This study enrolled patients from three tertiary care centers in China: The People’s Hospital and the First Affiliated Hospital of Zhengzhou University, Henan, China and the First Affiliated Hospital of Luzhou Medical College, Sichuan, China. This study was conducted from March 2011 to May 2013. IBS-D was diagnosed according to the Rome III criteria (mainly including abdominal pain, diarrhea and without any organic alteration)[12], and anxiety was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth edition (DSM-IV) criteria[13].

Patients were eligible for enrollment if they (1) were aged between 18 and 65 years; (2) had a Hamilton Rating Scale for Anxiety (HAM-A) score between 14 and 24 (moderate anxiety)[14]; (3) had negative routine fecal and occult blood test within 3 mo prior to the study; (4) had no organic diseases by enteroscopy within three months prior to study, or no hepatobiliary and pancreatic diseases by laboratory studies and ultrasonographic evaluations; and (5) received no agents that influence motility of the gastrointestinal tract and digestion and/or anti-anxiety/depressive drugs within 4 wk prior to study entry. Major exclusion criteria were (1) allergy to tandospirone and/or pinaverium bromide; (2) the presence of functional dyspepsia (FD); (3) breast-feeding or pregnancy or be going to be pregnant in the period of the study; (4) clinically significant diseases or any psychiatric disorder other than anxiety; (5) previous abdominal surgery; and (6) daily alcohol consumption > 40 g and/or history of drug abuse. Patients were also excluded if they used other psychotropic medications in the previous week (14 d for monoamine oxidase inhibitors and 28 d for fluoxetine), or required ongoing use of psychotropic medications.

All participating institutions had implemented good clinical practice and were eligible for conduction of clinical trials. The study was compliant with the Declaration of Helsinki, and approved by local ethical committees and institutional review boards at the participating institutions. All study participants or their legal surrogates provided written informed consent.

Eligible subjects were blinded to this study and randomized at an allocation ratio of 1:1 to receive pinaverium (a calcium channel blocker for helping to restore the normal contraction process of the bowel) and tandospirone (arm A) or pinaverium and placebo (arm B). Tandospirone or placebo was given thrice daily at a fixed dose of 10 mg and pinaverium was given thrice daily at a fixed dose of 50 mg. The duration of treatment was 8 wk. Patients who missed more than five consecutive days of treatment in 8 wk of the study (non-compliant) were withdrawn from the trial.

Patients were assessed for eligibility at a screening visit, with eligible patients returning for a baseline assessment approximately one week, and then evaluated at week 8 for a total of four visits. The primary study endpoints were response rates for abdominal pain and diarrhea. The secondary study endpoints were the response rates for anxiety.

Abdominal pain was assessed using a 10-point abdominal pain numeric rating scale (NRS) from 0 (none) to 10 (worst possible pain), and mild (NRS score, 1-3), moderate (NRS score, 4-6) and severe pain (NRS score, 7-10) were then assigned a score of 1, 2 or 3, respectively. In addition, the frequency of abdominal pain was assigned a score of 0, 1, 2 and 3, respectively, if the pain occurred 0, 1-2, 3-4 and ≥ 5 times per week. The abdominal pain score represented the sum of the severity and frequency of pain in a patient. Diarrhea was assessed by stool consistency, frequency and urgency. Normal/hard feces, roughly normal feces, soft feces, loose feces and watery feces were assigned a score of 0, 1, 2, 3 or 4, respectively. Defecations were assigned a score of 0, 1, 2, 3 or 4 if they occurred ≤ 1-2, 3-4, 5-6 and ≥ 7 times daily. The absence or presence of urgency was assigned a score of 0 or 1. The diarrhea score represented the combination of scores for stool consistency, frequency and urgency of a patient. Furthermore, anxiety was evaluated using the HAM-A scale.

For abdominal pain and diarrhea, clinical response was evaluated based on the treatment associated-reduction rate (TARR), which was defined as the post-treatment scores minus the pretreatment scores and then divided by the pretreatment scores and multiplied by 100%. Complete response (CR) had a TARR ≥ 75%, partial response (PR) had a TARR ≥ 50% but <75%, slight response (SR) had a TARR ≥ 25% but < 50% and non-response (NR) had a TARR < 25%. The response rate = CR_{Abdominal pain or diarrhea} + PR_{Abdominal pain or diarrhea}. The overall response rate = CR (abdominal pain plus diarrhea) + PR (abdominal pain plus diarrhea). Clinical response in anxiety was evaluated using the same methods as those for abdominal pain and diarrhea.

Adverse events were monitored at baseline and week 2 and 8 using the Treatment Emergent Symptom Scale (TESS) (NIMH, 1973). Safety assessments were based mainly on the occurrence, frequency, and severity of adverse events and were also based on laboratory parameters including hematology, hepatorenal function, electrolytes, urinalysis, fecal tests and electrocardiography, and treatment-emergent adverse events were recorded. For all adverse events, where necessary, patients were withdrawn from the study.

Sample size calculation was based on the assumption of a 40% response in the arm A vs 20% in arm B using the Z statistic to compare dichotomous variables with α = 0.05 (two-tailed) and β = 0.20. The estimated sample size was 81 patients per arm.

Randomization procedures were performed using a computer code generated by a study statistician who did not have contact with the study subjects. Trial name and all involved parameters were set. Participating centers were pre-added in the system. Common users of the system at each center were granted corresponding permission and user-names in advance. They accessed the system, input patient demographic data, and selected items according to the inclusion/exclusion criteria. The system then automatically decided whether a patient was eligible to participate in the study.

The statistical analysis was carried out using SPSS14.0 software. The statistical analyses were pre-specified and performed on an intention-to-treat basis with the inclusion of all patients who underwent randomization. Both full and per-protocol analyses were used. The full analysis sets included all patients who were randomized to treatment and had a baseline assessment and at least one post-baseline assessment. The per-protocol sets included all evaluable patients who completed at least three weeks of active treatment and were not excluded as protocol violators. Unless otherwise specified, all efficacy results reported herein are based on the full analysis, whereas, for patients who withdrew or were lost to follow-up, we used the last observation carried forward approach. Descriptive statistics were used to summarize some safety measures. The χ² test was used in the statistical analysis and P < 0.05 was considered statistically significant. The homogeneity of the HAM-A score obtained from different investigators was analyzed using Kendall’s W test, with W > 90% considered as having homogeneity.

The study flowchart is shown in Figure 1. Among 274 subjects screened, 200 were eligible for the study. One hundred patients were assigned to receive tandospirone and pinaverium, and 100 to receive tandospirone. Thirty patients (18 in arm A and 12 in arm B) withdrew due to adverse events, lack of efficacy, protocol violation, lost to follow-up or withdrawal consent. In total, 82 patients in arm A and 88 patients in arm B completed the study. Demographic and baseline characteristics of the 170 participants are shown in Table 1. The median age of the study subjects was 45.6 (range: 19-65) years and there were slightly more male patients (54.1%, 92/170) than female patients (45.9%, 78/170). Patients in the two arms were well balanced in demographic characteristics. The mean baseline HAM-A score was 21.8 ± 5.2 for arm A and 20.9 ± 4.7 for arm B with no apparent difference between the two arms (P = 0.21). The mean baseline abdominal pain and diarrhea score was comparable between arm A (8.3 ± 2.0) and arm B (8.0 ± 2.1) (P = 0.18).

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Figure 1 CONSORT diagram showing the flow of subjects in each stage of the trial.

Forty-three patients in arm A and twenty-nine patients in arm B had a 50% or greater reduction in the abdominal pain score at week 8. The response rate was 43.0% for arm A and 29.0% for arm B in the intention-to-treat population (P < 0.05), and was 52.4% for arm A and 33.0% for arm B in the per-protocol sets (P < 0.05) (Table 2).

Fifty patients in arm A and 34 patients in arm B had a 50% or greater reduction in the diarrhea score at week 8. The response rate was 50.0% for arm A and 34.0% for arm B in the intention-to-treat population (P < 0.05), and was 61.0% for arm A and 38.6% for arm B per-protocol sets (P < 0.01) (Table 2).

The overall response rate in patients with abdominal pain and diarrhea was 52.0% for arm A and 37.0% for arm B in the intention-to-treat population (P < 0.05), and was 63.4% for arm A and 42.0% for arm B in the per-protocol sets (P < 0.01) (Table 2).

The Kendall coefficient was > 90%, indicating the homogeneity of the HAM-A score among investigators. Sixty-one patients in arm A and 21 patients in arm B had a 50% or greater reduction in the HAM-A score at week 8. The response rate was 61.0% for arm A and 21.0% for arm B in the intention-to-treat population (P < 0.01), and was 74.4% for arm A and 23.9% for arm B in the per-protocol sets (P < 0.01) (Table 3).

The treatments were well tolerated and no significant adverse events were reported. Treatment-emergent adverse events included somnolence (four in arm A), vertigo (two in arm A), vomiting (one in arm A and one in arm B) and aggravated abdominal pain (one subject in arm B), which resulted in discontinuation (vertigo, vomiting and aggravated abdominal pain) or was resolved two weeks later (somnolence).

The etiology of irritable bowel syndrome (IBS) is unknown. IBS-diarrhea (IBS-D) is an isotype of IBS. No effective therapy is available for IBS-D, and commonly used medications including pinaverium and trimebutine are unfavorable for refractory IBS and are associated with frequent recurrences. Along with the “biomedical model” changing to the “biopsychosocial medical model”, the influence of psychological stress on IBS has been followed with interest.

Recently, many studies found that IBS is associated with psychological stress, anxiety and depression. IBS-D is often accompanied by anxiety. More researchers are now attempting to determine whether IBS-D may respond to anti-anxiety/-depression therapies.

Few randomized, controlled and multicenter studies have focused on the efficacy of anti-anxiety agents in IBS-D patients. As a third-generation anti-anxiety agent, tandospirone has not been used for the treatment of IBS in studies. The authors conducted a prospective, randomized, controlled study to evaluate the efficacy of tandospirone in patients with IBS-D and anxiety.

Tandospirone treatment in IBS-D patients with anxiety could lead meaningful improvements in anxiety as well as a significant reduction in abdominal pain and diarrhea. This may provide a novel therapeutic option for IBS-D patients with anxiety.

This is a well-written paper. The topic is timely and of general interest. This randomized controlled trial could have contribution to the management of IBS-D.