Efficacy of Curcuma longa in treatment of postprandial distress syndrome: An open-label randomized-controlled trial

Background: Proton pump inhibitors are effective for functional dyspepsia but ineffective in relieving postprandial distress syndrome. Curcuma longa might be effective for postprandial distress syndrome. The objective of this study was to compare the efficacy of Curcuma longa and simethicone for postprandial distress syndrome in an open-label randomized-controlled trial. Methods: This trial was conducted between July 2018 and February 2019. In total, 78 patients were randomly assigned to receive 4 weeks of treatment with 750 or 1,500 mg oral Curcuma longa per day or 240 mg simethicone per day. The patients assessed their symptoms using the dyspepsia Global Overall Symptom scale at baseline, week 2, and week 4. After stopping medication for 2 weeks, the patients assessed recurrent symptoms and day of recurrence by themselves at the end of week 6. Results: In total, 78 patients underwent randomization (27 in 750 mg Curcuma longa, 26 in 1500 mg Curcuma longa, and 25 in simethicone groups). After 2 weeks, there were no significant differences in all mean changes of symptoms scores (95%CI) of postprandial distress syndrome [-4.1 (-4.5, -2.6) vs -4.3 (-5.2, -3.3) vs -4.2 (-4.8, -3.5), P=0.954]. Over a period of 4 weeks, the reduction in mean scores was greater among participants receiving simethicone (although not statistically significant) compared with two intervention groups [-4.6 (-5.7, -3.6) vs -5.4 (-6.6, -4.1) vs -6.2 (-7.2, -5.2), P=0.122]. The rate of recurrence was significantly lower in simethicone than the two Curcuma longa groups (42.9 vs 45.5 vs 13.6%, P=0.047). There was no serious adverse event reported in all three groups. Conclusions: Curcuma longa had a similar effect on treatment outcomes to simethicone after 2 and 4 weeks, but the recurrence rate of symptoms was significantly higher without serious adverse events. Registration: Registered with the Thai Clinical Trials Registry on 31 January 2018; TCTR20180131001.


Introduction
Dyspepsia is a common functional gastrointestinal disorder which affects 20% of the global population 1 . Although dyspepsia is not a life-threatening condition, it disrupts the quality of life and also socioeconomic impaction for suffering patients 2-4 . The United States population spends $18 billion annually on dyspepsia management 4 . In Thailand, the prevalence of dyspepsia is higher than global prevalence, affecting more than half of the Thai population 5 .
Rome IV criteria for diagnosis classifies functional dyspepsia (FD) into two groups based on symptoms; (1) postprandial distress syndrome (PDS), consisting of postprandial fullness and early satiety, and (2) epigastric pain syndrome (EPS) 6 . Currently, proton pump inhibitors (PPI) are regarded as an effective treatment for FD but ineffective in relieving PDS symptoms 6 . Therefore, physicians frequently consider prescribing other agents for these patients.
Pathogenesis of FD is likely complex and multifactorial. The factors that cause PDS comprise delayed gastric emptying time, impaired gastric accommodation, and gut inflammation 6 . In addition, psychosocial factors such as anxiety, depression and psychiatric disorders also induce pathogenesis 6 .
Curcuma longa is a Thai herb that effectively relieves flatulence 18 . Previous rodent studies [19][20][21] documented that Curcuma longa can decrease gut inflammation via its active ingredient curcumin (R = OCH 3 , R' = OCH 3 ). Curcumin inhibits many proinflammatory enzymes such as cyclooxygenase-2, 5-lipoxygenase, and inducible nitric oxide synthase enzymes etc. Not only does it have an anti-inflammatory effect, but curcumin also increases gastric emptying time and reduces depressive symptoms via the brain-gut axis 22 . Thus, Curcuma longa is commonly used for FD treatment.
Many human studies supported the efficacy of Curcuma longa compared with other agents for treatment of dyspepsia 19,22,23 . A trial in 2007 found that taking a 2-g Curcuma longa capsule daily for four weeks indicated no significant difference with ranitidine for dyspepsia relief 23 . A later study in 2016 showed that addition of curcumin on top of the standard anti-helicobacter regimen in patients with peptic ulcers was safe and improved symptoms of dyspepsia but did not enhance effect on the eradication of Helicobacter pylori infection 24 .
However, no current evidence of the efficacy of Curcuma longa as compared with simethicone for PDS symptoms. Thus, the aim of this present study was to assess the efficacy of Curcuma longa compared with simethicone in patients with PDS.

Patients
Adults (age 20-60 years) with FD, diagnosed during a routine clinical appointment by physicians working at any Social Medicine clinic of Khon Kaen Hospital (Khon Kaen, Thailand), on the basis of Rome IV criteria 6 , were screened by nurse officers for participation then enrolled in the study by the principal investigator. Inclusion criteria included postprandial distress syndrome, no alarm features, and discontinuation of all GI drugs at least one week before randomization. Patients with a history of either simethicone or Curcuma longa allergy, gastric malignancy, gallstone or biliary obstruction, pregnancy, and on breastfeeding period were excluded. Written informed consent was obtained from all patients.

Study design and oversight
The Khon Kaen Hospital Institute Review Board in human research approved the study protocol. This trial was registered with the Thai Clinical Trials Registry on 31 st January 2018; registration number, TCTR20180131001. This randomized, activecomparator, open-label trial was conducted at primary care clusters of Khon Kaen Hospital, and Nam Pong Community Hospital between July 2018 and February 2019. All the authors were involved in the design and performance of the study, which was conducted according to the Declaration of Helsinki. First research assistant (CT) used computer-generated simple randomization and sequentially labeled the number on opaque drug containers for concealment. After the principle investigator (NS) enrolled participants, the second research assistant (MJ) then assigned the concealed interventions in order. There was no deviation from the original trial protocol.

Study treatment and procedures
Patients were randomly assigned to take 750 mg Curcuma longa capsule per day, 1500 mg of Curcuma longa capsule per day or 240 mg of simethicone per day for four weeks. All patients were educated on lifestyle modification, such as stopping drinking and smoking, decreasing spicy foods and the volume eaten per meal, and trying to choose foods with softer consistentcy. Female participants were given a urine pregnancy test, and were excluded if result indicated positive. Baseline characteristics were measured together with BMI and global overall symptom (GOS) scale (described below). Medication was administered orally 30 to 60 minutes after each meal (250 mg (one Curcuma longa capsule per meal), 250 mg (two Curcuma longa capsule per meal), or 80 mg (one simethicone tablet per meal) three times per day). Patient's visits were scheduled at the start of treatment and at the end of 2, 4, and 6 weeks (2 weeks after stopping treatment). All patients discontinued medication after week 4 and reported for recurrence of symptoms at week 6. Patients also completed daily logs of symptoms and adverse events during the week preceding each visit. At each visit, the patient, with the principle investigator (NS), completed the seven-point GOS scale for dyspepsia (which ranges from 1 to 7, with 1 indicating no problem, 2 indicating minimal problem (can be easily ignored without effort), 3 indicating mild problem (can be ignored with effort), 4 indicating moderate problem (cannot be ignored but does not influence my daily activities), 5 moderately severe problem (cannot be ignored and occasionally limits my daily activities), 6 indicating severe problem (cannot be ignored and often limits my concentration on daily activities), and 7 indicating very severe problem (cannot be ignored and markedly limits my daily activities and often requires rest) 25 .
At the last visit, patients were asked to report their recurrence of symptoms and the date of recurrence after discontinuation of treatment.

Endpoints
We focused on PDS symptoms, measured using the GOS scale, so we combined the early satiety score and postprandial score as the composite outcome. The two primary endpoints were the comparison of mean changes of composite outcome between groups from baseline to week 2 and week 4. Secondary end points were rates and durations of recurrences at week 6, and also adverse effectsas assessed by a daily log of adverse events. Post-hoc analyses included the changes from baseline in each group at week 2 and week 4.

Statistical analysis
We calculated that a sample of 69 patients would provide adequate power for the proposed tests in this three-group study using the formula for sample size calculation to compare k means by one-way ANOVA pairwise, 2-sided equality 26 . By substitution of mean in treatment group (µ trt ) = -1.86 24 , mean in control group (µ con ) = -1.30 24 , SD in each group = 0.65 24 , α = 0.05 and β = 0.20, r = 1, n = 22 per group was be derived. SPSS version 24.0 was used. Mean changes from baseline to week 2 and week 4, in GOS scale, were analyzed with one-way ANOVA. Dichotomous endpoints (recurrent rates) were compared among the groups with the use of Chi-squared and Z-test. The duration of symptoms was compared using Kruskall-Wallis test. Means among the groups were also analyzed using one-way ANOVA. To compare means in each group (before and after), a paired t-test was used. Bonferroni post-hoc test was used for post-hoc analysis.

Study participants
A total of 94 patients with functional dyspepsia were assessed for eligibility. There were 16 patients excluded from study due to not meeting inclusion criteria (n= 14) and declined to participate (n=2). A total of 78 patients underwent randomization. There were 27 in the 750 mg Curcuma longa group, 26 in 1500 mg Curcuma longa group and 25 in the simethicone group; there were 6, 4, and 2 patients lost to follow-up in each group, respectively. Intention-to-treat was used for data analysis, with n=21 in 750 mg Curcuma longa, n=22 in 1500 mg Curcuma longa, and n=23 in simethicone ( Figure 1). The characteristics of the patients at baseline were similar across study groups (Table 1). However, in both Curcuma longa groups, patients were slightly overweight (BMI, 23.0-24.9 kg/m 2 ), while in the simethicone group, patients were normal weight (BMI, 18.5-22.9 kg/m 2 ). Participant characteristics, alongside all variables assessed, are available as Underlying data 27,28 .

Secondary outcomes
Comparison of before and after treatment using the GOS scale at the end of 2 weeks. In Table 2, the 750 mg Curcuma longa group showed a significant reduction in all items of GOS scale except nausea which similar in simethicone group. However, in the 1500 mg Curcuma longa group indicated a significant reduction in almost all items of GOS scale except excessive belching and nausea.
Comparison of before and after treatment using the GOS scale at the end of 4 weeks. Over a period of 4 weeks, the  participants among three groups showed significant improvement of their symptoms unless heartburn in 750 mg Curcuma longa, excessive belching and nausea in 1500 mg Curcuma longa, and nausea in simethicone ( Table 2).

Rate of recurrence.
After discontinuing treatment for 2 weeks (washout period), The patients with 1500 mg Curcuma longa reported the highest rate of recurrence, 45.5%, followed by the patients with 750 mg Curcuma longa, 42.9% and the lowest rate was in simethicone group, 13.6% (Table 4). In addition, the rate of symptom recurrence was found statistically significant among three groups (P=0.047).

Duration of recurrence.
There was no significant difference in the duration of recurrence between groups (Table 4).

Adverse events.
There was no any patient who needed to discontinue treatment due to the serious adverse events. Non-serious adverse events were reported in 8 cases (11.9%) from the patients who receive Curcuma longa, including nausea, diarrhea, fever, dizziness and headache (Table 5).

Discussion
The main limitation of this study is that it is an open-label trial, in which blinding was not performed. There was no cointervention, but few attrition biases. Although this is an open-label trial, we performed the allocation concealment and a good randomization that the results of similar characteristics among three treatment groups. Due to validity of the outcomes measured with precise 95% CIs in Table 3, our findings are summarizable and generalizable to all similar settings and populations.
The efficacy of Curcuma longa showed non-inferiority to simethicone according to the composite outcome of PDS symptoms among three treatment groups had no significant difference at week 2 and week 4. Our findings were similar to the findings of Sirijarugul and Pongchaidecha 23 and Khonche et al 24 .
The study data also provide evidence of four important aspects of dyspepsia treatment. First, from baseline characteristics, there were more female participants. This is similar to the most recent meta-analysis in 2014 1 . Data from this prior study indicated a greater prevalence of dyspepsia in the women from 312,415 samples (OR 1.24; 95% CI 1.13 to 1.36) 1 . The other characteristics were also accordant with previous studies 23,24 .
Second, our findings showed that Curcuma longa groups were also effective in different doses. Suprisingly, the 1500 mg group developed a higher symptom recurrence rate. Therefore, 750 mg Curcuma longa per day should be the recommended dose for FD.
Third, the simethicone group developed significant lower rate of symptom recurrence. To explain this phenomenon, these patients were normal weight from obesity Asian criteria (BMI, 18.5-22.9 kg/m 2 ) 29 . On the other hand, in both Curcuma longa groups, patients were slightly overweight (BMI 23.0-24.9 kg/m 2 ) that associated with the greater prevalence of GI symptoms 30,31 .
Finally, the three treatment groups were safe for all participants, similar to previous studies 19,[22][23][24] , indicating that Curcuma longa can be used generally.
Strengths of this study were; this was a randomized controlled trial that had a high quality of evidence, we studied a washout period, and we are the first who compare the efficacy of Curcuma longa and simethicone. On the other hand, our limitations were; having lower sample size than calculated due to loss to follow up patients that might have less power of study and dyspepsia associated with the multifactorial factor such as environment, various types of food, and participant behaviors. Despite we randomly assigned the treatments, it could not eliminate all confounders. So the outcomes could be imprecise.

Conclusion
In conclusion, Curcuma longa had significant effects on reduction of FD, similar to simethicone after 2 and 4 weeks, but the recurrence rate (i.e. the proportion of reappearance) of dyspeptic symptoms was slightly significantly higher without serious adverse events. This project contains the data dictionary for the underlying data, described above.

Acknowledgments
Authors appreciate all supports from Khon Kaen Hospital, patients, volunteers, first research assistant (Chutarat Tanchonnang) second research assistant (Manipa Jamsuwan) and all the staffs of all clinics involving in this study.

Somsook Santibenchakul
Department of Obstetrics and Gynaecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Very nice work! Just one issue: I was curious about the following sentence.
The patients with 1500 mg Curcuma longa reported the highest rate of recurrence, 45.5%, followed by the patients with 750 mg Curcuma longa, 42.9% and the lowest rate was in simethicone group, 13.6% (Table 4).
The percentages stated here were different from those in table 4. Could you please explain?

Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound? Yes

If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Yes

Are the conclusions drawn adequately supported by the results?
Yes