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Kang, Jeen, Koo, Koo, Kim, Kim, Kim, Moon, Park, Baek, Park, Lee, Lee, Choung, and Choi: Efficacy of Fenoverine and Trimebutine in the Management of Irritable Bowel Syndrome: Multicenter Randomized Double-blind Non-inferiority Clinical Study
Original Article

Korean J Gastroenterol 2013;62(5):278-287.

Published online: 4 October 2013

DOI: https://doi.org/10.4166/kjg.2013.62.5.278

Efficacy of Fenoverine and Trimebutine in the Management of Irritable Bowel Syndrome: Multicenter Randomized Double-blind Non-inferiority Clinical Study

Seong Hee Kang, Yoon Tae Jeen, Ja Seol Koo, Yang Seo Koo1, Kyoung Oh Kim2, You Sun Kim3, Seung Yeong Kim, Jeong Seop Moon3, Jong Jae Park, Il Hyun Baek2, Sung Chul Park4, Sung Joon Lee4, Jong Hun Lee5, Rok Seon Choung, Suck Chei Choi6

Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

1Gachon University School of Medicine, Incheon, Korea

2Hallym University College of Medicine, Chuncheon, Korea

3Inje University College of Medicine, Busan, Korea

4Kangwon National University College of Medicine, Chuncheon, Korea

5Dong-A University College of Medicine, Busan, Korea

6Wonkwang University College of Medicine, Iksan, Korea

Correspondence to: Yoon Tae Jeen, Department of Internal Medicine, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Korea. Tel: +82-2-920-5120, Fax: +82-2-953-1943, E-mail: ytjeen@korea.ac.kr

Received 21 August 2013       Revised 14 October 2013       Accepted 23 October 2013

Copyright © 2013 Korean Ophthalmological Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims

Antispasmodic agents have been used in the management of irritable bowel syndrome. However, systematic reviews have come to different conclusions about the efficacy in irritable bowel syndrome. Fenoverine acts as a synchronizer of smooth muscle in modulating the intracellular influx of calcium. We compared fenoverine with trimebutine for the treatment of patients with IBS.

Methods

A multicenter, randomized, double-blind, non-inferiority clinical study was conducted to compared fenoverine with trimebutine. Subjects were randomized to receive either fenoverine (100 mg three times a day) or trimebutine (150 mg three times a day) for 8 weeks. A total of 197 patients were analyzed by the intention-to-treat approach. The primary endpoint was the proportion of patients who had 30% reduction in abdominal pain or discomfort measured by bowel symptom scale (BSS) score at week 8 compared to the baseline. The secondary endpoints were changes of abdominal bloating, diarrhea, constipation, overall and total scores of BSS, and overall satisfaction.

Results

At week 8, fenoverine was shown to be non-inferior to trimebutine (treatment difference, 1.76%; 90% CI, −10.30–13.82; p=0.81); 69.23% (54 of 78 patients) of patients taking fenoverine and 67.47% (56 of 83 patients) of patients taking trimebutine showed 30% reduction in abdominal pain or discomfort compared to the baseline. There results of the secondary endpoints were also comparable between the fenoverine group and the trimebutine group.

Conclusions

Fenoverine is non-inferior to trimebutine for treating IBS in terms of both efficacy and tolerability.

Keywords: Fenoverine, Trimebutine, Irritable bowel syndrome, Clinical study

References

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Fig. 1.
Flow chart of patient disposition.
kjg-62-278f1.tif
Fig. 2.
Comparison of symptoms at baseline, week 4, and week 8 (intention-to-treat analysis) between the fenoverine group and the trimebutine group. Bowel symptom scale (BSS) scores (by visual analogue scale [VAS]) are mean values. *p＜0.0001 for comparison among.
kjg-62-278f2.tif
Table 1.
Demographic and Baseline Characteristics
Characteristic Fenoverine group (n=81) Trimebutine group (n=86) Total (n=167) p-valuea
Age (yr) 37.38±12.32 37.56±12.45 37.47±12.35 0.893b
Sex (female) 42 (51.85) 45 (52.33) 87 (52.10) 0.951c
BMI (kg/m2) 22.97±3.19 23.05±3.14 22.90±3.26 0.823b
History of cholecystectomy 0 (0) 0 (0) 0 (0)  
History of appendectomy 2 (1.2) 0 (0) 2 (2.3)  
History of depression 2 (1.2) 1 (1.2) 1 (1.2)  
History of anxiety 0 (0) 0 (0) 0 (0)  
IBS subtype        
  IBS-C 5 (6.17) 7 (8.14) 12 (7.19) 0.535d
  IBS-D 35 (43.21) 28 (32.56) 63 (37.72)  
  IBS-M 40 (49.38) 50 (58.14) 90 (53.89)  
  IBS-U 1 (1.23) 1 (1.16) 2 (1.20)  

Values are presented as mean±SD or n (%).

IBS, irritable bowel syndrome; IBS-C, IBS-constipation type; IBS-D, IBS-diarrhea type; IBS-M, IBS-mixed type; IBS-U, IBS-unspecified.

a Two sampled t-test or

b Wilcoxon rank-sum test for continuous variables

c chi-square test or

d Fisher's exact test for categorical variables; difference between treatment groups.

Table 2.
Result on Improvement Rate at Week 8 between the Fenoverine Group and the Trimebutine Group
Analysis set Improvement rate (IR)
 Difference of IR Non-inferiority (lower limit＞−20%) ) p-valuea
Fenoverine Trimebutine
Intention-to-treat 54/78 (69.23) 56/83 (67.47) 1.76 (−10.30–13.82) Yes 0.810
Per-protocol 49/65 (75.38) 44/64 (68.75) 6.63 (−6.33–19.60) Yes 0.401

Values are presented as n (%) or value (90% CI).

a Chi-square test.

Table 3.
Comparison of Symptoms Changes between the Fenoverine and Trimebutine Groups after Week 8 (ITT Analysis)
Time point LSM change from baseline
 LSM difference in change p‐ value
Fenoverine Trimebutine
Pain or discomfort −26.86±2.31 −25.24±2.23 −1.63 (−7.99–4.74) 0.614
Bloating −30.03±2.30 −26.57±2.22 −3.46 (−9.80–2.87) 0.282
Constipation −7.89±2.34 −3.79±2.25 −4.10 (−10.59–2.38) 0.214
Diarrhea −30.32±2.39 −28.72±2.31 −1.60 (−8.17–4.97) 0.631
Overall score −32.97±2.23 −29.08±2.16 −3.89 (−10.04–2.26) 0.214
Total score −92.31±6.59 −86.49±6.35 −5.82 (−24.02–12.37) 0.528

Values are presented as mean±SE or value (95% CI). ITT, intention‐ to‐ treat; LSM, least square mean.

Table 4.
The Effect of Fenoverine and Trimebutine according to IBS Subtype (at Week 8)
Time point LSM change from baseline
 LSM difference in change p‐ value
Fenoverine Trimebutine
Pain or discomfort −26.86±2.31 −25.24±2.23 −1.63 (−7.99, 4.74) 0.614
  IBS_D −30.62±3.53 −23.36±4.26 −7.26 (−18.44, 3.92) 0.198
  IBS_M −22.61±3.39 −24.94±2.95 2.33 (−6.53, 11.20) 0.602
Bloating −30.03±2.30 −26.57±2.22 −3.46 (−9.80, 2.87) 0.282
  IBS_D −32.88±3.32 −21.65±4.01 −11.23 (−21.75, −0.72) 0.037
  IBS_M −27.07±3.51 −27.30±3.05 0.23 (−8.95, 9.41) 0.961
Constipation −7.89±2.34 −3.79±2.25 −4.10 (−10.59, 2.38) 0.214
  IBS_D −8.85±3.76 −5.34±4.55 3.51 (−8.62, 15.64) 0.564
  IBS_M −15.18±3.37 −7.60±2.93 −7.57 (−16.41, 1.27) 0.092
Diarrhea −30.32±2.39 −28.72±2.31 −1.60 (−8.17, 4.97) 0.631
  IBS_D −30.70±3.38 −30.74±4.13 0.04 (−10.81, 10.89) 0.994
  IBS_M −33.06±3.73 −28.74±3.25 −4.32 (−14.06, 5.43) 0.381
Overall score −32.97±2.23 −29.08±2.16 −3.89 (−10.04, 2.26) 0.214
  IBS_D −31.54±3.16 −28.05±3.85 −3.49 (−13.63, 6.65) 0.493
  IBS_M −32.99±3.50 −29.57±3.04 −3.42 (−12.59, 5.75) 0.461
Total score −92.31±6.59 −86.49±6.35 −5.82 (−24.02, 12.37) 0.528
  IBS_D −84.25±8.95 −72.53±10.87 −11.72 (−40.34, 16.90) 0.415
  IBS_M −95.16±10.18 −90.06±8.83 −5.10 (−31.74, 21.53) 0.704

Values are presented as mean±SE or value (95% CI). IBS, irritable bowel syndrome; LSM, least square mean; IBS-D, IBS-diarrhea type; IBS-M, IBS-mixed type.

Table 5.
Treatment Satisfaction of Patients (ITT Analysis)
Time point Item Fenoverine group (n=81) Trimebutine group (n=86) p‐ valuea
Week 4 Improvement 58 (71.60) 66 (76.74) 0.579
  Mild 34 (58.62) 42 (63.64)  
  Moderate 18 (31.03) 18 (27.27)  
  Significant 6 (10.34) 6 (9.09)  
  No difference 21 (25.93) 20 (23.26)  
  Aggravation 2 (2.47) 0 (0.00)  
Week 8 Improvement 60 (76.92) 60 (72.29) 0.544
  Mild 23 (38.33) 30 (50.00)  
  Moderate 22 (36.67) 19 (31.67)  
  Significant 15 (25.00) 11 (18.33)  
  No difference 16 (20.51) 18 (21.69)  
  Aggravation 2 (2.56) 5 (6.02)  

Values are presented as n (%).

ITT, intention-to-treat.

a Cochran Mantel-Haenszel chi-square test. Difference between treatment groups after adjusted for gender, age (18–30 years/31–45 years/46–60 years).

Table 6.
Adverse Effects of Drugs
Preferred term Subjects with adverse effects
 p-value
Fenoverine (n=89) Trimebutine (n=95) Total (n=184)
Dizziness 2 (2.25) 0 (0.00) 2 (1.09) 0.232
Headache 4 (4.49) 2 (2.11) 6 (3.26) 0.432
Abdominal pain 2 (2.25) 2 (2.11) 4 (2.17) 1.000
Constipation 2 (2.25) 2 (2.11) 4 (2.17) 1.000
Diarrhea 3 (3.37) 4 (4.21) 7 (3.80) 1.000
Dyspepsia 4 (4.49) 2 (2.11) 6 (3.26) 0.432
Nausea 2 (2.25) 0 (0.00) 2 (1.09) 0.232
AST Iincreased 2 (2.25) 0 (0.00) 2 (1.09) 0.232
CPK increased 4 (4.49) 1 (1.05) 5 (2.72) 0.199
Triglycerides increased 1 (1.12) 2 (2.11) 3 (1.63) 1.000
Common cold 4 (4.49) 5 (5.26) 9 (4.89) 1.000
Nasal congestion 2 (2.25) 0 (0.00) 2 (1.09) 0.232
Skin laceration 0 (0.00) 2 (2.11) 2 (1.09) 0.497
Dermatitis 2 (2.25) 0 (0.00) 2 (1.09) 0.232
Itching 1 (1.12) 1 (1.05) 2 (1.09) 1.000
Wheals 2 (2.25) 0 (0.00) 2 (1.09) 0.232

Values are presented as n (%).

CPK, creatine phosphokinase.

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You Sun Kim
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