Irritable bowel syndrome (IBS) is a functional bowel disorder, characterized by abdominal pain and/or discomfort, associated with changes in bowel habits.1 2,3 4,5 6,7 8 9,10
Several plausible pathophysiological mechanisms have been linked to IBS, including digestive motor disturbances, visceral hypersensitivity, brain-gut axis dysfunction, low-grade inflammation in the gut mucosa, immune activation, and dysbiosis; notwithstanding, most probably IBS is a multifactorial disorder.11–14 15,16 17 18 19
Pinaverium bromide (PB) [N -(bromo-2-dimethoxy-4,5-benzyl)-N ([(dimethyl-6,6 norpinanyl-2)-2 ethoxy]-2 ethyl morpholinium bromide] is a quaternary ammonium derivative that acts as an antispasmodic agent by blocking both muscarinic receptors20 21 l -type (long-lasting)22 23 24
In contrast, simethicone (S), also known as activated dimethicone (dimethylpolysiloxane [(CH3 )2 [Si(CH3 )2 O]n]), is a chemically inert compound of silica gel not absorbed in the gastrointestinal tract. It is physiologically inactive and nontoxic when used orally. Its antifoaming action has been studied in vitro, showing that it has the property of decreasing the surface tension of liquid;25 26,27 28–30 31,32
The effectiveness of 100 mg pinaverium bromide and 300 mg of simethicone (PB+S) as a combination therapy for IBS has previously been shown in a nationwide open-label 4-week clinical trial in Mexico.33
MATERIALS AND METHODS
Study Design
This was a randomized, double-blind, placebo-controlled, parallel group, multicenter study conducted from November 2008 to December 2009. Patients were recruited among those consulting 19 physicians in Mexico (gastroenterologists 55.4%, general surgeons 26.6%, and endoscopists 18%). Those who met eligibility criteria and volunteered for the study were randomized to either PB+S or matching placebo for 12 weeks.
Patient Eligibility
Patients were eligible for inclusion if they were aged18 years or above and 50 years or below, had a body mass index (BMI) <35 kg/m2 , and fulfilled Rome III criteria for IBS. In addition, patients needed to have active IBS at enrollment. Active IBS was considered in the presence of abdominal pain and/or discomfort in at least 2 days during the week before baseline assessment. Although patients were recruited independently of the bowel habit subtype, these were classified according to Rome III as IBS with constipation (IBS-C), diarrhea (IBS-D), mixed (IBS-M), or unsubtyped (IBS-U). Endoscopic examination (either upper endoscopy and/or colonoscopy) was optional at the investigators’ discretion.
Patients were excluded if they had received any treatment for IBS (eg, pure PB, trimebutine, tegaserod, etc.) within the last 30 days before the start of the study protocol; if they presented any alarm symptoms such as anemia, rectal bleeding, unexplained weight loss, general health status impairment; and if they presented any abnormal laboratory parameters and/or vital signs considered as clinically relevant by the investigators. Other exclusion criteria included confirmed or suspected malignancy in any system or organ; women who were pregnant or suspected to be pregnant or breastfeeding; confirmed or suspected rectal or anal stenosis and/or esophageal varices; history of unspecified ulcerative colitis or Crohn’s disease, rectal or anal ulcers, or any related complications and/or celiac disease; history of major upper or lower abdominal surgery (except for appendectomy), gastrointestinal tract malformations, or intestinal obstruction; any severe or unstable organ or systemic condition (eg, diabetes, thyroid disease, cardiovascular disorders), history of alcohol or drug abuse or known allergies to any of the components of the study combination.
Study Medication
Study medication included 100 mg of pinaverium bromide and 300 mg of simethicone (PB+S) packed in gelatine capsules. PB+S and placebo were provided by Takeda Mexico SA de CV (formerly Nycomed) and were identical in shape and color. The assigned treatment was taken twice a day, 10 to 15 minutes before breakfast and dinner.
Randomization and Blinding
Patients were randomized to either PB+S or placebo in a 1:1 ratio. Allocation of patients to treatment groups was carried out using block randomization (blocks of 4). The randomization scheme (stratified by site) was generated using the SAS program (SAS Institute Inc., Cary, NC). This was a triple-blind study, in which all study personnel and participants and the Statistician (J.C.L.-A.) were blinded to the true identity of the treatment assigned until statistical analysis was finalized.
Prohibited Concomitant Medications
Any treatment likely to interfere with the study drug evaluation was prohibited during the study (eg laxatives, antidiarrheal medications, and antispasmodics). If absolutely necessary, patients were allowed to use concomitant treatments for other chronic diseases (eg, controlled diabetes mellitus, systemic arterial hypertension). In addition, patients were advised not to change their regular diet throughout the study period.
Data Collection and Efficacy Endpoints
Study visits were scheduled at randomization (V0, basal assessment) and then at weeks 4 (V1), 8 (V2), and 12 (V3). Throughout the duration of the study, patients had to report in a paper diary their evolution in all efficacy endpoints relating to the previous week. In addition, assessments by investigators were performed at each study visit, as described below.
Primary Efficacy Endpoint
The primary efficacy endpoint was the overall symptom improvement score reported by the patient at the end of the treatment period (week 12: V3) according to the following statement: ‘The treatment helped to improve my bowel problems’, using a 5-point Likert Scale (0: strongly disagree, 1: disagree, 2: neither agree nor disagree, 3: agree, and 4: strongly agree). Efficacy was considered to be achieved if the difference between the treatment groups in the effect size was at least 30%, favoring the PB+S group at V3.
Secondary Efficacy Endpoints
Secondary endpoints included the severity of individual symptoms (abdominal pain and bloating), frequency of Bristol stool types (stool consistency), and QoL. The severity of abdominal pain and bloating was evaluated by the patients using 10-cm Visual Analogue Scale (“nothing” to “extremely intense”), and by the physicians using 5-point Likert Scales (0: nothing, 1: mild, 2: moderate, 4: severe, and 5: very severe). Efficacy was considered to be achieved if the difference (effect size) between treatment groups in terms of severity of abdominal pain and/or bloating, assessed by the patients (Visual Analogue Scale score), was at least 30% (lower severity in the PB+S vs. placebo group) at V3. The same criterion applied to physician’s assessment (Likert Scales).
Stool consistency was assessed by both, the patients (daily) and the physicians (at each visit, evaluating the last 7 d) using the Bristol Scale, which is an appropriate instrument for capturing the stool consistency in IBS trials.34 33
To assess QoL, patients answered the Irritable Bowel Syndrome Quality of Life (IBS-QOL) questionnaire at randomization and at the end of treatment (V0 and V3, respectively). The IBS-QOL is a self-administered questionnaire35 36
Safety
Standard laboratory tests for blood chemistry and hematology were performed at inclusion (V0) and at the end of treatment (V3). Blood chemistry included serum creatinine, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and total bilirubin. Hematology workup included hemoglobin and blood cell count. All adverse events (AEs) and serious adverse events (SAEs) were actively searched and recorded during each study visit.
Statistical Analysis
For statistical analysis, 2 data sets were considered: a) The intention to treat (ITT) data set, including all randomized subjects who participated in at least 1 postbaseline assessment, corresponding to V1 (n=275); and the per protocol (PP) data set, including all patients who did not deviate from the planned protocol and were compliant with at least 80% of the study medication (n=216). Efficacy analyses for the primary and secondary variables were conducted with both ITT and PP data sets. For the ITT set, missing values were imputed by maximum likelihood estimation with regression of available repeated measurements (for intermediate, not at random missing values) or by last-observation-carried-forward method (if dropout). The effect size for each data set is reported; however, no differences in effect sizes were observed between the ITT and PP data sets (differences ranging from 0% to 2%) in all efficacy variables.
Sample Size and Statistical Power
The standardized measure of effect size used in the analysis of variance (ANOVA) was obtained by a root mean square standardized effect.37 33
Descriptive demographics were expressed as mean±SD. A factor analysis linked to a general linear model was used to correct for confounding variables such as age, sex, and BMI. Comparisons between fixed factors (treatment and IBS subtypes) were analyzed by multivariate ANOVA for repeated measurements, incorporating the main outcomes of all visits, using the Fisher post hoc test.
The effect size for overall symptom assessment, abdominal pain, and bloating measured by the patient and physicians, were calculated with partial η2 as follows (SS=squared sums): η2 p Effect /SSEffect +SSError . The partial η2 is used for ANOVA designs that have nonindependent measurements. For easier interpretation, they were transformed to Cohen d .38
The data from the Bristol Scale that were collected by the physicians at each study visit were analyzed as relative frequency distributions (density probability functions), and weekly changes in consistency and frequency were further analyzed according to the IBS subtype over the 12 weeks of treatment. Only the IBS-C, IBS-D and IBS-M subtypes were analyzed due to the high variability that was present in the IBS-U group. Unweighted means of the weekly stool consistency type
Finally, the score of each subscale of the IBS-QOL Scale was calculated using an SPSS program syntax based on the IBS-QOL scoring system. The raw score values were transformed into percentages, which allowed calculating a comparison dimension between subscales in spite of having a different number of questions.
Ethics
The protocol was approved by an independent ethics committee (Teaching, Research and Ethics Committee, General Hospital, Naucalpan-State of Mexico, Mexico), and the study was conducted in accordance with the International Conference on Harmonization, Guidelines for Good Clinical Practices, Declaration of Helsinki, and applicable local regulations. Before entry, all patients received detailed information with regard to the study and signed informed consent.
RESULTS
Patients’ Baseline Characteristics
Between November 2008 and December 2009, 300 patients were screened. Sample attrition is depicted in Figure 1 . Fifteen patients were screen failure (10 because of abdominal hysterectomy, 4 because of BMI >35 kg/m2 , and 1 because of age older than 50 y) and were excluded from the analyses. Therefore, 285 were randomized and entered the 12-week treatment period (women: 83%; age: 36.5±8.9 y old; BMI: 26.7±5 kg/m2 ) (Table 1 ). IBS-C was the most frequent subtype (43.5%) followed by IBS-M (31.2%), IBS-D (23.2%) and IBS-U (2.1%). The majority of patients were from central Mexico and were similarly distributed into the treatment groups.
FIGURE 1: Flowchart of patients through the study. AE indicates adverse event; ITT, intention to treat; PB+S, pinaverium bromide 100 mg plus simethicone 300 mg; SAE, serious adverse event.
TABLE 1: Baseline Characteristics of the Intention to Treat Population
Among the 285 patients who entered the study, 30 withdrew prematurely (13 in the PB+S and 17 in the placebo group) because of AEs (n=1), SAEs (n=2), lack of efficacy (n=4), consent is withdrawn (n=4), lost to follow-up (n=10), or noncompliance with the study treatment (n=9) (Fig. 1 , Table 2 ).
TABLE 2: Reasons For Patients’ Premature Withdrawal From the Study
Efficacy Results
Overall Symptom Improvement
There was a significant improvement over time in the overall symptom assessment in both treatment groups. However, the difference in effect size (Cohen d ) between the groups was a marginal 20% in favor of PB+S over placebo both in the PP and ITT data sets (both, P =0.13) and corresponding to a post hoc power of 20% for this endpoint (Fig. 2 ).
FIGURE 2: Overall irritable bowel syndrome symptom assessment by the patients. Values represent the mean overall improvement scores graded weekly by the patients using a Likert Scale. The total effect size reported as Cohen d was 20% between the treatment groups (P =0.13). Data are expressed as mean±SEM. V0=baseline visit, V1=4 weeks of treatment, V2=8 weeks of treatment, and V3=12 weeks. PB+S indicates pinaverium bromide 100 mg plus simethicone 300 mg.
Individual Symptoms
Patient assessment
PB+S was significantly superior to placebo (P =0.04) in improving the severity of abdominal pain, with a total effect size of 30% (ITT: 29%, PP: 31%) (Fig. 3A ), and with regard to the severity of bloating (P =0.02), with an effect size of 33% (ITT: 32%, PP: 33%) (Fig. 3B ).
FIGURE 3: Severity of abdominal pain and bloating assessed by the patients. Numbers represent the mean values of abdominal pain (A) and bloating (B) severity graded weekly by the patients with a 10-cm VAS. The total effect size reported as Cohen d was 31% for pain (P =0.038) and 33% for bloating (P =0.019), both favoring PB+S over placebo. Data are expressed as mean±SEM. V0=baseline visit, V1=4 weeks of treatment, V2=8 weeks of treatment, and V3=12 weeks. PB+S indicates pinaverium bromide 100 mg plus simethicone 300 mg; VAS, Visual Analogue Scale.
Physician assessment
Abdominal pain showed the highest difference between PB+S and placebo (P =0.009), with an effect size of 36% favoring PB+S (ITT: 36%, PP: 36%) (Fig. 4A ). As for bloating severity, the results were not significant (P =0.09), with a marginal total effect size of 26% (PP: 26%, ITT: 26%) (Fig. 4B ).
FIGURE 4: Severity of abdominal pain and bloating assessed by the physicians. Numbers represent the mean values of abdominal pain (A) and bloating (B) severity assessed by the physicians using 5-point Likert Scales. The baseline adjusted score (analysis of covariance) was 2.8. The total effect size was 36% for pain (P <0.009) and 26% for bloating (P <0.09), both favoring PB+S over placebo. Data are expressed as mean±SEM. V0=baseline visit, V1=4 weeks of treatment, V2=8 weeks of treatment, and V3=12 weeks. PB+S indicates pinaverium bromide 100 mg plus simethicone 300 mg.
Stool Consistency
Frequency distribution
Patients with IBS-C presented a clear predominance of Bristol types 1 and 2 at baseline (Figs. 5A, B ). During the first 4 weeks of treatment, a shift to the right, toward type 4 was observed, and the peak progressively sharpened in the PB+S group (Fig. 5A ). The placebo group showed a less sharpened peak curve, and differences between visits were less noticeable (Fig. 5B ). Thus, patients with IBS-C receiving PB+S showed a clear improvement.
FIGURE 5: Frequency distribution of the BSFS stool types according to IBS subtypes and treatment groups. The density function of probability for each IBS subtype and changes by visits (from A, B, D, E, G, and H) are shown with solid black lines (baseline). Relative differences between placebo and PB+S can be seen on the right side bar figures [IBS-C (C); IBS-D (F); IBS-M (I)]. The clusters of 3 bars represent V1 to V3 for each segment of the AUC. A change of 0.2 at the “y ” axis represents at least 20% change. The positive values (upper directions of the bars) are in favor of PB+S treatment, and the negative values (lower directions of the bars) represent an incremental AUC in favor of placebo. These changes must be compared with the left figures (A, B, D, E, G, and H) to understand the dynamics of the AUC functions. AUC indicates area under the curve; BSFS, Bristol Stool Form Scale; IBS, irritable bowel syndrome ; IBS-C, irritable bowel syndrome with constipation; IBS-D, irritable bowel syndrome with diarrhea; IBS-M, mixed-type irritable bowel syndrome ; PB+S, pinaverium bromide 100 mg plus simethicone 300 mg.
In IBS-D, the frequency distribution of the Bristol stool types at baseline was skewed to the right toward types 5 to 7 (Figs. 5D, E ). Once the treatment started, the curves were displaced toward the left, showing a Bristol stool type centered over type 4 from week 8 onwards (Fig. 5E ). It is worth mentioning that, despite the shift to the left, some subjects with Bristol types 6 and 7 remained as such, but with a lower frequency than at baseline. Both treatment groups showed a similar behavior; notwithstanding, the decrease in the frequency for the remnant Bristol types 6 and 7 was slightly larger with PB+S (Fig. 5D ).
Patients with IBS-M showed a trimodal baseline curve, with 1 peak on types 1 and 2, the second peak on types 3 to 5, and a third one (the most frequent) on types 6 and 7 (Fig. 5G ). The frequency curves shifted rapidly toward the center for both treatment groups (Figs. 5G, H ); however, the PB+S group remained with significantly greater dispersion than the placebo group at the end of the treatment period.
Relative changes
In the IBS-C group, there was a decrease of at least 20% in Bristol 1 to 3 segments of the AUC and a significant increase of Bristol 5 to 7 segments in favor of PB+S (Fig. 5C ). In the IBS-D, there was a decrease in the Bristol 1 to 3 segments in favor of placebo (Fig. 5F ), whereas in IBS-M, there was a slight increase in Bristol 5 to 7 segments of the AUC, favoring PB+S (Fig. 5I ).
IBS-QOL
All subscales and the OV score of the IBS-QOL improved significantly in both treatment groups without any significant difference between them (Table 3 ).
TABLE 3: IBS-QOL Subscale Score Values at Basal and Final Visits Using a Multivariate Approach
Safety Evaluation
Only 3.6% of the total sample (11/300) reported ≥1 AEs, 3.3% (5/150) in the PB+S group and 4% (6/150) in the placebo group. At least 1 non-SAE was reported by 5 patients in the PB+S group and by 6 patients in the placebo group. Only 2 patients experienced SAEs, corresponding to 1 patient in each treatment group (a case of acute pancreatitis in the active group and a brain aneurism in the placebo group); both withdrew from the study prematurely for these reasons (Table 2 ). They represented 0.6% (1/150) of each group. The case of acute pancreatitis was not considered to be related to the study medication.
DISCUSSION
This study demonstrates for the first time in a controlled trial in IBS-Rome III, the efficacy of the combination of PB+S over placebo in the treatment of abdominal pain and bloating assessed by the patients. Although there were no differences between PB+S and placebo on the overall symptom improvement of IBS, the primary outcome measure of this trial, using the frequency distribution of Bristol stool types (consistency), PB+S produced a shift toward Bristol stool types 3 to 5, mainly in the IBS-C and IBS-M patients. Finally, there were no differences in the IBS-QOL scores between the groups, and PB+S was safe and well-tolerated.
Because of the high response to placebo in previous IBS clinical trials, which has been reported in 37.5% (95% CI: 34.4, 40.6),39 40 41–43
The effect size of different monotherapies compared with placebo in different diseases has been previously analyzed in several meta-analyses. Achievement of effect sizes >30% are of relevance particularly for treatments addressing functional gastrointestinal disorders, wherein a significant improvement attributable to placebo can be expected.44,45 d for comparison with our current data.38,46,47 48,49
The significant effect on bloating with PB+S independently of the bowel habit subtype shown in the present study, is an important one, as few treatments have proven to be effective on this common symptom,50 51,52 53 54
The effect of PB+S in the higher frequency of Bristol stool types 3 to 5, mainly in the IBS-C and IBS-M patients, which was observed in the present study, is another important finding. One may speculate that the high dose (300 mg) of S used in the current trial helps patients to increase the frequency of bowel movements by dissolving the gas bubbles, thus facilitating bowel movements. The density function of stool types, which are shown for weekly probabilities used in the current trial (Fig. 5 ), may be useful for simulation analysis, as each IBS subtype shows a different pattern of response to active treatment and placebo when Bristol stool types are used. This density function allows dynamic changes expressed as an increase in relative frequency toward the center of the curve to be observed while treatment time is passing. It is clear that important changes occur in short periods of time, even days, for all IBS subtypes, and then they stabilize around Bristol types 3 to 5.
The fact that we included patients within the age range of 18 years or above and 50 years or below is a limitation, as the efficacy of the PB+S cannot be extrapolated to IBS patients older than 50 years of age. However, in a previous multicenter epidemiological study conducted in Mexico in the same clinics from which the patients for the current study were enrolled, we found a mean age of the IBS-Rome III patients to be at 36.9±8.8 years old.55 56–58
In conclusion, the combined therapy that includes PB+S has proven to be effective for the treatment of IBS. This study supports the concept that a treatment combination is a convenient approach for the treatment of IBS. Future analyses in clinical trials should include these kinds of methodologies for efficacy toward understanding the mechanism of improvement according to the IBS subtypes.
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