Clinical trial NCT01091077: A Pilot Study of the Grapefruit Flavonoid Naringenin for HCV Infection
Official title: A Pilot Study of the Grapefruit Flavonoid Naringenin for the Treatment of HCV Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatitis C Virus
HCV Infection
Chronic HCV
Hepatitis C
Keywords: dietary supplement
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Harvard University
First posted: 2010-03-23
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Eligibility criteria: 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.

Primary outcomes:
measure: Naringenin pharmacokinetic curves
timeFrame: 12 hours
Secondary outcomes:
measure: Safety
timeFrame: 12 hours
measure: Changes in HCV RNA levels
timeFrame: 12 hours
measure: Homeostatic model assessment-insulin resistance (HOMA-IR)
timeFrame: 24 hours
measure: Lipid levels: Cholesterol and triglyceride levels
timeFrame: 24 hours
measure: Liver enzyme levels
timeFrame: 24 hours
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Arthur Y Kim, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nahmias Y, Goldwasser J, Casali M, van Poll D, Wakita T, Chung RT, Yarmush ML. Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology. 2008 May;47(5):1437-45. doi: 10.1002/hep.22197.