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Study no. 17816 Page: 1 of 8 Date of study report: 30 Apr 2018 Study title: Sponsor s study number: NCT number: EudraCT number: Sponsor: Clinical phase: Study objectives: REGO-ACT, Assessment of physical activity during therapy with regorafenib for metastatic colorectal cancer 17816 NCT02347852 Not Applicable Bayer Non-interventional Primary Objective: To assess the average amount of physical activity of patients with mcrc during regorafenib treatment as measured using pedometer data and International Physical Activity Questionnaire (IPAQ) results. The primary endpoints were the amount of physical activity during regorafenib treatment based on: Median number of steps/day measured on a 1-week basis (i.e., from Days 1 7) as well as for additional 1-week intervals through the end of the study using a pedometer Median number of steps/day measured on a 4-week basis (i.e., from on Days 1 28) as well as for additional 4-week intervals through the end of the study using a pedometer International Physical Activity Questionnaire (IPAQ) score on Days 28, 56, and 84 in metabolic equivalents of a task (MET) minutes/week Delta IPAQ between Days 1 and 28, Days 1 and 56, and Days 1 and 84 in MET minutes/week Secondary Objectives: Potential secondary objectives of this study were to assess the relation between the level of physical activity on the one hand and quality of life (QoL, as assessed using the EQ-5D-3L questionnaire), the frequency of the adverse event (AE) fatigue, disease control rate (DCR), progressionfree survival (PFS), and overall survival (OS) on the other. The secondary endpoints were the relation between physical activity (in terms of both the median number of steps/day and MET minutes/week) and
Study no. 17816 Page: 2 of 8 QoL of life as measured by the EQ-5D-3L in CORRELATE (NCT02042144, Safety and Effectiveness of Regorafenib in Routine Clinical Practice Settings ) Incidence of the AE fatigue as reported in CORRELATE DCR, defined as the percentage of patients whose best response was a complete response (CR), partial response (PR), or stable disease (SD); stable disease must have been at least 6 weeks in duration as assessed in CORRELATE. PFS, defined as the time from the date of the first regorafenib dose to the date of progressive disease (PD) or death as estimated by the Kaplan-Meier method observed in CORRELATE OS, defined as the time from the start of regorafenib therapy to the date of death in CORRELATE. Patients who had not died by the analysis cut-off date were censored at their last contact date (Kaplan-Meier method) in CORRELATE. Test drug: Name of active ingredient(s): Dose: Route of administration: Duration of treatment: Reference drug: Indication: Diagnosis and main criteria for inclusion: Regorafenib (Stivarga, BAY73-4506) Regorafenib Treatment was done according to the label approved by EMA. The recommended dose of regorafenib is 160 mg taken once daily for 3 weeks, followed by 1 week off therapy. In this study, dosing decisions were at the discretion of the treating physicians. Oral The planned observation period for each patient enrolled into the study was 3 months (84 days) from enrolment into REGO-ACT to the end of REGO-ACT, regorafenib treatment, withdrawal of consent, or death, whichever occurred first. Not Applicable Metastatic Colorectal cancer Only patients included into CORRELATE in Austria may participate in this local study. Inclusion criteria of OS CORRELATE: Patients had been diagnosed with mcrc who have been previously treated with, or are not considered candidates for, other locally approved standard treatment(s) and for whom a treatment
Study no. 17816 Page: 3 of 8 Study design: Methodology: Study center(s): Publication(s) based on the study (references): decision in favor of regorafenib had been made per investigator s routine treatment practice. had given signed informed consent for enrolment into CORRELATE. Inclusion criteria of REGO-ACT: Patients enrolled in CORRELATE in Austria Signed patient informed consent for enrolment into REGO-ACT This is a local, prospective, non-interventional, multi-center, single arm pilot study All study sites participating in and enrolling patients into the international non-interventional CORRELATE study were offered participation in REGO-ACT. The purpose of the CORRELATE study was to investigate the safety and effectiveness of regorafenib in routine clinical practice. Overall, 5 Austrian study sites participated in this study. All of the 25 patients enrolled into this study had initially been enrolled into CORRELATE. Subjects filled in the International physical activity questionnaire at baseline, and then at each visit according to physician s discretion (following time schedule is recommended: every 28 days up to 84 days from enrolment into REGO-ACT to the end of REGO-ACT, regorafenib treatment, withdrawal of consent, or death, whichever occurred first). Additionally, for objective measurement of physical activity all patients received a CE-certified pedometer at baseline. The pedometer should be worn for 84 days from enrolment into REGO-ACT to the end of REGO-ACT, regorafenib treatment, withdrawal of consent, or death, whichever occurred first. Data capture of the pedometer will be performed at each visit. The aim is to quantitatively evaluate the amount of physical activity in this patient population. 5 study sites in Austria None at the time of report creation Study period: Study Start Date: 20-Jan-2015 Study Completion Date: 08-Sep-2016 Early termination: No
Study no. 17816 Page: 4 of 8 Number of subjects: Planned: 25 Criteria of evaluation: Efficacy: Safety: Statistical methods: Substantial protocol changes: Analyzed: 25 Primary: The number of steps/day as measured using a pedometer The self-administered International Physical Activity Questionnaire (IPAQ) MET minutes/week as recorded in the REGO-ACT study. Secondary: the relation between physical activity (in terms of both the median number of steps/day and MET minutes/week) and QoL of life as measured by the EQ-5D-3L in CORRELATE Incidence of the AE fatigue as reported in CORRELATE DCR, defined as the percentage of patients whose best response was a complete response (CR), partial response (PR), or stable disease (SD); stable disease must have been at least 6 weeks in duration as assessed in CORRELATE. PFS, defined as the time from the date of the first regorafenib dose to the date of progressive disease (PD) or death as estimated by the Kaplan- Meier method observed in CORRELATE OS, defined as the time from the start of regorafenib therapy to the date of death in CORRELATE. Patients who had not died by the analysis cutoff date were censored at their last contact date (Kaplan-Meiermethod) in CORRELATE. Adverse events All data were analyzed using descriptive statistics. Study was conducted according to final study protocol dated 02 Jan 2015 and included no substantial amendments Subject disposition and baseline Of the 25 patients enrolled, 16 patients (64%) were male and 9 patients (36%) were female. The mean age was 62.4±10.9 years (range, 43 88 years).
Study no. 17816 Page: 5 of 8 Efficacy evaluation [Primary]: Median number of steps/day Pedometer data were available for 22 of the 25 enrolled patients. The number of days with available pedometer data varied widely among the 22 patients, ranging from 6 to 100. In individual patients, the number of days with pedometer data slightly exceeded the number of days of study participation, with some patients returning the pedometer after the official study end and still wearing the pedometer during this time. Of the 11 patients who participated in the study for the entire scheduled duration of 84 days, 3 patients had pedometer results for 82, 84, and 100 days, 13 patients had pedometer data for 21 72 days, and 6 patients had pedometer data for 6 13 days. A total of 16 patients had pedometer data for at least 21 days. The median number of steps/day measured on a 1-week and 4-week basis remained relatively constant throughout the course of the study. However, wide variations between the minimum and maximum numbers of steps were seen (e.g., between 31 and 8131 steps/day on Days 1 7). From this analysis, it was unclear whether these were intra- or interindividual variations. Therefore, we also specifically looked at the step counts of each individual patient. When looking at patients individually, considerable variations were seen in the weekly and monthly median number of steps/day, particularly between patients. Interindividually, baseline median step counts/day on a 1-week basis ranged between 31 and 8131. When only patients with at least 3 weeks of available pedometer data were looked at (n=16), the baseline median number of steps/day on a 1- week basis ranged from 130 to 7239; 13 of these 16 patients had step counts above 1200, thus being well within the range reported for special populations in the literature. Intraindividually, median step counts on a 1-week basis varied over time in some patients, but remained relatively constant in others. To better understand the intra- and interindividual variations in the median number of steps/day seen at a 1-week basis, daily step counts per patient were also analyzed. Intraindividually, step counts/day in some patients varied by several thousands of steps/day, e.g., from 10 to 10,934 in one patient or from 2,093 to 14,931 in another patient). Interindividually, maximum step counts/day varied between 401 and 14,931. Although intraindividual step counts varied considerably on a day-to-day basis, the median number of steps/day analyzed on a 1-week basis appears to provide a good indication of a patient s general level of activity, with weekly step counts in the range of several thousands in some and several hundreds in other patients.
Study no. 17816 Page: 6 of 8 IPAQ results Of the 25 patients, 21 patients completed the IPAQ questionnaire at least once. During data analysis, it was found that many completed questionnaires were not directly evaluable because of implausible or incomplete responses. As a result of these inconsistencies, only a minority of completed IPAQs were considered to have yielded reliable results. At the same time, visit intervals varied considerably between patients, and the number of patients with available IPAQ results dropped throughout the course of the study. The primary endpoints including IPAQ results were therefore considered to defy reliable statistical analysis. [Secondary]: The relation between physical activity and other variables was analyzed only on the basis of the median number of steps/day, but not on the basis of IPAQ results. Relation between the median number of steps/day and QoL as measured using the EQ-5D-3L in CORRELATE To determine the relation between the median number of steps/day and QoL as measured by the EQ- 5D-3L, only EQ-VAS values were used. At the beginning of the study, moderately strong correlations between EQVAS and the median number of steps/day on Days 1 7 and 8 14 were seen. Moderately strong correlations between EQ-VAS and the median number of steps/day on Days 8 14 and 15 21 were also found at time point 3 of EQ-VAS assessment. Relation between step counts and the incidence of the AE fatigue as reported in CORRELATE Of the 25 enrolled patients, 14 patients (56%) reported fatigue in the course of the CORRELATE study. Of these 14 patients, 10 patients experienced fatigue during the course of the REGO-ACT study, and only 8 patients reported fatigue within their individual time periods of pedometer use. No significant correlations between the median number of steps/day and the presence of fatigue were found. Overall, however, patient numbers were too small and periods of observation too short to draw statistically reliable conclusions on the correlation between step counts and fatigue. Relation between the median number of steps/day and DCR, PFS, or OS as reported in CORRELATE Due to rapidly decreasing numbers of patients with pedometer data throughout the course of REGO- ACT, the high intra- and interindividual variations in step counts, and still incomplete CORRELATE response data at the end of the REGO-ACT study, correlations between the median number of steps/day and DCR, PFS, and OS could not reliably be determined. However, looking at patients individually, relations between step counts and DCR, PFS, or OS appear unlikely, with some patients displaying comparatively high levels of walking activity almost up to the time of their
Study no. 17816 Page: 7 of 8 disease progression or death and other patients showing very low levels or short durations of walking activity despite comparatively high levels of QoL or longer survival. Safety evaluation To avoid duplicate reporting, safety reporting was performed as part of the CORRELATE study only. Overall conclusions The primary aim of this pilot study was to obtain data on the extent of physical activity of patients with mcrc during regorafenib therapy. The study showed that, despite the severity of their disease, patients generally displayed remarkable levels of walking activity, with baseline levels in most patients within the range for special populations reported in the literature. In view of the widely differing baseline levels of walking activity between patients, the aim of exercise programs for the special patient population included in this study should be to tailor interventions to the specific needs, physical capacity, and preferences of each individual patient rather than prescribing normative stepcount targets for the entire population. While the pedometer results of this study established a baseline step count for the majority of our patients, a number of factors most importantly technical issues related to step counting and the lack of patient supervision due to the non-interventional nature of this study limited the utility of the pedometer in measuring long-term physical activity levels in this study and should be addressed in future research. The key limitations of this pilot study were its small sample size and its non-interventional character, which resulted in a relatively large proportion of missing data, widely varying visit intervals, implausible IPAQ entries, and ultimately only 3 patients with pedometer results spanning the entire 84-day observation period scheduled for the study. In view of these limitations, some of the predefined endpoints may have been too specific or complex and were ultimately not analyzable as originally planned. For example, completing the IPAQ, a tool also used in this study to estimate the patients level of physical activity, appeared to have been too demanding to complete for many patients, and future studies may benefit from simpler tools to document patient-reported levels of exercise. By contrast, the EQ-5D-3L questionnaire used in this study to measure the patients QoL is a concise and easyto-use tool, and its EQ-VAS component was the only variable in this study to show moderate correlations with the pedometer data obtained, and the relations between step counts and measures of subjective well-being therefore clearly warrant additional research. One focus of this study was on a common side effect of treatment with regorafenib, i.e., fatigue, which can markedly affect a patient s well-being and interfere with daily life. Available evidence suggests that physical exercise is beneficial for cancer patients and may mitigate cancer-related fatigue. Although this pilot study did not find a correlation between fatigue and walking activity, this may, at least in part, have been due the methodological aspect of fatigue having been reported as an AE during follow-up visits rather than being more closely and consistently monitored throughout the study, preferably on a daily basis. Therefore, future research may benefit from the use of tools
Study no. 17816 Page: 8 of 8 specifically developed to closely monitor fatigue. In addition, other AEs, such as pain, diarrhea, vertigo, dyspnea, or palmar-plantar erythrodysesthesia, may also have an effect on a patient s ability or willingness to exercise and merit inclusion in future studies. Overall, the preliminary data on the individual levels of walking activity of mcrc patients and the methodologically insights from this pilot study can serve as a starting point for the development of tailored exercise prescription programs designed to alleviate cancer-related side effects and improve patient well-being and quality of life.