A Pilot Study of the Grapefruit Flavonoid Naringenin for HCV Infection
A Pilot Study of the Grapefruit Flavonoid Naringenin for HCV Infection
Hepatitis C virus when it leaves the cells in the liver is bound to a type of fat. An
 component of grapefruit could block this fat and thus lower the amount of virus in the blood
 stream. We propose that treatment with this ingredient, called naringenin, could be used to
 block this fat and HCV in persons infected with hepatitis C.
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.