Paroxetine - Controlled Release in the Treatment of Irritable Bowel Syndrome (IBS)
Condition: Irritable Bowel Syndrome
MeSH terms: Irritable Bowel Syndrome; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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 Measures

      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
      events.

      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 tension.

      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.
    

Intervention name(s): Paroxetine CR; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; Placebo
Other intervention name(s): Paxil
Intervention MeSH terms: Paroxetine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: IBS