SYNOPSIS OF RESEARCH REPORT (PROTOCOL MV22009)

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2 SYNOPSIS OF RESEARCH REPORT (PROTOCOL MV22009) COMPANY: F. Hoffmann-La Roche, Ltd ME OF FINISHED PRODUCT: Pegasys ME OF ACTIVE SUBSTANCE(S): Peginterferon alfa-2a (FOR TIOL AUTHORITY USE ONLY) TITLE OF THE STUDY / REPORT No. / DATE OF REPORT INVESTIGATORS / CENTERS AND COUNTRIES PUBLICATION (REFERENCE) A Multicenter, Prospective, Observational, Non-Interventional Cohort Study Evaluating On-Treatment Predictors of Response in Subjects with HBeAg positive or HBeAg negative Chronic Hepatitis B Receiving Therapy with PEGASYS (Peginterferon alfa-2a 40KD) 219 centers across 26 countries (Austria, Bahrain, Bangladesh, Bosnia & Herzegovina, Bulgaria, China, Egypt, France, Germany, Hong Kong, India, Indonesia, Ireland, Jordan, Korea, Lebanon, Macedonia, Morocco, New Zealand, Pakistan, Poland, Portugal, Romania, Saudi Arabia, Thailand and United Kingdom) PERIOD OF TRIAL April 11, 2009 Nov 17, 2014 CLINICAL PHASE NIS OBJECTIVES Primary Objective To assess in routine clinical practice on-treatment predictors of HBsAg clearance in subjects with HBeAg positive or negative chronic hepatitis B virus infection (CHB) receiving therapy with Peginterferon alfa-2a (PEG IFN) and followed for up to 3 years after treatment cessation. Secondary Objective Evaluation of the incidence of sustained suppression of HBV D In subjects with HBeAg positive CHB: incidence of HBeAg seroconversion Evaluation of the incidence of normalization of serum ALT To assess in routine clinical practice pre-treatment predictors of HBsAg clearance in subjects with HBeAg positive or negative CHB who receive therapy with PEG IFN and are followed for up to 3 years To assess predictors of HBsAg seroconversion in subjects with HBeAg positive or negative CHB Evaluation of the incidence of clinical endpoints, where data available, in responders versus non-responders to treatment: Death, transplantation, HCC, liver decompensation, development of cirrhosis (in patients without cirrhosis at baseline) STUDY DESIGN International, multicenter, prospective, observational, noninterventional cohort study. PEG IFN treatment period as 1

3 prescribed by treating physician and treatment-free follow-up period of up to 3 years after treatment cessation. NUMBER OF SUBJECTS DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION TRIAL DRUG / STROKE (BATCH) No. DOSE / ROUTE / REGIMEN / DURATION REFERENCE DRUG / STROKE (BATCH) No. A total of 1,842 patients were enrolled: Of these 877 were HBeAg positive and 912 HBeAg negative, and 53 patients were of unknown HBeAg status. Adult subjects receiving treatment for CHB with PEG IFN according to local standard of care (SOC) and in line with the current summary of product characteristics (SPC) / local labeling who had no contra-indication to PEG IFN therapy as per the local label were eligible for this cohort. Main criteria were: Male and female subjects 18 years of age HBeAg positive or HBeAg negative serologically proven CHB with or without cirrhosis Elevated serum ALT >ULN (upper limit of normal) but 10 ULN according to local label Subjects with no contra-indications to PEG IFN therapy as detailed in the label (hypersensitivity to the active substance, to alpha interferons, or to any of the excipients; autoimmune hepatitis; severe hepatic dysfunction or decompensated cirrhosis of the liver; a history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months) Subjects who were not co-infected with HAV, HCV or HIV Subjects were not to receive concomitant therapy with telbivudine (because concomitant peginterferon therapy is contraindicated according to the telbivudine label) Female subjects not pregnant or breast feeding when PEG IFN treatment commenced, and aware of the requirement to use an effective method of contraception during therapy Written informed consent where local regulations allow or require it DOSE / ROUTE / REGIMEN / DURATION CRITERIA FOR EVALUATION EFFICACY: Primary Efficacy Endpoints HBsAg clearance 3 years post-treatment, defined as percentage of subjects who became HBsAg negative by the end of the observation period Secondary Efficacy Endpoints In all patients: HBsAg clearance, suppression of HBV D to <2,000 IU/mL, normalization of ALT, HBsAg seroconversion, 2

4 PHARMACODYMICS: PHARMACOKINETICS: SAFETY: STATISTICAL METHODS HBsAg <1,000 IU/mL, HBsAg <100 IU/mL, HBsAg <10 IU/mL, suppression of HBV D to <2,000 IU/mL and normalization of ALT In patients with HBeAg positive CHB: HBeAg loss, HBeAg seroconversion, HBeAg seroconversion and suppression of HBV D to <2,000 IU/mL Continuous variables analyzed in all patients: ALT ratio, HBsAg, HBV D Clinical endpoints: cirrhosis, liver transplantation, hepatocellular carcinoma (HCC), liver decompensation Safety Variables Adverse events (AEs), laboratory abnormalities (ALT flares), treatment discontinuations for safety reasons All endpoints were analyzed at end of treatment (), 6 months post-treatment, 1 year post-treatment, 2 years post-treatment, and 3 years post-treatment providing the response rate and 95% confidence interval of the response rate. Two methods were used to determine the number of analyzed patients : all patients in the analyzed population/group were used (patients with missing measurement for calculation of the endpoint were considered non-responders regarding the endpoint) o In the following text this approach is called analysis A. only patients in the analyzed population/group without missing measurements for calculation of the endpoint were used (analysis as observed ) o In the following text this approach is called analysis B. This approach of analyzing response rates by using these two different methods to determine the number of patients analyzed was chosen to account for the considerable amount of missing data observed in this observational study. Using this approach should give an idea of the range in which the true effect is located. Whenever in the following text response rates are given the response derived from analysis A is presented first, e.g. X% (analysis A) resp. Y% (analysis B).Exploratory subgroup analyses were performed for the primary efficacy endpoint and key secondary efficacy endpoints. Positive and negative predictive values of several post-baseline response criteria for different efficacy endpoints were calculated. Multiple logistic regression (MLR) analyses were performed to examine the predictive value of various baseline and on-treatment factors on different efficacy endpoints. The secondary objectives predictors of HBsAg seroconversion and evaluation of the incidence of clinical endpoints in responders versus non-responders to treatment could not be analyzed as originally planned because of very low incidence rates. 3

5 METHODOLOGY: All clinical information and laboratory parameters documented for this observational study prior to start of PEG IFN treatment and during this study were routinely assessed as SOC and not for the purpose of this study. Patient s medical history, demographics, and disease characteristics were extracted from the medical record, as well as the CHB treatment observations (dose and exposure), concomitant medication and AEs. To evaluate serological and virological treatment response the respective tests were done as routine procedures, test kits and frequency of measuring depending on SOC in the respective clinic/practice. Patients were observed for the duration of PEG IFN treatment and for up to 3 years afterwards. EFFICACY RESULTS: Primary Efficacy Endpoint HBeAg Positive Patients At 3 years post-treatment the rate of HBsAg clearance was 2% resp. 5% in HBeAg positive patients. Subgroup Analyses Patients harboring genotype A achieved the highest rates of HBsAg clearance at 3 years post-treatment: 14% resp. 25%. In patients harboring genotype B or C response rates were considerably lower: 2% resp. 6% or 1% resp. 3%. The lowest response rate was observed in genotype D: 0% resp. 0%. The majority of patients (n=697) received PEG IFN monotherapy and achieved HBsAg clearance at 3 years post-treatment as frequently as the total HBeAg positive population (2% resp. 5%). Patients receiving PEG IFN add-on to NUCs (nucleos(t)ide analogues) (n=30) showed a slightly higher response rate (3% resp. 8%). Patients who received PEG-IFN + NUC combination therapy from start (n=28) did not at all achieve HBsAg clearance at 3 years post-treatment. Considering duration of treatment, the largest homogeneous group of patients (n=379) received treatment for 48 weeks; this group achieved HBsAg clearance at 3 years post-treatment as frequently as the total HBeAg positive population (2% resp. 5%). Only a minority of 44 and 32 patient had their treatment prolonged to 72 weeks or 96 weeks, respectively. The patients prolonging to 72 weeks achieved a higher response rate (7% resp. 13%), whereas the 96 week group had a similar response rate (3% resp. 6%) to the 48 week group. Additionally, among patients receiving 48 weeks of PEG IFN monotherapy (treatment according to label, no additional anti HBV treatment at any time during PEG IFN) 5 resp. 7% achieved HBsAg clearance at 3 years post-treatment. Predictive Values of Early on Treatment Response In HBeAg positive patients, exploring suppression of HBsAg to <1500 IU/mL or <20,000 IU/mL at weeks 12 and 24 provided excellent prediction of non-response resulting in NPVs of 98% resp. 95% or higher. No good positive predictor of response was detected; PPVs were 8% resp. 16%. Logistic Regression Analyses Performing regression analyses on various pre- and on-treatment prognostic factors identified only one ontreatment factor as independent predictor of HBsAg clearance at 3 years post-treatment: Log10-drop HBsAg (Week 24) with an OR of resp (p = resp HBeAg Negative Patients At 3 years post-treatment he rate of HBsAg clearance was 5% resp. 10% in HBeAg negative patients. Subgroup Analyses Patients harboring genotype A achieved the highest rates of HBsAg clearance at 3 years post-treatment: 14% resp. 36%. In patients harboring genotype B the response rate was somewhat lower: 13% resp. 27%. The lowest response rates were observed in genotype C and D: 0% resp. 0% and <1% resp. 2%. The majority of patients (n=753) received PEG IFN monotherapy and achieved HBsAg clearance at 3 years post-treatment roughly as frequently as the total HBeAg negative population (4% resp. 9%). Patients receiving PEG IFN add-on to NUCs (n=47) achieved a higher response rate (11% resp. 19%). Patients who received PEG-IFN + NUC combination therapy from start (n=31) presented the lowest rate of HBsAg clearance at 3 years post-treatment (3% resp. 8%). 4

6 Considering duration of treatment, the majority patients (n=628) received treatment for 48 weeks; this group achieved HBsAg clearance at 3 years post-treatment as frequently as the total HBeAg negative population (5% resp. 10%). Only a minority of 15 and 12 patient received had their treatment prolonged to 72 weeks or 96 weeks, respectively. These patients achieved higher response rates: 13% resp. 22% in the 72 week group and 8% resp. 17% in the 96 week group. Additionally, among patients receiving 48 weeks of PEG IFN monotherapy (treatment according to label, no additional anti HBV treatment at any time during PEG IFN) 4% resp. 9% achieved HBsAg clearance at 3 years post-treatment. Predictive Values of Early on Treatment Response In HBeAg negative patients, exploring two degrees of HBsAg decline (any decline or decline 10%) from baseline to week 12 or 24 provided excellent prediction of non-response resulting in NPVs of 98% resp. 96% or higher. No good positive predictor of response was detected; PPVs were 8% resp. 16%. Logistic Regression Analyses Performing regression analyses on various pre- and on-treatment prognostic factors identified only one ontreatment factor as independent predictor of HBsAg clearance at 3 years post-treatment: HBsAg at week 24 with an OR of resp (p = resp ). Secondary Efficacy Endpoints Response Rates over Time Response rates over time are presented in the table below for HBeAg positive and for HBeAg negative patients. Overview of Response rates over Time Modified ITT HBeAg positive patients HBeAg negative patients N 844* N 872* Endpoints Related to HBsAg Response rates (%) HBsAg <1,000 U/mL HBsAg <100 U/mL HBsAg <10 U/mL # 14 resp resp resp resp resp resp resp resp resp resp resp. 9 3 resp. 8 2 resp. 9 3 resp resp resp resp resp resp resp resp resp resp resp resp resp resp. 9 4 resp resp resp. 15 *Patient numbers of mitt used for analysis A. Patient numbers used for analysis B can be considerably lower, depending on availability of data. # pt = post-treatment 5

7 Overview of Response rates over Time Modified ITT (cont.) HBeAg positive patients HBeAg negative patients N 844* N 872* Endpoints Related to HBsAg Response rates (%) (cont.) HBsAg Clearance HBsAg Seroconversion 3 resp. 4 3 resp. 5 3 resp. 6 2 resp. 5 2 resp. 5 2 resp. 5 2 resp. 5 2 resp. 6 2 resp. 5 1 resp. 5 3 resp. 5 4 resp. 7 4 resp. 8 4 resp. 7 5 resp resp. 5 3 resp. 9 2 resp. 8 1 resp. 5 2 resp. 9 Endpoints Related to HBV D ## Response Rates (%) HBV D 2,000 IU/mL 39 resp resp resp resp resp. 27 Endpoints Related to HBeAg Response Rates (%) 70 resp resp resp resp resp. 31 HBeAg Loss HBeAg Seroconversion HBeAg Seroconversion and HBV D 2,000 IU/mL N resp resp resp resp resp resp resp resp resp resp resp resp resp resp resp. 15 ## Patients who started concomitant treatment with NUCs have been considered non-responders for HBV D related endpoints after start of such treatment.. 6

8 Overview of Response rates over Time Modified ITT (cont.) HBeAg positive patients HBeAg negative patients Endpoints Related to ALT Response rates (%) N 751** N 610** Normalization of ALT Normalization of ALT and HBV D 2,000 IU/mL 34 resp resp resp resp resp resp resp resp resp resp. 22 ** - Patients from mitt with Baseline ALT > ULN 37 resp resp resp resp resp resp resp resp resp resp. 28 HBeAg Positive Patients Subgroup Analyses Subgroup analysis for genotypes revealed that patients harboring genotype A or B generally had the highest HBsAg related response rates whereas patients harboring genotype D generally showed the lowest response. Additionally, the genotype B subgroup had the highest response rates for all HBeAg related endpoints. When generating subgroups of treatment regimens, patients treated with PEG IFN monotherapy achieved considerably higher rates of suppression of HBV D (<2,000 IU/mL) at all time points from 6 months post-treatment than patients of the subgroups Combo PEG + NUC and PEG add-on to NUC (at 3 years posttreatment 14% resp. 29% vs. 0% resp. 0% and 7% resp. 13%). Predictive Values of Early on Treatment Response for Selected Secondary Endpoints 3 Years Post- Treatment When considering HBeAg seroconversion, the best prediction of non-response was achieved by using the cut-off of HBsAg <20,000 IU/mL at week 24 (NPV 91% resp. 76%). Positive prediction of response was moderate; HBsAg of <1500 IU/mL at weeks 12 and 24 yielded PPVs of 20% resp. 55% and 21% resp. 55%. For the combined endpoint HBV D <2,000 IU/mL and HBeAg seroconversion, the best prediction of non-response was achieved again by using the cut-off of HBsAg <20,000 IU/mL at week 24 (NPV 98% resp. 94%). No reliable positive predictor of response was identified: the highest PPVs were observed for HBsAg <1500 IU/mL at weeks 12 and 24 (13% resp. 39% and 14% resp. 40%). Investigating response prediction for the endpoint HBV D <2,000 IU/mL, suppression of HBsAg to <1500 IU/mL at weeks 12 and 24 provided moderate prediction of response: PPV 22% resp. 45% and 24% resp. 48%. No reliable predictor for non-response (NPV >90%) was detected. Logistic Regression Analysis Logistic regression analyses were performed on various baseline and on-treatment prognostic factors to examine which factor, or combination of factors, had a significant effect on HBsAg clearance at various post-treatment time points. In HBeAg positive patients, log10-drop HBsAg at week 24 remained in the model as only independent predictive factor for all three response endpoints investigated. Odds ratios for the different endpoints see below: 7

9 Endpoint Odds Ratio P-Value HBsAg clearance 6 months post-treatment resp resp HBsAg clearance 1 year post-treatment resp resp HBsAg clearance 2 years post-treatment resp resp HBeAg Negative Patients Subgroup Analyses No clear effect of genotypes on response regarding secondary efficacy endpoints could be seen. When generating subgroups of treatment regimens, patients receiving PEG add-on to NUC achieved the highest HBsAg related response rates compared to patients receiving Pegasys monotherapy or combination treatment with NUCs. Whereas considering the endpoints HBV D < 2,000 IU/mL and normalization of ALT and HBV D 2,000 IU/mL, patients treated with PEG IFN monotherapy achieved the highest response rates. Predictive Values of Early on Treatment Response for Selected Secondary Endpoints 3 Years Post- Treatment Exploring two degrees of HBsAg decline (any decline or decline 10%) from baseline to week 12 or 24 provided only low prediction of response for both endpoints investigated: For the endpoint suppression of HBV D <2,000 IU/mL PPVs were in the range of 13% - 14% resp. 27% - 32%, for the endpoint HBV D <2,000 IU/mL and normalization of ALT PPVs were in the range of 10% - 14% resp. 20% - 31%. NPVs were below 90% resp. 80% for both endpoints. Logistic Regression Analysis In HBeAg negative patients no independent predictor of response was identified. Clinical Endpoints The numbers of patients for whom liver fibrosis assessments are available vary greatly between visits. Additionally, they are rather low, never exceeding 18% of the total population. Therefore, absolute patient numbers are reported in this section. In general, patients were reported to be cirrhotic only once at the visit following the diagnosis. Thus, the number of patients reported with cirrhosis at a visit mostly represents the number of newly diagnosed cirrhotics. However, reporting was not uniform; some cirrhotic patients were reported as such at several visits. Therefore, the numbers of cirrhosis reported somewhat overestimate the true incidence. Numbers of patients diagnosed with cirrhosis were low for all visits, ranging from 3 10 patients in HBeAg positive patients and from 3 14 patients in HBeAg negative patients. Overall, less patients were reported with cirrhosis or transition to cirrhosis during the treatment period than during the post-treatment follow-up period. All other liver related endpoints were rare events, occurring in <1% of the population. In total, 4 HBeAg positive and 7 HBeAg negative patients developed HCC during the study. Decompensated liver disease was reported in 7 HBeAg positive and 2 HBeAg negative patients. Only one HBeAg negative patient underwent liver transplantation during the study. PHARMACODYMIC RESULTS: 8

10 PHARMACOKINETIC RESULTS: SAFETY RESULTS: The majority of patients experienced at least one AE during the PEG IFN treatment or the follow up period. A total of 4,780 AEs were reported in 1,295 patients (72%). Most AEs occurred during treatment: 4,141 versus 697 with onset post-treatment. The proportion of patients experiencing at least one AE was comparable between HBeAg positive and negative patients: 72% versus 73%. Common AEs (incidence at least 5% in any patient group) were thrombocytopenia, leukopenia, neutropenia, WBC decreased, anaemia, pyrexia, headache, asthenia, fatigue, alopecia, influenza like illness, myalgia, weight decreased, decreased appetite, pruritus, depression, nausea, arthralgia, alanine aminotransferase increased, and gamma-glutamyltransferase increased. Twelve patients (3 HBeAg positive, 9 negative) died during the observation period of this study. In 11 of these patients the SAE(s) leading to death were reported unrelated to trial treatment, in one HBeAg negative patient who was reported to have died due to the events metastasis to the lung and multi-organ failure (in a patient suffering from hepatocellular carcinoma) the relationship to metastasis to the lung was reported as related (remote). Of the 11 patients with fatal SAEs unrelated to PEG INF, 4 patients (1 HBeAg positive, 3 negative) died from hepatocellular carcinoma; in one of the HBeAg negative patient encephalopathy was given as additional fatal SAE. The other two HBeAg positive patients died from cardiorespiratory arrest and malignant melanoma. Septic shock together with coma hepatic, a ruptured cerebral aneurysm, gastric cancer and two road traffic accidents were reported as cause of death in 5 HBeAg negative patients. There were few patients (6% in total, 6% of HBeAg positive patients, 7% of HBeAg negative patients) reporting SAEs (total of 160 SAEs in 116 patients). The incidence of AEs leading to treatment discontinuation or dose modification was low: 6% and 8% with no notable differences between HBeAg positive and negative patients. Increases of ALT to >5 10xULN or even to >10xULN (flare) were rare events observed in 9% or 3% of patients on-treatment, in 6% and 2% post-treatment. CONCLUSIONS: PEG IFN treatment of CHB given according to local label and SOC was shown to be efficacious and safe in this non-interventional cohort study. At 3 years post-treatment, HBeAg negative patients achieved HBsAg clearance more frequently than HBeAg positive patients: 5% resp. 10% versus 2% resp. 5%. Patients harboring genotype A achieved the highest rates of HBsAg clearance at 3 years post-treatment, genotype D the lowest ones. Similarly, patients receiving PEG IFN add-on to NUCs fared better than patients receiving PEG IFN monotherapy. For HBV D and ALT related endpoints response rates were broadly similar between HBeAg positive and negative patients. Considering HBsAg clearance and seroconversion, suppression of HBV D, and normalization of ALT, response rates were comparable to those reported from interventional studies as far as comparison was possible for the time point of the so-called sustained response, i.e. 6 months post-treatment. For all response endpoints, the only factor indicative of response was suppression of HBsAg on-treatment, either as suppression to below a cut (at weeks 12 and 24) or as extent of decline from baseline. The overall safety profile of PEG IFN in this real life cohort was consistent with the currently approved label, with no new safety signals detected. 9