4-Methylumbelliferone as a Treatment for Chronic HBV/HCV
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|ClinicalTrials.gov Identifier: NCT00225537|
Recruitment Status : Unknown
Verified April 2006 by MTmedical Institute of Health.
Recruitment status was: Active, not recruiting
First Posted : September 23, 2005
Last Update Posted : September 11, 2006
|First Submitted Date ICMJE||June 30, 2005|
|First Posted Date ICMJE||September 23, 2005|
|Last Update Posted Date||September 11, 2006|
|Study Start Date ICMJE||September 2005|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Same as current|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||4-Methylumbelliferone as a Treatment for Chronic HBV/HCV|
|Official Title ICMJE||Evaluation of 4-Methylumbelliferone for Treatment of Chronic Hepatitis B (HBV) and Chronic Hepatitis C (HCV)|
Open-label studies, anecdotal reports, and in vitro scientific research indicate that 4-methylumbelliferone (active ingredient of the dietary supplement Heparvit®) may prevent and reverse the symptoms and complications of chronic infection with hepatitis B virus (HBV)and hepatitis C virus (HCV). This effect has been observed among naïve patients as well as those who are non-responders to interferon, commonly used as first-line therapy for HBV and HCV. In order to scientifically address the efficacy of this 4-methylumbelliferone on chronic viral hepatitis, a randomized, placebo-controlled, blinded study is needed.
It is hypothesized that 4-methylumbelliferone may reduce the impact and aggressiveness of HBV and HCV upon the liver, thereby slowing the progression to potentially life threatening liver diseases such as cancer and cirrhosis. This is a preliminary study designed to determine any indications under controlled conditions that may warrant further detailed clinical studies.
(i). Chronic hepatitis B
Chronicity of HBV following acute infection is strongly age-related; the majority (90%) of infants acquiring HBV perinatally go on to develop chronic infection, while most persons who acquire HBV later in life resolve their infection [ref 1]. Patients with chronic HBV have a 15-25% lifetime risk of liver cirrhosis and hepatic cancer. An estimated 5,000 people die each year from complications of chronic HBV infection (cirrhosis and hepatocellular carcinoma).
Three drugs have been approved by the Food and Drug Administration (FDA) for treatment of chronic HBV: interferon-α (IFN-α), lamivudine, and adefovir dipivoxil. Only one-third of chronic HBV patients develop a sustained response to IFN-α treatment, and adverse effects are common [ref 2]. Use of the newer orally-administered nucleoside analogues (lamivudine or adefovir dipivoxil) typically causes rapid initial clearance of virus and is associated with fewer adverse effects; however, seroconversion rates are low, and long-term therapy with lamivudine (required for sustained responses) frequently results in resistance [ref 2]. Adefovir dipivoxil has, so far, not shown the high rate of resistance observed with lamivudine, but it is expected that resistance will eventually develop [ref 3]. In summary, major problems with currently approved therapy of HBV include expense, toxicity, and development of resistance.
(ii). Chronic hepatitis C
Chronic viral hepatitis due to hepatitis C is an enormous medical problem, affecting approximately 170 million people worldwide (WHO) [ref 4]. In the U.S., an estimated 2.7 million people suffer from chronic HCV, with 10,000-12,000 deaths per year attributable to the disease (ref 5). Chronic HCV infections in the U.S. are usually acquired through injectable drug use, sexual contact, or receipt of contaminated blood products (before antibody screening was initiated in 1990). Most persons exposed to HCV (75%) develop asymptomatic chronic infection. Eventually, 15%-20% will die of cirrhosis and liver cancer without intervention [ref 4].
Only two drugs are licensed for treatment of chronic hepatitis C: IFN-α (standard or pegylated) and ribavirin. Sustained responses to IFN-α monotherapy have occurred in up to 35% of patients; higher responses can be observed with combination treatment (pegylated IFN-α and ribavirin) [ref 6,7]. Responses to combination therapy is closely linked with HCV genotype (types 2 and 3 most responsive). A significant number of patients relapse or do not respond to standard treatment, and retreatment is typically less effective than initial therapy [ref 8].
Umbelliferones (7-hydroxycoumarins) [ref 9] are substances present in many species of plants, especially umbelliferae, fabaceae, and oleaceae, which include such common plants as manna ash, sweet woodruff, German chamomile, celery, parsley, and others. In nature, umbelliferones help protect plants from cellular damage, infestation, trauma, and infection. Their 7-hydroxycoumarin derivatives (4-methylumbelliferones) [ref 10] are used in liver therapy, as reagents, plant growth factors, sunscreens, choleretics, and spasmolytics. They are also used as light-protective agents, in the calibration of medical lasers, and in analytical chemistry for the quantitation of nitric acid.
Products containing 4-methylumbelliferone as their active substance have been available in the USA and Europe since 1990, as dietary supplements (under trade names Heparvit®, Heparmed®, DetoxPro®). These products are promoted as supporting liver function and improving detoxification. In many parts of Europe, products containing 4-methylumbelliferone are also available as drugs, and used as spasmolytics and choleretics [ref 11] (improving liver detoxification systems through increased bile production).
7-hydroxycoumarins are also natural metabolites in the body that play important roles in the metabolism of ethanol, chemotherapeutic drugs, acetaminophen, anabolic steroids, and other hepatotoxic drugs [ref 12]. Indeed, measurement of concentrations of 4-methylumbelliferyl glucuronide (a metabolic product of 4-methylumbelliferone) is a common assay for determining the level of toxicity of liver-toxic drugs [ref 13].
The broad potential medical benefits of 4-methylumbelliferone as a hepatoprotectant, anti-inflammatory agent, chemotherapeutic agent, and antiviral substance have been described [ref 13,14]. More recent studies indicate that 4-methylumbelliferone (and other 7-hydroxycoumarin derivatives) may be effective against Helicobacter pylori [ref 15], several types of cancer [ref 15-19], and Alzheimer’s disease [ref 20].
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Single Group Assignment
Primary Purpose: Treatment
|Intervention ICMJE||Drug: 4-Methylumbelliferone (Heparvit®)|
|Study Arms ICMJE||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Unknown status|
|Original Enrollment ICMJE||Same as current|
|Study Completion Date ICMJE||August 2007|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years to 65 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00225537|
|Other Study ID Numbers ICMJE||UTHSCSA 045-900-246|
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||MTmedical Institute of Health|
|PRS Account||MTmedical Institute of Health|
|Verification Date||April 2006|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP