1. SYNOPSIS. AWB-ML21645 Date: April 20, 2016 Title of the observational study

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1 1. SYNOPSIS AWB-ML21645 Date: April 20, 2016 Title of the observational study INVESTIGATORS SPONSOR Noninterventional study on the quality assurance of the therapy of chronic hepatitis C with Peg-(40kd)-Interferon alfa-2a (Pegasys ) and Ribavirin (e.g. Copegus ) with main focus gastroenterologists a project in bng, Part III The documentation was performed at 515 sites (444 officebased physicians and 71 clinic physicians) distributed over the entire area of the Federal Republic of Germany. Roche Pharma AG, Emil-Barell-Str Grenzach-Wyhlen MATERIAL AND METHODS Study population Ethics Study design Study objectives Men and women from 18 years of age with chronic active virus hepatitis C with substantiated virus replication. Inclusion criteria: Patients of both genders at an age 18 years Chronic active virus hepatitis C with substantiated virus replication Exclusion criteria: Pregnancy, breastfeeding or women at an age able to conceive without reliable contraception of the woman or the partner. Contraindications for the application of Pegasys, as well as with combination therapy for the application of Ribavirin (e.g. Copegus ) A positive vote of the ethics committee of the Westphalia- Lippe medical association and the medical faculty of the Westphalian Wilhelms-University Münster is available. National, multicentre, open-label, noninterventional study. Primary study objectives Investigation of the effectiveness and tolerability of the therapy of chronic hepatitis C with Peg-Interferon alfa-2a (Pegasys ), usually in the combination with Ribavirin (Copegus ), with patients who are being treated by gastroenterologists at main focus practices, respectively day clinics under everyday conditions. Secondary study objectives Gaining of understanding about the therapeutic habits with hepatitis C and about the compliance of the patients. In harmonisation with the existing recommendations, development of measures for quality improvement in the care of hepatitis C patients. Cause and error analyses for individual practices and clinic day clinics, to optimise the general care quality with the therapy of hepatitis C with Peg-Interferon alfa- Clinical Study Report ML Report Number 1 - v1.5, April 20 th 2016 Page 15 of 234

2 2a (Pegasys ) and Ribavirin (Copegus ). Systematic recording of understanding on the safety profile of Peg-Interferon alfa-2a (Pegasys ) and Ribavirin (Copegus ). Investigational medicinal product & treatment Duration of the study Statistical methodology Pegasys 135 micrograms, respectively 180 micrograms injection solution in a ready to use syringe for injection once a week in combination with the oral administration of Ribavirin. Start of the noninterventional study: January 01, 2008 (First- Patient-In, FPI). End of the observational study was on September 26, 2013 (Last-Patient-Out, LPO). The end of inclusion (Last-Patient-In, LPI) was initially planned for December 31, 2009, was however, extended by amendment until December 31, All collected data are descriptively summarised using mean, standard deviation, minimum, maximum, median, 1st and 3rd Quartile for quantitative data and absolute and relative frequencies (percentages) for qualitative data. For the tolerability analysis adverse drug reactions are provided displaying the number and proportion of patients with at least one event by MedDRA preferred term and system organ class. These overview tables were additionally stratified by seriousness. RESULTS Patient disposition The analysis presented here is based on the data from 9620 patients, who were surveyed within the scope of a noninterventional study (NIS) on the therapy of chronic hepatitis C with Pegasys and Ribavirin and with whom the documentation was completed by the investigator (main analysis set). In 26.5% of all patients treated with Pegasys the treatment was prematurely discontinued. The most frequent reasons for a therapy discontinuation were deficient virological response (42.3% of the patients with therapy discontinuation) and lost-to-follow-up (21.2%). In 63.7% of the patients the treatment was completed as planned, in 9.8% of the patients the documentation of the therapy was not completed within the scope of the observation time period. Demographic data and original data 66.0% of the patients were of male and 34.0% of female gender. The mean (±SD) age was 42.2 (±11.4) years. The mean height was (±9.1) cm and the mean body weight was 76.7 (±14.8) kg. The mean Body Mass Index (BMI) was 25.4 (±4.3) kg/m 2. A proportion of 35.8% of the patients were shown to have a different native language than German, in most cases Russian (20.7%). In approximately 8.1% of the patients knowledge of the German language was either not present or only poor. For Russian, Turkish respectively English speaking patients a patient information and declaration of Clinical Study Report ML Report Number 1 - v1.5, April 20 th 2016 Page 16 of 234

3 informed consent was available in the respective language. In 59.2% of the patients an infection with the HC-Virus genotype 1 was present, in 5.7% there was a genotype 2 infection, in 30.2% a genotype 3 infection, in 4.4% a genotype 4 infection, and in respectively 0.2% a genotype 5 infection, respectively genotype 6 infection was present (in 0.2% of the patients a genotyping was missing). The proportion of the patients with high virus burden (HCV- RNA > 400,000 IU/ml) was at 60.0%. I.v. drug abuse (43.8%) and blood products (10.6%) were the most frequently documented means of transmission for a hepatitis C infection. In 31.6% of the patients the cause of the infection was unknown. The median duration of infection was 10.0 years. At the entry examination clinical signs for cirrhosis of the liver were found in 4.8% (n=457/9620) of all patients. In 63.3% of the patients concomitant diseases were reported. The most frequently documented diseases were drug and/or alcohol abuse (50.9%), psychiatric diseases (25.9%) and cardiovascular diseases (14.1%). 86.7% of the patients were not pre-treated with an anti-viral therapy, 6.9% were therapy relapsers and 5.1% were nonresponders to a previous hepatitis C therapy. Medication Effectiveness The median starting dosage of Pegasys was 180 µg/week in patients with the virus genotype 1/4/5/6, as well as also in patients with genotype 2/3. The median treatment duration with Pegasys was 47 weeks in genotype 1/4/5/6 patients and 24.1 weeks in genotype 2/3 patients. In most cases Copegus was prescribed as Ribavirin in the combination with Pegasys (95.5%; n=9161/9591). The median starting dosage of Ribavirin was 1200 mg/d for the genotype 1/4/5/6 infected, and 1000 mg/d for the genotype 2/3 infected patients. The PEG-RBV combination therapy was discontinued in 26.5% (n=2549/9620) of the patients. 63.7% (n=6131/9620) of the patients reached the planned end of the therapy with the PEG-RBV combination therapy. The most frequent discontinuation reasons for the PEG-RBV combination therapy were virological nonresponse (42.3%; n=1079/2549) and lost-to-follow-up (21.2%; n=540/2549). After 4 treatment weeks (±5 days) evaluable data on HCV- PCR data, respectively on a possible therapy discontinuation were available for 6442 of the 9620 patients. In 2579 of these patients a virological response was observed, i.e. HCV-RNA viral load was under the limit of detection of used PCR technique. Therefore the Rapid Virological Response (RVR) was 40.0% (n=2579/6442), respectively 26.8% (n=2579/9620) in relation to the main analysis set, i.e. considering all patients still in the study, but without evaluable value as non-responder. After 12 weeks (±10 days) evaluable data on HCV-PCR Clinical Study Report ML Report Number 1 - v1.5, April 20 th 2016 Page 17 of 234

4 data, respectively data on a possible therapy discontinuation were available for 7383 patients. In 5260 of these patients there was a virological response, defined as a HCV-RNA viral load decline under the limit of detection, or as viral load decline 2 log from baseline viral load. This Early Virological Response (EVR) after 12 weeks therapy was 71.2% (n=5260/7383), respectively 54.7% (n=5260/9620) in relation to the main analysis set. At the end of the treatment (EoT) the response rate (EoTR), defined as HCV-RNA viral load undetectable at the end of therapy was 59.2% based on all 9620 patients of the main analysis set (HCV genotype (GT) %; GT %; GT %; GT %; GT %; GT %). The Sustained Virological Response (SVR), defined as HCV-RNA viral load undetectable 24 weeks after the end of treatment was 41.4% based on all patients (n=3979/9620). For patients with GT 1 the SVR was 38.2%, for GT %, for GT %, for GT %, for GT % and for GT %. Tolerability At all visits the following clinical symptoms were solicited: Fatigue/exhaustion, fever, rigor, skin changes, loss of hair, joint pain, muscle pain, abdominal complaints, nausea, reflux, weight loss, headache, sleeplessness, irritability, restlessness, depression, depressive mood, psychosis as well as other symptoms. For all solicited symptoms lower incidences were reported at the follow-up observation 24 weeks after the end of treatment compared to baseline. The compliance was assessed by the treating physicians after 24, 36 and 48 weeks as being "very good (all medication taken)" in approximately 65% of the patients. At the end of the therapy the compliance in 56.4% of the patients was assessed as being "very good (all medication taken)". Over the course of the observational study relevant laboratory parameters were measured at different time points: GPT (=ALT), GOT (= AST), Gamma-GT, haemoglobin, erythrocytes, thrombocytes, leucocytes, neutrophile, TSH, Quick, AP, bilirubin, creatinine, serum ferritin, serum iron, transferrin, Alpha-feto protein, albumin, blood glucose (fasting), HbA1c, triglycerides, cholesterol, HDL, LDL, uric acid, CRP. The levels of the measured values as well as their changes over the course of the observational study were in the expected ranges. For example, at baseline a mean value of U/l was measured for GPT, at EoT a value of 45.7 U/l and at the follow-up a value of 43.8 U/l. In total, 502 serious adverse drug reactions (SADRs) were documented in 341 of the 9620 patients, resulting in an incidence rate of 3.5%. The most frequently reported individual SADRs (based on MedDRA Preferred Terms) were anaemia (0.3%, n=33), pneumonia (0.3%, n=26) and depression (0.2%, n=18). In total, over the course of the Clinical Study Report ML Report Number 1 - v1.5, April 20 th 2016 Page 18 of 234

5 observational study 39 cases of death were recorded. 32 of these were included in the main analysis set. In 16 of these 32 fatal cases a causal relationship with Pegasys was assessed by the investigators. In total, 10 female patients reported pregnancies within this study, 4 of these during the follow-up period. Quality-of-life DISCUSSION The assessment of the quality of life within the scope of the entry examination using the items no impairment, low, moderate or strong showed no impairment in 36.3% of the patients. In comparison to the entry examination an increase of the complaint free patients to 56.8% was shown at the end of the follow-up observation using the categories free of symptoms, improved, but not free of symptoms, unchanged or deteriorated. The mean physical component summary score of the SF-36 Questionnaire was 49 at the entry examination, 45 after approximately 12 weeks,47 at the end of the treatment (EoT) and increased to 51 at the follow-up visit. The mean mental component summary score was 41 at the entry examination, 36 after approximately 12 weeks, 37 at the end of the treatment (EoT) and increased to 44 at the follow-up visit. With 400,000 to 500,000 virus carriers of chronic Hepatitis C (chc) in Germany the observational study presented here with 9620 patients comprises approximately 2% of this patient population. The largest proportion of the patients documented in this study are carriers of genotype 1 (59.2%). At the time of the entry examination 60.0% of the patients had a high viral load. I.v. drug abuse and blood products were the most frequent means of transmission. As 35.8% of the patients have a different native language than German, the improvement of the dialogue between physician and patient, e.g. with suitable translation aids, appears to be an important step towards the improvement of the care. The Sustained Virological Response (SVR) 24 weeks after the end of the treatment was 41.4% based on all patients in the main analysis set with SVR-rates of 38.2% for GT 1 and 34.9% for GT 4, as well as 54.8% for GT 2 and 45.9% for GT 3 patients. The virological response observed under reallife conditions is therefore somewhat lower than the data reported in clinical studies (Fried et al., 2002; Hadziyannis et al., 2004). The documented adverse drug reactions did not reveal any new risks not yet reported in clinical studies. Serious adverse drug reactions occurred in 3.5% of the patients; they were therefore less frequent than the 6% known from clinical studies, which however, may be related to an underreporting within the real-life setting. Over the course of the observational study 39 cases of death were documented. The results of the NIS reveal new insights in the therapy of Hepatitis C in everyday clinical practice: With 35.8% more Clinical Study Report ML Report Number 1 - v1.5, April 20 th 2016 Page 19 of 234

6 CONCLUSIONS than a third of the patients have a different native language than German, in most cases Russian (20.7%). With 43.8% the group of the patients with drug abuse constitutes the largest proportion of the treated HCV patients. 63.3% of the patients had serious concomitant diseases, which represented an exclusion criterion in the marketing authorisation studies. This real-world data reveal that the management of multiple diseases is a component of everyday clinical practice in the care of patients with chronic hepatitis C. The high proportion of patients with very good compliance indicates that within the scope of the therapeutic care it been possible has in many cases to convince the patients about the importance of the therapy, whereby measures of quality improvement such as multilanguage patient information material has probably contributed to this. In this noninterventional study Pegasys alone or in combination with ribavirin showed an effectiveness under real-life conditions almost comparable to the efficacy demonstrated in pivotal clinical trials. The slightly lower response rates with regard to SVR may be attributable to the less controlled study setting with higher drop-out rates or the different patient population included in noninterventional studies based on less strict selection criteria, e.g. patients having more comorbidities. No new hitherto unknown adverse drug reactions were observed. Rates of reported events were lower as observed in clinical trials. This may be due to an underreporting, in particular of non-serious events, which is quite common in observational studies. Overall the data from this noninterventional study does not give any cause to change the current assessment of the benefit-risk profile of Pegasys in the treatment of chronic hepatitis C. Clinical Study Report ML Report Number 1 - v1.5, April 20 th 2016 Page 20 of 234