Cirrhosis, Hepatitis, Hepatitis B, Chronic
Conditions
Brief summary
This research study was conducted to compare the safety and effectiveness of the investigational medication, LdT (Telbivudine) versus Lamivudine, a drug currently approved by the US, European and Asian Health Authorities for the treatment of Hepatitis B infection. The results for patients taking LdT will be compared to results for patients taking lamivudine.
Detailed description
Multicenter, multinational, randomized, double-blind study designed to compare the safety and efficacy of telbivudine (600 mg/day) versus lamivudine (100 mg/day) for 104 weeks in adults with decompensated chronic hepatitis B and evidence of cirrhosis. Patients were pre-stratified by screening Child-Turcotte-Pugh score (CTP score \< 9 or ≥ 9) and ALT level (within normal limits (WNL) or \> 1.0 x ULN) to help assure similar degrees of hepatic insufficiency and liver inflammation on both treatment arms. After 104 weeks of treatment, participants were followed-up with for an additional 16 weeks.
Interventions
DRUGTelbivudine
600mg/day oral tablet for 104 weeks
DRUGLamivudine
100mg/day oral tablet for 104 weeks
DRUGPlacebo
Telbivudine matching placebo or lamivudine matching placebo tablet.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Documented decompensated chronic hepatitis B defined by all of the following: 1. Clinical history compatible with decompensated chronic hepatitis B related cirrhosis; 2. Child-Turcotte-Pugh score \> 7 points. * Evidence of hepatic cirrhosis or portal hypertension. Other protocol-defined inclusion criteria may apply.
Exclusion criteria
* Patient is pregnant or breastfeeding. * Patient is coinfected with hepatitis C virus (HCV), hepatitis D virus (HDV), or Human immunodeficiency virus (HIV). * Patient previously received lamivudine, adefovir, or an investigational anti-hepatitis B virus (HBV) nucleoside or nucleotide analog at any time * Patient has received interferon or other immunomodulatory treatment for HBV infection in the 12 months before Screening for this study. Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Response | From Baseline to Week 52 | Clinical response defined as achieving all of the following 3 criteria on at least 2 consecutive visits or at the last on-treatment visit: Serum hepatitis B virus (HBV) DNA \< 4 log10 copies/mL, normal Alanine transaminase (ALT) level (ALT ≤ Upper Limit of Normal (ULN)), and improvement (a 2- point or greater reduction in Child-Turcotte-Pugh (CTP) score) or stabilization (not more than a 1-point change in CTP score), compared to the baseline value. CTP scores range from 5-15, higher scores indicate more liver impairment. For Improvement/Stabilization, either of the individual criteria were met. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Initial Clinical Response | From Baseline to Week 104 | Time to Clinical Response defined as the number of days elapsed from the baseline visit to achieving initial Clinical Response. |
| Duration of Initial Clinical Response | Baseline to Week 104 | Kaplan-Meier method was used. The duration was calculated as: date of last visit before initial loss of clinical response - date of initial clinical response occurred+1. If a patient did not lose clinical response, it was then censored at the efficacy overall censoring date. |
| Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | From Baseline to weeks 52 and 104 | Child-Turcotte-Pugh (CTP) uses 2 clinical variables, ascites and encephalopathy, and 3 laboratory parameters, serum bilirubin, albumin, and prothrombin time. Each variable is assigned a score from 1 to 3, with the combined score comprising the CTP score range of 5 to 15 points. Higher scores indicate more impaired liver function. Worsening of CTP score was defined as a 2-point or greater increase from baseline, improvement in CTP score was defined as a 2-point or greater reduction from baseline, and stabilization of CTP score was defined as a change of 1-point or less from baseline. |
| Number of Participants With Improvement, Stabilization, and Worsening in a Modified (3-component) CTP Score | Baseline and Week 104 | Modified CTP was calculated using the 3 biochemical-components (serum bilirubin, albumin, and prothrombin). Total scores range from 3-9; higher scores indicate more liver impairment. Improvement was defined as 2-point or greater reduction in score from baseline. Stabilization comprises a score change of 1-point or less from baseline. Worsening of CTP score was defined as a 2-point or greater increase from baseline. The rationale for assessing changes in this modified (3-component) CTP score is that this maneuver removed the two subjective components of CTP scoring (ascites and encephalopathy). |
Countries
Australia, Canada, China, France, Germany, India, Israel, Latvia, Malaysia, New Zealand, Poland, Russia, Singapore, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States, Vietnam
Participant flow
Pre-assignment details
232 patients randomized. One randomized patient in the telbivudine treatment group discontinued prior to commencing treatment and was excluded from the intent to treat (ITT) population. Three randomized patients (two in lamivudine group and one in telbivudine group) had no HBV DNA assessments after baseline and were excluded from ITT population.
Participants by arm
| Arm | Count |
|---|---|
| Telbivudine 600 mg Participants received Telbivudine 600 mg and a matching placebo to lamivudine orally once a day for up to 104 weeks, followed by a 16-week follow-up period. | 114 |
| Lamivudine 100 mg Participants received Lamivudine 100 mg and matching placebo to Telbivudine orally once a day for up to 104 weeks, followed by a 16-week follow-up period. | 114 |
| Total | 228 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 4 |
| Overall Study | Creatinine Clearance < 30 or Dialysis | 0 | 1 |
| Overall Study | Death | 13 | 17 |
| Overall Study | Liver Transplantation | 3 | 3 |
| Overall Study | Lost to Follow-up | 4 | 4 |
| Overall Study | Non-Compliance | 2 | 0 |
| Overall Study | Patient, Investigator, Sponsor request | 8 | 6 |
| Overall Study | Treatment failure | 4 | 5 |
| Overall Study | Virologic Breakthrough | 14 | 16 |
Baseline characteristics
| Characteristic | Telbivudine 600 mg | Lamivudine 100 mg | Total |
|---|---|---|---|
| Age Continuous | 49.6 years STANDARD_DEVIATION 10.88 | 51.9 years STANDARD_DEVIATION 9.98 | 50.8 years STANDARD_DEVIATION 10.48 |
| Age, Customized < 30 years | 6 Participants | 2 Participants | 8 Participants |
| Age, Customized > 50 years | 64 Participants | 68 Participants | 132 Participants |
| Age, Customized Between 30 and 50 years | 44 Participants | 44 Participants | 88 Participants |
| Sex: Female, Male Female | 27 Participants | 33 Participants | 60 Participants |
| Sex: Female, Male Male | 87 Participants | 81 Participants | 168 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 99 / 115 | 97 / 116 |
| serious Total, serious adverse events | 59 / 115 | 68 / 116 |
Outcome results
Primary
Number of Participants With Clinical Response
Clinical response defined as achieving all of the following 3 criteria on at least 2 consecutive visits or at the last on-treatment visit: Serum hepatitis B virus (HBV) DNA \< 4 log10 copies/mL, normal Alanine transaminase (ALT) level (ALT ≤ Upper Limit of Normal (ULN)), and improvement (a 2- point or greater reduction in Child-Turcotte-Pugh (CTP) score) or stabilization (not more than a 1-point change in CTP score), compared to the baseline value. CTP scores range from 5-15, higher scores indicate more liver impairment. For Improvement/Stabilization, either of the individual criteria were met.
Time frame: From Baseline to Week 52
Population: The analysis was on the intention-to-treat (ITT) population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Telbivudine 600 mg | Number of Participants With Clinical Response | Clinical Response | 65 Participants |
| Telbivudine 600 mg | Number of Participants With Clinical Response | HBV DNA < 4log10copies/mL | 85 Participants |
| Telbivudine 600 mg | Number of Participants With Clinical Response | Normal ALT | 78 Participants |
| Telbivudine 600 mg | Number of Participants With Clinical Response | Improvement/stabilization in CTP | 96 Participants |
| Telbivudine 600 mg | Number of Participants With Clinical Response | Improvement in CTP (reduction ≥ 2) | 34 Participants |
| Telbivudine 600 mg | Number of Participants With Clinical Response | Stabilization in CTP (absolute change ≤ 1) | 56 Participants |
| Lamivudine 100 mg | Number of Participants With Clinical Response | Improvement in CTP (reduction ≥ 2) | 43 Participants |
| Lamivudine 100 mg | Number of Participants With Clinical Response | Clinical Response | 62 Participants |
| Lamivudine 100 mg | Number of Participants With Clinical Response | Improvement/stabilization in CTP | 96 Participants |
| Lamivudine 100 mg | Number of Participants With Clinical Response | HBV DNA < 4log10copies/mL | 82 Participants |
| Lamivudine 100 mg | Number of Participants With Clinical Response | Stabilization in CTP (absolute change ≤ 1) | 48 Participants |
| Lamivudine 100 mg | Number of Participants With Clinical Response | Normal ALT | 81 Participants |
Secondary
Duration of Initial Clinical Response
Kaplan-Meier method was used. The duration was calculated as: date of last visit before initial loss of clinical response - date of initial clinical response occurred+1. If a patient did not lose clinical response, it was then censored at the efficacy overall censoring date.
Time frame: Baseline to Week 104
Population: The analysis was on intention-to-treat (ITT) population. Only patients who achieved clinical response were considered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Telbivudine 600 mg | Duration of Initial Clinical Response | 473.1 Days | Standard Error 26.13 |
| Lamivudine 100 mg | Duration of Initial Clinical Response | 456.3 Days | Standard Error 24.97 |
Secondary
Number of Participants With Improvement, Stabilization, and Worsening in a Modified (3-component) CTP Score
Modified CTP was calculated using the 3 biochemical-components (serum bilirubin, albumin, and prothrombin). Total scores range from 3-9; higher scores indicate more liver impairment. Improvement was defined as 2-point or greater reduction in score from baseline. Stabilization comprises a score change of 1-point or less from baseline. Worsening of CTP score was defined as a 2-point or greater increase from baseline. The rationale for assessing changes in this modified (3-component) CTP score is that this maneuver removed the two subjective components of CTP scoring (ascites and encephalopathy).
Time frame: Baseline and Week 104
Population: The analysis was done on the intention-to-treat (ITT) population. Last Observation Carried Forward (LOCF) was utilized for missing data, with the exception of missing observations due to treatment failure, death or AE, which were imputed as worsening CTP.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Telbivudine 600 mg | Number of Participants With Improvement, Stabilization, and Worsening in a Modified (3-component) CTP Score | Improvement at Week 104 | 30 Participants |
| Telbivudine 600 mg | Number of Participants With Improvement, Stabilization, and Worsening in a Modified (3-component) CTP Score | Stabilization at Week 104 | 57 Participants |
| Telbivudine 600 mg | Number of Participants With Improvement, Stabilization, and Worsening in a Modified (3-component) CTP Score | Worsening at Week 104 | 27 Participants |
| Lamivudine 100 mg | Number of Participants With Improvement, Stabilization, and Worsening in a Modified (3-component) CTP Score | Improvement at Week 104 | 31 Participants |
| Lamivudine 100 mg | Number of Participants With Improvement, Stabilization, and Worsening in a Modified (3-component) CTP Score | Stabilization at Week 104 | 54 Participants |
| Lamivudine 100 mg | Number of Participants With Improvement, Stabilization, and Worsening in a Modified (3-component) CTP Score | Worsening at Week 104 | 29 Participants |
Secondary
Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104
Child-Turcotte-Pugh (CTP) uses 2 clinical variables, ascites and encephalopathy, and 3 laboratory parameters, serum bilirubin, albumin, and prothrombin time. Each variable is assigned a score from 1 to 3, with the combined score comprising the CTP score range of 5 to 15 points. Higher scores indicate more impaired liver function. Worsening of CTP score was defined as a 2-point or greater increase from baseline, improvement in CTP score was defined as a 2-point or greater reduction from baseline, and stabilization of CTP score was defined as a change of 1-point or less from baseline.
Time frame: From Baseline to weeks 52 and 104
Population: The analysis was done per intention-to-treat (ITT) population. Last Observation Carried Forward (LOCF) was utilized for missing data, with the exception of missing observations due to treatment failure, death or AE, which were imputed as worsening CTP.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Telbivudine 600 mg | Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | Improvement At Week 52 | 36 Participants |
| Telbivudine 600 mg | Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | Stabilization At Week 52 | 60 Participants |
| Telbivudine 600 mg | Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | Worsening At Week 52 | 18 Participants |
| Telbivudine 600 mg | Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | Improvement At Week 104 | 44 Participants |
| Telbivudine 600 mg | Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | Stabilization At Week 104 | 42 Participants |
| Telbivudine 600 mg | Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | Worsening At Week 104 | 28 Participants |
| Lamivudine 100 mg | Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | Stabilization At Week 104 | 38 Participants |
| Lamivudine 100 mg | Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | Improvement At Week 52 | 44 Participants |
| Lamivudine 100 mg | Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | Improvement At Week 104 | 46 Participants |
| Lamivudine 100 mg | Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | Stabilization At Week 52 | 52 Participants |
| Lamivudine 100 mg | Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | Worsening At Week 104 | 30 Participants |
| Lamivudine 100 mg | Number of Participants With Improvement, Stabilization, and Worsening in Child-Turcotte-Pugh (CTP) Score at Week 52 and Week 104 | Worsening At Week 52 | 18 Participants |
Secondary
Time to Initial Clinical Response
Time to Clinical Response defined as the number of days elapsed from the baseline visit to achieving initial Clinical Response.
Time frame: From Baseline to Week 104
Population: The analysis was on intention-to-treat (ITT) population. Only the observed time to initial clinical response was summarized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Telbivudine 600 mg | Time to Initial Clinical Response | 137.5 Days | Standard Deviation 126.14 |
| Lamivudine 100 mg | Time to Initial Clinical Response | 125.2 Days | Standard Deviation 111.24 |