Effects of a Probiotic Fermented Milk on Functional Constipation

A Randomized, Double-blind, Placebo-Controlled Study

Mena Mustapha Mazlyn; Lee Hun-Leong Nagarajahl Arshad Fatimah; A Karim Norimah; Khean-Lee Goh

J Gastroenterol Hepatol. 2013;28(7):1141-1147.

Results

Subjects' Flow and Characteristics

Between March 6 and April 7 of 2010, 384 potential subjects were screened, out of which 215 did not meet diagnostic criteria of functional constipation. Of the 169 positively diagnosed with Rome II-defined functional constipation, 27 were excluded as they did not meet other eligibility criteria, mainly BMI (12) and CCQ^[19] score (8). A further 41 people declined to participate, while one moved away from the trial location after the screening and was not able to participate. A total of 100 subjects who met all eligibility criteria and consented to participate were enrolled in the study and randomized. Fifty were assigned to probiotics group and the remaining 50 to control group. A total of 90 subjects (47 in probiotics group, 43 in control) were analyzed as intent-to-treat population. A flow diagram reflecting the subjects' passage through the trial is reported in Figure 1.

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Figure 1.

Flow chart of subjects' progression in the trial.

Both groups were well balanced in terms of demography and anthropometry (Table 1) as well as constipation-related conditions at screening (Table 2). Duration of constipation shown in Table 2 is the duration of time that subjects' perceived that they experienced constipation based on their individual understanding of the disorder and not the duration of constipation based on clinical diagnosis. Subjects' who were "unaware" were those who had perceived their symptoms to be natural occurrences in the course of normal bowel movement, although they had been diagnosed with Rome II-defined functional constipation during screening and experienced symptoms of constipation with onset of at least 12 months prior to screening.

Safety Evaluation

All subjects were treatment-compliant (> 99%). None were withdrawn. All AEs were mild or moderate, and considered coincidentally related to the study drink. Most frequent AE was loose stool, reported in 24 subjects (51.1%) in probiotics group and 26 subjects (60.5%) in control. Out of total stools, loose stools accounted for a small percentage, 5.2% and 9.1% in the probiotics and control group, respectively. The percentage of loose stools during baseline period (7.0% in probiotics group and 9.2% in control group) was comparable with the percentage during the intervention, and thus, the study drinks were not considered associated with the loose stools. Other AEs were flu symptoms, fever, stomach ache, and bloating.

Efficacy

The means of primary and secondary efficacy outcomes in both probiotics and control groups were compared at four time points (baseline, week 2, and week 4 of intervention and postintervention or withdrawal period), and the effect sizes were estimated using Cohen's d. The results are summarized in Table 3. Results of assessments at week 1 and week 3 of treatment are not shown, as the overall changes are sufficiently represented by assessments at week 2 (mid-point of treatment) and week 4 (end of treatment).

Primary Efficacy Outcomes

Compared with respective baselines, CCQ^[19] severity score improved significantly in both probiotics and control groups. When compared with control, a trend of improvement in CCQ^[19] score and associated decrease in P value over time was observed with probiotics. The improvement versus control did not reach statistical significance at α = 5% level; however, re-evaluation at α = 10% level revealed significant improvement at week 4 (P = 0.058). The magnitude of treatment effect in terms of improvement of CCQ^[19] score was small (d = 0.39 at week 4) favoring probiotics and could be attributed to chance.

Both probiotics and control group showed significant increase in stool frequency versus baseline. Probiotics did not increase stool frequency significantly versus control, and in fact at one point of time at week 2, control had significantly higher stool frequency compared with probiotics (P < 0.05).

Secondary Efficacy Outcomes

Compared with baseline, stool consistency improved significantly with probiotics but not with control. However, compared with control, the improvement in stool consistency with probiotic intake was not significant within the 4-week intervention. Magnitude of change in stool consistency, or effect size, was small but statistically significant in favor of probiotics, d = 0.19, 95% confidence interval (CI) 0.00–0.35 (week 4) and d = 0.29, 95% CI 0.11–0.52 (1 week postintervention). A clear trend of increase in effect size over time was observed throughout the intervention.

Stool quantity increased significantly versus baseline in both probiotics and control groups initially. However, the improvement was sustained throughout the intervention only in the probiotics group. This may indicate the presence of a placebo effect in the first half of the intervention period. Probiotics did not increase stool quantity significantly compared with control.

Post-hoc Exploratory Analyses

Post-hoc exploratory analysis of the CCQ^[19] component symptoms was conducted, and the results are shown in Table 4 as mean changes from baseline at the final week of intervention (week 4). Only one component of CCQ^[19] showed significant improvement with probiotics administration, that is, severity of incomplete evacuation (P < 0.01 at week 4).

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Table 1. Subjects' demographic and anthropometric data at screening
Parameter	Probiotics	Control
Total no. of subjects	47	43
Males	5	7
Females	42	36
Age (years)a	31.8 ± 9.4	31.7 ± 9.4
Ethnicity (no. of subjects)
Malays	22	17
Chinese	20	24
Indian	5	2
Body weight (kg)^a	56.8 ± 9.3	58.1 ± 9.5
Height (m)^a	1.60 ± 0.06	1.59 ± 0.09
Body mass index (kg/m²)^a	22.3 ± 3.4	22.9 ± 3.2
Waist-to-hip ratio^a	0.81 ± 0.06	0.82 ± 0.08

^aMean ± standard deviation.
Discrete and continuous data were analyzed using χ² test and Mann–Whitney U-test, respectively.

Table 2. Subjects' constipation-related data at screening
Parameters	Probiotics	Control
Severity of constipation (CCQ score)^a	10.5 ± 3.4	10.1 ± 3.1
Frequency of constipation symptoms^bc (%)
Hard or lumpy stools	89.4	74.4
Feeling of incomplete emptying after defecation	85.1	86.0
Straining during defecation	85.1	74.4
Fewer than three defecations a week	68.1	69.8
Sensation of blockage when defecating	83.0	69.8
Abdominal fullness, bloating	63.8	55.8
Need to press on or around anus or vagina to try to remove stool in order to complete defecation	46.8	44.2
Duration of constipation^bd
Less than 5 years	25.5	18.6
Between 5 and 25 years	42.6	48.8
Others (unaware, etc)	31.9	32.6

^aMean ± standard deviation, assessment period was the 3 months preceding screening.
^bPercentage of subjects.
^cSymptom was present at least one-fourth of the time in the preceding 3 months.
^dSelf perceived based on subjects' own understanding of constipation.
Discrete and continuous data were analyzed using χ² test and Mann–Whitney U-test, respectively.
CCQ, Chinese Constipation Questionnaire.¹⁹

Table 3. Mean comparisons of end-point measures between probiotics and control groups and their effect sizes
End-points	Probioticsa	Controla	P value	Effect sized (95% CI)
Primary end-point measures
Severity of constipation (CCQ score)
Baseline	5.06 ± 2.75	5.21 ± 2.82	0.955	–
Week 2 of treatment	3.83 ± 3.29*	3.96 ± 3.40*	0.856	0.04 (−1.00–0.98)
Week 4 of treatment	2.33 ± 2.62,*	3.38 ± 2.78*	0.058	0.39 (−0.47–1.18)
Withdrawal period	3.78 ± 3.46*	3.73 ± 3.04*	0.966	−0.02 (−0.96–1.04)
Weekly stool frequency
Baseline	3.84 ± 1.78	3.91 ± 1.94	0.919	–
Week 2 of treatment	4.21 ± 1.78	5.22 ± 2.52,*	0.035	−0.46 (−0.98–0.30)
Week 4 of treatment	4.56 ± 1.99*	4.83 ± 2.24*	0.737	−0.13 (−0.72–0.57)
Withdrawal period	4.20 ± 2.18	4.55 ± 2.32*	0.528	−0.16 (−0.83–0.56)
Secondary end-point measures
Stool consistencyb
Baseline	2.61 ± 0.60	2.63 ± 0.62	0.842	–
Week 2 of treatment	2.62 ± 0.72	2.67 ± 0.72	0.594	−0.06 (−0.27–0.16)
Week 4 of treatment	2.97 ± 0.64*	2.86 ± 0.51	0.483	0.19 (0.00–0.35)***
Withdrawal period	2.92 ± 0.61*	2.73 ± 0.73	0.188	0.29 (0.11–0.52)***
Weekly stool quantityc
Baseline	10.09 ± 5.33	11.90 ± 7.11	0.340	–
Week 2 of treatment	11.82 ± 6.02*	14.90 ± 9.43*	0.163	−0.39 (−2.12–2.49)
Week 4 of treatment	13.36 ± 6.54*	14.80 ± 9.74	0.830	−0.17 (−2.13–2.84)
Withdrawal period	12.43 ± 7.38	13.60 ± 9.57	0.737	−0.14 (−2.40–2.83)

Student's t-test (paired samples) or Wilcoxon signed-rank test; *P < 0.05, versus baseline.
Student's t-test (independent samples) or Mann–Whitney U-test **P < 0.10, versus control or versus treatment.
***P < 0.05, versus control.
^aMean ± standard deviation.
^bAssessed by a 5-point scale modified according to Bristol stool form scale:²⁰ 1 indicates hard lumps; 2 lumpy, hard sausage; 3 normal sausage; 4 soft blobs; and 5 watery or mushy.
^cExpressed as number of balls (40-mm diameter) to the first decimal place using ping-pong ball as reference.
^dCohen's d.
CCQ, Chinese Constipation Questionnaire;¹⁹ –, not applicable.

Table 4. Post-hoc exploratory analysis of CCQ component symptoms
CCQ component scores^a	Baseline	Week 4 of treatment	P value
i) False alarm^a
Probiotics	0.89 ± 0.87	0.28 ± 0.63	0.518
Control	0.71 ± 0.70	0.35 ± 0.66	0.518
ii) Less than three defecations per week^b
Probiotics	0.89 ± 1.31	0.65 ± 1.49	0.883
Control	1.12 ± 1.53	0.70 ± 1.54	0.883
iii) Incomplete defecation^b
Probiotics	1.19 ± 0.74	0.40 ± 0.58	0.003*
Control	1.28 ± 0.91	1.05 ± 1.11	0.003*
iv) Lumpy/hard stoolsb
Probiotics	1.29 ± 0.89	0.67 ± 0.94	0.8
Control	1.22 ± 0.84	0.83 ± 0.81	0.8
v) Frequency of laxative usagec
Probiotics	0.02 ± 0.15	0.00 ± 0.00	1.000
Control	0.02 ± 0.15	0.00 ± 0.00	1.000
vi) Abdominal bloatingb
Probiotics	0.78 ± 0.90	0.33 ± 0.64	0.362
Control	0.86 ± 0.90	0.45 ± 0.71	0.362

Student's t-test (independent samples) or Mann–Whitney U-test; *P < 0.05 versus control.
^aMean ± standard deviation.
^bAssessed with 5-point ordinal scale; for (i), (iii), (iv) and (vi): 0 indicates none, 1 mild, 2 moderate, 3 severe, and 4 very severe; for (ii): 0 indicates never, 1 less than half the time, 2 half the time, 3 more than half the time, and 4 all the time.
^cCalculated based on number of times used averaged over a 2-week period.
CCQ, Chinese Constipation Questionnaire.¹⁹