RCT of Caloric Restriction vs. Alternate-Day Fasting in Non-Alcoholic Fatty Liver Disease

Rationale:

Non alcoholic fatty liver disease (NAFLD) has a prevalence of up to 80% in patients with T2DM
and obesity and can lead to steatohepatitis (NASH) and fibrosis as well as cirrhosis and
hepatocellular carcinoma. As NAFLD is associated with increased risk of cardiovascular
disease and mortality and as NAFLD-induced liver disease is anticipated to be the most common
indication for liver transplantation over the next decade, treatment options are desperately
needed but very few are available.

Weight loss with caloric restriction (CR) is the preferred treatment of NAFLD, however
successful maintenance of a significant weight loss is difficult to achieve. Additionally,
despite significant association between degree of weight loss and improvements in NASH and
NAFLD, there is extensive overlap in the response among populations. This suggests that it
may not be weight loss in general, but rather the mechanistic underpinnings of the weight
loss that potentiate the therapeutic effects. A study comparing dietary carbohydrate
restriction vs CR in obese subjects with NAFLD found that, despite similar weight loss
between groups, there was greater hepatic triglyceride reduction with carbohydrate
restriction and this reduction was highly correlated with plasma ketone concentrations.
Hence, although weight loss is ostensibly important, there might be additional factors beyond
just weight loss per se causing the improvements in NASH. Therefore, rather than weight loss,
reduction in intrahepatic triglyceride will be the primary endpoint of this proposal.

Progression to NASH and beyond is largely due to a spectrum of metabolic abnormalities
including ectopic hepatic fat accumulation, insulin resistance, and abnormal lipid
metabolism. A recent animal study showed blunted ketogenesis in NASH and suggested the
overall etiology was due to inefficient oxidation and disposal of free fatty acids in the
liver. A fasting paradigm, or facilitating times of ketosis that could then normalize lipid
metabolism, might be one of the additional factors beyond weight loss that ensures
improvements in NAFLD and NASH.

Intermittent fasting (IF) is a dietary intervention whereby food is restricted for varying
timeframes, including alternate day fasting (ADF) where no or very few calories are given for
a day or more with ad lib feeding in between. In animal models, IF has been shown to have
numerous beneficial effects, many in excess of those seen with CR. In a mouse model of NAFLD,
IF resulted in improvements in hepatic steatosis and inflammation along with gene expression
changes showing enhanced activation of lipid oxidation and reduction of lipid synthesis.
These benefits may be due to "flipping the metabolic switch" from glucose to ketone
utilization for primary cellular energy needs. Data are only beginning to emerge on the
effects of IF in humans, and very few studies have focused on ketone production as a mediator
of positive outcomes. There are no data on the effect of ADF on NAFLD.

Specific Aims:

SA1: To compare the effect of ADF vs CR on metabolic changes including liver fat, glucose
homeostasis, lipid metabolism, and inflammation in patients with NAFLD and T2DM SA1a: To
determine changes in hepatic triglyceride by MRS after 4 weeks of ADF and after 4 weeks of ad
lib diet SA1b: To determine changes in glucose homeostasis SA1c: To determine changes in
whole body lipid metabolism and inflammation SA2: To determine the safety, tolerability, and
effectiveness on weight loss of ADF vs CR SA2a: To determine safety of ADF SA2b: To compare
changes in body weight, body composition, physical activity, physical functioning and
physical fitness SA2c: To determine effect on eating behaviors, hunger/satiety, and body
image SA2d: To determine effect on cognition and quality of life

Inclusion Criteria:

- Patient must give study-specific informed consent on an IRB-approved consent prior to
any research related procedures or study treatment.

- Patient must be at least 18 years at the time of consent Adenocarcinoma of the
prostate with AJCC Clinical Stage T1to T3b disease with histological evaluation via
biopsy or repeat biopsy within 12 months prior to registration. Refer to Appendix IV
for clarification on study eligibility and AJCC stage group.

- Patients must undergo a pretreatment diagnostic MRI of the prostate on a 1.5T to 3T
Tesla machine within 6 months prior to study registration.

- A focal IPT must be visible on MRI within the prostate and/or seminal vesicles and
this MRI must be obtained within 6 months of planning CT scan.

- A biopsy of the dominant lesion is recommended but not required. If an ultrasound
guided sextant biopsy was positive for prostatic adenocarcinoma in the area of the MRI
identified intraprostatic lesion, this will be acceptable and another guided biopsy
targeting the MRI identified disease will not be necessary.

- Patients with at least one of the following high-risk factors: cT3a-T3b OR Gleason
9-10 OR PSA > 30 OR more than 1 high-risk factors must be present: clinical stage of
T3, Gleason score 8-10, or PSA 20 ng/ml or greater.

- Hemoglobin must be ≥ 10 g/ml within 4 months prior to registration.

- Zubrod performance status must be 0-1 within 4 months prior to registration.

- If patient has child-producing potential, they must be willing to use medically
acceptable contraception during treatment and must be advised to use it for at least 1
year thereafter. This is not applicable if the patient is not sexually active or has
had a vasectomy. Please document as such.

- Patients must be able to start treatment within 16 weeks of registration.

Exclusion Criteria:

- T4 prostate disease on CT, MRI, or physical exam.

- Patients unable to undergo MRI of the prostate.

- Patients with a greater than 25% change in prostate volume from the pretreatment MRI
of the prostate demonstrating the IPT and the treatment planning MRI. Patients in this
case must undergo a repeat diagnostic MRI on a 1.5T to 3.0T Tesla machine and an IPT
must still be visible.

- IPT that is more than 75% of the prostate volume when measured on the CT simulation
scan.

- Evidence of distant metastasis (M1).

- Patients with positive nodes on cross-sectional imaging.

- Previous prostate cancer local treatment including prostatectomy, hyperthermia, high
intensity focused ultrasound, brachytherapy, external-beam radiation therapy, and/or
cryotherapy.

- Prior pelvic radiation therapy.

- No prior myocardial infarction within the last 6 months, congestive heart failure, or
end stage renal disease.

- Active inflammatory bowel disease (diverticulitis, Crohn's disease, ulcerative
colitis) affecting the rectum.

- Bilateral hip replacement

- Prior intrapelvic surgery. This includes the following:Bladder surgery,Transrectal or
rectal surgery other than prostate biopsy, Polypectomy or hemorrhoid removal or
banding

- Prior transurethral resection of the prostate (TURP) or laser ablation for benign
prostatic hyperplasia (BPH).

- Patients receiving continuous and current anticoagulation with warfarin sodium
(Coumadin), heparin sodium, clopidogrel bisulfate (Plavix), dabigatran etexilate
mesylate (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa),
enoxaparin sodium (Lovenox), prasugrel (Effient), ticagrelor (Brilinta), aspirin/er
dipyridamole (Aggrenox), or fondaparinux sodium (Arixtra).

- Patients with posterior or posterolateral extracapsular extension of prostate cancer.
If this is present, it must resolve on diagnostic MRI after 2 to 3 months of
neoadjuvant androgen deprivation therapy prior to enrollment. Refer to Appendix V for
definition of extracapsular extension