Trial Outcomes & Findings for Viral Kinetics Study of Telbivudine and Entecavir in Adults With Chronic Hepatitis B (NCT NCT00412529)

Results Overview

Baseline HBV DNA is defined as the last pre-dose assessment of HBV DNA.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

44 participants

Primary outcome timeframe

Baseline (day 1) to Week 12 (day 85)

Results posted on

2015-03-13

Participant Flow

Participant milestones

Participant milestones
Measure	Telbivudine Telbivudine 600 mg once daily for 12 weeks.	Entecavir Entecavir 0.5 mg once daily for 12 weeks.
Overall Study STARTED	23	21
Overall Study COMPLETED	23	21
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Viral Kinetics Study of Telbivudine and Entecavir in Adults With Chronic Hepatitis B

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Telbivudine n=23 Participants Telbivudine 600 mg once daily for 12 weeks.	Entecavir n=21 Participants Entecavir 0.5 mg once daily for 12 weeks.	Total n=44 Participants Total of all reporting groups
Age, Continuous	36.2 Years STANDARD_DEVIATION 9.62 • n=99 Participants	33.4 Years STANDARD_DEVIATION 8.82 • n=107 Participants	34.9 Years STANDARD_DEVIATION 9.25 • n=206 Participants
Sex: Female, Male Female	5 Participants n=99 Participants	9 Participants n=107 Participants	14 Participants n=206 Participants
Sex: Female, Male Male	18 Participants n=99 Participants	12 Participants n=107 Participants	30 Participants n=206 Participants

PRIMARY outcome

Timeframe: Baseline (day 1) to Week 12 (day 85)

Population: Intent to Treat (ITT) population included all patients who received at least one dose of study drug and had at least one post-baseline assessment of serum HBV DNA. The randomized treatment was used in the analyses of this population.

Baseline HBV DNA is defined as the last pre-dose assessment of HBV DNA.

Outcome measures

Outcome measures
Measure	Telbivudine n=23 Participants Telbivudine 600 mg once daily for 12 weeks.	Entecavir n=21 Participants Entecavir 0.5 mg once daily for 12 weeks.
Change in Mean Hepatitis B Virus (HBV) DNA Levels Baseline (day 1)	10.290 log10 copies/mL Standard Deviation 1.6477	9.721 log10 copies/mL Standard Deviation 1.7141
Change in Mean Hepatitis B Virus (HBV) DNA Levels At Week 12	3.669 log10 copies/mL Standard Deviation 0.8817	3.194 log10 copies/mL Standard Deviation 1.1729
Change in Mean Hepatitis B Virus (HBV) DNA Levels Change from Baseline to week 12	-6.621 log10 copies/mL Standard Deviation 1.5610	-6.527 log10 copies/mL Standard Deviation 1.5365

SECONDARY outcome

Timeframe: Baseline (day 1) to Weeks 2, 4, 8

Population: Intent to Treat (ITT) population included all patients who received at least one dose of study drug and had at least one post-baseline assessment of serum HBV DNA. The randomized treatment was used in the analyses of this population.

Baseline HBV DNA is defined as the last pre-dose assessment of HBV DNA.HBV DNA reductions, considered as the repeated measures, from baseline to Weeks 2, 4, 8.

Outcome measures

Outcome measures
Measure	Telbivudine n=23 Participants Telbivudine 600 mg once daily for 12 weeks.	Entecavir n=21 Participants Entecavir 0.5 mg once daily for 12 weeks.
Change in Mean HBV DNA Level Change from Baseline to week 2 :(N=20, 21)	-3.999 log10 copies/mL Standard Deviation 1.3917 • Interval 3.04 to 4.3	-3.974 log10 copies/mL Standard Deviation 1.3460 • Interval 3.32 to 4.58
Change in Mean HBV DNA Level Change from Baseline to week 4 : (N= 23, 21)	-5.273 log10 copies/mL Standard Deviation 1.3071 • Interval 4.55 to 5.58	-4.875 log10 copies/mL Standard Deviation 1.5781 • Interval 4.58 to 5.61
Change in Mean HBV DNA Level Change from Baseline to week 8 : (N= 23, 21)	-6.161 log10 copies/mL Standard Deviation 1.4937 • Interval 5.23 to 6.26	-5.976 log10 copies/mL Standard Deviation 1.5288 • Interval 5.44 to 6.5

SECONDARY outcome

Timeframe: From Baseline to Week 12

Population: Intention-to-treat (ITT) population included all patients who received at least one dose of study drug and had at least one post-baseline assessment of serum HBV DNA. The randomized treatment was used in the analyses of this population.

In AUC efficacy analyses, all the visits from baseline to Week 12 visit (including the planned and the repeated) with a non-missing HBV DNA level were included.

Outcome measures

Outcome measures
Measure	Telbivudine n=23 Participants Telbivudine 600 mg once daily for 12 weeks.	Entecavir n=21 Participants Entecavir 0.5 mg once daily for 12 weeks.
The Area Under the Curve (AUC) of HBV DNA Change.	-453.5 (log10 copies/mL) * days Standard Deviation 103.13 • Interval 369.5 to 462.42	-442.6 (log10 copies/mL) * days Standard Deviation 131.30 • Interval 395.87 to 488.79

SECONDARY outcome

Timeframe: From Baseline to Week 12

Population: Intention to treat (ITT) population included all patients who received at least one dose of study drug and had at least one post-baseline assessment of serum HBV DNA. The randomized treatment was used in the analyses of this population.

Outcome measures

Outcome measures
Measure	Telbivudine n=23 Participants Telbivudine 600 mg once daily for 12 weeks.	Entecavir n=21 Participants Entecavir 0.5 mg once daily for 12 weeks.
Change in Alanine Aminotransferase (ALT) Levels Baseline	163.1 IU/L Standard Deviation 125.29	170.2 IU/L Standard Deviation 152.74
Change in Alanine Aminotransferase (ALT) Levels At Week 12	55.1 IU/L Standard Deviation 63.92	54.0 IU/L Standard Deviation 36.92
Change in Alanine Aminotransferase (ALT) Levels Change from Baseline to Week 12	-108.0 IU/L Standard Deviation 147.87	-116.3 IU/L Standard Deviation 162.81

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: Intent to Treat (ITT) population.

Viral kinetic parameters were estimated with a bi-phasic mathematical model: V(t) = (1-ε)pI(t) - cV(t) I(t) = (1- η)TV(t) - δI(t) V serum viral load, I productively infected cells, ε efficiency factor of blocking virus production, p viral production rate, c viral clearance rate, η efficiency factor of blocking de novo infection, β de novo infection rate, T uninfected target cells, δ rate of infected cell loss. Maximum-likelihood estimation for the viral kinetic parameters entailed fitting a nonlinear differential equation system via the least-squares approach from serum HBV DNA data.

Outcome measures

Outcome measures
Measure	Telbivudine n=23 Participants Telbivudine 600 mg once daily for 12 weeks.	Entecavir n=21 Participants Entecavir 0.5 mg once daily for 12 weeks.
Characterization of Very Early Viral Kinetics: Estimation of Viral Clearance	0.809 clearance per day Standard Deviation 0.3904	1.002 clearance per day Standard Deviation 0.8162

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: Intent to Treat (ITT) population. The value for the rate of infected cell loss for 1 patient in telbivudine arm was not used in calculation of summary statistics for this variable as this patient showed a deviation from the biphasic pattern in viral kinetic modeling.

Viral kinetic parameters were estimated with a bi-phasic mathematical model: V(t) = (1-ε)pI(t) - cV(t) I(t) = (1- η)TV(t) - δI(t) V serum viral load, I productively infected cells, ε efficiency factor of blocking virus production, p viral production rate, c viral clearance rate, η efficiency factor of blocking de novo infection, β de novo infection rate, T uninfected target cells, δ rate of infected cell loss. Maximum-likelihood estimation for the viral kinetic parameters entailed fitting a nonlinear differential equation system via the least-squares approach from serum HBV DNA data.

Outcome measures

Outcome measures
Measure	Telbivudine n=22 Participants Telbivudine 600 mg once daily for 12 weeks.	Entecavir n=21 Participants Entecavir 0.5 mg once daily for 12 weeks.
Characterization of Very Early Viral Kinetics: Estimation of the Rate of Infected Cell Loss	0.075 infected cell loss per day Standard Deviation 0.0231	0.071 infected cell loss per day Standard Deviation 0.0227

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: Intent to Treat (ITT) population.

Viral kinetic parameters were estimated with a bi-phasic mathematical model of HBV DNA by using compartments of free virus, infected cells, and uninfected target cells. The model parameter of interest was the effectiveness of the drug in blocking virus production from infected cells (efficacy, ε). Blocking efficiency was within the range between 0 and 1.

Outcome measures

Outcome measures
Measure	Telbivudine n=23 Participants Telbivudine 600 mg once daily for 12 weeks.	Entecavir n=21 Participants Entecavir 0.5 mg once daily for 12 weeks.
Characterization of Very Early Viral Kinetics: Estimation of the Efficiency Factor of Blocking Virus Production	0.991 percentage of blocking efficiency Standard Deviation 0.0133	0.992 percentage of blocking efficiency Standard Deviation 0.0090

SECONDARY outcome

Timeframe: At Week 12

Population: Intent to Treat (ITT) population included all patients who received at least one dose of study drug and had at least one post-baseline assessment of serum HBV DNA. The randomized treatment was used in the analyses of this population.

PCR negative was considered \<300 copies/mL. PCR positive was considered =\>300 copies/mL.

Outcome measures

Outcome measures
Measure	Telbivudine n=23 Participants Telbivudine 600 mg once daily for 12 weeks.	Entecavir n=21 Participants Entecavir 0.5 mg once daily for 12 weeks.
Number of Patients Who Are Polymerase Chain Reaction (PCR) Negative <300 copies/mL	2 Participants	6 Participants
Number of Patients Who Are Polymerase Chain Reaction (PCR) Negative >= 300 copies/mL	21 Participants	15 Participants

Adverse Events

Telbivudine

Serious events: 1 serious events

Other events: 4 other events

Deaths: 0 deaths

Entecavir

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Telbivudine n=23 participants at risk Telbivudine 600 mg once daily for 12 weeks.	Entecavir n=21 participants at risk Entecavir 0.5 mg once daily for 12 weeks.
General disorders Chest discomfort	4.3% 1/23 • 12 weeks Safety population included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment (i.e., adverse event or laboratory assessment).	0.00% 0/21 • 12 weeks Safety population included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment (i.e., adverse event or laboratory assessment).
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.3% 1/23 • 12 weeks Safety population included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment (i.e., adverse event or laboratory assessment).	0.00% 0/21 • 12 weeks Safety population included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment (i.e., adverse event or laboratory assessment).

Other adverse events

Other adverse events
Measure	Telbivudine n=23 participants at risk Telbivudine 600 mg once daily for 12 weeks.	Entecavir n=21 participants at risk Entecavir 0.5 mg once daily for 12 weeks.
Gastrointestinal disorders Nausea	0.00% 0/23 • 12 weeks Safety population included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment (i.e., adverse event or laboratory assessment).	9.5% 2/21 • 12 weeks Safety population included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment (i.e., adverse event or laboratory assessment).
Infections and infestations Upper respiratory tract infection	4.3% 1/23 • 12 weeks Safety population included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment (i.e., adverse event or laboratory assessment).	9.5% 2/21 • 12 weeks Safety population included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment (i.e., adverse event or laboratory assessment).
Investigations Alanine aminotransferase increased	13.0% 3/23 • 12 weeks Safety population included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment (i.e., adverse event or laboratory assessment).	4.8% 1/21 • 12 weeks Safety population included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment (i.e., adverse event or laboratory assessment).
Investigations Blood creatine phosphokinase increased	0.00% 0/23 • 12 weeks Safety population included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment (i.e., adverse event or laboratory assessment).	14.3% 3/21 • 12 weeks Safety population included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment (i.e., adverse event or laboratory assessment).

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER