Combination Herbal Therapy (CHT) Versus Placebo in Patients With Irritable Bowel Syndrome (IBS)
Combination Herbal Therapy (CHT) Versus Placebo in Patients With Irritable Bowel Syndrome (IBS)
This is an 8-week double-blind, placebo-controlled, randomized, parallel-group study with an
 additional two week baseline observation period to evaluate the safety of combination herbal
 therapy (CHT) versus placebo and short and long-term efficacy in terms of improved IBS,
 overall quality of life (QOL) and symptomatology.
Background:

 IBS (Irritable Bowel Syndrome) is a disorder of motility of the entire GI tract that produces
 cramping, abdominal pain, constipation, and/or diarrhea and sometimes passing of mucus in
 bowel movements. In most people with IBS, the GI tract is highly sensitive to many stimuli,
 including diet and distension from gas. Among dietary suspects are high-fat or other
 high-calorie meals, dairy products, wheat, citrus fruits, coffee, and tea which can trigger
 spasms of the colon muscle. During an episode, GI tract contractions become stronger and more
 frequent, and the resulting rapid motility may lead to diarrhea. When colon motility is
 reduced, bowel movements do not occur regularly, resulting in constipation. Cramping appears
 to be induced by strong contractions and increased sensitivity of pain receptors in the large
 intestine. IBS can be triggered or intensified by stress due to communications between the
 central nervous system and the nervous system of the small and large intestines. This is
 sometimes referred to as a brain-gut connection and is supported by inspection of
 electroencephalogram (EEG) traces which showed significantly greater EEG abnormality in IBS
 patients (29.2%) than in controls (4.2%) [p<0.02]. The degree of abnormality was positively
 correlated with colonic motility only in IBS patients (p<0.05) allowing the authors to
 conclude that there is an electrophysiologic brain-gut interaction in IBS.

 IBS can cause great physical discomfort and embarrassment to many of its sufferers, but is
 not life threatening.

 There is no current consensus as to an organic cause of this syndrome and there generally
 appears to be no sign of disease upon physical examination except for tenderness over the
 large intestine. The diagnosis is symptom-based, usually through identification of the ROME
 II criteria for IBS. These criteria which have been accepted worldwide by clinicians and
 researchers as the standard for IBS diagnosis are as follows: 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.

 In addition the following symptoms cumulatively support the diagnosis of IBS:

 -  Abnormal stool frequency (for research purposes "abnormal" may be defined as >3/day and
 <3/week);

 -  Abnormal stool form (lumpy/hard or loose/ watery stool);

 -  Abnormal stool passage (straining, urgency, or feeling of incomplete evacuation);

 -  Passage of mucus;

 -  Bloating or feeling of abdominal distension.

 The prevalence rate of IBS in 1998 in the U.S. was approximately 5,700 cases per 100,000
 persons, with a much higher rate in Caucasians than in Hispanics or Afro-Americans. The total
 direct cost of IBS, including costs of inpatient and outpatient health services utilization
 and prescription medication, was greater than $1.6 billion annually in 1998 in the U.S.,
 while the indirect costs, primarily absenteeism from work, are estimated at over $20 billion.
 (1 AGA: The burden of gastrointestinal diseases) IBS is treated primarily in the physician's
 office, with patient education, assurance and/or dietary and lifestyle modifications being
 the rule for mild cases, but prescription medicines being offered in more moderate cases.
 Prescription therapy for theses patients generally falls under two categories - drugs
 affecting gut physiology and psychological treatment. Very severe cases may be treated by
 centrally-acting agents (i.e., tricyclic antidepressants [TCAs] or selective serotonin
 reuptake inhibitors) together with psychological methods.

 Among the medications generally used to affect gut physiology or abdominal pain are
 antispasmodics, tricyclic antidepressants (TCAs), loperamide, Cholestyramine (for patients
 with cholecystectomy or who may have idiopathic bile acid malabsorption) and serotonergic
 agents (5-HT3 receptor antagonists and 5-HT4 receptor agonists). These agents show relative
 success in improving individual symptoms only, and are only effective in specific subgroups
 of patients (e.g.- for diarrhea-predominant, but not constipation-predominant IBS, or visa
 versa). Due to the heterogeneity of IBS, an effective therapy for one may often lead to
 deterioration in another. For example, Alosetron, an extensively studied 5-HT3 antagonist
 which has shown statistically significant improvement in women with diarrhea-predominant IBS,
 causes constipation in 20-30% of patients, and there has been no clear evidence of a benefit
 for men.

 There are many known side effects of anticholinergic antispasmodics and TCAs, such as:
 headache, dry mouth, cough, blurred vision, constipation, dysuria; postural hypotension;
 tachycardia, decreased libido; erectile failure; increased sensitivity to the sun; weight
 gain; sedation, increased sweating. Loperamide side effects include: Stomach ache, nausea,
 vomiting, bloating, constipation, dry mouth, drowsiness or dizziness, and cholestyramine has
 been known to cause constipation, heartburn, indigestion, nausea, vomiting, and stomach pain,
 and has caused tumors in animal studies. These profiles suggest the need for a safer, more
 tolerable and more comprehensive therapy for IBS.

 Psychological treatments are initiated when symptoms are severe enough to impair
 health-related quality of life. Mental health referral may also be made for treatment of
 associated psychiatric disorders such as major depression. These methods include
 cognitive-behavioral treatment, dynamic (interpersonal) psychotherapy, hypnosis, and stress
 management/relaxation. Though benefit has been seen with these therapeutic methods in the
 relief of abdominal pain, diarrhea and anxiety, constipation has not been improved, and the
 effect on various subgroups of patients has not been investigated. (4 AGA Med Pos Stat)

 CHT:

 Some Botanical therapies, specifically combination therapies, have been tested for treatment
 of IBS with positive results. STW 5 (9 plant extracts) and STW 5-II (6 plant extracts) were
 significantly better than placebo in reducing abdominal pain and IBS symptoms after 4 weeks
 of therapy.

 Additionally, various botanical therapies have been shown to be effective to different
 degrees for relief of symptoms and for improved quality of life in non-ulcer and functional
 dyspepsia (a condition similar to IBS). These include the following therapies tested in
 trials which received a rating above three in the Jadad score (a validated instrument scoring
 from 0-5 for assessment of clinical trial quality): celandine extract, turmeric, peppermint
 and caraway oils, Iberogast (peppermint leaves, caraway fruit, with or without bitter candy
 tuft fruit, licorice root, lemon balm leaves, angelica root, celandine herbs, milk thistle
 fruit and chamomile flowers), peppermint & caraway & wormwood & fennel, peppermint oil and
 ginger extract, artichoke leaf extract and many others with lower Jadad score ratings.

 A number of herbs have been used successfully in IBS, as well. These include peppermint oil
 (enteric coated), globe artichoke leaf extract, and Chinese herbal medicine.

 The active ingredients of CHT has been used in folklore medicine for many centuries for
 treatment of gastrointestinal diseases and is approved by the Israel Ministry of Health for
 marketing and distribution through the pharmacy . A dose toxicity test conducted in rats
 showed a no-observed-adverse-effect-level in male rats at doses much higher than the dose
 utilized in this study (measured per Kg body mass).

 Considering the ethno-pharmacological and preclinical evidence for efficacy in a broad array
 of conditions and safety of the principal active ingredient, we, the investigators at
 Hadassah Medical Organization, have decided to embark upon a clinical development plan geared
 towards the investigation of the gastrointestinal protective and other therapeutic properties
 and safety of the principal active ingredient. The first study is the efficacy trial herein
 described.

 Rationale for the study:

 HCT is a new combination botanical drug substance that promises to be of value in treating
 various pathologies of the gastrointestinal tract, due to it's presumed "gastroprotective"
 and/or "gastrosynchronic" qualities. To test this hypothesis, a once daily oral dose of HCT
 will be self-administered to patients with IBS. The dose used is presumed to be exceptionally
 safe and is 37 times lower than the standard daily dose.

 STUDY OBJECTIVE:

 To determine the safety, tolerability and effectiveness, of 25 mg per day of HCT (20 mg
 principal active ingredient) compared to placebo in subjects with ROME II IBS criteria.

 Basic Design Characteristics and Rationale:

 This will be a double-blind, placebo-controlled, randomized, parallel group study to assess
 the safety and efficacy of CHT. 100 subjects with ROME II criteria IBS will provide informed
 consent and undergo screening procedures. Subjects fulfilling eligibility requirements will
 be randomized to one of the two treatment arms (will receive a subject number). After a
 two-week baseline observation period, and reconfirmed eligibility, subjects will be allotted
 enough study drug for the self administration of a daily dose of 25 mg CHT or placebo, for 4
 weeks. The Week 4 clinic visit will be followed by a four week follow-up period without
 treatment. The day of randomization will be the week -2 visit and start of study treatment
 will be at the Week 0 study visit.

 Throughout the study the following tools will be utilized (and variables assessed): a subject
 diary (for documentation of concomitant medications and concomitant medication changes and
 adverse events) the IBS-36 Questionnaire (for assessment of treatment-induced changes in the
 IBS-specific Quality of Life score), and a 6-point Likert Scale for IBS symptoms severity
 scoring. This tool and has been developed specifically for this study, based, in part, on
 similar scales in the published literature.

 This early phase study is well-designed to investigate the safety and tolerability of HCT and
 to gain statistically significant efficacy data. The population chosen is large enough to
 detect a clinically significant difference in response between the active study drug and the
 placebo arms. The rationale for this design at such an early stage of development is based
 upon the recommendations of the FDA for phase I clinical studies of botanical drug
 substances.
Inclusion Criteria:

 -  Men or women aged 18-70

 -  Diagnosis of irritable bowel syndrome based on the following criteria (ROME II): At
 least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal
 discomfort or pain (at least once per week) with at least 2 of the following features:

 -  Relief with defecation;

 -  Onset associated with a change in stool frequency;

 -  Onset associated with a change in stool consistency.

 -  At least two of the following on at least 25% of occasions or days in the last 3
 months:

 -  Fewer than three bowel movements a week;

 -  More than three bowel movements a day;

 -  Hard or lumpy stools;

 -  Loose (mushy) or watery stools;

 -  Straining during a bowel movement;

 -  Urgency;

 -  Feeling of incomplete bowel movement;

 -  Passing mucus during a bowel movement;

 -  Abdominal fullness, bloating or swelling.

 -  Women of childbearing potential must be using an acceptable method of contraception.

 Exclusion Criteria:

 -  History of severe or intractable IBS, defined as continuous, unremitting and severe
 abdominal pain greater than 12 hours/day

 -  Concurrent diagnosis of any bowel disturbance that would interfere with the assessment
 or safety of the study

 -  History of laxative abuse

 -  Previous abdominal surgery (uncomplicated appendectomy, hysterectomy or
 cholecystectomy at least 6 months prior to entry acceptable)

 -  History of metabolic or inflammatory disease that may affect bowel motility, eg.,
 inflammatory bowel disease, diabetes mellitus, sarcoidosis

 -  Use of the following concomitant medications: medications that can affect
 gastrointestinal (GI) motility; other investigational drug use (30 day "washout"
 required); medications affecting visceral perception; antidepressants; selective
 serotonin reuptake inhibitors; opioids; narcotic analgesics; antispasmodic and
 anticonvulsant agents; insulin or other hypoglycemic therapy; thyroid hormones;
 central nervous system (CNS) depressants.

 -  Other significant illness as determined by Investigator

 -  Pregnancy

 -  History of drug or alcohol abuse within 2 years

 -  Insufficient knowledge of English or Hebrew to complete self-assessments to
 participate in study

 -  Any other reason for which Investigator feels that subject's compliance is at question
 or safety may be compromised.