A Study of the Safety and Efficacy of plus Tenofovir in Adults with Chronic Hepatitis B Virus Infection with Previous Nucleoside/Nucleotide Treatment Failure () FINAL CLINICAL STUDY REPORT EUDRACT Number: 2009-015705-40 Name of Product: Phase of Development: 3b Date of First Observation: 17 May 2010 Date of Last Observation: 18 February 2014 Indication Studied: Chronic hepatitis B virus infection Study Design: Single-arm, open-label, multicenter study. Patients with chronic hepatitis B virus infection received oral entecavir 1 mg plus oral tenofovir 300 mg once daily for 96 weeks and were followed up to a maximum of 24 weeks off-treatment, with the primary endpoint at Week 48. Sponsor s Contact: Date of Final Report: 28 August 2014 This study was performed in accordance with Good Clinical Practice, including the archiving of essential documents.
2 SYNOPSIS Title of Study: A Study of the Safety and Efficacy of plus Tenofovir in Adults with Chronic Hepatitis B Virus Infection with Previous Nucleoside/Nucleotide Treatment Failure () Investigators: A list of the sites and the names of the Investigators are provided in Appendix 16.1.4. Study Sites: This study was conducted at 30 sites in Poland, Germany, France, Italy, the Netherlands, and Romania. Publication (Reference): None Studied Period (date of first patient enrolled to date last patient Phase of Development: 3b completed study): 17 May 2010 to 18 February 2014 Objectives: Primary: To describe the efficacy of the combination therapy of entecavir (ETV) plus tenofovir disoproxil fumarate (TDF) at 48 weeks of treatment in controlling the viral load (hepatitis B virus [HBV] deoxyribonucleic acid [DNA] < 50 IU/mL) in chronic HBV-infected patients who have failed previous treatment Secondary: Proportion of patients with HBV DNA < 50 IU/mL at Weeks 24 and 96 Proportion of patients who achieve HBV DNA < the lower limit of detection (LLD) as defined by the COBAS TaqMan assay in use at the central lab at Weeks 24, 48, and 96 To evaluate the changes in hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) status at Weeks 24, 48, and 96 To evaluate the emergence of resistant mutations during treatment with ETV/TDF To evaluate the mean change of viral load from baseline To assess the long-term safety of the combination therapy of ETV/TDF Methodology: This was a single-arm, open-label, multicenter study in which patients were to receive ETV/TDF combination therapy for 96 weeks and were to be followed up to a maximum of 24 weeks off-treatment, with the primary endpoint at Week 48. Two interim analyses were performed (i.e., when the first 20 patients had completed Week 24 and when all patients had completed Week 48, the primary endpoint). Results from all endpoints in the study are presented in this final CSR. At the Week 96 visit (end of study dosing), further treatment with commercially available therapies was to be at the discretion of the Investigator. Patients who discontinued study drug at or before Week 96 and who did not receive an alternative anti-hbv therapy were to be followed on-study for up to 24 weeks of postdosing follow-up. All patients were to complete the first post-dosing visit at Week 6. Patients who had initiated alternative anti-hbv therapy prior to Week 6 were to leave the study following completion of the visit activities. Patients who had not initiated alternative anti-hbv therapy by the time of the Week 6 follow-up visit were to continue to be followed for a total of 24 weeks after discontinuation of study drug in off-treatment follow-up. 28 August 2014 Page 3
Number of Patients: At least 90 patients were to be enrolled, with a minimum of 60 and a maximum of 100 eligible patients treated. A total of 144 patients were enrolled, and 92 patients were treated with ETV/TDF therapy. Diagnosis and Main Criteria for Inclusion: Chronic HBV infection, with HBeAg-positive or HBeAg-negative disease Treatment failure to current nucleoside/nucleotide treatment regimen Men and women 18 years of age Compensated liver function Test Product, Dose, Mode of Administration, and Batch Numbers: ETV 1 mg tablets and TDF 300 mg tablets; 1 tablet of each study drug taken by mouth once daily for 96 weeks. The ETV batch numbers were 0A62104, 0M42464, 1H57438, 2A71804, 2H63418, and 9D54826. The TDF batch numbers were 9K50898, 10VR001D, 0L62256, 10VR056D, 11VR034D, 11VR049D, A128472D, and 9H40294. Duration of Treatment: For each patient, there were 3 periods: a screening period of up to 4 weeks, a treatment period of 96 weeks, and a follow-up period of up to 24 weeks. Reference Therapy, Dose, Mode of Administration, and Batch Number: None. Criteria for Evaluation: Efficacy: Primary Efficacy Endpoint Proportion of patients who achieved a virologic response defined as HBV DNA < 50 IU/mL (approximately 300 copies/ml) by polymerase chain reaction (PCR) at Week 48 using the Roche COBAS TaqMan - High Pure System (HPS) assay Secondary Efficacy Endpoints Proportion of patients with HBV DNA < 50 IU/mL at Weeks 24 and 96 Proportion of patients who achieved HBV DNA < LLD as defined by the COBAS TaqMan assay in use at the central lab at Weeks 24, 48, and 96 Proportion of HBeAg loss and HBeAg seroconversion at Weeks 24, 48, and 96 for HBeAg-positive patients at baseline Proportion of HBsAg loss and HBsAg seroconversion at Weeks 24, 48, and 96 Proportion of patients with emergence of resistant mutations during treatment with ETV plus TDF Change from baseline in mean log 10 HBV DNA at Week 12 Safety: Number and percent of patients with adverse events (AEs), serious adverse events (SAEs), laboratory abnormalities, and discontinuations due to AEs. Statistical Methods: Sample Size The sample size was based on the primary endpoint, the proportion of patients who achieved a virological response defined as HBV DNA < 50 IU/mL at Week 48. Approximately 90 enrolled patients were estimated to result in a sample size of at least 60 enrolled and treated patients, allowing for a screen failure rate of 28 August 2014 Page 4
approximately 30%. Sixty enrolled and treated patients were to provide an exact binomial 95% confidence interval (CI) within 13.3% of the observed response rate. In an open-label cohort study, the response rate in patients with advanced liver disease treated by ETV plus TDF was 80%. If the observed response rate was 80%, the exact binomial 95% CI would range from 67.7% to 89.2%. General Methods Continuous variables were summarized with univariate statistics (e.g., mean, median, standard error, standard deviation, quartiles, minimum, and maximum). Categorical variables were summarized either with counts and percents or with proportions (number with event divided by number evaluable) and percents, depending on the analysis. Longitudinal analyses of efficacy and safety parameters used pre-defined visit week windows. Laboratory parameters were summarized using United States (US) values and units for consistency with other ETV studies, as well as using SI values and units for communication purposes in Europe. Laboratory abnormalities were graded using modified World Health Organization (WHO) criteria, except for lactate, calcium, and international normalization ratio (INR) abnormalities, which were graded using the Division of Acquired Immunodeficiency Syndrome (DAIDS) criteria. Patients must have had a baseline measurement in order to be evaluable for longitudinal summaries of parameter values and changes from baseline. No hypothesis testing or formal subgroup comparison was performed in this study. Exact binomial 95% CIs were presented for proportions of efficacy endpoints. Efficacy Methods HBV DNA measured by PCR was reported in IU/mL, with the limit of quantification (LOQ) = 29 IU/mL and LLD = 6 IU/mL. Analyses of secondary endpoints were done using the LLD as reported in the assay package insert at the time of analysis. HBV DNA measurements were transformed by the log 10 scale when analyzed as a continuous variable. Analyses of binary efficacy endpoints focused on treated patients, and utilized the method of Non-Completer = Failure (NC = F), whereby all treated patients were included in the denominator, and patients with missing measurements were counted as non-responders for the specific endpoints. Sensitivity analyses were performed that included all treated patients, using the method of Non-Completer = Missing (NC = M), if applicable. Safety Methods Safety analyses included deaths, SAEs, AEs leading to discontinuation, AEs by relationship to study treatment, AEs by grade, and treatment-emergent clinical laboratory abnormalities. For the on-treatment period, AEs by intensity, AEs leading to discontinuation of study therapy, SAEs, and treatment-emergent laboratory abnormalities were presented through the Week 48 visit, after the Week 48 visit, and for all data collected through Week 96. Analyses for the through the Week 48 visit and all data collected through Week 96 categories were based on all treated patients, whereas analyses for the after Week 48 category were based on a reduced cohort, i.e., those with > 54 weeks of dosing (the upper bound of the Week 48 window). SUMMARY OF RESULTS An interim analysis was performed when at least the first 20 treated patients had completed Week 24. A total of 37 patients were evaluated in this interim analysis, and the results were presented in a separate interim topline summary. Another interim analysis was performed after all patients had completed 48 weeks 28 August 2014 Page 5
of treatment (the primary endpoint), and the results were presented in a separate interim clinical study report. Results from all endpoints in the study are presented in this final CSR. Disposition and Baseline Demographics: Of the 144 patients enrolled in the study, 92 (63.9%) patients were treated with ETV/TDF combination therapy; the major reasons for failing study eligibility were physical and laboratory test findings not suitable for the study (n=30) and not in the target population (n=21). Table 1 summarizes patient disposition from start of treatment to the end of study. Of the 92 treated patients, 3 (3.3%) patients discontinued from the study before Week 48, 3 (3.3%) patients discontinued at or after Week 48 and before Week 96, and 86 (93.5%) patients completed treatment. A total of 85 (92.4%) patients entered the post-dosing follow-up, and 46 (50.0%) patients completed the postdosing follow-up (through 24 weeks). A total of 45 (48.9%) patients entered the off-treatment follow-up; these patients had an off-treatment assessment at least 6 days after the last dose and 1 day prior to alternative therapy. Table 1: Patient Disposition (Start of Treatment to End of Study) Treated Patients Status (%) ETV/TDF (N=92) Treated 92 (100.0) Discontinued Before Week 48 3 (3.3) Adverse Event 1 (1.1) Protocol Violation 1 (1.1) Withdrawal of Consent 1 (1.1) Discontinued at or After Week 48 and Before Week 96 3 (3.3) Pregnancy 1 (1.1) Withdrawal of Consent 1 (1.1) Lost to Follow-up 1 (1.1) Discontinued at or After Week 96 0 Completed Treatment 86 (93.5) Entered Post-dosing Follow-up 85 (92.4) Completed Post-dosing Follow-up (through 24 weeks) 46 (50.0) Did not Complete Post-dosing Follow-up 39 (42.4) Lost to Follow-up 1 (1.1) Withdrawal of Consent 6 (6.5) Other 32 (34.8) Entered Off-treatment Follow-up 45 (48.9) The mean age was 43.6 years (range: 18 to 84). The majority of patients were male and white, and the country with highest enrollment was Poland. Demographics are summarized in Table 2. 28 August 2014 Page 6
Table 2: Patient Demographics Treated Patients ETV/TDF (N=92) Age (years) Mean (Standard error) 43.6 (1.554) Median 42.0 Minimum, Maximum 18, 84 Gender: N (%) Male 69 (75.0) Female 23 (25.0) Race: N (%) White 70 (76.1) Black or African American 9 (9.8) Hispanic or Latino 1 (1.1) Asian 12 (13.0) Country: N (%) France 10 (10.9) Germany 23 (25.0) Italy 1 (1.1) Netherlands 6 (6.5) Poland 32 (34.8) Romania 20 (21.7) Note: Percentages are based on patients with measurements. At baseline, mean HBV DNA was 4.413 log 10 IU/mL (range: 1.45 to 9.30 log 10 IU/mL). The majority of patients were HBeAg-positive. All patients were HBsAg-positive. Over half of the patients were HBV subtype D and had partial virological response to prior treatment at study entry. Baseline HBV disease characteristics are summarized in Table 3. Table 3: Patient HBV Disease Characteristics at Baseline Treated Patients ETV/TDF (N=92) Baseline HBV DNA by PCR (log 10 IU/mL) Mean (Standard Error) 4.413 (0.22715) Median 3.674 Minimum, Maximum 1.45, 9.30 Baseline Hepatitis B e Antigen: N (%) Positive 56 (62.2) Negative 34 (37.8) Missing 2 28 August 2014 Page 7
Table 3: Patient HBV Disease Characteristics at Baseline Treated Patients (Cont.) ETV/TDF (N=92) Baseline Hepatitis B e Antibody: N (%) Positive 32 (36.4) Negative 56 (63.6) Indeterminate 2 Missing 2 Baseline Hepatitis B Surface Antigen: N (%) Positive 92 (100.0) Negative 0 Baseline Hepatitis B Surface Antibody: N (%) Positive 0 Negative 91 (100.0) Missing 1 Baseline HBV Subtype: N (%) Subtype A 21 (32.3) Subtype B 2 (3.1) Subtype C 1 (1.5) Subtype D 35 (53.8) Subtype E 4 (6.2) Subtype G 1 (1.5) Subtype H 1 (1.5) Indeterminate 3 Insufficient HBV DNA 23 Missing 1 Prior Treatment Failure: N (%) Primary non-response 9 (9.9) Virological breakthrough 30 (33.0) Partial virological response 52 (57.1) Missing 1 Note: Percentages are based on patients with measurements. Exposure: Overall, the mean time on ETV/TDF therapy was 92.56 weeks (range: 1.6 101.3). The mean average daily dose was 1.00 mg (range: 0.6 1.0 mg) for ETV and 298.65 mg (range: 193.3 300.0 mg) for TDF. 28 August 2014 Page 8
Efficacy Results: Efficacy endpoints are summarized in Table 4. At Week 48, 70/92 (76.1%) of ETV/TDF patients achieved the primary endpoint, a reduction of HBV DNA to < 50 IU/mL. At Week 96, 84.8% of patients achieved a reduction of HBV DNA to < 50 IU/mL. Through Week 96, 7 patients met the criteria for genotypic testing: 2 patients had both primary non response and virological breakthrough, 3 patients had only primary non-response, and 2 patients had only virological breakthrough. No treatment-emergent genotypic resistance was observed in these patients. Table 4: Efficacy Endpoints - Treated Patients Efficacy Endpoint No. with Response/ No. Evaluable (%) (N=92) 95% CI Primary Endpoint HBV DNA < 50 IU/mL at Week 48 (NC=F) 70/92 (76.1) (66.1, 84.4) Secondary Endpoints HBV DNA < 50 IU/mL at Week 24 (NC=F) 59/92 (64.1) (53.5, 73.9) HBV DNA < 50 IU/mL at Week 96 (NC=F) 78/92 (84.8) (75.8, 91.4) HBV DNA Change from Baseline (log 10 IU/mL) at Week 12 Mean (SD) Median Min, Max HBV DNA Change from Baseline (log 10 IU/mL) at Week 24 Mean (SD) Median Min, Max HBV DNA Change from Baseline (log 10 IU/mL) at Week 48 Mean (SD) Median Min, Max HBV DNA Change from Baseline (log 10 IU/mL) at Week 96 Mean (SD) Median Min, Max N=89-2.230 (1.5339) -1.909-6.29, 1.86 N=89-2.581 (1.8019) -2.047-6.65, 0.62 N=88-2.829 (2.0537) -2.049-7.86, 0.58 N=84-2.965 (2.1431) -2.465-7.86, 0.25 HBV DNA < LLD (6 IU/mL) (NC=F) Week 24 11/92 (12.0) (6.1, 20.4) Week 48 17/92 (18.5) (11.1, 27.9) Week 96 15/92 (16.3) (9.4, 25.5) HBeAg Loss (HBeAg+ at Baseline) (NC=F) Week 24 2/56 (3.6) (0.4, 12.3) 28 August 2014 Page 9
Table 4: Efficacy Endpoints - Treated Patients (Cont.) Week 48 3/56 (5.4) (1.1, 14.9) Week 96 5/56 (8.9) (3.0, 19.6) HBe Seroconversion (HBeAg+ at Baseline) (NC=F) Week 24 2/56 (3.6) (0.4, 12.3) Week 48 2/56 (3.6) (0.4, 12.3) Week 96 1/56 (1.8) (0.0, 9.6) HBsAg Loss (NC=F) Week 24 1/92 (1.1) (0.0, 5.9) Week 48 0/92 --- Week 96 2/92 (2.2) (0.3, 7.6) HBs Seroconversion (NC=F) Week 24 1/92 (1.1) (0.0, 5.9) Week 48 0/92 --- Week 96 1/92 (1.1) (0.0, 5.9) Treatment-emergent Genotypic Resistance Week 48 0/5 Week 96 0/7 28 August 2014 Page 10
Safety Results: No deaths were reported on treatment. One death was reported after the post-dosing follow-up period (after the patient completed the study) due to an SAE of hepatocellular carcinoma (HCC) that began on treatment. On treatment, 3 patients had 5 SAEs through the Week 48 visit (hemorrhoids, inguinal hernia, cataract [1 patient reported 2 events], and appendicitis); and 3 patients had 3 SAEs after Week 48 (2 events of HCC and 1 radius fracture). None of these on-treatment SAEs was considered related to study therapy by the Investigator. During post-dosing follow-up, 1 patient had an SAE (decreased neutrophils) that was considered related to study therapy by the Investigator. One patient discontinued study therapy prior to the Week 48 visit due to treatment-emergent AEs (TEAEs) (nausea, vertigo, decreased appetite, somnolence, and insomnia) that were considered related to study therapy by the Investigator. No patient discontinued study therapy due to a TEAE after Week 48. Overall, the incidence of TEAEs and treatment-related TEAEs was higher through Week 48 (67.4% and 30.4%, respectively) compared to after Week 48 (31.8% and 3.4%, respectively). Through Week 48, the most common TEAEs ( 7%) were fatigue, nausea, and dyspepsia, all of which were known side-effects of treatment with ETV as well as TDF. After Week 48, the most common TEAE was nasopharyngitis (6.8%). The only treatment-related TEAEs reported in > 5% of patients were fatigue (9.8%) and nausea (7.6%); all occurrences of these 2 treatment-related TEAEs were reported through Week 48. Most TEAEs were Grade 1 or 2 in intensity. On treatment, Grade 3 to 4 TEAEs were reported for 3 patients through Week 48 (appendicitis, arthralgia, and depression; all Grade 3); and for 3 patients after Week 48 (inflammation, radius fracture, and HCC; only HCC was Grade 4). None of these Grade 3 or 4 TEAEs were considered related to study therapy by the Investigators. On treatment, no patient had an ALT flare; during the post-dosing follow-up period, 1 patient had an ALT flare. One patient had a bone-related AE of radius fracture that was not considered related to the study therapy by the Investigator. Two patients had malignant hepatic neoplasms on treatment after Week 48 (also considered HBV disease progression) that were not considered related to the study therapy by the Investigators. On treatment, the most common laboratory abnormalities were total bilirubin > 2 x baseline (12.2%) and ALT > 2 x baseline (10.0%). Laboratory values that worsened from normal at baseline to Grade 1 to 4 on treatment that were reported in > 10% of patients were lactate, WBC, ALT, total bilirubin, hypocarbia, and hyperglycemia. Only 2 patients had laboratory values (lipase) that worsened from normal at baseline to Grade 3 to 4 on treatment. Twenty-three of 84 (27.4%) patients had a TmPO4/GFR < 0.8 mmol/l at Week 96. At baseline, of 90 patients with urine sampling, 5 patients were positive for glucosuria; treatment-emergent glucosuria was reported in 41/81 (50%) patients. Two patients had glucosuria during off-treatment follow up; both were detected after the end of dosing visit. One pregnancy was reported during the study in a female patient; no obstetrical or maternal complications were reported during this pregnancy, and the patient delivered a full-term, normal male baby. No notable trends were observed in vital signs during the study. Safety is summarized in Table 5. 28 August 2014 Page 11
Table 5: Overview of Safety On Treatment Through Week 48 (N=92) n (%) ETV/TDF After Week 48 (N=88) n (%) All (N=92) n (%) Death 0 (0.0) 0 (0.0) 0 (0.0) SAE 3 (3.3) 3 (3.4)* 6 (6.5) TEAE leading to discontinuation of study therapy 1 (1.1) 0 (0.0) 1 (1.1) TEAE leading to interruption of study therapy 2 (2.2) 0 (0.0) 2 (2.2) Any TEAE 62 (67.4) 28 (31.8) 65 (70.7) Most common TEAEs ( 5% overall) Nasopharyngitis 6 (6.5) 6 (6.8) 11 (12.0) Fatigue 9 (9.8) 0 (0.0) 9 (9.8) Nausea 8 (8.7) 0 (0.0) 8 (8.7) Dyspepsia 7 (7.6) 0 (0.0) 7 (7.6) Arthralgia 6 (6.5) 2 (2.3) 7 (7.6) Asthenia 6 (6.5) 0 (0.0) 6 (6.5) Diarrhea 5 (5.4) 1 (1.1) 6 (6.5) Headache 5 (5.4) 1 (1.1) 6 (6.5) Bronchitis 4 (4.3) 2 (2.3) 6 (6.5) Dizziness 5 (5.4) 0 (0.0) 5 (5.4) Abdominal pain upper 4 (4.3) 1 (1.1) 5 (5.4) TEAE of Grade 3 or 4 intensity 3 (3.3) 3 (3.4) 6 (6.5) Any related TEAE 28 (30.4) 3 (3.4) 29 (31.5) Related TEAE of Grade 2-4 intensity 12 (13.0) 1 (1.1) 13 (14.1) Related TEAE of Grade 3-4 intensity 0 (0.0) 0 (0.0) 0 (0.0) ALT Flares 0 (0.0) 0 (0.0) 0 (0.0) Bone-related AEs 0 (0.0) 1 (1.1) 1 (1.1) Malignant Neoplasms 0 (0.0) 2 (2.3) 2 (2.2) Hepatic Disease Progressions 0 (0.0) 2 (2.3) 2 (2.2) *A patient with an SAE of HCC that began after Week 48 on treatment was reported as having died due to this event after the post-dosing follow-up period (after the patient completed the study). 28 August 2014 Page 12
Conclusions: At Week 48, 76.1% of patients achieved the primary endpoint, a reduction of HBV DNA to < 50 IU/mL. At Week 96, 84.8% of patients achieved a reduction of HBV DNA to < 50 IU/mL. Through Week 96, none of the 7 patients who met the criteria for genotypic resistance testing developed treatment-emergent resistance to ETV or TDF. Daily ETV/TDF combination therapy was safe and tolerable. Most TEAEs were Grade 1 or 2 in intensity, and the only treatment-related TEAEs reported in > 5% of patients were fatigue (9.8%) and nausea (7.6%). The incidence of bone-related TEAEs, malignant neoplasms, and hepatic disease progression during the study was low. Date of Final Report: 28 August 2014 28 August 2014 Page 13