Clinical Surveillance vs. Anticoagulation for Low-risk Patients With Isolated Subsegmental Pulmonary Embolism (SAFE-SSPE)

May 20, 2026 updated by: Drahomir Aujesky

Clinical Surveillance vs. Anticoagulation for Low-risk Patients With Isolated Subsegmental Pulmonary Embolism: a Multicenter Randomized Placebo-controlled Non-inferiority Trial

The clinical significance of pulmonary embolism (PE) limited to the subsegmental pulmonary arteries, so called isolated subsegmental pulmonary embolism (SSPE), remains controversial. Whether isolated SSPE represents "true" PE, a clinically more benign form of PE, a physiologic lung clearing process, or a false positive result (artifact) is currently unclear and hence, whether patients with isolated SSPE benefit from anticoagulant treatment is uncertain. Despite growing evidence from observational studies that withholding anticoagulation may be a safe option in selected patients with isolated SSPE (i.e., those without concomitant deep vein thrombosis, cancer, etc.), most patients with isolated SSPE receive anticoagulant treatment, which is associated with an increased risk of bleeding. The overall objective of the randomized controlled SAFE-SSPE trial is to evaluate the efficacy and safety of clinical surveillance without anticoagulation compared to anticoagulation treatment in low-risk patients with isolated SSPE.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
276

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.
  • Name: Drahomir Aujesky, Prof. MD MSc
  • Phone Number: +41 31 632 88 84
  • Email: SAFE-SSPE@insel.ch

Study Contact Backup

  • Name: Tobias Tritschler, Dr. MD MSc
  • Phone Number: +41 31 63 2 01 46
  • Email: SAFE-SSPE@insel.ch

Study Locations

  • Belgium
      • Liège, Belgium
        • Recruiting
        • Centre Hospitalier Universitaire de Liege
        • Contact:
          • Raphaelle Lopez Iglesias, MD
        • Principal Investigator:
          • Raphaelle Lopez Iglesias, MD
    • Brussels Capital
      • Woluwe-Saint-Lambert, Brussels Capital, Belgium, 1200
        • Recruiting
        • Cliniques universitaires Saint-Luc
        • Contact:
          • Andrea Penaloza Baeza, Prof., MD
        • Principal Investigator:
          • Andrea Penaloza Baeza, Prof., MD
  • Canada
      • Ottawa, Canada
        • Recruiting
        • The Ottawa Hospital
        • Contact:
          • Marc Carrier, Prof. MD MSc
        • Principal Investigator:
          • Marc Carrier, Prof. MD MSc
  • France
      • Brest, France
        • Recruiting
        • Centre Hospitalier Regional Et Universitaire De Brest
        • Contact:
          • Francis Couturaud, Prof. MD
        • Principal Investigator:
          • Francis Couturaud, Prof., MD
      • Clermont-Ferrand, France
        • Recruiting
        • CHU Gabriel-Montpied
        • Contact:
          • Jeannot Schmidt, Prof., MD
        • Principal Investigator:
          • Jeannot Schmidt, Prof., MD
      • Dijon, France
        • Recruiting
        • Centre Hospitalier Universitaire de Dijon
        • Principal Investigator:
          • Nicolas Falvo, MD
        • Contact:
          • Nicolas Falvo, MD
      • Lyon, France
        • Recruiting
        • Hospital Edouard Herriot
        • Principal Investigator:
          • Judith CATELLA, MD
        • Contact:
          • Judith Catella, MD
      • Marseille, France
        • Recruiting
        • Hôpitaux universitaires de Marseille Timone AP-HM
        • Contact:
          • Gabrielle Sarlon, Prof., MD
        • Principal Investigator:
          • Gabrielle Sarlon, Prof., MD
      • Rouen, France
        • Recruiting
        • CHU de Rouen
        • Contact:
          • Sébastien Miranda, MD
        • Principal Investigator:
          • Sébastien Miranda, MD
      • Saint-Priest-en-Jarez, France
        • Recruiting
        • CHU ST Etienne - Hôpital Nord
        • Contact:
          • Laurent Bertoletti, Prof., MD
        • Principal Investigator:
          • Laurent Bertoletti, Prof., MD
    • Le Kremlin-Bicêtre
      • Le Kremlin-Bicêtre, Le Kremlin-Bicêtre, France, 94270
        • Recruiting
        • Hôpital Bicêtre - APHP
        • Contact:
        • Principal Investigator:
          • Mitja Jevnikar, MD
  • Netherlands
      • Dordrecht, Netherlands
        • Recruiting
        • Albert Schweitzer Ziekenhuis Dordrecht
        • Contact:
          • P.E. Westerweel, MD
        • Principal Investigator:
          • P.E. Westerweel, MD
      • Enschede, Netherlands
        • Recruiting
        • Medisch Spectrum Twente
        • Contact:
          • H.P.A.A. van Veen, MD
        • Principal Investigator:
          • H.P.A.A. van Veen, MD
      • Leiden, Netherlands
        • Recruiting
        • Leiden University Medical Center
        • Contact:
          • F. A. Klok, Prof. MD PhD
        • Principal Investigator:
          • F. A. Klok, Prof., MD, PhD
      • Rotterdam, Netherlands
        • Withdrawn
        • Erasmus Universitair Medisch Centrum
      • The Hague, Netherlands
        • Withdrawn
        • Haaglanden Medisch Centrum
      • Zwolle, Netherlands
        • Recruiting
        • Isala Klinieken Zwolle
        • Contact:
          • M. F. Boosma, MD
        • Principal Investigator:
          • M. F. Boosma, MD
  • Switzerland
      • Altdorf, Switzerland
        • Withdrawn
        • Cantonal Hospital of Uri
      • Baden, Switzerland
        • Recruiting
        • Cantonal Hospital of Baden
        • Contact:
          • Maria Wertli, Prof. MD
        • Principal Investigator:
          • Maria Wertli, Prof., MD
      • Basel, Switzerland
        • Recruiting
        • University Hospital of Basel
        • Contact:
          • Roland Bingisser, Prof., MD
        • Principal Investigator:
          • Roland Bingisser, Prof., MD
      • Bern, Switzerland
        • Completed
        • Tiefenau Hospital
      • Burgdorf, Switzerland
        • Recruiting
        • Regional Hospital of Emmental
        • Contact:
          • Robert Escher, PD Dr. MD
        • Principal Investigator:
          • Robert Escher, PD, MD
      • Delémont, Switzerland
        • Terminated
        • Hospital of Delémont
      • Geneva, Switzerland
        • Recruiting
        • Geneva University Hospital
        • Contact:
          • Marc Righini, Prof. MD
        • Principal Investigator:
          • Marc Righini, Prof., MD
      • Neuchâtel, Switzerland
        • Recruiting
        • Hospital of Neuchâtel
        • Contact:
          • Jacques Donzé, Prof. MD MSc
        • Principal Investigator:
          • Jacques Donzé, Prof., MD, MSc
    • Basel
      • Liestal, Basel, Switzerland
        • Recruiting
        • Cantonal Hospital of Liestal
        • Contact:
          • Jörg Leuppi, Prof. MD PhD
        • Principal Investigator:
          • Jörg Leuppi, Prof., MD, PhD
    • Canton of Aargau
      • Aarau, Canton of Aargau, Switzerland
        • Recruiting
        • Cantonal Hospital of Aarau
        • Contact:
          • Philippe Schütz, Prof. MD MPH
        • Principal Investigator:
          • Philippe Schütz, Prof., MD, MPH
    • Canton of Bern
      • Bern, Canton of Bern, Switzerland, 3010
        • Recruiting
        • University Hospital Inselspital
        • Contact:
          • Drahomir Aujesky, Prof. MD MSc
        • Principal Investigator:
          • Drahomir Aujesky, Prof., MD, MSc
      • Biel/Bienne, Canton of Bern, Switzerland
        • Recruiting
        • Hospital of Bienne
        • Contact:
          • Daniel Genné, Prof. MD
        • Principal Investigator:
          • Daniel Genné, Prof., MD
    • Canton of Fribourg
      • Fribourg, Canton of Fribourg, Switzerland
        • Withdrawn
        • Cantonal Hospital of Fribourg
    • Canton of Lucerne
      • Lucerne, Canton of Lucerne, Switzerland
        • Withdrawn
        • Cantonal Hospital of Lucerne
    • Canton of Solothurn
      • Olten, Canton of Solothurn, Switzerland
        • Withdrawn
        • Cantonal Hospital of Olten
    • Canton of St. Gallen
      • Sankt Gallen, Canton of St. Gallen, Switzerland
        • Recruiting
        • Cantonal Hospital of St. Gallen
        • Contact:
          • Claudio S. Rüegg, MD
        • Principal Investigator:
          • Claudio S. Rüegg, MD
    • Canton of Vaud
      • Lausanne, Canton of Vaud, Switzerland
        • Recruiting
        • University Hospital of Lausanne
        • Contact:
          • Marie Méan, MD MER
        • Principal Investigator:
          • Marie Méan, MD, MER
      • Nyon, Canton of Vaud, Switzerland
        • Withdrawn
        • Hospital of Nyon
    • Canton of Zurich
      • Winterthur, Canton of Zurich, Switzerland
        • Recruiting
        • Cantonal Hospital of Winterthur
        • Contact:
          • Bettina Portocarrero, MD
        • Principal Investigator:
          • Bettina Portocarrero, MD
      • Zurich, Canton of Zurich, Switzerland
        • Recruiting
        • Triemli Hospital
        • Contact:
          • Lars Huber, PD MD
        • Principal Investigator:
          • Lars Huber, PD, MD
      • Zurich, Canton of Zurich, Switzerland
        • Withdrawn
        • University Hospital Zurich
    • Thurgau
      • Frauenfeld, Thurgau, Switzerland
        • Recruiting
        • Cantonal Hospital of Frauenfeld
        • Contact:
          • Andreas Kistler, PD MD
        • Principal Investigator:
          • Andreas Kistler, PD, MD
    • Valais
      • Sion, Valais, Switzerland
        • Withdrawn
        • Hospital of Sion

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Informed Consent as documented by signature
  2. Age ≥18 years
  3. Objective diagnosis of symptomatic or asymptomatic isolated SSPE

Exclusion Criteria:

  1. Presence of leg deep vein thrombosis (DVT) or upper extremity DVT (subclavian vein or above)
  2. Active cancer, defined as cancer treated with surgery, chemotherapy, radiotherapy, or palliative care during the last 6 months
  3. ≥1 prior episode of unprovoked VTE (absence of a transient or permanent risk factor)
  4. Clinical instability (systolic blood pressure <100 mm Hg or arterial Oxygen saturation <92% at ambient air) at the time of presentation
  5. Active bleeding or at high risk of bleeding
  6. Severe renal failure (creatinine clearance <30ml/min)
  7. Severe liver insufficiency (Child-Pugh B or C)
  8. Concomitant use of strong CYP3A4 inhibitors or strong CYP3A4 inducers
  9. Known hypersensitivity to rivaroxaban
  10. Need for therapeutic anticoagulation for another reason
  11. Therapeutic anticoagulation for >72 hours for any reason at the time of screening
  12. Hospitalized for >72 hours prior to the diagnosis of isolated SSP (hospital-acquired VTE)
  13. Known pregnancy or breast feeding (pregnancy test to be performed for women of childbearing potential)
  14. Lack of safe contraception in women of childbearing potential
  15. Refusal or inability to provide informed consent
  16. Prior enrolment in this trial

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Anticoagulation
Patients in the anticoagulation group will receive rivaroxaban 15 mg twice daily for the first 21 days, followed by 20 mg once daily for an overall treatment duration of 90 days.
Drug: Rivaroxaban
Anticoagulation
Placebo Comparator: No anticoagulation
Patients in the group without anticoagulation will receive placebo twice daily for the first 21 days, followed by one tablet daily for an overall treatment duration of 90 days.
Drug: Placebo
Study drug without active agent

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Recurrent venous thromboembolism
Time Frame: Within 90 days of randomization
Proportion of recurrent, clinically symptomatic, objectively confirmed venous thromboembolism (defined as recurrent fatal or nonfatal pulmonary embolism or lower limb deep vein thrombosis)
Within 90 days of randomization

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Clinically significant bleeding
Time Frame: Within 90 days of randomization
Proportion of the composite of major and clinically relevant non-major bleeding
Within 90 days of randomization
All-cause mortality
Time Frame: Within 90 days of randomization
Proportion of deaths (all causes of death will be considered)
Within 90 days of randomization

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Health-related quality of life
Time Frame: Within 90 days of randomization
Pulmonary embolism related quality of life as assessed by the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire
Within 90 days of randomization
Functional status
Time Frame: Within 90 days of randomization
Functional status as assessed by the post-venous thromboembolism functional status scale
Within 90 days of randomization
Initial length of stay (LOS)
Time Frame: Within 90 days of randomization
Defined as the time/date of discharge minus time/date of admission at the emergency department
Within 90 days of randomization
Subsequent overall hospitalizations
Time Frame: Within 90 days of randomization
Number of overall hospitalizations
Within 90 days of randomization
Emergency departments and physician outpatient visits
Time Frame: Within 90 days of randomization
Number of emergency department and physician outpatient visits
Within 90 days of randomization
Return to work or usual activities
Time Frame: Within 90 days of randomization
Time (days) to return to work in workers and usual activities (household) in non-workers
Within 90 days of randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Drahomir Aujesky

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Bayer
The Ottawa Hospital
University of Bern
Leiden University Medical Center
Schweizerischer Nationalfonds

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Drahomir Aujesky, Prof. MD MSc, Inselspital, Bern University Hospital, University of Bern

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 15, 2020

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 1, 2028

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
May 1, 2028

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 4, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 6, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 10, 2020

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 22, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 20, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2019-02297

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

After publication of the study results, a de-identified patient-level data set relating to the primary publication along with the latest version of the study protocol, the informed consent form, the statistical analysis plan, the code used for the analyses, and the Data Management and Quality Plan describing all data management aspects of the study will be made publicly available for replication of the study results and secondary data analyses in the Bern Open Repository and Information System (BORIS) Research Data, an online non-commercial data repository that meets Swiss National Science Foundation requirements for FAIR Data Principles (www.force11.org/group/fairgroup/fairprinciples)

IPD Sharing Time Frame

After publication of the study results

IPD Sharing Access Criteria

Data will be publicly available for replication of the study results and secondary data analyses in the Bern Open Repository and Information System (BORIS) Research Data

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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