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International Journal of Food Sciences and Nutrition
ISSN: 0963-7486 (Print) 1465-3478 (Online) Journal homepage: http://www.tandfonline.com/loi/iijf20
A randomised, double-blind, placebo-controlled clinical study: the effects of a synbiotic, Lepicol, in adults with chronic, functional constipation
Sally Cudmore, Andrea Doolan, Seán Lacey & Fergus Shanahan
To cite this article: Sally Cudmore, Andrea Doolan, Seán Lacey & Fergus Shanahan (2016): A randomised, double-blind, placebo-controlled clinical study: the effects of a synbiotic, Lepicol, in adults with chronic, functional constipation, International Journal of Food Sciences and Nutrition, DOI: 10.1080/09637486.2016.1244661 To link to this article: http://dx.doi.org/10.1080/09637486.2016.1244661
Published online: 24 Oct 2016.
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Date: 25 October 2016, At: 12:44
INTERNATIONAL JOURNAL OF FOOD SCIENCES AND NUTRITION, 2016 http://dx.doi.org/10.1080/09637486.2016.1244661
RESEARCH ARTICLE
A randomised, double-blind, placebo-controlled clinical study: the effects of a synbiotic, Lepicol, in adults with chronic, functional constipation , Andrea Doolan a , Se an Lacey c and Fergus Shanahan a,b,d a Atlantia Food Clinical Trials, Cork, Ireland; b APC Microbiome Institute, University College Cork, Cork, Ireland; c Department of Mathematics, Cork Institute of Technology, Cork, Ireland; d Cork University Hospital, School of Medicine, University College Cork, Cork, Ireland Sally Cudmore a,b
ABSTRACT The study objective was to evaluate the safety and effects of Lepicol V R (pysllium fibre, inulin and 5 probiotic strains) in adults with chronic, functional constipation during a 4 week intervention. 69 subjects with functional constipation according to Rome III criteria were randomised to receive Lepicol ( n ¼ 35) or placebo ( n ¼ 34) daily. Both groups had improved frequency of bowel move- ments, with an increase of 1.082 bowel movements in the Lepicol group over placebo after one week, and 1.079 more than placebo after week 2, but with no significant difference at week 4. Both groups showed significant improvements in quality of life scores at 4 weeks, with the aver- age score being 12.033% better in the Lepicol group, which also had 15.2% improvement in intensity of symptoms and 28.5% increase in satisfaction with quality of life compared to the pla- cebo. Symptoms of constipation improved to a greater degree and there was a significant reduc- tion in laxative use in the Lepicol group.
ARTICLE HISTORY Received 28 June 2016 Revised 27 September 2016 Accepted 1 October 2016 Published online 25 October 2016 KEYWORDS Constipation; Lepicol; symbiotic; fibre; probiotic; clinical trial
Background Chronic constipation is physically and psychologically difficult for sufferers as it can interfere significantly with daily life and overall well-being. It is common in the general population with a reported incidence which varies from 2 to 27 % (Talley et al. 1993; Hunt et al. 2007; Pinto Sanchez & Bercik 2011; Ford et al. 2014); women, overweight and elderly individuals are more commonly affected (Talley et al. 1996; Choung et al. 2007; Phatak & Pashankar 2014). Health care costs related to constipation are also substantial, with an estimated $700 million spent annually on laxatives alone in the USA (Crowell et al. 2009) and £67 mil- lion spent in the UK (Gudsoorkar & Quigley 2013). In the absence of symptoms such as bleeding, anaemia, fever, and weight loss, chronic constipation is usually a functional disorder, without specific cause. Most people report having at least three bowel move- ments per week, so that two or fewer is often consid- ered abnormal in western cultures. However, frequency of bowel movements is not the sole indica- tor of constipation. Hard or lumpy stools, effort required in expelling them, sense of incomplete evacu- ation, and accompanying abdominal discomfort, bloat- ing and distension may be important accompaniments
to infrequent bowel movements. About one third of constipated patients seek medical attention, whereas the majority use over-the-counter medications or sup- plements, such as laxatives, probiotics, fibre or homeo- pathic remedies (Heaton et al. 1992; Frank et al. 1999; Pare et al. 2001; Irvine et al. 2002; Quigley 2011; Quigley 2012). Food-based products purported to have a beneficial effect on gastrointestinal health, have become increasingly popular. In light of global demo- graphic trends, with an ageing population and rising obesity levels, increases in the prevalence of constipa- tion may be anticipated. Synbiotics are defined as “ mixtures of probiotics and prebiotics that beneficially affect the host by improving the survival and implantation of live micro- bial dietary supplements in the gastrointestinal tract, by selectively stimulating the growth and/or by acti- vating the metabolism of one or a limited number of health-promoting bacteria, thus improving host welfare ” (Gibson & Roberfroid 1995). The synbiotic, Lepicol V R , is a combination of fibre (psyllium), prebiot- ics (inulin) and five probiotic strains that were selected to provide synergistic effects in alleviating constipation. Psyllium husk is a soluble, gel-forming fibre with high water holding capacity that can
CONTACT Sally Cudmore, PhD s.cudmore@ucc.ie APC Microbiome Institute, Biosciences Building, University College Cork, Ireland 2016 Informa UK Limited, trading as Taylor & Francis Group
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considered eligible for the study and were then asked to keep pre-study symptom diaries for 2 weeks, which recorded all bowel movements and any medication/ laxative use, and to refrain from consuming any pro- biotic-containing product or dietary fibre supplements. Subjects returned for a baseline visit (visit 2) within 3 weeks and the pre-study diary was examined to establish eligibility for study entry. If eligible (based on Rome III criteria), subjects were randomised to receive either Lepicol or placebo (1:1), and received a 4-week supply of product in sachets with instructions for oral dosing. Subjects completed the Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment of Constipation – Quality of Life (PAC-QOL) questionnaires, and a survey on con- comitant medication/laxatives. They also completed daily a symptom diary for the duration of the study. The participants were permitted to take their usual laxative medication, as necessary, but additional pro- biotic products and/or dietary fibre supplements were not permitted. During the 4-week intervention period subjects were contacted twice by telephone to assess compliance with consumption of study product and completion of the symptom diaries. At the final visit (visit 3) after 28 days, any unused study product was returned with completed daily dia- ries, and the PAC-QOL and PAC-SYM questionnaires (Table 1) were undertaken. Volunteers were remuner- ated e 150 upon completion of the study. Trial subjects Subjects enrolled into the study were healthy males and females aged between 18 and 80 (Table 2) who met the Rome III diagnostic criteria for functional constipation within the previous 3 months, as follows: (1) subjects had fewer than three defecations per week and one or more of the following; (i) Straining during at least 25 % of defecations, (ii) lumpy or hard stools in at least 25 % of defecations, (iii) sensation of incomplete evacuation for at least 25 % of defecations, (iv) sensation of anorec- tal obstruction/blockage for at least 25 % of defecations, (v) manual manoeuvre to facilitate at least 25 % of defe- cations (e.g. digital evacuation, support of the pelvic floor); (2) loose stools were rarely present without the use of laxatives; and (3) there were insufficient criteria for irritable bowel syndrome (Table 3). Exclusion criteria included the use of a probiotic or prebiotic product or a dietary fibre supplement in the 4 weeks prior to the baseline visit (visit 2); women who were pregnant, lactating or wishing to become pregnant during the study; hypersensitivity to any of the compo- nents of the test product; significant acute or chronic,
facilitate stool softening and bulking in patients with chronic constipation (McRorie et al. 1998) and a sys- tematic review of its use in idiopathic constipation indicated an improvement in symptoms such as straining, pain, stool consistency and an increase in mean stool number per week (Suares & Ford 2011). Consumption of specific strains of lactobacilli or bifi- dobacteria, which are normal residents of the human intestine, has been linked with improvements in bowel movements, improved function of intestinal immune barrier and prevention of colon cancer (Petschow et al. 2013). The ingestion of prebiotics, such as chic- ory root inulin, can stimulate the growth of beneficial bifidobacteria and lactobacilli in the colon (Marteau et al. 2011). This clinical study was designed to assess the efficacy and safety of a synbiotic, Lepicol, versus placebo in adults with chronic constipation after 4 weeks consumption. Methods Trial design, ethical approval and registration This was a 4-week, randomised, double-blind, pla- cebo-controlled, parallel group trial conducted at a single site (Atlantia Food Clinical Trials clinic) in Cork, Ireland between February 10th (first subject, first visit) and July 17th (last subject, last visit) 2014. This study was conducted according to the guidelines laid down in the Declaration of Helsinki, and in accordance with the principles of Good Clinical Practise (GCP). All procedures involving human sub- jects were approved by the Clinical Research Ethics Committee of the Cork Teaching Hospitals (CREC). Written informed consent was obtained from all sub- jects. The trial was registered on clinicaltrials.gov under registration identification number NCT02073006, http://clinicaltrials.gov/ct2/home. All the participants, research nurses, medical personnel, personnel entering data and the project manager were blinded to the interventions. An initial screening of subjects who responded to advertisements in the local press was conducted by telephone and suitable volunteers (based on age and reported number of bowel movements per week) were invited to attend a screening visit (visit 1) at which the study and inclusion/exclusion criteria were explained, and informed consent was obtained from each study participant. Medical history, demographic data and concomitant medication were recorded and urinary pregnancy tests were performed for women of childbearing age. Subjects who met the Rome III diag- nostic criteria for functional constipation were
INTERNATIONAL JOURNAL OF FOOD SCIENCES AND NUTRITION 3
Table 1. Schedule of visits, and activities carried out during each visit. Day visit no. – description Day -14 to -21 1 – Screening Day 0 2 – Baseline
Day 28 3 – End of Study
Visit Window
þ 7 days
þ 7 days
Informed Consent Inclusion/Exclusion
X X X X X X
X
General medical history Demographic data Urine pregnancy test Subject daily diary provided
X X X X
PAC-QOL PAC-SYM
X X
Study product administered Study product returned Adverse events/SAE recorded
X X X
X X
Prior/Concomitant Medications Record
X
Table 2. Summary of subject demographics. Treatment group Demographic Lepicol ( n ¼ 35)
(Protexin), Somerset, UK) twice daily, approximately 30 min before a main meal (morning and evening). The sachet was stirred into a glass of cold water and con- sumed, followed by an additional glass of water imme- diately. The subjects consumed the first dose in the clinic where the product was dissolved in 240 ml of water, and followed by an equal volume of water. Each 5 g sachet contained 3.45 g of psyllium husks ( Plantago ovata forsk ), 1.5 g of inulin and 6 10 8 CFU combined total of the following probiotic strains, Lactobacillus rhamnosus PXN 54 (NCIMB 30188), Bifidobacterium bifidum PXN 23 (NCIMB 30179), Lactobacillus acid- ophilus PXN 35 (NCIMB 30184), Lactobacillus planta- rum PXN 47 (NCIMB 30187) and Lactobacillus bulgaricus PXN 39 (NCIMB 30186). These strains have demonstrated antimicrobial activity against a number of pathogens, possibly through the production of lactic and acetic acid (Tejero-Sarinena et al. 2012). In add- ition, these strains have shown good survivability in vitro at pH 2.0 (Probiotics International Ltd, data on file). The placebo (also provided by Probiotics International Ltd) was provided in 5 g sachets and con- tained 4.975 g of fine rice starch and 0.025 g of magne- sium stearate (an excipient to assist in the flow during the manufacturing process). The packaging of both products was identical. Efficacy assessments and endpoints Daily symptoms were recorded in a subject diary which included the number of bowel movements, and for each bowel movement they were asked to score the Bristol stool type (7 point scale), and to indicate if they had any of the following Rome III symptoms for the bowel movement – straining, incomplete evacu- ation, blockage in rectum, support pelvic floor/digital assistance. Subjects also recorded in their daily diaries if they used any medication or laxatives or felt unwell during the period. At the baseline and final study
Placebo ( n ¼ 34) 31 (91.2%)
p -Value
.673 a .614 a .398 b .505 c
Gender – female Race – Caucasian
33 (94.3%) 34 (97.1%)
32 (94.1%)
Age
45.09 ± 15.09 71.57 ± 14.80 164.78 ± 7.10
42.21 ± 12.88 72.76 ± 16.07 167.45 ± 8.02
Weight (kg) Height (cm)
.148 b Data are expressed as mean ± standard deviation for continuous variables, and categorical variables as absolute frequency and percent (for group).
a Fisher ’ s exact test. b Independent t -test. c Mann – Whitney test.
unstable and untreated disease or any condition which contraindicated, in the investigator ’ s judgement, entry to the study; malignant disease or any concomitant end-stage organ disease; obstructive or metabolic aeti- ology for constipation; history of laxative abuse (greater than the daily dosage recommended on the label for any laxative); history of drug and/or alcohol abuse at the time of enrolment; having a condition or have taken a medication that the investigator believes would interfere with the objectives of the study, pose a safety risk or confound the interpretation of the study results; individuals who, in the opinion of the investigator, were considered to be poor attendees or unlikely for any reason to be able to comply with the trial; subjects may not be receiving treatment involving experimental drugs; if the subject participated in a recent experimen- tal trial, this must have been completed not less than 90 days prior to this study. All subjects were requested to refrain from con- suming any probiotic-containing product but other- wise to maintain their routine diet and physical activity during the study period. Study product The participants were instructed to consume a 5 g sachet of Lepicol V R (Probiotics International Ltd
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Table 3. Summary of subject baseline constipation characteristics and use of laxatives in the two weeks prior to the intervention.
Lepicol ( n ¼ 35) No. of subjects (%)
Placebo ( n ¼ 34) No. of subjects (%)
Total ( n ¼ 69) No. of subjects (%)
Baseline characteristics
p Value
Rome III criteria Straining during at least 25% of defecations? Have lumpy or hard stools in at least 25% of defecations? Have the sensation of incomplete evacuation for at least 25% of defecations? Have the sensation of anorectal obstruction/blockage for at least 25% of defecations? Use manual manoeuvers to facilitate at least 25% of defecations (e.g. digital evacuation, support of the pelvic floor)? Are loose stools rarely present without the use of laxatives? Does the subject have insufficient criteria for irritable bowel syndrome? Fewer than 3 defecations per week?
1.000 a 1.000 a
33 (94.3%) 33 (94.3%)
34 (100.0%) 34 (100.0%)
67 (97.1%) 67 (97.1%)
1.000 a
35 (100.0%)
34 (100.0%)
69 (100.0%)
1.000 a
8 (22.9%)
8 (23.5%)
16 (23.2%)
1.000 a
4 (11.4%)
3 (8.8%)
7 (10.1%)
1.000 a 1.000 a
35 (100.0%) 35 (100.0%)
34 (100.0%) 34 (100.0%)
69 (100.0%) 69 (100.0%)
1.000 a
35 (100.0%)
34 (100.0%)
69 (100.0%)
Laxative use Reported use of laxatives
< .001 a < .001 b
70 (78.7%) 2.00±1.41 1.91±0.51
19 (21.3%) 0.56±0.75 1.85±0.47
89 (100.0%) 1.29±1.14 1.89±0.49
Average reported use of laxatives per subject Average no. of bowel movements per week
.525 c For Rome III criteria, data are expressed as no. of individuals (% of the total no. of individuals in that group) who reported each symptom. Reported use of laxatives is the total number of reported uses for all the subjects during the pre-treatment, and the (% of the total use). Average reported use of laxa- tives per subject and Average no. of bowel movements are the mean ± SD.
a Binomial test. b Poisson-test. c Mann – Whitney test.
Secondary endpoints The secondary endpoints included to establish if Lepicol V R could: (i) improve stool consistency, as measured by the Bristol Stool Form Scale, where subjects recorded consistency in the daily diary; (ii) improve subjects ’ quality of life as measured by the PAC-QOL questionnaire; (iii) improve subjects ’ con- stipation symptoms as measured by the PAC-SYM questionnaire; (iv) reduce laxative use by the subjects. Safety assessments The clinical team assessed each subject-reported adverse event (AE) and categorised it according to severity into one of three categories; mild, moderate or severe. Its relationship to the study treatment was also determined as unrelated, possible or definite. Statistical methods and data analysis Sample size was calculated using SAS Statistical soft- ware (SAS Institute Inc., Cary, NC) based on increas- ing bowel movements per week, which was defined as the primary outcome in the current study. For a
visits (visits 2 and 3) subjects also completed the fol- lowing validated questionnaires – Patient Assessment of Constipation Symptoms (PAC-SYM) (Frank et al. 1999) and Patient Assessment of Constipation – Quality of Life (PAC-QOL) (Marquis et al. 2005). The PAC-SYM questionnaire is a 12-item self-report instrument divided into abdominal, rectal and stool symptoms. Items were rated on a 5-point Likert scale (0 – 4) with responses scored from 0 (absence of symp- tom) to 4 (very severe symptoms). The abdominal, rectal and stool domain scores are the mean scores of each domain. The overall score is the mean of all 12 items. The PAC-QOL is a 28 item questionnaire with four subscales (worries and concerns, physical discom- fort, psychosocial discomfort, and satisfaction) and an overall scale, providing a comprehensive assessment of the burden of constipation on patients' everyday func- tioning and well-being. Both questionnaires have been validated and shown to be internally consistent, repro- ducible, valid and responsive to improvements over time (Frank et al. 1999; Marquis et al. 2005).
Primary endpoint The primary endpoint was to evaluate if Lepicol could increase the number of bowel movements by 1.5 per week versus placebo by week 4 of the treatment.
INTERNATIONAL JOURNAL OF FOOD SCIENCES AND NUTRITION 5
parallel group design, it was calculated that a sample size of 30 evaluable patients per group would have 80 % power, with an estimated standard deviation of 2.0, to detect a true treatment difference of 1.5 bowel movements per week. To allow for dropouts, 5 more subjects were recruited per group. The calculations assumed a 2-sided significance test carried out at the 5 % level. Subjects were randomised by a computer generated schedule to either the treatment or placebo groups (1:1) and were balanced using a block size of 6. All the statistical analyses were carried out using SPSS Version 22 for Windows (SPSS Inc., Chicago, IL). All the tests were two-sided and performed at the 5 % level of significance. Due to sphericity not being assumed, the Greenhouse – Geisser test was used to determine whether or not a statistical differ- ence existed in the number of bowel movements per week using the treatment group as a fixed factor and the number of bowel movements in pre-treatment as the baseline covariate. Cohen ’ s d was used to deter- mine the strength of any statistically significant result (Small effect: 0.2 d < 0.5; Medium effect: 0.5 d < 0.8; Large effect: d 0.8). Similar analysis was used to determine whether or not a statistical difference existed between groups in the average distance a reported Bristol stool type was away from type 1 each week. Subscores obtained from the PAC-QOL and PAC- SYM questionnaires were analysed using ANCOVA or an appropriate non-parametric test with the pre-study scores used as the covariate. The overall incidence of treatment-related adverse events were analysed by the Fisher ’ s Exact test.
randomised subjects completed the study and were included in data analysis (Figure 1).
Clinical response Primary outcome
There was an improvement in the number of bowel movements per week in the Lepicol group versus the placebo group of 1.082 in week 1 ( p ¼ .021) and 1.079 in week 2 ( p ¼ .049), with the baseline being the num- ber of bowel movements in the pre-treatment (Table 4, Figure 2). There was a trend towards an improvement in the Lepicol group from the pre-treatment to week 3 (increase of 0.87 bowel movements, p ¼ .112) and week 4 (increase of 0.69 bowel movements, p ¼ .259) versus placebo, but this was not significant. Secondary outcomes Stool consistency – Subjects reported the consistency of each bowel movement in their daily diaries using the Bristol Stool Form Scale (stool types 1 – 7, with the hardest stool being type 1 and softest type 7). Figure 3 indicates that there was a trend in both groups for the stool to become softer (i.e. move away from type 1), with the greatest improvement seen in the Lepicol group in week 2, when the average stool type was type 3, while the majority of bowel movements in the pla- cebo group were reported as closer to type 2. But no statistical difference ( p ¼ .217) was found between groups from week to week (with the pre-treatment taken as the baseline) in the distance the reported stool type was away from type 01. Quality of life Subjects ’ overall quality of life percentage score (across all 5 subcategories combined) was 12.033 % better in the Lepicol group versus placebo (Table 5). When the QOL subcategories were analysed there was a statistic- ally significant improvement of 15.2 % in the Lepicol versus placebo for “ intensity of symptoms ” ( p ¼ .030). There was an improvement of 10.5 % for the “ effects on daily life ” , but this was not significant ( p ¼ .055). Subjects in the Lepicol group were 8.6 % more content with their “ feelings on constipation ” and 13.1 % more content with “ life with constipation ” , but neither were significant (feelings p ¼ .155, life with constipation p ¼ .067). For “ satisfaction with their quality of life ” , a statistically significant increase of 28.5 % was found between the groups at the end of the study ( p ¼ .003
Results Subjects
From a total of 217 initial telephone interviewees, 92 were suitable for invitation for a screening visit (exclu- sions – 106 reported > 3 bowel movements/week, 3 IBS diagnoses, 8 disallowed medication, 3 chronic unstable disease, 2 had no symptoms in the previous 3 months, 3 unable to attend visits/communication issues). Twenty-three subjects did not meet the inclu- sion/exclusion criteria after the 2-week screening period (9 > 3 bowel movements/week following a 2 week diary, 9 screen fails, 5 chose not to enter study). Sixty-nine subjects were randomised to receive either test product ( n ¼ 35) or placebo ( n ¼ 34) and were included in the intent-to-treat population. All
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Figure 1. CONSORT diagram for subject selection, treatment and analysis.
Table 4. Between group analyses on average number of bowel movements per week. 95% Confidence Interval for Difference
Mean difference in no. of bowel movements/week (Lepicol-Placebo)
Week
p -Value
Lower Bound
Upper Bound
Effect size
1 2 3 4
1.079 1.082 0.870 0.686
.021 .049 .112 .295
0.164 0.006
1.994 2.157 1.948 1.983
0.571 0.484 0.389 0.255
0.209 0.611
Figure 2. Average and confidence interval of the number of bowel movements per week in the Lepicol test and placebo groups. p ¼ .021; p ¼ .049 (obtained using ANCOVA).
INTERNATIONAL JOURNAL OF FOOD SCIENCES AND NUTRITION 7
Figure 3. Average and confidence interval of stool consistency using a weighted average distance (weighted according to the fre- quency of each stool type) for stool type away from type 01 on the Bristol Stool Scale.
Table 5. Pairwise comparison of Lepicol versus Placebo on QOL score with results from the pre- treatment used as the baseline covariate. 95% Confidence Interval for Difference
% ScoreMean Difference (Lepicol - Placebo)
QOL category All categories
p -Value Lower Bound Upper Bound Effect size
12.033 15.176 10.509 8.595 13.060 28.488
.051 .030 .055 .155 .067 .003
24.096 28.855 21.229 20.516 27.036 47.224
0.031
0.514 0.545 0.492 0.364 0.464
Intensity of symptoms
1.498 0.212
Effect on daily life
Feelings
3.326 0.916
Life with constipation
Satisfaction 0.749 The analysis was carried out by standardising the total scores of the subcategories. A negative % score indicates an improvement in QOL. 9.752
(painful bowel movements, burning sensation, bleed- ing/tearing) and stool symptoms (incomplete bowel movement, stool too hard, stool too small, straining and false alarm). While the overall constipation scores improved for both groups throughout the study ( p ¼ .001), constipation symptoms were lower by 12.32 % in the Lepicol group versus placebo group ( p ¼ .039) as shown in Table 6. When broken into the three categories it was found that on aver- age subjects ’ abdominal symptoms were improved by 13.1 % ( p ¼ .005) and rectal symptoms by 8.7 % ( p ¼ .044) in the Lepicol group over placebo. Stool
with a medium effect size of .749). These data are shown in Figure 4, which indicates that the effect size for each of the QOL sub-categories is greater in the Lepicol group than in the placebo. Constipation symptoms The constipation symptoms were assessed using the PAC-SYM questionnaire at the start (visit 2) and end (visit 3) of the 4 week intervention period. This questionnaire is divided into three categories with a total of 12 questions; abdominal symptoms (discom- fort, pain, bloating, cramps), rectal symptoms
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S. CUDMORE ET AL.
Figure 4. Effect size for QOL sub-categories. The effect size was based on the difference within each treatment group over the five subcategories (using the Wilcoxon test). Cohen ’ s d determined the classification of the effect size (strength of the result). A statistic- ally significant difference exists between the two groups if the p -value from the statistical test is less than .05. Effect size quantifies the statistical difference – i.e. when the effect size is deemed as large, that means that a large difference exists between the two groups.
Table 6. Pairwise comparisons on PAC SYM scores.
95% Confidence Interval for Difference
% Score Mean Difference (Lepicol - Placebo)
PAC-SYM category
p -Value Lower Bound Upper Bound Effect size
All symptoms
12.318 13.098 8.717 10.722
.039 .005 .044 .109
23.989 22.098 17.199 23.916
0.647 4.098 0.236 2.472
0.549 0.721 0.510
Abdominal symptoms
Rectal symptoms Stool symptoms
0.414 Results from the pre-treatment phase were used as the baseline covariate. Abdominal symptoms are discomfort, pain, bloating, cramps; rectal symptoms are painful bowel movements, burning sensations, bleeding/tearing; and stool symptoms are incomplete bowel movements, stool too hard, stool too small, straining and false alarm. “ All symptoms ” are all 12 symptoms. A negative % score difference indicates an improvement in symptoms.
symptoms improved by 10.7 % in the Lepicol group versus placebo, but this was statistically insignificant ( p ¼ .109). Figure 5 indicates that for the 12 subcategories of the PAC-SYM, there was a larger effect size in almost all the constipation symptoms in the Lepicol group versus placebo, with the exception of two subcatego- ries (stool too small and painful bowel movements), where the effect size difference was small. Laxative use Overall there were 148 reported uses of laxatives in this study (aloe vera cleanse, annusol, ducolax, duphu- lac, movicol, fuca, lactulose, motilium, pineapple juice, senokot, supos). Chi-squared tests showed that the
highest proportion of laxative use (60 % of total) within the groups was during the 2-week pre-screen- ing phase (Table 7). Within the Lepicol treatment group the proportional use of laxatives decreased from 70 reported uses by 10 subjects (64.2 % of the total reported uses of laxatives in the group) in pre-treat- ment, to 32 uses by 7 subjects in week 2 (29.4 % of total usage in group), to 7 reported uses by 2 subjects in week 4 (6.4 % ). This decrease was found to be stat- istically significant ( p < .001). The high use of laxative in the Lepicol group was primarily due to one subject, but if this subject ’ s data was excluded the result was still significant. This subject consumed 28 doses of laxative (Ducolax, Duphalax, Movicol) in the 2 week run in period, versus 3 doses in the 4 week interven- tion period, but as did not exceed the recommended
INTERNATIONAL JOURNAL OF FOOD SCIENCES AND NUTRITION 9
Figure 5. PAC-SYM subcategory effect sizes. The effect size was based on the difference within each treatment group over the 12 subcategories (using the Wilcoxon test). Cohen ’ s d determined the classification of the effect size.
Table 7. Laxative use.
No. of reports of Laxative use (% within each group) Lepicol Placebo Total
Pre-treatment (weeks – 2 to 0)
70 (64.2%) 32 (29.4%)
19 (48.7%) 9 (23.1%) 11 (28.2%) 39 (100.0%)
89 (60.1%) 41 (27.7%) 18 (12.2%) 148 (100%)
Weeks 1 – 2 Weeks 3 – 4
7 (6.4%)
Total
109 (100.0%)
p -Value < .001 Number of reported uses of laxatives (and also expressed as the % use within each group) for each phase of the study. < .001 .116
Discussion The results of this double blind, placebo controlled, parallel clinical study, while they did not meet the pri- mary endpoint, did demonstrate that subjects who consumed 10 g (2 sachets) of a commercially available synbiotic, Lepicol, for 4 weeks experienced an improvement in the symptoms of chronic constipation versus placebo. The product contained fibre (psyllium husks), prebiotic (inulin) and 5 probiotic strains ( Lactobacillus rhamnosus PXN 54, Bifidobacterium bifidum PXN 23, Lactobacillus acidophilus PXN 35, Lactobacillus plantarum PXN 47 and Lactobacillus bul- garicus PXN 39). The fibre, prebiotic and probiotic strains separately have been previously associated with an improvement in constipation (McRorie et al. 1998; Marteau et al. 2011; Suares & Ford 2011; Petschow 2013). The results of a previous study with the same five probiotic strains in men with chronic constipation suggested that the product is effective in improving stool frequency and consistency in the male sample,
daily dose or study eligibility criteria the subject was not excluded from the study. In the placebo group there was a statistically insignificant drop ( p ¼ .116) in the proportional use of laxatives, from 48.7 % by 7 subjects (of the total reported uses of laxatives) in pre- treatment to 23.1 % by 3 subjects (weeks 1 – 2) to 28.2 % by 3 subjects (weeks 3 – 4). Safety data There were 51 reports of adverse events (AE) in total (23 Lepicol, 28 placebo) and no serious adverse events (SAE), with no statistical difference between groups ( p ¼ .575). Of the AEs, which varied from nettle stings to back pain, 98 % were categorised as mild by the clinical team ( p < .001), which also categorised 80.4 % of the AEs (82.6 % Lepicol, 78.6 % placebo) as unrelated or unlikely to be related to the treatment (Table 8). Overall, there was no significant difference between the groups ( p > .999).
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but that study did not include females, a population subgroup that typically has a higher incidence of con- stipation (Fateh et al. 2011). Both the test and placebo groups were well matched for baseline demographics (age, weight, height, gender and race). The study included mainly women, but the subjects were rando- mised consecutively with no gender selection bias. There was a substantial placebo effect observed in this study, with significant improvements in all end- points seen in both groups. Placebo effects are com- mon in gastrointestinal diseases and can be as high as 84 % in functional gastrointestinal diseases, such as IBS (Musial et al. 2007). In this study, one of the factors which may have influenced the considerable placebo effect was the increased volume of fluid consumed by all subjects, as each of the two doses of investigational product (Lepicol or placebo) was consumed with 400 – 500 ml of liquid, thereby increasing the overall consumption of liquid by up to 1 l per day. Low fluid intake is considered a risk factor for constipation as it is linked to slow colonic transit and low stool output. In order to reduce the potential effects of increased fluid intake we recommend that for future studies the Lepicol dose is taken in a single serving, reducing the additional fluid intake by half, and that the additional fluids are also consumed in the 2-week run-in phase. The subjects in the study were not stratified based on laxative use in the pre-treatment phase, and there was a higher proportion of laxative use in the Lepicol group, and this may have masked some of the effect of intervention versus placebo. While the study did not meet its primary endpoint, as there was no statistical difference in the number of bowel movements per week at the end of the study (week 4), there was a significant improvement in the Lepicol group versus the placebo for the first 2 weeks of the study. This indicated that Lepicol had an effect within 1 week of consumption, which increased after two weeks, after which the effect plateaued. This pla- teauing trend was also true of the placebo group. This suggests that the ingredients in Lepicol provided faster resolution to the symptoms of constipation, than did the placebo. Table 8. Relatedness of adverse events to the treatments. No. of AEs Relatedness of adverse events (AE) Lepicol Placebo Total Unrelated/unlikely to be treatment 19 22 41 Possibly related to treatment 4 a 6 b 10 Total no of AEs 23 28 51 p Values were calculated using Fisher ’ s Exact test ( p > .999). a Diarrhoea, heartburn, stomach upset 2. b Diarrhoea, headcold, headache, stomach upset 3.
While there was no significant improvement in the stool consistency, with both groups reporting a softer stool type, there was a trend for a greater improve- ment in the Lepicol group of almost two types on the Bristol Stool Type Scale (Figure 4). The Quality of Life of the subjects was assessed at the start (visit 2) and end (visit 3) of the intervention period using the PAC-QOL questionnaire, which has 28 questions in five categories (intensity of symptoms, effects on daily life, feelings, life with constipation and satisfaction with the treatment). While the overall QOL improved for both groups, on average there was a greater improvement in the subjects consuming Lepicol over those consuming placebo. There were statistically significant improvements in the Lepicol group for 2 of the sub-categories indicating that Lepicol provided relief from the symptoms of consti- pation, leading to a better quality of life for the subjects. There were also improvements in three sub- categories (feelings on constipation, life with constipa- tion and effects on daily life) but these were not significant versus placebo. Constipation Symptoms were improved by 12.32 % in the Lepicol group, com- pared to placebo. When divided into the subcatego- ries, there was a statistical improvement in the abdominal and rectal symptoms, which include dis- comfort, pain, bloating, cramps painful bowel move- ments, burning sensations, and bleeding/tearing. For ten of the twelve PAC-SYM subcategories, there was a larger effect size in the improvement of constipation symptoms in the Lepicol group. So, the Lepicol pro- vided considerable relief from a variety of symptoms often experienced during constipation. There was a statistically significant decrease in laxa- tive usage in the Lepicol group from 64.2 % (of total usage) in the pre-treatment phase to 6.4 % (of total) in week 4. In contrast, the reduction in the placebo group was not statistically significant. The effect with Lepicol is particularly noteworthy because there was a much greater use of laxatives in this group before the intervention, primarily due to one individual, but if this subject is omitted from the statistical analysis the drop in laxative use was still significant for the Lepicol group. This drop in laxative usage is of clinical importance, considering the widespread use of laxa- tives in patients suffering from constipation (Roerig et al. 2010). Laxatives account for 45 % of the patient costs in Western Europe in the first year after the diagnosis of constipation (Dik et al. 2014). Such over- use may become self-perpetuating with some individu- als becoming laxative-dependent.
INTERNATIONAL JOURNAL OF FOOD SCIENCES AND NUTRITION 11
Funding This study was funded in full by Probiotics International Ltd., [n/a] which also provided the intervention and placebo products for this clinical study. This sponsor company was not involved in the conduct of the research, data analysis or manuscript preparation.
Constipation is often related to diet and physical activity, and while subjects were asked not to change their habitual diet or level of physical activity for the duration of this study, these were not analysed during this study, and should be taken into consideration in future studies. Another limitation of this study was the small numbers of participants – the study was powered to detect a change in bowel movements of 1.5 per week, but this endpoint was not met with the study numbers ( n ¼ 35 per group) and high placebo effect. We suggest a follow-up study powered to the high-pla- cebo effect seen (the data from this study suggests n ¼ 67 per group), and with a psyllium only arm as a control, which has previously shown to provide a simi- lar increase in BM per week. We also recommend that the stool is tested for the presence/absence of the pro- biotic strains before and after the study. Conclusions While this study did not reach its primary endpoint of increasing bowel movements per week (due to the low subject numbers and high placebo effect), it did dem- onstrate that a twice daily consumption of the synbi- otic, Lepicol, improved the quality of life of subjects with constipation. Lepicol did increase bowel move- ments per week significantly in the first 2 weeks in subjects with chronic, functional constipation but the significance was not maintained over placebo in weeks 3 and 4. Lepicol also improved the overall quality of life scores (PAC-QOL) and constipation symptoms (PAC-SYM) at 4 weeks, and reduced the use of laxa- tives during the study versus placebo. In addition, Lepicol was safe. Therefore, this food supplement, containing fibre, prebiotic and five probiotic strains, has the potential to offer relief from symptoms of functional constipation. Acknowledgements We would like to thank research nurse, Mary Tuohy, who was involved in the recruitment of the subjects and con- ducted the clinical visits, and Emily Goodbody, clinical research assistant and nutritionist, who assisted with this clinical study. Disclosure statement Fergus Shanahan, Sally Cudmore and Andrea Doolan are co-founders and shareholders of Atlantia Food Clinical Trials Ltd. Se an Lacey is founder and Director of Lacey Maths and Stats Consultancy. Fergus Shanahan has received research funding from the following companies; GSK, Sigmoid Pharma, Trino Therapeutics, Alimentary Health and the Kerry Group.
ORCID Sally Cudmore http://orcid.org/0000-0002-3131-7428 Fergus Shanahan http://orcid.org/0000-0003-0467-0936
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