Irritable bowel syndrome (IBS) is an extremely common disorder in the U.S population,
affecting somewhere between 9-22% based on community based studies. IBS has a chronic
relapsing course and overlaps with other functional gastrointestinal disorders. It accounts
for high direct medical expenses and indirect costs including a significant degree of
absenteeism. Most studies have suggested that there is a slight predominance among women,
especially those that have suffered some form of physical or sexual trauma. It has been
estimated that up to 25-40% of patients seen by gastroenterologists' are affected by IBS,
and that 70-90% of these patients may have a psychiatric comorbidity, most commonly major
depression and panic disorder, but also including schizophrenia, double depression,
dysthymia and alcohol abuse.
Abdominal pain and disturbance of bowel habits characterize the symptoms of IBS in the
absence of demonstrable structural pathology. The diagnosis of IBS relies upon clinical
criteria alone, as there is no "gold standard" in laboratory findings. The diagnosis is
dependent upon identifying characteristic symptoms, and then differentiating IBS from other
structural bowel disorders. Previously, the diagnosis of IBS was based upon a consortium
recommendation that examined and defined diagnostic criteria for over 100 functional
gastrointestinal disorders. These criteria became the most definitive in the area of
functional disorders and are referred to as the Rome Criteria. During the time since this
consensus, these criteria have been modified, and in 1999 became the foundation for the
second set of diagnostic criteria by consensus, now referred to as the Rome II criteria. The
revised Rome II criteria include only the first part of the original criteria, but now
require the presence of two out of three symptoms relating abdominal pain to bowel symptoms.
We designed our study and a Randomized, double-blind, parallel-group, flexible-dose,
placebo-controlled 12-week study.
Primary and Secondary Efficacy Measures Primary
Change from baseline in:
• Mean composite pain scores (on IVRS) Secondary
Change from baseline in:
- Associated symptoms of IBS (diarrhea, constipation, incomplete emptying, etc.) scores
- IBS Quality of Life scores
- Clinical Global Impression scores of 1 or 2
- Beck Depression Inventory II
- Beck Anxiety Inventory
Safety and tolerability will be assessed through:
- Recording of spontaneous adverse events throughout the screening, run-in, and treatment
phases of the study
- Conducting the DOTES at defined points during the study
All subjects withdrawn from the study will be followed until complete resolution of adverse
Study Schedule This is a placebo-controlled, double-blinded prospective 12-week study
examining the efficacy of paroxetine extended release form in patients with IBS. Patients
meeting the Rome II criteria for IBS will be recruited from the Duke University Medical
Center Division of Gastroenterology and from the community. Patients found to satisfy these
criteria will be referred for enrollment into this study. The study will be explained and
informed consent obtained. A detailed history about the gastrointestinal symptoms and a
physical exam will be performed. Laboratory evaluations (CBC, chemistry, fecal occult blood,
urinalysis and EKG) will be obtained.
All patients will undergo a MINI at baseline to diagnose any comorbid Axis I psychiatric
disorders, and a physical and sexual abuse history will be elicited. The patients will then
have 1 week of symptom charting using the Interactive Voice Response System (IVRS) to
measure baseline severity of IBS symptoms. Following that, patients will receive a
single-blind placebo for a 1 week period. Those patients having a >25% improvement in
composite pain scores at the end of the placebo week or a CGI of 1 or 2 will be terminated
from the study. Following the 1 week single-blind placebo lead-in, non-responders will be
randomized to active drug or placebo for an additional period of 12 weeks. The patients will
continue to fill out a daily symptom diary using the IVRS and, in addition, will have weekly
visits (biweekly after week 4) to assess symptoms, side-effects, and improvement over the
entire 12-week double-blind period. Those in the active treatment group will receive doses
of Paxil CR in increments of 12.5 mg daily for the first week and increased at 12.5 mg
increments at visit weeks to a maximum of 50 mg daily, as determined by the investigator.
The investigator will adjust dosage based on clinical response. Following the completion of
the double-blind phase, patients on placebo and non-responders to the study drug will be
tapered off the study drug back to 0 over 2 weeks, and they will be referred to their
Primary Care Physician, Internist or Gastroenterologist to be prescribed treatment for
Irritable Bowel Syndrome. Patients on active drug (Paroxetine CR) who were successful
responders during the double-blind phase will be eligible to continue on open label Paxil CR
for an additional period of 6 months plus 2 weeks and will be followed on a monthly basis.
They will complete the IVRS symptom diary for a week during each follow-up month for an
additional 6 months. Those who completed the double-blind phase during the 1st half of the
month (days 1-14) will complete the IVRS symptom diary for the first week beginning the 1st
of the next month; those who completed the double-blind phase during the second half of the
month (days 15-31) will complete the IVRS symptom diary for the first week beginning the 1st
of the month following the next month. At the end of the 6-month period, study medication
for these patients will be tapered back to 0 over 2 weeks, and they will be referred to
their Primary Care Physician, Internist or Gastroenterologist to be prescribed treatment for
the Irritable Bowel Syndrome. Placebo responders in the double-blind phase will not be
eligible to enter the 6-month open label maintenance phase.
Clinical response will be measured in several ways. Abdominal pain severity will be
measured with an ordinal scale rated from 1-9 (1=mild pain/discomfort, 9=very severe
pain/discomfort). Abdominal pain frequency will be measured on a four-point scale (1=pain or
discomfort present only occasionally, 2=pain or discomfort present less than half the day,
3= pain or discomfort present more than half the day, 4=pain or discomfort almost all day).
The same ordinal scale will be used to quantify the distress or discomfort caused by feeling
of incomplete evacuation, bloating or abdominal discomfort, and general level of stress or
Sample Size Computation and Power Analysis Power considerations The calculations that follow
are computed for the current design with an anticipated difference in pre-and post-treatment
on the mean composite pain scores (on IVRS) of 25% (i.e. a reduction of score from 100 to
75). The means and standard deviations for this computation rely on our previous open-label
studies of paroxetine and citalopram in IBS.
Assuming a strong effect size (0.5) of the primary variable (mean composite pain scores) and
alpha set at 0.05, a projected sample size of 50 can detect the main effects with a power of
greater than 0.95. If a lower effect size is assumed (0.4), a projected sample size of 55
can detect main effects with a power of approximately 0.94. Note that power may be reduced
by attrition of the sample (i.e. dropouts) and also may be limited in testing secondary
hypotheses where a further stratification of sample may be necessary (i.e. if the data is
examined separately in men and women)
It may be more appropriate to have a sample size of 60 which allows for a 20% attrition rate
and can still detect an effect size of 0.4 for the primary variable in the
treatment-completer group with a power greater than 90.
Statistical analyses The study's main hypothesis is that paroxetine (Paxil CR) treatment
will be more effective than placebo in reducing symptoms of IBS.
All statistical tests will be two sided at the 0.05 level of significance. Descriptive
statistics will be used to provide a profile of demographic and outcome measures. Pearson
product moment correlational analyses will be conducted to examine the relationships among
variables. Baseline assessments between the two groups will be compared using chi square for
categorical variables and independent t tests (two tailed) for continuous variables. Between
group (medication/placebo) comparisons for primary and secondary variables will employ
analysis of variance (ANOVA) with repeated measures. Assessments will be taken at baseline
and end of week 1, 2, 3, 4, 6, 8, 10, and 12. Within group analyses (pre and
end-of-treatment) will employ two tailed t tests.
To control for the possibility that current psychopathology might affect subject responding
on interview and self-report instruments and otherwise modulate the treatment effects, the
distribution of BDI-II and BAI scores and life time Axis I diagnoses in the placebo and
control groups will be examined. The potential influence of any unequally distributed
variables will be controlled via analyses-of covariance (ANCOVA) using the unequally
distributed variables as covariates.
After the primary analysis other exploratory analyses will be conducted to test potential
hypotheses for further studies.
Each patient must satisfy all the following criteria before entry into the study:
1. Patients must have given their written informed consent to enter the study (after
verification of the diagnosis criteria).
2. Male or female patients, aged 18 to 75 years of age at last birthday.
Female patients of child-bearing potential must use one of the following methods of
contraception for the duration of the study:
- Oral contraceptive (combined or progesterone only)
- Parenteral progesterone-only contraceptive (e.g. Norplant®, Depo-Provera®)
- Intra-uterine device
- Double barrier method of contraceptive (e.g. condom plus spermicide, condom plus
diaphragm, etc.) Female patients of child-bearing potential will be defined as
those who are not post-menopausal or those who have not undergone a hysterectomy
or surgical sterilization. (Note: to be considered post-menopausal, a woman
would have to be naturally free of menses for at least 2 years).
3. Patients presenting with Irritable Bowel Syndrome as defined by the modified Rome II
At least 12 weeks, which need not be consecutive, in the preceding 12 months of
abdominal discomfort or pain that has two of three features:
- Relieved with defecation; and/or
- Onset associated with a change in frequency of stool; and/or
- Onset associated with a change in form (appearance) of stool.
The following symptoms cumulatively support the diagnosis of IBS:
- Abnormal stool frequency
- Abnormal stool form
- Abnormal stool passage
- Passage of mucus
- Bloating or feeling of abdominal distention
In order to proceed into the double-blind phase of the study, patients must have
recorded at least 5 days' data for abdominal pain and Overall Assessment of symptoms
on the IVRS during the placebo run-in period. In addition, the patient must
demonstrate a <25% improvement in composite pain scores in placebo run-in period as
compared to screening week.
4. Patients who have experienced symptoms of IBS for a duration of greater than one year
(from the date of the Screening visit) and for whom this is documented in the medical
5. Patients must be willing and able to maintain their usual diet (and, if indicated,
maintain a lactose-free diet) during the course of the study.
6. All patients must have had either a full colonoscopy or flexible sigmoidoscopy with
barium enema performed at some time in the past. Additionally, they must have these
procedures repeated prior to the screening visit if:
- the patient has experienced a recent change in bowel habits (recent means within
6 months of entry to the study) or
- the patient is aged 55 or above (at their last birthday) and has not had these
investigations carried out within 5 years of entry to the study.
7. Patients must be willing and able to comply with the study procedures.
A patient will be excluded from the study if any one of the following criteria applies to
1. Patients with severe concurrent disease defined as any disease which, in the
investigator's opinion, is unstable and/or life-threatening, or is serious enough to
jeopardize efficacy or safety assessments during the study. This definition may
include, but is not limited to:
- Any major GI disorder (including history of inflammatory bowel disease
[colitis], celiac disease, complicated colonic diverticular disease)
- History of abdominal surgery which, in the investigator's opinion, may interfere
with the assessment of IBS symptoms during the study
- Uncontrolled diabetes
- Uncontrolled hypertension
- Uncontrolled thyroid disease
- History of cancer (with the exception of basal or squamous cell carcinoma)
- A history of any serious psychiatric disorder (including schizophrenia, bipolar
disorder [including current suicidal ideation or patients who have attempted
suicide within 12 months of entry to the study] and any psychiatric disorder
severe enough to warrant psychiatric hospital treatment, as an in-patient within
12 months of entry to the study)
2. Patients with current psychotic disorders, bipolar disorders, alcohol or drug
dependence/abuse, anorexia nervosa or bulimia as identified by completing the Mini
International Neuropsychiatric Interview at the screening visit.
3. Patients with clinically significant abnormal blood test results at entry to the
study, in the opinion of the investigator.
4. Patients with anatomical lesions of the colon (except non-complicated diverticular
disease) or microscopic colitis or inflammatory bowel disease as assessed by
investigations carried out prior to the screening visit.
5. Patients with a history of lactose intolerance prior to the screening.
6. Patients with any history of drug or alcohol abuse in the past 6 months.
7. Patients on antidepressants for the treatment of mood or anxiety disorders.
8. Patients receiving any medication which may interfere with the assessment of IBS
symptoms during the study, and which cannot be stopped. These medications include the
- All antidepressant medication (including selective serotonin re-uptake
inhibitors (SSRIs). Where antidepressant medication has been previously
prescribed, the following timelines should be adhered to: a 42-day wash out
period from Prozac™ (fluoxetine) before randomization into the study; a 2 week
wash-out for other antidepressants.
- Drugs with putative effect on transit (including, but not limited to,
erythromycin, metoclopramide, cisapride, dicyclomine hydrochloride, hyoscyamine
sulfate, etc.), anti-diarrheals (including, but not limited to dephenoloxilate
with atropine, loperamide, bismuth, kaolin and pectin, etc.), and laxatives
(oral or rectal). Bulking agents (including ispaghula husk, psyllium and dietary
bran supplements) may be continued during the study, provided that the patient
has been taking a stable dose for at lease 3 months prior to entering the study
and that this dose does not change during the study. Patients taking bulking
agents on an "as needed" basis must refrain from taking these medications during
9. Patients who have taken an investigational drug within 30 days (or 5 half-lives,
whichever is the longer) of entry to the study, or who are due to receive such a drug
during the study.
10. Female patients who are pregnant or lactating.
The investigator should call the study monitor if he/she has any questions regarding