Evaluation of the Efficacy of Probiotics in Treating Constipation in Elderly Patients With Multiple Chronic Co-morbidities: a Randomized Control Trial
Phase: NA
Conditions: Aging, Constipation, Multi-Core Disease
Sponsor: Universiti Kebangsaan Malaysia Medical Centre

 
 
 
 
 
 
 
 
 
 
Official Title of the study: 
Evaluation of the efficacy of probiotics in treating constipation in elderly patients with 
multiple chronic co-morbidities: a randomized control trial 
NCT no: Nil 
Date of Document: 
22nd July 2019 
 
 

Study Protocol 
 
1. Study design 
 
This is a randomized double-blinded clinical trial study.  
 
 
 
 
 
 
2. Study population and subjects 
Background and selection of study centers 
The study will be conducted at the outpatient clinics, medical and surgical wards in Universiti 
Kebangsaan Malaysia Medical Centre. 
 
 
3. Target population 
3.1 The target populations are older patients aged 60 years or above with at least 2 chronic 
medical illnesses (Appendix A) and who complain of constipation that persists for several 
weeks or longer. 
3.2  These patients are those who attending the medical/surgical outpatient clinics or being 
admitted to the medical/surgical wards in UKM Medical Centre during the study period. 
 
The participants will be assigned to either interventional group or control randomly and the 
random selection is pre-determined prior to recruitment. 
 
4 Inclusion criteria. 
4.1   Elderly patients aged 60 years or above and able to give consent. 
4.2   Patients who complain of constipation as per Mayo’s clinic definition: 
“Infrequent bowel movements of fewer than three bowel movements per week or difficult 
passage of stools that persists for several weeks or longer”. (13) 
4.3 Patients who have at least 2 chronic illnesses such as Diabetes Mellitus, Hypertensions, 
Chronic Kidney disease, Chronic Lung disease, or any medical illness which are prone to have 
constipation. 
 
 

5. Exclusion criteria. 
5.1 Patients with constipation of organic cause such as colorectal carcinoma, colonic ischaemia, 
inflammation, post radiation stricture, obstruction or presence of external compression. 
5.2 Patients with constipation of neurological causes such as cerebrovascular disease and stroke, 
Parkinson’s disease, autonomic neuropathy and spinal cord lesions. 
5.3   Patients who is taking calcium supplements more than 1500mg a day. 
5.4   Patients who are immune-compromised or critically ill. 
5.5   Patients who are on opioid analgesia. 
5.6   Patients with psychiatric illness. 
5.7 Patients who are on any form of medications at point of entering the study that altered the 
normal bowel movement (either decreasing or increasing the peristalsis of the gut) 
5.8 Patients who refuse to enter or consent for the study. 
 
6.  Subject withdrawal and Drop out 
Subjects will be withdrawn from the study in the event of: 
1. Consent is withdrawn by the patient. 
2. Patients will be withdrawn from the study if they experience intolerable or excessive 
side effects due to the probiotics. 
Subject drop out is predicted at 10% and is taken into consideration in the sample size 
calculation. 
 
7.  Study Intervention 
Patient will be randomized into a treatment or control group. No other treatments such as 
laxatives or enemas are given to all patients.   
1. Treatment group. 
a. Each patient will receive probiotics  in form of granular powdered microbial 
cell preparation (Hexbio®) – Specialized formulation of six microbial strains 
containing: 
i. Lactobacillus acidophilus BCMC® 12130 
ii. Lactobacillus casei BCMC® 12313 
iii. Lactobacillus lactis BCMC® 12451 

iv. Bifidobacterium bifidum BCMC® 02290 
v. Bifidobacterium infantis BCMC® 02129 
vi. Bifidobacterium longum BCMC® 02120 
b. Dosage: 1 sachet twice a day after meals for 1 week. 
 
2. Control group 
a. Each patient will receive placebo sample of similar appearance and 
composition but do not contain probiotics. 
 
 
 
 
8.  Efficacy, Safety and Other Assessments 
 
8.1 Primary end point 
A completed questionnaire on patient’s demographic and medical illness data, stool output/day, 
stool consistency per output/day and constipated related symptoms scoring/day over the period 
of 7 study days. 
 
8.2 Safety 
Patients will be counseled that generally safety profile of probiotics seems to be good. Based on 
the available trials, no adverse effects were noted. There might be a concern issue of safety in 
immune-compromised patients or those critically ill, which they will be excluded in this study. 
 
Patients will be withdrawn from the study if they experience intolerable or any possible 
excessive side effects due to probiotics. 
 
 
9. Assessment variables and methods of assessing. 
 
9.1 Targeted patients will be assessed with a questionnaire (Appendix C) on gastrointestinal 
symptoms, well-being and stool habits. The stool consistency will be scored by a seven-point 
scale according to the Bristol Stool Form Scale (Appendix B). Severity of constipation will be 
categorized into four groups (severe, moderate, mild and no symptoms). Symptoms specifically 

related to constipation such as bloating and flatulence will be recorded in detail. Severity of 
symptom is measured by Likert score of frequency (Very frequently, frequently, occasionally, 
rarely and never). 
 
9.2 Each individual patient will be required to fill in the questionnaire at the beginning of the 
trial. Subsequently, patient will be required to fill up the stool chart and recorded their symptoms 
in a given dairy daily during the study period. Training on how to use and record the dairy will 
be conducted upon embarking into the study. A contact number will be advised to the 
participants to aid their understanding. The dairy will be collected at day 7 upon completion of 
the study. 
 
Other assessment 
1. Assessment of the presence of underlying medical illness will be done at the initial 
presentation, assessed by questionnaire about the medical history and physical 
examination. 
 
10. Study conduct  
 
10.1Elderly patients attending medical/surgical clinics or being admitted to the medical/surgical 
wards PPUKM will be screened. Those with underlying medical illnesses and suspected to 
have constipation are selected. Random selection of the participants either for intervention 
group or control will be pre-determining during screening. 
10.2A written consent is obtained. ( Appendix E) 
10.3The patients’ demographic data and medical history will be obtained by conducting an 
interview and a physical examination. 
10.4In the first interview, patient will also be asked to complete a questionnaire on the 
gastrointestinal symptoms, stool consistency and severity of constipation.  
Patients will be given 7 days’ supply of placebo or probiotics, which patient are required 
to take each sachet of Hexbio® or placebo twice per day for 7 days. 
10.5A training of using the daily stool dairy will be done at the beginning of study. Upon 
completion (day 7) the dairy will be collected and data will be analyzed.  

 
 
 
 
 
FLOW CHART 
 
 
 
 
 
 
Figure 1. Flow chart of the study methodology. 

 
GLOSSARY OF TERMS 
1. Probiotics 
Living microorganisms that enter the gastrointestinal tract in an active form in sufficient 
numbers to exert positive effect. 
2. Constipation 
A condition in which there is difficulty in emptying the bowels, usually associated with 
hardened feces.  
3. Functional Constipation 
A condition that fulfill the Rome III criteria for functional constipation. 
Refer to Appendix A 
4. Bristol Stool 
A medical aid designed to classify the form of human feces into seven categories. Refer 
to Appendix B 
5. Advanced Chronic Illness 
An occurring when one or more conditions become serious enough that general health 
and functioning decline, and treatments begin to lose their impact.  
6. Colony Forming Unit (CFU)  
A unit used to estimate the number of viable bacteria or fungal cells in a sample. 
 
 
 
 
 
 
 
 
 
 
 
 

APPENDIX A  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
List of medical illness associated with constipation. 
1. Diabetes Mellitus 
2. Hypertension 
3. Chronic Kidney disease 
4. Chronic Lung disease 
5. Chronic Heart Failure 
6. Hypothyroidism 
7. Scleroderma 
8. Hyperparathyroidism 
9. Uraemia 
10. Hypocalcaemia 
11. Hypokalaemia 

APPENDIX B 
  
 
 
 
 
 
 
 
 
 
 
 
Bristol chart adapted from http://www.cbc.ca/stevenandchris/content/images/poop_101_1.jpg 

APPENDIX C 
 
 
EVALUATING THE EFFECT OF PROBIOTICS IN CHRONIC CONSTIPATION 
ELDERLY PATIENTS WITH MULTIPLE CO-MORBIDITIES  
Data Collection Form                 
 
 
 
 
 
Study Number:                                                        Patient’s Sticker:  
Socio-demography: 
Age:  
Gender: Male / Female 
Ethnic : Malay / Indian/ Chinese/ Others ( please state: __________) 
Clinical characteristic 
Medical illness: 
 
If yes, please tick: 
 
 
 
        Durations ( years ) 
 
 
Diabetes Mellitus 
 
(    )  
 
 
(     
) 
 
 
Asthma 
 
 
(    ) 
 
 
(     
) 
 
 
Hypertension  
 
(    ) 
 
 
(     
) 
 
 
Dyslipidaemia  
 
(    ) 
 
 
(     
) 
 
 
Chronic Kidney disease 
(    ) 
 
 
(     
) 
 
 
Others (please specify): ______________________ (     
) 
                                                                                  ______________________ (            ) 
                              
Symptoms associated with constipation:  
(*at least in 25% of defecations – Rome III diagnostic criteria of functional constipation) 
 
If yes, please tick: 
 
 
 
 
Straining 
 
 
 
 
 
(    ) 
 
 
Lumpy or hard stools  
 
 
 
(    ) 
 
 
Sensation of incomplete evacuation   
 
(    ) 
 
 
Sensation of anorectal obstruction/ blockage 
(    )  
 
 
Manual maneuvers to facilitate defecations  
(    ) 
 
 
Fewer than 3 defecations per week  
 
(    ) 
Duration: _________months/ years 
 
 
 
 
 
Previous treatment:  
 
 
 
frequency: 
 
Laxatives 
 
(    ) 
 
 
(        ) days/months/years 
 
Probiotics 
 
(    ) 
 
 
(        ) days/months/years 
 
High fibre diets  
(    ) 
 
 
(        ) days/months/years 
 
Enemas 
 
(    ) 
 
 
(        ) days/months/years 

 APPENDIX D 
 
 
EVALUATING THE EFFECT OF PROBIOTICS IN CHRONIC CONSTIPATION 
ELDERLY PATIENTS WITH MULTIPLE CO-MORBIDITIES  
QUESTIONNAIRES 
Study Number:                                                        Patient’s Sticker:  
1. How frequent is your bowel movements per week?  
  1-2 times 
         2 times                 once per 
         less than                   less than 
per 1-2 days        per week                    week 
    once per week     once per months 
2. Do you need assistance in evacuation?  (enema/digital-manual maneuvers)   
 
   Never 
        Rarely             Occasionally               Frequently         Very frequently            
3. Do you have sensation of anorectal obstruction/ blockage?               
   Never 
        Rarely             Occasionally               Frequently         Very frequently      
         
4. Feeling of incomplete evacuation?               
   Never 
        Rarely             Occasionally               Frequently         Very frequently            
             
5. Do you have lumpy or hard stools?  
   Never 
        Rarely             Occasionally               Frequently         Very frequently            
6. Any straining or squeezing on defecation attempts?   
   Never 
           1-3                          3-6                          6-9                 More than 9     

 
 
 
 
1. How long have you had constipation?               
Less than           6-12 months            1-2 years                 3-5 years                  More than    
 6months                                                                                                               5 years     
       
2. Do you have bloating in your stomach?               
   Never 
        Rarely             Occasionally               Frequently         Very frequently 
 
 
3. Do you have flatulence?               
   Never 
        Rarely             Occasionally               Frequently         Very frequently 
        
4. Do you have stomach cramps?               
   Never 
        Rarely             Occasionally               Frequently         Very frequently 
5. How many unsuccessful attempts of evacuation within 24hours?               
   Never 
        Rarely             Occasionally               Frequently         Very frequently 
6. Do you have abdominal pain?                    
   Never 
        Rarely             Occasionally               Frequently         Very frequently 
7. How long do you spend in the lavatory per attempt? (minutes)               
Less than 5 
          5-10                       10-20                       20-30               More than 30  

 
 
Statistical analysis Plan 
 
 
The collected data was analysed using IBM SPSS Statistics for Windows version 21.0 
software (IBM Corp., Armonk, NY, USA) and Microsoft Office Excel 2010software (Microsoft, 
Redmond, WA, USA). Statistical significance was set at p = <0.050.  
All of the data was assessed for normality via the usual processes. 
The baseline characteristic differences between the two groups were evaluated using the 
Mann-Whitney U and chi-squared tests. The median results of the improvement in stool 
frequencies and stool consistency between the treatment and placebo group were compared using 
the Mann-Whitney U test. The constipation-related symptom improvements were analysed using 
the chi-squared test. 
Intention to treat analysis was used in this trial, where only the final results within the 
group which they were randomized, receiving the treatment and completed the treatment 
assignment were analysed. Participants who deviates from the protocol as being non-compliance 
or withdrew consent were not included into the analysis.