughout the 16-week study.

### Primary efficacy variable(s)

[SGA of relief efficacy variable]{.underline}

Patients responded weekly to the following question:

*\"Please consider how you felt this past week in regard to your IBS, in
particular your overall well-being, and symptoms of abdominal
discomfort, pain and altered bowel habit. Compared to the way you
usually felt before entering the study, how would you rate your relief
of symptoms during the past week?\"*

Possible answers were: completely relieved, considerably relieved,
somewhat relieved, unchanged or worse.

The response definitions used in the Phase 3 trials are shown in Table
6-3.

###### Table 6-3. SGA of relief: response definition for primary efficacy variable {#table-6-3.-sga-of-relief-response-definition-for-primary-efficacy-variable .unnumbered}

+------+---------------+-----------------------------------------------+
| *    | **Term**      | **Response criteria**                         |
| *Stu |               |                                               |
| dy** |               |                                               |
+------+---------------+-----------------------------------------------+
| B351 | *             | complete or considerable relief               |
|      | **Original*** | [\>]{.underline} 50% of the time at study     |
|      | SGA of relief | endpoint^1^                                   |
+------+---------------+-----------------------------------------------+
| B301 | SGA of relief | complete or considerable relief               |
| B307 |               | [\>]{.underline} 50% of the time at study     |
|      |               | endpoint^1^                                   |
|      |               |                                               |
|      |               | OR                                            |
|      |               |                                               |
|      |               | complete or considerable or somewhat relief   |
|      |               | 100% of the time at study endpoint^1^         |
+------+---------------+-----------------------------------------------+

^1^ Endpoint is defined as last 4 available weekly SGA scores, or all
weekly SGA scores if fewer than 4 were available.

[SGA of abdominal discomfort/pain]{.underline}

Efficacy was assessed weekly by a self-administered 100 mm VAS with
verbal descriptors. Patients placed a vertical mark on the line in
response to the following question:

*\"How much of a problem was your abdominal discomfort/pain over the
last week?\"*

+-------+-----+-------+-------+------------+----------+-----+-------+
|       |     |       |       |            |          |     |       |
+-------+-----+-------+-------+------------+----------+-----+-------+
| A     |     |       | Very  | Mild       | Moderate | Sev | Very  |
| bsent |     |       |       |            |          | ere |       |
|       |     |       | Mild  |            |          |     | s     |
|       |     |       |       |            |          |     | evere |
+-------+-----+-------+-------+------------+----------+-----+-------+

Patients were considered responders for the SGA of abdominal
discomfort/pain if there was a reduction of [\>]{.underline} 40% and an
absolute reduction of [\>]{.underline} 20 mm in mean VAS at endpoint
compared with baseline. The SGA of abdominal discomfort/pain was a
primary efficacy variable in study B351 and a secondary efficacy
variable in studies B301 and B307.

-   The ***original*** SGA of relief and the SGA of abdominal
    discomfort/pain were the two primary efficacy variables utilized in
    study B351.

```{=html}
<!-- -->
```
-   The SGA of relief was the single primary efficacy variable utilized
    in studies B301 and B307.

#### Rationale for modification of analysis plan

Study B351 was the first of the Phase 3 studies to be completed and
analyzed. The results of study B351 showed a consistent pattern of
improvement for tegaserod compared with placebo for the primary and
secondary outcome measures (see Section 7.2.1 for study results).
However, response rates in the tegaserod groups were not significantly
different from placebo for the primary efficacy variables.

Response rates were relatively low in all treatment groups; in
particular, the response rates in the placebo group (22%, ***original***
SGA of relief; 19%, SGA of abdominal discomfort/pain) were low compared
to placebo response rates in Phase 2 tegaserod studies (30% - 34%) and
available information in the literature for IBS trials (30% - 70%).[^22]
These findings suggested that the ***original*** response definition
(complete or considerable relief [\>]{.underline} 50% of the time at
endpoint) for the SGA of relief and the response definition for the SGA
of abdominal discomfort/pain were too stringent and, therefore, lacked
sensitivity to detect a significant treatment difference.

To enhance the sensitivity of the SGA of relief efficacy variable, the
"somewhat relieved" response was prospectively (ie, prior to database
lock and unblinding) included in the responder definition for the SGA of
relief in studies B301 and B307. Thus, the SGA of relief response
definition was an attempt to capture not only significant relief in
terms of magnitude of response ([\>]{.underline} 50%
complete/considerable relief) but also persistent positive relief (100%
at least somewhat relief). Persistent improvement on a global endpoint
that encompasses well being and integrates the patient's symptoms
(abdominal discomfort/pain and altered bowel habit) was thought to
represent an important clinical benefit to the patient.

The clinical relevance of the SGA of relief response definition was
supported by the strong associations observed between a positive
response on the SGA of relief and improvement in multiple secondary
efficacy variables in study B351 (Table 6-4). Compared with
nonresponders, responders reported clinically important and
statistically significant greater improvement in days of significant
abdominal discomfort and pain and average magnitude of the pain score,
days of significant abdominal bloating and average magnitude of the
bloating score, and altered bowel habit (reduction in days without a
bowel movement and days with hard stools) . These strong associations
were reproducible in studies B301 and B307, and so performed similarly
on two continents. These results are comparable to published
associations with an "adequate relief" endpoint.[^23]

###### Table 6-4. Associations between SGA of relief response and other efficacy variables (B351) {#table-6-4.-associations-between-sga-of-relief-response-and-other-efficacy-variables-b351 .unnumbered}

  ---------------------------- ----------- ------ -------------- -------- ----------
  Efficacy Variable            Responder          Nonresponder            P-value

                               \% change   N      \% change from N        
                               from               baseline                
                               baseline                                   

  VAS Score -- SGA abd         -47.5       314    -6.4           440      \<0.0001
  discomfort/pain                                                         

  Days with significant pain   -35.4       314    9.2            445      \<0.0001

  Daily pain score             -40.5       314    -0.2           445      \<0.0001

  Days with significant        -32.2       313    2.5            444      \<0.0001
  bloating                                                                

  Daily bloating score         -38.1       313    -1.8           444      \<0.0001

  VAS Score -- SGA bowel habit -46.6       314    -6.0           440      \<0.0001

  Days with no bowel movement  -43.6       310    -15.1          439      \<0.0001

  Days with hard or very hard  -66.4       314    -22.7          444      \<0.0001
  stool                                                                   
  ---------------------------- ----------- ------ -------------- -------- ----------

Further, as shown in Table 6-5, the associations indicated that patients
understood the scale and perceived somewhat relief as a positive
response. Thus, a persistent (100% of the time), positive (at least
somewhat) response seemed clinically appropriate to include as part of
the response definition.

###### Table 6-5. Associations between SGA of relief response in last study week and other efficacy variables (B351) {#table-6-5.-associations-between-sga-of-relief-response-in-last-study-week-and-other-efficacy-variables-b351 .unnumbered}

+--------------------------+------+---------+-------+--------+------+
| Efficacy Variable        | Resp |         |       |        |      |
|                          | onse |         |       |        |      |
| (% change from baseline) | on   |         |       |        |      |
|                          | SGA  |         |       |        |      |
|                          | of   |         |       |        |      |
|                          | re   |         |       |        |      |
|                          | lief |         |       |        |      |
+--------------------------+------+---------+-------+--------+------+
|                          | Comp | Consi   | Som   | Unc    | W    |
|                          | lete | derable | ewhat | hanged | orse |
|                          |      |         |       |        |      |
|                          | n =  | n = 164 | n =   | n =    | n =  |
|                          | 48   |         | 222   | 256    | 61   |
+--------------------------+------+---------+-------+--------+------+
| VAS Score -- SGA abd     | -    | -49.5   | -22.6 | -5.3   | 7.6  |
| discomfort/pain          | 78.6 |         |       |        |      |
+--------------------------+------+---------+-------+--------+------+
| Days with significant    | -    | -40.3   | -7.4  | 18.1   | 2.5  |
| pain                     | 73.0 |         |       |        |      |
+--------------------------+------+---------+-------+--------+------+
| Daily pain score         | -    | -44.3   | -15.6 | 3.6    | 8.0  |
|                          | 71.8 |         |       |        |      |
+--------------------------+------+---------+-------+--------+------+
| Days with significant    | -    | -37.4   | -7.4  | 6.1    | 2.7  |
| bloating                 | 61.2 |         |       |        |      |
+--------------------------+------+---------+-------+--------+------+
| Daily bloating score     | -    | -41.2   | -19.0 | 0.7    | 7.3  |
|                          | 64.3 |         |       |        |      |
+--------------------------+------+---------+-------+--------+------+
| VAS Score -- SGA bowel   | -    | -49.5   | -22.6 | -3.4   | 6.2  |
| habit                    | 75.2 |         |       |        |      |
+--------------------------+------+---------+-------+--------+------+
| Days with no bowel       | -    | -46.1   | -27.6 | -10.2  | -    |
| movement                 | 61.9 |         |       |        | 16.2 |
+--------------------------+------+---------+-------+--------+------+
| Days with hard or very   | -    | -69.9   | -50.3 | -19.2  | -2.9 |
| hard stool               | 71.2 |         |       |        |      |
+--------------------------+------+---------+-------+--------+------+

A second change to the analysis plan for studies B301 and B307 was that
the SGA of abdominal discomfort/pain was eliminated as a primary
efficacy variable and retained as a secondary efficacy variable.
Although not sensitive as a primary outcome measure, the SGA of
abdominal discomfort/pain was thought to be useful to retain as a
secondary efficacy variable to help assess effects on the specific
symptom of abdominal discomfort and pain. The use of a global measure
(ie, SGA of relief) for the primary efficacy variable in treatment
trials of IBS is in accord with the recent recommendation of the Rome
Committee on the Design of Treatment Trials of Functional
Gastrointestinal Disorders (Rome II).Error: Reference source not found
Further, the SGA of relief efficacy variable already includes the
consideration of abdominal discomfort/pain.

### Secondary efficacy variables 

The SGA of bowel habit was self-administered weekly using a VAS with
descriptors (similar to SGA of abdominal discomfort/pain), in which
patients responded to a question regarding their altered bowel habit.

Patients recorded on a daily basis the following:

-   intensity of abdominal discomfort/pain (6-point scale: 0 = none, 1 =
    very mild, 2 = mild, 3 = moderate, 4 = severe, 5 = very severe),

-   intensity of abdominal bloating (6-point scale: 0 = none, 1 = very
    mild, 2 = mild, 3 = moderate, 4 = severe, 5 = very severe),

-   number of bowel movements, and

-   average daily stool consistency (7-point scale: 1 = watery, 2 =
    loose, 3 = somewhat loose, 4 = neither loose nor hard, 5 = somewhat
    hard, 6 = hard, 7 = very hard)

Days with significant abdominal discomfort/pain and days with
significant abdominal bloating were defined as [\>]{.underline} mild
(ie, [\>]{.underline} 2 on a 6-point scale). The percent of days with
hard/very hard stools was also calculated.

A tertiary variable was QOL scores, as measured by the IBS-QOL
instrument, at randomization and at the end of the study.

### Statistical methodology in adequate and well-controlled trials

**Populations and endpoints:**

The intent-to-treat (ITT) population, defined as all randomized
patients, was the primary population.

Two types of endpoints were defined in the individual protocols:

Endpoint for SGA of scores: The last 4 available weekly SGA
responses/scores in the post-randomization period, or all weekly
responses/scores if fewer than 4 weekly scores were available.

Endpoint for daily diary scores: Daily diary scores obtained in the last
28 days of the post-randomization diary or all available daily scores
obtained in the post-randomization diary, if fewer than 28 days were
available.

**Statistical methods:**

All primary efficacy variables in the Phase 3 studies were dichotomous
response variables based on SGA response criteria and adjustment rules.

Specifically, in study B351, two primary efficacy variables were
prospectively defined and analyzed:

(1) ***Original*** SGA of relief (A responder for ***original*** SGA of
    relief was a patient who had considerable or complete relief
    [\>]{.underline} 50% of the time at endpoint, and fulfilled the
    adjustment rules),

(2) SGA of abdominal discomfort/pain (A responder for SGA of abdominal
    discomfort/pain was a patient who had a reduction of
    [\>]{.underline} 40% and an absolute reduction of [\>]{.underline}
    20 mm in mean VAS at endpoint compared with baseline, and fulfilled
    the adjustment rules).

In studies 301 and B307, a single primary efficacy variable was
prospectively defined and analyzed:

\(1\) SGA of relief (A responder for SGA of relief was a patient who had
considerable or complete relief [\>]{.underline} 50% of the time at
endpoint or had at least somewhat relief 100% of the time at endpoint,
and fulfilled the adjustment rules).

The adjustment rules were:

-   had at least one post-baseline SGA available,

-   duration of exposure to study medication was 28 days,

-   laxative intake was 5 days during the treatment period and no
    laxative intake during the last 4 weeks of treatment (adjustment for
    laxative intake was included as one of the adjustment criteria at
    the request of FDA).

    As planned in the study protocol, each efficacy variable was
    analyzed by comparing the tegaserod groups versus the placebo group.
    The Mantel-Haenszel test stratified by center was performed. To
    ensure the overall two-sided type I error less than or equal to
    0.05, Holm's multiple comparison procedure, adjusting for two
    primary variables and two tegaserod doses, was used in study B351,
    and Hochberg's multiple comparisons procedure, adjusting for two
    tegaserod doses, was used in studies B301 and B307.

    Secondary efficacy variables, as specified in the protocol, were
    derived from the daily diary scores as well as from weekly SGAs.
    Each efficacy variable was analyzed by comparing the tegaserod
    groups versus the placebo group. The between-treatment comparisons
    for the dichotomous secondary variables were performed using the
    Mantel-Haenszel test stratified by center, while the numeric
    variables were analyzed by means of an Extended Mantel-Haenszel
    stratified by center. Holm's multiple comparison procedure,
    adjusting for two tegaserod comparisons, was used for each of the
    secondary efficacy variables in study B351. No multiple comparison
    procedure was used in the analysis for any of the secondary efficacy
    variables in studies B301 and B307.

#### Unadjusted responder rates {#unadjusted-responder-rates .unnumbered}

Provided as additional assessments, unadjusted responder rates at
endpoint for the ***original*** SGA of relief, SGA of relief, and SGA of
abdominal discomfort/pain were also calculated and similarly analyzed.
The unadjusted responder rates were calculated by applying the
corresponding SGA response criterion only. No adjustment rules were used
in determining the unadjusted responder status. Patients without any
post-baseline SGAs were, therefore, not imputed as non-responders and
were excluded from the unadjusted responder analysis.

Monthly responder rates for the ***original*** SGA of relief, SGA of
relief, and SGA of abdominal discomfort/pain were summarized by
treatment in each study. As the adjustment rules are endpoint specific,
the monthly responder rates were unadjusted responder rates, i.e. the
responders were determined by applying only the corresponding SGA
response criterion to each monthly interval.

Mean scores for each of the daily diary variables were summarized
weekly. The corresponding p-values comparing teagserod to placebo for
change from baseline in mean score, are also presented for descriptive
purposes.

# Phase 3 efficacy analysis

A summary of the results of the individual Phase 3 studies (B351, B301
and B307) is provided, followed by sensitivity analyses, a comparative
analysis of the efficacy variables, post-hoc analyses, responses in
population subgroups and conclusions.

## Phase 3 individual study results

#### Demographics and baseline variables {#demographics-and-baseline-variables .unnumbered}

The demographics and baseline characteristics of the patients were
similar among the 3 studies. As shown in Table 7-1, the patients in each
study were largely female with a mean age of 43-46 years, had a mean
duration of disease greater than 10 years and had similar baseline
severity of disease. The percentage of black patients was highest in
study B351. There were no relevant differences among treatment groups in
demographics and baseline characteristics in the individual studies.

###### Table 7-1. Demographics and baseline characteristics in Phase 3 studies {#table-7-1.-demographics-and-baseline-characteristics-in-phase-3-studies .unnumbered}

  -------------------------------------- ----------- ----------- -----------
  **Demographic/Baseline variable**      **B351      **B301      **B307
                                         (N=799)**   (N=881)**   (N=841)**

  Age (yrs)\                             43 ± 13\    46 ± 14\    45 ± 13\
  Age [\>]{.underline} 65 years\         7%\         11%\        11%\
  Female\                                87%\        83%\        84%\
  Race: Caucasian\                       88%\        98%\        90%\
  Race: Black\                           9%\         1%\         6%\
  Race: Other\                           3%\         1%\         4%\
  Weight (kg)\                           71 ± 16\    68 ± 14\    70 ± 16\
  Duration of IBS (months)               175 ± 158   158 ± 147   166 ± 154

  Abdominal discomfort/pain VAS score    63 ± 13\    60 ± 13\    61 ± 13\
  (mm)\                                  64 ± 14\    60 ± 14\    62 ± 14\
  Bowel habit VAS score (mm)\            24 ± 6\     24 ± 6\     24 ± 6\
  No. of days/28 days with               25 ± 6\     23 ± 7\     24 ± 6\
  significant^1^ discomfort/pain\        13 ± 7\     12 ± 7\     11 ± 7\
  No. of days/28 days with               23 ± 18\    22 ± 16\    25 ± 20\
  significant^1^ bloating\               31 ± 29     28 ± 29     29 ± 28
  No. of days without bowel movements/28                         
  days\                                                          
  No. of bowel movements/28 days\                                
  % of days^2^ with hard/very hard                               
  stools                                                         

  Results expressed as mean ± SD^\                               
  1^defined as at least mild (daily                              
  score 2 on 6-point scale); ^2^                                 
  denominator is days with bowel                                 
  movements                                                      
  -------------------------------------- ----------- ----------- -----------

######   {#section .unnumbered}

#### Laxative intake {#laxative-intake .unnumbered}

As shown in Table 7-2, laxative use was similar among the treatment
groups in each study.

###### Table 7-2. Number (and percentage of patients) with laxative use by study period  {#table-7-2.-number-and-percentage-of-patients-with-laxative-use-by-study-period .unnumbered}

  ------- ---------------- -------------- ---------------- ----------------
  Study   **Study period** **Placebo\     **Tegaserod\     **Tegaserod\
                           **             4 mg/d**         12 mg/d**

  B351                     n=267          n=265            n=267

          Baseline\        83 (31.1)\     76 (28.7)\       74 (27.7)\
          Treatment period 84 (31.5)      71 (26.8)        70 (26.2)

  B301                     n=288          n=299            n=294

          Baseline\        83 (28.8)\     91 (30.4)\       89 (30.3)\
          Treatment period 78 (27.1)      82 (27.4)        81 (27.6)

  B307                     n=284          n=282            n=275^1^

          Baseline\        69 (24.3)\     57 (20.2)\       72 (26.2)^1^\
          Treatment period 64 (22.5)      68 (24.1)        66 (24.0)^1^
  ------- ---------------- -------------- ---------------- ----------------

^1^Study B307: 4-12 mg/d titration group

##   {#section-1 .unnumbered}

### Study B351 Results

#### A randomized, double-blind, placebo-controlled, multicenter study to assess the safety and efficacy of SDZ HTF 919 at two dose levels and placebo in subjects with constipation-predominant irritable bowel syndrome {#a-randomized-double-blind-placebo-controlled-multicenter-study-to-assess-the-safety-and-efficacy-of-sdz-htf-919-at-two-dose-levels-and-placebo-in-subjects-with-constipation-predominant-irritable-bowel-syndrome .unnumbered}

A total of 1093 patients enrolled in the study of which 799 were
randomized to tegaserod 4 mg/day, tegaserod 12 mg/day or placebo.
Patient disposition by treatment for all randomized patients is
displayed in Table 7-3.

The overall discontinuation rate from double-blind treatment was similar
among the three treatment groups. The reasons for discontinuation were
also generally similar among the groups, although more patients
discontinued treatment due to adverse events in the 12 mg/day group (7%)
compared to the 4 mg/day (3%) and placebo (3%) groups.

###### Table 7-3. Summary of patient disposition and primary reasons for discontinuations by treatment group (study B351) {#table-7-3.-summary-of-patient-disposition-and-primary-reasons-for-discontinuations-by-treatment-group-study-b351 .unnumbered}

  ------------------------- ------------- -------------- ------------- -----------
                            **Placebo**   **Tegaserod\   **Tegaserod   **Total**
                                          4 mg/d**       12 mg/d**     

                            **N (%)**     **N (%)**      **N (%)**     **N (%)**

  Randomized into           267           265            267           799
  double-blind period (ITT                                             
  population)                                                          

  Completed the treatment   214 (80.1%)   208 (78.5%)    211 (79.0%)   633 (79.2%)
  period                                                               

  Discontinued prematurely  53 (19.9%)    57 (21.5%)     56 (21.0%)    166 (20.8%)
  during the treatment                                                 
  period (total)                                                       

  Adverse events            9 (3.4%)      9 (3.4%)       19 (7.1%)     37 (4.6%)

  Abnormal laboratory       0             1 (0.4%)       2 (0.7%)      3 (0.4%)
  values                                                               

  Unsatisfactory            14 (5.2%)     10 (3.8%)      8 (3.0%)      32 (4.0%)
  therapeutic effect                                                   

  Subject withdrew consent  12 (4.5%)     15 (5.7%)      13 (4.9%)     40 (5.0%)

  Lost to follow-up         13 (4.9%)     17 (6.4%)      8 (3.0%)      38 (4.8%)

  Protocol violation        5 (1.9%)      5 (1.9%)       6 (2.2%)      16 (2.0%)
  ------------------------- ------------- -------------- ------------- -----------

**Efficacy results**

The results for the two primary efficacy variables, the ***original***
SGA of relief and SGA of abdominal discomfort/pain at endpoint in the
ITT population, are shown in Table 7-4. The responder rates for the
tegaserod 4 mg/day and 12 mg/day groups were higher than for placebo for
both efficacy variables. However, these differences did not reach
statistical significance, according to the Holm's multiple comparison
procedure.

###### Table 7-4. Responder rate for primary efficacy variables (*original* SGA of relief and SGA of abdominal discomfort/pain) at endpoint (study B351) {#table-7-4.-responder-rate-for-primary-efficacy-variables-original-sga-of-relief-and-sga-of-abdominal-discomfortpain-at-endpoint-study-b351 .unnumbered}

+--------------------------+-------------+-------------+-------------+
|                          | **Placebo\  | *           | *           |
|                          | \           | *Tegaserod\ | *Tegaserod\ |
|                          | (N=267)**   | 4 mg/d\     | 12 mg/d\    |
|                          |             | (N=265)**   | (N=267)**   |
+--------------------------+-------------+-------------+-------------+
| ***Original* SGA of      |             |             |             |
| relief**                 |             |             |             |
+--------------------------+-------------+-------------+-------------+
| Responder rate^1^ (n)    | 22.1% (59)  | 29.4% (78)  | 26.2% (70)  |
+--------------------------+-------------+-------------+-------------+
| Treatment difference     |             | 7.5%        | 4.1%        |
| from placebo^2^          |             |             |             |
+--------------------------+-------------+-------------+-------------+
| P-value^2^               |             | 0.050       | 0.266       |
+--------------------------+-------------+-------------+-------------+
| **SGA of abdominal       |             |             |             |
| discomfort/pain**        |             |             |             |
+--------------------------+-------------+-------------+-------------+
| Responder rate^1^ (n)    | 18.7% (50)  | 23.4% (62)  | 25.1%(67)   |
+--------------------------+-------------+-------------+-------------+
| Treatment difference     |             | 4.8%        | 6.4%        |
| from placebo^2^          |             |             |             |
+--------------------------+-------------+-------------+-------------+
| P-value^2^               |             | 0.185       | 0.075       |
+--------------------------+-------------+-------------+-------------+
| ^1^ Adjusted for missing |             |             |             |
| SGAs, treatment          |             |             |             |
| duration, laxative use.  |             |             |             |
|                          |             |             |             |
| ^2^ Treatment difference |             |             |             |
| (weighted by center) in  |             |             |             |
| responder rate and       |             |             |             |
| p-value (nominal         |             |             |             |
| p-value) refer to the    |             |             |             |
| comparison between the   |             |             |             |
| tegaserod dose and       |             |             |             |
| placebo at endpoint.     |             |             |             |
| Holm's multiple          |             |             |             |
| comparison procedure,    |             |             |             |
| adjusting for two        |             |             |             |
| primary variables and    |             |             |             |
| two tegaserod doses, was |             |             |             |
| used to determine        |             |             |             |
| whether a treatment      |             |             |             |
| difference was           |             |             |             |
| statistically            |             |             |             |
| significant at the level |             |             |             |
| of 0.05.                 |             |             |             |
+--------------------------+-------------+-------------+-------------+

As previously discussed, the primary efficacy variables in this study
established a high hurdle for response and may have lacked sensitivity
to detect treatment differences. To explore this further, the SGA of
relief definition of response (complete or considerable relief at least
50% of the time or at least somewhat relief 100% of the time at
endpoint) was retrospectively analyzed. The results are summarized in
Table 7-5. A positive dose-response was observed, with a 12% treatment
difference for the tegaserod 12 mg/day group compared with placebo.

###### Table 7-5. Responder rate for SGA of relief at endpoint (study B351) {#table-7-5.-responder-rate-for-sga-of-relief-at-endpoint-study-b351 .unnumbered}

+------------------------------+------------+------------+------------+
|                              | **Placebo\ | **         | **         |
|                              | **         | Tegaserod\ | Tegaserod\ |
|                              |            | 4 mg/d**   | 12 mg/d**  |
+------------------------------+------------+------------+------------+
|                              | N=267      | N=265      | N=267      |
+------------------------------+------------+------------+------------+
| Responder rate^1^ (n)        | 33.3% (89) | 38.9%      | 45.7%      |
|                              |            | (103)      | (122)      |
+------------------------------+------------+------------+------------+
| Treatment difference from    |            | 6.0%       | 12.4%      |
| placebo^2^                   |            |            |            |
+------------------------------+------------+------------+------------+
| P-value^2^                   |            | 0.157      | 0.004\*    |
+------------------------------+------------+------------+------------+
| ^1^ Adjusted for missing     |            |            |            |
| SGAs, treatment duration,    |            |            |            |
| laxative use.                |            |            |            |
|                              |            |            |            |
| ^2^ Treatment difference     |            |            |            |
| (weighted by center) in      |            |            |            |
| responder rate and p-value   |            |            |            |
| (nominal p-value) refer to   |            |            |            |
| the comparison between the   |            |            |            |
| tegaserod dose and placebo   |            |            |            |
| at endpoint. Holm's multiple |            |            |            |
| comparison procedure,        |            |            |            |
| adjusting for two primary    |            |            |            |
| variables and two tegaserod  |            |            |            |
| doses, was used to determine |            |            |            |
| whether a treatment          |            |            |            |
| difference was statistically |            |            |            |
| significant at the level of  |            |            |            |
| 0.05.                        |            |            |            |
|                              |            |            |            |
| \* Indicates a statistically |            |            |            |
| significant difference       |            |            |            |
| compared to placebo based on |            |            |            |
| Hochberg's multiple          |            |            |            |
| comparison procedure,        |            |            |            |
| adjusting for two tegaserod  |            |            |            |
| doses, at the significance   |            |            |            |
| level of 0.05.               |            |            |            |
+------------------------------+------------+------------+------------+

Monthly responder rates for both the ***original*** SGA of relief and
the SGA of relief are shown in Figure 7-1. For the ***original*** SGA of
relief (Figure 7-1A), both tegaserod groups had higher response rates
compared with placebo at each monthly interval, but no clear
dose-response profile was observed.

In contrast, for the SGA of relief (Figure 7-1B), a positive
dose-response profile over time was observed with the tegaserod 12
mg/day group consistently having the highest response rates at each
monthly interval.

####### Figure 7-1A. Unadjusted responder rate for *original* SGA of relief by monthly interval ![](media/image4.wmf) {#figure-7-1a.-unadjusted-responder-rate-for-original-sga-of-relief-by-monthly-interval .unnumbered}

\*p-value \< 0.05 compared to placebo

####### Figure 7-1B. Unadjusted responder rate for SGA of relief by monthly interval (study B351) {#figure-7-1b.-unadjusted-responder-rate-for-sga-of-relief-by-monthly-interval-study-b351 .unnumbered}

![](media/image5.wmf)\*p-value \< 0.05 compared to placebo

Figure 7-2 presents the weekly percentage of patients with at least
somewhat relief. A large placebo response was seen at week 1, which
increased over the next several weeks and then stabilized. For the
tegaserod 12 mg/day group, a significant difference from placebo was
seen at week 1, and for most weeks in the study.

####### ![](media/image6.wmf)Figure 7-2. Weekly percentage of patients with at least somewhat relief (study B351) {#figure-7-2.-weekly-percentage-of-patients-with-at-least-somewhat-relief-study-b351 .unnumbered}

\*p\<0.05 compared to placebo

Monthly results for the SGA of abdominal discomfort/pain are shown in
Figure 7-3A, with results shown weekly in Figure 7-3B. Response rates
were higher in the tegaserod 12 mg/day group compared with placebo at
all monthly timepoints and for many weekly timepoints.

####### Figure 7-3A. Unadjusted responder rate for SGA of abdominal discomfort/pain monthly interval (study B351)  {#figure-7-3a.-unadjusted-responder-rate-for-sga-of-abdominal-discomfortpain-monthly-interval-study-b351 .unnumbered}

![](media/image7.wmf)\*p\< 0.05 compared to placebo

####### ![](media/image8.wmf) {#section-2 .unnumbered}

\*p value \<0.05 compared to placebo

**Secondary efficacy variables**

The results of between-treatment comparisons of the secondary efficacy
variables at endpoint are shown in Table 7-6.

In addition to the SGA of abdominal discomfort/pain, abdominal
discomfort/pain was also evaluated in the daily diary as days of
significant abdominal discomfort/pain whereby significant was defined as
at least mild. A similar evaluation was performed for days of
significant abdominal bloating. The average decrease from baseline for
both days of significant discomfort/pain and bloating was significantly
greater in the tegaserod 12 mg/day group than in the placebo group;
these differences were not statistically significant for the 4 mg/day
group.

Effects of tegaserod on bowel habits were evaluated in several ways.
Both tegaserod treatment groups had greater treatment responses than
placebo patients with respect to the SGA of bowel habits, but
differences from placebo did not reach statistical significance.
Improvements in number of bowel movements, days without bowel movements
and the percent of days with hard stools in the tegaserod 12 mg/day
group were all significant at endpoint compared with the placebo group.
For the 4 mg/day group, the increase in bowel movements was significant
at endpoint compared with the placebo group.

###### Table 7-6. Summary of the between-treatment comparisons of secondary efficacy variables at endpoint (study B351, ITT population) {#table-7-6.-summary-of-the-between-treatment-comparisons-of-secondary-efficacy-variables-at-endpoint-study-b351-itt-population .unnumbered}

+----------------------+------+--------+---------+--------+---------+
|                      | **P  | **Tega |         | **Tega |         |
|                      | lace | serod\ |         | serod\ |         |
|                      | bo** | 4      |         | 12     |         |
|                      |      | mg/d** |         | mg/d** |         |
+----------------------+------+--------+---------+--------+---------+
|                      |      |        | Dif     |        | Dif     |
|                      |      |        | ference |        | ference |
|                      |      |        | from    |        | from    |
|                      |      |        | pla     |        | pla     |
|                      |      |        | cebo^3^ |        | cebo^3^ |
+----------------------+------+--------+---------+--------+---------+
| Mean percent change  | 3.9% | -      | 19.1%   | -      | 20.8%   |
| from baseline in     |      | 15.2%\ |         | 16.9%\ |         |
| number of days with  |      | (p=    |         | (p=0.  |         |
| significant^1^       |      | 0.147) |         | 017)\* |         |
| discomfort/pain      |      |        |         |        |         |
+----------------------+------+--------+---------+--------+---------+
| Mean percent change  | -    | -      | 9.3%    | -      | 9.5%    |
| from baseline in     | 5.6% | 14.9%\ |         | 15.1%\ |         |
| number of days with  |      | (p=    |         | (p=0.  |         |
| significant^1^       |      | 0.076) |         | 006)\* |         |
| bloating             |      |        |         |        |         |
+----------------------+------+--------+---------+--------+---------+
| Responder rate for   | 2    | 26.4%\ | 6.2%    | 24.7%\ | 4.5%    |
| SGA of bowel habit   | 0.2% | (p=    |         | (p=    |         |
|                      |      | 0.082) |         | 0.218) |         |
+----------------------+------+--------+---------+--------+---------+
| Mean percent change  | -2   | -      | 6.8%    | -      | 9.8%    |
| from baseline in     | 1.4% | 28.2%\ |         | 31.2%\ |         |
| number of days       |      | (p=    |         | (p=0.  |         |
| without bowel        |      | 0.053) |         | 002)\* |         |
| movements            |      |        |         |        |         |
+----------------------+------+--------+---------+--------+---------+
| Mean percent change  | 4    | 68.9%\ | 24.1%   | 69.3%\ | 24.5%   |
| from baseline in     | 4.8% | (p=0.  |         | (p\<   |         |
| number of bowel      |      | 003)\* |         | 0.     |         |
| movements            |      |        |         | 001)\* |         |
+----------------------+------+--------+---------+--------+---------+
| Mean percent of      | 1    | 12.7%\ | 6.2%    | 11.3%\ | 7.6%    |
| days^2^ with hard or | 8.9% | (p=    |         | (p=0.  |         |
| very hard stool      |      | 0.068) |         | 003)\* |         |
+----------------------+------+--------+---------+--------+---------+
| ^1^ Defined as at    |      |        |         |        |         |
| least mild (daily    |      |        |         |        |         |
| score                |      |        |         |        |         |
| [\>]{.underline} 2   |      |        |         |        |         |
| on 6-point scale).   |      |        |         |        |         |
|                      |      |        |         |        |         |
| ^2^ Denominator is   |      |        |         |        |         |
| days with bowel      |      |        |         |        |         |
| movements.           |      |        |         |        |         |
|                      |      |        |         |        |         |
| ^3^ Positive values  |      |        |         |        |         |
| in favor of          |      |        |         |        |         |
| tegaserod.           |      |        |         |        |         |
|                      |      |        |         |        |         |
| Note: P-values are   |      |        |         |        |         |
| the nominal p-values |      |        |         |        |         |
| for the comparison   |      |        |         |        |         |
| between the          |      |        |         |        |         |
| tegaserod dose and   |      |        |         |        |         |
| placebo at endpoint. |      |        |         |        |         |
|                      |      |        |         |        |         |
| \* Indicates a       |      |        |         |        |         |
| statistically        |      |        |         |        |         |
| significant          |      |        |         |        |         |
| difference compared  |      |        |         |        |         |
| to placebo based on  |      |        |         |        |         |
| Holm's multiple      |      |        |         |        |         |
| comparison           |      |        |         |        |         |
| procedure, adjusting |      |        |         |        |         |
| for two tegaserod    |      |        |         |        |         |
| doses, at the        |      |        |         |        |         |
| significance level   |      |        |         |        |         |
| of 0.05.             |      |        |         |        |         |
+----------------------+------+--------+---------+--------+---------+

Weekly results for secondary efficacy variables are displayed in Figures
7-4 to 7-8. Mean daily abdominal discomfort/pain scores were
consistently lower over the 12 weeks in the 12 mg/day group than in the
placebo group, with an effect seen as early as Week 1 (Figure 7-4).
Smaller differences from placebo in mean scores were seen for the 4
mg/day group. Mean daily bloating scores were lower for the 12 mg/day
group than the placebo group during the first and third months of the
study (Figure 7-5).

#######   {#section-3 .unnumbered}

####### ![](media/image9.wmf)Figure 7-4. Mean daily abdominal pain scores by week (B351) {#figure-7-4.-mean-daily-abdominal-pain-scores-by-week-b351 .unnumbered}

\*p-value \<0.05 compared to placebo (change from baseline)

####### ![](media/image10.wmf) {#section-4 .unnumbered}

\*p-value compared to placebo (change from baseline)

Similar to the findings at endpoint, response rates on the SGA of bowel
habits (Figure 7-6), were higher in the tegaserod groups compared with
placebo, but not significantly so for most of the weeks in the study.

####### Figure 7-6. SGA of bowel habits by week (study B351) {#figure-7-6.-sga-of-bowel-habits-by-week-study-b351 .unnumbered}

![](media/image11.wmf)\*p \< 0.05 compared to placebo

The effect of tegaserod on stool frequency is illustrated in Figure 7-7.
A dose-dependent increase in the number of bowel movements was observed
at Week 1, which decreased thereafter but remained significantly higher
than placebo throughout the treatment period. The tegaserod groups had
similar effects beyond Week 3. Results for stool consistency generally
paralleled those for number of bowel movements (Figure 7-8). Tegaserod
decreased stool consistency in a dose-dependent manner in Week 1, with
similar effects for both tegaserod groups seen thereafter throughout the
treatment period.

####### Figure 7-7. Weekly number of bowel movements (study B351) {#figure-7-7.-weekly-number-of-bowel-movements-study-b351 .unnumbered}

![](media/image12.wmf)

\*p-value \<0.05 compared to placebo (change from baseline)

**Figure 7-8. Weekly mean stool consistency (study B351)**

![](media/image13.wmf)

\*p-value \<0.05 compared to placebo (change from baseline)

Scale: 1=watery, 2=loose, 3=somewhat loose, 4= neither loose nor hard,
5=somewhat hard, 6=hard, 7=very hard

**Discussion/Conclusion, Study B351**

Results for the primary efficacy variables, ***original*** SGA of relief
and SGA of abdominal discomfort/pain, failed to reach statistical
significance. However, a consistent pattern of improvement was observed
in the tegaserod groups across the primary and secondary efficacy
variables. Statistically significant improvements in the important
symptoms of IBS, including abdominal discomfort/pain, abdominal bloating
and bowel habits (stool frequency and stool consistency), were seen in
the tegaserod 12 mg/day treatment group compared with placebo. The
consistency of the data both in the weekly SGAs and the daily diary
variables, as well as the effects at multiple timepoints, indicated that
the data are robust. However, the low responder rates in the tegaserod
groups and especially in the placebo group for the primary efficacy
variables suggested that the definition of response was too stringent to
detect true treatment effects. A retrospective analysis in which the
responder definition for the SGA of relief was revised to include
persistent somewhat relief was conducted; this analysis revealed
clinically meaningful and statistically significant differences between
the tegaserod 12 mg/day group and placebo. Since the revised definition
of response was thought to be clinically meaningful and appeared to be a
more sensitive measure of treatment effect, it was adopted as the
primary efficacy variable in studies B301 and B307.

### Study B301 Results

#### A randomized, double-blind, placebo-controlled, multicenter study to assess the safety and efficacy of SDZ HTF 919 at two dose levels and placebo in subjects with constipation-predominant irritable bowel syndrome {#a-randomized-double-blind-placebo-controlled-multicenter-study-to-assess-the-safety-and-efficacy-of-sdz-htf-919-at-two-dose-levels-and-placebo-in-subjects-with-constipation-predominant-irritable-bowel-syndrome-1 .unnumbered}

A total of 1122 patients enrolled in the study of which 881 were
randomized to tegaserod 4 mg/day, tegaserod 12 mg/day or placebo.
Patient disposition by treatment for all randomized patients is
displayed in Table 7-7.

More patients discontinued therapy in the tegaserod 4 mg/day group (18%)
than in the tegaserod 12 mg/day group (14%) or placebo group (13%). The
most common reason for discontinuation was adverse events, with a higher
frequency in the 4 mg/day tegaserod group (9%) compared with the 12
mg/day (5%) and placebo (4%) groups. The number of discontinuations due
to unsatisfactory therapeutic effect and other reasons was similarly
distributed among the three treatment groups.

###### Table 7-7. Summary of patient disposition and primary reasons for discontinuations by treatment group (study B301) {#table-7-7.-summary-of-patient-disposition-and-primary-reasons-for-discontinuations-by-treatment-group-study-b301 .unnumbered}

  ------------------------- ------------- -------------- ------------- -----------
                            **Placebo**   **Tegaserod\   **Tegaserod   **Total**
                                          4 mg/d**       12 mg/d**     

                            **N (%)**     **N (%)**      **N (%)**     **N (%)**

  Randomized into           288           299            294           881
  double-blind period (ITT                                             
  population)                                                          

  Completed the treatment   251 (87.2%)   246 (82.3%)    254 (86.4%)   751 (85.2%)
  period                                                               

  Discontinued prematurely  37 (12.8%)    53 (17.7%)     40 (13.6%)    130 (14.8%)
  during the treatment                                                 
  period (total)                                                       

  Adverse Events            12 (4.2%)     26 (8.7%)      15 (5.1%)     53 (6.0%)

  Unsatisfactory            8 (2.8%)      8 (2.7%)       7 (2.4%)      23 (2.6%)
  therapeutic effect                                                   

  Subject withdrew consent  7 (2.4%)      5 (1.7%)       10 (3.4%)     22 (2.5%)

  Protocol Violation        4 (1.4%)      7 (2.3%)       5 (1.7%)      16 (1.8%)

  Lost to follow-up         6 (2.1%)      5 (1.7%)       3 (1.0%)      14 (1.6%)

  Patient's condition no    0             1 (0.3%)       0             1 (0.1%)
  longer required drug                                                 

  Death                     0             1 (0.3%)       0             1 (0.1%)
  ------------------------- ------------- -------------- ------------- -----------

**Efficacy results**

The results for the primary efficacy variable, the SGA of relief at
endpoint in the ITT population, are given in Table 7-8. Both tegaserod
treatment groups had greater responder rates than the placebo group. The
differences from placebo in responder rates for both the 4 mg/day and
the 12 mg/day tegaserod group were statistically significant.

###### Table 7-8. Responder rate for SGA of relief at endpoint (study B301) {#table-7-8.-responder-rate-for-sga-of-relief-at-endpoint-study-b301 .unnumbered}

+----------------------------+-------------+-------------+-------------+
|                            | **Placebo\  | *           | *           |
|                            | \           | *Tegaserod\ | *Tegaserod\ |
|                            | (N=288)**   | 4 mg/d\     | 12 mg/d\    |
|                            |             | (N=299)**   | (N=294)**   |
+----------------------------+-------------+-------------+-------------+
| Responder rate^1^ (n)      | 30.2% (87)  | 38.8% (116) | 38.4% (113) |
+----------------------------+-------------+-------------+-------------+
| Treatment difference from  |             | 9.1%        | 8.3%        |
| placebo^2^                 |             |             |             |
+----------------------------+-------------+-------------+-------------+
| P-value                    |             | 0.018\*     | 0.033\*     |
+----------------------------+-------------+-------------+-------------+
| ^1^ Adjusted for missing   |             |             |             |
| SGAs, treatment duration,  |             |             |             |
| laxative use.              |             |             |             |
|                            |             |             |             |
| ^2^ Treatment difference   |             |             |             |
| (weighted by center) in    |             |             |             |
| responder rate and p-value |             |             |             |
| (nominal p-value) refer to |             |             |             |
| the comparison between the |             |             |             |
| tegaserod dose and placebo |             |             |             |
| at endpoint.               |             |             |             |
|                            |             |             |             |
| \* Indicates a             |             |             |             |
| statistically significant  |             |             |             |
| difference compared to     |             |             |             |
| placebo based on           |             |             |             |
| Hochberg\'s multiple       |             |             |             |
| comparison procedure,      |             |             |             |
| adjusting for two          |             |             |             |
| tegaserod doses, at the    |             |             |             |
| significance level of      |             |             |             |
| 0.05.                      |             |             |             |
+----------------------------+-------------+-------------+-------------+

The adjustment rules reduced the responder rate to a greater extent in
the tegaserod groups than in the placebo group. Despite the similarity
in laxative use in the overall population (Table 7-2), it was the
laxative adjustment rule (laxative use \> 5 days during the treatment
period and/or at least once during the last 4 weeks of treatment) that
had the major impact on reducing the treatment differences in responder
rates between the tegaserod groups and placebo. Responder rates not
adjusted for laxatives (i.e., includes adjustment criteria for missing
SGAs and treatment duration \< 28 days but not the laxative adjustment)
were 33.3%, 43.5% and 44.9% in the placebo, tegaserod 4 mg/day, and 12
mg/day groups, respectively with treatment differences from placebo of
10.2 for 4 mg/day and 11.6 for 12 mg/day. The impact of the adjustment
rules on responder rates is discussed more fully in section 7.2 (Table
7-17).

Monthly responder rates are given in Figure 7-9. Responder rates for the
12 mg/day group were significantly higher for all months, and for the 4
mg/day group significantly higher for month 2 and month 3, than the
corresponding placebo rates.

####### Figure 7-9. Unadjusted responder rate for SGA of relief by monthly interval ![](media/image14.wmf) {#figure-7-9.-unadjusted-responder-rate-for-sga-of-relief-by-monthly-interval .unnumbered}

\*p-value \<0.05 compared to placebo

Figure 7-10 displays the weekly percentage of patients who experienced
at least somewhat relief. A treatment effect is seen at week 1, which
persists for both tegaserod groups over the 12-week treatment period.

####### ![](media/image15.wmf) {#section-5 .unnumbered}

\*p-value \<0.05 compared to placebo

Responder rates for the ***original*** SGA of relief, considerably or
completely relieved at least 50% of the time, at endpoint for the ITT
population are shown below in Table 7-9.

###### Table 7-9. Responder rates for the *original* SGA of relief at endpoint (ITT population) {#table-7-9.-responder-rates-for-the-original-sga-of-relief-at-endpoint-itt-population .unnumbered}

  ------------------------------ ------------- ------------- -------------
                                 **Placebo**   **Tegaserod 4 **Tegaserod
                                               mg/d**        12 mg/d**

                                 N=288         N=299         N=294

  Response rate^1^ (n)           20.5% (59)    27.8% (83)    26.2% (77)

  Treatment difference in                      7.6%          5.5%
  responder rate^2^                                          

  P-value                                      0.028^\*^     0.116
  ------------------------------ ------------- ------------- -------------

> ^1^ Adjusted for missing SGAs, treatment duration, laxative use.
>
> ^2^ Treatment difference (weighted by center) in responder rate and
> p-value (nominal p-value) refer to the comparison between the
> tegaserod dose and placebo at endpoint.
>
> \* Indicates the nominal p-value \< 0.05.

**Secondary efficacy variables**

As shown in Table 7-10, the responder rate for the SGA of abdominal
discomfort/pain was higher than placebo for both tegaserod groups. This
difference from placebo reached statistical significance for the
tegaserod 12 mg/day treatment group.

###### Table 7-10. Responder rate for SGA of abdominal discomfort/pain at endpoint (study B301, ITT population) {#table-7-10.-responder-rate-for-sga-of-abdominal-discomfortpain-at-endpoint-study-b301-itt-population .unnumbered}

+------------------------------+------------+------------+------------+
|                              | **Placebo\ | **         | **         |
|                              | **         | Tegaserod\ | Tegaserod\ |
|                              |            | 4 mg/d**   | 12 mg/d**  |
+------------------------------+------------+------------+------------+
|                              | N = 287    | N = 299    | N = 294    |
+------------------------------+------------+------------+------------+
| Responder rate^1^ (n)        | 22.6% (65) | 29.8% (89) | 29.9% (88) |
+------------------------------+------------+------------+------------+
| Treatment difference in      |            | 7.0%       | 7.3%       |
| responder rate^2^            |            |            |            |
+------------------------------+------------+------------+------------+
| P-value                      |            | 0.055      | 0.044\*    |
+------------------------------+------------+------------+------------+
| ^1^ Adjusted for missing     |            |            |            |
| SGAs, treatment duration,    |            |            |            |
| laxative use.                |            |            |            |
|                              |            |            |            |
| ^2^ Treatment difference     |            |            |            |
| (weighted by center) in      |            |            |            |
| responder rate and p-value   |            |            |            |
| (nominal p-value) refer to   |            |            |            |
| the comparison between the   |            |            |            |
| tegaserod dose and placebo   |            |            |            |
| at endpoint.                 |            |            |            |
|                              |            |            |            |
| \* Indicates the nominal     |            |            |            |
| p-value \< 0.05.             |            |            |            |
+------------------------------+------------+------------+------------+

Monthly responder rates for the SGA of abdominal discomfort/pain are
shown in Figure 7-11A, with the weekly responder rates shown in Figure
7-11B. Monthly responder rates were higher for the 12 mg/day group
compared with placebo at all timepoints, with smaller treatment
differences between the 4 mg/day and placebo groups. Weekly responder
rates showed generally similar results.

####### Figure 7-11A. Unadjusted responder rate for SGA of abdominal discomfort/pain by monthly interval (study B301) {#figure-7-11a.-unadjusted-responder-rate-for-sga-of-abdominal-discomfortpain-by-monthly-interval-study-b301 .unnumbered}

![](media/image16.wmf)\*p-value \<0.05 compared to placebo

####### Figure 7-11B. SGA of abdominal discomfort/pain by week (study B301) {#figure-7-11b.-sga-of-abdominal-discomfortpain-by-week-study-b301 .unnumbered}

![](media/image17.wmf)

\*p-value \<0.05 compared to placebo

The results of between-treatment comparisons for the other secondary
efficacy variables at endpoint are shown in Table 7-11. Although the
average decrease from baseline for both days of significant
discomfort/pain and bloating was greater in the tegaserod groups
compared with placebo, these differences were not statistically
significant. For both tegaserod treatment groups, there was a higher
treatment response than placebo in regard to the SGA of bowel habit, but
the differences to placebo did not reach statistical significance.
Number of bowel movements and days without bowel movements both
significantly improved in the tegaserod groups compared with placebo.

###### Table 7-11. Summary of the between-treatment comparisons of secondary efficacy variables at endpoint (study B301) {#table-7-11.-summary-of-the-between-treatment-comparisons-of-secondary-efficacy-variables-at-endpoint-study-b301 .unnumbered}

+----------------------+------+--------+---------+--------+---------+
|                      | **P  | **Tega |         | **Tega |         |
|                      | lace | serod\ |         | serod\ |         |
|                      | bo** | 4      |         | 12     |         |
|                      |      | mg/d** |         | mg/d** |         |
+----------------------+------+--------+---------+--------+---------+
|                      |      |        | Dif     |        | Dif     |
|                      |      |        | ference |        | ference |
|                      |      |        | from    |        | from    |
|                      |      |        | pla     |        | pla     |
|                      |      |        | cebo^3^ |        | cebo^3^ |
+----------------------+------+--------+---------+--------+---------+
| Mean percent change  | -1   | -      | 8.5%    | -      | 8.2%    |
| from baseline in     | 0.4% | 18.9%\ |         | 18.6%\ |         |
| number of days with  |      | (p=    |         | (p=    |         |
| significant^1^       |      | 0.180) |         | 0.116) |         |
| discomfort/pain      |      |        |         |        |         |
+----------------------+------+--------+---------+--------+---------+
| Mean percent change  | 4.0% | -      | 14.7%   | -8.3%\ | 12.3%   |
| from baseline in     |      | 10.7%\ |         | (p=    |         |
| number of days with  |      | (p=    |         | 0.485) |         |
| significant^1^       |      | 0.128) |         |        |         |
| bloating             |      |        |         |        |         |
+----------------------+------+--------+---------+--------+---------+
| Responder rate for   | 2    | 28.8%  | 6.2%    | 26.2%  | 3.6%    |
| SGA of bowel habit   | 2.6% | (p=    |         | (p=    |         |
|                      |      | 0.096) |         | 0.337) |         |
+----------------------+------+--------+---------+--------+---------+
| Mean percent change  | -1   | -      | 11.4%   | -      | 3.2%    |
| from baseline in     | 9.2% | 30.6%\ |         | 22.4%\ |         |
| number of days       |      | (p=0.  |         | (p=0.  |         |
| without bowel        |      | 012)\* |         | 013)\* |         |
| movements            |      |        |         |        |         |
+----------------------+------+--------+---------+--------+---------+
| Mean percent change  | 4    | 59.2%\ | 17.2%   | 54.6%\ | 12.6%   |
| from baseline in     | 2.0% | (p=    |         | (p=    |         |
| number of bowel      |      | 0.     |         | 0.     |         |
| movements            |      | 001)\* |         | 009)\* |         |
+----------------------+------+--------+---------+--------+---------+
| Mean percent of      | 1    | 12.8%\ | 2.2%    | 13.7%\ | 1.3%    |
| days^2^ with hard or | 5.0% | (p=    |         | (p=    |         |
| very hard stool      |      | 0.084) |         | 0.803) |         |
+----------------------+------+--------+---------+--------+---------+
| ^1^ Defined as at    |      |        |         |        |         |
| least mild (daily    |      |        |         |        |         |
| score                |      |        |         |        |         |
| [\>]{.underline} 2   |      |        |         |        |         |
| on 6-point scale).   |      |        |         |        |         |
|                      |      |        |         |        |         |
| ^2^ Denominator is   |      |        |         |        |         |
| days with bowel      |      |        |         |        |         |
| movements.           |      |        |         |        |         |
|                      |      |        |         |        |         |
| ^3^ Positive values  |      |        |         |        |         |
| in favor of          |      |        |         |        |         |
| tegaserod.           |      |        |         |        |         |
|                      |      |        |         |        |         |
| Note: p-value        |      |        |         |        |         |
| (nominal p-value)    |      |        |         |        |         |
| refers to the        |      |        |         |        |         |
| comparison between   |      |        |         |        |         |
| the tegaserod dose   |      |        |         |        |         |
| and placebo at       |      |        |         |        |         |
| endpoint.\           |      |        |         |        |         |
| \* Indicates the     |      |        |         |        |         |
| nominal p-value \<   |      |        |         |        |         |
| 0.05.                |      |        |         |        |         |
+----------------------+------+--------+---------+--------+---------+

Weekly displays of the secondary efficacy variables are presented below.
Mean daily abdominal discomfort/pain scores were lower in the tegaserod
groups than in the placebo group throughout the 12 weeks (Figure 7-12).
Similarly, bloating scores were lower in the tegaserod groups than in
placebo (Figure 7-13).

####### ![](media/image18.wmf) {#section-6 .unnumbered}

\*p-value \<0.05 compared to placebo (change from baseline)

####### Figure 7-13. Mean daily bloating scores by week (study B301) {#figure-7-13.-mean-daily-bloating-scores-by-week-study-b301 .unnumbered}

![](media/image19.wmf)\*p-value \<0.05 compared to placebo (change from
baseline)

Weekly response rates for the SGA of bowel habits were also higher in
the tegaserod groups than in the placebo group (Figure 7-14).

####### Figure 7-14. SGA of bowel habit by week (study B301) {#figure-7-14.-sga-of-bowel-habit-by-week-study-b301 .unnumbered}

![](media/image20.wmf)\*p-value \<0.05 compared to placebo

The effects of tegaserod on the number of bowel movements and on stool
consistency are also illustrated in Figures 7-15 and 7-16. A
dose-dependent increase in bowel movements and decrease in stool
consistency occurred during Week 1, which remained different from
placebo for the 12-week treatment period.

####### Figure 7-15. Weekly number of bowel movements (study B301) {#figure-7-15.-weekly-number-of-bowel-movements-study-b301 .unnumbered}

![](media/image21.wmf)

![](media/image22.wmf)

####### Figure 7-16. Weekly mean stool consistency (study B301) {#figure-7-16.-weekly-mean-stool-consistency-study-b301 .unnumbered}

\*p-value \<0.05 compared to placebo (change from baseline)

Scale: 1=watery, 2=loose, 3=somewhat loose, 4= neither loose nor hard,
5=somewhat hard, 6=hard, 7=very hard

**Discussion/Conclusion, Study B301**

Compared with placebo, both the tegaserod 4 mg/day and 12 mg/day groups
had statistically significant higher response rates on the SGA of relief
at endpoint, the primary efficacy variable in this study. This effect
was observed in the tegaserod 12 mg/day group at the end of the first
month and was sustained over the 3 month treatment period; higher
response rates than placebo were seen at Month 1 (p\<0.01), Month 2
(p\<0.05) and at Month 3 (p\<0.01). For the tegaserod 4 mg/day group,
higher response rates than placebo were observed at Month 2 (p\<0.01)
and at Month 3 (p\<0.05).

Response rates on SGA of relief were adjusted for several factors,
including laxative intake. As overall laxative intake (both number of
patients and number of days) was similar among treatment groups and
laxatives are not clearly an escape medication for the abdominal pain of
IBS, it maybe reasonable to use the non-laxative adjusted treatment
difference to estimate the magnitude of effect. These differences,
compared to placebo, were 12% for tegaserod 12 mg/day and 10% for
tegaserod 4 mg/day (see Section 7.2, Table 7-17 Impact of adjustment
criteria on responder rate for SGA of relief in individual studies).

For the daily diary variables days with significant abdominal
discomfort/pain and days with significant bloating, trends in favor of
tegaserod were observed but these results were not statistically
significant at endpoint. Tegaserod 4 mg/day and 12 mg/day increased the
number of bowel movements and decreased the number of days without bowel
movements.

In summary, in this study, tegaserod 12 mg/day was effective in
relieving overall IBS symptoms, abdominal discomfort and pain, and in
improving stool frequency and stool consistency. Even though reaching
statistical significance for the primary efficacy variable, tegaserod 4
mg/day showed a less consistent effect across variables and time.

### Study B307 Results

#### A randomized, double-blind, placebo-controlled, multicenter study to assess the safety and efficacy of SDZ HTF 919 at two dose regimens and placebo in subjects with constipation-predominant irritable bowel syndrome {#a-randomized-double-blind-placebo-controlled-multicenter-study-to-assess-the-safety-and-efficacy-of-sdz-htf-919-at-two-dose-regimens-and-placebo-in-subjects-with-constipation-predominant-irritable-bowel-syndrome .unnumbered}

A total of 1163 patients enrolled in the study of which 845 were
randomized to tegaserod 4 mg/day, tegaserod 4-12 mg/day (titration
group) or placebo. Patient disposition by treatment for all randomized
patients is displayed in Table 7-12.

More patients discontinued double-blind treatment in the tegaserod 4
mg/day group (23%) than in the tegaserod 4-12 mg/day (17%) and placebo
(19%) groups, although withdrawals due to adverse events and lack of
efficacy were similar among the treatment groups.

###### Table 7-12. Summary of patient disposition and primary reasons for discontinuations by treatment group (study B307) {#table-7-12.-summary-of-patient-disposition-and-primary-reasons-for-discontinuations-by-treatment-group-study-b307 .unnumbered}

+-------------------------+----------+----------+----------+----------+
|                         | **P      | **Te     | **Te     | *        |
|                         | lacebo** | gaserod\ | gaserod\ | *Total** |
|                         |          | 4 mg/d** | 4-12     |          |
|                         |          |          | mg/d**   |          |
+-------------------------+----------+----------+----------+----------+
|                         | **N      | **N      | **N      | **N      |
|                         | (%)**    | (%)**    | (%)**    | (%)**    |
+-------------------------+----------+----------+----------+----------+
| Randomized into         | 285      | 283      | 277      | 845^1^   |
| double-blind period^1^  |          |          |          |          |
+-------------------------+----------+----------+----------+----------+
| ITT population          | 284      | 282      | 275      | 841      |
|                         | (99.6%)  | (99.6%)  | (99.3%)  | (99.5%)  |
+-------------------------+----------+----------+----------+----------+
| Completed the double    | 232      | 217      | 231      | 680      |
| period                  | (81.4%)  | (76.7%)  | (83.4%)  | (80.5%)  |
+-------------------------+----------+----------+----------+----------+
| Discontinued            | 53       | 66       | 46       | 165      |
| prematurely during the  | (18.6%)  | (23.3%)  | (16.6%)  | (19.5%)  |
| treatment period        |          |          |          |          |
| (total)                 |          |          |          |          |
+-------------------------+----------+----------+----------+----------+
| > Adverse Events        | 22       | 25       | 21       | 68       |
|                         | (7.7%)   | (8.8%)   | (7.6%)   | (8.0%)   |
+-------------------------+----------+----------+----------+----------+
| > Abnormal laboratory   | 0        | 0        | 2 (0.7%) | 2 (0.2%) |
| > values                |          |          |          |          |
+-------------------------+----------+----------+----------+----------+
| > Unsatisfactory        | 4 (1.4%) | 5 (1.8%) | 3 (1.1%) | 12       |
| > therapeutic effect    |          |          |          | (1.4%)   |
+-------------------------+----------+----------+----------+----------+
| > Subject withdrew      | 13       | 18       | 10       | 41       |
| > consent               | (4.6%)   | (6.4%)   | (3.6%)   | (4.9%)   |
+-------------------------+----------+----------+----------+----------+
| > Protocol violation    | > 0      | > 5      | > 1      | > 6      |
|                         |          | > (1.8%) | > (0.4%) | > (0.7%) |
+-------------------------+----------+----------+----------+----------+
| > Lost to follow-up     | 12       | 11       | 6 (2.2%) | 29       |
|                         | (4.2%)   | (3.9%)   |          | (3.4%)   |
+-------------------------+----------+----------+----------+----------+
| > Administrative        | 2 (0.7%) | 2 (0.7%) | 3 (1.1%) | 7 (0.8%) |
+-------------------------+----------+----------+----------+----------+

^1^ A total of 845 patients were randomized. One study center was
terminated early due to concern with possible noncompliance with Good
Clinical Practices. At the time of termination, 4 patients were
randomized but had not completed the study; these four patients were not
included in the ITT population.

**Efficacy results**

The responder rates for the primary efficacy variable, the SGA of relief
at endpoint in the ITT population, are given in Table 7-13. The
responder rate for the tegaserod 4-12 mg/day group was greater compared
with placebo, but this difference was not statistically significant. The
responder rates for the tegaserod 4 mg/day and placebo groups were
similar.

###### Table 7-13. Responder rate for SGA of relief at endpoint (study B307) {#table-7-13.-responder-rate-for-sga-of-relief-at-endpoint-study-b307 .unnumbered}

+--------------------------+-------------+-------------+-------------+
|                          | **Placebo\  | *           | *           |
|                          | \           | *Tegaserod\ | *Tegaserod\ |
|                          | (N=284)**   | 4 mg/d\     | 4-12 mg/d\  |
|                          |             | (N=282)**   | (N=275)**   |
+--------------------------+-------------+-------------+-------------+
| Responder rate^1^ (n)    | 37.0% (105) | 38.3% (108) | 42.2% (116) |
+--------------------------+-------------+-------------+-------------+
| Treatment difference     |             | 0.8%        | 6.0%        |
| from placebo^2^          |             |             |             |
+--------------------------+-------------+-------------+-------------+
| P-value^2^               |             | 0.837       | 0.142       |
+--------------------------+-------------+-------------+-------------+
| ^1^ Adjusted for missing |             |             |             |
| SGAs, treatment          |             |             |             |
| duration, laxative use.  |             |             |             |
|                          |             |             |             |
| ^2^ Treatment difference |             |             |             |
| (weighted by center) in  |             |             |             |
| responder rate and       |             |             |             |
| p-value (nominal         |             |             |             |
| p-value) refer to the    |             |             |             |
| comparison between the   |             |             |             |
| tegaserod dose and       |             |             |             |
| placebo at endpoint.     |             |             |             |
+--------------------------+-------------+-------------+-------------+

The percentage of patients titrated at Month 1 were 68%, 65% and 73% in
the tegaserod 4 mg/day, 4-12 mg/day and placebo groups, respectively.
Monthly responder rates for the SGA of relief are shown in Figure 7-17.
These monthly responder rates raise yielded two unusual findings:

-   an inconsistency in Month 1 responder rates between the tegaserod
    groups, as both groups received identical treatment (i.e., tegaserod
    4 mg/day) during study Month 1, and

-   ![](media/image23.wmf)

####### Figure 7-17. Unadjusted responder rate for SGA of relief by monthly interval (study B307) {#figure-7-17.-unadjusted-responder-rate-for-sga-of-relief-by-monthly-interval-study-b307 .unnumbered}

\*p-value \<0.05 compared to placebo

The weekly percentage of patients that were at least somewhat relieved
is shown in Figure 7-18.

####### Figure 7-18. Weekly percentage of patients with at least somewhat relief for SGA of relief (study B307) {#figure-7-18.-weekly-percentage-of-patients-with-at-least-somewhat-relief-for-sga-of-relief-study-b307 .unnumbered}

![](media/image24.wmf)\*p-value \<0.05 compared to placebo

As shown in Figure 7-18, at the time of dose-titration from Week 4 to
Week 5, there was an unusually large increase of 12% in the placebo
group compared with a decrease of 2% and increase of 4% in the tegaserod
4 mg/day and 4-12 mg/day groups, respectively. This increased placebo
response then persisted for the remainder of the study.

Table 7-14 presents the results in the titrated (or mock titrated in
tegaserod 4 mg/day and placebo groups) and non-titrated patients from
Week 2 to Week 7. It is apparent that it was the titrated patients in
the placebo group that had an unexpected increase in response at the
time of titration. For the (mock) titrated placebo patients, there was
an increase of 17% in the proportion of patients with at least somewhat
relief from 36% to 53% immediately after (mock) dose-titration from Week
4 to 5. Similar increases were not observed in the titrated placebo
patients at other weeks or in the titrated patients in the tegaserod
groups. These findings may be explained by heightened expectations at
the time of dose-titration, making interpretation of results after
dose-titration difficult.

###### Table 7-14. Weekly percentage of patients with at least somewhat relief for SGA of relief in titrated and non-titrated patients (study B307)  {#table-7-14.-weekly-percentage-of-patients-with-at-least-somewhat-relief-for-sga-of-relief-in-titrated-and-non-titrated-patients-study-b307 .unnumbered}

  ----------------- ------ -------- ------ -------- ------ --------- ------ --------- ------ -------- ------ --------
  **Treatment**            **Week 2        **Week 3        **Week           **Week 5         **Week 6        **Week 7
                           % (N)**         % (N)**         4^1^ %           % (N)**          % (N)**         % (N)**
                                                           (N)**                                             

  Placebo                                                                                                    

  Titrated                 35%             40%             **36%            **53%            54%             53%
                           (209)           (209)           (209)**          (206)**          (203)           (200)

  Not titrated             84% (49)        86% (49)        83% (47)         81% (48)         69% (48)        83% (48)

  Tegaserod 4 mg/d                                                                                           

  Titrated                 44%             42%             46% (193)        45% (190)        50%             49%
                           (193)           (193)                                             (187)           (185)

  Not titrated             86% (50)        86% (50)        90% (50)         82% (50)         84% (50)        84% (50)

  Tegaserod 4-12                                                                                             
  mg/d                                                                                                       

  Titrated                 43%             49%             48% (181)        53% (177)        53%             53%
                           (181)           (180)                                             (175)           (174)

  Not titrated      93%             93%             94%              93%              88%             84%    
                    (69)            (69)            (68)             (69)             (68)            (68)   
  ----------------- ------ -------- ------ -------- ------ --------- ------ --------- ------ -------- ------ --------

N = total number of patients in titrated or nontitrated group for that
week.

^1^ Dose-titration at end of Week 4.

Results for the ***original*** SGA of relief, (complete or considerable
relief at least 50% of the time), for the ITT population at endpoint are
shown below in Table 7-15.

###### Table 7-15. Responder rates for the *original* SGA of relief at endpoint (ITT population) {#table-7-15.-responder-rates-for-the-original-sga-of-relief-at-endpoint-itt-population .unnumbered}

  ------------------------------ ------------- ------------- -------------
                                 **Placebo**   **Tegaserod 4 **Tegaserod
                                               mg/d**        4-12 mg/d**

                                 N=284         N=282         N=275

  Response rate^1^ (n)           28.2% (80)    25.5% (72)    26.5% (73)

  Treatment difference in                      -3.0          -1.4
  responder rate^2^                                          

  P-value                                      0.422         0.703
  ------------------------------ ------------- ------------- -------------

> ^1^ Adjusted for missing SGAs, treatment duration, laxative use.
>
> ^2^ Treatment difference (weighted by center) in responder rate and
> p-value (nominal p-value) refer to the comparison between the
> tegaserod dose and placebo at endpoint.

**Secondary efficacy variables**

Results for the secondary efficacy variables at endpoint are presented
in Table 7-16. The results on the SGA of abdominal discomfort/pain, SGA
of bowel habits and daily diary variables of abdominal pain and bloating
were variable, but none of the differences at endpoint between tegaserod
groups and placebo were statistically significant. Tegaserod 4-12 mg/day
group did significantly increase the number of bowel movements and
decrease the number of days without bowel movements compared with
placebo at endpoint.

###### Table 7-16. Summary of the between-treatment comparisons of secondary efficacy variables at endpoint (study B307, ITT population) {#table-7-16.-summary-of-the-between-treatment-comparisons-of-secondary-efficacy-variables-at-endpoint-study-b307-itt-population .unnumbered}

+------------------------+------+--------+---------+--------+--------+
|                        | **   | **Tega |         | **Tega |        |
|                        | Plac | serod\ |         | serod\ |        |
|                        | ebo\ | 4      |         | 4-12   |        |
|                        | **   | mg/d** |         | mg/d** |        |
+------------------------+------+--------+---------+--------+--------+
|                        |      |        | Dif     |        | Diff   |
|                        |      |        | ference |        | erence |
|                        |      |        | from    |        | from   |
|                        |      |        | pla     |        | plac   |
|                        |      |        | cebo^3^ |        | ebo^3^ |
+------------------------+------+--------+---------+--------+--------+
| Responder rate for SGA | 3    | 25.5%  | -5.1%   | 27.6%  | -3.0%  |
| of abdominal           | 0.6% | (p=    |         | (p     |        |
| discomfort/pain        |      | 0.141) |         | =.411) |        |
+------------------------+------+--------+---------+--------+--------+
| Responder rate for SGA | 2    | 27.0%  | 2.0%    | 24.0%  | -1%    |
| of bowel habits        | 5.0% | (p=    |         | (p=    |        |
|                        |      | 0.661) |         | 0.847) |        |
+------------------------+------+--------+---------+--------+--------+
| Mean percent change    | -1   | -      | 1.1%    | -      | 3.5%   |
| from baseline in       | 2.7% | 13.8%\ |         | 16.2%\ |        |
| number of days with    |      | (p=    |         | (p=    |        |
| significant^1^         |      | 0.884) |         | 0.273) |        |
| discomfort/pain        |      |        |         |        |        |
+------------------------+------+--------+---------+--------+--------+
| Mean percent change    | -1   | -      | -3.2%   | -8.0%\ | -5.8%  |
| from baseline in       | 3.8% | 10.6%\ |         | (p=    |        |
| number of days with    |      | (p=    |         | 0.513) |        |
| significant^1^         |      | 0.196) |         |        |        |
| bloating               |      |        |         |        |        |
+------------------------+------+--------+---------+--------+--------+
| Mean percent change    | -1   | -      | 6.3%    | -      | 7.6%   |
| from baseline in       | 4.4% | 20.7%\ |         | 22.0%\ |        |
| number of days without |      | (p=    |         | (p=0.  |        |
| bowel movements        |      | 0.053) |         | 018)\* |        |
+------------------------+------+--------+---------+--------+--------+
| Mean percent change    | 2    | 67.2%\ | 37.7%   | 59.4%\ | 29.9%  |
| from baseline in       | 9.5% | (p=0.  |         | (p\<0. |        |
| number of bowel        |      | 001)\* |         | 001)\* |        |
| movements              |      |        |         |        |        |
+------------------------+------+--------+---------+--------+--------+
| Mean percent of        | 1    | 13.8%\ | 2.4%    | 13.0%\ | 3.2%   |
| days^2^ with hard or   | 6.2% | (p=    |         | (p=    |        |
| very hard stool        |      | 0.692) |         | 0.218) |        |
+------------------------+------+--------+---------+--------+--------+
| Note: P-values are the |      |        |         |        |        |
| nominal p-values for   |      |        |         |        |        |
| the comparison between |      |        |         |        |        |
| the tegaserod dose and |      |        |         |        |        |
| placebo at endpoint.\  |      |        |         |        |        |
| \* Indicates the       |      |        |         |        |        |
| nominal p-value        |      |        |         |        |        |
| \<0.05.                |      |        |         |        |        |
|                        |      |        |         |        |        |
| ^1^ Defined as at      |      |        |         |        |        |
| least mild (daily      |      |        |         |        |        |
| score [\>]{.underline} |      |        |         |        |        |
| 2 on 6-point scale);   |      |        |         |        |        |
|                        |      |        |         |        |        |
| ^2^ Denominator is     |      |        |         |        |        |
| days with bowel        |      |        |         |        |        |
| movements.             |      |        |         |        |        |
|                        |      |        |         |        |        |
| ^3^ Positive value in  |      |        |         |        |        |
| favor of tegaserod.    |      |        |         |        |        |
+------------------------+------+--------+---------+--------+--------+

The secondary efficacy variables at weekly intervals are presented
below. Of note, for the weekly SGA of abdominal discomfort/pain (Figure
7-19), a large increase (11%) in responder rate occurred in the
tegaserod 4-12 mg/day group at the time of dose titration (ie, Week 4),
which did not occur in the tegaserod 4 mg/day and placebo groups. These
results are in contrast to those observed for the weekly percentage of
patients with at least somewhat relief (Figure 7-18). Differences from
placebo on the SGA of abdominal discomfort/pain were not apparent beyond
Week 6.

####### ![](media/image25.wmf) {#section-7 .unnumbered}

\*p-value \<0.05 compared to placebo

Mean abdominal discomfort/pain and bloating scores, weekly SGA of bowel
habits, stool frequency and stool consistency scores are shown below in
Figures 7-20 through 7-24. Pain scores were lower for the tegaserod 4-12
mg/day group than placebo for most of the study, with a higher score
noted at Week 12. Bloating scores were variable and tended to be higher
in the number of bowel movements and stool consistency scores were most
prominent early in the study, but did persist over the 12 weeks.

####### ![](media/image26.wmf) {#section-8 .unnumbered}

\*p-value compared to placebo (change from baseline)

####### Figure 7-21. Mean daily bloating scores by week (B307) {#figure-7-21.-mean-daily-bloating-scores-by-week-b307 .unnumbered}

![](media/image27.wmf)\*p-value compared to placebo (change from
baseline)

####### Figure 7-22. SGA of bowel habit by week (study B307) {#figure-7-22.-sga-of-bowel-habit-by-week-study-b307 .unnumbered}

![](media/image28.wmf)

\*p-value \<0.05 compared to placebo

####### Figure 7-23. Weekly number of bowel movements (study B307) {#figure-7-23.-weekly-number-of-bowel-movements-study-b307 .unnumbered}

![](media/image29.wmf)

\*p-value \<0.05 compared to placebo (change from baseline)

####### ![](media/image30.wmf) {#section-9 .unnumbered}

\*p-value \<0.05 compared to placebo (change from baseline)

Scale: 1=watery, 2=loose, 3=somewhat loose, 4= neither loose nor hard,
5=somewhat hard, 6=hard, 7=very hard

**Discussion/Conclusion, Study B307**

At endpoint, treatment differences between the tegaserod groups and
placebo on the primary and secondary outcome measures were variable and
did not reach statistical significance for the primary efficacy variable
for either tegaserod treatment group compared with placebo.

This study incorporated a dose-titration design. At Week 4, patients in
the tegaserod 4-12 mg/day group underwent dose-titration and those in
the tegaserod 4 mg/day and placebo groups underwent mock dose-titration,
according to response on the SGA of relief. All patients in the study
received the same number of tablets both before and after
dose-titration. For unexplained reasons, the titrated patients in the
placebo group had a substantial increase in response (% at least
somewhat relief) immediately following dose-titration, which was not
observed in the tegaserod groups and which persisted for the remainder
of the study. However, for the SGA of abdominal discomfort/pain, a large
increase in response was observed in the tegaserod 4-12 mg/day group at
the time of titration. These mixed results may relate in some way to
heightened expectations at the time of dose-titration, or other unknown
reasons such as chance findings. Interpretations of results from this
study are difficult.

## Sensitivity Analyses

**Impact of adjustment rules**

The magnitude of the treatment difference between tegaserod and placebo
was impacted by "adjustment rules" whereby a responder on the SGA of
relief was declared a nonresponder in the primary analysis for the
following:

-   there were no SGAs available

-   duration of treatment was \< 28 days

-   laxative intake was \> 5 days during the treatment period or
    [\>]{.underline} 1 day during the last 4 weeks of treatment.

The impact of these adjustment rules are shown in Table 7-17. Only
unadjusted responder rates do not include the entire ITT population (ie,
patients with missing SGAs were excluded from the unadjusted analysis,
but were declared nonresponders in the other analyses). The type of
adjustment factor applied did not affect statistical significance of the
treatment comparisons.

###### Table 7-17. Impact of adjustment criteria on responder rate for SGA of relief in individual studies (ITT population) {#table-7-17.-impact-of-adjustment-criteria-on-responder-rate-for-sga-of-relief-in-individual-studies-itt-population .unnumbered}

+-------------------+-----+---------+---------------+----------------+
|                   | **S | **      | **tegaserod 4 | **tegaserod 12 |
|                   | tud | placebo | mg/d %        | mg/d %         |
|                   | y** | %       | response**    | response**     |
|                   |     | r       |               |                |
|                   |     | esponse | **(N, diff.   | **(N, diff.    |
|                   |     | (N)**   | from          | from           |
|                   |     |         | placebo)**    | placebo)**     |
+-------------------+-----+---------+---------------+----------------+
| Unadjusted        | B   | 38.9    | 46.1 (245,    | 53.2\*\* (250, |
|                   | 351 | (257)   | 7.2)          | 14.3)          |
+-------------------+-----+---------+---------------+----------------+
| Adjusted for      |     | 37.5    | 42.6 (265,    | 49.8\*\* (267, |
| missing SGAs      |     | (267)   | 5.1)          | 12.3)          |
+-------------------+-----+---------+---------------+----------------+
| Not adjusted for  |     | 37.1    | 41.5 (265,    | 48.7\*\* (267, |
| laxatives ^1^     |     | (267)   | 4.4)          | 11.6)          |
+-------------------+-----+---------+---------------+----------------+
| Adjusted^2^       |     | 33.3    | 38.9 (265,    | 45.7\*\* (267, |
|                   |     | (267)   | 5.6)          | 12.4)          |
+-------------------+-----+---------+---------------+----------------+
| Unadjusted        | B   | 34.5    | 46.7\*\*      | 46.3\*\* (285, |
|                   | 301 | (281)   | (285, 12.2)   | 11.8)          |
+-------------------+-----+---------+---------------+----------------+
| Adjusted for      |     | 33.7    | 44.5\*\*      | 44.9\*\* (294, |
| missing SGAs      |     | (288)   | (299, 10.8)   | 11.2)          |
+-------------------+-----+---------+---------------+----------------+
| Not adjusted for  |     | 33.3    | 43.5\*\*      | 44.9\*\* (294, |
| laxatives ^1^     |     | (288)   | (299, 10.2)   | 11.6)          |
+-------------------+-----+---------+---------------+----------------+
| Adjusted^2^       |     | 30.2    | 38.8\* (299,  | 38.4\* (294,   |
|                   |     | (288)   | 8.6)          | 8.2)           |
+-------------------+-----+---------+---------------+----------------+
| Unadjusted        | B   | 41.2    | 44.9 (267,    | 48.5^3^ (266,  |
|                   | 307 | (274)   | 3.7)          | 7.3)           |
+-------------------+-----+---------+---------------+----------------+
| Adjusted for      |     | 39.8    | 42.6 (282,    | 46.9^3^ (275,  |
| missing SGAs      |     | (284)   | 2.8)          | 7.1)           |
+-------------------+-----+---------+---------------+----------------+
| Not adjusted for  |     | 39.4    | 41.5 (282,    | 45.8^3^ (275,  |
| laxatives ^1^     |     | (284)   | 2.1)          | 6.4)           |
+-------------------+-----+---------+---------------+----------------+
| Adjusted^2^       |     | 37.0    | 38.3 (282,    | 42.2^3^ (275,  |
|                   |     | (284)   | 1.3)          | 5.2)           |
+-------------------+-----+---------+---------------+----------------+

N = total number of patients.

^1^ Adjusted for missing SGAs and treatment duration

^2^ Adjusted SGA of relief, all three adjustment rules applied (primary
analysis). ^3^ 4-12 mg/d (titration group).

\* Statistically significant at the significance level of 0.05, using
Hochberg\'s multiple comparison procedure, adjusting for two tegaserod
doses; \*\* Indicates nominal p-value is also \< 0.01.

In general, however, the impact of the adjustment criteria was to
decrease the treatment differences between the tegaserod groups and the
placebo group. Differences from placebo in the 12 mg/day group response
rates that were not adjusted for laxative use were 12% in both studies
B351 and B301. Corresponding figures for differences from placebo in
unadjusted response rates were 14% and 12%, respectively, in studies
B351 and B301.

**Impact of study withdrawals**

Study withdrawals in the three Phase 3 studies ranged from 15%-21% over
the 12-week treatment period, which is not unexpected for IBS studies.
However, as it is important to assess the potential impact of these
study withdrawals on response rates, a sensitivity analysis was
conducted in which a) patients who discontinue due to adverse events or
lack of efficacy are considered nonresponders and in which b) all
discontinued patients were considered nonresponders. The results of
these analyses are similar to the primary analysis and indicate that the
discontinued patients did not impact study results (Table 7-18).

###### Table 7-18. Impact of premature withdrawals on results for SGA of relief in individual studies at endpoint  {#table-7-18.-impact-of-premature-withdrawals-on-results-for-sga-of-relief-in-individual-studies-at-endpoint .unnumbered}

+-----+---------------------------+-----------+-----------+-----------+
|     |                           | **        |           |           |
|     |                           | Responder |           |           |
|     |                           | rate at   |           |           |
|     |                           | e         |           |           |
|     |                           | ndpoint** |           |           |
+-----+---------------------------+-----------+-----------+-----------+
| **S |                           | **placebo | **        | **        |
| tud |                           | % (N)**   | tegaserod | tegaserod |
| y** |                           |           | 4 mg/d %  | 12 mg/d % |
|     |                           |           | (N)**     | (N)**     |
+-----+---------------------------+-----------+-----------+-----------+
| B   | SGA of relief             | 33.3      | 38.9      | 45.7\*\*  |
| 351 |                           | (267)     | (265)     | (267)     |
|     | Patients discontinued due |           |           |           |
|     | to AE or lack of efficacy | 33.0      | 38.9      | 44.9\*\*  |
|     | declared nonresponder     | (267)     | (265)     | (267)     |
|     |                           |           |           |           |
|     | All discontinued patients | 31.5      | 35.8      | 43.1\*\*  |
|     | declared nonresponders    | (267)     | (265)     | (267)     |
+-----+---------------------------+-----------+-----------+-----------+
| B   | SGA of relief             | 30.2      | 38.8\*    | 38.4\*    |
| 301 |                           | (288)     | (299)     | (294)     |
|     | Patients discontinued due |           |           |           |
|     | to AE or lack of efficacy | 29.5      | 37.1\*    | 38.4\*    |
|     | declared nonresponder     | (288)     | (299)     | (294)     |
|     |                           |           |           |           |
|     | All discontinued patients | 28.8      | 36.5\*    | 37.8\*    |
|     | declared nonresponders    | (288)     | (299)     | (294)     |
+-----+---------------------------+-----------+-----------+-----------+
| B   | SGA of relief             | 37.0      | 38.3      | 42.2^1^   |
| 307 |                           | (284)     | (282)     | (275)     |
|     | Patients discontinued due |           |           |           |
|     | to AE or lack of efficacy | 35.9      | 38.3      | 41.1^1^   |
|     | declared nonresponder     | (284)     | (282)     | (275)     |
|     |                           |           |           |           |
|     | All discontinued patients | 34.2      | 37.2      | 40.7^1^   |
|     | declared nonresponders    | (284)     | (282)     | (275)     |
+-----+---------------------------+-----------+-----------+-----------+

AE = adverse event. N = total number of patients. ^1^ 4-12 mg/d
(titration group).

\* Statistically significant at the significance level of 0.05, using
Hochberg\'s multiple comparison procedure, adjusting for two tegaserod
doses; \*\* indicates the nominal p-value is also \< 0.01.

**Patients completing the study**

Results for those patients completing the studies, as shown below in
Table 7-19, were generally similar to the ITT population, although
differences from placebo were greater in the completers population.

###### Table 7-19. Response for SGA of relief in Phase 3 studies at endpoint for completed patients^1^ {#table-7-19.-response-for-sga-of-relief-in-phase-3-studies-at-endpoint-for-completed-patients1 .unnumbered}

  ------------------- ----------- ------------- ------------- ----------- -----------
  **Study**           **placebo   **tegaserod 4 **tegaserod   **p value:  **p value:
                      %**         mg/d %**      12 mg/d^2^    4 mg/d vs   12 mg/d vs
                                                %**           placebo**   placebo**

  B351                39.3        45.7          54.5          .140        .002\*

  B301                33.1        44.3          43.7          .007\*      .012\*

  B307                41.8        48.4          48.5          .250        .111
  ------------------- ----------- ------------- ------------- ----------- -----------

^1^ Primary analysis, using three adjustment rules (missing SGAs,
treatment duration, laxative use); responder definition:
[\>]{.underline} 50% complete/considerable relief or at least 100%
somewhat relief at endpoint.

^2^ 4-12 mg/d (titration group) in study B307 included in 12 mg/d group.

\* statistically significant at the significance level of 0.05, using
the Hochberg\'s multiple comparison procedure; adjusting for two
tegaserod doses.

## Phase 3 studies comparative efficacy 

### Primary efficacy variable-SGA of relief

The SGA of relief was the primary efficacy measure in studies B301 and
B307; results from study B351 were retrospectively analyzed using the
SGA of relief definition of response. Response rates in the individual
studies for the SGA of relief are shown in Table 7-20.

###### Table 7-20. Response for SGA of relief in individual studies at endpoint^1^ {#table-7-20.-response-for-sga-of-relief-in-individual-studies-at-endpoint1 .unnumbered}

  ------------------- ----------- ------------- ------------- ----------- -----------
  **Study**           **Placebo   **Tegaserod 4 **Tegaserod   **p value:  **p value:
                      %**         mg/d %**      12 mg/d^2^    4 mg/d vs   12 mg/d vs
                                                %**           placebo**   placebo**

  B351                33.3        38.9          45.7          .157        .004\*

  B301                30.2        38.8          38.4          .018\*      .033\*

  B307                37.0        38.3          42.2          .837        .142
  ------------------- ----------- ------------- ------------- ----------- -----------

^1^ Primary analysis, using three adjustment rules (missing SGAs,
treatment duration, laxative use). Responder definition:
[\>]{.underline} 50% complete/considerable relief or at least 100%
somewhat relief at endpoint.

^2^ 4-12 mg/d (titration group) in study B307 included in 12 mg/d group.

\* Statistically significant at the significance level of 0.05, using
Hochberg\'s multiple comparison procedure, adjusting for two tegaserod
doses.

In the individual studies B351 and B301, the tegaserod 12 mg/day group
had a greater response rate than the placebo group at endpoint; the
difference from placebo in responder rate for the 12 mg/day tegaserod
group was statistically significant in both individual studies. The
tegaserod 4 mg/day group had a more variable result in terms of a
treatment effect compared with placebo in the two studies, with
statistical significance observed in study B301 but not in study B351.
Although a trend was noted for the 4-12 mg/day tegaserod
(dose-titration) group in study B307, results were not statistically
significant.

The weekly percentage of patients with at least somewhat relief for the
12 mg/day and 4-12 mg/day groups and placebo groups are shown in Figure
7-16. An early effect is apparent at Week 1. Despite differing placebo
response rates, differences from placebo were quite similar for the 12
mg/day group in studies B351 and B301. Similar results were seen for the
weekly percentage of patients with complete or considerable relief in
studies B351 and B301. In study B307, response rates in the placebo
group continued to increase throughout the study such that no treatment
difference was seen over the last several weeks of the study.

####### ![](media/image31.wmf)Figure 7-16. Weekly percentage of patients with at least somewhat relief in Phase 3 studies  {#figure-7-16.-weekly-percentage-of-patients-with-at-least-somewhat-relief-in-phase-3-studies .unnumbered}

#### ![](media/image32.wmf) {#section-10 .unnumbered}

### Secondary efficacy variables

#### Abdominal discomfort/pain and abdominal bloating {#abdominal-discomfortpain-and-abdominal-bloating .unnumbered}

Abdominal discomfort and pain was evaluated by the weekly SGA of
abdominal discomfort/pain and daily by the number of days with
significant (ie, at least mild) abdominal discomfort/pain. Abdominal
bloating was evaluated by the number of days with significant bloating
in the daily diary.

#### SGA of abdominal discomfort/pain {#sga-of-abdominal-discomfortpain .unnumbered}

The SGA of abdominal discomfort/pain was a second primary efficacy
variable in study B351 and designated as a secondary variable in studies
B301 and B307. Reflective of the high hurdle for response on this
efficacy variable, responder rates were low. However, results were
consistent between studies B351 and B301. Responder rates were higher in
the tegaserod 12 mg/day groups than the placebo groups at each monthly
timepoint and at endpoint in both studies (Figure 7-18). In study B301,
the treatment differences were significant at endpoint.

####### Figure 7-18. Response for SGA of abdominal discomfort/pain in Phase 3 studies by month and at endpoint {#figure-7-18.-response-for-sga-of-abdominal-discomfortpain-in-phase-3-studies-by-month-and-at-endpoint .unnumbered}

**B351 B301 B307**

![](media/image33.wmf)Endpt Adj - adjusted endpoint; adjusted for
missing SGAs, treatment duration and laxative intake.

^\*^p \< 0.05 compared to placebo

Response: [\>]{.underline} 40% reduction and at least 20 mm absolute
reduction from baseline on 100 mm VAS

#### Daily diary variables: Days with significant abdominal discomfort/pain and days with significant bloating {#daily-diary-variables-days-with-significant-abdominal-discomfortpain-and-days-with-significant-bloating .unnumbered}

As shown in Figures 7-19 and 7-20, results were highly consistent in
studies B351 and B301 with favorable effects seen in each study at all
monthly timepoints and at endpoint. The differences were statistically
significant at endpoint for the 12 mg/day-placebo comparison in study
B351 for both abdominal discomfort/pain and bloating. In study B307,
results were variable over time.

####### Figure 7-19. Days with significant abdominal discomfort/pain derived from daily diary in Phase 3 studies by month and at endpoint {#figure-7-19.-days-with-significant-abdominal-discomfortpain-derived-from-daily-diary-in-phase-3-studies-by-month-and-at-endpoint .unnumbered}

> **B351 B301 B307**

![](media/image34.wmf)

^\*^p \< 0.05 compared to placebo

Significant: at least mild ( [\>]{.underline} 2 on 6-point scale)

####### Figure 7-20. Days with significant abdominal bloating derived from daily diary in Phase 3 studies by month and at endpoint  {#figure-7-20.-days-with-significant-abdominal-bloating-derived-from-daily-diary-in-phase-3-studies-by-month-and-at-endpoint .unnumbered}

**B351 B301 B307**

![](media/image35.wmf)

^\*^p \< 0.05 compared to placebo

Significant: at least mild ([\>]{.underline} 2 on 6-point scale)

#### Bowel function {#bowel-function .unnumbered}

The effect of tegaserod on bowel function was evaluated by the weekly
SGA of bowel habits and by daily recording of stool frequency and
consistency.

**SGA of bowel habits**

Response rates tended to be higher for the tegaserod groups than
placebo, but were not significantly different at endpoint (Figure 7-21).
Once again, studies B351 and B301 yielded consistent results.

####### Figure 7-21. Response for SGA of bowel habits in Phase 3 studies by month and at endpoint {#figure-7-21.-response-for-sga-of-bowel-habits-in-phase-3-studies-by-month-and-at-endpoint .unnumbered}

**B351 B301 B307**

![](media/image36.wmf)

Adj endpt - adjusted endpoint; adjusted for missing SGAs, treatment
duration and laxative intake.

^\*^p \< 0.05 vs. placebo

Response: [\>]{.underline} 40% reduction and at least 20 mm absolute
reduction from baseline on 100 mm VAS

### Efficacy variables summary

The statistical significance of and direction of response for the weekly
SGA assessments and daily diary efficacy variables are shown in Table
7-21. Results for studies B351 and B301 were highly consistent. Although
statistical significance was not achieved for the treatment differences
between the tegaserod groups and placebo for all efficacy variables, it
is notable that the results were always more favorable for the tegaserod
groups for all SGA and daily diary variables in these two studies of
identical design. Results for study B307 at endpoint were variable
across efficacy parameters.

###### Table 7-21. Summary of efficacy variables in Phase 3 studies at endpoint {#table-7-21.-summary-of-efficacy-variables-in-phase-3-studies-at-endpoint .unnumbered}

  --------------------- ---------- --------- ---------- -------- ---------- --------
                        **B351**             **B301**            **B307**   

  **Efficacy variable** **4 mg/d** **12      **4 mg/d** **12     **4 mg/d** **4-12
                                   mg/d**               mg/d**              mg/d**

  **SGA efficacy                                                            
  variables (weekly)**                                                      

  SGA of relief         **+**      \<0.01    \<0.05     \<0.05   **+**      **+**

  [\>]{.underline} 50%  \<0.05     **+**     \<0.05     **+**    **-**      **-**
  complete or                                                               
  considerable relief                                                       
  (***original*** SGA                                                       
  of relief)                                                                

  100% At least         **+**      \<0.01    \<0.05     \<0.05   **+**      **+**
  somewhat relief                                                           

  SGA of abdominal      **+**      **+**     **+**      \<0.05   **-**      **-**
  discomfort/pain                                                           

  SGA of bowel habits   **+**      **+**     **+**      **+**    **+**      **-**

  **Daily diary                                                             
  variables**                                                               

  Mean % change from    **+**      \<0.05    **+**      **+**    **+**      **+**
  baseline in days                                                          
  significant abdominal                                                     
  pain                                                                      

  Mean % change from    **+**      \<0.01    **+**      **+**    **-**      **-**
  baseline in days                                                          
  significant abdominal                                                     
  bloating                                                                  

  Mean % change from    \<0.01     \<0.001   \<0.001    \<0.01   \<.05      \<.001
  baseline in number of                                                     
  bowel movements                                                           

  Mean % change from    **+**      \<0.01    \<0.05     \<0.05   **+**      \<.05
  baseline in number of                                                     
  days without BMs                                                          

  Mean percent of days  **+**      \<0.01    **+**      **+**    **+**      **+**
  with hard or very                                                         
  hard stools                                                               
  --------------------- ---------- --------- ---------- -------- ---------- --------

+: Treatment difference in positive direction for tegaserod compared to
placebo, nominal p [\>]{.underline} 0.05 compared to placebo

-: Treatment difference in positive direction for placebo compared to
tegaserod

## Post-hoc analyses

After the unblinding of study B351, the data was examined and a more
sensitive endpoint defined. The revised endpoint, the SGA of relief
(\>50% complete or considerable relief or 100% at least somewhat
relief), was designated prospectively as the primary efficacy variable
for studies B301 and B307. To gain more insight in the strength of
evidence, several post-hoc analyses were performed. As these are
post-hoc analyses, the sponsor acknowledges that the results need to be
interpreted with caution.

### Pooled analyses

Pooling of results of the three Phase 3 studies was performed to
investigate the presence of a drug effect. Under the null hypothesis of
no treatment effect, such a pooling is justified despite the difference
in design between B307 and studies B301, B351 and further, as the
pre-specified primary efficacy variables for each study were evaluated.

Thus, Studies B351, B301 and B307 were pooled by dose group and analyzed
based on the respective primary efficacy variables. Accordingly, in this
pooled analysis, for study B351 both the original SGA of relief (\>50%
complete or considerable relief) and the SGA of abdominal
discomfort/pain were used; for studies B301 and B307, the SGA of relief
(\>50% complete/considerable relief or 100% at least somewhat relief)
was used. The pooled population was analyzed at endpoint and also
longitudinally. For the longitudinal analysis, the respective responder
criteria were applied to Month 1, Month 2 and Month 3. Missing data were
imputed by carrying the last observation forward. To adjust for laxative
use, patients with more than 5 days of laxative use were considered as
non-responders for any of the months.

Pooled results for the tegaserod 12 mg/day and 4-12 mg/day combined
group showed highly statistically significant differences compared with
the placebo groups, indicative of a positive drug effect (Table 7-22).

###### Table 7-22. Pooled analysis of Phase 3 primary efficacy variables: statistical significance of treatment comparisons {#table-7-22.-pooled-analysis-of-phase-3-primary-efficacy-variables-statistical-significance-of-treatment-comparisons .unnumbered}

  ---------------------------- ---------------------------- ---------------------------- ----------------------------
  **Endpoint analysis**                                     **Longitudinal analysis**    

  **[p-value]{.underline}**: 4 **[p-value]{.underline}**:   **[p-value]{.underline}**: 4 **[p-value]{.underline}**:
  mg/d vs. placebo             12 mg/d^1^ vs. placebo       mg/d vs. placebo             12 mg/d^1^ vs. placebo

  0.0141                       0.0028                       0.0085                       \<0.0001

                                                                                         
  ---------------------------- ---------------------------- ---------------------------- ----------------------------

Efficacy variables:

B351: Original SGA of relief; SGA of abdominal discomfort/pain (1 was
assigned as the response score if responded to both variables, 0.5 if
only responded to one of the variables, and 0 if no response to either
variable.)

B301/B307: SGA of relief

^1^4-12 mg/d titration group in study B307

### Supportive Analyses

To further evaluate the consistency of the SGA of relief response data,
and to put these data into context, two additional post-hoc analyses
were performed:

-   At a recent (November 16, 1999) Gastrointestinal Drugs Advisory
    Committee meeting, the evaluation of a new drug (alosetron) for IBS
    was discussed. The primary analysis of the efficacy data presented
    at the meeting was based on a longitudinal analysis, using a monthly
    responder approach. Accordingly, this same analysis was subsequently
    performed for studies B351, B301 and B307. The number of months that
    a patient was a monthly responder was calculated and a score
    assigned: 0 = no monthly response, 1 = 1 monthly response, 2 = 2
    monthly responses and 3 = 3 monthly responses. For months with all
    missing SGAs, the last month's value was carried forward. The scores
    were compared among the treatment groups. For the SGA of relief
    efficacy variable, treatment differences for the 12 mg/day and 4-12
    mg/day tegaserod groups compared with placebo were statistically
    significant (p\<0.02) in all three studies (Table 7-23).

-   Since the SGA of relief was collected on a weekly basis, it is
    natural and logical to assess efficacy based on percent of weeks at
    which a patient showed a positive response Two cutoffs were used in
    this approach.

(a) Percentage of weeks a patient was at least somewhat relieved was
    calculated, and compared between treatment groups.

(b) Percentage of weeks a patient was completely relieved or
    considerably relieved was calculated, and compared between treatment
    groups.

As shown in Table 7-24, for weeks with at least somewhat relief,
treatment differences between the 12 mg/day and 4-12 mg/day tegaserod
groups and placebo were statistically significant (p\<0.01) in all three
studies. Similar results (p\<0.02) were also obtained when comparing the
percentage of weeks patients responded either completely relieved or
considerably relieved.

###### Table 7-23. Statistical significance for between treatment comparison in number of months with response in individual studies {#table-7-23.-statistical-significance-for-between-treatment-comparison-in-number-of-months-with-response-in-individual-studies .unnumbered}

  --------------------------------------------------------------------------
  **Study**   **Efficacy           **p value: 4 mg/d    **p value: 12 mg/d
              variable**           vs. placebo**        vs. placebo**
  ----------- -------------------- -------------------- --------------------
  B351        Original SGA of      .107 (N=265)         .047 (N=267)
              relief                                    

  B351        SGA of relief        .353 (N=265)         .013\* (N=267)

  B301        SGA of relief        .008^\*^(N=299)      \<.001\* (N=294)

  B307        SGA of relief        .479(N=282)          .008^1^\* (N=275)
  --------------------------------------------------------------------------

N = total number of patients.

Original SGA of relief: [\>]{.underline}50% complete/considerable relief

SGA of relief: [\>]{.underline}50% complete/considerable relief or 100%
at least somewhat relief

^1^ 4-12 mg/d (titration group).

\* Indicates statistical significance at 0.05 level compared with
placebo, with adjusting for multiple comparisons.

###### Table 7-24. Mean percentage of weeks with at least somewhat relief or with complete/considerable relief in individual studies  {#table-7-24.-mean-percentage-of-weeks-with-at-least-somewhat-relief-or-with-completeconsiderable-relief-in-individual-studies .unnumbered}

+-----+----------------+---------------+---------------+-------------+
| **S | **Variable**   | **placebo %   | **tegaserod 4 | **tegaserod |
| tud |                | (N)**         | mg/d % (N)**  | 12 mg/d %   |
| y** |                |               |               | (N)**       |
+-----+----------------+---------------+---------------+-------------+
| B   | At least       | 53.2 (257)    | 59.7 (245)    | 65.0 (250)  |
| 351 | somewhat       |               | (p=0.021)\*   | (           |
|     | relief         | 18.7 (257)    |               | p\<0.001)\* |
|     |                |               | 24.6 (245)    |             |
|     | Complet        |               | (p=0.020)\*   | 25.0 (250)  |
|     | e/considerable |               |               | (p=0.015)\* |
|     | relief         |               |               |             |
+-----+----------------+---------------+---------------+-------------+
| B   | At least       | 45.5 (281)    | 54.6 (285)    | 55.4 (285)  |
| 301 | somewhat       |               | (p=0.005)\*   | (           |
|     | relief         | 15.7 (281)    |               | p\<0.001)\* |
|     |                |               | 19.2 (285)    |             |
|     | Complet        |               | (p=0.061)     | 22.7 (285)  |
|     | e/considerable |               |               | (           |
|     | relief         |               |               | p\<0.001)\* |
+-----+----------------+---------------+---------------+-------------+
| B   | At least       | 50.9 (274)    | 53.2 (267)    | 59.7^1^     |
| 307 | somewhat       |               | (p=0.278)     | (266)       |
|     | relief         | 19.4 (274)    |               | (p=0.003)\* |
|     |                |               | 20.3 (267)    |             |
|     | Complet        |               | (p=0.854)     | 24.9^1^     |
|     | e/considerable |               |               | (266)       |
|     | relief         |               |               | (p=0.018)\* |
+-----+----------------+---------------+---------------+-------------+

N = total number of patients.

^1^ 4-12 mg/d (titration group).

\* Indicates a statistical significance at 0.05 level compared with
placebo, with adjusting for multiple comparisons.

## Responses in population subgroups

To explore treatment effects within subgroups, analyses assessing the
SGA of relief was performed following stratification for gender, age,
race, baseline severity of disease, baseline stool frequency and stool
consistency, dietary fiber intake and use of concomitant psychotropic
(SSRI and tricyclic antidepressant) and acid-suppressant medications.

**Influence of demographic factors**

Approximately 85% of the population in the three Phase 3 studies were
female. Results for the pooled analysis by gender across the three Phase
3 studies at month 1 and at endpoint are shown in Figure 7-22. Among
female patients, results were consistent across studies and over time.
In contrast, results in male patients were less consistent. While no
treatment effect was apparent at endpoint, a greater response was noted
at month 1 for tegaserod than for placebo treated male patients.

####### Figure 7-22. Pooled (B351, B301, B307) response for unadjusted SGA of relief by gender at month 1 and at endpoint {#figure-7-22.-pooled-b351-b301-b307-response-for-unadjusted-sga-of-relief-by-gender-at-month-1-and-at-endpoint .unnumbered}

![](media/image37.wmf)

Note: For B307, 4-12 mg/d group pooled with 4 mg/d group at month 1 and
4-12 mg/d at endpoint

Thus, the positive treatment effect observed with tegaserod was due
primarily to its efficacy in females. While it appears that tegaserod
may be more effective in female than in male IBS patients, given the
relatively small number of male patients (15% of population), available
data are insufficient to make firm conclusions regarding the efficacy of
tegaserod in men. Differences in baseline variables, such as the degree
of constipation symptoms, may account in part for the apparent smaller
and less consistent treatment effect observed in males.

Elderly patients ([\>]{.underline} 65 years of age) accounted for less
than 10% of the population. Similar to the findings in male patients,
results were not consistent over time, with a greater effect seen at
endpoint than at month 1. No meaningful comparisons can be made for
black patients, given the small number of black patients treated with
tegaserod.

**Influence of other factors**

It has been suggested that those patients with more severe abdominal
discomfort/pain are more resistant in terms of response to drug therapy;
patients with more severe disease were not excluded from the Phase 3
studies. For the tegaserod 12 mg/day group, it did not appear that those
patients with more severe abdominal discomfort/pain responded less well
than those with less severe discomfort/pain. Fiber intake also did not
impact the efficacy of tegaserod. Similarly, it did not appear that
frequently used concomitant medication (psychotropics and acid
suppressants) impacted the efficacy of tegaserod.

However, patients (11% of study population) with looser stools during
baseline (mean stool consistency \< 3.5 on 7-point scale) did less well
than those with more "normal" (consistency score of 3.5 -- 4.5) and
those with harder (\> 4.5) stools during baseline.

## Efficacy Discussion/Conclusions

The Phase 3 program was a global program conducted primarily in North
America and in Europe. The studies were designed to enroll and randomize
patients with a history of C-IBS by Rome criteria (ie, abdominal
discomfort/pain and constipation). In this regard, the presence of at
least mild abdominal pain during the baseline period (no exclusion for
severe pain) was required to ensure the diagnosis of IBS; patients were
not excluded based on baseline diary entries of stool consistency or
number of bowel movements. Common concomitant medications in this
population, such as tricyclic antidepressants and SSRIs were allowed.
Thus, the Phase 3 program attempted to enroll a wide spectrum of
patients that would reflect those likely to be treated with the drug in
clinical practice.

Study B301 showed clear evidence for efficacy in a well-controlled
prospective study on the primary efficacy endpoint. Both the tegaserod 4
mg/day and 12 mg/day groups had statistically significant higher
response rates on the SGA of relief at endpoint than the placebo group.
For the tegaserod 12 mg/day group, higher response rates compared with
placebo were seen at each monthly interval. Secondary efficacy variables
were consistently more favorable for the tegaserod groups than for
placebo, although not all differences from placebo achieved statistical
significance. For the tegaserod 12 mg/day group, statistically
significant treatment differences compared with placebo were observed
for the SGA of abdominal discomfort/pain.

Results in study B351 were highly consistent with those in study B301,
especially for the tegaserod 12 mg/day group. For the SGA of relief
(retrospective analysis in B351), the tegaserod 12 mg/day group had
statistically significantly higher response rates than the placebo
group. In addition, statistically significant improvements were noted in
multiple daily diary variables, including days with significant
abdominal discomfort/pain, days of significant abdominal bloating, stool
frequency and consistency.

Response rates for the tegaserod groups in study B307, a dose-titration
study, on the primary efficacy variable (SGA of relief) were not
statistically significantly different from placebo. However, an unusual
increase in placebo response after dose-titration make interpretation of
study results difficult.

The SGA of relief results were consistent between studies B351 and B301
and consistent over time. To further evaluate the data, a number of
sensitivity analyses and supportive analyses were performed.

-   To assess the impact of early withdrawals, all such patients were
    declared nonresponders; treatment results for the SGA of relief in
    studies B351 and B301 were little changed and treatment differences
    between tegaserod groups and the placebo group remained
    statistically significant.

-   An analysis was performed as a result of the presentation of
    efficacy data for the evaluation of a new drug (alosetron) for IBS
    at a recent (November 16, 1999) Gastrointestinal Drugs Advisory
    Committee meeting. The primary analysis of the efficacy data was
    based on a monthly responder approach. When a similar analysis was
    performed for the tegaserod studies, results were statistically
    significant (p\<0.02) for the tegaserod 12 mg/day group, and 4-12
    mg/day group, compared with the placebo group in all three studies
    for the SGA of relief.

In an additional supportive analysis, the percentage of weeks with at
least somewhat relief and the percentage of weeks with complete or
considerable relief over the entire 12-week treatment period were
calculated. Both the percentage of weeks with at least somewhat relief
and the percentage of weeks with complete or considerable relief were
greater (p\<0.02) in the tegaserod 12 mg/day group (and 4-12 mg/day
group) than in the placebo group in all three studies.

Thus, the various supportive and sensitivity analyses confirmed that the
results for the SGA of relief were consistent and robust.

The magnitude of the treatment difference for the SGA of relief at
endpoint between the tegaserod 12 mg/day group and placebo group was 8%
and 12% in studies B301 and B351, respectively. Response rates not
adjusted for laxative use showed an identical treatment difference of
12% between tegaserod 12 mg/day and placebo at endpoint in the two
studies.

The onset of action of tegaserod was apparent after one week of
treatment. At Week 1, the percentage of patients with at least somewhat
relief was greater in the tegaserod groups than in the placebo group in
all three studies. This effect was sustained in the tegaserod 12 mg/day
groups for the 12-week study duration in studies B351 and B301.

Finally, it is important to note that the secondary efficacy variables
were used (ie, same question and scale for weekly SGAs and daily diary
variables) and administered in the same way (ie, self-administered via
patient diary) in each study. For the daily diary variables (days with
significant abdominal discomfort/pain, days with significant bloating,
stool frequency and consistency) and the SGA of abdominal
discomfort/pain and SGA of bowel habits, favorable results for tegaserod
12 mg/day compared with placebo were consistently seen in study B351 and
B301.

Overall, the totality of the data provides strong evidence that
tegaserod is effective in the treatment of patients with C-IBS. The SGA
of relief is a global assessment that integrates the important symptoms
of IBS (abdominal discomfort and pain, altered bowel habit) and
encompasses overall well being. Although performed as a retrospective
analysis in study B351, results for the SGA of relief were consistent
between studies B351 and B301, consistent over time and supported by the
secondary efficacy variables in both studies.

# Safety Analysis

The table below summarizes the number of subjects (patients and healthy
subjects) exposed to tegaserod during the clinical development program.

###### Table 8-1. Duration of exposure: all subjects  {#table-8-1.-duration-of-exposure-all-subjects .unnumbered}

+------------+------------------+------------------+------------------+
| **Duration | **Placebo**      | **Tegaserod\     | **All            |
| of         |                  | All groups**     | treatments**     |
| exposure** | **n=1185**       |                  |                  |
|            |                  | **n=3510**       | **n =4606**      |
+------------+------------------+------------------+------------------+
|            | **n (%)**        | **n (%)**        | **n (%)**        |
+------------+------------------+------------------+------------------+
| 1 day      | 1185 (100.0)     | 3507 (100.0)     | 4603 (100.0)     |
+------------+------------------+------------------+------------------+
| 7 days     | 1103 (93.1)      | 3113 (88.8)      | 4129 (89.7)      |
+------------+------------------+------------------+------------------+
| 30 days    | 930 (78.5)       | 2541 (72.5)      | 3427 (74.5)      |
+------------+------------------+------------------+------------------+
| 85 days    | 661 (55.8)       | 1874 (53.2)      | 2517 (54.7)      |
+------------+------------------+------------------+------------------+
| 180 days   | 18 (1.5)         | 418 (11.9)       | 443 (9.6)        |
+------------+------------------+------------------+------------------+
| 270 days   | 0                | 338 (9.6)        | 342 (7.4)        |
+------------+------------------+------------------+------------------+
| 335 days   | 0                | 302 (8.6)        | 306 (6.7)        |
+------------+------------------+------------------+------------------+
| 365 days   | 0                | 185 (5.3)        | 193 (4.2)        |
+------------+------------------+------------------+------------------+

The evaluation of the safety of tegaserod in the treatment of C-IBS is
based primarily on the results of studies of at least 12 weeks duration
in patients with C-IBS: three placebo-controlled Phase 3 studies (B301,
B307, B351), two placebo-controlled Phase 2 studies (B251, B202) and one
long-term, open-label study (B209).

## Demographics, disposition and exposure

### Safety population demographics

The demographic characteristics of the pooled Phase 3 population were
comparable in the different dosage groups, as is shown in Table 8-2.

###### Table 8-2. Demographic characteristics: pooled Phase 3 studies {#table-8-2.-demographic-characteristics-pooled-phase-3-studies .unnumbered}

<table style="width:100%;">
<colgroup>
<col style="width: 22%" />
<col style="width: 12%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 13%" />
<col style="width: 0%" />
<col style="width: 13%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 12%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Variable</strong></td>
<td><p><strong>Placebo<br />
</strong></p>
<p>N=837</p></td>
<td colspan="2"><strong>Tegaserod<br />
4 mg/d</strong><br />
N=844</td>
<td><strong>Tegaserod<br />
12 mg/d</strong><br />
N=560</td>
<td colspan="3"><strong>Tegaserod titration<br />
4/12 mg/d</strong><br />
N=275</td>
<td><strong>Tegaserod<br />
All groups</strong><br />
N=1679</td>
<td colspan="2"><strong>All</strong><br />
N=2516</td>
</tr>
<tr class="even">
<td><strong>Sex</strong> n (%)<br />
Male<br />
Female</td>
<td>130 (15.5)<br />
707 (84.5)</td>
<td colspan="2">135 (16.0)<br />
709 (84.0)</td>
<td>83 (14.8)<br />
477 (85.2)</td>
<td colspan="3">42 (15.3)<br />
233 (84.7)</td>
<td>260 (15.5)<br />
1419 (84.5)</td>
<td colspan="2">390 (15.5)<br />
2126 (84.5)</td>
</tr>
<tr class="odd">
<td><strong>Race</strong> n (%)<br />
Caucasian<br />
Black<br />
Other</td>
<td>770 (92.0)<br />
43 (5.1)<br />
24 (2.9)</td>
<td colspan="2">774 (91.7)<br />
43 (5.1)<br />
27 (3.2)</td>
<td>532 (95.0)<br />
18 (3.2)<br />
10 (1.8)</td>
<td colspan="3">244 (88.7)<br />
17 (6.2)<br />
14 (5.1)</td>
<td>1550 (92.3)<br />
78 (4.6)<br />
51 (3.0)</td>
<td colspan="2">2320 (92.2)<br />
121 (4.8)<br />
75 (3.0)</td>
</tr>
<tr class="even">
<td><strong>Age</strong> (yr)<br />
Mean<br />
SD<br />
Range</td>
<td>45.0<br />
13.28<br />
18-85</td>
<td colspan="2">44.3<br />
13.46<br />
17-89</td>
<td>44.8<br />
13.19<br />
13-85</td>
<td colspan="3">45.6<br />
13.83<br />
19-83</td>
<td>44.7<br />
13.43<br />
13-89</td>
<td colspan="2">44.8<br />
13.38<br />
13-89</td>
</tr>
<tr class="odd">
<td><strong>Age category</strong> n (%)<br />
12-&lt;18 yr<br />
18-&lt;65 yr<br />
65-&lt;75 yr<br />
&gt;=75 yr</td>
<td>0<br />
753 (90.0)<br />
70 (8.4)<br />
14 (1.7)</td>
<td colspan="2">1 (0.1)<br />
764 (90.5)<br />
67 (7.9)<br />
12 (1.4)</td>
<td>2 (0.4)<br />
511 (91.3)<br />
38 (6.8)<br />
9 (1.6)</td>
<td colspan="3">0<br />
245 (89.1)<br />
18 (6.5)<br />
12 (4.4)</td>
<td>3 (0.2)<br />
1520 (90.5)<br />
123 (7.3)<br />
33 (2.0)</td>
<td colspan="2">3 (0.1)<br />
2273 (90.3)<br />
193 (7.7)<br />
47 (1.9)</td>
</tr>
<tr class="even">
<td><strong>Duration of C-IBS</strong> (yr)<br />
Mean<br />
SD<br />
Range</td>
<td>13.9<br />
12.86<br />
0.3-61.0</td>
<td>13.6<br />
12.46<br />
0.3-66.8</td>
<td colspan="3">14.1<br />
12.97<br />
0.2-68.0</td>
<td>13.9<br />
13.03<br />
0.5-60.0</td>
<td colspan="3">13.8<br />
12.72<br />
0.2-68.0</td>
<td>13.8<br />
12.76<br />
0.2-68.0</td>
</tr>
</tbody>
</table>

The population was predominantly female, Caucasian, middle-aged, with
chronic disease. The characteristics of the Phase 2 population was
similar.

### Extent of exposure

The Phase 3 studies were of 12 weeks duration, with 81% of patients
completing the studies; 67% completed 85 days as shown in Table 8-3. In
the pooled Phase2/3 studies, 1470 patients had been treated with
tegaserod overall for at least 85 days, with 74 of those patients on 24
mg/day.

###### Table 8-3. Duration of exposure: Pooled Phase 3 studies in C-IBS {#table-8-3.-duration-of-exposure-pooled-phase-3-studies-in-c-ibs .unnumbered}

[\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_]{.underline}

  ------------ -------------- ---------------- ---------------- -------------- -------------- ---------------
  **Duration   **Placebo**\   **Tegaserod**\   **Tegaserod**\   **Tegaserod    **Tegaserod\   **All\
  of\          N=837\         4 mg/d\          12 mg/d\         titration**\   All groups**\  treatments**\
  exposure**   n (%)          N=844\           N=560\           4/12 mg/d\     N=1679\        N=2516\
                              n (%)            n (%)            N=275\         n (%)          n (%)
                                                                n (%)                         

  \>=1 day\    837 (100)\     843 (100)\       560 (100)\       274 (100)\     1677 (100)\    2514 (100)\
  \>=7 days\   825 (98.6)\    816 (96.8)\      541 (96.6)\      270 (98.5)\    1627 (97.0)\   2452 (97.5)\
  \>=30 days\  781 (93.3)\    759 (90.0)\      511 (91.3)\      255 (93.1)\    1525 (90.9)\   2306 (91.7)\
  \>=85 days   564 (67.4)     555 (65.8)       380 (67.9)       184 (67.2)     1119 (66.7)    1683 (66.9)
  ------------ -------------- ---------------- ---------------- -------------- -------------- ---------------

For long-term study information, please see Section 8.7.

### Disposition of patients

The disposition of patients, is summarized, by dosage group for the
pooled Phase 3 studies in Table 8-4.

In the Phase 3 studies, discontinuations due to adverse events (AEs)
were marginally more frequent in the tegaserod-treated patients than in
those on placebo (6.8% v 5.1%) but without any dose-relationship. AEs,
which led to discontinuations, are reviewed below. In Phase 2 the
discontinuation rates due to AEs were similar with 8.3% for tegaserod
and 9.3% for placebo.

###### Table 8-4. Disposition of patients: pooled Phase 3 studies in C-IBS {#table-8-4.-disposition-of-patients-pooled-phase-3-studies-in-c-ibs .unnumbered}

+-----------------+-------+-------+-------+-------+-------+-------+
| **Dispos        | **Pla | **    | **Te  | *     | *     | *     |
| ition/Principal | cebo\ | Tegas | gaser | *Tega | *Tega | *All\ |
| reason**        | gro   | erod4 | od**\ | serod | serod | tr    |
|                 | ups** | m     | **12m | ti    | All   | eatme |
|                 |       | g/d** | g/d** | trati | gro   | nts** |
|                 | N     |       |       | on**\ | ups** |       |
|                 | =837\ | N     | N     | *     |       | N=    |
|                 | n (%) | =844\ | =560\ | *4-12 | N=    | 2516\ |
|                 |       | n (%) | n (%) | mg    | 1679\ | n (%) |
|                 |       |       |       | /d**\ | n (%) |       |
|                 |       |       |       | N     |       |       |
|                 |       |       |       | =275\ |       |       |
|                 |       |       |       | n (%) |       |       |
+-----------------+-------+-------+-------+-------+-------+-------+
| **Completed**\  | 697   | 671   | 465   | 231   | 1367  | 2064  |
| **Total         | (8    | (7    | (8    | (8    | (8    | (8    |
| discontinued**\ | 3.3)\ | 9.5)\ | 3.0)\ | 4.0)\ | 1.4)\ | 2.0)\ |
| Adverse event\  | 140   | 173   | 95    | 44    | 312   | 452   |
| Death\          | (1    | (2    | (1    | (1    | (1    | (1    |
| Withdrawal of   | 6.7)\ | 0.5)\ | 7.0)\ | 6.0)\ | 8.6)\ | 8.0)\ |
| consent\        | 43    | 60    | 34    | 21    | 115   | 158   |
| Protocol        | (     | (     | (     | (     | (     | (     |
| violation\      | 5.1)\ | 7.1)\ | 6.1)\ | 7.6)\ | 6.8)\ | 6.3)\ |
| Unsatisfactory  | 0\    | 1     | 0\    | 0\    | 1     | 1     |
| effect\         | 32    | (     | 23    | 10    | (     | (     |
| Failure to      | (     | 0.1)\ | (     | (     | 0.1)\ | 0.0)\ |
| return\         | 3.8)\ | 38    | 4.1)\ | 3.6)\ | 71    | 103   |
| Abnormal        | 9     | (     | 11    | 1     | (     | (     |
| laboratory      | (     | 4.5)\ | (     | (     | 4.2)\ | 4.1)\ |
| value\          | 1.1)\ | 16    | 2.0)\ | 0.4)\ | 28    | 37    |
| Administration  | 26    | (     | 15    | 3     | (     | (     |
| problems        | (     | 1.9)\ | (     | (     | 1.7)\ | 1.5)\ |
|                 | 3.1)\ | 22    | 2.7)\ | 1.1)\ | 40    | 66    |
| Subject\'s      | 29    | (     | 10    | 6     | (     | (     |
| condition^1^    | (     | 2.6)\ | (     | (     | 2.4)\ | 2.6)\ |
|                 | 3.5)\ | 33    | 1.8)\ | 2.2)\ | 49    | 78    |
|                 | 0\    | (     | 2     | 2     | (     | (     |
|                 | 1     | 3.9)\ | (     | (     | 2.9)\ | 3.1)\ |
|                 | (0.1) | 1     | 0.4)\ | 0.7)\ | 5     | 5     |
|                 |       | (     | 0     | 1     | (     | (     |
|                 | 0     | 0.1)\ |       | (0.4) | 0.3)\ | 0.2)\ |
|                 |       | 1     | 0     |       | 2     | 3     |
|                 |       | (0.1) |       | 0     | (0.1) | (0.1) |
|                 |       |       |       |       |       |       |
|                 |       | 1     |       |       | 1     | 1     |
|                 |       | (0.1) |       |       | (0.1) | (0.0) |
+-----------------+-------+-------+-------+-------+-------+-------+

^1^ Subject's condition no longer requiring further therapy.

##  Adverse events

### Methodology

An adverse event (AE) was defined as any adverse medical change from the
patient's baseline (or pretreatment) condition which occurred during the
course of the study, after initiation of treatment, whether considered
treatment-related or not.

### Most commonly reported AEs

The most commonly reported AEs in the pooled Phase 3 studies (≥5% in
either the tegaserod or placebo patients) are summarized in Table 8-5.

###### Table 8-5. Adverse events reported at frequency ≥5% in any dosage group: pooled Phase 3 studies {#table-8-5.-adverse-events-reported-at-frequency-5-in-any-dosage-group-pooled-phase-3-studies .unnumbered}

  ------------------- ---------- ------------ ------------ ------------ -----------
  Adverse event       Placebo    Tegaserod\   Tegaserod\   Tegaserod    Tegaserod
                                 4 mg/d       12 mg/d      titration\   All dosages
                                                           4/12 mg/d    

                      N=837\     N=844\       N=560\       N=275\       N=1679\
                      n (%)      n (%)        n (%)        n (%)        n (%)

  Headache\           177        181 (21.4)\  130 (23.2)\  47 (17.1)\   358 (21.3)\
  Abdominal pain\     (21.1)\    168 (19.9)\  105 (18.8)\  59 (21.5)\   332 (19.8)\
  Diarrhea\           152        96 (11.4)\   68 (12.1)\   32 (11.6)\   196 (11.7)\
  Nausea\             (18.2)\    78 (9.2)\    55 (9.8)\    21 (7.6)\    154 (9.2)\
  Flatulence\         45 (5.4)\  63 (7.5)\    40 (7.1)\    22 (8.0)\    125 (7.4)\
  Back pain\          72 (8.6)\  53 (6.3)\    45 (8.0)\    15 (5.5)\    113 (6.7)\
  Influenza-like      55 (6.6)\  55 (6.5)\    42 (7.5)\    10 (3.6)\    107 (6.4)\
  symptoms\           45 (5.4)\  50 (5.9)\    27 (4.8)\    26 (9.5)\    103 (6.1)\
  URT infection\      46 (5.5)\  48 (5.7)\    34 (6.1)\    18 (6.5)\    100 (6.0)\
  Dyspepsia\          70 (8.4)\  54 (6.4)\    32 (5.7)\    8 (2.9)\     94 (5.6)\
  Dizziness\          47 (5.6)\  26 (3.1)     20 (3.6)     14 (5.1)     60 (3.6)
  Pharyngitis         46 (5.5)\                                         
                      26 (3.1)                                          
  ------------------- ---------- ------------ ------------ ------------ -----------

Diarrhea is the only AE that appears to be clearly more frequent in the
tegaserod than in the placebo groups (11.7% v 5.4%) but without any
apparent dose-relationship. The periods during which diarrhea was first
reported by patients in the Phase 3 studies are summarized in Table 8-6.
This shows that almost half of the cases of diarrhea in the tegaserod
patients were reported for the first time during the first week of
treatment, with over half of these being reported on the first day.
After the first week, the frequency of first occurrence of diarrhea was
only marginally greater in the tegaserod patients compared to the
placebo patients. The median duration of the first diarrhea episode was
the same for tegaserod and placebo (2 days each). The majority of
patients (tegaserod 75%, placebo 72%) reported only a single episode of
diarrhea.

###### Table 8-6. First occurrence of diarrhea (number and %), by time interval and treatment: pooled Phase 3 studies {#table-8-6.-first-occurrence-of-diarrhea-number-and-by-time-interval-and-treatment-pooled-phase-3-studies .unnumbered}

  -----------------------------------------------------------------------
  **\                 **Placebo\                **Tegaserod\
  Time at onset\      \                         \
  (days)**            (N=837)**                 (N=1679)**
  ------------------- ------------------------- -------------------------
                      n (%)                     n (%)

  1                   2 (0.2)                   57 (3.4)

  2-7                 2 (0.2)                   30 (1.8)

  8-29                22 (2.6)                  46 (2.7)

  30-59               11 (1.3)                  34 (2.0)

  ≥60                 8 (1.0)                   28 (1.7)
  -----------------------------------------------------------------------

## Discontinuations due to AEs

The rate of discontinuation due to AEs was not high overall, but the
rate was marginally increased in the tegaserod-treated patients relative
to placebo in the pooled Phase 3 studies. The same tendency is noted for
the pooled Phase 2/3 studies.

The most frequent AEs leading to discontinuation (≥5% of patients
treated) in the pooled Phase 2/3 studies are summarized in Tables 8-7.
GI symptoms of IBS (diarrhea, abdominal pain, flatulence, nausea, and
dyspepsia) were among the most frequent causes of discontinuation. Most
of the other common AEs leading to discontinuation were non-specific
(dizziness, headache, fatigue, dyspnea, non-specific back or chest pain,
asthenia etc). The high rate of discontinuations because of female
reproductive disorders reflects largely the obligatory discontinuation
for any woman becoming pregnant while on study, this being recorded as
an AE. The most evident imbalance between the tegaserod and placebo
groups is that of discontinuations because of diarrhea, however the
discontinuation rate due to diarrhea was low, 2.1%.

###### Table 8-7. Adverse events which led to discontinuation in at least 0.5% of patients in any treatment group: pooled Phase 2/3 studies {#table-8-7.-adverse-events-which-led-to-discontinuation-in-at-least-0.5-of-patients-in-any-treatment-group-pooled-phase-23-studies .unnumbered}

+--------------------------------------+---------------+---------------+
| Body System/Adverse Event            | Placebo       | Tegaserod\    |
|                                      |               | n=2198\       |
|                                      | N=988\        | n (%)         |
|                                      | n(%)          |               |
+--------------------------------------+---------------+---------------+
| Discontinuations because of any AE   | 62 (6.3)      | 184 (8.4)     |
+--------------------------------------+---------------+---------------+
| GI disorders                         | 34 (3.4)      | 103 (4.7)     |
+--------------------------------------+---------------+---------------+
| Diarrhea                             | 6 (0.6)       | 46 (2.1)      |
+--------------------------------------+---------------+---------------+
| Abdominal pain                       | 19 (1.9)      | 37 (1.7)      |
+--------------------------------------+---------------+---------------+
| Flatulence                           | 7 (0.7)       | 25 (1.1)      |
+--------------------------------------+---------------+---------------+
| Nausea                               | 8 (0.8)       | 9 (0.4)       |
+--------------------------------------+---------------+---------------+
| CNS disorders                        | 20 (2.0)      | 37 (1.7)      |
+--------------------------------------+---------------+---------------+
| Dizziness                            | 12 (1.2)      | 16 (0.7)      |
+--------------------------------------+---------------+---------------+
| Headache                             | 9 (0.9)       | 16 (0.7)      |
+--------------------------------------+---------------+---------------+
| General disorders                    | 7 (0.7)       | 20 (0.9)      |
+--------------------------------------+---------------+---------------+
| Skin disorders                       | 9 (0.9)       | 16 (0.7)      |
+--------------------------------------+---------------+---------------+
| Female reproductive disorders        | 6 (0.6)       | 11 (0.5)      |
+--------------------------------------+---------------+---------------+
| Unintended pregnancy                 | 5 (0.5)       | 8 (0.4)       |
+--------------------------------------+---------------+---------------+
| Psychiatric disorders                | 7 (0.7)       | 7 (0.3)       |
+--------------------------------------+---------------+---------------+
| Musculo-skeletal disorders           | 4 (0.4)       | 7 (0.3)       |
+--------------------------------------+---------------+---------------+

## Deaths/Serious adverse events

### Deaths

There was one death in the completed studies:

-   A patient in study B301 committed suicide after 36 days in the
    study. She had a 14-year history of mild depression, and had
    received tricyclic antidepressant drug therapy. Her childhood had
    been marked by the suicide of her mother. The investigator did not
    consider this event to be related to tegaserod.

There were no other deaths in the studies ongoing up to 31 March 2000.

###  Serious adverse events

The frequency of serious adverse events (SAE) was similar between
tegaserod and placebo both in Phase 2 and Phase 3. In the long-term
studies, the frequency was approximately twice as high as would be
expected because of the longer treatment duration (Table 8-8).

###### Table 8-8. Frequency of SAEs: All completed studies {#table-8-8.-frequency-of-saes-all-completed-studies .unnumbered}

  ----------------------- --------------------- --------------------- ---
                          Placebo\              Tegaserod             
                          N=1185                                      

  Phase 3                 13/837 (1.6%)         30/1670 (1.8%)        

  Phase 2                 5/151 (3.3%)          10/519 (1.9%)         

  Long-term               \-                    28/675 (4.1%)         
  ----------------------- --------------------- --------------------- ---

Many AES, particularly GI disorders, were classified as serious because
patients were hospitalized for diagnostic work-up of symptoms for which
no serious organic cause could be identified. Those SAEs reported in
tegaserod patients are summarized in Table 8-9. Overall 4 SAEs were
considered to be possibly or probably related to the study medication:
abdominal pain (n=2), gastritis (n=1), supraventricular tachycardia
(n=1) and hypoglycemia (n=1). One SAE was fatal (see above).

###### Table 8-9. Individual SAEs in all completed studies (tegaserod patients) {#table-8-9.-individual-saes-in-all-completed-studies-tegaserod-patients .unnumbered}

+---------------+-------------------+--------------+------------------+
| **Body        | **Patient No      | **Adverse    | **Patient No     |
| System**      | (dose)**          | event**      | (dose)**         |
|               |                   |              |                  |
| **Adverse     |                   |              |                  |
| event**       |                   |              |                  |
+===============+===================+==============+==================+
| **Gastr       |                   |              |                  |
| ointestinal** |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Abdominal     | B301/104/9 (4);   | Hiatal       | B351/529/13 (12) |
| pain          | B351/513/34 (12); | hernia       |                  |
|               | B                 |              |                  |
|               | 307/748/21\*(12); |              |                  |
|               | B209/13/14\*      |              |                  |
|               | (12); B251/40/6   |              |                  |
|               | (24)              |              |                  |
+---------------+-------------------+--------------+------------------+
| Appendicitis  | B209/11/39 (12)   | Ileus        | B209/28/6 (12)   |
+---------------+-------------------+--------------+------------------+
| D             | B204/6/6 (12)     | Nausea       | B251/5/1 (24)    |
| iverticulitis |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Constipation  | B209/10/19 (12)   | Pancreatic   | B301/112/9 (4)   |
|               |                   | cyst         |                  |
+---------------+-------------------+--------------+------------------+
| Flatulence    | B209/7/1 (4)      | Rectocele    | B351/517/24 (12) |
+---------------+-------------------+--------------+------------------+
| Gastritis     | W352/1/17\* (12)  | Sub-ileus    | B251/30/3 (12);  |
|               |                   |              | B251/42/7 (1)    |
+---------------+-------------------+--------------+------------------+
| Ga            | B351/531/24 (4)   |              |                  |
| stroenteritis |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| **Car         |                   |              |                  |
| diovascular** |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Angina        | B307/763/5 (4)    | SV           | B204/10/5\* (12) |
| pectoris      |                   | tachycardia, |                  |
|               |                   | syncope      |                  |
+---------------+-------------------+--------------+------------------+
| Fluid         | W354/1/17 (12)    | Tach         | B301/114/9 (4)   |
| overload &    |                   | yarrhythmia, |                  |
| CHF           |                   | atrial       |                  |
|               |                   | fibrillation |                  |
+---------------+-------------------+--------------+------------------+
| Hypertension  | B209/28/23 (12)   | Thro         | B209/13/7 (12)   |
|               |                   | mbophlebitis |                  |
+---------------+-------------------+--------------+------------------+
| Myocardial    | B251/24/6 (4)     |              |                  |
| infarction    |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| **Central     |                   |              |                  |
| nervous       |                   |              |                  |
| system**      |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Headache      | B202/11/7 (24)    | Neuropathy   | B307/714/2 (4)   |
|               |                   | (cervical    |                  |
|               |                   | hernia)      |                  |
+---------------+-------------------+--------------+------------------+
| **Endocrine** |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Goiter        | B209/31/18 (12)   |              |                  |
+---------------+-------------------+--------------+------------------+
| **Female      |                   |              |                  |
| r             |                   |              |                  |
| eproductive** |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Mastitis      | B351/517/18 (12)  | Threatened   | B209/13/19 (4)   |
|               |                   | miscarriage  |                  |
+---------------+-------------------+--------------+------------------+
| Menorrhagia   | B209/26/19 (12)   | Ovarian cyst | B209/11/39 (12); |
|               |                   |              | B209/26/6 (12);  |
|               |                   |              | B209/28/4 (12);  |
|               |                   |              | B307/721/2 (12); |
|               |                   |              | B351/518/27 (12) |
+---------------+-------------------+--------------+------------------+
| Miscarriage   | B351/503/13 (12); |              |                  |
|               | B351/518/26 (12); |              |                  |
|               | B307/715/28 (4);  |              |                  |
+---------------+-------------------+--------------+------------------+
| **General**   |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Accidental    | B209/4/4 (12);    | Chest pain   | B209/28/31(4);   |
| trauma        | B251/44/5 (1);    |              | B209/27/7 (4);   |
|               | B301/134/15 (12)  |              | B301/174/1 (4);  |
|               |                   |              | B307/734/15 (4)  |
+---------------+-------------------+--------------+------------------+
| *             |                   |              |                  |
| *Hematology** |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Anemia        | B301/207/2(4)     |              |                  |
| (syncope)     |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| **Li          |                   |              |                  |
| ver/biliary** |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| C             | B209/21/6 (12);   | Gallbladder  | B351/524/1 (12)  |
| holelithiasis | B209/28/31 (4)    | dysfunction  |                  |
+---------------+-------------------+--------------+------------------+
| **Metabolic** |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Hypoglycemia  | B251/32/4\* (1)   |              |                  |
+---------------+-------------------+--------------+------------------+
| **Musc        |                   |              |                  |
| uloskeletal** |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Abdominal     | B251/42/7 (1)     | Cos          | B209/29/6 (4)    |
| hernia        |                   | tochondritis |                  |
+---------------+-------------------+--------------+------------------+
| Back pain     | B209/20/14 (12)   |              |                  |
+---------------+-------------------+--------------+------------------+
| **Neoplasms** |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Basal cell    | B209/28/18 (4)    | Cervical     | B301/142/9 (12)  |
| carcinoma     |                   | carcinoma    |                  |
+---------------+-------------------+--------------+------------------+
| Breast        | B251/16/9 (24);   |              |                  |
| carcinoma     | B251/22/11 (24);  |              |                  |
|               | B351/503/5 (4)    |              |                  |
+---------------+-------------------+--------------+------------------+
| **            |                   |              |                  |
| Psychiatric** |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| An            | B307/730/2 (4/12) | Suici        | B301/147/1\*\*   |
| xiety/bipolar |                   | de/attempted | (4)              |
| disorder      |                   | suicide      |                  |
+---------------+-------------------+--------------+------------------+
| Depression    | B209/28/23 (12);  |              |                  |
|               | B209/2/3 (4);     |              |                  |
|               | B351/524/3 (4)    |              |                  |
+---------------+-------------------+--------------+------------------+
| **            |                   |              |                  |
| Respiratory** |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Pneumonia     | B307/705/2 (4)    | Pulmonary    | B351/524/6 (4)   |
|               |                   | granuloma    |                  |
+---------------+-------------------+--------------+------------------+
| **Skin &      |                   |              |                  |
| appendages**  |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Ke            | B251/4/3 (4)      | Urticaria    | B209/2/13 (4)    |
| ratoacanthoma |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| **Urinary     |                   |              |                  |
| system**      |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Ne            | B251/33/1 (24)    | Urinary      | B209/20/8 (12)   |
| phrolithiasis |                   | tract        |                  |
|               |                   | infection    |                  |
+---------------+-------------------+--------------+------------------+
| Prostatitis   | B209/4/5 (4)      |              |                  |
+---------------+-------------------+--------------+------------------+
| **Vision**    |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Retinal       | B301/102/10 (4)   |              |                  |
| hemorrhage    |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| **Elective    |                   |              |                  |
| procedures**  |                   |              |                  |
+---------------+-------------------+--------------+------------------+
| Abortion      | B209/9/9 (12)     | Hysterectomy | B307/792/7 (4);  |
|               |                   |              | B204/2/8 (4)     |
+---------------+-------------------+--------------+------------------+
| Kidney        | W354/1/11 (12)    | Rectocele    | B209/2/5 (4)     |
| transplant    |                   | surgery      |                  |
+---------------+-------------------+--------------+------------------+

\*) possibly or probably related to study drug. \*\*) fatal

All SAEs reported to the sponsor for those studies ongoing on 31 October
1999, were judged to be unrelated or unlikely to be due to the study
medication. None of the available histories suggest a drug relationship,
with most of the events being expected or the consequence of
circumstances extraneous to the studies. The SAEs observed in the
ongoing studies had a similar pattern and frequency.

### Pregnancies

A total of 20 pregnancies were reported (13 in the phase 3 studies and 7
in the long‑term studies). Fifteen (0.4%) patients in the total
tegaserod group and 5 (0.4%) patients in the placebo group became
pregnant during these studies. The frequency of pregnancies was similar
across treatment groups. All pregnant patients were withdrawn from the
studies.

Four patients (3/15 in the total tegaserod group and 1/5 in the placebo
group) experienced complications (miscarriages). Two of the three
patients in the total tegaserod group who reported miscarriages had
predisposing histories. Overall there were 4 and 1 elective abortions in
the tegaserod and the placebo group, respectively and 6 and 3 healthy
babies born, respectively. In two of the tegaserod cases, the outcome is
unknown.

## Clinical laboratory data

Standard laboratory variables of serum biochemistry, hematology and
urinalysis were measured in all studies.

In Phase 3, pooled analyses of serum biochemistry and hematology showed
the mean changes in both tegaserod and placebo groups to be negligible
for all variables with notable abnormalities rare and no suggestion of a
drug effect.

In particular, analysis of changes in liver enzyme values (serum
transaminase activity, total bilirubin and alkaline phosphatases) did
not indicate any treatment effect (data not shown).

Urinalysis did not show any treatment imbalance.

Results of the Phase 2 and long-term studies were similar.

Discontinuations for laboratory abnormalities

In Phase 2/3 and the long-term studies 11 patients discontinued because
of laboratory abnormalities (Table 8-10). There was no evidence that
these were due to treatment with tegaserod although for one of them, a
case of hypereosinophilia without any clinical manifestation of
hypersensitivity, the data did not allow an adequate assessment as no
rechallenge was undertaken.

###### Table 8-10. Discontinuations due to laboratory abnormalities (Phase 2/3 and long-term studies)  {#table-8-10.-discontinuations-due-to-laboratory-abnormalities-phase-23-and-long-term-studies .unnumbered}

  -------------- ---------- --------------- -------------- ------------------------------
  **Variable**   **Dose**   **Subj No.**    **Max.         **Comment**
                                            abnormal\***   

  ALT            12 mg      B351/523/0033   100 U/L        baseline abnormal; no
                                                           worsening on treatment

  CPK            4 mg       B351/550/0003   626 U/L        baseline abnormal; normal on
                                                           treatment

                 12 mg      B351/522/0037   293 U/L        baseline abnormal; similar on
                                                           treatment

                 4 mg       B307/733/0028   6070 U/L       vigorous exercise

  Bilirubin      PBO        B202/016/0004   2.9 mg/dL      Gilbert syndrome

  Cholesterol    1 mg       B202/005/0004   8.0 mmol/L     similar at baseline

  Glucose        1 mg       B251/032/0004   2.3 mmol/L     Continued after d/c

  WBC            4 mg       B307/733/0007   2.1 10\*9/L    baseline abnormal; similar on
                                                           treatment

  Eosinophils    4 mg       B209/017/0001   1.39 10\*9/L   after d/c: 0.53 10\*9/L

  Platelets      4 mg       B301/167/0006   34 10\*9/L     single value, probable lab
                                                           error

  Hct            4 mg       B301/207/0002   0.35 L/L       similar at baseline

  \*) after                                                
  beginning of                                             
  treatment with                                           
  study                                                    
  medication                                               
  -------------- ---------- --------------- -------------- ------------------------------

## Other Safety Assessments

### Blood Pressure

While animal studies did not show a cardiovascular effect of tegaserod
at human therapeutic doses, early studies in healthy subjects using the
i.v. formulation, and a few cases of healthy subjects exposed to single
oral doses of [\>]{.underline} 25 mg tegaserod indicated that in rare
instances, tegaserod treatment may be associated with symptomatic
reductions in blood pressure.

For this reason, in the Phase 2 and 3 programs, particular attention was
paid to a comprehensive recording and analysis of the effects of
tegaserod on blood pressure and pulse rate. An orthostatic blood
pressure reduction was defined as a reduction in standing relative to
supine systolic pressure of 20 mm Hg and/or a reduction in diastolic
blood pressure of 10 mm Hg.[^24]

In phase 2/3 studies, the frequency of notably abnormal systolic or
diastolic blood pressures supine or standing (3-minute value) was very
similar between the tegaserod and placebo groups. There was no
suggestion for tegaserod having an effect on blood pressure or pulse
rate. In the phase 3 studies, the frequency of orthostatic blood
pressure lowering during the course of the 12‑week treatment was 35% in
the tegaserod group and 36% in the placebo group.

#### Symptoms suggestive of orthostatic hypotension (OH)

In the Phase 3 studies AEs suggestive of OH were reported with similar
frequencies in the tegaserod and placebo groups. The most common AE was
dizziness, which was reported with similar frequencies in both treatment
groups; (postural) hypotension was more frequent with placebo (Table
8-11). On the other hand, syncope was more frequently reported in the
tegaserod group than the placebo group (0.5% vs. 0.1%). In all but one
case, fainting was reported as an isolated event and in no case was a
therapy prescribed nor did any patient discontinue the study prematurely
because of this event. In the 8 patients on tegaserod the drug
relationship was classified by the investigator as "none" (n=2),
"unlikely" (n=4), and "possibly" (n=2); one patient was known to have an
orthostatic dysregulation, and in one patient fainting occurred during
blood sampling. In 6/8 patients the blood pressure was unchanged
compared to baseline, in the remaining patients it was slightly reduced
without signs for an orthostatic reaction.

###### Table 8-11. Number (%) of patients with adverse events suggestive of orthostatic hypotension in Phase 3 studies {#table-8-11.-number-of-patients-with-adverse-events-suggestive-of-orthostatic-hypotension-in-phase-3-studies .unnumbered}

+-----------------------------------------------+----------+----------+
|                                               | **Teg    | **P      |
|                                               | aserod** | lacebo** |
+-----------------------------------------------+----------+----------+
|                                               | **       | *        |
|                                               | N=1679** | *N=837** |
|                                               |          |          |
|                                               | **n      | **n      |
|                                               | (%)**    | (%)**    |
+-----------------------------------------------+----------+----------+
| Total patients with symptoms suggestive of    | 107      | 55 (6.6) |
| orthostatic hypotension                       | (6.4)    |          |
+-----------------------------------------------+----------+----------+
| Dizziness                                     | 95 (5.6) | 46 (5.5) |
+-----------------------------------------------+----------+----------+
| Syncope                                       | 8 (0.5)  | 1 (0.1)  |
+-----------------------------------------------+----------+----------+
| Hypotension                                   | 7 (0.4)  | 7 (0.8)  |
+-----------------------------------------------+----------+----------+
| Hypotension postural                          | 0        | 2 (0.2)  |
+-----------------------------------------------+----------+----------+
| Circulatory failure                           | 0        | 1 (0.1)  |
+-----------------------------------------------+----------+----------+

####  {#section-11 .unnumbered}

#### Discontinuations due to orthostatic hypotension in the Phase 2/3 and long-term study B209

The frequency of patients who discontinued from the studies due to a
single AE suggestive of OH was slightly higher (0.4%) in the tegaserod
group, than in the placebo group (0.1%). The frequency of patients
discontinued from the studies due to one or more AEs including at least
one AE suggestive of OH was the same in the tegaserod and placebo groups
(1%). The percentage of tegaserod patients who discontinued long-term
treatment for these symptoms was lower.

## Long-term safety (study B209)

A total of 567 patients with C-IBS were safety analyzable in the
12-month open-label study B209. The selection criteria were similar to
those in the Phase 3 studies, with the exception of an upper age limit
of 70 years.

A total of 377 patients received tegaserod for 6 months (180 days) and
152 for 365 days. A total of 298 patients were treated for at least 335
days (Table 8-12). Compliance was good, with only 6% of patients
receiving less than 75% of the prescribed tegaserod.

###### Table 8-12. Duration of exposure in long-term study B209  {#table-8-12.-duration-of-exposure-in-long-term-study-b209 .unnumbered}

+----------------------------------+-----------------------------------+
| **Duration of exposure**         | **Tegaserod**\                    |
|                                  | N=567                             |
|                                  |                                   |
|                                  | n (%)                             |
+----------------------------------+-----------------------------------+
| 1 day                            | 567 (100)                         |
+----------------------------------+-----------------------------------+
| 7 days                           | 560 (98.8)                        |
+----------------------------------+-----------------------------------+
| 30 days                          | 530 (93.5)                        |
+----------------------------------+-----------------------------------+
| 85 days                          | 466 (82.2)                        |
+----------------------------------+-----------------------------------+
| 180 days                         | 377 (66.5)                        |
+----------------------------------+-----------------------------------+
| 270 days                         | 329 (58.0)                        |
+----------------------------------+-----------------------------------+
| 335 days                         | 298 (52.6)                        |
+----------------------------------+-----------------------------------+
| 365 days                         | 152 (26.8)                        |
+----------------------------------+-----------------------------------+

Ninety-one percent were female, 93% Caucasian, mean age 44 years, and
the mean disease duration of 12 years.

Overall, 304/579 (53%) of patients completed the study as planned. The
main reasons for discontinuation were lack of effect (12%), adverse
events (11%), withdrawal of consent (11%), and lost to follow-up (8%).
The discontinuation rate due to AEs, was higher than the 7% of
tegaserod-treated patients in Phase 2/3 studies (Table 8-6), but
consistent when considering the longer duration of the study.

The overall proportion of patients reporting AEs was 80%. GI complaints
were the most common (40% of patients), followed by CNS disorders (30%).
Headache (30%) was the most frequently reported AE (Table 8-13).

###### Table 8-13. Most frequently (≥5% of patients) reported adverse events: long-term study (B209) in C-IBS {#table-8-13.-most-frequently-5-of-patients-reported-adverse-events-long-term-study-b209-in-c-ibs .unnumbered}

  ----------------------------------------------- -----------------------
  **Adverse event**                               **Tegaserod**\
                                                  (N = 567)

                                                  **n (%)**

  Total patients with adverse events              452 (79.7)

  Headache                                        167 (29.5)

  Abdominal pain                                  97 (17.1)

  Upper resp. tract. infection                    92 (16.2)

  Diarrhea                                        83 (14.6)

  Back pain                                       49 (8.6)

  Sinusitis                                       47 (8.3)

  Nausea                                          46 (8.1)

  Flatulence                                      43 (7.6)

  Dyspepsia                                       41 (7.2)

  Rhinitis                                        39 (6.9)

  Influenza-like symptoms                         34 (6.0)

  Pharyngitis                                     30 (5.3)

  Insomnia                                        29 (5.1)
  ----------------------------------------------- -----------------------

Discontinuations because of AEs occurred in 11.5% of patients. The most
frequent AEs responsible were diarrhea 3.5%, abdominal pain 2.8%,
flatulence 2.6%, and headache 1.1%.

SAEs have been previously reviewed. Of note was the hospitalization of 3
women because of symptomatic ovarian cysts. The overall findings are
discussed section 8.8.2.

Standard 12-lead ECGs were carried out before and during treatment and
the findings together with AEs of cardiac arrhythmia have been analyzed
and are discussed in section 8.8.1.

The second open-label long-term study (B204) was discontinued
prematurely for administrative reasons. One-hundred seventy patients had
been enrolled, and the maximal treatment duration for these subjects was
less then 6 months. The results were similar to those obtained in study
B209.

Overall, the safety profile obtained from the analysis of the long-term
studies was consistent with that obtained from the placebo-comparative
analyses in the pooled Phase 2/3 studies.

## Notable safety issues

### Electrocardiography

#### Preclinical cardiac repolarization studies

Some gastro-prokinetic drugs, like cisapride and erythromycin, are known
to induce QT interval prolongation, sometimes associated with Torsade de
Pointes (TdP). Recent evidence suggests that these drugs block delayed
rectifier potassium currents (*I~K~*) in the heart (without involvement
of 5-HT~4~ receptors), thereby causing a slowing of cardiac
repolarization. Three *in vitro* studies were carried out to
specifically address the potential to impair cardiac repolarization:

-   The first study was designed to directly examine the effects of
    tegaserod on *I*~Kr~, the component of the delayed rectifier
    potassium currents which were inhibited by drugs associated with QT
    interval prolongation and TdP. The effects on the corre­sponding
    potassium channel, encoded by the human ether-a-go-go-related gene
    (HERG) and stably transfected into mammalian cells (HEK 293 cells),
    were in­vestigated using whole cell patch clamp methodology.

-   Tegaserod was assessed for effects on intracellularly recorded
    action potential parameters in Guinea-pig isolated papillary muscle
    preparations electrically paced at 1 Hz.

-   The effects of tegaserod, its main human metabolite
    (5‑methoxyindole-3-carboxylic acid glucuronide), cisapride and
    erythromycin on cardiac repolarization were examined using the
    isolated perfused rabbit heart (Langendorff) model.

The results of the three *in vitro* models showed that tegaserod had no
potential to impair cardiac repolarization at therapeutic
concentrations. The results of an *in vivo* safety pharmacology study in
conscious dogs addressing potential effects on ECG parameters also
confirmed that tegaserod and its main human metabolite lack QT interval
prolongation activity at therapeutic plasma concentrations.

#### Phase 3 and long-term ECG evaluations

In the Phase 3 studies an ECG was obtained 1.5 to 2.5 hours
(corresponding to approximate T~max~) after the first and last doses of
study drug. In the Phase 3 studies, and in study B209, an independent
company interpreted the ECG tracings using the Sigmascan technique. An
abnormal PR interval was defined as an interval \>200 msec, an abnormal
QRS interval as an interval \>120 msec, and an abnormal QTc interval as
an interval \>499 msec. A cutoff for the uncorrected QT interval was not
defined. In addition, for the QTc interval, prolongations from baseline
were classified as normal, borderline prolonged, or prolonged according
to the Committee for Proprietary Medicinal Products (CPMP)
recommendations[^25].

#### Ventricular rate and PQ-, QRS-, and QT-intervals (Phase 3 and study B209) {#ventricular-rate-and-pq--qrs--and-qt-intervals-phase-3-and-study-b209 .unnumbered}

In Phase 3 studies the changes in mean ventricular rate and mean PQ-,
QRS-, and QT‑intervals were comparable for the tegaserod and placebo
groups. In the long‑term study data were similar to the Phase 3 studies
showing no treatment-related effect on ECG intervals.

#### QTc interval (Phase 3 and study B209) {#qtc-interval-phase-3-and-study-b209 .unnumbered}

The changes in mean QTc intervals were comparable in the tegaserod and
placebo groups. The percentages of patients with an increase in the QTc
interval of 30 to 60 msec or an increase of \>60 msec from baseline, the
percentage of patients with at least one borderline or prolonged QTc
interval after the first dose of the study drug, the number of patients
with normal baseline values and at least one borderline or prolonged QTc
interval value were comparable in the tegaserod and placebo groups. The
frequency of any newly occurring QTc intervals of \>499 msec was low.
There was no dose-response relationship between the tegaserod 4 and 12
mg/day groups. The long-term data (B209) was similar to the Phase 3 data
showing no treatment effect on ECG intervals. QTc interval data are
summarized, by treatment group, in Table 8-14.

###### Table 8-14. Summary of QTc interval data in Phase 3 and study B209 {#table-8-14.-summary-of-qtc-interval-data-in-phase-3-and-study-b209 .unnumbered}

+---------------------+--------+--------+-------+----------+---+--------+---+
|                     | **     |        |       |          | * |        |   |
|                     | Pooled |        |       |          | * |        |   |
|                     | Phase  |        |       |          | S |        |   |
|                     | 3      |        |       |          | t |        |   |
|                     | stu    |        |       |          | u |        |   |
|                     | dies** |        |       |          | d |        |   |
|                     |        |        |       |          | y |        |   |
|                     |        |        |       |          | B |        |   |
|                     |        |        |       |          | 2 |        |   |
|                     |        |        |       |          | 0 |        |   |
|                     |        |        |       |          | 9 |        |   |
|                     |        |        |       |          | * |        |   |
|                     |        |        |       |          | * |        |   |
+---------------------+--------+--------+-------+----------+---+--------+---+
|                     | **Pla  | **4    | **12  | **All    |   | **All  |   |
|                     | cebo** | mg/d** | m     | teg      |   | tegas  |   |
|                     |        |        | g/d** | aserod** |   | erod** |   |
|                     | **N    | **N    |       |          |   |        |   |
|                     | =837** | =844** | **N=  | **       |   | **N    |   |
|                     |        |        | 560** | N=1679** |   | =675** |   |
|                     | **     | **     |       |          |   |        |   |
|                     | n(%)** | n(%)** | **n   | **n(%)** |   | **     |   |
|                     |        |        | (%)** |          |   | n(%)** |   |
+---------------------+--------+--------+-------+----------+---+--------+---+
| Baseline (mean, SD, | 399 22 | 401 23 | 399   | 400 24   |   | 396 22 |   |
| msec)               |        |        | 24    |          |   |        |   |
+---------------------+--------+--------+-------+----------+---+--------+---+
| Change from         | 3.1    | 1.6    | 3.8   | 2.1 22.2 |   | -0.7   |   |
| baseline, at        | 22.7   | 22.98  | 21.2  |          |   | 20.1   |   |
| endpoint (mean, SD, |        |        |       |          |   |        |   |
| msec)               |        |        |       |          |   |        |   |
+---------------------+--------+--------+-------+----------+---+--------+---+
| Increase by 30 to   | 155    | 163    | 107   | 308      |   | 67     |   |
| 60 msec             | (18.7) | (19.6) | (     | (18.6)   |   | (12.5) |   |
|                     |        |        | 19.5) |          |   |        |   |
+---------------------+--------+--------+-------+----------+---+--------+---+
| Increase by \>60    | 11     | 5      | 7     | 15 (0.9) |   | 4      |   |
| msec                | (1.3)  | (0.6)  | (1.3) |          |   | (0.7)  |   |
+---------------------+--------+--------+-------+----------+---+--------+---+
| Normal at baseline  | 5      | 3      | 2     | 7 (0.4)  |   | 0      |   |
| to prolonged at     | (0.6)  | (0.4)  | (0.4) |          |   |        |   |
| least once during   |        |        |       |          |   |        |   |
| study^2^            |        |        |       |          |   |        |   |
+---------------------+--------+--------+-------+----------+---+--------+---+
| Normal at baseline  | 33     | 31     | 20    | 59 (3.5) |   | 9      |   |
| to borderline at    | (4.0)  | (3.8)  | (3.6) |          |   | (1.7)  |   |
| least once during   |        |        |       |          |   |        |   |
| study^1^            |        |        |       |          |   |        |   |
+---------------------+--------+--------+-------+----------+---+--------+---+
| Borderline at       | 3      | 4      | 0     | 5 (0.3)  |   | 0      |   |
| baseline to         | (0.4)  | (0.5)  |       |          |   |        |   |
| prolonged at least  |        |        |       |          |   |        |   |
| once during the     |        |        |       |          |   |        |   |
| study^1,\ 2^        |        |        |       |          |   |        |   |
+---------------------+--------+--------+-------+----------+---+--------+---+
|                     |        |        |       |          |   |        |   |
+---------------------+--------+--------+-------+----------+---+--------+---+

^1^ Borderline: males 430 to 450 msec; females 450 to 470 msec.\
^2^ Prolonged: males \>450 msec; females \>470 msec.

#### ECG abnormalities

Frequency of ECG abnormalities

In the Phase 3 studies, the frequency of newly occurring or worsening
ECG abnormalities was similar for the tegaserod and the placebo groups.

The most frequent newly occurring ECG abnormalities were changes in T
wave morphology (i.e., flattening, inversion, biphasic, or other) which
however was similar between tegaserod and placebo. Other abnormalities
seen in \>1% of patients in the tegaserod group were ST-segment
depression and first degree AV block. The frequency of ST-segment
depression was slightly higher in the tegaserod group than in the
placebo group .

In elderly patients (\>65 years) the overall frequency of ECG
abnormalities was higher in the tegaserod group than in the placebo
group (21% vs. 12%) primarily due to a larger number of patients with
ST‑segment depression and/or T-wave alterations. According to an
external consultant in cardiology (Dr. J. Morganroth, Philadelphia)
there is no signal that tegaserod causes ST-T wave changes.

Similar results were obtained in the Phase 2 studies and the long-term
studies.

### Ovarian cysts

In the Integrated Summary of Safety (ISS) of the NDA submission, nine
cases of ovarian cyst were reported (8 tegaserod, one placebo patient),
all of them in women aged 50 or less. Five of these cases (all tegaserod
patients) were considered as serious because they required surgery.
Since the submission, additional information (from case record forms,
pathology and hospital discharge reports) has been obtained and
submitted to the FDA, permitting a fuller interpretation.

Although more cases of ovarian cyst were reported in tegaserod patients,
comparison of the reporting frequencies does not suggest a treatment
effect (Table 8-15).

###### Table 8-15. Numbers (percentage) of female patients with ovarian cysts {#table-8-15.-numbers-percentage-of-female-patients-with-ovarian-cysts .unnumbered}

  -----------------------------------------------------------------------
                              placebo               Tegaserod
  --------------------------- --------------------- ---------------------
  Controlled studies                                

  Phase 3                     1^(2)^/707 (0.14)     1^(1)^/1419 (0.07)

  Phase 2                     0/140                 2^(3)^/456 (0.44)

  Combined Phase 2/3          1/847 (0.12)          3/1875 (0.16)

  Uncontrolled, long-term     \-                    1^(4)^/611 (0.16)
  studies                                           

  1: B351/518/27 2:                                 
  B301/163/10 3: B251/32/2,                         
  B251/32/7 4: B209/28/4                            
  -----------------------------------------------------------------------

Functional, non-neoplastic, ovarian cysts are a relatively common
finding in women and are generally physiologic and related to ovulatory
processes. Patients are normally managed by observation with surgical
resection only in cases of large, symptomatic cysts not regressing
spontaneously. Of the above patients only two (B351/518/27, B209/28/4)
came into the category of having functional cysts requiring surgery and
both of them had been shown to have the condition before entry into the
study.

## Safety summary and conclusions

The data presented have been drawn from over 4000 subjects of whom over
3000 were IBS patients in well-controlled studies. The dose range
investigated in healthy subjects included multiples (more then 10 times)
above the therapeutic dose. The focus of the safety analysis has been on
the target population, which included both women and men, aged 18 years
and older, including approximately 10% elderly patients. The
characteristics of the study population were largely reflective of the
general IBS population. In the Phase 3 studies, which formed the core of
the safety database, patients, apart from fulfilling the criteria of
C-IBS, were largely unselected with respect to concomitant diseases or
co-medications. Thus, this study population was representative for what
is seen in the general practice in terms of IBS.

Based on its pharmacological profile, tegaserod acts as a
5HT~4~-receptor partial agonist specifically in the GI tract in terms of
stimulation of motility, intestinal secretion and inhibition of visceral
afferents. Even though 5HT~4~-receptors can be found in other tissues
(e.g., CNS, atria), the general pharmacology investigations revealed
that tegaserod lacked systemic effects regarding CNS, renal function,
the respiratory, cardiovascular or the endocrine system.

At therapeutic doses, the tolerability and safety profile of tegaserod
has been proved to be favorable with, apart from a transient increase in
bowel motility reported as diarrhea during the initiation of therapy, an
AE profile similar to placebo. Analysis of the individual and pooled
databases in the controlled and long-term studies did not suggest any
pharmacological effect, which might indicate that tegaserod treatment
induces organ dysfunction or toxicity.

-   Of the AEs considered drug-related by the investigator or leading to
    discontinuation from the study, only diarrhea was identified as
    being clearly more frequent with tegaserod than with placebo.
    Tegaserod-induced diarrhea appears early after the start of
    treatment. It does not seem to represent a significant safety
    problem, seldom leading (≤ 3%) to patients discontinuing treatment.

-   The frequency of SAEs was low, and comparable for tegaserod and
    placebo patients in the Phase 2/3 placebo-controlled studies (1.8%).

-   Laboratory evaluations did not suggest that tegaserod had a systemic
    effect.

-   As expected, and in line with the pharmacokinetic findings which had
    shown only negligible blood-brain barrier permeation in the rat,
    treatment tegaserod was devoid of any CNS effects.

-   ECG analyses and the AE profile did not suggest that tegaserod had
    any proarrhythmic effect in general or one which may have suggested
    a stimulatory effect on the atria. Tegaserod exposure was associated
    with a slightly higher frequency ST-T-wave alterations, which were,
    however, not considered clinically relevant.

Special safety issues that had been identified during the development
program as a result of preclinical or early clinical findings have been
addressed in this document, and did not reveal any safety concerns, but
rather confirmed the robustness of the safety profile:

-   Analyses of the ECGs in Phase 3 and a regression analysis of plasma
    concentrations vs. QTc interval changes in several populations did
    not show any unfavorable effect on cardiac repolarization,
    especially the QTc interval.

-   Orthostatic tests did not show any effect of tegaserod on the
    frequency of notably low blood pressures or episodes of symptoms
    that can be associated with OH. The overall frequency of AEs
    suggestive for OH was similar between tegaserod and placebo.

Tegaserod appears to be well tolerated at the doses recommended for
therapy and devoid of any organ toxicity that would preclude its
long-term use in the treatment of functional GI disorders.

# Benefits/Risk Assessment

IBS is a common chronic GI disorder having a broad spectrum of severity,
which can be associated with significant disability and health care
costs. Since no drugs are available which have been shown to be globally
effective in this disorder, there is a major medical need for an
effective treatment.

The tolerability and safety profile of tegaserod proved to be very
favorable. Apart from an initial increase in the bowel motility reported
as diarrhea, the AE profile of tegaserod is similar to placebo.
Hematological, biochemical, and cardiovascular parameters did not show
any signs of specific toxicity. The absence of effects of tegaserod on
the cardiac repolarization (QTc interval) is an important
pharmacodynamic feature in comparison to other prokinetic agents, such
as cisapride.

Overall, the totality of the data provides strong evidence that
tegaserod is effective in the treatment of patients with IBS who
identify abdominal pain and discomfort, and constipation as their
predominant symptoms. This statement is supported by the consistency of
the data between studies, at multiple timepoints (endpoint and monthly)
and between the weekly SGA and daily diary efficacy variables. The SGA
of relief is a global outcome measure that integrates the key symptoms
of IBS and encompasses overall well-being. Tegaserod has been shown to
have a clinically and statistically significant effect compared to
placebo on the patient's assessment of relief. This effect was
associated with a consistent improvement of the key symptoms of IBS,
such as abdominal pain and discomfort and bowel function. This effect
was evident already after the first week of therapy and was sustained
throughout the treatment period.

In conclusion, tegaserod has a favorable risk-benefit ratio that appears
to justify its recommendation for the treatment of IBS patients.

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    Appendix 1

    Rome Diagnostics Criteria for IBS

    To qualify, subjects must meet all three criteria based on the IBS
    Questionnaire as described below:

    Criterion 1. Question 1 = yes; and

    Criterion 2. Question 2, 3, 4: yes for one or more; and

    Criterion 3. Question 5: yes for two or more of a, c, or e.

    IBS Questionnaire

    In the past three months have you had continuous or repeated
    discomfort or pain in your lower abdomen? (Caution: this includes
    diffuse (upper and lower) abdominal pain/discomfort. Purely
    epigastric/upper abdominal pain is not acceptable).

    a\. Yes

    b\. No (If no, stop, the subject does not meet the definition of IBS
    used for this study).

    Is this discomfort or pain typically relieved by a bowel movement?

    a\. Yes

    b\. No

    Is this discomfort or pain typically associated with a change in the
    frequency of bowel movements (i.e. having more or fewer bowel
    movements)?

    a\. Yes

    b\. No

    Is this discomfort typically associated with a change in the
    consistency of the stool (i.e. softer or harder)?

    a\. Yes

    b\. No

    Would you say that at least one fourth (1/4) of the occasions or
    days in the last three months you have any of the following? (Check
    all that apply)

    a\. Less than 3 bowel movements a week (0 - 2)

    b\. More than three bowel movements a day

    c\. Hard or lumpy stools

    d\. Loose or watery stools (see also Exclusion Criterion No. 1)

    e\. Straining during a bowel movement

    f\. Urgency - having to rush to the bathroom for a bowel movement

    g\. Feeling of incomplete bowel movement

    h\. Passing mucus (white material) during a bowel movement

    i\. Abdominal fullness, bloating or swelling.