Combination Herbal Therapy (CHT) Versus Placebo in Patients With Irritable Bowel Syndrome (IBS)
Condition: Colonic Diseases, Functional
MeSH terms: Irritable Bowel Syndrome; Colonic Diseases; Colonic Diseases, Functional
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): CHT - herbal therapy
Intervention type(s): Drug
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment