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Clot regression effects of rivaroxaban in the treatment of venous thromboembolism in patients with cancer (CRERIT-VTE cancer): study protocol

Introduction Anticoagulant therapy in patients with cancer with venous thromboembolism (VTE) increases the risk of both VTE recurrence and haemorrhagic complication. Direct oral anticoagulants (DOACs) have been shown to be effective in preventing VTE recurrence, and comparable to conventional therapy in preventing VTE recurrence in patients with advanced cancer. Rivaroxaban is a DOAC that causes thrombus regression, possibly through a profibrinolytic effect. Thrombus regression with initial treatment is essential for VTE patients. However, the thrombolytic effect of DOAC for VTE patients with cancer has not been fully examined. Therefore, in this study, we investigate the thrombolytic effect of rivaroxaban in patients with cancer who develop VTE. Methods and analysis This study is a single-arm, open-label, prospective interventional study. Forty patients aged from 20 to 75 years old at the time of consent who have been diagnosed with acute VTE and have active cancer are included. Patients are excluded if they have received thrombolytic therapy, have creatinine clearance of less than 30 mL/min, have expected a life expectancy of less than 6 months or have deep vein thrombosis limited to the distal lower leg. Eligible patients receive standard treatment with rivaroxaban (15 mg two times daily for 3 weeks, followed by 15 mg QD). The primary study endpoint is clot regression ratio as evaluated by contrast-enhanced CT imaging. CT imaging is obtained at baseline, 21±4 and 90±14 days after the start of rivaroxaban treatment. Secondary endpoints are the recurrence of VTE and haemorrhagic complications. Ethics and dissemination This study was approved by the institutional review board of the Kyoto Prefectural University of Medicine. Study results will be disseminated through peer-reviewed journals. Trial registration number UMIN000027793

In patients with venous thromboembolism (VTE), about 10 to 20% are complicated by active cancer. Anticoagulant therapy in cancer patients with VTE creates a risk for both VTE recurrence and haemorrhagic complication. Direct oral anticoagulants (DOAC) have been shown to be effective in preventing VTE recurrence, and comparable to conventional therapy in preventing VTE recurrence in patients with advanced cancer.
Rivaroxaban is a DOAC that produces thrombus regression, possibly through a pro-fibrinolytic effect on the thrombus. Thrombus regression with initial treatment is an important issue for VTE patients. However, the thrombolytic effect of DOAC for VTE patients with cancer has not been fully examined. Therefore, in this study, we investigate the thrombolytic effect of rivaroxaban in patients with cancer who develop VTE.

Methods and analysis
This study is a single arm, open label, prospective interventional study.  expectancy is less than 6 months, or whose deep vein thrombosis (DVT) is limited to the distal lower leg. Eligible patients receive standard treatment with rivaroxaban (15 mg BID for 3 weeks followed by 15 mg QD). The primary study endpoint is clot regression ratio as evaluated by contrast-enhanced computed tomography (CT) imaging.
CT imaging is obtained at baseline, 21 ± 4 days and 90 ± 14 days after the start of treatment with rivaroxaban. Secondary endpoints are recurrence of VTE and haemorrhagic complications.    [1,2,3] In cancer patients with VTE, anticoagulant therapy presents a risk for both VTE recurrence and haemorrhagic complications. Previous studies have reported that low-molecular-weight heparin (LMWH) reduced VTE recurrence without increasing the risk of haemorrhage in cancer patients, [4] substantiating LMWH as a recommended monotherapy for VTE. [5] In recent years, direct oral anticoagulants (DOACs) were also shown to be effective in preventing VTE recurrence. In the EINSTEIN-DVT [6] and EINSTEIN-PE [7] studies in which rivaroxaban, a Factor Xa inhibitor, was compared with LMWH plus warfarin for VTE recurrence, rivaroxaban was non-inferior to combination therapy with enoxaparin and warfarin for VTE recurrence and superior for haemorrhagic complications. In a subgroup analysis of these studies, rivaroxaban was comparable in reducing VTE recurrence and led to fewer haemorrhagic complications as compared to combination therapy with enoxaparin plus warfarin in cancer patients at high risk of thrombosis and haemorrhage. [8] Although rivaroxaban was shown to be effective and safe in this population, its utility in reducing thrombosis in cancer patients Recently, it has been prospectively indicated that some DOAC have efficacy and safety comparable to conventional LMWH therapy in preventing VTE recurrence in patients with advanced cancer. Oral edoxaban was non-inferior to subcutaneous LMWH when examining the composite outcome of recurrent VTE and major bleeding, [9] and rivaroxaban was also associated with relatively low VTE recurrence but higher nonmajor bleeding compared with LMWH. [10] Moreover, in the context of prophylaxis, apixaban was reported to have a lower rate of VTE than placebo in patients with cancer who were initiating chemotherapy and had an intermediate-to-high risk of VTE. In addition, thromboprophylaxis with rivaroxaban led to a lower incidence of VTE or death in high-risk ambulatory patients with cancer during the intervention period. [11] Thrombus regression with rivaroxaban has been studied in the J-EINSTEIN study of Japanese patients. In the study, an imaging test combining ultrasound and lung imaging on day 22 after rivaroxaban administration revealed the percentage of patients with normalization was 26.7% in the rivaroxaban group compared to 15.8% in the conventional treatment group. This suggests that rivaroxaban could have a pro-fibrinolytic effect on thrombi. [12] Because a residual thrombus in the acute phase can lead to post-thrombotic syndrome, thrombus regression with initial treatment is an patients with cancer has not been fully examined. Therefore, in this study, we will investigate the thrombolytic effect of rivaroxaban in patients with cancer who develop VTE. We believe the results of this study will greatly contribute to improving symptoms and prognosis in cancer patients by examining the clot regression effects of rivaroxaban in the treatment of venous thromboembolism.

Objectives
The aim of this study is to investigate the thrombolytic effect of rivaroxaban in patients with cancer who develop VTE (symptomatic and asymptomatic).

Study design
This is a single arm, open label, prospective interventional study. Figure 1 shows a flow chart of the study.

Endpoints
The primary endpoint is clot regression ratio as evaluated by contrast-enhanced CT imaging. CT imaging is obtained at baseline, 21 ± 4 days and 90 ± 14 days after the start of treatment with rivaroxaban. The ratio of clot volume regression is calculated at 3 weeks and 3 months after the start of treatment by comparing with the clot volume at  intracranial haemorrhage, retroperitoneal haemorrhage, or bleeding to death. Non-major bleeding is defined as bleeding not meeting the criteria for major bleeding.

Eligibility criteria
Inclusion criteria are as follows: 1) Patients with cancer who have been diagnosed with acute VTE (symptomatic and asymptomatic) and have active cancer. Active cancer is defined as patients who have either been diagnosed with cancer within 180 days prior to obtaining consent or patients who have been treated for cancer within 180 days. This includes new, recurrent, and metastatic cancer.
2) Patients who have not been treated for VTE.  2) Patients who have taken rivaroxaban within 30 days prior to obtaining written consent.
3) Patients who received thrombolytic therapy within 30 days prior to obtaining written consent. 4) Creatinine clearance less than 30 ml / min. 5) Life expectancy less than 6 months. 6) Distal DVT limited to the lower leg. 7) Patients on warfarin treatment.

8) Patients with serious complications (hepatic dysfunction [corresponding to
Child-Pugh classification B or C], active haemorrhage [intracranial haemorrhage, gastrointestinal haemorrhage, etc.], or systolic blood pressure greater than or equal to 180 mmHg or diastolic blood pressure greater than or equal to 110 mmHg) 9) Women who are pregnant or lactating or who may be pregnant (i.e. within 12 months of last menstruation) or men who may be pregnant with partners and cannot agree to contraception during the study period.  12 10) Patients who, after being included in this study, agree to participate in another interventional study during the same timeframe. 11) Patients who, after being included in this study, plan on having surgery during the same timeframe.
12) Presence of a contraindication or allergy to contrast media. 13) Due to other safety concerns, the investigator determines that participation in this study is inappropriate.

Treatment protocol
VTE patients with cancer who were transported to a participating hospital, hospitalized and visited are included. After obtaining written consent for participating in this study and registering at the case registration centre, protocol treatment is promptly started.
Patients receive the standard treatment with rivaroxaban approved in Japan (15 mg BID for 3 weeks after the start of treatment, followed by 15 mg QD). Protocol treatment is continued for 90 ± 14 days after the start of rivaroxaban treatment. If the examination of the patient before the start of administration does not pass the inclusion and exclusion criteria, protocol treatment will not be performed. For patients who have discontinued treatment early, a reason should be described.

Quantification of thrombus volume
Thrombus volume is quantified using a Ziostation 2 (3D medical imaging workstation, manufactured by Ziosoft Inc., Version 2.9) and by manually tracing the intravenous clot in the contrast-enhanced CT image. All pulmonary artery thrombi and leg vein thrombi are traced to calculate total thrombus mass volume. If there is no thrombus in the CT image, the thrombus volume is zero. The measurement results are monitored for accuracy.

Statistical analysis
Because this study is an exploratory study, the number of cases was determined based on the feasibility of the institution. A previous study [13] has reported that at 3 weeks of rivaroxaban administration, the clot regression rate on CT assessment was 59% (standard deviation: SD 37%). In the above study, subjects were not limited to cancer-bearing patients, and DVT patients were excluded. Because our study is limited to patients with cancer and high thromboembolic risk, the average thrombolysis rate was set at 20% (SD 37%). The number of required patients is 38, which corresponds to a one-sided significance level of 0.025 and a power of 0.9. The sample size was thus set at 40 cases to account for some cases of analysis exclusion. The population to be analysed is defined as the full analysis set (FAS) for efficacy and the safety analysis set (SAF) for adverse events. The FAS includes all patients who received protocol treatment, with the exclusion of those who are found to be ineligible after enrolment and those for whom all information after enrolment is missing. The SAF includes all patients who received protocol treatment.
The clot regression ratio is defined as the ratio of regressed thrombus volume at either 3 weeks or 3 months after the start of rivaroxaban compared to thrombus volume at baseline. The clot regression rate for both 3 weeks and 3 months after the start of rivaroxaban is expressed as a percentage, and the mean and 95% confidence intervals for the whole population are calculated. If either 95% confidence interval is greater than 0%, we conclude that thrombus regression is statistically significant. If the null hypothesis is defined as having a clot regression rate of 0%, this corresponds to a test  15 with a one-sided significant level of 0.025 without adjusting the test multiplicity to account for this being an exploratory study. The frequency, percentage and 95% confidence intervals for the percentage of symptomatic VTE recurrence and haemorrhagic complications are calculated during the study period. The incidence and severity of all adverse events for the SAF are collected during the study period.

Patient and public involvement
This research was done without patient involvement. Patients were not invited to comment on the study design and were not consulted to develop patient relevant outcomes or interpret the results. Patients were not invited to contribute to the writing or editing of this document for readability or accuracy.

ETHICS AND DISSEMINATION
This study is based on the ethical principles based on the Helsinki Declaration and its revised version. This study was approved by each institutional ethics committee that participated and was disclosed to the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000027793). In order to receive continuous review by the Ethics Review Committee, the research manager conducts a yearly overview of the study's status and reports in writing to the head of the organization.
Before participating in the study, the investigator informs subjects using the explanatory document and provides enough time to ask questions to make an informed decision.

Objectives
The aim of this study is to investigate the thrombolytic effect of rivaroxaban in patients with cancer who develop VTE (symptomatic and asymptomatic).

Study design
This is a single arm, open label, prospective interventional study. Figure 1 shows a flow chart of the study.
13) Due to other safety concerns, the investigator determines that participation in this study is inappropriate.

Treatment protocol
Patients who meet both inclusion and exclusion criteria are included and are started on treatment protocol. After obtaining written consent for participating in this study and registering at the case registration centre, protocol treatment is promptly started.
Patients receive the standard treatment with rivaroxaban approved in Japan (15 mg BID for 3 weeks after the start of treatment, followed by 15 mg QD, this is different from other countries especially Western countries). Protocol treatment is continued for 90 ±

Statistical analysis
Because this study is an exploratory study, the number of cases was determined based on the feasibility of the institution. A previous study [15] has reported that at 3 weeks of rivaroxaban administration, the clot regression rate on CT assessment was 59% (standard deviation: SD 37%). In the above study, subjects were not limited to cancer-bearing patients, and DVT patients were excluded. Because our study is limited to patients with cancer and high thromboembolic risk, the average thrombolysis rate was set at 20% (SD 37%). The number of required patients is 38, which corresponds to a one-sided significance level of 0.025 and a power of 0.9. The sample size was thus set at 40 cases to account for some cases of analysis exclusion. The population to be analysed is defined as the full analysis set (FAS) for efficacy and the safety analysis set (SAF) for adverse events. The FAS includes all patients who received protocol treatment, with the exclusion of those who are found to be ineligible after enrolment and those for whom any information after enrolment, such as treatment initiation, cannot be obtained. The SAF includes all patients who received protocol treatment at least one dose of treatment. The clot regression ratio is defined as the ratio of regressed thrombus volume at either 3 weeks or 3 months after the start of rivaroxaban compared to thrombus volume at baseline. The clot regression rate for both 3 weeks and 3 months after the start of rivaroxaban is expressed as a percentage, and the mean and 95% confidence intervals for the whole population are calculated. If either 95% confidence interval is greater than 0%, we conclude that thrombus regression is statistically significant. If the null hypothesis is defined as having a clot regression rate of 0%, this corresponds to a test with a one-sided significant level of 0.025 without adjusting the test multiplicity to account for this being an exploratory study. The frequency, percentage and 95% confidence intervals for the percentage of symptomatic VTE recurrence and haemorrhagic complications are calculated during the study period. The incidence and severity of all adverse events for the SAF are collected during the study period.

Patient and public involvement
This research was done without patient involvement. Patients were not invited to comment on the study design and were not consulted to develop patient relevant outcomes or interpret the results. Patients were not invited to contribute to the writing or editing of this document for readability or accuracy. guideline, LMWH is recommended as anticoagulation treatment for VTE patients with cancer rather than vitamin K antagonist or DOAC [5]. However, LMWH has not been approved for the treatment of VTE in Japan. Recently, it has been reported that some DOACs are non-inferior with respect to the composite of VTE recurrence and major bleeding in patients with cancer [9,10].
For the patients with VTE, clot regression is an important issue. The presence of residual thrombus leads to a risk factor for DVT recurrence. If the DVT recurrence occurs, it will cause not only reappearance of symptom but also post-thrombotic syndrome (PTS) at a high rate [16]. On the other hand, incomplete resolution of pulmonary artery thrombus leads to chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is a progressive disease with poor prognosis, classified as Group 4 pulmonary hypertension in the clinical classification of pulmonary hypertension [17].
To avoid these complications, clot regression in the acute phase of VTE is very important. Cancer patients with VTE have a risk of both thrombogenicity and haemorrhage. Therefore, it can greatly contribute to improvements in symptoms and Oral rivaroxaban for the treatment of VTE has been shown to be equivalent in efficacy and safety to unfractionated heparin plus warfarin with a single drug approach.
Although approved dose of rivaroxaban in Japan (15 mg BID for 3 weeks followed by 15 mg QD) is different from other countries especially Western countries, the result of J-EINSTEIN study [12] was consistent with EINSTEN study. In regard to cancer patients with VTE, rivaroxaban was associated with low VTE recurrence and same major bleeding risk, but higher minor bleeding, compared with LMWH [10]. However, the efficacy of Japanese dose of rivaroxaban in cancer patients with VTE is not well investigated. In this study, we will examine whether Japanese dose of rivaroxaban can be used effectively and safely for the VTE patients with cancer.
We have some limitations in this study. At first, it is exploratory in nature with a small number of patients. To evaluate the effect of rivaroxaban on reduction of clot burden, we have to perform comparative study. We cannot use placebo due to ethical reason. Our aim in this study is to evaluate an efficacy of rivaroxaban on the clot regression in the usual clinical practice. This includes a fibrinolytic effect both of rivaroxaban and biological function. In the clinical situation, we do not need to separate Before participating in the study, the investigator informs subjects using the explanatory document and provides enough time to ask questions to make an informed decision.
After confirming that the subject fully understands the content, written consent is obtained from the patient for participation in this study. The parties concerned with this study take full consideration of the subject's personal information and privacy protection in accordance with relevant laws and regulations. In addition, the information obtained in this study will not be provided to third parties, except when requested by a public organization. Study results will be disseminated through peer-reviewed journals.

FUNDING STATEMENT
This study is conducted using normal insurance practices. Based on the contract for the investigator-initiated clinical trial, the research manager conducted a study commissioned by Bayer. Bayer give funding about consignment expenses, such as data management, monitoring and statistical analysis.

Ethics and dissemination
This study was approved by the institutional review board of the Kyoto Prefectural University of Medicine, which was disclosed to the University Hospital Medical Information Network Clinical Trials Registry (UMIN000027793). Study results will be disseminated through peer-reviewed journals. Recently, it has been indicated in the prospective studies that some DOAC have efficacy and safety comparable to conventional LMWH therapy in preventing VTE recurrence in patients with advanced cancer. Oral edoxaban was non-inferior to subcutaneous LMWH when examining the composite outcome of recurrent VTE and major bleeding, [9] and rivaroxaban was also associated with relatively low VTE recurrence but higher nonmajor bleeding compared with LMWH. [10] Moreover, in the context of prophylaxis, apixaban was reported to have a lower rate of VTE than placebo in patients with cancer who were initiating chemotherapy and had an intermediate-to-high risk of VTE. [11] In addition, thromboprophylaxis with rivaroxaban led to a lower incidence of VTE or death in high-risk ambulatory patients with cancer during the intervention period. [12] Thrombus regression with rivaroxaban has been studied in the J-EINSTEIN study that was investigated the efficacy of low dose rivaroxaban for the treatment of VTE in Japanese patients.
[13] In the study, an imaging test combining ultrasound and lung imaging on day 22 after rivaroxaban administration revealed the percentage of patients with complete resolution of thrombus was 26.7% in the rivaroxaban group

Objectives
The aim of this study is to investigate the thrombolytic effect of rivaroxaban in patients with cancer who develop VTE (symptomatic and asymptomatic).

Study design
This is a single arm, open label, prospective interventional study. Figure 1 shows a flow chart of the study.

Endpoints
The primary endpoint is clot regression ratio as evaluated by contrast-enhanced CT imaging. CT imaging is obtained at baseline, 21 ± 4 days and 90 ± 14 days after the start of treatment with rivaroxaban. The ratio of clot volume regression is calculated at 3 weeks and 3 months after the start of treatment by comparing with the clot volume at Thrombosis and Hemostasis (ISTH) as fatal bleeding, and/or symptomatic bleeding in a critical area or organ, such as intracranial, retroperitoneal, and/or bleeding causing a fall in hemoglobin level of 2 g/mL or more, or leading to transfusion of two or more units of whole blood or red cells. [15] Non-major bleeding is defined as bleeding not meeting the criteria for major bleeding.

Eligibility criteria
Inclusion criteria are as follows: 12) Presence of a contraindication or allergy to contrast media.
13) Due to other safety concerns, the investigator determines that participation in this study is inappropriate.

Treatment protocol
Patients who meet both inclusion and exclusion criteria are included and are started on treatment protocol. After obtaining written consent for participating in this study and registering at the case registration centre, protocol treatment is promptly started.
Patients receive the standard treatment with rivaroxaban approved in Japan (15 mg BID

Quantification of thrombus volume
Thrombus volume is quantified using a Ziostation 2 (3D medical imaging workstation, manufactured by Ziosoft Inc., Version 2.9) and by manually tracing the intravenous clot

Statistical analysis
Because this study is an exploratory study, the number of cases was determined based on the feasibility of the institution. A previous study [17] has reported that at 3 weeks of rivaroxaban administration, the clot regression rate on CT assessment was 59% (standard deviation: SD 37%). In the above study, subjects were not limited to cancer-bearing patients, and DVT patients were excluded. Because our study is limited to patients with cancer and high thromboembolic risk, the average thrombolysis rate was set at 20% (SD 37%). The number of required patients is 38, which corresponds to a one-sided significance level of 0.025 and a power of 0.9. The alternative hypothesis is that the one-sided test is natural because we want to claim that the thrombus has regressed rather than the thrombus has changed. The sample size was thus set at 40 The clot regression ratio is defined as the ratio of regressed thrombus volume at 3 weeks and 3 months after the start of rivaroxaban compared to thrombus volume at baseline. The clot regression rate for both 3 weeks and 3 months after the start of rivaroxaban is expressed as a percentage, and the mean and 95% confidence intervals for the whole population are calculated based on t-distribution. If either 95% confidence interval is greater than 0%, we conclude that thrombus regression is statistically significant. That is, it is identical to paired t-test for each clot regression rate. If the null hypothesis is defined as having a clot regression rate of 0%, this corresponds to a test with a one-sided significant level of 0.025 without adjusting the test multiplicity to account for this being an exploratory study. The frequency, percentage and 95% confidence intervals for the percentage of symptomatic VTE recurrence and bleeding rate compared with patients less than 75 years old in ROCKET AF trial, we excluded patients 75 years old or older in this study due to safety concern [14]. Overall, it can greatly contribute to improvements in symptoms and prognosis of cancer patients with VTE by examining the clot regression effects and safety of rivaroxaban in the clinical practice.
Oral rivaroxaban for the treatment of VTE has been shown to be equivalent in efficacy and safety to unfractionated heparin plus warfarin with a single drug approach.
Although approved dose of rivaroxaban in Japan (15 mg BID for 3 weeks followed by 15 mg QD) is different from other countries especially Western countries, the result of J-EINSTEIN study [12] was consistent with EINSTEN study. In regard to cancer patients with VTE, rivaroxaban was associated with low VTE recurrence and same major bleeding risk, but higher minor bleeding, compared with LMWH [10]. However, the efficacy of Japanese dose of rivaroxaban in cancer patients with VTE is not well investigated. In this study, we will examine whether Japanese dose of rivaroxaban can be used effectively and safely for the VTE patients with cancer.
We have some limitations in this study. At first, it is exploratory in nature with a small number of patients. To evaluate the effect of rivaroxaban on reduction of clot burden, we have to perform comparative study. We cannot use placebo due to ethical reports in writing to the head of the organization. Before participating in the study, the investigator informs subjects using the explanatory document and provides enough time to ask questions to make an informed decision. After confirming that the subject fully understands the content, written consent is obtained from the patient for participation in this study. The parties concerned with this study take full consideration of the subject's personal information and privacy protection in accordance with relevant laws and regulations. In addition, the information obtained in this study will not be provided to third parties, except when requested by a public organization. Study results will be disseminated through peer-reviewed journals.

FUNDING STATEMENT
This study is conducted using normal insurance practices. Based on the contract for the investigator-initiated clinical trial, the research manager conducted a study commissioned by Bayer Yakuhin, Ltd. Bayer Yakuhin, Ltd give funding about consignment expenses, such as data management, monitoring and statistical analysis.     Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure) 13

Objectives
The aim of this study is to investigate the thrombolytic effect of rivaroxaban in patients with cancer who develop VTE (symptomatic and asymptomatic).

Study design
This is a single arm, open label, prospective interventional study. Figure 1 shows a flow chart of the study.

Endpoints
The primary endpoint is clot regression ratio as evaluated by contrast-enhanced CT  Thrombosis and Hemostasis (ISTH) as fatal bleeding, and/or symptomatic bleeding in a critical area or organ, such as intracranial, retroperitoneal, and/or bleeding causing a fall in hemoglobin level of 2 g/mL or more, or leading to transfusion of two or more units of whole blood or red cells. [15] Non-major bleeding is defined as bleeding not meeting the criteria for major bleeding.

Eligibility criteria
Inclusion criteria are as follows: 13) Due to other safety concerns, the investigator determines that participation in this study is inappropriate.

Treatment protocol
Patients who meet both inclusion and exclusion criteria are included and are started on treatment protocol. After obtaining written consent for participating in this study and registering at the case registration centre, protocol treatment is promptly started.
Patients receive the standard treatment with rivaroxaban approved in Japan (15 mg BID

Quantification of thrombus volume
Thrombus volume is quantified using a Ziostation 2 (3D medical imaging workstation, manufactured by Ziosoft Inc., Version 2.9) and by manually tracing the intravenous clot

Statistical analysis
Because this study is an exploratory study, the number of cases was determined based on the feasibility of the institution. A previous study [17] has reported that at 3 weeks of rivaroxaban administration, the clot regression rate on CT assessment was 59% (standard deviation: SD 37%). In the above study, subjects were not limited to cancer-bearing patients, and DVT patients were excluded. Because our study is limited to patients with cancer and high thromboembolic risk, the average thrombolysis rate was set at 20% (SD 37%). The number of required patients is 38, which corresponds to a one-sided significance level of 0.025 and a power of 0.9. The alternative hypothesis is that the one-sided test is natural because we want to claim that the thrombus has regressed rather than the thrombus has changed. The sample size was thus set at 40  The clot regression ratio is defined as the ratio of regressed thrombus volume at 3 weeks and 3 months after the start of rivaroxaban compared to thrombus volume at baseline. The clot regression rate for both 3 weeks and 3 months after the start of rivaroxaban is expressed as a percentage, and the mean and 95% confidence intervals for the whole population are calculated based on t-distribution. If either 95% confidence interval is greater than 0%, we conclude that thrombus regression is statistically significant. That is, it is identical to paired t-test for each clot regression rate. If the null hypothesis is defined as having a clot regression rate of 0%, this corresponds to a test with a one-sided significant level of 0.025 without adjusting the test multiplicity to account for this being an exploratory study. The frequency, percentage and 95% confidence intervals for the percentage of symptomatic VTE recurrence and bleeding rate compared with patients less than 75 years old in ROCKET AF trial, we excluded patients 75 years old or older in this study due to safety concern [14]. Overall, it can greatly contribute to improvements in symptoms and prognosis of cancer patients with VTE by examining the clot regression effects and safety of rivaroxaban in the clinical practice.
Oral rivaroxaban for the treatment of VTE has been shown to be equivalent in efficacy and safety to unfractionated heparin plus warfarin with a single drug approach.
Although approved dose of rivaroxaban in Japan (15 mg BID for 3 weeks followed by 15 mg QD) is different from other countries especially Western countries, the result of J-EINSTEIN study [12] was consistent with EINSTEN study. In regard to cancer patients with VTE, rivaroxaban was associated with low VTE recurrence and same major bleeding risk, but higher minor bleeding, compared with LMWH [10]. However, the efficacy of Japanese dose of rivaroxaban in cancer patients with VTE is not well investigated. In this study, we will examine whether Japanese dose of rivaroxaban can be used effectively and safely for the VTE patients with cancer.
We have some limitations in this study. At first, it is exploratory in nature with a small number of patients. To evaluate the effect of rivaroxaban on reduction of clot burden, we have to perform comparative study. We cannot use placebo due to ethical reports in writing to the head of the organization. Before participating in the study, the investigator informs subjects using the explanatory document and provides enough time to ask questions to make an informed decision. After confirming that the subject fully understands the content, written consent is obtained from the patient for participation in this study. The parties concerned with this study take full consideration of the subject's personal information and privacy protection in accordance with relevant laws and regulations. In addition, the information obtained in this study will not be provided to third parties, except when requested by a public organization. Study results will be disseminated through peer-reviewed journals.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59

DATA SHARING STATEMENT
Our manuscript describes a study protocol. Therefore, we cannot elaborate on unpublished data yet.

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial n/a  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59

Ethics and dissemination
This study was approved by the institutional review board of the Kyoto Prefectural University of Medicine, which was disclosed to the University Hospital Medical Information Network Clinical Trials Registry (UMIN000027793). Study results will be disseminated through peer-reviewed journals.  [4], substantiating LMWH as a recommended monotherapy for VTE [5].
In recent years, direct oral anticoagulants (DOACs) have also been shown to be effective in preventing VTE recurrence. In the EINSTEIN-DVT [6] and EINSTEIN-PE [7] studies in which rivaroxaban, a Factor Xa inhibitor, was compared to LMWH plus warfarin for VTE recurrence, rivaroxaban was non-inferior to combination therapy with enoxaparin and warfarin for VTE recurrence and superior for haemorrhagic complications. In a subgroup analysis of these studies, rivaroxaban was comparable in reducing VTE recurrence and led to fewer events of haemorrhage in comparison to combination therapy with enoxaparin plus warfarin in cancer patients at a high risk of thrombosis and haemorrhage [8]. Although rivaroxaban was shown to be effective and safe in this population, its utility in reducing thrombosis in cancer patients has not been Recently, it has been indicated in prospective studies that some DOACs have efficacy and safety comparable to conventional LMWH therapy in preventing VTE recurrence in patients with advanced cancer. Oral edoxaban was non-inferior to subcutaneous LMWH when examining the composite outcome of recurrent VTE and major bleeding [9], while rivaroxaban was also associated with relatively low VTE recurrence but higher nonmajor bleeding in comparison to LMWH [10]. Moreover, in the context of prophylaxis, apixaban has been reported to have a lower rate of VTE than placebo in patients with cancer who were initiating chemotherapy and had an intermediate-to-high risk of VTE [11]. In addition, thromboprophylaxis with rivaroxaban led to a lower incidence of VTE or death in high-risk ambulatory patients with cancer during the intervention period [12].
Thrombus regression with rivaroxaban has been studied in the J-EINSTEIN study that investigated the efficacy of low dose rivaroxaban for the treatment of VTE in Japanese patients [13]. In this study, an imaging test combining ultrasound and lung imaging on day 22 after rivaroxaban administration revealed the percentage of patients with complete resolution of thrombus was 26.7% in the rivaroxaban group compared to 15.8% in the unfractionated heparin plus warfarin group. This suggests that rivaroxaban could have a pro-fibrinolytic effect on thrombi [14]. As residual thrombus in the acute phase can lead to post-thrombotic syndrome, thrombus regression with the initial treatment is important for VTE patients. However, the thrombolytic effect of DOAC for VTE patients with cancer has not been fully examined. Therefore, in this study, we investigate the thrombolytic effect of rivaroxaban in patients with cancer who develop VTE. We believe the results of this study will greatly contribute to improving prognosis and reducing symptoms in cancer patients by examining the clot regression effects of rivaroxaban in the treatment of venous thromboembolism.

OBJECTIVE
The aim of this study is to investigate the thrombolytic effect of rivaroxaban in patients with cancer who develop VTE (symptomatic and asymptomatic).

Study design
This is a single arm, open label, prospective interventional study. Figure 1 shows a flow chart of the study.

Endpoints
The primary endpoint of the study is to assess the clot regression ratio as evaluated by contrast-enhanced CT imaging. CT imaging is obtained at baseline, 21 ± 4 days and 90 ± 14 days after the start of treatment with rivaroxaban. The ratio of clot volume regression is calculated at 3 weeks and 3 months after the start of treatment by comparing the clot volume to baseline. Secondary endpoints include the recurrence of symptomatic VTE and haemorrhagic complications. Recurrence of PE is defined as a new defect in pulmonary angiography, CT or lung perfusion scintigraphy with normal  and/or symptomatic bleeding in a critical area or organ, such as intracranial, retroperitoneal, and/or bleeding causing a fall in hemoglobin level of 2 g/mL or more, or leading to transfusion of two or more units of whole blood or red cells [15].
Non-major bleeding is defined as bleeding which do not meeting the criteria of major bleeding.
10) Patients who, after being included in this study, agree to participate in another interventional study during the same timeframe. 11) Patients who, after being included in this study, plan on having surgery during the same timeframe. 12) Patients with a contraindication or allergy to contrast media. 13) Due to other safety concerns, the investigator may determine that participation in this study is inappropriate.

Treatment protocol
Patients who meet inclusion criteria but do not meet exclusion criteria are included and are started on treatment protocol. After obtaining written consent for participating in  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   13 this study and registering at the case registration centre, protocol treatment is promptly started. Patients receive the standard treatment of rivaroxaban approved in Japan (15 mg BID for 3 weeks after the start of treatment, followed by 15 mg QD, this is different from other countries especially western countries). Protocol treatment is continued for 90 ± 14 days after the start of rivaroxaban treatment. For patients who have discontinued treatment early, a reason should be described. We plan to complete patient registration by 31 March 2020.
Patients' background, current treatments and data from contrast-enhanced CT examinations are collected at the time of study registration, 21 ± 4 days after and 90 ± 14 days after the start of treatment with rivaroxaban. In the patients with proximal DVT, a contrast-enhanced CT after diagnosis by ultrasound is carried out to investigate the presence of pulmonary embolism. At the time of that scanning, a thrombus in the lower limb is concomitantly evaluated. If subsegmental PE is detected at baseline, we include these patients and re-evaluate the thrombus at time of follow up CT. CT data to quantify thrombus volume are collected at the Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   14 Thrombus volume is quantified using a Ziostation 2 (3D medical imaging workstation, manufactured by Ziosoft Inc., Version 2.9) and by manually tracing the intravenous clot in the contrast-enhanced CT image. All pulmonary artery thrombi and leg vein thrombi are traced to calculate the total thrombus mass volume. If there is no thrombus in the CT image, the thrombus volume is determined as zero. Measurement results are checked by the thrombus evaluation committee and monitored for their accuracy. It should be noted that staff measuring the thrombus and evaluating the thrombus are not informed of which subject's thrombus volume at which evaluation point and therefore kept blinded.

Statistical analysis
Because this is an exploratory study, the number of cases was determined based on the feasibility of the institution. A previous study [17] has reported that at 3 weeks of rivaroxaban administration, the clot regression rate on CT assessment was 59% (standard deviation (SD) 37%). In the study by van Es J [17], subjects were not limited to cancer-bearing patients, and DVT patients were excluded. Due to our study being specific to patients with cancer and high thromboembolic risk, the average thrombolysis rate is set at 20% (SD 37%). The number of required patients is 38, which corresponds to a one-sided significance level of 0.025 and a power of 0.9. The alternative hypothesis  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  is that the one-sided test is natural as we want to show that the thrombus has regressed rather than the thrombus has simply changed. The sample size is thus set at 40 cases to account for some analysis exclusion. The population to be analysed is defined as the full analysis set (FAS) for efficacy and the safety analysis set (SAF) for adverse events. The FAS includes all patients who received the protocol treatment, with the exclusion of those who are found to be ineligible after enrolment and those for whom any information after enrolment, such as treatment initiation, cannot be obtained. The SAF includes all patients who received at least one dose of the treatment.
The clot regression ratio is defined as the ratio of regressed thrombus volume at 3 weeks and 3 months after the start of rivaroxaban compared to thrombus volume at baseline. The clot regression rate for both 3 weeks and 3 months after the start of rivaroxaban is expressed as a percentage, and the mean and 95% confidence intervals for the whole population are calculated based on t-distribution. If either 95% confidence interval is greater than 0%, we conclude that thrombus regression is statistically significant. That is, it is identical to paired t-test for each clot regression rate. If the null hypothesis is defined as having a clot regression rate of 0%, this corresponds to a test with a one-sided significance level of 0.025 without adjusting the test multiplicity to account for this being an exploratory study. The frequency, percentage and 95%  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   16 confidence intervals for the percentage of symptomatic VTE recurrence and haemorrhagic complications are calculated during the study period. The incidence and severity of all adverse events for the SAF are collected during the study period.

Patient and public involvement
This research is done without patient involvement. Patients are not invited to comment on the study design and are not consulted to assess the burden of the intervention or to develop patient relevant outcomes or interpret the results. Patients are not invited to contribute to the writing or editing of this document for readability or accuracy. Study results will be disseminated to the participants through publicly accessible medical journals.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59

DISCUSSION
In this study, we are investigating the thrombolytic effect of rivaroxaban in patients with cancer who develop VTE. The American College of Chest Physician (ACCP) guideline states that LMWH is recommended as an anticoagulation treatment for VTE patients with cancer rather than vitamin K antagonist or DOAC [5]. However, LMWH has not yet been approved for the treatment of VTE in Japan. Recently, it has been reported that some DOACs are non-inferior with respect to VTE recurrence and major bleeding events in patients with cancer [9,10].
For patients with VTE, clot regression is an important issue. The presence of residual thrombus leads to an increased risk of DVT recurrence. In the case of DVT recurrence, it can cause not only reappearance of symptoms but also post-thrombotic syndrome (PTS) [18]. Incomplete resolution of a pulmonary artery thrombus can also lead to chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is a progressive disease with poor prognosis, classified as group 4 pulmonary hypertension in the clinical classification of pulmonary hypertension [19]. To avoid these complications, clot regression in the acute phase of VTE is essential. Cancer patients with VTE have a risk of both thrombogenicity and haemorrhage. Because patients over 75 years old who received rivaroxaban had higher bleeding rate compared with younger  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 18 patients in the ROCKET AF trial, we excluded patients 75 years old or older in this study due to this safety concern [14]. Overall, it could greatly contribute to improvements in symptoms and prognosis of cancer patients with VTE to examine the clot regression effects and safety of rivaroxaban in the clinical practice.
Oral rivaroxaban for the treatment of VTE has been shown to be equivalent in efficacy and safety to unfractionated heparin plus warfarin with a single drug approach.
Although approved dose of rivaroxaban in Japan (15 mg BID for 3 weeks followed by 15 mg QD) differs from other countries especially western countries, the result of the J-EINSTEIN study [12] was consistent with the EINSTEN study. In regard to cancer patients with VTE, rivaroxaban was associated with lower VTE recurrence and consistent major bleeding risk, but higher minor bleeding risk, compared with LMWH [10]. However, the efficacy of the Japanese dose of rivaroxaban in cancer patients with VTE has not been well investigated. In this study, we will examine whether the Japanese dose of rivaroxaban can be used effectively and safely for the treatment of VTE patients with cancer.