Rivaroxaban or Aspirin As Thromboprophylaxis in Multiple Myeloma

Multiple Myeloma in Relapse Clinical Trial

— RithMM  

Official title:

Rivaroxaban for Improvement of Thromboembolism Outcomes in Patients With Multiple Myeloma on Lenalidomide-based Therapy: RithMM Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03428373
• Other study ID #: 110804
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: January 17, 2019
• Est. completion date: September 30, 2024

Study information

• Verified date: February 2024
• Source: Lawson Health Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The intended study is designed as a a phase IV pragmatic multicenter randomized controlled clinical trial, comparing the impact of two different therapies including ASA vs. Rivaroxaban in newly diagnosed or relapsed and refractory multiple myeloma patients treated with Lenalidomide Dexamethasone (Len-Dex) combination therapy. The pilot feasibility study was conducted in preparation for this randomized controlled trial designed to assess the effect of an intervention.

Description:

RithMM is a phase IV, pragmatic, multicenter, open label Canadian trial. The study started with a pilot feasibility phase where 3 centres (London, Ottawa and Halifax) enrolled 34 patients within 12 months. Utilizing a roll-over design, the full RithMM trial will require a total of 304 patients to demonstrate that rivaroxaban 10 mg daily for 6 months is superior to ASA 81 mg daily for 6 months in preventing any thromboembolic events in newly diagnosed myeloma (NDMM) and relapsed/refractory (RRMM) patients on Len-Dex -based therapy. The study will require 8 participating centres in order to be able to achieve our recruitment goal within 12 to 18 months. Patients with NDMM or RRMM receiving Len-Dex based combination therapy with or without combination with other anti-myeloma drugs will be assessed for eligibility to be enrolled in the study. The research team intends to rollover the participants of our feasibility study into this current full randomized control trial comparing the efficacy outcome for the RithMM trial is the overall incidence of cardiovascular events, which includes arterial or venous thromboembolic events. By conducting this trial, the investigators plan to externally validate the International Myeloma Working Group (IMWG) criteria model for thromboembolic risk by assessing the relevance of measuring pre-specified myeloma and thrombosis activity biomarkers (D-Dimer, beta-2 microglobulin, C-reactive protein (CRP), LDH) at every follow-up visit and their potential association with thromboembolism (TE) risk.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 57
• Est. completion date: September 30, 2024
• Est. primary completion date: December 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

1. Diagnosis of Multiple Myeloma

2. Scheduled to start on Len-Dex therapy

3. Be = 18 years of age

4. Able to provide written informed consent

5. Pre-clinical laboratory must meet the following criteria at enrollment

• Platelet count >50 × 109/L
• Creatinine clearance (CrCl) >15mL/min using Cockcroft-Gault Equation

Exclusion Criteria:

1. Major bleeding event within the previous 3 months prior to commencement of Len Dex therapy

2. Documented severe liver disease in the past 6 months (eg. acute clinical hepatitis, chronic active hepatitis, or cirrhosis)

3. Patient with a history of antiphospholipid syndrome especially if he/she is triple positive for lupus anticoagulant, anticardiolipin antibodies, and/or anti-b2 glycoprotein I antibodies.

4. A history of malignancy (with the exception of MM) within 2 years before randomization or any previously diagnosed malignancy with evidence of residual disease. Patients with a history of basal cell or squamous carcinoma are not excluded.

5. Patient with history of gastric or duodenal ulcer within 2 years

6. Plasma cell leukemia; systemic amyloidosis

7. Patient on therapeutic anticoagulation for treatment of VTE or ATE, or stroke prevention in non-valvular atrial fibrillation. Patients with a previous history of VTE who are not on any active anticoagulant therapy will not be excluded.

8. Patient on antiplatelet agents due to an absolute indication (e.g.; coronary stent, carotid stent).

9. Patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp such as ketoconazole, itraconazole, posaconazole or ritonavir)

10. Patient on single agent lenalidomide

11. Life expectancy less than 3 months as determined by the investigator.

12. Unstable medical or psychological condition that would interfere with trial participation, as determined by the investigator

13. Patient not able or not willing to give consent to participate in the study

14. Uncontrolled cardiovascular disease within 6 months prior to enrollment

15. Uncontrolled or poorly controlled diabetes or renal disease

16. Major surgery within 2 weeks before randomization

17. Known allergies, hypersensitivity, or intolerance to any of the study drugs.

18. Patients not able or not willing to give consent to participate in the Study.

Related Conditions & MeSH terms

• Multiple Myeloma
• Multiple Myeloma in Relapse
• Multiple Myeloma Progression
• Multiple Myeloma Stage I
• Multiple Myeloma Stage II
• Multiple Myeloma Stage III
• Multiple Myeloma With Failed Remission
• Neoplasms, Plasma Cell

Intervention

Drug:
• Rivaroxaban
Rivaroxaban 10mg daily
• ASA
ASA 81mg

Locations

Country	Name	City	State
Canada	London Health Sciences Centre	London	Ontario

Sponsors (5)

Lead Sponsor	Collaborator
Lawson Health Research Institute	Dalhousie University, Hamilton Health Sciences Corporation, Niagara Health System, The Ottawa Hospital

Country where clinical trial is conducted

Canada, 

References & Publications (8)

Al-Ani F, Bermejo JM, Mateos MV, Louzada M. Thromboprophylaxis in multiple myeloma patients treated with lenalidomide - A systematic review. Thromb Res. 2016 May;141:84-90. doi: 10.1016/j.thromres.2016.03.006. Epub 2016 Mar 5. — View Citation

Arain M, Campbell MJ, Cooper CL, Lancaster GA. What is a pilot or feasibility study? A review of current practice and editorial policy. BMC Med Res Methodol. 2010 Jul 16;10:67. doi: 10.1186/1471-2288-10-67. — View Citation

Kamat AV Rivaroxaban Is an Effective and Well Tolerated Anti Thrombotic Agent in Patients on Lenalidomide Therapy and in Multiple Myeloma Blood 2014 124:5095;

Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract. 2004 May;10(2):307-12. doi: 10.1111/j..2002.384.doc.x. — View Citation

Leleu X, Rodon P, Hulin C, Daley L, Dauriac C, Hacini M, Decaux O, Eisemann JC, Fitoussi O, Lioure B, Voillat L, Slama B, Al Jijakli A, Benramdane R, Chaleteix C, Costello R, Thyss A, Mathiot C, Boyle E, Maloisel F, Stoppa AM, Kolb B, Michallet M, Lamblin — View Citation

Levine MN, Gu C, Liebman HA, Escalante CP, Solymoss S, Deitchman D, Ramirez L, Julian J. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost. 2012 May;10(5):807-14. doi: 10.111 — View Citation

Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, Harousseau J, Zonder JA, Cavo M, Zangari M, Attal M, Belch A, Knop S, Joshua D, Sezer O, Ludwig H, Vesole D, Blade J, Kyle R, Westin J, Weber D, Bringhen S, Niesvizky R, Waage — View Citation

Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicina — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of venous thromboembolic (VTE) and/or arterial thromboembolic (ATE) events in patients with Multiple Myeloma placed on the Rivaroxaban vs Aspirin after starting with Len-Dex therapy	At each visit, patients will be asked standardized questions to capture the presence of primary. During these interviews the study coordinator will collect data related to resource utilization (e.g. health care services use) and ask whether the patient had a diagnosis of VTE, ATE or a bleeding event during this period. Any hospital or medical office encounters associated to any of the above-mentioned complaints will be checked and any test or procedures done will be recorded (e.g; echocardiogram, ECG, CT scan, MRI, transfusion).	6 months
Primary	Number of participants with treatment-related adverse events as assessed by CTCAE v6.0	Frequency and severity of adverse events and serious AEs based on hospital admission and patient-self reporting events	6 months
Secondary	External validation of the IMWG criteria for risk assessment of thromboembolic events in multiple myeloma patients	Subgroup analysis stratifying patients into low and high risk of thromboembolic events to assess any potential difference in the efficacy and safety outcomes.	6 months
Secondary	Assessment of correlation of between levels of biomarkers of myeloma and thrombosis with the risk of ATE or VTE	The bio-markers are: D-dimer, LDH, B2 microglobulin and C-reactive protein (CRP) will be collected	6 months