Clinical Study Synopsis

Transcription

1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.

2 Bayer HealthCare Websynopsis Websynopsis Study Sponsor: Bayer HealthCare Study Number: (311941/ BF0703) NCT number: NCT EudraCT number: Not Applicable 1 Study Phase: Official Study Title: Product Name of Observed Product: Name of Active Ingredient: Dose and Mode of Administration: Reference Therapy Reference Therapy: Observational study Betaferon prospective study on Adherence, Coping and Nurse support Interferon beta-1b (Betaferon, Bay ) Interferon beta-1b Recommended dose 250 µg, every other day (eod), by subcutaneous injection Not applicable Duration of Treatment: Duration of treatment was at the discretion of the attending physician and subject choice. Studied Period: Date of first subject first visit: 16 Jun 2008 Study Completion date: 09 Oct 2014 Study Centre(s): Study Design: 272 investigational sites with subjects enrolled in 28 countries: 4 centres in Argentina, 15 centres in Belgium, 3 centres in Bosnia and Herzegovina, 7 centres in China, 8 centres in Colombia, 15 centres in Czech Republic, 16 centres in Egypt, 27 centres in France, 14 centres in Israel, 34 centres in Italy, 2 centres in Jordan, 33 centres in Korea (Republic of), 3 centres in Kuwait, 11 centres in Lebanon, 4 centres in Libya, 22 centres in Mexico, 2 centres in Netherlands, 2 centres in New Zealand, 2 centres in Norway, 9 centres in Portugal, 6 centres in Saudi Arabia, 7 centres in Slovakia, 5 centres in Slovenia, 1 centre in Spain, 6 centres in Syria, 9 centres in Taiwan (Province of China), 3 centres in United Kingdom, 2 centres in Venezuela. This was a prospective, non-interventional, international, multicentre study in subjects with MS who received regular supporting telephone interviews with MS nurses. Methodology: Indication: Study visits were planned for Baseline (Visit 1) and thereafter at Months 6, Month 12, Month 18, and Month 24. A face-to-face treatment interview with the subject was performed by the study nurse at start of study. Regular Nurse telephone interviews occurred to offer support and counselling to the subject. The phone call also served to remind subjects about the treatment. The telephone interviews were performed monthly for the first 6 months of documentation and every second month thereafter. Relapsing Remitting Multiple Sclerosis (RRMS) and Clinically isolated syndrome suggestive of Multiple sclerosis (CIS)

3 2 Bayer HealthCare Websynopsis Main Inclusion This observational study (OS) included subjects in the early stages of MS who had Criteria: started Betaferon treatment for the first time during the previous 6 months. Subjects who had a first clinical event suggestive of MS (according to Betaferon summary of product characteristics [SmPC]) and subjects with relapsing-remitting MS (RRMS) within the first two years of diagnosis (Revised McDonald Criteria or Poser Criteria) could be included in the study. Subjects previously on another disease modifying drug (DMD) could also be documented in the study. Subject selection had to be in line with the respective national approval status in each country, and the prescription of medicine to a subject had to be clearly separate from the decision to include them in the study. Study Objectives: The overall objective of the study was to analyse the influence of selected factors on treatment adherence to Betaferon (interferon beta [IFNB]-1b) in MS. To analyse the impact of standardised additional information and frequent nurse contact on treatment adherence To analyse the influence of subjects way of coping and depression on treatment adherence To evaluate the ability of a newly developed questionnaire (Risk of Dropout Questionnaire [RODQ]) to predict early treatment termination To ascertain rates of early treatment termination in relation to adherence standards in centres and countries Safety: To gather observational safety, tolerability and clinical data on Betaferon as part of an examination of their impact on treatment adherence. Evaluation Criteria: Primary outcome measure: The proportion of subjects adhering to Betaferon treatment at 6, 12, 18 and 24 months, based on patient diaries. Secondary outcome measures: Other outcome measures were based on the patient-completed Ways of Coping Questionnaire (WCQ) and the Hospital Anxiety and Depression Scale (HADS); physician-completed clinical outcomes were based on the annual relapse rate (ARR), the Expanded Disability Status Scale (EDSS) scores and EDSS progression, freedom from disease, and the disease course (the proportion of clinically isolated syndrome [CIS] subjects converting to clinically definite MS [CDMS], and the proportion of RRMS subjects converting to secondary progressive MS (SPMS). Rate of early treatment termination; rate of study dropout; Please provide corresponding results section. Further outcome measures were the nurse-completed RODQ and the centre-completed Modified Adherence Questionnaire. Safety: Occurrence of adverse events (AEs) Statistical Methods: The statistical analyses were of explorative nature. No hypotheses were prespecified, and the type I error level was not controlled. All outcome variables were summarized by means of descriptive statistics (n, Mean [SD], 95% CI for the mean if appropriate, Median, 1st and 3rd Quartile, Minimum and Maximum) or frequencies (n and percentage). Statistical modelling procedures were used to explore the relationships of target variables to prognostic covariates. Depending on the character of the target variable, the following regression models were applied: Cox proportional hazard (PH) regression for time to event variables Poisson regression for ARR Logistic regression for response P-values, Hazard-, odds- and risk ratios, respectively, and corresponding 95%

4 Bayer HealthCare Websynopsis Confidence Intervals (CI) were provided. Number of It was planned to enrol 1500 subjects. In total, 1723 subjects were enrolled and Participants: 1646 were included in any analysis. Early Termination: Not Applicable Substantial Protocol Changes: In protocol amendment 01 (dated 15 November 2010), the planned number of subjects was raised from 600 to 1500, in order to guarantee sufficiently precise estimates and to account for drop-out rates. Study Results Results Summary Subject Disposition and Baseline A total of 1723 subjects enrolled in the study, of which 1646 were included in any analysis; 744 subjects discontinued the study prematurely; 888 subjects completed study treatment; 943 subjects completed the study. The baseline demographic data did not differ essentially between the analysis sets. The intention to treat (ITT) set, consisting of subjects who had an assessment at a clinical or telephone visit after baseline, contained 1545 subjects. In this set, mean age (SD) at baseline was 35.2 (11.0), and 1041/1544 (67.4%) of subjects were female. The mean (SD) duration of MS since diagnosis was 1.58 (3.30) years; the mean (SD) number of relapses during the past two years was1.8 (1.0). The mean (SD) EDSS at baseline was 2.12 (1.47), and 421/1540 (27.3%) had a baseline EDSS 3. In the safety set, mean age (SD) at baseline was 35.3 years (11.0), and 1060/1568 (67.6%) of subjects were female. The mean (SD) duration of MS since diagnosis was 1.61 (3.34) years; the mean (SD) number of relapses during the past two years was 1.8 (1.0). The mean (SD) EDSS at baseline was 2.12 (1.47), and 429/1563 (27.4%) had a baseline EDSS 3. At baseline, of the 1646 subjects included in any analysis, 269 (16.3%) had CIS and 1327 (80.6%) had RRMS; 1430 (86.9%) had not previously used DMD and 214 (13.0%) had previously used DMD. Results Summary Objectives In total 728/1646 (44.2%) subjects discontinued Betaferon treatment up to Month 24. Amongst the subjects from the BEACON study who had had at least one nurse interview (n=1204), 405/1204 (33.6%) had discontinued Betaferon treatment by 24 months. In the subjects who did not have any nurse interview (n= 442), 323 (73.1%) had discontinued Betaferon treatment by 24 months. The estimated survival rates were consistently lower in the subjects without any nurse interview at 6, 12, 18 and 24 months. Using the Cox PH model without stratification variables, the interviewed subjects were times (95% CI: 0.275; 0.370, p<0.05) as likely to discontinue Betaferon treatment at any time point as the subjects who did not receive any interview. However, these comparisons should only be interpreted with caution, as both groups could have been unbalanced with regard to baseline and other characteristics. A HADS depression score 6 at baseline increased the likelihood of premature discontinuation in the univariate model variables (HR [95%CI: 1.086;1.554] (p=0.0042, n=1114) as well as in the model including all baseline predictor variables (HR [95%CI: 1.020;1.470](p=0.0302, n=1114). Influence of subjects way of coping and depression on treatment adherence: In the ITT set, on analysis of the different WCQ coping strategies, the confrontive coping, the escapeavoidance, and the positive reappraisal average score all followed a similar pattern, with subjects who prematurely discontinued Betaferon treatment in Year 2 or Year 1 or 2 having a higher median score at baseline than subjects who completed treatment.*. In addition, the escape-avoidance score analysis showed a higher median score at baseline (1.10 [range 0.0 to 2.4], N=194) in the subjects who discontinued Betaferon during Year 1 than those who completed (1.00 [range 0.0 to 2.8], N=747).* The positive reappraisal score showed a higher median average score change from baseline to last visit between the subjects who discontinued in Year 2 (0.00 [range -2.1 to 2.3], N=289) and Year 1 or 2 (0.00 [range -2.1 to 2.3], N=394) compared to those who completed (-0.10 [range -3.0 to 2.3}, N=703).* In the ITT set, a significantly higher percentage of subjects who discontinued Betaferon treatment during Year 2 (18.7%, 67/358), and Year 1 or 2 (17.4%, 102/585) had abnormal depression status at baseline, compared to those who completed treatment (13.3%, 109/817) (p=0.005, and p=0.007, respectively). At last visit, a significantly higher percentage of subjects who discontinued treatment in Year 1 (19.3%, 27/140), Year 2 (22.3%, 78/350) or in Year 1 or 2 (21.4%, 105/490) had abnormal depression status compared to those who completed treatment (12.2%, 102/834) (p=0.022, p<0.001, and p<0.001, respectively). *The Wilcoxon rank sum test indicated significant differences between these groups.evaluation of the 3

5 4 Bayer HealthCare Websynopsis ability of the RODQ to predict early treatment termination: In the ITT set, subjects who terminated Betaferon treatment prematurely had a higher median RODQ total score at last telephone contact during Year 1 (median 3.0, range 0-10, n=184), Year 2 (median 2.0, range 0-10, n=207), and Year 1 or 2 (median 3.0, range 0-10, n=391) than subjects who completed the treatment (median 1.0, range 0-8, n=720).* The subjects who discontinued treatment prematurely during these time periods also had a higher median RODQ total score during the last six months (Year 1, median 4.0, range 0-10, n=198) (Year 2, median 3.0, range 0-10, n=227) (Year 1 or 2, median 4.0, range 0-10, n=425), compared to the completing subjects (median 2.0, range 0-8, n=771).* The ability of the RODQ to predict early treatment termination was not confirmed. *The Wilcoxon rank sum test indicated significant differences between these groups.early treatment termination rates in relation to adherence standards in centres and countries 145 centres participated in adherence evaluation; 17 centres had all sub-scores good, 18 centres had one or more sub-scores good, and 100 centres had one or more sub-scores bad. There was no clear trend apparent in the proportion of prematurely discontinued subjects within centres based on these criteria. Results Summary Safety Overall, 455 AEs were reported in 236/1569 (15.0%) subjects during the study in the case report forms. Adverse events from the MedDRA 17.0 system organ class General disorders and administration site conditions were reported most commonly (119 events reported by 89/1569 [5.7%] subjects). On MedDRA preferred term (PT) basis, the most common AEs were influenza like illness (in 39 [2.5%] subjects); headache (in 32 [2.0%] subjects); depression (in 19 [1.2%] subjects); injection site reaction and multiple sclerosis relapse (in 18 [1.1%] subjects ) each; and injection site erythema (in 11 [0.7%] subjects). In total, 34/1569 (2.2%) subjects experienced at least one severe AE; 46 severe AEs were reported. The percentage of subjects with at least one AE related to Betaferon was 10.5% (164/1569 subjects); 244 AEs were related to Betaferon. In total, 29/1569 (1.8%) subjects had SAEs recorded on the case report form; 52 SAEs were reported in these subjects, the most common being multiple sclerosis relapse, and depression, which both occurred in 3/1569 (0.2%) subjects. It should be noted that multiple sclerosis relapse was not consistently reported by investigators, as it is considered a disease characteristic. Serious AEs related to Betaferon were recorded in 8/1569 (0.5%) subjects. In addition, 16 SAEs among 7 subjects were not documented in the CRFs but were reported directly to the Bayer Pharmacovigilance department by the investigators. Six subjects died during the study: 2 subjects for whom the event was reported in the CRF (PTs were unevaluable event and accidental death ) and 4 subjects identified in the pharmacovigilance database (PTs: diabetic coma, suicide, pneumonia, and respiratory arrest). Results Summary Other Clinical outcomes (all data given in this section pertain to the ITT set) ARR: 85.4% (1245/1458) of subjects had no relapse during the study. EDSS score and progression: The EDSS score had progressed by 1 point between baseline and last visit in 206/1451 (14.2%) of subjects. In the majority of subjects (1040/1451 [71.7%]), the EDSS remained stable. Disease free: The proportion of subjects with data available for both EDSS and relapse who were disease free at their individual last visit was 1128/1451 (77.7%). Disease course: According to the revised McDonald criteria (2005), 77/242 (31.8%) of CIS subjects converted to MS; according to the revised Poser criteria (1983), 34/227 (15.0%) of CIS subjects converted to CDMS.

6 Bayer HealthCare Websynopsis Conclusions: This OS showed that standardised additional information and frequent nurse contact had an impact on adherence to Betaferon treatment over a period of 2 years, when comparing subjects who received this support to those who did not.. Analysis of responses to the WCQ indicated that subjects tending to use confrontive, escape-avoidance and positive reappraisal coping strategies could be more likely to discontinue treatment than subjects using other coping strategies. Similarly, the results from the HADS questionnaire indicate that a higher percentage of subjects with abnormal status regarding depression at baseline are more likely to discontinue treatment. The RODQ median score was found to be higher in subjects who discontinued treatment at the time of discontinuation. However, the score did not predict treatment discontinuation. Regardless of whether treatment centres had good or bad adherence scores, there was no clear trend apparent in the proportion of prematurely discontinued subjects within them.. Partially incomplete data collection and the limitations inherent in a non-randomised observational study in terms of potential confounding mean that the study results should be interpreted with caution. Publication(s): None at the time of report creation Date Created or 29 September 2015 Date Last Updated: 5

7 Appendix to Clinical Study Synopsis Product Identification Information Product Type US Brand/Trade Name(s) Brand/Trade Name(s) ex-us Generic Name Main Product Company Code Biological product Betaseron Betaseron, Betaferon Interferon beta 1b BAY Other Company Code(s) ZK Chemical Description Recombinant protein Other Product Aliases Date of last Update/Change: 12 Sep 2013