Lamivudine and Adefovir Dipivoxil Fixed Dose Combination

NCT ID: NCT01353742

Last Updated: 2017-08-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-02-21
• Study Completion Date: 2011-04-12

Brief Summary

This is a phase I study being conducted to support the clinical development program of a FDC product of the nucleoside analogue lamivudine and the nucleotide analogue adefovir dipivoxil. To establish bioequivalence, the exposure of lamivudine and adefovir dipivoxil when administered as the FDC will be compared to that of Heptodin (lamivudine) and Hepsera (adefovir dipivoxil) when administered separately. In this study, the FDC product will contain 100mg lamivudine/10mg adefovir dipivoxil.

Total 40 healthy adult subjects will be enrolled. The study will include a screening visit and two treatment sessions. The screening visit will be conducted up to 3 weeks prior to the first dose of Session 1. All subjects will receive Regimen A through B according to the randomization schedule. Eligible subjects will be enrolled in the study and randomized to receive the following treatment regimens in table below in one of the following treatment sequences: AB, or BA. There will be a seven to ten days washout period between each treatment session. Pharmacokinetic sampling for measurement of plasma lamivudine and adefovir dipivoxil concentrations will be conducted over a 48-hour period following the morning administration of study medication in each study session. During this time, all subjects will remain in the unit for pharmacokinetic (PK) sample collection. The total duration (from screening to the end of the study) of each subject's participation will be approximately four weeks.

Detailed Description

Chronic hepatitis B (CHB) infection is common, with an estimated global prevalence of more than 400 million people, or approximately 5% of the world's population. Chronic hepatitis B virus (HBV) carriers with evidence of ongoing viral replication are at highest risk for the development of active liver inflammation (i.e., hepatitis B) and progressive liver disease. They are also the major contributor to the spread of HBV infection.

The goals of therapy in CHB include suppression of HBV replication, reduction of necroinflammatory processes in the liver, and prevention of progression to serious liver disease or death. The HBV polymerase has an error rate that is intermediate between that of human immunodeficiency virus (HIV) and herpes virus polymerases,; this predicts that patients with CHB infection are likely to exhibit some degree of antiviral resistance to nucleoside or nucleotide monotherapies. Indeed, patients on long-term lamivudine therapy have been found to have HBV variants (YMDD variants) with reduced sensitivity to lamivudine in vitro, and have exhibited variably diminished therapeutic responses.

A fixed dose combination (FDC) formulation of lamivudine and adefovir dipivoxil for the treatment of CHB. Lamivudine (Heptodin) an active triphosphate (3TC-TP) incorporating into growing DNA chains results in premature chain termination thereby inhibiting HBV DNA synthesis. Adefovir dipivoxil (Hepsera) is an orally bioavailable pro-drug of adefovir, a nucleotide analog of adenosine monophosphate. It can inhibit both the reverse transcriptase and DNA polymerase activity and is incorporated into HBV DNA causing chain termination.

A FDC would therefore combine the established benefits of two important anti-HBV antiviral drugs, representing the first combination product for the treatment of CHB. In addition to the enhanced efficacy afforded by combination therapy, the use of a combination product could enhance convenience and compliance and ensure that patients receive the two drugs needed.

This study will evaluate the bioequivalence of a FDC containing (lamivudine 100 mg/adefovir dipivoxil 10 mg) compared to Heptodin100 mg and Hepsera 10 mg. This dose was selected as both Heptodin 100 mg and Hepsera 10 mg are approved in the PRC for the treatment of CHB. Based on extensive clinical experience with the use of both drugs either as monotherapy or in combination, it is anticipated that the co-administration of both agents in the FDC formulation will be well-tolerated.

Conditions

Hepatitis B, Chronic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Lamivudine and Adefovir dipivoxil

One 100mg Lamivudine tablet and One 10mg Adefovir dipivoxil tablet

Group Type: ACTIVE_COMPARATOR

Lamivudine

Intervention Type: DRUG

100mg tablet

Adefovir dipivoxil

Intervention Type: DRUG

10mg tablet

Fixed dose combination

One capsule (100mg lamivudine and 10mg adefovir dipivoxil)

Group Type: EXPERIMENTAL

Fixed dose combination (Lamivudine and Adefovir dipivoxil)

Intervention Type: DRUG

100mg/10mg capsule

Interventions

Lamivudine

100mg tablet

Intervention Type: DRUG

Adefovir dipivoxil

10mg tablet

Intervention Type: DRUG

Fixed dose combination (Lamivudine and Adefovir dipivoxil)

100mg/10mg capsule

Intervention Type: DRUG

Other Intervention Names

Heptodin; Hepsera; FDC

Eligibility Criteria

Inclusion Criteria

• Healthy as determined by a responsible physician.
• Male 18 and 55 years of age.
• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods.
• Body weight >50 kg (110 lbs) and body mass index (BMI) between 19.0 and 25.0.
• Capable of giving written informed consent.
• QT interval corrected according to Bazzett's formula (QTcB) or QT interval corrected according to Fridericia's formula (QTcF) <450 msec; or QTc <480 msec in subjects with Bundle Branch Block.
• AST, ALT, alkaline phosphatase and bilirubin <=1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

Exclusion Criteria

• Any clinically relevant abnormality identified on the screening history, physical or laboratory examination, or any other medical condition or circumstance making the subject unsuitable for participation in the study.
• Treatment with any prescription or non-prescription drugs (including vitamins, herbal and dietary supplements, as well as grapefruit-containing products) within 7 days or five half-lives prior to first dose of study medication and until the end of the study. Excluded from this list is acetaminophen at doses of <=2 grams/day.
• Treatment with an investigational drug within 30 days or five half-lives (whichever is longer) preceding Day 1 of treatment period 1.
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
• History of regular alcohol consumption exceeding 7 drinks/week for women or 14 drinks/week for men (1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor) within 6 months of screening.
• Positive urine drug screen (UDS) or breath alcohol test at screening. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
• Positive for hepatitis B, hepatitis C or HIV.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Electrocardiogram findings as follows (a single repeat is allowed for eligibility determination):

Parameter Males Heart rate <45 and >100 beats per minute PR Interval <120 and >220 msec QRS duration <70 and >120 msec QTc interval (Bazett) >450 msec

• Evidence of previous myocardial infarction (does not include ST segment changes associated with repolarization).
• Any conduction abnormality (including but not specific to left or right complete bundle branch block, atrio-ventricular block [second degree or higher], Wolf Parkinson White syndrome).
• Sinus pauses >3 seconds.
• Any significant arrhythmia which, in the opinion of the principal Investigator and GlaxoSmithKline medical monitor, will interfere with the safety for the individual subject.
• Non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular ectopic beats).

• Documented history of low blood pressure (BP; average systolic BP<=90 mmHg and/or diastolic BP <=45 mm Hg) or blood pressure below these values at time of screening.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• History of asthma or chronic obstructive pulmonary disease.
• History of sensitivity to heparin, heparin- induced thrombocytopenia, or sensitivity to any of the study medications or components thereof.
• History of anaphylaxis or anaphylactic reactions or severe allergic responses to drugs.
• History of angioedema.
• Unwillingness or inability to follow the procedures outlined in the protocol or inability to provide written informed consent.
• Subject is mentally or legally incapacitated

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Shatin, New Territories, , Hong Kong

Countries

Hong Kong

References

Fok BS, Gardner S, Piscitelli S, Chen S, Chu TT, Chan JC, Tomlinson B. Pharmacokinetic properties of single-dose lamivudine/adefovir dipivoxil fixed-dose combination in healthy Chinese male volunteers. Clin Ther. 2013 Jan;35(1):68-76. doi: 10.1016/j.clinthera.2012.12.001. Epub 2012 Dec 28.

Reference Type: BACKGROUND

PMID: 23274144 (View on PubMed)

Study Documents

Document Type: Informed Consent Form

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Clinical Study Report

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Individual Participant Data Set

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Statistical Analysis Plan

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Dataset Specification

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Annotated Case Report Form

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Study Protocol

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Related Links

https://www.clinicalstudydatarequest.com

Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Other Identifiers

114957

Identifier Type: -

Identifier Source: org_study_id