Colonic Diseases, Functional Clinical Trial
Official title:
A Phase I, Double-Blind, Placebo-Controlled, Randomized, Parallel-Group Study to Evaluate the Safety and Efficacy of a Combination Herbal Therapy (CHT), Versus Placebo in Improving the Overall Quality of Life and Symptoms 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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment
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