Evaluating the Metabolic Effects of Polylactose: A Novel Prebiotic
Evaluating the Metabolic Effects of Polylactose: A Novel Prebiotic
This study will evaluate the feasibility and obtain a preliminary estimate of efficacy of
 feeding 15 g/day of a new novel prebiotic dietary fiber, termed polylactose, in 40 children
 (8-12 years old) with obesity (body mass index [BMI]-percentile >/= 95th) who have magnetic
 resonance imaging (MRI)-confirmed non-alcoholic fatty liver disease [NAFLD] (hepatic fat
 fraction >/= 5.5%), compared to a placebo of 15 g/d of cellulose, an inert dietary fiber.
Approximately 13% of all children (2 - 19 years old) are afflicted with NAFLD with the
 prevalence of NAFLD increasing to 60-80% among youth with obesity. NAFLD is characterized by
 excessive deposition of fat in the liver, which is an independent risk factor for the
 development of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Unchecked,
 NAFLD can progress into more severe forms of liver disease, including NASH, cirrhosis, and
 hepatocellular carcinoma, which eventually can lead to liver transplantation or death.
 Unfortunately, treatment of NAFLD through lifestyle interventions is extremely challenging
 and minimally effective even under intensive conditions. Bariatric surgery has shown promise
 as a treatment approach in adults, but remains controversial for a treatment of NAFLD in
 pediatrics.Even if bariatric surgery is proven effective, the overall impact will be low
 since a very small proportion of adolescents with obesity opt for this extreme treatment.
 Moreover, surgery is not indicated in youth with milder forms of obesity or younger children
 and since NAFLD occurs across the entire age-spectrum and is not exclusive to youth with
 obesity, a large need would be unmet by surgical treatment options. Therefore, novel
 non-surgical approaches that complement lifestyle modification therapy are needed in order to
 advance the field in a meaningful way and to provide care to a wide-range of youth with
 NAFLD. However, no safe or effective pharmacotherapy treatment options are presently
 available for youth with NAFLD, leaving a tremendous gap in care. Therefore, altering the gut
 microbiome through administration of a prebiotic dietary fiber is an attractive treatment
 option.

 To date, no medications have been successful at producing meaningful improvements in NAFLD
 among youth. Similarly, in adults, existing pharmacotherapy options elicit some improvement
 in liver enzymes and/or histology but have failed to demonstrate widespread efficacy.
 Moreover, most medications are not indicated for children under the age of 12, and
 pediatricians are adverse to using them until all other treatment options have failed.
 Therefore, alternative approaches must be taken in this difficult-to-treat clinical
 population to identify more effective treatment options. A prebiotic dietary fiber may offer
 a potential novel treatment option for NAFLD in children with obesity.

 Subjects who are interested in participating in the study will be asked to come in for a
 screening visit where their parent will sign a parental consent form and the child will sign
 an assent form. Blood will be drawn for safety tests and biomarker sampling. Urine and stool
 will also be collected. A portable glucose monitor will be placed to collect timed glucose
 results. Subjects will have an MRI to confirm their NAFLD and their BMI will be calculated.
 Subjects will undergo a dual x-ray absorptiometry (iDXA) scan and lifestyle counseling.
 Subjects enrolled in this study will be randomly assigned (1:1) to receive either polylactose
 or the placebo. Subjects will take the polylactose or the placebo in foods provided by the
 study team (made in a food-grade space utilizing good manufacturing practices to minimize
 cross contamination). Subjects will take polylactose/placebo for 26 weeks. They will come
 have blood drawn for safety tests and biomarkers at weeks 8 and 26. They will have urine and
 stool samples collected at weeks 8, 20 and 26. Assessments of their glucose levels will be
 done via a wearable glucose monitor between the screening/randomization and week 4, and again
 between week 20 and week 26. MRI scans of the liver iDXA scans will be repeated at weeks 8
 and 26. Lifestyle counseling and assessment of adverse events, compliance with taking the
 study product/placebo and tolerability of the intervention will take place at weeks 4, 8, 13,
 20 and 26.
Inclusion Criteria:

 -  Age 8-12 years old

 -  Diagnosis of obesity: BMI percentile >/= 95th (using age- and sex- based Center for
 Disease Control definitions) or BMI >/= 30 kg/m2

 -  Elevated alanine aminotransferase (ALT) more than twice the upper limit of normal by
 gender (>/= 44 U/L for girls, >/= 50 U/L for boys) within 6 months prior to screening
 or diagnosis of NAFLD from ultrasound or MRI within 6 months of screening or
 participants with biopsy-proven NASH within 12 months of screening

 Exclusion Criteria:

 -  ALT > 250 U/L at screening

 -  History of significant alcohol intake or current use

 -  Impaired fasting glucose (> 100 mg/dL)

 -  Diabetes (type 1 or 2)

 -  Current or recent (< 60 months prior to enrollment) use of weight loss medication(s)

 -  Vitamin E supplementation

 -  Previous bariatric surgery

 -  Use of metformin

 -  Metal or magnetic implants, devices or objects inside of or on the body, which are not
 MRI compatable

 -  Recent initiation (< 3 months prior to enrollment) of anti-hypertensive or lipid
 medication(s)

 -  Known hypothalamic or pituitary dysfunction

 -  Tobacco use

 -  Gilbert's syndrome

 -  Any known causes of liver disease (except NAFLD and NASH)

 -  Significant renal dysfunction as calculated by estimated glomerular filtration rate
 (eGFR) < 90 mL/min/1.73 m2

 -  Diagnosed monogenic obesity

 -  History of cancer

 -  Untreated thyroid disorder

 -  Current or recent (< 6 months prior to enrollment) use of medication(s) associated
 with weight gain (e.g. atypical anti-psychotics)