A Dose Determination Study of Chinese Herbal Medicine for Functional Constipation

Study Overview
=================
Brief Summary
-----------------
Functional constipation (FC) is common with 14.3% estimated prevalence in Hong Kong, but treatment for this condition in conventional medicine is suboptimal. Complementary and alternative medicines, especially Chinese herbal medicine (CHM) are used frequently by patients with FC, but there is little research evidence about these commonly used CHM. The purpose of the study is evaluate the efficacy and safety of CHM, as well as determining the optimal dosage.

Detailed Description
-----------------
Functional constipation (FC) is a common complaint in clinical practice, with the estimated prevalence 14.3% in Hong Kong, as nearly affecting 1 million Hong Kong People in different extent. It is comparable with western population, which is 15% in North America. By the definition of Rome II criteria, FC comprises a group of functional disorders, which presents as persistent difficult, infrequent or seemingly incomplete defecation. Constipation is often perceived to be benign, easily treated condition with short-term treatment being relatively straightforward. However, the fact is the management of FC is perplexed as some subjects complain of constipation more than decade. Moreover, chronic constipation can develop into more serious bowel complaints, such as faecal impaction, incontinence and bowel perforations. There is also accumulating evidence shown that constipated subjects have significantly higher anxiety and depression scores and lower quality of life. Therefore, the demand of effective agents to normalize bowel function is extremely large. Conventional treatment for constipation mainly relies on dietary fibre and laxatives. Although there is no credible evidence that any serious problem is associated with their prolonged use, the treatment of it has been suboptimal. First, a recent systematic review pointed out that there were paucity of trials for many commonly used agents, therefore, their use might not be well validated. Second, many patients with severe constipation do not respond adequately or lose of effectiveness after a short period of time. Third, many patients who intake dietary fibre complain of flatulence, distension, bloating and poor taste. As a result, the compliance is low as about 50%. Fourth, the use of osmotic laxatives, such as polyethylene glycol, become increasingly popular due to fewer side effects and better taste, however, the prices are much more expensive than other medications. Many constipation sufferers seek help from alternative medicine, especially from Chinese herbal medicine. For example, according to a telephone survey in Hong Kong, more than 85% of constipated subjects seek for coping strategies, such as asking for medical consultations, taking prescribed medicine and seeking for alternative therapy, involving Chinese medicine. Traditional Chinese medicine (TCM) is particularly attractive as their effectiveness in treating functional disorders and retaining balance of body functions. The CHM used in study is derived from classic text of Chinese medicine (Shang Han Lun, Discussion of Cold-induced Disorders), which can moisten the intestines, drain heat, promote the movement of qi and unblock the bowel. It is well known that randomized controlled trial (RCT) is the gold standard to test the efficacy of intervention, thus in this project, we attempt to follow the basic requirements of RCT to testify the efficacy and safety of CHM on FC, as well as to determine the optimal dosage. We believe such study will benefit the advancement of CHM, or even as the foundation of research study in future.

Official Title
-----------------
A Randomized Controlled Trial of Chinese Herbal Medicine in Three-dose Regimen for the Treatment of Functional Constipation

Conditions
-----------------
Constipation

Intervention / Treatment
-----------------
* Drug: MaZiRenWan (MZRW) Low dose
* Drug: MaZiRenWan (MZRW) Median dose
* Drug: MaZiRenWan (MZRW) High dose


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Clinical diagnosis of functional constipation with Rome II criteria General stool type belongs to Type 1 to 4 according to Bristol Stool Form Scale Complete spontaneous bowel movement≦2 movements per week Exclusion Criteria: Anti-diarrhoeal therapy Drug-induced constipation Medical history of important bowel pathology, such as inflammatory bowel disease, congenital or acquired megacolon / megarectum Medical history of previous abdominal surgery Taking chronic medications that contain any kind of herbs, mineral, or specific vitamin supplements Medical history of carbohydrate malabsorption, hormonal disorder, cancer, diabetes mellitus, hypothyroidism, asthma, renal impairment and/or any other serious diseases History of laxative abuse History of allergy to Chinese herbal medicine Psychiatric or addictive disorders Pregnancy or breast-feeding Any other serious diseases

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MaZiRenWan (MZRW) Low dose<br>MaZiRenWan (MZRW) Low dose 2.5g sachet by mouth, twice daily for 8 weeks | Drug: MaZiRenWan (MZRW) Low dose<br>* Dissolved MaZiRenWan (MZRW) granule (2.5g/sachet) in 150 ml hot water, take orally twice daily for 8 weeks<br>* Other names: Hemp Seed Pill;|
| Experimental: MaZiRenWan (MZRW) Median dose<br>MaZiRenWan (MZRW) Median dose 5.0g sachet by mouth, twice daily for 8 weeks | Drug: MaZiRenWan (MZRW) Median dose<br>* Dissolved MaZiRenWan (MZRW) granule (5.0g/sachet) in 150 ml hot water, take orally twice daily for 8 weeks<br>* Other names: Hemp Seed Pill;|
| Experimental: MaZiRenWan (MZRW) High dose<br>MaZiRenWan (MZRW) High dose 7.5g sachet by mouth, twice daily for 8 weeks | Drug: MaZiRenWan (MZRW) High dose<br>* Dissolved MaZiRenWan (MZRW) granule (7.5g/sachet) in 150 ml hot water, take orally twice daily for 8 weeks<br>* Other names: Hemp Seed Pill;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder for Complete Spontaneous Bowel Movement (CSBM) | Participants with a mean increase of CSBM>=1 movement per week compared with the last 14 days of the run-in period were defined as responders.CSBM referred to the feeling that defecation led to complete passage of stool rather than partial or incomplete evacuation without the use of any laxative or enema within 24 hours. | Week3-10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder for Complete Spontaneous Bowel Movement (CSBM) | Participants with a mean increase of CSBM>=1 movement per week compared with the last 14 days of the run-in period were defined as responders. CSBM referred to the feeling that defecation led to complete passage of stool rather than partial or incomplete evacuation without the use of any laxative or enema within 24 hours. | Week11-18 | 
| Bowel Movement |  | Baseline(Week1-2), Within treatment(Week3-10) & Within follow-up(Week11-18) | 
| Complete Spontaneous Bowel Movement (CSBM) | CSBM referred to the feeling that defecation led to complete passage of stool rather than partial or incomplete evacuation without the use of any laxative or enema within 24 hours. | Baseline(Week1-2), Within treatment(Week3-10) & Within follow-up(Week11-18) | 
| Global Symptoms Improvement | Participants were asked to rate their impression of change in constipation by comparing with their baseline (Wk2) at the visits during the treatment (Wk6), end of treatment (Wk10) and end of follow-up (Wk18) with scores from 0 to 6 represented markedly worse or better respectively. The response categories were collapsed to simply improved for score 4 to 6, same for score 3 or worse for score 0 to 2. | Week6, 10 & 18 | 
| Severity of Constipation | It was a 7-point ordinal scale from 0=not at all to 6=very severe. | Baseline(Week2), Within treatment(Week6), End of treatment(Week10) & End of follow-up(Week18) | 
| Sensation of Straining | It was a 7-point ordinal scale from 0=not at all to 6=very severe. | Baseline(Week2), Within treatment(Week6), End of treatment(Week10) & End of follow-up(Week18) | 
| Incomplete of Evacuation | It was a 7-point ordinal scale from 0=not at all to 6=very severe. | Baseline(Week2), Within treatment(Week6), End of treatment(Week10) & End of follow-up(Week18) | 
| Sensation of Bloating | It was a 7-point ordinal scale from 0=not at all to 6=very severe. | Baseline(Week2), Within treatment(Week6), End of treatment(Week10) & End of follow-up(Week18) | 
| Sensation of Abdominal Pain/Cramping | It was a 7-point ordinal scale from 0=not at all to 6=very severe. | Baseline(Week2), Within treatment(Week6), End of treatment(Week10) & End of follow-up(Week18) | 
| Passing of Gas | It was a 7-point ordinal scale from 0=not at all to 6=very severe. | Baseline(Week2), Within treatment(Week6), End of treatment(Week10) & End of follow-up(Week18) | 
| Adverse Effects (e.g. Renal and Liver Function Tests) |  | pre-treatment & post-treatment | 
| Blood Urea Level |  | Pre-treatment(Week2) & Post-treatment(Week10) | 
| Blood Creatinine Level |  | Pre-treatment(Week2) & Post-treatment(Week10) | 
| Serum Glutamic Pyruvic Transaminase(SGPT) Level |  | Pre-treatment(Week2) & Post-treatment(Week10) | 
| Serum Glutamic Oxaloacetic Transaminase(SGOT) Level |  | Pre-treatment(Week2) & Post-treatment(Week10) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Randomized Controlled Trials, Medicine, Chinese Traditional, Medicine, Herbal, Constipation