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S. CUDMORE ET AL.
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.
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