A Study of Colesevelam in Fecal Incontinence

Fecal incontinence (FI) is a common symptom that can significantly impair quality of life.
There is very limited, mostly uncontrolled, evidence to support the approaches currently used
to manage FI. The alpha-2 adrenergic agonist clonidine decreased the frequency of loose
stools in FI patients with diarrhea. Among patients with diarrhea, clonidine decreased the
proportion of days with FI; however results were not statistically significant. Uncontrolled
studies suggest that the bile acid binding resin colesevelam also increased stool consistency
in patients with functional diarrhea. In this study, the investigators propose to compare the
effects of a combination of colesevelam and clonidine to placebo on bowel symptoms in
patients with urge or combined type of FI. The investigators hypothesis is that combination
treatment with clonidine and colesevelam is better than placebo in reducing stool frequency
and rectal urgency in FI.

A. Phase 1

Inclusion Criteria:

i) Females aged 18-80 years with urge predominant or combined (i.e. urge plus passive) FI,
as defined by a validated questionnaire, for at least 1 year duration will be eligible to
participate.

Exclusion Criteria:

(i) History of clinically serious cardiovascular or pulmonary disease or EKG showing 2nd
degree atrioventricular block or higher.

(ii) Current or past history of rectal cancer, scleroderma, inflammatory bowel disease,
small bowel obstruction, congenital anorectal abnormalities, Grade 2 rectal prolapse,
history of rectal resection or pelvic irradiation (iii) Neurological disorders - Spinal
cord injuries, dementia (Mini-Mental status score <21), multiple sclerosis, Parkinson's
disease, peripheral neuropathy (iv) Conditions precluding safe use of clonidine, i.e.,
symptomatic hypotension, or systolic blood pressure of <100 mm Hg on initial visit in Phase
1 of study (v) Currently pregnant or nursing women (vi) Prior history of intolerance to
clonidine or colesevelam (vii) Medications Absolute - opioid analgesics. Relative - other
antihypertensive agents (i.e. if there is concern about synergistic effects and
hypotension). Patients using drugs with anticholinergic effects will be excluded if they
are used at high doses (e.g. nortriptyline greater than 50 mg/day or amitriptyline greater
than 25 mg/day). Patients who use lower doses will be eligible to participate provided the
dose will be stable during the study

B. Phase 2

Inclusion Criteria:

i) Females aged 18-80 years with urge predominant or combined (i.e. urge plus passive) FI
for at least 1 year, as defined by questionnaire

Exclusion criteria:

(i) Positive urine pregnancy screen

C. Phase 3

Inclusion criteria:

(i) Completion of at least 5 out of 7 days of the diary in the preceding week and 10 out of
14 in the preceding 2 weeks (ii) At least 1 episode of FI per week averaged over 2 weeks
(iii) Average Bristol stool score of 3 or higher (iv) Average stool frequency of ≥1/day

Exclusion criteria (if at least one is satisfied):

(i) Missing data in bowel diaries, i.e. if patient did not record bowel symptoms data for
more than 2 days in 1 week or 4 days over 2 weeks (ii) Greater than 6 liquid [Bristol 6 or
7]) stools daily (iii) Average of less than 1 bowel movement daily (iv) Average Bristol
stool score <3 as assessed from analysis of bowel diaries

D. Phase 4

Inclusion criteria:

(i) All patients who complete at least 1 week of treatment with study drugs or placebo

Exclusion criteria:

(i) Patients who completed less than 1 week of treatment with study drugs or placebo