Title

An Effectiveness and Safety Study of Chinese Herbal Medicine for Functional Constipation
Chinese Herbal Medicine for Functional Constipation: A Randomized, Double-blind, Placebo Controlled Trial
  • Phase

    Phase 2
  • Study Type

    Interventional
  • Intervention/Treatment

    mazirenwan ...
  • Study Participants

    120
Functional constipation (FC) is a common complaint in clinical practice, but treatment for this condition in conventional medicine is suboptimal. Complementary and alternative medicines, especially Chinese herbal medicine (CHM) are used frequently by patients, however, there is little research evidence about these commonly used CHM. The purpose of the study is evaluate the efficacy and safety of an ancient CHM formula, MaZiRenWan (MZRW), by comparing with placebo.
Constipation is a common gastrointestinal complaint in clinical practice, which affects in estimated 12%-19% of American, 14% of Asian, and up to 27% of the population depending on demographic factor, sampling, and definition. With the unsatisfactory response to current symptomatic treatments, many patients seek help from traditional Chinese medicine (TCM), mostly by taking Chinese herbal medicine (CHM).

According to the TCM theory, constipation can be broadly divided into two types, excessive and deficient, based on the underlying aetiology. The former is characterized by the presence of Heat or pathological accumulation of Qi. Heat causes constipation by drying the Intestines and the stool. Patients present with hard, dry, pellet like stool, red complexion, dry mouth or halitosis, red tongue with a dry yellow coat, and slippery and rapid pulse. Qi stagnation causes constipation by disrupting the normal movement and descent of Stomach and Intestinal Qi. Patients present difficulty in passing stools, feelings of incomplete evacuation, abdominal distension or pain, frequent belching and flatulence, tongue with thin coat and wiry pulse. The latter, deficient constipation, is delineated as the dryness from insufficient fluid lubrication in the form of blood or lack of propulsion power from the deficiency of Qi or Yang. Besides, the treatment approaches vary from syndrome to syndrome.

The formula of MaZiRenWan (MZRW) composed of six Chinese herbs is firstly recorded in a TCM classic, Discussion of Cold-induced Disorders (Shang Han Lun), and it has been commonly used for constipation in excessive pattern throughout Asia since the Han Dynasty (A.D. 200). By combining the actions of these herbs, MZRW can moisten the Intestines, drain heat, promote the movement of Qi and unblock the bowel. Although previous studies show that MZRW has purgative and laxative effects and may be useful for functional constipation (FC), there are significant methodological weaknesses. Furthermore, the dose of CHM intervention being investigated from the first randomized controlled trial (RCT) published in 1983 is always based on the practitioner's experience, TCM literatures, or experts' comments, but not the results from stringent clinical trials, such as dose determination study. Therefore, the evidence produced will be attenuated or even misleading if improper dose is taken.

In the present study, the efficacy and safety of MZRW in optimal dosage were justified by comparing with placebo under strict clinical trial design.
Study Started
Jul 31
2008
Primary Completion
Nov 30
2009
Study Completion
Dec 31
2009
Results Posted
Dec 16
2011
Estimate
Last Update
Jun 24
2016
Estimate

Drug MaZiRenWan (MZRW)

MZRW granule dissolved in 150ml hot water (oral), 7.5g/sachet, twice daily

  • Other names: Hemp Seed Pill

Drug Placebo

Placebo granule dissolved in 150ml hot water (oral), 7.5g/sachet, twice daily

  • Other names: MZRW Placebo

MaZiRenWan (MZRW) Experimental

MZRW granule, 7.5g/sachet

Placebo Placebo Comparator

Placebo granule, 7.5g/sachet

Criteria

Inclusion Criteria:

Meet of Rome III diagnostic criteria of functional constipation
Meet the diagnosis of Excessive Constipation according to the TCM theory
Age of 18 to 65 years (inclusive)
Complete spontaneous bowel movement (CSBM)≦2times/wk
Severity of constipation≧4pts (7 pts scale from 0 to 6pts) and the overall scoring of constipation-related symptoms≧8pts (6items in 7pts scale) for self symptom assessment in the run-in period
Normal colonic evaluation (colonoscopy or barium enema) within 5 years
Normal liver and renal function in blood test within 3 months

Exclusion Criteria:

Drug-induced constipation
Secondary causes of constipation (i.e. medical history of diabetes mellitus and thyroid disease)
Abdominal surgery (i.e. Caesarean operation)
Severe disease (i.e. cancer and acute present asthma)
Allergy to CHM (i.e. G6PD deficiency)
Pregnancy or breast-feeding
Psychiatric or addictive disorders

Summary

MaZiRenWan (MZRW)

Placebo

All Events

Event Type Organ System Event Term MaZiRenWan (MZRW) Placebo

Responder of Complete Spontaneous Bowel Movement (CSBM)

Patients with a mean increase of ≧1 complete spontaneous bowel movement(CSBM)/wk compared with the baseline(wk1-2) will be 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.

MaZiRenWan (MZRW)

Non-responder

34.0
participants

Responder

26.0
participants

Placebo

Non-responder

55.0
participants

Responder

5.0
participants

Blood Creatinine Level

MaZiRenWan (MZRW)

Post-treatment (Wk10)

66.9
μmol/L (Mean)
Standard Deviation: 9.20

Pre-treatment (Wk2)

66.67
μmol/L (Mean)
Standard Deviation: 9.48

Placebo

Post-treatment (Wk10)

64.62
μmol/L (Mean)
Standard Deviation: 7.40

Pre-treatment (Wk2)

66.05
μmol/L (Mean)
Standard Deviation: 7.91

Responder of Complete Spontaneous Bowel Movement (CSBM)

Participants with a mean increase of complete spontaneous bowel movement (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.

MaZiRenWan (MZRW)

Non-responder

42.0
participants

Responder

18.0
participants

Placebo

Non-responder

51.0
participants

Responder

9.0
participants

Bowel Movement

MaZiRenWan (MZRW)

Baseline(Wk1&2)

2.79
movements per week (Mean)
Standard Deviation: 1.26

Within follow-up(Wk11-18)

3.65
movements per week (Mean)
Standard Deviation: 2.23

Within treatment(Wk3-10)

4.72
movements per week (Mean)
Standard Deviation: 2.37

Placebo

Baseline(Wk1&2)

3.31
movements per week (Mean)
Standard Deviation: 1.61

Within follow-up(Wk11-18)

3.61
movements per week (Mean)
Standard Deviation: 1.61

Within treatment(Wk3-10)

3.73
movements per week (Mean)
Standard Deviation: 1.54

Complete Spontaneous Bowel Movement (CSBM)

MaZiRenWan (MZRW)

Baseline (Wk1&2)

0.33
movements per week (Mean)
Standard Deviation: 0.66

Within follow-up (Wk11-18)

1.06
movements per week (Mean)
Standard Deviation: 1.67

Within treatment(Wk3-10)

1.62
movements per week (Mean)
Standard Deviation: 1.98

Placebo

Baseline (Wk1&2)

0.52
movements per week (Mean)
Standard Deviation: 0.69

Within follow-up (Wk11-18)

0.75
movements per week (Mean)
Standard Deviation: 1.18

Within treatment(Wk3-10)

0.72
movements per week (Mean)
Standard Deviation: 1.08

Changes on Individual Symptom Scores

It was a 7-point ordinal scale from 0=not at all to 6=very severe.

MaZiRenWan (MZRW)

Incomplete of evacuation (Baseline)

4.4
Units on a scale (Mean)
Standard Deviation: 1.12

Incomplete of evacuation (Wk10)

3.02
Units on a scale (Mean)
Standard Deviation: 1.51

Incomplete of evacuation (Wk18)

3.62
Units on a scale (Mean)
Standard Deviation: 1.29

Incomplete of evacuation (Wk6)

3.18
Units on a scale (Mean)
Standard Deviation: 1.40

Passing of gas (Baseline)

2.93
Units on a scale (Mean)
Standard Deviation: 1.75

Passing of gas (Wk10)

2.55
Units on a scale (Mean)
Standard Deviation: 1.43

Passing of gas (Wk18)

2.73
Units on a scale (Mean)
Standard Deviation: 1.46

Passing of gas (Wk6)

2.73
Units on a scale (Mean)
Standard Deviation: 1.52

Sensation of abdominal pain/cramping (Baseline)

1.98
Units on a scale (Mean)
Standard Deviation: 1.76

Sensation of abdominal pain/cramping (Wk10)

1.22
Units on a scale (Mean)
Standard Deviation: 1.28

Sensation of abdominal pain/cramping (Wk18)

1.5
Units on a scale (Mean)
Standard Deviation: 1.54

Sensation of abdominal pain/cramping (Wk6)

1.8
Units on a scale (Mean)
Standard Deviation: 1.60

Sensation of bloating (Baseline)

3.62
Units on a scale (Mean)
Standard Deviation: 1.30

Sensation of bloating (Wk10)

2.23
Units on a scale (Mean)
Standard Deviation: 1.65

Sensation of bloating (Wk18)

2.92
Units on a scale (Mean)
Standard Deviation: 1.67

Sensation of bloating (Wk6)

2.53
Units on a scale (Mean)
Standard Deviation: 1.68

Sensation of nausea (Baseline)

1.0
Units on a scale (Mean)
Standard Deviation: 1.54

Sensation of nausea (Wk10)

0.53
Units on a scale (Mean)
Standard Deviation: 0.97

Sensation of nausea (Wk18)

0.97
Units on a scale (Mean)
Standard Deviation: 1.48

Sensation of nausea (Wk6)

0.68
Units on a scale (Mean)
Standard Deviation: 1.21

Sensation of straining (Baseline)

4.2
Units on a scale (Mean)
Standard Deviation: 0.84

Sensation of straining (Wk10)

2.55
Units on a scale (Mean)
Standard Deviation: 1.52

Sensation of straining (Wk18)

3.33
Units on a scale (Mean)
Standard Deviation: 1.28

Sensation of straining (Wk6)

2.6
Units on a scale (Mean)
Standard Deviation: 1.43

Severity of constipation (Baseline)

4.47
Units on a scale (Mean)
Standard Deviation: 0.79

Severity of constipation (Wk10)

2.93
Units on a scale (Mean)
Standard Deviation: 1.43

Severity of constipation (Wk18)

3.57
Units on a scale (Mean)
Standard Deviation: 1.47

Severity of constipation (Wk6)

2.82
Units on a scale (Mean)
Standard Deviation: 1.52

Placebo

Incomplete of evacuation (Baseline)

4.07
Units on a scale (Mean)
Standard Deviation: 1.22

Incomplete of evacuation (Wk10)

3.45
Units on a scale (Mean)
Standard Deviation: 1.55

Incomplete of evacuation (Wk18)

3.43
Units on a scale (Mean)
Standard Deviation: 1.57

Incomplete of evacuation (Wk6)

3.47
Units on a scale (Mean)
Standard Deviation: 1.49

Passing of gas (Baseline)

2.97
Units on a scale (Mean)
Standard Deviation: 1.67

Passing of gas (Wk10)

2.27
Units on a scale (Mean)
Standard Deviation: 1.68

Passing of gas (Wk18)

2.4
Units on a scale (Mean)
Standard Deviation: 1.60

Passing of gas (Wk6)

2.53
Units on a scale (Mean)
Standard Deviation: 1.70

Sensation of abdominal pain/cramping (Baseline)

1.43
Units on a scale (Mean)
Standard Deviation: 1.58

Sensation of abdominal pain/cramping (Wk10)

1.07
Units on a scale (Mean)
Standard Deviation: 1.47

Sensation of abdominal pain/cramping (Wk18)

0.82
Units on a scale (Mean)
Standard Deviation: 1.35

Sensation of abdominal pain/cramping (Wk6)

1.12
Units on a scale (Mean)
Standard Deviation: 1.42

Sensation of bloating (Baseline)

3.47
Units on a scale (Mean)
Standard Deviation: 1.33

Sensation of bloating (Wk10)

2.7
Units on a scale (Mean)
Standard Deviation: 1.81

Sensation of bloating (Wk18)

2.65
Units on a scale (Mean)
Standard Deviation: 1.83

Sensation of bloating (Wk6)

2.82
Units on a scale (Mean)
Standard Deviation: 1.76

Sensation of nausea (Baseline)

0.83
Units on a scale (Mean)
Standard Deviation: 1.45

Sensation of nausea (Wk10)

0.78
Units on a scale (Mean)
Standard Deviation: 1.30

Sensation of nausea (Wk18)

0.73
Units on a scale (Mean)
Standard Deviation: 1.53

Sensation of nausea (Wk6)

1.03
Units on a scale (Mean)
Standard Deviation: 1.57

Sensation of straining (Baseline)

3.82
Units on a scale (Mean)
Standard Deviation: 1.20

Sensation of straining (Wk10)

3.28
Units on a scale (Mean)
Standard Deviation: 1.46

Sensation of straining (Wk18)

3.32
Units on a scale (Mean)
Standard Deviation: 1.37

Sensation of straining (Wk6)

3.12
Units on a scale (Mean)
Standard Deviation: 1.35

Severity of constipation (Baseline)

4.4
Units on a scale (Mean)
Standard Deviation: 0.74

Severity of constipation (Wk10)

3.47
Units on a scale (Mean)
Standard Deviation: 1.36

Severity of constipation (Wk18)

3.63
Units on a scale (Mean)
Standard Deviation: 1.39

Severity of constipation (Wk6)

3.7
Units on a scale (Mean)
Standard Deviation: 1.49

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.

MaZiRenWan (MZRW)

Improved (Wk10)

48.0
participants

Improved (Wk18)

30.0
participants

Improved (Wk6)

49.0
participants

Same (Wk10)

12.0
participants

Same (Wk18)

25.0
participants

Same (Wk6)

11.0
participants

Worse (Wk10)

Worse (Wk18)

5.0
participants

Worse (Wk6)

Placebo

Improved (Wk10)

32.0
participants

Improved (Wk18)

31.0
participants

Improved (Wk6)

28.0
participants

Same (Wk10)

24.0
participants

Same (Wk18)

27.0
participants

Same (Wk6)

27.0
participants

Worse (Wk10)

4.0
participants

Worse (Wk18)

2.0
participants

Worse (Wk6)

5.0
participants

Success of Blinding

The success of blinding was evaluated for both investigator and patients as to whether MZRW or placebo had been taken.

MaZiRenWan (MZRW)

Investigator with correct guessing

42.0
participants

Subjects with correct guessing

32.0
participants

MaZiRenWan (MZRW)

Investigator with correct guessing

42.0
participants

Subjects with correct guessing

32.0
participants

Placebo

Investigator with correct guessing

27.0
participants

Subjects with correct guessing

16.0
participants

Placebo

Investigator with correct guessing

27.0
participants

Subjects with correct guessing

16.0
participants

Serum Glutamic Pyruvic Transaminase(SGPT) Level

MaZiRenWan (MZRW)

Post-treatment (Wk10)

14.7
U/L (Mean)
Standard Deviation: 5.50

Pre-treatment (Wk2)

15.82
U/L (Mean)
Standard Deviation: 7.81

Placebo

Post-treatment (Wk10)

13.68
U/L (Mean)
Standard Deviation: 4.55

Pre-treatment (Wk2)

14.05
U/L (Mean)
Standard Deviation: 4.87

Blood Urea Level

MaZiRenWan (MZRW)

Post-treatment (Wk10)

4.01
mmol/L (Mean)
Standard Deviation: 0.97

Pre-treatment (Wk2)

3.87
mmol/L (Mean)
Standard Deviation: 1.03

Placebo

Post-treatment (Wk10)

4.24
mmol/L (Mean)
Standard Deviation: 1.11

Pre-treatment (Wk2)

3.98
mmol/L (Mean)
Standard Deviation: 0.93

Serum Glutamic Oxaloacetic Transaminase (SGOT)

MaZiRenWan (MZRW)

Post-treatment (Wk10)

17.2
U/L (Mean)
Standard Deviation: 3.45

Pre-treatment (Wk2)

17.82
U/L (Mean)
Standard Deviation: 4.05

Placebo

Post-treatment (Wk10)

17.12
U/L (Mean)
Standard Deviation: 4.27

Pre-treatment (Wk2)

17.77
U/L (Mean)
Standard Deviation: 3.91

Total

120
Participants

Age, Continuous

37.13
years (Mean)
Standard Deviation: 10.99

Bowel movement

3.05
movements per week (Mean)
Standard Deviation: 1.46

Complete spontaneous bowel movement (CSBM)

0.42
movements per week (Mean)
Standard Deviation: 0.68

Duration of constipation

14.38
years (Mean)
Standard Deviation: 10.39

No. of days taking rescue therapy

0.89
days per week (Mean)
Standard Deviation: 1.24

Severity of constipation

4.43
Units on a scale (Mean)
Standard Deviation: 0.76

Sex: Female, Male

Overall Study

MaZiRenWan (MZRW)

Placebo

Drop/Withdrawal Reasons

MaZiRenWan (MZRW)

Placebo