A Diet Low in Fermentable Oligo-, Di-, and Mono ... Syndrome and Diarrhea Shanti Eswaran, MD,...

Accepted Manuscript

A Diet Low in Fermentable Oligo-, Di-, and Mono-saccharides and PolyolsImproves Quality of Life and Reduces Activity Impairment in Patients with IrritableBowel Syndrome and Diarrhea

Shanti Eswaran, MD, William D. Chey, MD, Kenya Jackson, BS, Sivaram Pillai,MD, Samuel W. Chey, Theresa Han-Markey, MS, RD

PII: S1542-3565(17)30791-7DOI: 10.1016/j.cgh.2017.06.044Reference: YJCGH 55326

To appear in: Clinical Gastroenterology and HepatologyAccepted Date: 25 June 2017

Please cite this article as: Eswaran S, Chey WD, Jackson K, Pillai S, Chey SW, Han-Markey T, ADiet Low in Fermentable Oligo-, Di-, and Mono-saccharides and Polyols Improves Quality of Lifeand Reduces Activity Impairment in Patients with Irritable Bowel Syndrome and Diarrhea, ClinicalGastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2017.06.044.

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http://dx.doi.org/10.1016/j.cgh.2017.06.044

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Title: 1

A Diet Low in Fermentable Oligo-, Di-, and Mono-saccharides and Polyols Improves 2

Quality of Life and Reduces Activity Impairment in Patients with Irritable Bowel 3

Syndrome and Diarrhea 4

5

Authors 6

Eswaran, Shanti MD1 7

Chey, William D MD1 8

Jackson, Kenya BS1 9

Pillai, Sivaram MD1 10

Chey, Samuel W.1 11

Han-Markey, Theresa MS, RD2 12

13

Affiliations: 14 1University of Michigan Health System, Division of Gastroenterology, Ann Arbor, MI, 15

USA 16 2University of Michigan Health System, Michigan Clinical Research Unit and Nutrition 17

Obesity Research Center, Ann Arbor, MI, USA 18

19

Funding: Michigan Nutrition Obesity Research Center Grant (P30 DK089503), Clinical 20

and Translational Science Award Grant (2UL1TR000433-06), Prometheus Therapeutics 21

and Diagnostics (San Diego, CA, USA). 22

Clinicaltrials.gov: NCT01624610 23

Corresponding author: 24

Shanti Eswaran, MD 25

3912 Taubman Center SPC 5362 26

Ann Arbor, MI 48109 27

[email protected] 28

29

Author contributions: 30

SE: Principal investigator, study design, acquisition of data, analysis and interpretation of 31

data, drafting of manuscript, statistical analysis, obtained funding. 32

WDC: Principal investigator, study concept and design, analysis and interpretation of 33

data, drafting and revision of the manuscript, supervision of study. 34

THM: Study design, dietitian advice, dietary analysis, revision of the manuscript. 35

SP: Data entry 36

SC: Data entry 37

KJ: Statistical analysis, revision of the manuscript. 38

39

Conflict of Interest: 40

SE: no conflicts of interest 41

WDC: consultant and grant funding from Nestlé S.A., Sweden. 42

THM: no conflicts of interest 43

SP: no conflicts of interest 44

SC: no conflicts of interest 45

KJ: no conflicts of interest 46

47

48

49

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Abstract: 50

51

52

Background & Aims: We investigated the effects of a diet low in fermentable oligo-, di-, 53

and mono-saccharides and polyols (FODMAPs) vs traditional dietary recommendations, 54

on health-related quality of life (QOL), anxiety and depression, work productivity, and 55

sleep quality in patients with IBS and diarrhea (IBS-D). 56

57

Methods: We conducted a prospective, single-center, single-blind trial of 92 adult 58

patients with IBS-D (65 women; median age, 42.6 years) randomly assigned to groups 59

placed on a diet low in FODMAPs or a modified diet recommended by the National 60

Institute for Health and Care Excellence (mNICE) for 4 weeks. IBS-associated QOL 61

(IBS-QOL), psycho-social distress (based on the Hospital Anxiety and Depression 62

Scale), work productivity (based on the Workplace Activity Impairment Questionnaire), 63

and sleep quality were assessed before and after diet periods. 64

65

Results: Eighty-four patients completed the study (45 in the low-FODMAP group and 39 66

in the mNICE group). At 4 weeks, patients on the diet low in FODMAPs had a larger 67

mean increase in IBS-QOL score than patients on the mNICE diet (15 v 5; 95% CI, –68

17.4 to –4.3). A significantly higher proportion of patients in the low-FODMAP diet group 69

had a meaningful clinical response, based on IBS-QOL score, than in the mNICE group 70

(52% v 21%; 95% CI, –.52 to –08). Anxiety scores decreased in the low-FODMAP diet 71

group compared to the mNICE group (95% CI, 0.46– 2.80). Activity impairment was 72

significantly reduced with the low-FODMAP diet (–22.89) compared to the mNICE diet (–73

9.44; 95% CI, 2.72–24.2). 74

75

Conclusion: In a randomized, controlled trial, a diet low in FODMAPs led to significantly 76

greater improvements in HRQOL, anxiety, and activity impairment compared with a diet 77

based on traditional recommendations for patients with IBS-D. Clinicaltrials.gov no: 78

NCT01624610 79

80

KEY WORDS: nutrition, functional disorder, psychology, treatment 81

82

83

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Introduction 84

85

Irritable bowel syndrome (IBS) is a common gastrointestinal illness of heterogeneous 86

pathogenesis which is characterized by the presence of characteristic symptoms 87

including abdominal pain and altered bowel habits.1 Though IBS does not shorten life 88

expectancy or identify patients at increased risk of developing other organic diseases 89

like colorectal cancer2 or inflammatory bowel disease, it can profoundly affect the quality 90

of life of affected individuals.3,4 Further validating the importance of IBS, affected patients 91

consume substantially greater health care resources, undergo more surgical procedures, 92

and have reduced work productivity with higher rates of both absenteeism and 93

presenteeism than persons without IBS.5,6 Based upon these facts, it is not surprising 94

that IBS patients account for billions of dollars in direct and indirect health care 95

expenditure each year in the US.7 96

97

The reduced quality of life reported in IBS patients extends across a wide range of 98

domains as measured by validated generic and disease specific instruments. IBS 99

patients report that their symptoms negatively affect their mood, body image, ability to 100

eat an unrestricted diet, sexual functioning, relationships, and ability to conduct and 101

enjoy their daily activities at work.3,8,9 The decreases in quality of life reported by IBS 102

patients are undoubtedly influenced by a number of factors outside of their lower 103

gastrointestinal symptoms. For example, IBS patients have a substantially increased risk 104

of co-morbid functional gastrointestinal disorders such as functional heartburn and 105

functional dyspepsia, somatic pain conditions such as migraine headache, fibromyalgia, 106

and interstitial cystitis,10 and psychological distress including anxiety, depression, and 107

somatization.11 In addition, sleep disorders, which, like IBS, are known to exert negative 108

effects on quality of life, are reported more commonly in IBS patients than in otherwise 109

healthy persons.12,13 The reasons underlying the increased prevalence of GI and non-GI 110

co-morbidities in IBS patients remain poorly defined but central and peripheral gut-111

related mechanisms have been postulated.14-16 112

113

Up to 2/3 of IBS patients associate symptom onset or exacerbation with eating a 114

meal.17,18 Fermentable oligo-, di-, and mono-saccharides and polyols (FODMAPs) are 115

poorly absorbed, osmotically active,19 short-chain carbohydrates which are rapidly 116

fermented by colonic bacteria producing short chain fatty acids and gases which can 117

trigger symptoms in IBS patients through osmotic effects and luminal distention.20 We 118

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and others have reported improvements in the main symptoms of IBS after dietary 119

FODMAP restriction.21-24 However, there are currently little data addressing the effects 120

of the low FODMAP diet on other aspects of the IBS illness experience including quality 121

of life, psychological distress, work productivity, or sleep.25 122

123

We hypothesized that a low FODMAP diet would improve disease specific QOL, 124

psychological distress, work productivity, and sleep to a greater degree than standard 125

dietary recommendations for IBS based upon modified guidance from the National 126

Institute for Health and Care Excellence (mNICE) in patients with IBS-D. 127

128

Methods 129

This was a randomized controlled superiority trial with a parallel design conducted in a 130

1:1 fashion. The primary gastrointestinal symptom results from this trial are reported 131

elsewhere.24 In this manuscript, we report results from pre-specified secondary 132

endpoints addressing disease-specific quality of life, psychological distress, work 133

productivity, and sleep quality. The protocol was approved by the University of Michigan 134

Hospital and Health Systems Institutional Review Board and registered with 135

Clinicaltrials.gov (NCT01624610). All authors had access to the study data and 136

reviewed and approved the final manuscript. 137

138

Patient Population 139

Adult patients meeting the Rome III criteria for IBS-D26 (as assessed by a 140

gastroenterologist) were consecutively recruited from the gastroenterology and primary 141

care clinics at the University of Michigan and via local print and online advertising. 142

Inclusion criteria included symptoms compatible with the diagnosis of IBS with diarrhea 143

(IBS-D) by the Rome III criteria and if relevant, a willingness to maintain a stable dosage 144

of antidepressants during the study. Further inclusion and exclusion criteria are 145

described in the Supplementary Materials. 146

147

Study Protocol 148

Eligible patients were asked to participate in a study that would test the efficacy of 2 149

diets thought to help IBS symptoms. Instruction regarding the 2 diet interventions was 150

provided by specially trained research dieticians. In the hopes of mimicking real-world 151

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conditions, dietitians were not blinded to the study intervention though the investigators 152

analyzing the data were blinded to randomization. After informed consent was obtained, 153

potential subjects entered a two-week screening period during which IBS symptoms 154

were assessed. Further information about randomization and dietitian education can be 155

found in the Supplementary Materials. 156

157

Pre-specified Assessments: 158

Disease specific quality of life, anxiety and depression, activity impairment, and sleep 159

quality were measured before and after the 4 week intervention. We utilized the IBS-160

QOL questionnaire, the Hospital Anxiety and Depression Scale (HADS), the Work 161

Productivity and Activity Impairment (WPAI) questionnaire, and an 11-point numerical 162

rating scale (NRS) for sleep quality and fatigue. Further explanation of these 163

instruments and pre-specified comparisons can be found in the Supplementary 164

Materials. 165

166

Statistical Analysis 167

The endpoints reported were collected from all patients at baseline and at the end of 168

treatment, but the trial was not powered to detect these changes as this was a 169

secondary analysis. Therefore, the presented analyses are considered to be exploratory 170

in nature. Quantitative data are presented as mean (SD) unless otherwise stated. 171

Baseline comparisons were made using an intention-to-treat analysis, utilizing χ2 test 172

and student’s t test, for categorical and continuous variables respectively. Normality of 173

the distribution was demonstrated with a Folded F statistic. 174

95% Confidence intervals for categorical outcomes were made by computing confidence 175

limits based on binomial proportions and risk differences within groups. 95% confidence 176

intervals for continuous variables were computed utilizing student’s t-test and paired t-177

test. All patients who were randomized and who received dietary instructions were 178

included in the responder comparisons, where dropouts were considered to be non-179

responders (intention-to-treat analysis). For comparisons of questionnaire data at the 180

end of the intervention period vs baseline, only patients who completed the intervention 181

were included (per-protocol analysis). All statistical analyses were performed using SAS 182

(version 9.4, SAS Institute, Cary, NC). 183

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184

Results 185

Of the 171 subjects enrolled and screened between October 2012 and November 2015, 186

92 subjects (65 women (71%), median age 42.6 years (range 19-75 years), 68 187

Caucasian (74%)) were deemed eligible and randomized [Figure 1]. Eighty-four patients 188

completed the study period (45 low FODMAP, 39 mNICE); QOL data were obtained in 189

88 patients. There were more dropouts in the low FODMAP arm (5 subjects) than the 190

mNICE arm (2 subjects). Demographics and baseline QOL measures were similar 191

between groups [Table 1], except that there were more obese patients in the mNICE 192

group. 193

194

The primary endpoint of adequate relief and other clinical endpoints have been reported 195

previously.24 Though there were no significant differences in the proportion of those 196

reporting adequate relief (p=0.31) or composite endpoint responders (p=0.11), the low 197

FODMAP diet resulted in a significantly higher proportion of abdominal pain responders 198

compared to the mNICE group (51% v 23%, p=0.008). There were similar significantly 199

greater improvements observed in the low FODMAP group for bloating, consistency, 200

frequency, and urgency than in the mNICE group. 201

202

Nutritional Data 203

Baseline energy, nutrient, and FODMAP intake were similar between groups, but by the 204

end of the 4-week study period, daily ingested total carbohydrates and measurable 205

FODMAPs (fructose, lactose, monosaccharides, polyols) were significantly lower in the 206

low FODMAP arm compared to the mNICE arm.24 207

208

Disease Specific Quality of Life 209

The mean IBS-QOL score at 4 weeks improved significantly in both groups, but the 210

magnitude of improvement was significantly greater in the low FODMAP arm compared 211

to the mNICE arm (15.9 v 5 points, [95% CI (-17.4, -4.3)] [Figure 2a]. In the low 212

FODMAP arm, significant improvements were observed in all IBS-QOL domains except 213

for food avoidance [Figure 3]. Improvements were seen in the mNICE arm as well for 214

several domains (dysphoria, interference with activity, and health worry), but the 215

magnitude of improvement in the low FODMAP group was significantly greater for the 216

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dysphoria, interference with activity, body image, and social reaction domains. 217

Interestingly, food avoidance did not significantly increase or decrease throughout the 218

study for either group. At 4 weeks, the proportion of patients with at least 14-point 219

improvement (meaningful clinical response, MCR) was greater in the low FODMAP 220

group compared to the mNICE group (52% v 21%, [95% CI (-.52, -.08)] [Figure 2b]. 221

The low FODMAP group reached an MCR for the domains for dysphoria, interference 222

with activity, body image and social reaction; the mNICE group did not reach MCR for 223

any IBS-QOL domains. 224

225

Anxiety and Depression 226

At 4 weeks, anxiety scores as measured by HADS improved significantly for subjects on 227

the low FODMAP diet (9.13 to 7.73 (-1.4), [95% CI (-2.1,-.59)]), while anxiety in the 228

mNICE group did not change significantly (9.31 to 9.54 (0.23), [95% CI (-.64, 1.10) 229

[Figure 4a]. The between-group difference in the magnitude of improvement in anxiety 230

scores was also statistically significant (1.63, [95% CI (0.46, 2.80)]). The proportion of 231

patients with anxiety scores ≤8 was not significantly different between the low FODMAP 232

group and mNICE arms (52% [95% CI (.37, .68)] v 37% [95% CI (.21, .53)]). 233

234

Depression scores improved in both groups compared to baseline, but was only 235

significantly improved in the low FODMAP arm [Figure 4b]. The between-group 236

difference in the magnitude of improvement in depression scores was not statistically 237

significant [95% CI (-.70, -1.30)]. The proportion of patients with depression scores ≤8 238

was similar in the low FODMAP group compared to the mNICE group (85% [95% CI 239

(.67, .93)] v 80% [95% CI (.73, .96)]). 240

241

Work Productivity and Activity Impairment 242

WPAI scores collected at baseline and after the 4 week intervention demonstrated no 243

significant improvement in absenteeism, presenteeism, or work productivity with either 244

the low FODMAP or mNICE diets [Table 2a]. However, while activity impairment scores 245

at 4 weeks compared to baseline improved with both diet interventions, the magnitude of 246

benefit reported by the low FODMAP group was significantly greater than that reported 247

by the mNICE group (13.5, 95% CI [2.72, 24.2)]) [Table 2b]. 248

249

Sleep and Fatigue 250

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Compared to baseline, the mean sleep and fatigue scores at 4 weeks for the low 251

FODMAP group improved significantly, though the magnitude of change between the 2 252

groups was not statistically significantly different [95% CI (-.29, 1.2); 95% CI (-.46, 1.13), 253

respectively] [Table 3]. For sleep quality as measured by the modified Sleep 254

Questionnaire, the low FODMAP diet but not the mNICE diet group experienced 255

improvements in overall sleep quality [95% CI (-1.62, -.1)], daytime fatigue [95% CI (-.56, 256

-.07)] and trouble falling asleep [95% CI (-.65, -.03)] at 4 weeks when compared to 257

baseline. However, the magnitude of improvement from baseline to 4 weeks between 258

the 2 treatment groups was not significantly different [95% CI (-.17, 1.58); 95% CI (-.09, 259

.61); 95% CI (-.09, 0.67), respectively]. 260

261

Correlations 262

No correlation was detected between symptom response to dietary intervention (as 263

measured by improvement in abdominal pain or by reporting of adequate relief of IBS 264

symptoms) and improvement in quality of life, psychological indices, or baseline 265

antidepressant use. 266

267

Discussion 268

269

In this post-hoc analysis of pre-specified secondary outcomes, we found that the low 270

FODMAP diet led to significant improvements in quality of life, anxiety, and activity 271

impairment compared to a diet intervention based upon modified NICE guidelines. This 272

work extends the benefits of the low FODMAP diet beyond improving specific GI 273

symptoms to more patient-centered outcomes. 274

275

Given that IBS is a symptom-based diagnosis, clinical trials have tended to focus on the 276

ability of an intervention to improve the cardinal GI symptoms of IBS. While improving GI 277

symptoms is certainly important to IBS patients, focusing only on GI symptoms may fail 278

to recognize the true impact of IBS on patient’s daily lives and ability to function. In 279

addition, it is clear that the illness experience of many IBS patients extends beyond their 280

GI symptoms to include mental health issues27 and sleep.28 For these reasons, studies 281

which take a holistic view of the impact of an intervention on quality of life, mental health 282

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issues, daily functioning, and sleep are critical to understanding the true benefits of an 283

intervention to an IBS patient’s overall illness experience. 284

285

The low FODMAP diet led to significantly greater improvements in disease specific 286

quality of life than the mNICE diet across all domains of the IBS-QOL questionnaire 287

except food avoidance. For the IBS-QOL, a meaningful clinical response (MCR) has 288

been defined as an increase in score of >14.29 Patients randomized to the low FODMAP 289

diet were more than twice as likely to experience an MCR. Furthermore, those 290

randomized to the low FODMAP diet reached the threshold for an MCR for dysphoria, 291

interference with activity, body image and social reaction, while the MNICE group did not 292

achieve an MCR for any individual IBS-QOL domains. These data demonstrate a 293

profound effect of the low FODMAP diet on IBS specific quality of life. We found the lack 294

of effect of the low FODMAP diet on food avoidance scores to be particularly interesting. 295

The low FODMAP diet is widely regarded to be highly restrictive and difficult for patients 296

to adhere to, dissuading many from even attempting it. Our data, along with that from 297

others,30 suggest that the low FODMAP diet might not be as burdensome to IBS-D 298

patients as is widely perceived and is no more burdensome than traditional dietary 299

advice offered to IBS patients. 300

301

There is very little other data addressing the impact of the low FODMAP diet on quality 302

of life in IBS patients. In an unblinded, controlled trial of IBS patients from Denmark31 303

who were randomized to the low FODMAP diet (n=42), a Lactobacillus rhamnosus GG 304

probiotic (n=41), or a usual Danish diet (n=40), there were no statistically significant 305

between-group differences in IBS-QOL scores at the end of the intervention period. 306

However, significant improvements in IBS-QOL scores compared to baseline were 307

observed with the low FODAMP diet but not the probiotic or usual Danish diet. The 308

reasons for the differences in results between our study and the Danish study are not 309

clear but might be attributable to differences in study populations (for example, our 310

patient population was older (42 years) than patients in the Danish study (37 years old)), 311

dietary habits between Denmark and the US, or differences in study protocols. 312

313

There are increasing data to support a link between food, the microbiome, and mood.32-314

34 In our study, the low FODMAP diet led to statistically significant decreases in anxiety 315

and depression scores at 4 weeks while there was no statistically significant 316

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improvement for the mNICE group. One issue that we cannot address in our study is 317

whether anxiety state or trait improved. HADS is unable to distinguish between these 318

two conditions and it is possible that while anxiety was improved by the low FODMAP 319

diet, patients could still have experienced anxiety, albeit to a lesser degree. Similar 320

improvement in HADS scores (but not state anxiety or depression) were observed with a 321

low FODMAP diet and gut-directed hypnotherapy in a recently published Australian 322

study.30 The mechanism/s which underlie these observations are unclear, though one 323

could plausibly suggest “top-down” or “bottom-up” models. It is entirely possible that by 324

improving GI symptoms, patients felt less anxious about eating a meal. On the other 325

hand, recent data have drawn a link between psychosocial distress, altered central 326

processing and modulation of nutrient related visceral sensory signals.30 Higher levels 327

of psychiatric comorbidity are associated with higher preprandial and postprandial GI 328

symptom burden in IBS patients.14 Restriction of FODMAPs may improve psychiatric 329

comorbidity,35 through modulation of the gut microbiome or mucosal immune system.36 330

Further studies to understand this interesting observation are warranted. 331

332

Decreases in work productivity and activity impairment are common in IBS and exact a 333

significant toll on patients and society. Few IBS treatments have demonstrated benefits 334

for these important outcomes.37 The low FODMAP diet led to a statistically significant 335

improvement in absenteeism and presenteeism at 4 weeks when compared to baseline. 336

However, between-group differences for absenteeism and presenteeism were not 337

statistically significant. Though the low FODMAP diet and the mNICE diet both led to 338

statistically significant improvements in activity impairment at 4 weeks when compared 339

to baseline, the magnitude of benefit with the low FODMAP diet was significantly greater 340

than the mNICE diet. This finding is consistent with the significant decrease in 341

interference with activity subscale scores found on the IBS-QOL with the low FODMAP 342

diet vs. the mNICE diet. Ours is the first study to show such robust benefits in activity 343

impairment and validates the important downstream consequences of the low FODMAP 344

diet to patients with IBS-D. 345

346

Sleep disturbances are common in IBS patients and may well contribute to reductions in 347

quality of life, work productivity, and activity impairment.12,13 In a preliminary assessment 348

utilizing selected questions from the validated Sleep-50 Questionnaire, we found that the 349

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low FODMAP diet improved overall sleep quality and fatigue at 4 weeks when compared 350

to baseline. However, between group differences were not significantly different. 351

352

Our study has several important limitations. While our endpoints were pre-specified, the 353

study was not powered for these secondary endpoints; thus, type II errors may have 354

occurred and thus, our study should be viewed as more of an exploratory than definitive 355

work. Also, the improvement noted in psychologic indices and disease specific QOL 356

were measured at 4 weeks only, and may not necessarily translate into long term 357

improvement (although long-term benefit for these endpoints has been noted in other 358

studies30). Given that meals were not supplied to subjects, complete blinding was not 359

possible, and bias may have been interjected by the dietitians or patients. Though 360

awareness of the low FODMAP diet has increased over time, it was relatively 361

unrecognized in Michigan during the time this trial was conducted. In addition, rather 362

than utilizing our clinical GI dieticians for this trial, we utilized a separate group of fully 363

trained research dieticians to instruct study participants on the diet interventions in the 364

hopes of reducing the likelihood of introducing bias towards one intervention or the 365

other. We were careful to have the dieticians tell patients that they were to be 366

randomized to one of two diet therapies for IBS (Diet 1 or Diet 2) and to avoid any 367

discussion of efficacy or research conducted regarding either intervention. The short 368

duration of the diet intervention could be viewed as a study limitation. However, the 4 369

week diet intervention period was chosen to reflect how the full FODMAP elimination 370

phase is intended to be used in clinical practice, It should be remembered that the low 371

FODMAP diet plan consists of 3 separate stages: an elimination phase during which all 372

FODMAPs are eliminated in the hopes of identifying IBS patients who are sensitive to 373

FODMAPs, a reintroduction phase in which responders to the elimination phase 374

undergo a structured reintroduction of foods containing individual FODMAPs in the 375

hopes of identifying their specific triggers, and a maintenance phase in which 376

information from the reintroduction phase is used to liberalize and tailor the diet thus 377

creating each individual IBS patient’s maintenance diet. Our study demonstrated 378

benefits of the FODMAP elimination phase, which is only intended for short-term use, to 379

symptoms and quality of life in IBS-D patients. Subsequent studies will be required to 380

better understand the reintroduction and maintenance phases of the low FODMAP diet 381

plan. Finally, although there was a significantly higher average BMI in the mNICE group, 382

there were no significant differences between the groups in categorical BMI. While there 383

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are no data to suggest that obese patients with IBS would respond differently to the two 384

dietary interventions, it is possible that this imbalance could have introduced unintended 385

bias. It is worth noting that there was no difference in response to either intervention 386

between obese (BMI ≥30) and non-obese patients (BMI <30), acknowledging that our 387

study was not designed or powered to adequately address this question. 388

In this US randomized, controlled trial, the low FODMAP diet vs. the mNICE diet 389

demonstrated significant benefits for quality of life, anxiety, and activity impairment in 390

patients with IBS-D. This study is one of the first to extend the benefits of the low 391

FODMAP diet beyond improving GI symptoms in IBS patients, and, will hopefully prompt 392

further investigation investigating the relationship of diet, GI symptoms, and quality of 393

life. When benefits for these important patient-centered outcomes are combined with the 394

improvements in GI symptoms reported by our group and others, it is logical to conclude 395

that the low FODMAP diet is an effective treatment intervention for patients with IBS-D. 396

397

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References: 402

1. Drossman DA. Functional Gastrointestinal Disorders: History, Pathophysiology, 403

Clinical Features and Rome IV. Gastroenterology. Feb 19 2016. 404

2. Power AM, Talley NJ, Ford AC. Association between constipation and colorectal 405

cancer: systematic review and meta-analysis of observational studies. Am J 406

Gastroenterol. Jun 2013;108(6):894-903. 407

3. El-Serag HB, Olden K, Bjorkman D. Health-related quality of life among persons with 408

irritable bowel syndrome: a systematic review. Aliment Pharmacol Ther. Jun 409

2002;16(6):1171-1185. 410

4. Gralnek IM, Hays RD, Kilbourne A, Naliboff B, Mayer EA. The impact of irritable 411

bowel syndrome on health-related quality of life. Gastroenterology. Sep 412

2000;119(3):654-660. 413

5. Pare P, Gray J, Lam S, et al. Health-related quality of life, work productivity, and 414

health care resource utilization of subjects with irritable bowel syndrome: baseline 415

results from LOGIC (Longitudinal Outcomes Study of Gastrointestinal Symptoms in 416

Canada), a naturalistic study. Clinical therapeutics. Oct 2006;28(10):1726-1735; 417

discussion 1710-1721. 418

6. Spiegel BM. The burden of IBS: looking at metrics. Curr Gastroenterol Rep. Aug 419

2009;11(4):265-269. 420

7. Hulisz D. The burden of illness of irritable bowel syndrome: current challenges and 421

hope for the future. Journal of managed care pharmacy : JMCP. Jul-Aug 422

2004;10(4):299-309. 423

8. IFFGD. IBS in the real world survey. IFFGD. Milwaukee, WI;2002. 424

9. Chang L. Review article: epidemiology and quality of life in functional 425

gastrointestinal disorders. Aliment Pharmacol Ther. Nov 2004;20 Suppl 7:31-39. 426

10. Riedl A, Schmidtmann M, Stengel A, et al. Somatic comorbidities of irritable bowel 427

syndrome: a systematic analysis. J Psychosom Res. Jun 2008;64(6):573-582. 428

11. Fond G, Loundou A, Hamdani N, et al. Anxiety and depression comorbidities in 429

irritable bowel syndrome (IBS): a systematic review and meta-analysis. European 430

archives of psychiatry and clinical neuroscience. Dec 2014;264(8):651-660. 431

12. Nojkov B, Rubenstein JH, Chey WD, Hoogerwerf WA. The impact of rotating shift 432

work on the prevalence of irritable bowel syndrome in nurses. Am J Gastroenterol. 433

Apr 2010;105(4):842-847. 434

13. Patel A, Hasak S, Cassell B, et al. Effects of disturbed sleep on gastrointestinal and 435

somatic pain symptoms in irritable bowel syndrome. Aliment Pharmacol Ther. Aug 436

2016;44(3):246-258. 437

14. Van Oudenhove L, Tornblom H, Storsrud S, Tack J, Simren M. Depression and 438

Somatization Are Associated With Increased Postprandial Symptoms in Patients 439

With Irritable Bowel Syndrome. Gastroenterology. Apr 2016;150(4):866-874. 440

15. Grinsvall C, Tornblom H, Tack J, Van Oudenhove L, Simren M. Psychological factors 441

selectively upregulate rectal pain perception in hypersensitive patients with 442

irritable bowel syndrome. Neurogastroenterol Motil. Dec 2015;27(12):1772-1782. 443

16. Van Oudenhove L, Crowell MD, Drossman DA, et al. Biopsychosocial Aspects of 444

Functional Gastrointestinal Disorders. Gastroenterology. Feb 18 2016. 445

17. Simrén M, Månsson A, Langkilde AM, et al. Food-related gastrointestinal symptoms 446

in the irritable bowel syndrome. Digestion. 2001;63(2):108-115. 447

18. Eswaran S, Tack J, Chey WD. Food: the forgotten factor in the irritable bowel 448

syndrome. Gastroenterology clinics of North America. Mar 2011;40(1):141-162. 449

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19. Barrett JS, Gearry RB, Muir JG, et al. Dietary poorly absorbed, short-chain 450

carbohydrates increase delivery of water and fermentable substrates to the 451

proximal colon. Aliment Pharmacol Ther. Apr 2010;31(8):874-882. 452

20. Ong DK, Mitchell SB, Barrett JS, et al. Manipulation of dietary short chain 453

carbohydrates alters the pattern of gas production and genesis of symptoms in 454

irritable bowel syndrome. J Gastroenterol Hepatol. Aug 2010;25(8):1366-1373. 455

21. Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG. A diet low in FODMAPs 456

reduces symptoms of irritable bowel syndrome. Gastroenterology. Jan 457

2014;146(1):67-75 e65. 458

22. Staudacher HM, Whelan K, Irving PM, Lomer MC. Comparison of symptom response 459

following advice for a diet low in fermentable carbohydrates (FODMAPs) versus 460

standard dietary advice in patients with irritable bowel syndrome. J Hum Nutr Diet. 461

May 25 2011. 462

23. Mazzawi T, Hausken T, Gundersen D, El-Salhy M. Effects of dietary guidance on the 463

symptoms, quality of life and habitual dietary intake of patients with irritable bowel 464

syndrome. Molecular medicine reports. Sep 2013;8(3):845-852. 465

24. Eswaran SL, Chey WD, Han-Markey T, Ball S, Jackson K. A Randomized Controlled 466

Trial Comparing the Low FODMAP Diet vs. Modified NICE Guidelines in US Adults 467

with IBS-D. Am J Gastroenterol. Dec 2016;111(12):1824-1832. 468

25. Bohn L, Storsrud S, Liljebo T, et al. Diet low in FODMAPs Reduces Symptoms of 469

Irritable Bowel Syndrome as Well as Traditional Dietary Advice: A Randomized 470

Controlled Trial. Gastroenterology. Aug 5 2015. 471

26. Drossman DA. The functional gastrointestinal disorders and the Rome III process. 472

Gastroenterology. Apr 2006;130(5):1377-1390. 473

27. Spiegel BM, Gralnek IM, Bolus R, et al. Clinical determinants of health-related quality 474

of life in patients with irritable bowel syndrome. Arch Intern Med. Sep 13 475

2004;164(16):1773-1780. 476

28. Bellini M, Gemignani A, Gambaccini D, et al. Evaluation of latent links between 477

irritable bowel syndrome and sleep quality. World J Gastroenterol. Dec 14 478

2011;17(46):5089-5096. 479

29. Drossman D, Morris CB, Hu Y, et al. Characterization of health related quality of life 480

(HRQOL) for patients with functional bowel disorder (FBD) and its response to 481

treatment. Am J Gastroenterol. Jul 2007;102(7):1442-1453. 482

30. Peters SL, Yao CK, Philpott H, Yelland GW, Muir JG, Gibson PR. Randomised clinical 483

trial: the efficacy of gut-directed hypnotherapy is similar to that of the low FODMAP 484

diet for the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. Jul 11 485

2016. 486

31. Pedersen N, Andersen NN, Vegh Z, et al. Ehealth: low FODMAP diet vs Lactobacillus 487

rhamnosus GG in irritable bowel syndrome. World J Gastroenterol. Nov 21 488

2014;20(43):16215-16226. 489

32. Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and 490

physiological abnormalities associated with neurodevelopmental disorders. Cell. 491

Dec 19 2013;155(7):1451-1463. 492

33. Bhat MI, Kapila R. Dietary metabolites derived from gut microbiota: critical 493

modulators of epigenetic changes in mammals. Nutrition reviews. May 01 494

2017;75(5):374-389. 495

34. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota 496

on brain and behaviour. Nature reviews. Neuroscience. Oct 2012;13(10):701-712. 497

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35. Ledochowski M, Widner B, Bair H, Probst T, Fuchs D. Fructose- and sorbitol-reduced 498

diet improves mood and gastrointestinal disturbances in fructose malabsorbers. 499

Scand J Gastroenterol. Oct 2000;35(10):1048-1052. 500

36. Collins SM, Bercik P. The relationship between intestinal microbiota and the central 501

nervous system in normal gastrointestinal function and disease. Gastroenterology. 502

May 2009;136(6):2003-2014. 503

37. Buono JL, Tourkodimitris S, Sarocco P, Johnston JM, Carson RT. Impact of linaclotide 504

treatment on work productivity and activity impairment in adults with irritable 505

bowel syndrome with constipation: results from 2 randomized, double-blind, 506

placebo-controlled phase 3 trials. American health & drug benefits. Aug 507

2014;7(5):289-297. 508

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Table 1a. Baseline demographics

Characteristic Low

FODMAP m-NICE

N = 50 N = 42 p-value

Average Age — years 41.6±14.70 43.8±15.2 p=.49

Average Age — no. of patients (%) p = .49

19 – 32 years 18 (36) 15 (35.7)

33 – 49 years 18 (36) 11 (26.2)

50 – 75 years 14 (28) 16 (38.1)

Sex — no. of patients (%) p=.29

Female 33 (66) 32 (76.2)

Male 17 (34) 10 (23.8)

Race — no. of patients (%) p=.35

white 39 (78) 29 (69.1)

black 4 (8) 6 (14.3)

Asian 0 (0) 3 (7.1)

Latino 3 (6) 1 (2.4)

Other 2 (4) 2 (4.8)

unknown 2 (4) 1 (2.4)

Average BMI — kg/m2 27.2 ±6.12 31.7 ±7.96 p=.003

BMI — no. of patients (%) p=.18

underweight (≤18.5 kg/m2) 1 (2) 0 (0)

healthy weight (18.6 – 24.9 kg/m2) 18 (36) 10 (24.4)

overweight (25 – 29.9 kg/m2) 16 (32) 10 (24.4)

obese (≥ 30 kg/m2) 15 (30) 21 (51.2)

Employment Status p=.50

Currently Working 33 (70) 26 (63)

Not Currently Working 14 (30) 15 (37)

Taking Antidepressant Medication — no. of patients (%) p=1.00

Taking Antidepressants 25 (50) 21 (50)

Not Taking Antidepressants 25 (50) 21 (50)

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Table 1b. Baseline Quality of Life Variables

Variable Name Low FODMAP m-NICE

n = 47 n = 41 p-value

IBS-QOL (Patrick, Drossman, et al)

Overall 54.0 ±18.4 54.4 ±20.4 p=.93

Dysphoria 56.4 ± 25.0 56.4 ± 27.3 p=1.00

Interference with Activity 47.0±23.2 47.8±23.8 p=.87

Body Image 52.7±21.0 48.9±41.3 p=.44

Health Worry 58.0±24.1 63.1±20.1 p=.29

Food Avoidance 34.4±26.3 35.8±24.7 p=.80

Social Reaction 60.5±23.9 63.4±23.6 p=.56

Sexual 68.8±30.2 66.2±56.9 p=.69

Relationship 69.1±19.5 63.7±26.9 p=.28

HADS (Mapi Research Institute)

Anxiety Score 9.0±3.4 9.1±4.3 p=.90

Depression Score 4.4±3.3 5.5±3.9 p=.18

WPAI:SHP (Reilly Associates)

Absenteeism 5.9±13.3 1.6±5.1 p=.09

Presenteeism 39.4±23.3 35±23.5 p=.48

Work Productivity Loss 41.5±24.5 35.8±22.8 p=.37

Activity Impairment 50.7±22.9 52.3±26.2 p=.77

Modified Sleep Questionnaire 7.4±2.1 7.7±2.2 p=.44

IVRS Sleep and Fatigue

Sleep Quality 5.4±1.5 5.1±1.6 p=.49

Fatigue 5.1±1.9 5.4±2.1 p=.41

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Work Productivity and Activity Impairment Questionnaire for Irritable Bowel Syndrome (WPAI-IBS)

Table 2a. Work Productivity Scores, Baseline vs. Week 4 (note: higher score is worse)

Low FODMAP

m-NICE Difference between

groups1

Variable Baseline

n=25

Week 4

n=24

Difference within group

(95% CI)

Baseline

n=22

Week 4

n=23


(95% CI)

absenteeism, mean ±SD

(work time missed) 5.59±14 5.10 ±12 -0.74 (-3.86, 2.38) 1.78±5 6.47±21 4.98 (-2.44, 12.4) 5.72 (-1.86, 13.3)

presenteeism, mean ±SD

(impairment while working) 38.4±23 26.3±23 -13.3 (-24.2, -2.43) 35.9±25 33.04±23 -.1.36 (-16.3, 13.56)( 12 (-5.78, 29.7)

productivity loss, mean ±SD

(overall work impairment) 40.3±24 28.3±25 -13.3 (-24.8, -1.86) 37.5±24 34.5±23 -.1.40 (-14.6, 11.8) 11.9 (-5, 28.8)

1 Difference between groups refers to the difference of the change in the average score from baseline at week 4 for low FODMAP and m-Nice subjects.

Table 2b. Activity Impairment, Baseline vs. Week 4 (note: higher score is worse)

Low FODMAP

m-NICE Difference between

groups1

Variable Baseline

n=38

Week 4

n=38


(95% CI)

Baseline

n=36

Week 4

n=36


(95% CI)

activity impairment, mean ±SD 52.6±22 29.7±24 -22.9 (-31.5, -14.3) 52.8±25 43.3±28 -9.44 (-16.1, -2.8) 13.5 (2.72, 24.2)

1 Difference between groups refers to the difference of the change in the average score from baseline at week 4 for low FODMAP and m-Nice subjects.

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Table 3. Mean Values for Selected Sleep and Fatigue related Variables, Baseline or Week 2 vs. Week 4

Low FODMAP

m-NICE

Difference

between

groups2

Baseline

n=38

Week 4

n=38

Avg. difference

within group

(95% CI)

Baseline

n=37

Week 4

n=37

Avg. difference

within group

(95% CI)

IVRS Questions

Sleep Quality, mean ±SD 5.34±2 4.38±2 -.96 (-1.47, -0.46) 5.14±2 4.61±2 -.53 (-1.06, 0) .43 (-.29, 1.2)

Fatigue, mean ±SD 5.06±2 4.19±2 -.87 (-1.4, -0.35) 5.44±2 4.90±3 -.54 (-1.16, .08) .33 (-.46, 1.13)

Modified Sleep Questionnaire

Overall Sleep QOL1, mean ±SD 7.32±2 6.42±2 -.90 (-1.62, -.17) 7.68±2 7.49±2 -.19 (-.70, .33) .71 (-.17, 1.58)

Poor Sleep Quality, mean ±SD 2.50±1 2.26±1 -.24 (-.55, .07) 2.68±1 2.59±1 -.08 (-.33, .17) .16 (-.24, .55)

Daytime Fatigue, mean ±SD 2.47±1 2.16±1 -.32 (-.56, -.07) 2.59±1 2.54±1 -.05 (-.31, .21) .26 (-.09, .61)

Trouble Falling Asleep, mean ±SD 2.34±1 2.00±1 -.34 (-.65, -.03) 2.41±1 2.35±1 -.05 (-.29, .18) .29 (-.09, 0.67)

1 Sum of all 3 questions from the Modified Sleep Questionnaire, maximum possible score = 12

2 between group differences refer to the difference between the average change from baseline between groups at week 4 for low FODMAP and

M-Nice subjects. This also includes the 95% confidence interval for the difference.

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Figure 1. CONSORT flow diagram

Assessed for eligibility (n=171)

Excluded (n= 79)

Not meeting inclusion criteria (n=33)

Declined to participate (n=30)

Other reasons (n=16)

Analyzed (n=45)

Excluded from analysis (give reasons) (n=0)

Lost to follow-up (give reasons) (n=3) Not returning calls (n=1) Started antibiotics (n=1) Too expensive (n=1)

Discontinued intervention (give reasons) (n=2) Too limiting (n=1) Moved out of state (n=1)

Allocated to intervention (n=50)

Received allocated intervention (n=50)

Did not receive allocated intervention (give

reasons) (n=0)

Lost to follow-up (give reasons) (n=0)

Discontinued intervention (give reasons) (n=2)

Failed to make symptom reports (n=2)

Allocated to intervention (n=42)

Received allocated intervention (n=41)

Did not receive allocated intervention (give

reasons) (n=1)

Dietitian not available for counselling (n=1)

Analyzed (n=39)

Excluded from analysis (give reasons) (n=0)

Allocation

Analysis

Follow-Up

Randomized (n=92)

Enrollment

Low FODMAP mNICE

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Figure 2. (A) Comparison of IBS-QOL means at baseline and week 4. (B) The proportion of

patients improving by at least 14 points from baseline (meaningful clinical response) in IBS-QOL.

Figure 2A. Overall IBS-QOL Score (average and 95% Confidence Interval)

Figure 2B. Meaningful Clinical Response (proportion and 95% Confidence Interval)

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Figure 3. IBS Quality of Life Subscore Comparison of Change in Average Score from Baseline

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Figure 4a. Anxiety Score Comparison (average score and 95% confidence interval)

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Figure 4b. Depression Score Comparison (average score and 95% Confidence Interval)

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MICHIGAN METABOLOMIC AND OBESITY CENTER (MMOC)

MICHIGAN NUTRITION AND OBESITY RESEARCH CENTER (MNORC)

2012 PILOT/FEASIBILITY STUDY GRANT APPLICATION

PROPOSAL TITLE: Low FODMAP diet vs. usual care for patients with irritable bowel syndrome with diarrhea (IBS-D): a randomized, controlled trial and gastrointestinal microbiome analysis PRINCIPAL INVESTIGATOR: __Shanti Eswaran, MD__________________________ FACULTY POSITION: __Clinical Lecturer______________________________ DEPARTMENT: __Department of Medicine- Division of Gastroenterology

ADDRESS: ___3912 Taubman Center________________________

SPC NUMBER: ____5362_____________________________________

TELEPHONE/E-MAIL: [email protected]____________________

TOTAL FUNDING REQUESTED:

__$50,000_____________________________________

USE OF HUMAN SUBJECTS/PATIENTS: _________NO ____X______YES IF YES, IRB APPROVAL NUMBER____pending_______DATE_______________ USE OF VERTEBRATE ANIMALS: ___X______NO __________YES IF YES, IACUC APPROVAL NUMBER________________DATE_______________ HAS THIS PROPOSAL BEEN SUBMITTED PREVIOUSLY TO ANY PEER REVIEW AGENCY? ___X___NO _____YES IF YES, WHAT AGENCY__ DATE SUBMITTED _____ DATE WHEN OUTCOME WILL BE KNOWN _______ The applicant agrees to accept responsibility for the scientific and technical conduct of the research project and agrees to all terms and conditions of grants awarded by the Michigan Metabolomic and Obesity Center. SIGNATURE OF APPLICANT ________________________________________________________DATE___________ SIGNATURE OF DEPARTMENT CHAIR: ________________________________________________________DATE___________

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Type of Submission (Check One): 1._________BioMedical (basic biomedical research) 2._____X____Clinical and Translational APPLICANT ELIGIBILITY (Check One): 1.___X_____NEW INVESTIGATOR BEGINNING CAREER IN NUTRITION/OBESITY RESEARCH 2.________ESTABLISHED INVESTIGATOR TRANSFERRING EXPERTISE TO RESEARCH

ON NUTRITION/OBESITY 3.________ESTABLISHED NUTRITION/OBESITY INVESTIGATOR PROPOSING A PROJECT

THAT IS NOT AN EXTENSION OR OUTGROWTH OF CURRENT RESEARCH IN HIS/HER LABORATORY

IF OPTION 2 OR 3 IS SELECTED, PROVIDE BELOW A BRIEF JUSTIFICATION FOR YOUR CHOICE. (Do not exceed the space remaining on this page):

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B. SCIENTIFIC ABSTRACT:

As irritable bowel syndrome (IBS) symptoms are often refractory to conventional therapies, there has been increasing interest in the role of diet in IBS. In particular, foods that are high in fermentable oligo-, di-, and mono-saccharides and polyols (FODMAPs) may exacerbate symptoms of IBS. Thus, a diet with a restricted FODMAP content has recently gained attention for the treatment IBS. The mechanism by which symptoms are improved is unclear, but this diet may improve symptoms by exerting changes on the GI microbiome.

Aims:

Primary Objective: 1. Compare the proportion of patients with irritable bowel syndrome (IBS-D) reporting adequate relief on a diet low in fermentable oligo-, di-, and mono-saccharides and polyols (FODMAPs) vs. usual care.

Secondary Objectives: 2) Assess the effect of a low FODMAP diet in patients with diarrhea-predominant IBS on the gastrointestinal microbiota and blood based biomarkers. 3) Compare the efficacy of a low FODMAP diet vs. standard dietary advice in patients with diarrhea-predominant IBS on pre-specified clinical and quality of life endpoints. Methods: This is a prospective randomized control trial of adults meeting the Rome III criteria for irritable bowel syndrome with diarrhea (IBS-D). After a 2 week screening period and randomization, during which the severity of symptoms will be assessed and eligibility determined, patients will be randomized to usual care or a diet low in FODMAP content for a period of 4 weeks. The primary endpoint will be a comparison of the proportion of patients in each group reporting adequate relief of their IBS symptoms. For the secondary clinical outcomes, a responder definition incorporating abdominal pain and stool consistency as proposed by the FDA will be utilized. Key IBS-D symptoms will be assessed daily and adequate relief of IBS-D symptoms will be assessed weekly during the randomization period. We will also determine if a difference can be detected with high probability in the relative abundance and variety of specific bacterial taxa between the two groups before and after the 4 week dietary intervention. In addition, blood samples will be collected before randomization to measure relevant biomarkers of immune activation.

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C. DETAILED BUDGET FOR DIRECT COSTS ONLY

PERSONNEL

TYPE APPT. (mont

hs)

Effort on Project

(Calendar Months)

INST. BASE

SALARY

DOLLAR AMOUNT REQUESTED (omit cents)

NAME ROLE ON PROJECT

SALARY REQUESTED

FRINGE BENEFITS

TOTAL

Shanti Eswaran

Principal Investigator

5%

0

William Chey

Co-investigator

0%

Lina Nahlawi

Study Coordinator

50% 44,434

22,217

6,665

27,883

SUBTOTALS

22,217

6,665

27,883

SUPPLIES (Itemize by category) Storage (MCRU) Symptom Monitoring

90 700

OTHER EXPENSES (Itemize by category) MCRU fee for dietician: $31.09 (per dietary evaluation) x 3 evaluations x 100 patients

9,327

PATIENT CARE COSTS

INPATIENT

OUTPATIENT $120 compensation per patient (90 pts) 12,000

TOTAL DIRECT COSTS

50,000

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BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors.

Follow this format for each person. DO NOT EXCEED FOUR PAGES.

NAME

Shanti Eswaran POSITION TITLE

Clinical Lecturer eRA COMMONS USER NAME (credential, e.g., agency login)

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)

INSTITUTION AND LOCATION DEGREE (if applicable) MM/YY FIELD OF STUDY

University of California at Berkeley Berkeley, CA

BA 05/1997 Molecular and Cell Biology

University of Michigan Ann Arbor, MI

MD

06/2002

Medicine

University of Michigan Ann Arbor, MI

Residency

6/2005 Internal Medicine

College of Physicians and Surgeons Columbia University New York, NY

Fellowship 6/2008 Gastroenterology

Please refer to the application instructions in order to complete sections A, B, C, and D of the Biographical Sketch. A) Personal Statement

The goal of the proposed research is to investigate the effect of a dietary intervention for irritable bowel syndrome and diarrhea (IBS-D). Specifically, we plan to conduct a randomized, controlled trial and biomarker analysis comparing the response of IBS-D patients to a diet low in fermentable oligo-, di-, and mono-saccharides and polyols (FODMAPs) diet versus standard dietary advice. I have a broad background in gastroenterology and during my first years as a faculty member, I focused mostly on clinical and collaborative efforts. The primary focus of my clinical practice has been functional gastrointestinal diseases (FGIDs) and I recently published a review of the impact of food on irritable bowel syndrome. My current goals include translating this experience to clinical research, developing a clinical academic career with a focus on the role of food in IBS. The resources available to faculty at the University of Michigan will allow me to lead and administer this project. My mentor Dr. William Chey, who is a co-investigator, has conducted multiple trials in this area and has contributed to guidelines for trial design in FGIDs. I have

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chosen Dr. Richard Saad and Teresa Han-Markey, MD, RD to aid in statistical analysis and dietician expertise, respectively. The Michigan Clinical Research Unit (MCRU), which provides the clinical staff, resources, and infrastructure necessary to conduct human clinical research protocols at the University of Michigan, will be utilized as well. The MCRU provides research dieticians and services to conduct nutrition assessments using three day food diaries and validated dietary intake analyses. The MCRU also provides specimen collection, processing, and a core laboratory for samples, providing short and long term storage. In summary, my clinical experience, mentorship, and available resources will enable me to lead the proposed project. B) Positions and Honors Employment History: 7/2008-7/2009 Clinical Instructor, Northwestern Medical Faculty Foundation, Division of

Gastroenterology, Chicago, IL 8/2009-Present Clinical Lecturer, University of Michigan, Division of Gastroenterology, Ann Arbor, MI Other Experience and Memberships: 2011-Present Rome Foundation Working Team for the Role of Food in Functional

Gastrointestinal Disorders, member 2011-Present Nutrition Advisory Committee member, University of Michigan Hospitals Honors: 1996 President’s Undergraduate Fellowship Grant for personal research project

conducted at University of California at Berkeley 1997 Chaikoff Award for outstanding undergraduate honors thesis and academic

achievement, University of California at Berkeley 1997 Graduated with Honors 2005 Poster of Distinction at ACG Annual Meeting, Honolulu 2007 Recipient of Crohn’s & Colitis Foundation of America Visiting Fellowship 2007-2008 Chief Gastroenterology Fellow, Columbia University Medical Center C) Peer Reviewed Publications

1) Elmunzer J, Padhya KT, Lewis JJ, Rangnekar AS, Saini SD, Eswaran SL, Scheiman JM,

Pagani FD, Haft JW, Waljee AK. Endoscopic Findings and Clinical Outcomes in Ventricular Assist Device Recipients with Gastrointestinal Bleeding. Dig Dis Sci. 2011 Jul 27. PMID:21792619

2) Harris A, Eswaran S, et al. Mesalamine-induced pneumonitis and serum sickness-like reaction.

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Gastroenterology & Hepatology. 3(11): 875-877. 2007 November. PMCID: PMC3104150 3) Chey, Eswaran, Howden, Inadomi, Fendrick, Scheiman. Primary care physician perceptions of NSAID and aspirin-associated toxicity: results of a national survey. Alimentary Pharmacology & Therapeutics. 23(5): 655-668. 2006 March. 4) Shaw MK, Lorens JB, Dhawan A, DalCanto R, Tse HY, Tran AB, Bonpane C, Eswaran SL, Brocke S, Sarvetnick N, Steinman L, Nolan GP, Fathman CG. Local delivery of interleukin 4 by retrovirus-transduced T lymphocytes ameliorates experimental autoimmune encephalomyelitis. Journal of Experimental Medicine. 185: 1711-4. 1997 May 5. PMC2196296 5) Smith DF, Burke J, Actor JK, Stults N, Eswaran S, Jennings VM, Hunter RL. Bioluminescent hybridization immunoassays for the detection and quantification of Mycobacterium and Malaria RT-PCR amplified RNA

during in vivo infection. Clinical Chemistry. 42: 1894 (1996). D) Research Support Pending funding: Funding for related research is pending from the Rome Foundation for $50,000. This grant was applied for in December 2011 and will be awarded in April 2012.

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BIOGRAPHICAL SKETCH Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2.

Follow this format for each person. DO NOT EXCEED FOUR PAGES.

NAME William D. Chey, MD

POSITION TITLE

Professor of Internal Medicine eRA COMMONS USER NAME

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)

INSTITUTION AND LOCATION DEGREE (if applicable) YEAR(s) FIELD OF STUDY

University of Pennsylvania BA 1982 Biology Emory University School of Medicine MD 1986 Medicine

A. PERSONAL STATEMENT:

Dr. Chey has had a long track record of conducing trials which address the pathophysiology, diagnosis and treatment of irritable bowel syndrome. He has participated in the Rome III process which developed the current diagnostic criteria for the functional bowel disorders and is a member of the advisory board overseeing the Rome IV process. He was a member of the national task force which created the Evidence-based monograph on the management of IBS produced by the American College of Gastroenterology in 2009. His recent clinical and research interests have turned to the role of food in the irritable bowel syndrome. Dr. Chey supervises a rapidly growing program of dietary interventions for functional GI disorders at the University of Michigan. He was recently appointed co-chair of the Rome Foundation working group addressing the role of food in functional GI disorders. This working group is currently producing a document which is expected to be published in early 2013.

B. POSITIONS:

1986-1989: Resident in Internal Medicine, Emory Affiliated Hospitals, Atlanta, Georgia

1990-1993: Fellow in Gastroenterology, University of Michigan, Ann Arbor, Michigan

1989-1990: Senior Associate in Internal Medicine, Juha Kokko, Professor and Chairman of Medicine, Emory University School of Medicine, Atlanta, Georgia

1993-1996: Lecturer in Internal Medicine, University of Michigan, Ann Arbor, MI

1996-2001: Assistant Professor, Department of Internal Medicine, University of Michigan, Ann Arbor, MI

2001-2007 Associate Professor, Department of Internal Medicine, University of Michigan, Ann Arbor, MI

2007-present Professor, Department of Internal Medicine, University of Michigan, Ann Arbor, MI

HONORS:

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1994-1996 Glaxo Institute for Digestive Health Award for Clinical Research

2001-2012 Elected to “Best Doctors”. Best Doctors, Inc, Aiken, SC

2002, 2007 Honored as one of the “Best Doctors in Detroit”, Hour Detroit Magazine

2003 Selected to the Rome III Committee on Functional GI Disorders

2003 Award for “Excellence in Teaching” from 2003 University of Michigan GI fellowship class

2003 Michigan Chapter American College of Physicians – “Governor’s Award”

2004, 2005 Rewarded for teaching excellence – Department of Internal Medicine, University of Michigan Internal Medicine Residency Program

2005 Award for “Excellence in Mentorship” from 2005 University of Michigan GI fellowship class

2007 ACG/Novartis Motility Award, American College of Gastroenterology

2009 ACG/Salix Leadership Training Award

2010 Selected Co-editor-in-chief: American Journal of Gastroenterology

2010 “75 Best Gastroenterologists in America” Becker’s ASC Review (http://www.beckersasc.com/gastroenterology-and-endoscopy/75-of-the-best-gastroenterologists-in-america.html)

2010-2012 “America’s Top Doctors” Castle Connolly

C. SELECTED PEER REVIEWED PUBLICATIONS (out of 122, in chronological order):

1. Ford AC, Chey WD, Talley NJ, Malhotra A, Spiegel BMR, Moayyedi P. Utility of diagnostic tests for celiac disease in Irritable Bowel Syndrome: Systematic review and meta-analysis. Arch Int Med 2009;169:651-8.

2. Brandt L, Chey WD. Foxx-Orenstein AE, ACG IBS Task Force. An evidence-based review of the management of irritable bowel syndrome. Am J Gastroenterol 2009;104 (supplement 1):S1-S35.

3. Spiegel B, Camilleri M, Bolus R…Chey WD (5/9)…Whitehead WE. Psychometric evaluation of patient reported outcomes in IBS randomized controlled trials: A Rome Foundation Working Group Report. Gastroenterology 2009;137:1944-53. PMCID: PMC2793276.

4. Spiegel B, Bolus R, Harris LA, Lucak S, Mayer E, Naliboff B, Esrailian E, Chey WD, Lembo A, Karsan H, Tillisch K, Talley J, Chang L. Measuring IBS Patient Reported Outcomes with an Abdominal Pain Numeric Rating Scale: Results from the PROOF Cohort. Aliment Pharmacol Ther, 2009;30:1159-70. PMCID: PMC2793273.

5. Saad R, Rao S, Hasler WL…Chey WD (15/15). How well do stool form or stool frequency

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correlate with colonic transit: Results from a multi-center study using the SmartPill Wireless pH/Pressure Capsule & radio-opaque Sitzmarker test in healthy controls and constipated patients. Am J Gastroenterol 2010;105:403-11.

6. Luther J, Higgins P, Moayyedi P, Vakil N, Chey WD. Clarithromycin-based triple therapy vs. Bismuth-based quadruple therapy for H. pylori infection: A meta- analysis. Am J Gastroenterol 2010;105:65-73.

7. Chey WD (1/7), Howden CW, Tack J…Earnest D. Long-Term Tegaserod Treatment for Dysmotility-like Functional Dyspepsia: Results of Two Identical 1-year Cohort Studies. Dig Dis Sci 2010;55:684-97.

8. Chey WD, Nojkov B, Cash BD. The yield of colonoscopy in patients with nonconstipated IBS: Results from a prospective, controlled US multicenter trial. Am J Gastroenterol, 2010;105:859-65. PMCID: PMC2887227

9. Nojkov B, Rubenstein J, Chey WD, Hoogerwerf W. The effect of shift work on the prevalence and clinical impact of Functional Bowel Disorders in nurses. Am J Gastroenterol, 2010;105:842-7. PMCID: PMC2887235

10. Kloetzer L, Chey WD, McCallum RW, Koch KL, Wo JM, Sitrin M, Katz LA, Lackner JM, Parkman HP, Wilding GE, Semler JR, Hasler WL, Kuo B. Motility of the antroduodenum in healthy and gastroparetics characterized by wireless motility capsule. Neurogastroenterol Motil 2010;22:527-e117.

11. Spiegel B, Bolus R, Agarwal N, Harris LA, Lucak S, Esrailian E, Chey WD, Lembo A, Karsan H, Tillisch K, Talley J, Sayuk G, Chang L. Measuring Symptoms in Irritable Bowel Syndrome: Development of a Framework for Clinical Trials. Aliment Pharmacol Ther, 2010;32:1275-91.

12. Pimental M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, Mareya S, Shaw AL, Bortey E, Forbes WP. Treatment of non-constipation Irritable Bowel Syndrome with the non-absorbed antibiotic Rifaximin. New Engl J Med, 2011;364:22-32.

13. Chey WD, Camilleri M, Chang L, Rikner L, Graffner H. A Double-Blind Randomized Placebo-controlled Phase IIb Study of the IBAT inhibitor A3309 in Patients with Chronic Idiopathic Constipation (CIC). Am J Gastroenterol 2011;106:1803-12. PMCID: PMC3188811

14. Eswaran S, Tack J, Chey WD. Food: The forgotten factor in IBS. Gastroenterol Clinics North Am 2011;40:141-62.

15. Cash BD, Rubenstein JH, Young PE, Gentry A, Nojkov B, Lee D, Dobhan R, Chey WD. The prevalence of abnormal celiac antibodies and celiac disease in patients with suspected irritable bowel syndrome: a prospective multi-center US study. Gastroenterol 2011;141:1187-93. PMCID: PMC3186819

C. Research Support

Ongoing Research Support 1. NIH for “Development and Initial Validation of PROMIS GI Distress Scale”

Principle Investigator: Dinesh Khanna, MD, MS and Brennan Spiegel MD, MSHS

External Consultant: William D. Chey, M.D.

Funding Period: 9/1/09 – 6/30/13

2. Ironwood Pharmaceuticals for “Development and validation of the Automated Evaluation of GastroIntestinal Symptoms (AEGIS) Platform”

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Principal Investigator: William D. Chey, MD & Brennan Spiegel, MD

Funding period: 7/1/11 – 6/30/14

Selected Completed Research Support

1. Allergan Pharmaceuticals for “A multicenter, multiple-dose, double-blind, randomized, placebo controlled, parallel group study of the safety and efficacy of oral AGN 203818 given twice daily for 4 weeks for the relief of IBS pain”

Principal Investigator: WD Chey, MD

Funding period: 5/1/07-5/08

Please see study title for a description of the study.

2. Alizyme for “A phase III, multicenter, open label, extention study to evaluate the long-term safety of renzapride in women with constipation-predominant IBS”

Principal Investigator: WD Chey, MD; Co-investigators: R Saad, MD

Funding period: 5/1/06-6/30/08


3. Microbia, Inc. for “A randomized, multi-center, double-blind, placebo controlled dose-range-finding parallel-design, phase 2 trial of oral linaclotide acetate administered to patients with irritable bowel syndrome with constipation”




4. Microbia, Inc. for “A randomized, multi-center, double-blind, placebo controlled dose-range-finding parallel-group, phase 2 trial of oral linaclotide acetate administered to patients with chronic constipation”




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5. Novartis for “The effects of tegaserod on orocecal transit in elderly patients with chronic constipation”

Principal Investigator: WD Chey, MD; Co-investigators: H Parkman, I Bottoli, D Joseph



6. TAP for “NSAID and aspirin utilization amongst US primary care physicians: A follow-up survey”




7. Salix for “A phase 2, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of 3 different doses of rifaximin bid for 2 or 4 weeks in the treatment of patients with IBS-D”




8. Sucampo Pharmaceuticals for “An open-label study of lubiprostone for constipation-predominant irritable bowel syndrome”




9. TAP Pharmaceuticals for “Non-steroidal anti-inflammatory drug and aspirin utilization amongst US primary care physicians: A follow-up survey”


Co-investigators: N Elnachef, JS Scheiman, AM Fendrick, CW Howden, MD

Funding Period: 4/06-8/08


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10. Prometheus Laboratories for “Procurement of blood samples for use in the development of a gastrointestinal disease test panel”

Principle Investigator: WD Chey, MD

Funding period: 9/1/07- 4/08


11. Pharmos Corporation “A double-blind, randomized, placebo-controlled phase 2b study of 100, 200, and 300 mg BID Dextofisopam in female outpatients with irritable bowel syndrome”




12. Bill & Melinda Gates Foundation for “A clinical trial of H. pylori eradication in Latin America”

Principal Investigator: Laurence Baker, DO

Study Executive Officer & Steering Committee: William D. Chey, MD

Funding period: 12/08 – 11/10


13. American Gastroenterological Association for “The differences in physiologic mechanisms underlying chronic constipation in elderly versus younger adults with constipation”

Principal Investigator: Richard Saad, MD

Project Mentor: William D. Chey, MD



14. American College of Gastroenterology for “Pilot study to determine the key characteristics which aid in the diagnosis of constipated patients with dyssynergic defecation”

Principal Investigator: Monthira Maneerattanaporn, MD

Project Mentor: William D. Chey, MD


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This study seeks to identify the key clinical characteristics and features of the digital rectal examination which allow an accurate diagnosis of dyssynergic defecation.

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F1: Aims

Primary Objective: Compare the proportion of patients with irritable bowel syndrome (IBS-D) reporting adequate relief on a diet low in fermentable oligo-, di-, and mono-saccharides and polyols (FODMAPs) vs. usual care.

Secondary Objectives: -Assess the effect of a low FODMAP diet in patients with diarrhea-predominant IBS on the gastrointestinal microbiota and blood based biomarkers. -Compare the efficacy of a low FODMAP diet vs. standard dietary advice in patients with diarrhea-predominant IBS on pre-specified clinical endpoints (abdominal pain, abdominal discomfort, stool consistency, stool frequency, fecal urgency, and bloating) and quality of life endpoints. -Perform an exploratory analysis to identify biomarkers which identify a subgroup of IBS-D patients who are more likely to respond to dietary interventions.

F2: Significance and Innovation:

IBS is a symptom based diagnosis characterized by the presence of abdominal pain or discomfort in association with altered bowel habits.1,2 Given the absence of any universally agreed upon objective physical, radiographic, or laboratory biomarkers of disease, IBS is defined by the presence of typical symptoms rather than a specific physiologic abnormality. With prevalence estimates of 10-15% in the general population, IBS has been shown to negatively impact on quality of life and individuals’ abilities to carry out daily activities. Further, IBS is responsible for a substantial health resource and economic burden.3,4

Several factors have been suggested to play a role in the pathogenesis of IBS, including disturbed motility, alterations in the brain-gut axis, genetic factors, impaired gut barrier function, immunologic dysregulation, psychosocial factors, and the gut microbiome. The heterogeneity in phenotype and pathogenesis has created significant challenges in drug therapy development for IBS. We and others have found that IBS patients frequently desire a more holistic approach to their care than is often offered by providers trained in Western medicine. Up to 2/3 of IBS patients associate symptom onset or exacerbation with eating a meal.5 Because of this, patients often are interested in learning about potential dietary interventions for their IBS symptoms.6 Current dietary advice for IBS patients includes modification of dietary fiber intake, lactose elimination, avoidance of trigger foods, regular meals, and minimizing consumption of caffeine and fat. Unfortunately, these standard dietary recommendations are not evidence-based and oftentimes prove ineffective for IBS patients.7-9

Recently, a more comprehensive dietary approach has been developed as a treatment for IBS. This approach restricts the intake of foods that are high in fermentable oligo-, di-, and mono-saccharides and polyols (FODMAPs) which may exacerbate the symptoms of IBS (see appendix A). FODMAPs are short-chain carbohydrates with common functional properties in that they are poorly absorbed, osmotically active,10 and rapidly fermented by bacteria.11 Fermentation of these substrates results in gas production and an increased fluid load with secondary luminal distension and resultant peristalsis involving the distal small bowel and

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proximal colon. It has been postulated that these physiological effects might underlie the symptoms of IBS in a subset of sufferers. Recent studies provide support for the use of the low FODMAP diet in patients with IBS-D symptoms, although these studies are small, utilize non-validated endpoints and have largely been conducted by a single center in Australia. Given the intrinsic differences in genetics, the gut microbiome, and diet between populations, validation of this approach would seem appropriate before widespread adoption can be endorsed.

Acknowledging that fermentation results from the interaction between ingested substrates and the gut microbiome, it is reasonable to hypothesize that the low FODMAP diet might exert its beneficial clinical effects by altering the gut microbiome, which some have found to be altered in IBS patients when compared to controls.12

,13 In fact, recent work suggests that dietary changes

can alter the GI microbiome in healthy subjects within 24 hours.14 Studies suggest that fundamental differences in the composition of the human microbiome may be associated with the IBS disease phenotype in adults.15 Abdominal pain in IBS may be associated with alterations in visceral sensitivity or pain perception induced by the composition of the gut microbiome. In IBS-D patients, previous studies yielded evidence of diminished quantities of Lactobacillus spp in adult patients, whereas patients with IBS-C had increased proportions of Veillonella spp.16 Studies with probiotics suggest that manipulation of intestinal microbial communities may modulate visceral hypersensitivity17 and alter the disease course in IBS.18 However, more information is needed about how the human microbiome contributes to the constellation of symptoms in IBS, particularly in how it relates to diet. Specific nutritional interventions may provide efficacious microbial manipulation strategies for the treatment of IBS and, the effects of dietary manipulation on the gut microbiome in IBS patients have not been carefully investigated. More specifically, the effect of a low FODMAP diet on the GI microbiome has thus far not been evaluated in healthy volunteers or patients with IBS.

We propose a methodologically rigorous, appropriately powered randomized, controlled trial to assess the impact on the gut microbiome of a low-FODMAP diet vs. usual care in patients with IBS-D. We hypothesize that a low-FODMAP diet will create a meaningful and measurable change the gut microbiome, potentially offering a mechanism through which symptom response is mediated. We also hypothesize that a low FODMAP diet will lead to a greater proportion of patients reporting significant improvement in IBS symptoms than standard dietary advice. Finally, we will use this trial to collect serum samples to assess a number of different biomarkers in the hopes of generating hypotheses regarding physiology based IBS subgroups and predictors of response or failure to dietary interventions. F3: Plans for Future Funding of the Project: The primary investigator will be applying for a career development award with the American College of Gastroenterology or American Gastroenterological Association later this year. The MNORC award would significantly strengthen these applications. Data generated from this study will serve as preliminary data for future grant proposals to NIH, specifically for an RO1 and/or a K23 award. In preliminary discussions with officials at NIDDK, there has been interest expressed in a large scale, randomized, controlled study which would assess the impact of the low FODMAP diet in IBS-D patients on rigorous clinical endpoints, serum, stool and tissue biomarkers, and the gut microbiome. The preliminary data generated from the current study proposal will be indispensable to further applications for NIH funding.

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F4: Previous work relevant to the proposal Dr. Eswaran is a member of the faculty and Functional Bowel Disorders team in the Division of Gastroenterology at the University of Michigan. She is interested in developing a clinical academic career with a focus on the role of food in IBS. She recently was appointed to the Rome Foundation Working Group which will prepare a white paper summarizing the literature on the role of food in functional GI disorders. Dr. Eswaran also serves on the Nutrition Advisory Committee at the University of Michigan.

Dr. Chey is a Professor of Medicine and director of the GI physiology laboratory at the University of Michigan. He participated on the Clinical Study Design and Bowel Symptoms committees of the Rome III process. He has extensive experience in designing and conducting randomized control trials in patients with IBS. His group at the University of Michigan has extensive experience in the use of the low FODMAP diet as a treatment for IBS patients. Both Drs. Eswaran and Chey recently conducted a review of the impact of diet on IBS symptoms.19

This project will be supported by several other key collaborators. Dr. Richard J. Saad, MD, MS is an Assistant Professor of Medicine at the University of Michigan and has advanced training in clinical research methodology and statistical analysis. Dr. Saad will provide statistical support for this trial. Theresa Han-Markey, MS, RD is a registered dietician and Lecturer in the School of Public Health at the University of Michigan who has extensive experience in clinical research assessing dietary interventions in a number of disease states. She will provide research design and clinical support for our trial. Finally, we have asked Susan Shepherd, PhD, BApp Sci, M Nut & Diet, the inventor of the low FODMAP diet, to provide advice on the standardized teaching materials that will be utilized in this trial. Dr. Shepherd will also serve as a clinical resource should questions or practical issues regarding implementation of the diet arise in preparation for or during the trial.

F5: Experimental Design

Design: Randomized control trial

Patient population (also see Human Subjects category, below):

Adults meeting the Rome III criteria for irritable bowel syndrome with diarrhea (IBS-D) will be recruited from the general gastroenterology clinic, functional bowel disorders clinic, and Michigan Bowel Control Program clinic at the University of Michigan Health System.

Inclusion Criteria:

• Males or females at least 18 years of age • Meet Rome III criteria for IBS,2 as assessed by a gastroenterologist:

o Recurrent abdominal pain or discomfort at least three days per month in the last three months associated with two or more of the following:

� 1. Improvement with defecation � 2. Onset associated with a change in frequency � 3. Onset associated with a change in form(appearance) of stool

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• Fulfill the Rome III stool consistency criteria for IBS –D o Loose (mushy) or watery stools at least 25% o Hard or lumpy stool <25% of bowel movements o Symptoms of at least six months duration

• Willingness to maintain a stable dosage of IBS medications during the pretreatment baseline period, including tricyclic antidepressants; “rescue” medications permitted (ie Loperamide 2mg up to 4 times per day prn diarrhea)

• Ability to provide written informed consent for study participation • Capable of independently completing all requirements of the study including returning for

required visits • Documentation of normal colonoscopy/flexible sigmoidoscopy with biopsies within five

years • Documentation of normal TSH, CBC, electrolyte panel • Negative evaluation for celiac disease either with normal TTG, EMA, and/or duodenal

biopsy. Exclusion Criteria:

� Unable to understand or provide written informed consent � Pregnancy � IBS with constipation or mixed subtype � Comorbid medical problems that may affect gastrointestinal transit or motility:

o Inflammatory bowel disease o Extraintestinal disease known to affect the gastrointestinal system (ie,

scleroderma, unstable thyroid disease, diabetes mellitus, etc.) o Severe renal or hepatic disease

� Previous abdominal surgery other than appendectomy, cholecystectomy, and gynecologic/urologic surgery

� Previous treatment with a low FODMAP diet � Concurrent medications not permitted including probiotics, antibiotics, and narcotics � Active participation in another form of dietary therapy � Patients who have undergone surgery to the GI tract except appendectomy or

cholecystectomy if performed more than six months prior to enrollment. Experimental Protocol (see Appendix B and Appendix C) Consecutive patients with IBS-D will be recruited from the outpatient clinics of the University of Michigan Health System. Eligible IBS-D patients will be asked to participate in a study that will test the efficacy a novel diet recommended for IBS (the low FODMAP diet). As this is a diet trial, the dieticians and patients will not be blinded. However, the physicians analyzing the data will be blinded as to which group the patients were randomized. Patients will be offered additional dietary counseling on the alternate diet upon completion of the study period if they so desire. Upon completion of the study, all patients will be paid a volunteer fee of $120. Visit #1: After providing written informed consent, baseline and descriptive data will be obtained including age, sex, race, pertinent medical history, prior treatments, vital signs, weight, use of

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concurrent medications and supplements, duration of symptoms, attitude towards food causing IBS symptoms, and baseline symptoms. After this visit patients will enter a two week screening period during which severity of symptoms will be assessed (see Table 1 “Timeline of the assessment of clinical endpoints”). Eligible patients must rate their average daily abdominal pain/discomfort as a 4 or higher on an 11 point numerical rating scale (NRS) (0-no pain, 10-intolerable pain) and average daily stool consistency as Bristol Stool Form Scale (BSFS) 5, 6 or 7. Patients will record symptoms daily using an interactive voice response system (IVRS). It is assumed that approximately 50% of participants will not fulfill these inclusion criteria after the screening period. IBS-D patients who fulfill the entry criteria will be randomized via computer generation in a 1:1 ratio to usual care or the study diet Visit #2 (0 weeks): Initial visit with the registered dietician (RD) at the Michigan Clinical Research Unit (MCRU). Standard dietary compliance measures used in the counseling environment are to include prospectively recorded 3 day food diaries and 24 hour dietary recall. Body weight over the course of the study will also be followed. Food diaries will be analyzed via Nutrition Data System for Research (NDSR) computer program, measuring fructose, lactose, sucrose, pectins, sorbitol, and added sugars. � Three day prospectively collected food diary collected by RD. � Primary and secondary endpoint data (see below), IBS-QOL, Hospital Anxiety and

Depression scale (HAD), Workplace Activity Impairment (WPAI) questionnaire, Sleep Assessment, BMI obtained.

� Patient will receive written and verbal instructions on their assigned dietary intervention. � Stool sample obtained � Biological samples for biomarker analysis obtained (blood) � Patient to record symptoms daily using an interactive voice response system (IVRS).

Visit #3 (2 weeks): 2nd visit with RD at MCRU

� Three day food diary collected � 24 hour dietary recall obtained � Vital signs and BMI checked � Primary and secondary endpoint data collected � Assess rescue medication use � Assess adverse events � Stool sample obtained

Visit #4 (4 weeks): 3rd (final) visit with RD at MCRU � Three day food diary obtained � 24 hour dietary recall obtained � Vital signs and BMI checked � Primary and secondary endpoint data, IBS-QOL, HAD, WPAI, Sleep Assessment collected � Stool sample obtained � Blood sample obtained � Assess rescue medication use � Assess adverse events

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Table 1. Timeline of the assessment of clinical endpoints

Daily (Screening & Randomization Periods)

Weekly (Randomization Period only)

Before/After Randomization Period

Abdominal pain Adequate relief Sleep quality

Stool Consistency IBS-QOL

Stool frequency Workplace Activity Index

HAD7

Bloating

Urgency

Fatigue Abdominal discomfort

Primary Endpoint: 1) Adequate relief of overall IBS symptoms: A responder will be prospectively defined as

having “adequate relief” during 50% or more of the evaluation period (weeks 3-4). The following global response question will be asked at the end of each treatment week:

• “In regard to all your IBS symptoms, as compared with the way you felt before you started the diet, have you, in the past seven days, had adequate relief of your IBS symptoms?”

• The proportion of patients in each group reporting adequate relief of their IBS symptoms will be compared.

Secondary Clinical Endpoints

2) Composite endpoint: A responder will report a ≥30% reduction in mean daily abdominal pain score and a decrease in mean daily BSFS value of ≥1 compared to baseline for ≥2 of 4 treatment weeks. The proportion of responders between the 2 groups will be compared.

3) Abdominal pain: An abdominal pain responder will report a ≥30% reduction in mean daily abdominal pain score compared to baseline for ≥2 of 4 treatment weeks. The proportion of

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responders between the two groups will be compared. Between group differences in the proportion of patients with a ≥30% reduction in mean daily abdominal pain score compared to baseline at the end of each treatment week will also be assessed.

4) Stool consistency: For stool consistency, a responder will be defined as one who reports a decrease in mean daily BSFS value of 1 or more compared to baseline for ≥2 of 4 treatment weeks. The proportion of responders between the 2 groups will be compared. Between group differences in the proportion of patients with a decrease in BSFS value of ≥1 compared to baseline at the end of each treatment week will also be assessed.

5) Stool frequency: The number of bowel movements will be recorded each day by IVRS. The change from baseline in mean daily stool frequency for each treatment week will be compared for the two groups.

6) The change from baseline in daily NRS scores averaged over each treatment week for abdominal discomfort, urgency, bloating, and fatigue will be compared between the 2 groups.

7) IBS-QOL scores, HAD scores, WPAI questionnaire, and Sleep Assessment questionnaires will be compared between groups before and after the dietary intervention.

Biomarkers

Stool : The effect of a low FODMAP diet on the gut microbiome (number and species) in the context of IBS is not known. A change in the microbiota may be a mechanism through which symptom response is mediated. PhyloChip™ Assay (Second Genome Inc., San Bruno, CA) is a hybridization based technology and analysis- algorithm designed to assess changes in the gut microbiome. This microarray-based method identifies and measures the relative abundance of more than 59,000 individual microbial taxa in any sample. This approach relies on the analysis of the entire 16S ribosomal RNA gene sequence which is present in every bacterial genome. The 16S rRNA gene contains variable regions that enable classification of the taxa present in the sample. The assay design including well-characterized reference controls allow quantification in comparison analysis. The microarray-based hybridization approach ensures that measurements on important low abundance bacteria are not overwhelmed by commonplace, dominant microbial community members. This microarray consists of 1.1 million oligonucleotide probes capable of identifying ~60,000 of Bacteria and Archaea, and provides a comprehensive census for presence and relative abundance of most known prokaryotes in a massive parallel assay. This assay has been validated by several studies in the pediatric IBS population,13 a validated rat model of IBS,20 and the gastric bacterial community.21

We hypothesize that the gut microbial signature will be altered in IBS-D patients for patients on a low-FODMAP diet compared to that of usual care. We will be measuring the shift in the relative abundance (richness) and variety (diversity) of gut microbial taxa in patients with irritable bowel syndrome (IBS-D) in response to dietary intervention. Stool microbiome would be collected and analyzed using the PhyloChip Assay. The relative abundance of specific bacterial taxa would be compared between the 2 groups and between the time points (baseline and immediately upon completion of the diet). Correlation analysis with patient data will also be carried out. Because of the significant cost associated with this assay, this analysis will be performed retrospectively on a limited number of patients according to their response to dietary intervention: 5 patients randomized to usual care, 5 patients who responded to dietary intervention, and 5 patients who did not respond to dietary intervention.

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Serum Biomarker Panel: Recent attempts have been made to identify a serological biomarker profile (Prometheus Therapeutics & Diagnostics, San Diego, CA) which accurately identifies patients with IBS. Preliminary results using a first generation 10 biomarker algorithm revealed a sensitivity and specificity for differentiating IBS from non-IBS of 50% and 88% respectively. The positive predictive value was 81%, and the negative predictive value was 64% at 50% IBS prevalence in the validation cohort. Overall accuracy was 70%22. Though these performance characteristics would not be acceptable for routine clinical practice, they were promising enough to justify further attempts to revise and improve the biomarker algorithm. Preliminary data from a second generation test which utilizes 34 markers was recently presented as an abstract at United European Gastroenterology Week. This study revealed an AUC of 0.81 (95% CI 0.75-0.87) in discriminating IBS patients from healthy controls. We intend to perform this biomarker test at enrollment in all study subjects to assess whether specific combinations of biomarkers can positively or negatively predict response to the low-FODMAP diet.

Saliva Genetic Analysis: Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme of 5HT (5-hydroxytryptamine, serotonin) synthesis in enterchromaffin (EC) cells. Patients with IBS-D may have increased intestinal 5-HT production. The SNP -347C/A (a proximal promoter SNP that exhibits differential TPH1 expression) shown to be functional in tissue culture assays was associated with IBS status and correlated with bowel habit predominance in patients with IBS-D. The C allele is associated with increased TPH1 expression and increased intestinal 5-HT production, therefore correlating with the IBS-D phenotype. We will be looking for a proximal promoter (SNP 347C/A) that exhibits differential TPH1 expression).

Follow-up Questionnaire: After completion of the study period, subjects will be given the opportunity to complete an optional questionnaire regarding recurrence of symptoms and attitude toward the diet. This will be administered by phone, email, or mail and subjects will not be compensated. The questions will be as follows: 1) What group of FODMAPs did you miss the most?

2) When you reintroduced FODMAPs (groups of carbohydrates), did your symptoms recur?

if yes, which group of FODMAPs (carbohydrates) triggered your symptoms?

if yes, how long did it take for symptoms to recur?

3) Which symptom came back first?

bloating

abdominal pain

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diarrhea

gas

fatigue

other

4) How difficult was the diet to follow (rank 1 through 5, with 1 being easiest and 5 most difficult)?

Timeline

It is assumed that the subject recruitment and study period would be approximately one year. Once enrollment is reached, data will be analyzed and prepared for presentation and publication.

Human Subjects, Sample Size Calculation, and Statistical Analysis:

The University of Michigan Division of Gastroenterology is composed of 61 gastroenterologists and 18 fellows. The outpatient GI clinics at the University and 13 ancillary sites provide approximately 30,000 outpatient visits per year, of which about 1/3 are new patient visits. Potential subjects will be identified during these clinic visits and subjects will be approached for participation.

From previously published literature we are assuming a response rate of 40% with standard dietary advice and a response rate of 70% from a FODMAP diet, yielding a difference of 30%. From this it was determined that to detect a difference of 20% with at least an 80% power and alpha of 0.05, 45 subjects are needed in each treatment arm. Anticipating a dropout rate of 10%, this equates to a sample size of 50 for each of the two treatment arms.

Differences in the response rates for each of the following: the primary endpoint (adequate relief), abdominal pain, stool consistency, and composite endpoint will be assessed using the Chi-square test. The student t-test will be used to compare the mean scores for stool frequency, abdominal discomfort, urgency, bloating, fatigue, IBS-QOL, WPAI, HAD, and sleep quality. P values of <0.05 will be considered statistically significant.

Based on previous work of Second Genome, we hypothesize that large microbiome variations will be observed where species populations will more than double when comparing the pre and post intervention groups. We will apply analysis of variance (ANOVA) as the measure of statistical significance

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Appendix A -- Foods rich in FODMAPs by category

FODMAP Fructose Polyols Lactose Fructans and Galactans

High FODMAP food sources

Apples, pears, watermelon, mango, cherries, honey, asparagus, fruit juices, dried fruits, high-fructose corn syrup

Sugar alcohols (sorbitol, maltitol, mannitol, xylitol, and isomalt), stone fruits, blackberries, apple, pear, avocado, mushrooms, cauliflower

Milk (cow, goat, sheep), yogurt, custard, icecream, soft cheeses (ricotta, cottage)

Wheat, rye, barley, garlic, onions, artichokes, , inulin, soy, leeks, shallots, legumes, lentils, chickpeas, cabbage, Brussels sprouts, broccoli, peas, fennel, beetroot, pistachio nuts, chicory

Alternative lower FODMAP food sources

Citrus, berries, bananas, grapes, honeydew, cantaloupe, kiwifruit

Sweeteners, such as sugar, glucose, other artificial sweeteners not ending in “-ol” (sucralose, aspartame are okay)

Lactose-free dairy products, rice milk, hard cheeses

Starches, such as rice, corn, potato, quinoa. Vegetables, such as winter squash, lettuce, spinach, cucumbers, bell peppers, green beans, tomato, eggplant, zucchini/courgette, potato, pumpkin, turnip, swede, parsnip, carrot

All non-processed meats are generally low in FODMAPs.

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Appendix B: Schematic of study design

Initial office

visit

2 week

screening phase

Randomization

1:1

Usual CareLow FODMAP

Diet

Demographic data, meds, PMHx, etc.

Assess average daily amount of abdominal

pain (4 or higher) and stool consistency (BSS

5, 6, or 7)

Assume 10% drop out rate

through the study period

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Appendix C. Timeline of randomization period

References:

1. Drossman DA. The functional gastrointestinal disorders and the Rome III process.

Gastroenterology. Apr 2006;130(5):1377-1390.

2. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel

disorders. Gastroenterology. Apr 2006;130(5):1480-1491.

3. Chang L. Review article: epidemiology and quality of life in functional gastrointestinal disorders.

Aliment Pharmacol Ther. Nov 2004;20 Suppl 7:31-39.

4. Maxion-Bergemann S, Thielecke F, Abel F, Bergemann R. Costs of irritable bowel syndrome in

the UK and US. Pharmacoeconomics. 2006;24(1):21-37.

5. Chey WD, Olden K, Carter E, Boyle J, Drossman D, Chang L. Utility of the Rome I and Rome II

criteria for irritable bowel syndrome in U.S. women. Am J Gastroenterol. Nov 2002;97(11):2803-

2811.

6. Halpert A, Dalton CB, Palsson O, et al. What patients know about irritable bowel syndrome (IBS)

and what they would like to know. National Survey on Patient Educational Needs in IBS and

development and validation of the Patient Educational Needs Questionnaire (PEQ). Am J

Gastroenterol. Sep 2007;102(9):1972-1982.

7. Bentley SJ, Pearson DJ, Rix KJ. Food hypersensitivity in irritable bowel syndrome. Lancet. Aug 6

1983;2(8345):295-297.

8. Petitpierre M, Gumowski P, Girard JP. Irritable bowel syndrome and hypersensitivity to food.

Ann Allergy. Jun 1985;54(6):538-540.

0 wks

• 1st RD visit: 3 day food diary, 24 hour dietary recall• Primary and secondary end point data• Receive verbal and written materials on each diet• Weight check• Biomarkers obtained, including stool samples

2 wks

• 3 day food diary, 24 hour dietary recall• Weight check• Primary and secondary endpoint data• Assess rescue medications/adverse events

4wks

• 3 day food diary, 24 hour dieatary recall • Weight check• Primary and secondary end point data• Diet perception• Stool sample obtained, blood sample obtained• Assess rescue medications/adverse events

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9. Zwetchkenbaum JF, Burakoff R. Food allergy and the irritable bowel syndrome. Am J

Gastroenterol. Sep 1988;83(9):901-904.

10. Barrett JS, Gearry RB, Muir JG, et al. Dietary poorly absorbed, short-chain carbohydrates

increase delivery of water and fermentable substrates to the proximal colon. Aliment Pharmacol

Ther. Apr 2010;31(8):874-882.

11. Ong DK, Mitchell SB, Barrett JS, et al. Manipulation of dietary short chain carbohydrates alters

the pattern of gas production and genesis of symptoms in irritable bowel syndrome. J

Gastroenterol Hepatol. Aug 2010;25(8):1366-1373.

12. Parkes GC, Brostoff J, Whelan K, Sanderson JD. Gastrointestinal microbiota in irritable bowel

syndrome: their role in its pathogenesis and treatment. Am J Gastroenterol. Jun

2008;103(6):1557-1567.

13. Saulnier DM, Kolida S, Gibson GR. Microbiology of the human intestinal tract and approaches for

its dietary modulation. Curr Pharm Des. 2009;15(13):1403-1414.

14. Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial

enterotypes. Science. Oct 7 2011;334(6052):105-108.

15. Salonen A, de Vos WM, Palva A. Gastrointestinal microbiota in irritable bowel syndrome:

present state and perspectives. Microbiology. Nov 2010;156(Pt 11):3205-3215.

16. Malinen E, Rinttila T, Kajander K, et al. Analysis of the fecal microbiota of irritable bowel

syndrome patients and healthy controls with real-time PCR. Am J Gastroenterol. Feb

2005;100(2):373-382.

17. Verdu EF, Bercik P, Verma-Gandhu M, et al. Specific probiotic therapy attenuates antibiotic

induced visceral hypersensitivity in mice. Gut. Feb 2006;55(2):182-190.

18. Brenner DM, Chey WD. Bifidobacterium infantis 35624: a novel probiotic for the treatment of

irritable bowel syndrome. Rev Gastroenterol Disord. Winter 2009;9(1):7-15.

19. Eswaran S, Tack J, Chey WD. Food: the forgotten factor in the irritable bowel syndrome.

Gastroenterol Clin North Am. Mar 2011;40(1):141-162.

20. Nelson TA, Holmes S, Alekseyenko AV, et al. PhyloChip microarray analysis reveals altered

gastrointestinal microbial communities in a rat model of colonic hypersensitivity.

Neurogastroenterol Motil. Feb 2011;23(2):169-177, e141-162.

21. Maldonado-Contreras A, Goldfarb KC, Godoy-Vitorino F, et al. Structure of the human gastric

bacterial community in relation to Helicobacter pylori status. ISME J. Apr 2011;5(4):574-579.

22. Lembo AJ, Neri B, Tolley J, Barken D, Carroll S, Pan H. Use of serum biomarkers in a diagnostic

test for irritable bowel syndrome. Aliment Pharmacol Ther. Apr 15 2009;29(8):834-842.

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G. Resources. We are planning to utilize MCRU resources for clinical space and dietician expertise. Given the funding limit of $50,000 with this MNORC research award, costs for the stool analysis and serum biomarker analysis outlined above will be covered through separate arrangements with the manufacturers. Letters of support for stool (Second Genome) and blood testing (Prometheus Laboratories) are included with this grant submission.

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Supplementary information

Patient Population:

Documentation of a normal colonoscopy or flexible sigmoidoscopy with normal colonic mucosal biopsies

within 5 years as well as normal CBC, electrolyte panel, TSH and a negative evaluation for celiac disease

(either TTG IgA, endomysial antibody, and/or duodenal biopsy) were also necessary to be eligible.

Exclusion criteria included symptoms compatible with IBS with mixed or constipation subtype, comorbid

medical problems affecting gastrointestinal transit/motility (scleroderma, poorly controlled diabetes),

inflammatory bowel disease, severe renal or hepatic disease, previous abdominal surgery (other than

appendectomy, cholecystectomy (if less than 6 months prior to enrollment), and gynecologic/urologic

surgery), and previous treatment with a low FODMAP diet. Pregnant patients and those currently taking

probiotics, antibiotics, or narcotics were also excluded. Active participation in another form of dietary

therapy at the time of enrollment (ie, gluten-free, low carbohydrate, high protein) was not allowed.

Methods:

To be eligible for randomization, both an average daily abdominal pain score of 4 or higher on an 11-

point numerical rating scale (NRS) (0-no pain, 10-intolerable pain) and an average daily stool

consistency, assessed by Bristol Stool Form Scale (BSFS), of ≥5 were required. IBS-D patients who

fulfilled the entry criteria were randomized via computer generation in a 1:1 ratio to low FODMAP diet

or mNICE guidelines for IBS.

Randomized patients met with a trained research dietitian (RD) at the Michigan Clinical Research Unit

(MCRU) and were counseled on their allocated diet. Patients were informed that they were going to be

randomized to one of two dietary interventions for patients with IBS-D: Diet 1 or Diet 2. Using

standardized instructions, the mNICE group was instructed to eat small frequent meals, avoid trigger

foods, and avoid excess alcohol and caffeine. Foods containing FODMAPs were not specifically excluded

as part of the mNICE instructions provided to study participants. For the low-FODMAP diet, instruction

was administered in a standardized manner according to published materials from Monash University27

but subjects were given teaching materials created from the University of Michigan. Dietary compliance

measures used in the counseling environment included prospectively recorded 3-day food diaries. Food

diaries were analyzed via the Nutrition Data System for Research (NDSR) computer program, measuring

fructose, lactose, sucrose, pectins, sorbitol, and added sugars. At the completion of week 2, a 2nd

visit

was conducted to answer questions, assess adverse events (AEs), and obtain information regarding

dietary intake. At the completion of the 4-week study period, subjects met with the RD to collect and

assess the prospectively recorded 3-day food diaries and 24-hour dietary recall along with collection of

QOL endpoints.

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Pre-Specified Endpoints:

The IBS-QOL questionnaire is a validated condition-specific quality-of-life measure for IBS with

established internal consistency and reproducibility.28-30 The IBS-QOL contains 41 descriptive IBS-

specific quality of life items and uses a 5-point Likert response scale. A higher score on this scale

correlates with a better quality of life. Meaningful clinical improvement is seen by a change in IBS-QOL

score greater than 10-14.29

This questionnaire was administered before and after the 4-week

intervention. Improvements in mean scores, change in score, and proportion of subjects reporting 10-

and 14-point improvement were compared between the two interventions.

Anxiety and Depression

In order to measure participants’ anxiety and depression, the Hospital Anxiety and Depression Scale

(HADS) was used at baseline and at week 4.31

HADS is a self-reported rating scale of 14 items used to

identify and quantify depression and anxiety (seven items for each subscale). It is considered an

effective screening measure for anxiety and depression and has been widely used.32,33

It has two

subscales, which evaluate anxiety and depression, with a higher score indicating more severe symptoms.

The scores for each subscale range from 0 to 21; a cut off score of 8 was used for each subscale. The

proportion of patients reporting 8 or lower was compared between the 2 groups, as was the change in

mean score from baseline.

Work Productivity and Activity Impairment

Health-related work productivity loss includes time lost from work (absenteeism) and reduced on-the-

job effectiveness (presenteeism). The Work Productivity and Activity Impairment (WPAI) questionnaire

measures work time missed and work and activity impairment because of a specified health problem

during the past 7 days.34

The WPAI:IBS consists of six question and result overall work impairment

(productivity loss) score, with higher scores indicating greater impairment.

Derived from the questionnaire are four metrics: absenteeism (the percentage of work time missed due

to health in the past seven days), presenteeism (the percentage of impairment suffered while at work

due to health in the past seven days), overall work impairment (the total percentage of missed time due

to absenteeism or presenteeism in the past seven days), and activity impairment (the percentage of

impairment suffered during daily activities in the past seven days). Each metric varies from 0% to 100%

with higher scores indicating greater impairment. Only respondents currently employed (full-time, part-

time, or self-employed) provide information on absenteeism, presenteeism, and overall work

impairment (since one must be employed in order for health to affect work productivity). All

respondents provide information on activity impairment. Both between group and within group scores

were compared before and after dietary intervention.

Sleep and Fatigue

Sleep and Fatigue were measured daily during the baseline and study period via an 11-point numerical

rating system (NRS, 0=best, 10=worst). In addition, three items from the Modified Sleep-50

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questionnaire were used to assess overall sleep quality (“Generally, I sleep badly,” “I feel sleepy during

the day and struggle to remain alert,” and “I have difficulty falling asleep”), and was administered before

and after the 4-week dietary intervention and scored from 0-3 (3 being worst). The Sleep-50

questionnaire is designed to screen for multiple sleep disorders over the prior 4 weeks.35 Difference-

from-baseline scores were compared between groups.

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