A Pilot Study of the Grapefruit Flavonoid Naringenin for HCV Infection

The hepatitis C virus is actively secreted by the liver of infected patients while bound to
very low density lipoprotein (vLDL). The grapefruit flavonoid naringenin could be used to
block vLDL secretion and lower the circulating viral titer.

Hypothesis:

Treatment with naringenin will block vLDL and HCV secretion in persons infected with HCV.

Primary Objective

To study the safety and pharmacokinetics of a single-dose of naringenin

Secondary Objectives

1. To study the changes in circulating HCV titers during the transition from a fasted to
fed state.

2. To study the changes in circulating HCV titers after administration of the grapefruit
flavonoid naringenin.

3. To study effects of naringenin on vLDL secretion.

This is a single-arm, cross over study where placebo is administered during a transition
from a fasted to a fed state, then the protocol is repeated with a single dose of naringenin
plus cyclodextrin, using the previous measurements as his/her own control

Inclusion Criteria:

- HCV infection as documented by any licensed ELISA test kit any time prior to study
entry.

- Documentation of chronic high-titer HCV infection, as defined as a positive HCV viral
load >400,000 IU/ML measured within 2 years prior to study entry and after the last
interferon-based treatment course.

- HCV genotype - all genotypes are eligible for this trial

- Prior (but not current) treatment with interferon-based therapies are allowed

- Subjects with documented or suspected hepatic cirrhosis must have a Modified
Child-Pugh-Turcotte (CPT) Score of 5 or less within 42 days prior to study entry.

Exclusion Criteria:

- Presence of known causes of significant liver disease including chronic or acute
hepatitis B, acute hepatitis A, autoimmune hepatitis, hemochromatosis, or homozygote
alpha-1 antitrypsin deficiency.

- Evidence of decompensated liver disease manifested by presence of or history of
ascites, variceal bleeding, or hepatic encephalopathy, and/or a Child-Pugh score of 6
or higher.

- History of major organ transplantation, including liver, with an active, functioning
graft

- Candidates for liver transplant, as evidenced by active listing

- Receipt of HCV treatment within 28 days prior to study entry.

- Breast-feeding.

- Pregnancy, or considering getting pregnant within 1 month

- Use of lipid-lowering drugs (i.e. HMG-CoA reductase inhibitors, fibrates, omega-3
fatty acids, bile acid sequestrants, ezetimibe, and niacin derivatives), within 3
months prior to study entry

- Use of drugs with known interactions with grapefruit juice

- Known HIV infection

- Active drug or alcohol use or dependence that, in the opinion of the site
investigator, would interfere with adherence to study requirements.

- History of an adverse reaction to citrus fruits

- History of uncontrolled seizure disorder.

- Uncontrolled depression or other psychiatric disorder such as untreated Grade 3
psychiatric disorder, Grade 3 disorder not amenable to medical intervention, or any
hospitalization within the past 52 weeks that in the opinion of the site investigator
might preclude tolerability of study requirements.

- History of autoimmune processes, including but not limited to Crohn's disease,
ulcerative colitis, severe psoriasis, rheumatoid arthritis, that have been
exacerbated by previous interferon use.

- Any systemic antineoplastic or immunomodulatory treatment or radiation within 24
weeks prior to study entry.

- Serious illness including malignancy, active symptomatic coronary artery disease
within 24 weeks prior to study entry, or other chronic medical conditions that may
preclude completion of the protocol in the investigator's opinion.

- Past history of estrogen-responsive breast cancer

- Use of antidiabetic medications within 12 weeks prior to study entry.

- Fasting plasma glucose ≥126 mg/dL within 42 days prior to study entry or currently or
previously treated at any time for diabetes with measures other than diet. NOTE:
Women with a history of gestational diabetes not requiring any treatment for diabetes
before or after pregnancy are eligible for participation. Subjects with
diabetes/hyperglycemia occurring in the context of short-term use of corticosteroids,
growth hormone, or other diabetogenic medication, but not requiring any treatment for
diabetes after discontinuation of the implicated medication, are eligible to
participate. Subjects with diabetes/hyperglycemia following an episode of
pancreatitis who no longer require treatment for diabetes are eligible.

- Known osteoporosis or receipt of treatment of osteopenia or osteoporosis within 12
weeks prior to study entry with the following medications: risedronate (Actonel®),
ibandronate (Boniva®), etidronate (Didronel®), raloxifene (Evista®), teriparatide
(Forteo®), aledronate (Fosamax®), calcitonin (Miacalcin®).

- Inability to tolerate consumption of an ice cream-based milkshake.

- Regular and excessive use of alcohol defined as self-reported alcohol intake >120 g
of alcohol/week in a male or >60 g alcohol/week in a female within 12 weeks
immediately prior to study entry.

- Unwilling to restrict alcohol use during the study to ≤120g alcohol/week in a male or
≤60 g alcohol/week in a female.

- Unwilling to restrict diet during the study (both Step 1 and Step 2).

- Known glucocorticoid use in supraphysiologic doses (prednisone >10 mg/day or
equivalent doses of other glucocorticoids) within 12 weeks prior to study entry.

- Known glucocorticoid use in physiologic replacement doses (prednisone ≤10 mg/day or
equivalent doses of other glucocorticoids) initiated within 28 days prior to study
entry. NOTE: Individuals on physiologic replacement doses of glucocorticoids
initiated more than 28 days prior to study entry will not be excluded.

- History of congestive heart failure corresponding to New York Heart Association Class
II or greater

- Current use of prohibited concomitant medications

- Current participation in experimental studies that include treatments not approved by
the FDA or any blinded treatments.

- Body mass index (BMI) > 35 kg/m2.

- Known allergy to food contained within the standard meal (i.e. chicken, soy)

- Subjects with a history of clinically significant cardiac disease, including a family
history of Long QT Syndrome, and/or evidence of the following ECG abnormalities at
screening:

- QTcF (QT corrected using Fridericia's formula, Fridericia's formula:
QTcF=QT/(RR^0.333) of > 450 msec; complete or incomplete left or right bundle
branch block; intraventricular conduction delay with QRS duration of > 120 msec;
bradycardia (< 45 beats per minute);

- pathologic Q-waves (Q-wave of > 40 msec or depth of > 0.4 to 0.5 V);

- arrhythmia (an isolated premature ventricular contraction on screening/Day 1 is
not exclusionary) ;

- ventricular pre-excitation;

- second or third degree heart block.