Medically Ill Hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis With Rivaroxaban ThErapy: The MICHELLE Trial (MICHELLE)

• ClinicalTrials.gov Identifier: NCT04662684
• Recruitment Status: Active, not recruiting
• First Posted: December 10, 2020
• Last Update Posted: August 3, 2021
• Sponsor: Science Valley Research Institute
• Collaborator: Bayer
• Information provided by (Responsible Party): Eduardo Ramacciotti, Science Valley Research Institute

Tracking Information

• First Submitted Date: December 8, 2020
• First Posted Date: December 10, 2020
• Last Update Posted Date: August 3, 2021
• Actual Study Start Date: October 16, 2020
• Estimated Primary Completion Date: August 10, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 9, 2020)

Venous thromboembolism and VTE related-death [ Time Frame: at day 35 +/- post hospital discharge ]

a composite efficacy endpoint of symptomatic VTE, VTE-related death, and/or VTE detected by mandatory bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram on day 35+/-4 post-hospital discharge

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 9, 2020)

Major bleeding [ Time Frame: at day 35 +/- post hospital discharge ]

Incidence of major bleeding according to ISTH criteria.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: December 9, 2020)

• A composite of myocardial infarction, stroke, arrhythmias, heart failure, venous thromboembolism (VTE), and all-cause death. [ Time Frame: at day 35 +/- post hospital discharge ]
  A composite of myocardial infarction, stroke, arrhythmias, heart failure, venous thromboembolism (VTE), and all-cause death.
• Days alive out of the hospital (DAOH) at 35 +/-4 days [ Time Frame: at day 35 +/- post hospital discharge ]
  Days alive out of the hospital (DAOH) at 35 +/-4 days
• D-dimer (Biomarker) [ Time Frame: at day 35 +/- 4 post hospital discharge ]
  plasma level of D-dimers in ng/mL
• C reactive protein (Biomarker) [ Time Frame: at day 35 +/- 4 post hospital discharge ]
  plasma level of C Reactive Protein in μg/mL
• PAI-1 (Biomarker) [ Time Frame: at day 35 +/- 4 post hospital discharge ]
  plasma level of PAI-1 in units/mL
• TFPI (Biomarker) [ Time Frame: at day 35 +/- 4 post hospital discharge ]
  plasma level of TFPI in units/mL
• Thrombomodulin (Biomarker) [ Time Frame: at day 35 +/- 4 post hospital discharge ]
  plasma level of Thrombomodulin in nM/mL
• IL-6 (Biomarker) [ Time Frame: at day 35 +/- 4 post hospital discharge ]
  plasma level of IL-6 in pg/mL

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Medically Ill Hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis With Rivaroxaban ThErapy: The MICHELLE Trial
• Official Title: Medically Ill Hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis With Rivaroxaban ThErapy: The MICHELLE Trial
• Brief Summary: The Michelle trial is expected to provide high-quality evidence around the role of extended thromboprophylaxis in COVID-19 and will help guide medical decisions in clinical practice.

Detailed Description

Background: The devastating COVID-19 pandemic is associated with a high prothrombotic state. It is unclear if the coagulation abnormalities occur because of the direct effect of SARS-CoV 2 or indirectly by the cytokine storm and endothelial damage, or by a combination of mechanisms. There is a clear indication of in-hospital pharmacological thromboprophylaxis for every patient with COVID-19 after bleed risk assessment. However, there is much debate regarding the best dosage regimen, and there is no consensus on the role of extended VTE prophylaxis.

Design: This study aims to evaluate the safety and efficacy of rivaroxaban 10 mg OD for 35+/-4 days versus no intervention after hospital discharge in COVID-19 patients who were at increased risk for VTE and have received standard parenteral VTE prophylaxis during hospitalization, with a composite efficacy endpoint of symptomatic VTE, VTE-related death, and/or VTE detected by mandatory bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram on day 35+/-4 post-hospital discharge.

Summary: The Michelle trial is expected to provide high-quality evidence around the role of extended thromboprophylaxis in COVID-19 and will help guide medical decisions in clinical practice.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This study aims to evaluate the safety and efficacy of rivaroxaban 10 mg OD for 35+/-4 days versus no intervention after hospital discharge in COVID-19 patients who were at increased risk for VTE and have received standard parenteral VTE prophylaxis during hospitalization, with a composite efficacy endpoint of symptomatic VTE, VTE-related death, and/or VTE detected by mandatory bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram on day 35+/-4 post-hospital discharge.

Masking: None (Open Label)
Masking Description:

open-label

Primary Purpose: Prevention

Condition

• Covid19
• Venous Thromboembolism

Intervention

Drug: Rivaroxaban 10 MG

No intervention

Other Name: No intervention

Study Arms

• Experimental: Rivaroxaban
  Rivaroxaban 10mg OD for 35+/- 4 days post-hospital discharge
  Intervention: Drug: Rivaroxaban 10 MG
• No Intervention: No intervention
  control

• Publications *: Ramacciotti E, Barile Agati L, Calderaro D, Aguiar VCR, Spyropoulos AC, de Oliveira CCC, Lins Dos Santos J, Volpiani GG, Sobreira ML, Joviliano EE, Bohatch Júnior MS, da Fonseca BAL, Ribeiro MS, Dusilek C, Itinose K, Sanches SMV, de Almeida Araujo Ramos K, de Moraes NF, Tierno PFGMM, de Oliveira ALML, Tachibana A, Chate RC, Santos MVB, de Menezes Cavalcante BB, Moreira RCR, Chang C, Tafur A, Fareed J, Lopes RD; MICHELLE investigators. Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial. Lancet. 2022 Jan 1;399(10319):50-59. doi: 10.1016/S0140-6736(21)02392-8. Epub 2021 Dec 15.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 9, 2020): 320
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 30, 2021
• Estimated Primary Completion Date: August 10, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male and nonpregnant female patients 18 years of age or older
• Positive reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay for SARS-CoV-2 in a respiratory tract sample
• Pneumonia confirmed by chest imaging
• Additional risk factors for VTE, as indicated by a total modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) risk score of 4 or higher
• Have received thromboprophylaxis with low-molecular-weight heparin, fondaparinux, or unfractionated heparin during the index hospitalization

Exclusion Criteria:

• Age < 18 years
• Refusal of informed consent
• Physician decision that involvement in the trial was not in the patient's best interest
• Patients with a medical indication for anticoagulation therapy at the time of inclusion (for example, diagnosis of venous thromboembolism, atrial fibrillation, mechanical valve prosthesis)
• Platelets < 50,000 / mm3
• Patients with contraindications to anticoagulation (active bleeding, liver failure, blood dyscrasia, or prohibitive hemorrhagic risk in the investigator's assessment)
• Active cancer (excluding non-melanoma skin cancer) defined as cancer, not in remission or requiring active chemotherapy or adjunctive therapies such as immunotherapy or radiotherapy.
• Use of strong inhibitors of cytochrome P450 (CYP) 3A4 and/or glycoprotein P (P-gp) (eg protease inhibitors, ketoconazole, Itraconazole) and/or use of P-gp and strong inducers of CYP3A4 (how but not limiting rifampicin/rifampicin, rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine or St. John's wort)
• Creatinine clearance <30 ml / min
• Pregnancy or breastfeeding
• known HIV infection
• Presence of one of the following uncontrolled or unstable cardiovascular diseases: stroke, ECG confirmed acute ischemia or myocardial infarction, and/or clinically significant dysrhythmia

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil

Administrative Information

• NCT Number: NCT04662684
• Other Study ID Numbers: 21589 Michelle Trial
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Undecided
• Plan Description: Red Cap open file

• Responsible Party: Eduardo Ramacciotti, Science Valley Research Institute
• Study Sponsor: Science Valley Research Institute
• Collaborators: Bayer

Investigators

• Study Chair: Eduardo Ramacciotti, MD, Ph.D; Science Valley Research Institute

• PRS Account: Science Valley Research Institute
• Verification Date: August 2021