Is Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1–3 years old? A randomized, parallel, double-blinded, placebo-controlled, two arm clinical trial

Abu Sadat Mohammad Sayeem Bin Shahid; Shahnawaz Ahmed; Sampa Dash; Yuka Kishimoto; Sumiko Kanahori; Tahmeed Ahmed; Abu Syed Golam Faruque; Mohammod Jobayer Chisti

doi:10.1371/journal.pone.0280934

. 2023 Jan 27;18(1):e0280934. doi: 10.1371/journal.pone.0280934

Is Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1–3 years old? A randomized, parallel, double-blinded, placebo-controlled, two arm clinical trial

Abu Sadat Mohammad Sayeem Bin Shahid ^1,^*, Shahnawaz Ahmed ², Sampa Dash ³, Yuka Kishimoto ⁴, Sumiko Kanahori ⁴, Tahmeed Ahmed ¹, Abu Syed Golam Faruque ¹, Mohammod Jobayer Chisti ¹

Editor: Samuel Bosomprah⁵

PMCID: PMC9882758 PMID: 36706123

Abstract

Background

Fibersol-2 has innumerable beneficial effects on human health. It is a fermentable, non-viscous, water-soluble, indigestible dextrin containing 90% dietary fiber produced from corn starch. We aimed to evaluate whether additional intake of Fibersol-2 along with oral rehydration solution treatment can reduce the duration of watery diarrhea and daily stool output in children 1–3 years as well as recovery of such children within 72 hours, compared to placebo.

Methods

This placebo-controlled double-blinded, randomized parallel two arm trial conducted in Kumudini Women’s Medical College Hospital in rural Bangladesh between March and October, 2018 used 5 gm of either Fibersol-2 or placebo dissolved in 50-ml drinking water which was given orally to ninety-two children with watery diarrhea on enrollment twice daily for a period of 7 days. Randomization was done using a randomization table. We randomly allocated 45 (49%) and 47 (51%) children in Fibersol-2 and placebo groups, respectively. Outcome measures were duration of resolution of watery diarrhea, daily stool output and the proportion of children recovered within 72 hours. Primary and safety analyses were by intention to treat. This trial was registered at ClinicalTrials.gov, number NCT03565393.

Results

There was no significant difference observed in terms of duration of resolution of diarrhea (adjusted mean difference 8.20, 95% CI -2.74 to 19.15, p = 0.14, adjusted effect size 0.03); the daily stool output (adjusted mean difference 73.57, 95% CI -94.17 to 241.32, p = 0.38, adjusted effect size 0.33) and the proportion of children recovered within 72 hours (adjusted odds ratio 0.49, 95% CI = 0.12 to 1.96, p = 0.31, adjusted risk difference -0.06 (95% CI -0.19 to -0.06), after regression analysis between Fibersol-2 and placebo.

Conclusion

No beneficial role of Fibersol-2 was observed in diarrheal children aged 1–3 years.

Trial registration

This trial is registered at ClinicalTrials.gov, number NCT03565393. The authors confirmed that all ongoing and related trials for this drug/intervention are registered. https://clinicaltrials.gov/ct2/show/NCT03565393.

Introduction

Dietary fiber, a non-digestible carbohydrate, has been used in decades for the beneficial effect on health with physiological importance because such compounds have low energy values. These indigestible carbohydrates generally reach the large intestine in an undigested and unabsorbed forms and are often used in many low-calorie food and beverages [1–3].

Researchers have stated that dietary fiber, especially digestive-resistant maltodextrin has innumerable beneficial effects on human health, such as improving intestinal regularity by increasing faecal bulk, stimulating peristalsis and shortening gastrointestinal transit time [4,5]. Fibersol-2 (resistant maltodextrin or indigestible dextrin) is a non-viscous, water-soluble, fermentable dietary fiber produced from corn starch.

A prebiotic beneficially affects the host by enhancing the growth of large bowel bacteria, including Bifidobacterium and Lactobacillus, thus conferring beneficial effects on the health of the host [6]. Prebiotics are known to result in a decrease in pathogenic bacteria, such as Clostridium perfringens. They can act by decreasing pH causing increased production of short chain fatty acid (SCFA) resulting in enhanced competition for nutrients. Fibersol-2 reaches the large intestine and half of it undergoes fermentation by intestinal flora [7,8]. Ohkuma et al. in 1990 observed changing pattern of microbial flora caused by administration of resistant maltodextrin. and further studies conducted by other researchers confirmed that Fibersol-2 has pre-biotic activity in humans [9–11]. Hypothetically, Fibersol-2 as a prebiotic is assumed to exert the beneficial effect on mucosal immune response to the intestine. The evidence showed that partially hydrolyzed guar gum (PHGG) with added oral rehydration solution (ORS) can enhance early recovery of acute diarrhea in severely malnourished children in terms of reducing the duration of diarrhea and stool output [12].

Although fiber rich diet is widely recommended, the efficacy of fiber supplements has not been tested sufficiently in children. Fibers are expected to be fermented by colonic bacteria producing SCFAs those will stimulate sodium and water absorption in the colon leading to early recovery from diarrhea [13].

According to a systematic review, children admitted to hospital with diarrhea and dehydration, reduced osmolarity rehydration solution with diarrhea is associated with reduced need for unscheduled intravenous infusions, lower stool volume, and less vomiting in comparison with standard world health organization (WHO) rehydration solution. Children with acute diarrhea, therefore, may be benefited from a reduced osmolarity ORS [14–17]. Dietary fibers can act by changing the nature of the contents of the gastrointestinal tract and by changing how other nutrients and chemicals are absorbed [18]. Advantages of consuming fiber are the production of healthy compounds during fermentation, increased bulk of stool, softening of stool, shortening of transit time through the intestinal tract, blocking of intestinal mucosal adherence, translocation of potentially pathogenic bacteria, and modulation of intestinal inflammation [19–23].

We aimed to examine whether additional intake of Fibersol-2 along with ORS can reduce the duration of watery diarrhea and daily stool output in children aged 1–3 years as well as recovery of such children within 72 hours, compared to placebo.

Materials and methods

Ethical consideration

Institutional review board of International Centre for Diarrhoeal Disease Research, Bangladesh approved the study (PR-16091). Informed written consent was obtained from parents or caregivers prior enrolling the participating children.

Study design

A placebo-controlled, randomized, double-blinded parallel clinical trial to examine whether Fibersol-2 along with ORS can reduce the duration of watery diarrhea and daily stool output in children aged 1–3 years as well as proportion of such children recovered within 72 hours was conducted during the period of March to October, 2018. After screening, ninety-five children with acute watery diarrhea were randomly assigned to either groups, irrespective of sex and socio-demographic background (Fig 1).

Eligibility criteria for the clinical efficacy trial

Inclusion criteria

Children aged 1–3 years of either sex having acute watery diarrhea [24] with no sign or some signs of dehydration
Received written informed consent from parents

Exclusion criteria

Children with bloody diarrhea, severe diseases (severe sepsis, meningitis, severe pneumonia with respiratory distress requiring intensive care and ancillary support such as oxygen inhalation, oro-pharyngeal suction etc.)
The child is in a situation that could interfere with the optimal participation to the study or constitute a particular risk of non-compliance
Currently participating in another clinical trial, and
Parents refused to give informed written consent

Study setting

We conducted this study in a rural tertiary facility in Bangladesh located nearly sixty kilo-meter northwest of Dhaka, the capital city of Bangladesh. Kumudini Women’s Medical College Hospital, the tertiary level sentinel health facility, is one of the oldest and largest tertiary level facilities in rural Bangladesh having 750 beds. We conducted this study in rural Bangladesh which represents nearly 80% of our total national population.

Intervention

Fibersol-2 (digestion resistant maltodextrin) or placebo (regular maltodextrin) dissolved in 50-ml drinking water were given orally to the study children twice daily in the morning and evening (10 gm per day) for 7 days.

Outcomes

Outcome measures were duration of resolution of watery diarrhea, daily stool output and the proportion of children recovered within 72 hours.

Sample size determination

Based on the results of a previous clinical trial on modified ORS solution in children with watery diarrhea [12], we anticipated that there would be a 25% relative reduction in 48-hour stool output after receiving Fibersol-2, compared to placebo. Considering 5% level of significance, 90% power and 10% drop out, the sample size was estimated to be 46 in each group. Thus, on the basis of the reduction in stool output, the total sample size was estimated to be 92.

Randomization and masking

An experienced researcher from icddr,b, not involved in this study, prepared the randomization list using the randomization table [25]. The same independent researcher ensured the blinding by naming the study drugs ‘A’ and ‘B’ and the study personnel did not know the identity of ‘A’ and ‘B’. The sequential randomization of ‘A’ and ‘B’ was indicated on a slip of paper, kept inside the sealed envelope. The independent researcher involved in the process wrote the sequential study number outside those envelopes. The sealed envelopes were kept under lock and key by the research team. After obtaining the informed written consent from the parents or caregivers the research physician opened the sealed envelopes in front of a non-study health worker as per randomization list and allocated the concealment as ‘A’ or ‘B’. Thus, the interventions were masked for both the study investigators and the caregivers.

At the end of the study it is revealed that study group ‘B’ belongs to Fibersol-2 and study group ‘A’ belongs to placebo. Study group ‘B’, received Fibersol-2 (5 gm) dissolved in 50 ml drinking water, twice daily (suitable dose from the tolerability and acceptability trial of phase 1). Study group ‘A’, received placebo (5 gm of regular maltodextrin) dissolved in 50 ml drinking water twice daily (same dose of Fibersol-2).

Patient management

If any child vomited within 10 minutes of oral intake, we repeated the similar dose for consumption after an hour of rejection. If the child vomited again within 10 minutes of previous intake, we stopped giving the intervention further. A structured questionnaire was administered at the time of enrollment to mothers to collect information on demographics, socio-economic context, clinical features and antimicrobial use prior to hospitalization and during hospitalization. Study physicians took detailed medical history of the enrolled children to determine the duration and type of diarrhea and stool frequency. Physical examination was conducted on enrollment and on the last follow-up day of 7-day observation period. Nutritional status of the study children was also measured using the standard procedures. Dehydration was assessed according to the WHO guidelines followed in the hospital [26]. In children with some dehydration, the fluid deficit was corrected with ORS in an amount 10 ml/kg/hour for the first hour, then 5 ml/kg/hour until the deficit was corrected. In addition, ongoing stool losses were replaced with ORS 5–10 ml/kg after each watery stool. For high purging children, the ORS intake was adjusted according to the ongoing stool loss. During discharge from hospital caregivers were instructed to give their child ORS @ 1 tsf/kg per loose stool, if any, during the rest of 7-days intervention period at home. Mothers were advised to continue breastfeeding at home. In addition to collect information from the hospital, our field research staff visited the households of study children to assemble information about their health status by administering the field-tested questionnaire.

Our study staff member kept observing and monitoring vital clinical parameters of the study participants at periodic intervals round the clock (24 hours) during their hospital stay. To ensure proper patient care, they maintained a roster duty with staff members. Study physicians were responsible for consenting as well as clinical assessments related to their health status, including improvements of their dehydration status and provided treatment. Apart from that they also provided treatment for other illness, when required. Study nurses were accountable for keeping vital signs and providing study drug to the children in front of their parents or caregivers at hospital and community with appropriate dose and on schedule time. They also closely monitored the participants for any unwanted events and informed study physicians.

The study consisted of 7-days intervention period followed by observation period of 7 days (in total 14 days). We discharged the study children from the hospital as soon as dehydration was corrected and there was improvement of the concurrent illness. Sometimes on request we allowed the parents or caregivers to take away their children from hospital before complete recovery from diarrhea, if the child was playful and there was no dehydration. Our study nurses along with field organizers visited the household of the study participants and monitored the vital signs of the study children twice daily. They also measured the stool output every 8 hours interval at home during the intervention period of 7 days and once daily during the observation period for next 7 days.

Measurements

Fluid intake

ORS was given to the study participants after measuring with a calibrated cylinder and the amount of intake was recorded 8 hours interval.

Output (stool, urine, and vomitus)

In the hospital, stool was collected in a bucket of known weight beneath the cholera cot with a central hole and was measured at every 8 hours interval with an electronic scale having a precision of 1 gm. Urine was collected by a pediatric urine collector bag and measured with a calibrated cylinder in ml. Vomitus was collected in a pre-weighted bowl and measured with an electronic scale in gram. Clinical evaluation was performed in every morning and evening. Resolution of diarrhea was defined as the passage of two consecutive soft/formed stools or no stool for last 24 hours. Caregivers collected stool and urine in poly bag every 8 hours interval as per direction from the research team at home. Our health workers measured the stool and urine output every 8 hours interval after being collected by caregivers at home. Therapeutic success was defined as the cessation of diarrhea within 7 days of inclusion in the study intervention. Duration of diarrhea was calculated in hours from the time of randomization to the last watery or loose stool within 7 days. Children were considered withdrawn from the study when their parents or legal guardian withdrew consent, or the child was withdrawn from the study for the treatment of any complications. Data (intake and output) of such children was not included in the analysis (per protocol analysis).

Operational definitions

Acute watery diarrhea

Passage of three or more abnormally loose or watery stool in the last 24 hours.

Resolution of diarrhea

Defined as the passage of two consecutive soft/formed stools or no stool for the last 24 hours.

Abdominal distension

Accumulation of air (gas) or fluid in the abdominal cavity causing its outward expansion beyond the normal girth of the stomach and waist. Distension is the objective enlargement of the abdomen.

Rumbling

Noise produced by the movement of the gastrointestinal contents while propelling through the small intestine by a series of muscle contractions. It was measured through history taking from the parents and by performing abdominal auscultation.

Bloating

Bloating is the presence of abnormal general swelling or increase in the diameter of the abdominal area. It was also evaluated by regular measurement of abdominal girth. It is the subjective feeling that the abdomen feels more fuller than it should be, but does not necessarily mean that the abdomen is enlarged.

Stool consistency

Physical form of the stool, such as solid, paste, loose/watery, identified by the parents as well as treating physicians.

The consistency of each stool was assessed and recorded as follows:

Type 1 (Formed) = Stool having its own shape.
Type 2 (Soft) = Stool that can’t be poured, but takes the shape of a container.
Type 3 (Watery/liquid) = Stool that can be spilled from one container to another.

Type 1 and type 2 stools were considered normal, not constitute as diarrhea. Type 3 stool was usual in bacterial/viral diarrhea.

Statistical analysis

All the data were entered into SPSS for Windows (version 20.0; SPSS Inc., Chicago) and Epi-Info (version 7.0, USD, Stone Mountain, GA). For categorical variables, differences in proportions were compared by the Chi-square/Fisher’s exact test and represented by frequency with percentage. For normally distributed continuous variables, differences of mean were compared by the Student’s t-test and represented by mean with standard deviation (SD); the Mann-Whitney test was used for comparison of differences for those continuous variables that were not normally distributed and represented by median with inter quartile range (IQR) (Tables 1 and 2). For continuous outcome variables, we calculated unadjusted and adjusted mean differences with 95% confidence intervals (CIs) and adjusted effect sizes by multivariable linear regression model (Table 3). For categorical outcome variable, we calculated unadjusted and adjusted odds ratios (OR) by multivariable binary logistic regression model. We also calculated adjusted risk differences (Table 4). Additionally, we evaluated OR, CIs and p-values between placebo and intervention groups for abdominal symptoms in different intervention days with doses (Table 5). Statistical significance for all analyses was taken at 5% level (p<0·05).

Table 1. Baseline characteristics.

Characteristics	Placebo (n = 47)	Fibersol-2 (n = 45)
Age in months (median, IQR)	15 (13, 21)	14 (12, 21)
Male gender	29 (62)	28 (62)
Family size (mean, SD)	5.02 (1.54)	5.60 (1.96)
Number of sleeping rooms (mean, SD)	2.15 (0.98)	2.33 (1.13)
Maternal illiteracy	1 (2)	1 (2)
Paternal illiteracy	3 (6)	6 (13)
Use of non-sanitary facility	11 (23)	9 (20)
Deep tube well	39 (83)	39 (86)
Wealth quintile
Rich	10 (21.3)	8 (17.8)
Upper middle	9 (19.1)	10 (22.2)
Middle	12 (25.5)	6 (13.3)
Lower middle	7 (14.9)	12 (26.7)
Poor	9 (19.1)	9 (20.0)
Domestic livestock
Cow / Buffalo	18 (38)	15 (33)
Goat	5 (10)	4 (9)
Chicken / Duck	23 (49)	22 (49)
Pigeon	3 (6)	5 (11)
Cat	46 (98)	43 (96)
Dog	44 (94)	45 (100)
Anthropometry Height in cm (mean, SD)	78.61 (4.95)	78.79 (6.23)
Weight in kg (mean, SD)	9.73 (1.47)	9.82 (1.66)
MUAC in cm (mean, SD)	14.97 (1.45)	14.74 (1.09)
Nutritional status
Height-for-age z-score (mean, SD)	-0.58 (1.19)	-0.51 (1.07)
Weight-for-length/height z-score (mean, SD)	-0.53 (1.20)	-0.47 (1.14)
Weight-for-age z-score (mean, SD)	-0.67 (1.19)	-0.59 (1.03)
Stunting	3 (6)	3 (7)
Underweight	7 (15)	2 (4)
Wasting	7 (15)	2 (4)

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Table 2. Volume of ORS intake, amount of vomitus, urine output and stool output during the intervention period of 7 days.

Variables	Placebo (n = 47)	Fibersol-2 (n = 45)
ORS intake in ml (mean, SD) (median, IQR)	1690.43 (1528.25) 1230 (700, 1970)	2015.80 (2108.40) 1380 (870, 2225)
*Amount of vomitus in gram (mean, SD)	66.83 (120.15)	38.96 (60.85)
Urine output in ml (mean, SD) (median, IQR)	2481.04 (282.07) 2460 (2305, 2630)	2429.91 (337.95) 2406 (2288, 2640)
Stool output in gram in hospital (mean, SD) Stool output in gram at home (mean, SD)	701.85 (505.40) 393.46 (208.50)	898.42 (834.78) 424.51 (280.46)

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Values were expressed as mean (SD), (median, IQR); SD, Standard deviation; IQR, Inter quartile range; ORS, Oral rehydration solution.

* Only 21 children in group A and 19 children in group B had vomiting.

Table 3. Regression analysis for continuous outcomes.

Characte ristics	Fibersol-2	Place bo	Unadjusted difference		Adjusted difference		Adjusted effect size
Characte ristics	Fibersol-2	Place bo	95% CI	p-value	95% CI	p-value
Duration of resolution of diarrhea mean (SE)	44.15 (3.65)	35.68 (3.98)	8.47 (-2.28 to 19.23)	0.121	8.20 (-2.74 to 19.15)	0.140	0.03
Daily stool output mean (SE)	794.64 (82.40)	680.0 (59.20)	114.60 (-85.66 to 314.86)	0.259	73.57 (-94.17 to 241.32)	0.386	0.33

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Data were mean (SE) unless otherwise stated. SE, Standard Error.

Table 4. Regression analysis for categorical outcome.

Characteristics	Fibersol-2	Placebo	Unadjusted odds ratio		Adjusted odds ratio
Characteristics	Fibersol-2	Placebo	95% CI	p-value	95% CI	p-value	Adjusted risk difference (95% CI)
Patients recovered within 72 hours	37 (82)	43 (91)	0.43 (0.12 to 1.54)	0.196	0.49 (0.12 to 1.96)	0.313	-0.06 (-0.19 to -0.06

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Data were n (%), unless stated otherwise.

Table 5. Characteristics of gastrointestinal symptoms after ingestion of study drugs during the intervention period in both the groups.

Characteristics	Placebo (n = 47)	Fibersol-2 (n = 45)	OR (95% CI)	p-value
At day 1, 1^st dose
Presence of abdominal distension	1 (2)	0 (0)	-	0.511
Presence of abdominal pain	1 (2)	2 (4)	0.48 (0.05–5.09)	0.484
Presence of abdominal rumbling	3 (6)	1 (2)	2.87 (0.31–26.60)	0.325
Presence of abdominal bloating	6 (13)	3 (7)	1.92 (0.51–7.20)	0.265
At day 1, 2^nd dose
Presence of abdominal distension	0 (0)	2 (4)	-	0.237
Presence of abdominal pain	1 (2)	1 (2)	0.96 (0.06–14.85)	0.742
Presence of abdominal rumbling	1 (2)	1 (2)	0.96 (0.06–14.85)	0.742
Presence of abdominal bloating	2 (4)	2 (4)	0.96 (0.14–6.51)	0.675
At day 2, 1^st dose
Presence of abdominal distension	0 (0)	3 (7)	-	0.113
Presence of abdominal pain	1 (0)	0 (0)	-	0.511
Presence of abdominal rumbling	1 (2)	1 (2)	0.96 (0.06–14.85)	0.742
Presence of abdominal bloating	1 (2)	4 (9)	0.24 (0.03–2.06)	0.167
At day 2, 2^nd dose
Presence of abdominal distension	0 (0)	1 (2)	-	0.489
Presence of abdominal pain	0 (0)	1 (2)	-	0.489
Presence of abdominal rumbling	2 (4)	1 (2)	1.92 (0.18–20.39)	0.516
Presence of abdominal bloating	3 (6)	2 (4)	1.44 (0.25–8.20)	0.521
At day 3, 1^st dose
Presence of abdominal distension	1 (2)	0 (0)	-	0.511
Presence of abdominal pain	0 (0)	2 (4)	-	0.237
Presence of abdominal rumbling	2 (4)	1 (2)	1.92 (0.18–20.39)	0.516
Presence of abdominal bloating	1 (2)	2 (4)	0.48 (0.05–5.09)	0.484
At day 3, 2^nd dose
Presence of abdominal distension	0 (0)	0 (0)	-	-
Presence of abdominal pain	1 (2)	1 (2)	0.96 (0.06–14.85)	0.742
Presence of abdominal rumbling	3 (6)	1 (2)	2.87 (0.31–26.60)	0.325
Presence of abdominal bloating	1 (2)	1 (2)	0.96 (0.06–14.85)	0.742
At day 4, 1^st dose
Presence of abdominal distension	0 (0)	0 (0)	-	-
Presence of abdominal pain	0 (0)	0 (0)	-	-
Presence of abdominal rumbling	2 (4)	1 (2)	1.92 (0.18–20.39)	0.516
Presence of abdominal bloating	2 (4)	1 (2)	1.92 (0.18–20.39)	0.516
At day 4, 2^nd dose
Presence of abdominal distension	0 (0)	0 (0)	-	-
Presence of abdominal pain	0 (0)	0 (0)	-	-
Presence of abdominal rumbling	2 (4)	0 (0)	-	0.258
Presence of abdominal bloating	2 (4)	2 (4)	0.96 (0.14–6.51)	0.675
At day 5, 1^st dose
Presence of abdominal distension	0 (0)	0 (0)	-	-
Presence of abdominal pain	0 (0)	0 (0)	-	-
Presence of abdominal rumbling	1 (2)	2 (4)	0.48 (0.05–5.09)	0.484
Presence of abdominal bloating	1 (2)	1 (2)	0.96 (0.06–14.85)	0.742
At day 5, 2^nd dose
Presence of abdominal distension	0 (0)	1 (2)	-	0.489
Presence of abdominal pain	0 (0)	1 (2)	-	0.489
Presence of abdominal rumbling	0 (0)	1 (2)	-	0.489
Presence of abdominal bloating	1 (2)	2 (4)	0.48 (0.05–5.09)	0.484
At day 6, 1^st dose
Presence of abdominal distension	0 (0)	1 (2)	-	0.489
Presence of abdominal pain	0 (0)	0 (0)	-	-
Presence of abdominal rumbling	0 (0)	0 (0)	-	-
Presence of abdominal bloating	1 (2)	2 (4)	0.48 (0.05–5.09)	0.484
At day 6, 2^nd dose
Presence of abdominal distension	0 (0)	0 (0)	-	-
Presence of abdominal pain	0 (0)	0 (0)	-	-
Presence of abdominal rumbling	0 (0)	0 (0)	-	-
Presence of abdominal bloating	0 (0)	0 (0)	-	-
At day 7, 1^st dose
Presence of abdominal distension	0 (0)	2 (4)	-	0.237
Presence of abdominal pain	0 (0)	0 (0)	-	-
Presence of abdominal rumbling	1 (2)	0 (0)	-	0.511
Presence of abdominal bloating	0 (0)	2 (4)	-	0.237
At day 7, 2^nd dose
Presence of abdominal distension	0 (0)	0 (0)	-	-
Presence of abdominal pain	0 (0)	1 (2)	-	0.489
Presence of abdominal rumbling	0 (0)	0 (0)	-	-
Presence of abdominal bloating	0 (0)	0 (0)	-	-

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Values were expressed as number of subjects as n; p-value was assessed by t-test or Chi-square test.

Results

Distribution of gender, family size and household wealth quintiles were comparable between the groups. Other indicators of socio-economic-demographic characteristics, like maternal and paternal illiteracy, number of sleeping rooms, use of non-sanitary facilities and use of deep tube well water for domestic purposes were also comparable between the groups (Table 1). Diarrheal children who received placebo or Fibersol-2 were similar at enrollment in regards to age, mid upper arm circumference (MUAC), height/length, body weight, length/height-for-age z-score, weight-for-length/height z-score, and weight-for-age z-score, respectively. Distribution of underweight, wasting, and stunting was comparable between the groups (Table 1). Throughout the intervention period the volume of ORS intake was 1230 (700, 1970) ml vs. 1380 (870, 2225) ml among the children who received placebo and Fibersol-2, respectively (Table 2). The amount of vomitus, urine and stool output in hospital and at home in both the groups was also comparable (Table 2). There was no significant difference observed in terms of duration of resolution of diarrhea (adjusted mean difference 8.20, 95% CI -2.74 to 19.15, p = 0.14, adjusted effect size 0.03); the daily stool output (adjusted mean difference 73.57, 95% CI -94.17 to 241.32, p = 0.38, adjusted effect size 0.33) (Table 3) and the proportion of children recovered within 72 hours (adjusted OR: 0.49, 95% CI = 0.12 to 1.96, p = 0.31, adjusted risk difference -0.06 (95% CI -0.19 to -0.06), after regression analysis between Fibersol-2 and placebo (Table 4).

No significant difference was observed in terms of development of gastrointestinal symptoms, such as abdominal pain, distension, rumbling and bloating during the intervention period of 7 days between the two groups (Table 5).

Safety of the trial

We evaluated same number of healthy and diarrheal children (30 each) 1–3 years old for the digestive tolerability and acceptability of Fibersol-2 before initiation of the randomized trial, where we found the product was safe and well tolerated based on disappearance or improvements in abdominal symptoms, like distension, pain, rumbling and bloating in both groups of children (journal.pone.0274302), henceforth these were the variables selected to monitor the safety of the trial.

Discussion

In our randomized double-blind placebo-controlled parallel trial we aimed to evaluate the efficacy of Fibersol-2 along with ORS treatment to reduce the duration of watery diarrhea and stool output in children of 1–3 years as well as recovery of children within 72 hours where no beneficial role of Fibersol-2 was seen in reducing the outcomes, compared to placebo. The mean duration of resolution of diarrhea from the enrollment was comparable between placebo and Fibersol-2. All of the study participants recovered from watery stool within 7-day intervention period in the study. We do not have any ready reference to explain such a result other than relatively small sample size that caused reduced power of the study. There was the longer trend of diarrheal duration on enrollment observed in study children received Fibersol-2 compared to placebo. Interestingly, the result showed that the diarrheal duration on enrollment and the duration to recover from diarrhea were very similar for both groups. Therefore, the differences in diarrhea duration between groups on enrollment may have affected the outcomes, and the effectiveness of Fibersol-2 was not shown in the present study.

It is our speculation that the environmental changes such as climate change, home environment, household pets, the use of non-sanitary facility may affect the duration of diarrheal improvement. But as our study is a randomized controlled trial, the effects of environmental changes should be upon both group of children and it might not cause any change in the overall outcome of the study.

Slow fermentation pattern in large intestine is one of characteristics of Fibersol-2 among various fermentable soluble dietary fibers. A study conducted in humans showed slower fermentation rate of Fibersol-2 compared to other soluble non digestible carbohydrates such as fructo oligosaccharides, guar gum, and PHGG [27]. Fibersol-2 provides source of fermentable carbohydrates to the distal part of large intestine resulting in production of SCFAs throughout the intestine and facilitates absorption of sodium chloride and water in the colon thus help in forming solid stool. They serve as an essential energy source for the colonocytes and also excite epithelial cell proliferation, thus SCFAs help in mucosal protection as well as in building mucosal lining in both large and small gut [28]. A study conducted by Alam NH et al. in Bangladesh suggested that PHGG supplemented in ORS and other unabsorbed carbohydrates can appreciably help in improving the health condition of severely malnourished young diarrheal children by reducing duration of diarrhea and decreasing stool output. However, the study didn’t observe any significant reduction in stool weight nor explain specific advantageous role of PHGG in severely malnourished children [12]. In that particular study PHGG was supplemented in ORS, while in the present study Fibersol-2 was dissolved in 50-ml drinking water and administered separately from ORS.

One of the major limitations of this study was accuracy in collecting stool from the female children. Despite several strict attempts to measure the stool volume accurately, mixing of urine particularly in case of female children with the stool by chance might have taken place which made the stool amount more than actual. Moreover, the study did not examine the presence of bacterial or viral diarrheagenic pathogens, thus, the study failed to identify the etiologic differentials in diarrheal duration and stool output. Potential inflation of a type I error may occur as a result of multiple testing of subgroup comparisons, treatment arms, outcomes and analyses of the same outcome at different times. This can be prevented by complete and accurate reporting of the analyses being outlined in the registered trial protocols and mitigated by various statistical adjustment methods.

Conclusions

Although, Fibersol-2 was found to be digestively well-tolerable and safe in children, the study observed no beneficial role of Fibersol-2 in reducing the duration of watery diarrhea and stool output as well as recovery of children within 72 hours, compared to placebo. Further studies with large sample are imperative to refute or accept our observations.

Supporting information

S1 Checklist. CONSORT 2010 checklist of information to include when reporting a randomised trial*.

(DOCX)

Click here for additional data file.^{(38.6KB, docx)}

S1 Appendix

(DOCX)

Click here for additional data file.^{(37.4KB, docx)}

S1 File. Study Questionnaire English and Bengali.

(PDF)

Click here for additional data file.^{(2.6MB, pdf)}

S2 File. Trial study protocol.

(DOCX)

Click here for additional data file.^{(105.5KB, docx)}

Acknowledgments

We would like to express our sincere thanks to all research physicians, nurses, other research and hospital staff for their invaluable support and contribution during patient enrollment and data collection. We would like to express our gratitude to care-givers/mothers of the study participants for their consent to enroll their children in the study.

Abbreviations

WHO: World Health Organization
PHGG: Partially hydrolized guar gum
ORS: Oral rehydration solution
MUAC: Mid upper arm circumference

Data Availability

The data set contained personal information of the study participants. Our institutional review board will not have the provision to disclose any kind of information. Thus, our policy is not to make availability of the data set in the manuscript, the supplemental files, or a public repository. However, data related to this manuscript are available upon request and for researchers who meet the criteria for access to confidential data may contact with Ms. Armana Ahmed (armana@icddrb.org) to the research administration of icddr,b (http://www.icddrb.org/).

Funding Statement

This research study was funded by Matsutani Chemical Industry Company Limited, Japan on behalf of ADM/Matsutani LLC, USA in the form of grants. The International Centre for Diarrhoeal Disease Research, Bangladesh receives unrestricted support from the Government of the People's Republic of Bangladesh, Global Affairs Canada, the Swedish International Development Cooperation Agency and the UK Department for International Development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0280934.r001

Decision Letter 0

Ivan D Florez

3 Mar 2021

PONE-D-21-01310

Does Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1-3 years old? a randomized, parallel, double-blinded, placebo- controlled, two arm clinical trial

PLOS ONE

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Reviewer #1: 1. On the assessment of patient´s response: In the introduction section, the authors mention in a rather casual way that they wanted to study this compound's effect on the duration of diarrhea and the stool output (lines 88-89 of the manuscript). In another paragraph, under the "measurements" section (lines 201- 202), the authors indicate that the primary outcomes are diarrhea duration, the proportion of patients recovered within 72 hours, and daily stool output. Therefore, this clinical trial has not one but three primary criteria of response. To measure diarrhea duration, the authors indicate that they did count the number of hours elapsed from randomization to the last watery stool (lines 196-197). The authors need to clarify if they were recording the physical characteristics of every single stool passed during the study. It looks to me that only the stool volume was measured and recorded. This clarification will also be useful for understanding how they calculated the proportion of patients recovered from diarrhea. Enrolled patients stayed in the hospital for some days and then discharged and followed up at home. This design introduces a potential major problem in measuring the stool volume. While in the hospital, stools were collected in buckets placed beneath a cholera cot (line 186); once the patients were at home, the stools were collected in plastic bags (lines 192-193). These are two different ways of measuring this study outcome. At best, the authors should calculate the stool output during the hospital stay separated from that collected at home and compare this variable between the two groups looking for inconsistencies.

2. On the required size of study: The authors do not provide a sample size calculation, which should include the study power and the Type I and Type II error levels for any of the three selected study outcomes; they only mention the number of subjects included in the trial (line 108). I suspect that the necessary number of subjects to ascertain the study hypothesis would differ for each study outcome since each uses a different metric (hours, proportion, and volume).

3. On the method used to prepare a list of random treatment assignements: The authors inform that this is a placebo-controlled, randomized, double-blind, parallel clinical trial (line 105). A person not involved otherwise in the study prepared the list of random treatment assignments using a random number table (lines 114-115). The treatment's name was written on a piece of paper and then placed inside a sealed envelope (lines 115-116). The authors must clarify whether the person who prepared the sealed envelopes wrote the sequential study number outside these envelopes.

4. On the allocation concealment: The study researcher had the envelopes containing the treatment assignments (line 117) and opened the correspondent envelope only after the next patient was enrolled and gave the consent (lines 118-120). However, the authors need to explain the procedure followed in greater detail.

5. On the double-blind nature of this study: This is not a double-blind clinical trial. In this study, the enrolled patients received either the experimental treatment (digestion resistant maltodextrin) or the control treatment (regular maltodextrin) in the form of a drinking solution, twice a day for seven days (lines 109-112). The study was not blinded for the research physician since he or she was in charge of opening the sealed envelopes containing the name of the treatment allocated to the next patient (lines 118-119). We do not know if the study was blinded to the caregivers and how. The authors need to clarify this. The authors also should explain why they did not opt for a double-blind design, which would be feasible if the sequential study drinking solutions were provided already prepared by the hospital's pharmacy labeled only with the sequential study number.

6. On the statistical analysis: Mean (standard deviation), and median (IQR) for continuous variables and OR (95% CI) for categorical variables are provided in the tables presenting the data analysis results. Since this study is negative (no superiority of the experimental treatment over the control treatment), the authors must estimate how large the type II error is for this study's size.

7. On the evaluation of safety: There is no section in the manuscript, neither in methods or results, that explicitly presents what and how to monitor the intervention's side effects. Table 5 shows the comparative results between the two treatment groups of four variables observed during the seven days of the study: abdominal distension, abdominal pain, abdominal rumbling, and abdominal bloating. The authors need to clarify if these were the variables selected to monitor the safety of the trial. I do not understand the difference between abdominal distension and abdominal bloating.

8. On the registration of this trial: I have verified that this trial is registered at ClinicalTrials.gov with the number NCT03565393

9. On the accessibility of the study protocol and primary data records: The study protocol is available as an annex (supporting information). The authors declared that this study's primary data records would be public with some restrictions and only upon request.

10. On the sources of funding and the role of funders: The sponsor of this study is mentioned in the manuscript. However, the authors do not note whether or not the funder had a role in designing the study protocol, data analysis, decision to publish, and preparing this manuscript.

Reviewer #2: Title: There's a typo in the title; did you intend for it to be; "Is Fibersol-2 efficacious..."

Abstract: The presentation of the numerical results should be improved, for example for the continuous outcomes you should report the mean, standard error, difference, 95% confidence intervals for the difference and p-value: "The mean (SE) duration of watery diarrhoea in the fibserol and control groups respectively were XX(xx) and YY(yy) respectively, a difference of ZZ, 95%CI zz to zz, p-value zzzz." For the binary outcome: "The proportions of children who recovered from watery diarrhoea within 72 hours in the fibersol and control arms were AA and BB respectively, odds/risk ratio/difference CC, 95%CI cc to cc, p-value cccc."

Introduction:

- there's a missing space between "fibre" and "produced" in line 60.

- first word of line 61 should be plural "prebiotics", or begin with "A prebiotic..."

- line 70: "the evidence", not plural.

- line 78: do you mean "in children admitted to hospital with diarrhoea and dehydration" or "dehydration due to diarrhoea", rather than "dehydrated diarrhoea"?

- line 84, you mean "healthy" not "healthful".

Methods

Although most of the required information is present, the reporting of the methods does not follow the order of sections recommended in the CONSORT guidelines, and the methods therefore feels rather jumbled up. For example, lines 108 to 112 under 'study design' belong to 'randomisation and masking', and the description of the eligibility criteria after randomisation and masking seems odd. Please have a look at the CONSORT statement at http://www.consort-statement.org/checklists/view/32--consort-2010/66-title and try to reorganise the methods to follow the suggested order.

Please include a clear description of how the sample size was determined - this is not currently reported. The numbers of children in each arm is a result and should not be included anywhere in the methods, e.g. in lines 121 and 123.

For the analysis, first, a table of descriptive characteristics of the sample, without any statistical tests comparing the groups, should be presented. These should be means and standard deviations for continuous variables, and counts and proportions for categorical ones, in each group and overall. This should be Table 1. It should be followed by a table showing the mean and SE of continuous outcomes in each group and the difference in means, 95% confidence intervals and p-values, both crude and adjusted, from a linear regression model. For the binary outcome the table should have the counts of events and proportions in each arm and the odds ratio or risk ratio or risk difference with the 95% confidence intervals and p-values, both crude and adjusted. It is these results that should then be summarised in the text and abstract.

Please avoid using the ± designation anywhere in the text as it implies a range of values which is not what you seem to mean in each case where it is used.

Please include the sources of funding and other support and the role of funders as a sub-section in the methods (e.g. the last subsection of methods).

Reviewer #3: Dear Editor

This study is a good example for the effects of different kind of supplementation to ORS for children with acute infectious diarrhea. Randomization, patient selection and end-points are great for pediatric diarrhea study. However I can not understand why the authors prefer to use this prebiotic for the treatment of diarrhea. Prebiotics have some beneficial effects on health (not innumerable), and majority of the effects of fiber are increased transit time (mainly proposed in children with constipationd or other FGIDs). This may be beneficial for diarrhea if combined with probiotic strains.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: Eduardo Salazar-Lindo

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 Jan 27;18(1):e0280934. doi: 10.1371/journal.pone.0280934.r002

Author response to Decision Letter 0

31 Oct 2021

Date: 31st October, 2021

Ivan D. Florez

Academic Editor, PLOS ONE

From:

Dr. Abu Sadat Mohammad Sayeem Bin Shahid

Corresponding Author

Subject: Response to the comments of academic editor and the reviewers of PLOS ONE on manuscript Ref: PONE-D-21-01310 titled “Is Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1-3 years old? A randomized, parallel, double-blinded, placebo-controlled, two arm clinical trial.”

Dear Ivan D. Florez,

Thank you for evaluating our manuscript and providing us with the opportunity to submit the revised manuscript after addressing academic editor’s and reviewer’s comments. We also express our sincere thanks to them for evaluating our manuscript. We are sending a track change version as well as a clean version of the manuscript that highlights the changes we have made from the previous version. We are also attaching this letter outlining a point-by-point response to the each point kindly raised by the academic editor and respected reviewers.

We hope that our response will be appropriate to qualify the manuscript for publication in your well-reputed journal.

We look forward to kindly hearing from you.

Thank you.

Responses to the comments of Academic Editor and the respected reviewers

Journal additional requirements:

1. Please clarify if the following authors were employed by Matsutani Chemical Industry Co Ltd, Hyogo, Japan at the time the study took place:

Yuka Kishimoto

Sumiko Kanahori

Abu Syed Golam Faruque

Mohammod Jobayer Chisti

Please also clarify if the above authors are currently employed Matsutani Chemical Industry Co Ltd.

Response: Thank you. Yuka Kishimoto and Sumiko Kanahori were employed by Matsutani Chemical Industry Co Ltd, Hyogo, Japan at the time the study took place and contributed as co-authors of the manuscript. They currently belong to the same institution. The rest of two were affiliated by International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) during the study period and currently belong to the same organization.

Journal requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Response: Thank you. It has been revised accordingly.

Response: Thank you. It has been uploaded as Supporting Information.

3. Please provide a sample size and power calculation in the Methods, or discuss the reasons for not performing one before study initiation.

Response: Thank you for the comment. It has been incorporated in line no 141-156, page no.7-8 and line no 305-306, page no.14 in clean version of the manuscript.

Response: Thank you. It has been revised accordingly in line no.1-2, page no. 1

As per the journal’s editorial policy, please include in the Methods section of your paper:

1) your reasons for your delay in registering this study (after enrolment of participants started);

2) confirmation that all related trials are registered by stating: “The authors confirm that all ongoing and related trials for this drug/intervention are registered".

Response: Thank you for the suggestions. As per as our knowledge we started the patient enrolment just after initiation of the registration process through our research administration. However, the process of accomplishment for the registration took long time and thus, the online system showed the delay in registration. Please accept our sincere apology for such unintentional error.

Response: Thank you for the comment. Our data contain a lot of personal information where we de-identified them during analysis. As per institutional policy data with personal information will be remained with our Research Administration (RA) due to ethical constraint and if someone wants to make the availability of the de-identified data, he/she may kindly communicate with the head of RA (aahmed@)icddrb.org).

Response: Thank you. Number of tables has been revised in the result section of the manuscript.

8. Thank you for stating the following in the Financial Disclosure:

We note that one or more of the authors have an affiliation to the commercial funders of this research study: Matsutani Chemical Industry Co. Ltd

Please also include the following statement within your amended Funding Statement.

If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.

Response: Thank you for the suggestions. It has been incorporated in line no 275-276, page no.13 in the clean version of the manuscript.

Response: Thank you for the comment. It has been incorporated in line no. 380-382, page no.18 in the clean version of the manuscript.

Response: Thank you for the suggestion. It has been revised accordingly in page no. 21-27 in the clean version of the manuscript.

Additional Editor Comments:

Response: Thank you.

Review Comments to the Author

Reviewer #1:

1. On the assessment of patient´s response: In the introduction section, the authors mention in a rather casual way that they wanted to study this compound's effect on the duration of diarrhea and the stool output (lines 88-89 of the manuscript). In another paragraph, under the "measurements" section (lines 201- 202), the authors indicate that the primary outcomes are diarrhea duration, the proportion of patients recovered within 72 hours, and daily stool output. Therefore, this clinical trial has not one but three primary criteria of response. To measure diarrhea duration, the authors indicate that they did count the number of hours elapsed from randomization to the last watery stool (lines 196-197). The authors need to clarify if they were recording the physical characteristics of every single stool passed during the study. It looks to me that only the stool volume was measured and recorded. This clarification will also be useful for understanding how they calculated the proportion of patients recovered from diarrhea. Enrolled patients stayed in the hospital for some days and then discharged and followed up at home. This design introduces a potential major problem in measuring the stool volume. While in the hospital, stools were collected in buckets placed beneath a cholera cot (line 186); once the patients were at home, the stools were collected in plastic bags (lines 192-193). These are two different ways of measuring this study outcome. At best, the authors should calculate the stool output during the hospital stay separated from that collected at home and compare this variable between the two groups looking for inconsistencies.

Response: Thank you for the comments and valuable suggestions. We visibly evaluated the both the consistency and volume of the stool (data available in the supplementary tables S2 & S3 under supporting information). The investigators have wealth of experiences in evaluating the resolution of diarrhea on the basis of these defined criteria. Both at hospital (cholera cots) and home (in plastic bag) the evaluation of consistency and volume of the stool was not so difficult and all our study personnel have performed this following our set criteria. Thus, we trust that there is no discrimination of evaluating the stool output between hospitalization and stay at home (please see table. 3 in page no. 23 in the clean version of the manuscript).

Response: Thank you for the comment. It has been incorporated in line no 141-156, page no.7-8 in clean version of the manuscript.

3. On the method used to prepare a list of random treatment assignments: The authors inform that this is a placebo-controlled, randomized, double-blind, parallel clinical trial (line 105). A person not involved otherwise in the study prepared the list of random treatment assignments using a random number table (lines 114-115). The treatment's name was written on a piece of paper and then placed inside a sealed envelope (lines 115-116). The authors must clarify whether the person who prepared the sealed envelopes wrote the sequential study number outside these envelopes.

Response: Thank you for the comment. It has been incorporated in line no.159-164, page no.8 in clean version of the manuscript.

Response: Thank you for the suggestion. It has been incorporated in line no. 159-167, page no.8 in clean version of the manuscript.

Response: Thank you for the comment. We are really sorry to create the misunderstanding. We have now revised the randomization and masking section with better clarity (please see line no. 159-173, page no.8 in clean version of the manuscript).

Response: Thank you for the comment. It has been incorporated in line no. 305-306, page no.14 in clean version of the manuscript.

Response: Thank you for the comments. As we evaluated same number of healthy and diarrheal children (30 each) 1-3 years old for the digestive tolerability and acceptability of Fibersol-2 before initiation of the randomized trial, where we found the product is safe and well tolerated based on disappearance or improvements in abdominal symptoms, like distension, pain, rumbling and bloating in both groups of children (PONE-D-21-01326), henceforth these were the variables selected to monitor the safety of the trial (please see line no.309-314, page no.14-15 in clean version of the manuscript), although we didn’t mention about the safety of the interventions in the protocol. Sorry for the unintentional error. Although, both abdominal distension and bloating seem to be synonymous, we have defined them separately for the study purpose on the basis of the evidence (www.medicinenet.com) and have been described in line no. 243-244, page no 11 & line no. 250-251, page no. 12 in clean version of the manuscript.

8. On the registration of this trial: I have verified that this trial is registered at ClinicalTrials.gov with the number NCT03565393

Response: Thank you.

Response: Thank you for the comment. It has been incorporated in line no. 275-276, page no.13 in clean version of the manuscript.

Reviewer #2:

Title: There's a typo in the title; did you intend for it to be; "Is Fibersol-2 efficacious..."

Response: Thank you. It has been revised accordingly in line no.1, page no.1

Abstract:

The presentation of the numerical results should be improved, for example for the continuous outcomes you should report the mean, standard error, difference, 95% confidence intervals for the difference and p-value: "The mean (SE) duration of watery diarrhoea in the fibersol and control groups respectively were XX(xx) and YY(yy) respectively, a difference of ZZ, 95% CI zz to zz, p-value zzzz." For the binary outcome: "The proportions of children who recovered from watery diarrhoea within 72 hours in the fibersol and control arms were AA and BB respectively, odds/risk ratio/difference CC, 95% CI cc to cc, p-value cccc."

Response: Thank you for the suggestion. It has been revised accordingly in line no. 40-46, page no. 2-3 in clean version of the manuscript.

Introduction:

- There’s a missing space between "fibre" and "produced" in line 60.

Response: Thank you. It has been corrected accordingly in line no 63, page no.3 in clean version of the manuscript.

- First word of line 61 should be plural "prebiotics", or begin with "A prebiotic..."

Response: Thank you. It has been corrected accordingly in line no 64, page no.4 in clean version of the manuscript.

- Line 70: "the evidence", not plural.

Response: Thank you. It has been corrected accordingly in line no 73, page no. 4 in clean version of the manuscript.

- Line 78: do you mean "in children admitted to hospital with diarrhoea and dehydration" or "dehydration due to diarrhoea", rather than "dehydrated diarrhoea"?

Response: Thank you. It has been revised accordingly in line no. 81, page no. 4 in clean version of the manuscript.

- Line 84, you mean "healthy" not "healthful".

Response: Thank you. It has been corrected accordingly in line no. 87, page no. 4 in clean version of the manuscript.

Methods

Response: Thank you for the suggestion. It has been revised accordingly in the CONSORT checklist.

Response: Thank you for the comment. It has been incorporated in line no 141-156, page no.7-8 in clean version of the manuscript. The number of children in each arm has been deleted from the method.

Response: Thank you for the suggestions. It has been incorporated in page no. 21-22 in clean version of the manuscript.

Please avoid using the ± designation anywhere in the text as it implies a range of values which is not what you seem to mean in each case where it is used.

Response: Thank you for the suggestion. It has been revised accordingly throughout the manuscript.

Please include the sources of funding and other support and the role of funders as a sub-section in the methods (e.g. the last subsection of methods).

Response: Thank you for the comment. It has been incorporated in line no 274-280, page no.13 in clean version of the manuscript.

Reviewer #3:

This study is a good example for the effects of different kind of supplementation to ORS for children with acute infectious diarrhea. Randomization, patient selection and end-points are great for pediatric diarrhea study. However I cannot understand why the authors prefer to use this prebiotic for the treatment of diarrhea. Prebiotics have some beneficial effects on health (not innumerable), and majority of the effects of fiber are increased transit time (mainly proposed in children with constipation or other FGIDs). This may be beneficial for diarrhea if combined with probiotic strains.

Response: Thank you for the comment. As it is pointed out, the typical physiological function of dietary fiber is the gastrointestinal transit time. It has been reported that Fibersol-2, fermentable soluble dietary fiber, used in this study also has the effect of shortening the gastrointestinal transit time in pre-clinical experiments and human studies. When the functions of improving constipation and improving diarrhea could look like opposite, it may be open a question to examine the effect of Fiberol-2 on diarrhea. However, the intestinal environment is actually the important factor associated with both constipation and diarrhea. Up to today, it has been reported that ingestion of Fibersol-2 increases the numbers of beneficial bacteria such as bifidobacteria in the large intestine and increases production of short-chain fatty acids as metabolites. Those help to regulate good environment in the large intestine and Fibersol-2 is a prebiotic.

When acute infectious diarrhea is developed; the balance in intestine becomes temporarily impaired. To recover from diarrhea, it is effective to normalize the intestinal environment as soon as possible, and probiotics such as lactic acid bacteria are generally administered. On the other hand, soluble dietary fiber (hydrolyzed guar gum) has been reported to be effective in recovering from acute infectious diarrhea. The mechanism is considered that the hydrolyzed guar gum is a prebiotic that increases the numbers of bifidobacteria, regulates the intestinal bacteria, and increases beneficial metabolites such as short-chain fatty acids.

Although Fibersol-2 is in the same category of prebiotic soluble dietary fiber as hydrolyzed guar gum, it has different physical properties and different fermentability by intestinal bacteria. Therefore, we have examined the effect of Fibersol-2 on acute infectious diarrhea for the first time in this study because Fibersol-2 has been reported to stimulate the growth of intestinal bacteria and affect the metabolites.

We agree that there is a possibility to be more effective by the combination of prebiotics and probiotics. Since we investigated the effect of prebiotic Fibersol-2 alone this time, it would be interesting to see the effect of combination with probiotics in the future research.

Attachment

Submitted filename: Response to Reviewers_31.10.2021.docx

Click here for additional data file.^{(29.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0280934.r003

Decision Letter 1

Ivan D Florez

17 Jan 2022

PONE-D-21-01310R1Is Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1-3 years old? A randomized, parallel, double-blinded, placebo- controlled, two arm clinical trialPLOS ONE

Dear Dr. Shahid,

Please submit your revised manuscript by Mar 03 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Ivan D. Florez, MD, MSc, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Additional Editor Comments:

Reviewers have provided some comments that need to be addressed. Please prepare a revised version with a point-by-point response to their comments.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: No

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: No

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #2: In the abstract, the lines reporting numerical results (41-42) should (1) for duration of watery diarrhoea and total watery stool output, instead of the statistics reported using ± which the authors don't indicate what they are, should report the difference in means with 95% confidence intervals in addition to the p-values; (2) for proportion recovered, the odds ratio (as stated in your statistical analysis section) with 95% confidence intervals in addition to the p-value. These can be obtained from appropriate regression models.

The statistical analysis is not appropriately described or presented. It should focus on (1) presenting the characteristics of participants in each treatment arm. Categorical variables should be presented as counts and proportions, and continuous ones as means with standard deviations or medians with IQRs as approporiate (this is usually reported in Table 1 and seems to have been done well). It is not normally necessary to conduct tests of normality of covariates; (2) the methods for estimating the treatment effects on the outcomes, with 95% confidence intervals and p-values. These would normally be appropriate regression models. The results tables coming out of these should report the count and proportion of binary outcomes in each arm, with unadjusted and adjusted effects, here odds ratios, with their 95% confidence intervals and p-values; for continuous outcomes, the means and standard errors (NOT standard deviations) of the outcome in each arm, along with the unadjusted and adjusted effect estimates (mean differences) with 95% confidence intervals and p-values; (3) how the sample size was determined - this is critial!

Thus, the results presented in Tables 2 to 4 are not appropriate. Please see https://www.sciencedirect.com/science/article/pii/S0140673618317823 for examples of typical approaches to presenting the results tables.

The statement in the statistical methods section about the power of the study is a result, and should be reported in the last paragraph of the results section.

Reviewer #3: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No

PLoS One. 2023 Jan 27;18(1):e0280934. doi: 10.1371/journal.pone.0280934.r004

Author response to Decision Letter 1

7 Jul 2022

Date: 7th July, 2022

Ivan D. Florez

Academic Editor, PLOS ONE

From:

Dr. Abu Sadat Mohammad Sayeem Bin Shahid

Corresponding Author

Subject: Response to the comments of the reviewer of PLOS ONE on manuscript Ref: PONE-D-21-01310-R2 titled “Is Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1-3 years old? A randomized, parallel, double-blinded, placebo-controlled, two arm clinical trial.”

Dear Ivan D. Florez,

Thank you for evaluating our manuscript and providing us with the opportunity to submit the revised manuscript after addressing respected reviewer’s comments. We also express our sincere thanks to the respected reviewers for evaluating our manuscript. We are sending both the track change and clean versions of the manuscript that highlights the changes we have made from the previous version. We are also attaching this letter outlining a point-by-point response to each point kindly raised by the respected reviewer.

We hope that our response will be appropriate to qualify the manuscript for publication in your well-reputed journal.

We look forward to kindly hearing from you.

Thank you.

Funding statement

"This research study was funded by Matsutani Chemical Industry Company Limited, Japan on behalf of ADM/Matsutani LLC, USA. The funders didn’t have any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

Responses to the comments of the respected reviewer

Reviewer #2:

In the abstract, the lines reporting numerical results (41-42) should (1) for duration of watery diarrhoea and total watery stool output, instead of the statistics reported using ± which the authors don't indicate what they are, should report the difference in means with 95% confidence intervals in addition to the p-values; (2) for proportion recovered, the odds ratio (as stated in your statistical analysis section) with 95% confidence intervals in addition to the p-value. These can be obtained from appropriate regression models.

Response: Thank you for the comment. It has been revised accordingly (please see line no. 40-47, page no. 2-3 in track change version of the manuscript).

The statistical analysis is not appropriately described or presented. It should focus on (1) presenting the characteristics of participants in each treatment arm. Categorical variables should be presented as counts and proportions, and continuous ones as means with standard deviations or medians with IQRs as appropriate (this is usually reported in Table 1 and seems to have been done well). It is not normally necessary to conduct tests of normality of covariates; (2) the methods for estimating the treatment effects on the outcomes, with 95% confidence intervals and p-values. These would normally be appropriate regression models. The results tables coming out of these should report the count and proportion of binary outcomes in each arm, with unadjusted and adjusted effects, here odds ratios, with their 95% confidence intervals and p-values; for continuous outcomes, the means and standard errors (NOT standard deviations) of the outcome in each arm, along with the unadjusted and adjusted effect estimates (mean differences) with 95% confidence intervals and p-values; (3) how the sample size was determined - this is critial! Thus, the results presented in Tables 2 to 4 are not appropriate.

Response: Thank you for the valuable suggestions. It has been revised accordingly (Table 1-4 in track change version of the manuscript). Also see line no. 273-275, page no. 13 in track change version of the manuscript.

The statement in the statistical methods section about the power of the study is a result, and should be reported in the last paragraph of the results section.

Response: Thank you for the suggestion. It has been revised accordingly (please see line no. 337-339, page no. 15 in track change version of the manuscript).

PLoS One. doi: 10.1371/journal.pone.0280934.r005

Decision Letter 2

Jamie Males

19 Oct 2022

PONE-D-21-01310R2Is Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1-3 years old? A randomized, parallel, double-blinded, placebo- controlled, two arm clinical trialPLOS ONE

Dear Dr. Shahid,

A number of outstanding concerns have been expressed regarding the statistical reporting in your study. Please respond carefully to these comments when preparing your revision.

Please submit your revised manuscript by Dec 02 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Jamie Males

Editorial Office

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: No

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: No

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #2: There are still some problems with the statistical reporting in this manuscript. First, the sample size determination is repeated in two places: in lines 133 to 149 and again in lines 252 to 254.

That aside, the sample size determination is poorly reported. For example, when the authors say they anticipated a 25% relative reduction in 48-hour stool output, they do not indicate the anticipated stool output before or after the 48 hour period which would be useful in attempting to replicate their calculations; so it is not possible to do so. Furthermore, when they say that they assumed the proportion of children recovered within 72 hours would be 35% in the placebo group compared to 70% in the fibersol-2 group (or even the information about the duration of watery diarrhoea), there is no external information to justify why they thought these would be the case; it almost seems as if these numbers have been plucked out of thin air to justify the study size post-hoc.

The description of the statistical analysis is still quite poor. For example, the authors say in line 256: "in qualitative variables, differences in proportions were compared by the chi-squared test." I'm assuming this refers to categorical variables. First of all, the authors need to be clear whether these were the descriptive variables of the participants - in which case there would be no need for tests of significance - or outcome variables, in which case in my previous review I recommended performing regressions and reporting the magnitudes of association (odds ratios/risk ratios/risk differences - only one of these) with 95% confidence intervals and p-values, both unadjusted and adjusted where possible. This point also applies to the next statement in line 256 about 'quantitative data' (which I assume means continuous outcomes) - again here, if these were descriptive, then means and standard deviations are to be reported; if these are the outcomes, then means and standard errors in each group, followed by mean differences from linear regression models with 95% confidence intervals and p-values should be reported.

(adding this after reading the rest of the manuscript - some of the information I have asked for above is present in the manuscript, but the current description of the methods makes it seem like it has been done incorrectly)

Tables 1, 2, 3 and 4 are well-reported, and consistent with what one would expect - but not consistent with the statistical methods described, given my comments above. Table 5 is also useful additional information, but no mention of this in the statistical methods.

Reviewer #3: Recent version of the manuscript would be pıublish in PLos One, if Editorial Board also agree to publish.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No

**********

PLoS One. 2023 Jan 27;18(1):e0280934. doi: 10.1371/journal.pone.0280934.r006

Author response to Decision Letter 2

19 Dec 2022

Date: 19th December, 2022

Jamie Males

PLOS ONE

From:

Dr. Abu Sadat Mohammad Sayeem Bin Shahid

Corresponding Author

Dear Jamie Males,

We hope that our response will be appropriate to qualify the manuscript for publication in your well-reputed journal.

We look forward to kindly hearing from you.

Thank you.

Responses to the comments of the respected reviewer

Reviewer #2:

Comment: There are still some problems with the statistical reporting in this manuscript. First, the sample size determination is repeated in two places: in lines 133 to 149 and again in lines 252 to 254.

Response: Thank you for the comment. We have now deleted the sample size determination statement from the statistical analysis section (please see line no. 248-250, page no.12 in track change version of the manuscript).

Comment: That aside, the sample size determination is poorly reported. For example, when the authors say they anticipated a 25% relative reduction in 48-hour stool output, they do not indicate the anticipated stool output before or after the 48-hour period which would be useful in attempting to replicate their calculations; so it is not possible to do so. Furthermore, when they say that they assumed the proportion of children recovered within 72 hours would be 35% in the placebo group compared to 70% in the fibersol-2 group (or even the information about the duration of watery diarrhoea), there is no external information to justify why they thought these would be the case; it almost seems as if these numbers have been plucked out of thin air to justify the study size post-hoc.

Response: Thank you for the valuable comment. We completely concur with you. Actually, sample size of 92 which was reflected in the manuscript was calculated on the basis of the potential stool output with proper reference. However, based on the previous recommendation from the respected reviewer, we also calculated the sample size based on other outcomes (duration of resolution of diarrhea and proportion of children recovered within 72 hours). Actually, we did not find any reference for these two outcomes and thus we calculated the sample size on the basis of assumptions. We want to admit that during the original design of the study ‘stool output’ was set as the lone primary outcome and other two were considered as secondary outcomes but in the final protocol somehow later two were also shown as primary outcomes. As we are not considering these two as primary outcomes, we have now revised the sample size determination statement (please see line no. 138-147, page no. 7 in track change version of the manuscript).

Comment: The description of the statistical analysis is still quite poor. For example, the authors say in line 256: "in qualitative variables, differences in proportions were compared by the chi-squared test." I'm assuming this refers to categorical variables. First of all, the authors need to be clear whether these were the descriptive variables of the participants - in which case there would be no need for tests of significance - or outcome variables, in which case in my previous review I recommended performing regressions and reporting the magnitudes of association (odds ratios/risk ratios/risk differences - only one of these) with 95% confidence intervals and p-values, both unadjusted and adjusted where possible. This point also applies to the next statement in line 256 about 'quantitative data' (which I assume means continuous outcomes) - again here, if these were descriptive, then means and standard deviations are to be reported; if these are the outcomes, then means and standard errors in each group, followed by mean differences from linear regression models with 95% confidence intervals and p-values should be reported.

Response: Thank you for the valuable comments and suggestions. It has been revised accordingly (please see line no. 263-276, page no. 12-13 in track change version of the manuscript).

Comment: Tables 1, 2, 3 and 4 are well-reported, and consistent with what one would expect - but not consistent with the statistical methods described, given my comments above. Table 5 is also useful additional information, but no mention of this in the statistical methods.

Response: Thank you for the valuable comment. It has been revised accordingly (please see line no. 263-276, page no. 12-13 in track change version of the manuscript).

PLoS One. doi: 10.1371/journal.pone.0280934.r007

Decision Letter 3

Samuel Bosomprah

12 Jan 2023

Is Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1-3 years old? A randomized, parallel, double-blinded, placebo- controlled, two arm clinical trial

PONE-D-21-01310R3

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PLoS One. doi: 10.1371/journal.pone.0280934.r008

Acceptance letter

Samuel Bosomprah

20 Jan 2023

PONE-D-21-01310R3

Is Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1-3 years old? A randomized, parallel, double-blinded, placebo-controlled, two arm clinical trial

Dear Dr. Shahid:

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. CONSORT 2010 checklist of information to include when reporting a randomised trial*.

(DOCX)

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S1 Appendix

(DOCX)

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S1 File. Study Questionnaire English and Bengali.

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S2 File. Trial study protocol.

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Attachment

Submitted filename: Response to Reviewers_31.10.2021.docx

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Data Availability Statement

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PERMALINK

Is Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1–3 years old? A randomized, parallel, double-blinded, placebo-controlled, two arm clinical trial

Abu Sadat Mohammad Sayeem Bin Shahid

Shahnawaz Ahmed

Sampa Dash

Yuka Kishimoto

Sumiko Kanahori

Tahmeed Ahmed

Abu Syed Golam Faruque

Mohammod Jobayer Chisti

Roles

Abstract

Background

Methods

Results

Conclusion

Trial registration

Introduction

Materials and methods

Ethical consideration

Study design

Fig 1. Trial profile.

Eligibility criteria for the clinical efficacy trial

Inclusion criteria

Exclusion criteria

Study setting

Intervention

Outcomes

Sample size determination

Randomization and masking

Patient management

Measurements

Fluid intake

Output (stool, urine, and vomitus)

Operational definitions

Acute watery diarrhea

Resolution of diarrhea

Abdominal distension

Rumbling

Bloating

Stool consistency

Statistical analysis

Table 1. Baseline characteristics.

Table 2. Volume of ORS intake, amount of vomitus, urine output and stool output during the intervention period of 7 days.

Table 3. Regression analysis for continuous outcomes.

Table 4. Regression analysis for categorical outcome.

Table 5. Characteristics of gastrointestinal symptoms after ingestion of study drugs during the intervention period in both the groups.

Results

Safety of the trial

Discussion

Conclusions

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Ivan D Florez

Roles

Author response to Decision Letter 0

Decision Letter 1

Ivan D Florez

Roles

Author response to Decision Letter 1

Decision Letter 2

Jamie Males

Roles

Author response to Decision Letter 2

Decision Letter 3

Samuel Bosomprah

Roles

Acceptance letter

Samuel Bosomprah

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK