Hepatitis B, ChronicPhase 1NCT01353742
Lamivudine and Adefovir Dipivoxil Fixed Dose Combination
A Phase 1 study testing Lamivudine, Adefovir dipivoxil and Fixed dose combination (Lamivudine and Adefovir dipivoxil) in people with Hepatitis B, Chronic, run by GlaxoSmithKline at 1 site in Hong Kong.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 55 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Hepatitis B, Chronic
- What is being tested?
- Lamivudine, Adefovir dipivoxil and Fixed dose combination (Lamivudine and Adefovir dipivoxil)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteHong Kong
- Study dates
- 21 Feb 2011to 12 Apr 2011
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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%).
Who cannot join
- 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.
Show all 23Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomized, Open-label, Single-dose, Two-period, Crossover Study to Demonstrate the Bioequivalence of the Fixed Dose Combination (FDC) of Lamivudine and Adefovir Dipivoxil (100mg/10mg) to Heptodin® (100mg ) and Hepsera® (10mg)
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.
Read the 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
- Being tested
- Lamivudine, Adefovir dipivoxil, Fixed dose combination (Lamivudine and Adefovir dipivoxil)
- Medical subject headings
- Hepatitis B, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LamivudineDrug
Also called Heptodin
100mg tablet
Adefovir dipivoxilDrug
Also called Hepsera
10mg tablet
Fixed dose combination (Lamivudine and Adefovir dipivoxil)Drug
Also called FDC
100mg/10mg capsule
| Study group | Role | What they receive |
|---|---|---|
| Lamivudine and Adefovir dipivoxil | Active comparator | One 100mg Lamivudine tablet and One 10mg Adefovir dipivoxil tablet Receives: Drug: Lamivudine; Drug: Adefovir dipivoxil |
| Fixed dose combination | Experimental | One capsule (100mg lamivudine and 10mg adefovir dipivoxil) Receives: Drug: Fixed dose combination (Lamivudine and Adefovir dipivoxil) |
What is being measured
The primary outcome is the main question the study is designed to answer.
AUC of lamivudine
Measured: 48 hours
Cmax of lamivudine
Measured: 48 hours
AUC of adefovir dipivoxil
Measured: 48 hours
Cmax of adefovir dipivoxil
Measured: 48 hours
Secondary outcomes (5)
PK parameters: t1/2 of lamivudine
Measured: 48 hours
Tolerability will be assessed by clinical data from Adverse Event reporting, nurse/physician observations, vital signs, ECGs, and clinical laboratory.
Measured: 48 hours
PK parameters: Tmax of lamivudine
Measured: 48 hours
PK parameters: Tmax of adefovir dipivoxil
Measured: 48 hours
PK parameters: t1/2 of adefovir dipivoxil
Measured: 48 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 May 2011 (estimated)
- Study start21 Feb 2011
- Primary completion12 Apr 2011
- Study completion12 Apr 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hepatitis B, ChronicStudies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- GSK Clinical Trials, Study director, GlaxoSmithKline
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01353742
- Sponsor's protocol ID
- 114957
- Status last verified
- Aug 2017
- First submitted
- 5 May 2011
- Last updated
- 4 Aug 2017
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Yes: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
Publications
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.
PubMed 23274144
Study at a glance
From the registry record, last updated by the sponsor on 4 Aug 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Open-label, Single-dose, Two-period, Crossover Study to Demonstrate the Bioequivalence of the Fixed Dose Combination (FDC) of Lamivudine and Adefovir Dipivoxil (100mg/10mg) to Heptodin® (100mg ) and Hepsera® (10mg)
- ClinicalTrials.gov ID
- NCT01353742
- Acronym / sponsor ID
- 114957
- Conditions
- Hepatitis B, Chronic
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Study start
- 21 Feb 2011 (actual)
- Primary completion
- 12 Apr 2011 (actual)
- Study completion
- 12 Apr 2011 (actual)
- First posted
- 16 May 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Lamivudine and Adefovir dipivoxil | Active comparator | Drug: Lamivudine, Drug: Adefovir dipivoxilOne 100mg Lamivudine tablet and One 10mg Adefovir dipivoxil tablet |
| Fixed dose combination | Experimental | Drug: Fixed dose combination (Lamivudine and Adefovir dipivoxil)One capsule (100mg lamivudine and 10mg adefovir dipivoxil) |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (23 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LamivudineAlso: Heptodin100mg tablet | Drug | Lamivudine and Adefovir dipivoxil |
| Adefovir dipivoxilAlso: Hepsera10mg tablet | Drug | Lamivudine and Adefovir dipivoxil |
| Fixed dose combination (Lamivudine and Adefovir dipivoxil)Also: FDC100mg/10mg capsule | Drug | Fixed dose combination |
Primary outcome
AUC of lamivudine
Time frame: 48 hours
Cmax of lamivudine
Time frame: 48 hours
AUC of adefovir dipivoxil
Time frame: 48 hours
Cmax of adefovir dipivoxil
Time frame: 48 hours
5 secondary outcomes
PK parameters: t1/2 of lamivudine
Time frame: 48 hours
Tolerability will be assessed by clinical data from Adverse Event reporting, nurse/physician observations, vital signs, ECGs, and clinical laboratory.
Time frame: 48 hours
PK parameters: Tmax of lamivudine
Time frame: 48 hours
PK parameters: Tmax of adefovir dipivoxil
Time frame: 48 hours
PK parameters: t1/2 of adefovir dipivoxil
Time frame: 48 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Aug 2017.
- Background: PubMed 23274144Fok 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.
- Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.Link provided by the sponsor.
- Results for study 114957 can be found on the GSK Clinical Study Register.Link provided by the sponsor.
- Individual participant dataSharing planned: Yes. Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
GSK Clinical Trials study director
GlaxoSmithKline
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Lamivudine, Adefovir dipivoxil and Fixed dose combination (Lamivudine and Adefovir dipivoxil) in people with Hepatitis B, Chronic, run by GlaxoSmithKline at 1 site in Hong Kong.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Aug 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Hong Kong. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
AUC of lamivudine (time frame: 48 hours). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01353742, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Aug 2017.