Trial Outcomes & Findings for Study of Combination Therapy With LdT Plus Adefovir Versus Adefovir Alone (NCT NCT00376259)

NCT ID: NCT00376259

Last Updated: 2011-06-30

Results Overview

Virologic breakthrough is defined as a minimum of 1 log reduction from baseline followed by a 1 log increase from nadir on at least 2 consecutive visits including the last treatment visit.

• Recruitment status: TERMINATED
• Study phase: PHASE3
• Target enrollment: 43 participants
• Primary outcome timeframe: 96 Weeks
• Results posted on: 2011-06-30

Participant Flow

Planned enrollment was 150 patients. At the time of study termination, 43 patients had been enrolled and randomized to study treatment and 42 patients received study drug (21 patients in the combination group and 21 in the monotherapy group).

One patient was randomized but never received study drug treatment because he was discontinued on the randomization day due to sponsor request.

Participant milestones

Measure	Combination Therapy Combination therapy: 600 mg of telbivudine (LdT) by mouth plus 10 mg of adefovir (ADV) by mouth once daily for 96 weeks.	Adefovir Monotherapy Adefovir monotherapy: 10 mg of adefovir by mouth once daily for 96 weeks.
Overall Study STARTED	22	21
Overall Study Received Study Drug	21	21
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	22	21

Reasons for withdrawal

Measure	Combination Therapy Combination therapy: 600 mg of telbivudine (LdT) by mouth plus 10 mg of adefovir (ADV) by mouth once daily for 96 weeks.	Adefovir Monotherapy Adefovir monotherapy: 10 mg of adefovir by mouth once daily for 96 weeks.
Overall Study Sponsor request - study termination	21	21
Overall Study Patient request	1	0

Baseline Characteristics

Study of Combination Therapy With LdT Plus Adefovir Versus Adefovir Alone

Baseline characteristics by cohort

Measure	Combination Therapy n=22 Participants Combination therapy: 600 mg of telbivudine (LdT) by mouth plus 10 mg of adefovir (ADV) by mouth once daily for 96 weeks.	Adefovir Monotherapy n=21 Participants Adefovir monotherapy: 10 mg of adefovir by mouth once daily for 96 weeks.	Total n=43 Participants Total of all reporting groups
Age Continuous	36.8 years STANDARD_DEVIATION 11.82 • n=5 Participants	39.0 years STANDARD_DEVIATION 10.93 • n=7 Participants	37.9 years STANDARD_DEVIATION 11.32 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	16 Participants n=7 Participants	35 Participants n=5 Participants

PRIMARY outcome

Timeframe: 96 Weeks

Population: This study was terminated early and no patients received 96 weeks of treatment. Therefore, the primary objective of evaluating virologic breakthrough by Week 96 could not be assessed. Consequently, all protocol-specified inferential analyses on the primary endpoint and all other key secondary efficacy endpoints could not be performed.

Virologic breakthrough is defined as a minimum of 1 log reduction from baseline followed by a 1 log increase from nadir on at least 2 consecutive visits including the last treatment visit.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to 12 weeks, 24 weeks, 48 weeks and 60 weeks

Population: Analysis population consists of the intent-to-treat population. Analysis of data for each time point includes participants who had both baseline and post baseline observation.

Efficacy was assessed by the change from baseline in mean HBV DNA concentration after 12, 24, 48 and 60 weeks of treatment.

Outcome measures

Measure	Adefovir Monotherapy n=21 Participants Adefovir monotherapy: 10 mg of adefovir by mouth once daily for 96 weeks.	Combination Therapy n=21 Participants Combination therapy: 600 mg of telbivudine (LdT) by mouth plus 10 mg of adefovir (ADV) by mouth once daily for 96 weeks.
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration At Baseline (N = 21, 20)	10.127 Log10 Copies/mL Standard Deviation 0.9697	10.240 Log10 Copies/mL Standard Deviation 1.5750
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration At Week 12	5.515 Log10 Copies/mL Standard Deviation 1.3188	4.405 Log10 Copies/mL Standard Deviation 0.9944
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration Change from Baseline to Week 12	-4.612 Log10 Copies/mL Standard Deviation 1.7725	-5.835 Log10 Copies/mL Standard Deviation 1.6435
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration At Baseline (N = 20, 20)	10.127 Log10 Copies/mL Standard Deviation 0.9697	10.279 Log10 Copies/mL Standard Deviation 1.6058
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration At Week 24	5.161 Log10 Copies/mL Standard Deviation 1.7364	3.678 Log10 Copies/mL Standard Deviation 1.0483
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration Change from Baseline to Week 24	-4.966 Log10 Copies/mL Standard Deviation 2.2851	-6.601 Log10 Copies/mL Standard Deviation 1.7873
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration At Baseline (N = 13, 9)	10.207 Log10 Copies/mL Standard Deviation 0.7520	10.652 Log10 Copies/mL Standard Deviation 1.5203
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration At Week 48	5.272 Log10 Copies/mL Standard Deviation 1.9581	3.274 Log10 Copies/mL Standard Deviation 1.0254
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration Change from Baseline to Week 48	-4.934 Log10 Copies/mL Standard Deviation 2.1153	-7.378 Log10 Copies/mL Standard Deviation 1.9303
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration At Baseline (N = 2, 3)	10.097 Log10 Copies/mL Standard Deviation 0.1484	9.605 Log10 Copies/mL Standard Deviation 0.7990
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration At Week 60	4.330 Log10 Copies/mL Standard Deviation 0.6110	3.360 Log10 Copies/mL Standard Deviation 0.3111
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration Change from Baseline to Week 60	-5.767 Log10 Copies/mL Standard Deviation 0.4650	-6.245 Log10 Copies/mL Standard Deviation 0.4879

SECONDARY outcome

Timeframe: 12 week, 24 week, 48 week and 60 weeks

Population: Analysis population consists of the intent-to-treat population. Analysis of data for each time point includes participants who had both baseline and post baseline observation for that timepoint.

Undetectable HBV DNA = HBV DNA <300 copies/ml. Serum aminotransferase (ALT) normalization is defined as ALT within normal limits on 2 successive visits for a pt. with an elevated ALT level (>=1.0 x ULN) at baseline (BL). Hepatitis B e antigen (HBeAg) loss is defined as the loss of detectable serum HBeAg in a pt. who was HBeAg +ve at BL. HBeAg seroconversion is defined as HBeAg loss with detectable HBeAb. Hepatitis B surface antigen (HBsAg) loss is defined as the loss of detectable serum HBsAg in a pt. who was HBsAg +ve at BL. HBsAg seroconversion is defined as HBsAg loss with detectable HBsAb.

Outcome measures

Measure	Adefovir Monotherapy n=21 Participants Adefovir monotherapy: 10 mg of adefovir by mouth once daily for 96 weeks.	Combination Therapy n=21 Participants Combination therapy: 600 mg of telbivudine (LdT) by mouth plus 10 mg of adefovir (ADV) by mouth once daily for 96 weeks.
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria Undetectable HBV DNA at week 12	5.0 Percentage of participants	4.8 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria Undetectable HBV DNA at week 24	10.0 Percentage of participants	15.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria Undetectable HBV DNA at week 48	0.0 Percentage of participants	38.5 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria Undetectable HBV DNA at week 60	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria Serum ALT normalization at week 12	25.0 Percentage of participants	40.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria Serum ALT normalization at week 24	35.0 Percentage of participants	55.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria Serum ALT normalization at week 48	33.3 Percentage of participants	69.2 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBeAg loss at week 48	0.0 Percentage of participants	23.1 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBeAg loss at week 60	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBeAg seroconversion at week 12	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBeAg seroconversion at week 24	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBeAg seroconversion at week 48	0.0 Percentage of participants	15.4 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBeAg seroconversion at week 60	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBsAg loss at week 12	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBsAg loss at week 24	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBsAg loss at week 48	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBsAg loss at week 60	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBsAg seroconversion at week 12	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBsAg seroconversion at week 24	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBsAg seroconversion at week 60	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria Serum ALT normalization at week 60	0.0 Percentage of participants	50.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBeAg loss at week 12	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBeAg loss at week 24	5.0 Percentage of participants	5.0 Percentage of participants
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria HBsAg seroconversion at week 48	0.0 Percentage of participants	0.0 Percentage of participants

SECONDARY outcome

Timeframe: Week 96

The study was not completed as planned and was terminated early with agreement from the European Medicines Agency (EMEA). Patients did not receive 96 weeks of treatment. Therefore, the primary objective of evaluating virologic breakthrough by Week 96 could not be assessed. Consequently, all protocol-specified inferential analyses on the primary endpoint and all other key secondary efficacy endpoints could not be performed.

Outcome measures

Outcome data not reported

Adverse Events

Combination Therapy

Serious events: 1 serious events

Other events: 14 other events

Deaths: 0 deaths

Adefovir Monotherapy

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Measure	Combination Therapy n=21 participants at risk Combination therapy: 600 mg of telbivudine (LdT) by mouth plus 10 mg of adefovir (ADV) by mouth once daily for 96 weeks.	Adefovir Monotherapy n=21 participants at risk Adefovir monotherapy: 10 mg of adefovir by mouth once daily for 96 weeks.
Injury, poisoning and procedural complications Hand fracture	4.8% 1/21 Safety population.	0.00% 0/21 Safety population.

Other adverse events

Measure	Combination Therapy n=21 participants at risk Combination therapy: 600 mg of telbivudine (LdT) by mouth plus 10 mg of adefovir (ADV) by mouth once daily for 96 weeks.	Adefovir Monotherapy n=21 participants at risk Adefovir monotherapy: 10 mg of adefovir by mouth once daily for 96 weeks.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/21 Safety population.	9.5% 2/21 Safety population.
Gastrointestinal disorders Dyspepsia	0.00% 0/21 Safety population.	9.5% 2/21 Safety population.
General disorders Fatigue	4.8% 1/21 Safety population.	14.3% 3/21 Safety population.
Hepatobiliary disorders Hepatic steatosis	9.5% 2/21 Safety population.	9.5% 2/21 Safety population.
Infections and infestations Nasopharyngitis	14.3% 3/21 Safety population.	0.00% 0/21 Safety population.
Infections and infestations Rhinitis	4.8% 1/21 Safety population.	9.5% 2/21 Safety population.
Infections and infestations Upper respiratory tract infection	23.8% 5/21 Safety population.	38.1% 8/21 Safety population.
Investigations Blood creatine phosphokinase increased	14.3% 3/21 Safety population.	4.8% 1/21 Safety population.
Respiratory, thoracic and mediastinal disorders Cough	9.5% 2/21 Safety population.	0.00% 0/21 Safety population.

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