Venous Thromboembolism (VTE)CLOVERNCT07310693
External Validation of the CLOVER Score for Detecting Occult Cancer in Venous Thromboembolism Patients
An observational study of Venous Thromboembolism (VTE) and Occult Cancer, run by Infanta Leonor University Hospital at 12 sites in Spain.
Trial summary
This study aims to externally validate the CLOVER score, a machine learning-based predictive model designed to identify patients with venous thromboembolism (VTE) who are at increased risk of having an occult cancer. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Venous Thromboembolism (VTE), Occult Cancer
- How many people
- 500 participants
- Where
- 12 sitesSpain
- Study dates
- 1 Dec 2025to 31 Dec 2028
- How long will I take part?
- 2 Years
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Adults (≥18 years) with objectively confirmed symptomatic venous thromboembolism (deep vein thrombosis or pulmonary embolism) who are consecutively recruited in participating hospitals in Spain. All participants undergo routine clinical evaluation, laboratory testing, and age- and sex-appropriate cancer screening according to standard practice. The population represents real-world patients with new-onset VTE without known or suspected cancer at baseline.
Who may be able to join
- Age ≥18 years.
- Objectively confirmed acute symptomatic venous thromboembolism (deep vein thrombosis and/or pulmonary embolism).
- Ability to provide written or electronic informed consent.
Who cannot join
- Suspicion of cancer during the initial diagnostic evaluation for VTE.
- Participation in another interventional study that may interfere with outcomes.
- Inability or refusal to provide informed consent.
Trial locations and contacts
12 sites in 1 country. Contact the study team or a site near you to ask about taking part.
12 sites in 1 country
Spain12 sites, 12 recruiting
- Recruiting
Hospital San Agustín
Avilés, Principality of Asturias
José Ferreiro Celeiro, MD, 985 12 30 00, jcaussie@hotmail.com
- Recruiting
Hospital Universitario Son Llatzer
Balea
Elena Cisneros de la Fuente, MD, ecisneros@hsll.es
- Recruiting
Hospital Clínic
Barcelona, Barcelona
JESUS AIBAR, MD, PhD, 932 27 54 00, JAIBAR@clinic.cat
- Recruiting
Hospital Universitario Infanta Leonor
Madrid, Madrid, 28051
Anabel Franco Moreno, MD, PhD, 686102661, afranco278@hotmail.com
- Recruiting
Hospital Universitario La Paz
Madrid, Madrid, 28051
Teresa Sancho, MD, 917 27 70 00, tsbueso@gmail.com
- Recruiting
Hospital Universitario Príncipe de Asturias
Madrid, Madrid, 28051
f garcia sanchez, MD, 91 887 81 00, fgarciasanchez@salud.madrid.org
- Recruiting
Hospital Universitatio del Sureste
Madrid, Madrid, 28051
Ana Mancebo Plaza, MD, 686102661 ext. 918 39 40 00, abmancebop@gmail.com
- Recruiting
Hospital Universitario de Móstoles
Madrid, Madrid
Andrea Pérez, MD, 916 64 86 00, a.perezrodr@gmail.com
- Recruiting
Hospital Universitario 12 de Octubre
Madrid
Jose Bascuñana Morejon de Giron, MD, PhD, josebascumor@gmail.com
- Recruiting
Hospital Universitario de Fuenlabrada
Madrid
Cristina De Ancos Aracil, MD, drcancos@gmail.com
- Recruiting
Hospital Clínico Universitario Virgen de la Arrixaca
Murcia, Murcia
Leticia Guirado Torrecillas, MD, 968 36 95 00, leticia.guiradotorrecillas@gmail.com
- Recruiting
Hospital Universitario Morales Meseguer
Murcia, Murcia
Javier Pagán, MD, PhD, 968 36 09 00, pagan02468@gmail.com
About this study
Official title: External Validation of a Predictive Model for Occult Cancer Risk in Patients With Venous Thromboembolism Developed Using Machine Learning
This study aims to externally validate the CLOVER score, a machine learning-based predictive model designed to identify patients with venous thromboembolism (VTE) who are at increased risk of having an occult cancer. The study includes a retrospective cohort of patients with acute symptomatic VTE diagnosed between 2000 and 2022, and a prospective cohort of consecutively recruited patients from December 2025 to December 2027. The CLOVER model will be applied to all participants, and its ability to discriminate between patients with and without occult cancer will be evaluated. The study also assesses clinicians' satisfaction with the web-based tool (CLOVER-Web) developed to facilitate the use of the score in clinical practice.
Read the detailed description
This study aims to externally validate the CLOVER score, a machine learning-based predictive model designed to identify patients with venous thromboembolism (VTE) who are at increased risk of having an occult cancer. The study combines a retrospective and a prospective cohort.
Retrospective cohort:
Patients aged ≥18 years with objectively confirmed symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism (PE) diagnosed between January 1, 2000, and August 31, 2022, in participating hospitals across Spain will be included. Patients from centers involved in the model derivation (Hospital Universitario Infanta Leonor and Hospital Universitario de Fuenlabrada) will be excluded. Cases are defined as patients with a histologically confirmed cancer diagnosis occurring between 1 and 24 months after the index VTE event. Controls are defined as patients without a cancer diagnosis during the same period. All variables required for the CLOVER model (age, D-dimer, systolic blood pressure, ALT, hemoglobin, creatinine, total cholesterol, platelet count, triglycerides, leukocyte count, weight, chronic lung disease, heart rate, sex, and previous VTE recurrence) will be extracted from electronic health records using a standardized data collection form. The CLOVER model will be applied to each patient to assess its discrimination for cancer prediction in the retrospective cohort.
Prospective cohort:
From December 1, 2025, to December 31, 2027, consecutive adult patients with objectively confirmed symptomatic VTE will be recruited in participating hospitals. All patients will undergo a standard clinical evaluation including medical history, physical examination, basic laboratory testing (complete blood count and biochemistry), chest X-ray, and age- and sex-appropriate cancer screening tests according to clinical practice guidelines. The CLOVER score will be calculated at the time of VTE diagnosis using a dedicated web-based tool (CLOVER-Web). Patients will be classified as "low risk" or "high risk" based on the optimal F1-score threshold (0.487), corresponding to a sensitivity of 51%, specificity of 95%, PPV of 46%, and NPV of 96%. All participants will be followed for at least two years to determine whether an occult cancer is diagnosed. Further diagnostic testing for suspected cancer will be performed at the discretion of the treating physician, regardless of CLOVER result.
Model performance and bias assessment:
The external validation will evaluate model discrimination using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the area under the ROC curve (AUC). Additional analyses will assess potential prediction bias across demographic and clinical subgroups (e.g., age, sex, comorbidities). Model calibration and temporal performance will also be reviewed, with predefined procedures for identifying deviations from expected behavior. Weekly reports during the prospective phase will alert investigators to performance drift or potential implementation issues in the web-based tool.
Clinician satisfaction:
A secondary objective is to evaluate clinician satisfaction with the CLOVER-Web tool. An online questionnaire specifically designed for this study will be administered to participating clinicians to assess usability, clarity, and clinical utility.
Ethical considerations:
The study follows the Declaration of Helsinki and Spanish regulations on biomedical research and data protection. Retrospective data collection will request exemption from informed consent due to the use of anonymized clinical information. Prospective participants will provide written or electronic informed consent. All data will be pseudonymized and stored securely.
- Conditions
- Venous Thromboembolism (VTE), Occult Cancer
- Keywords
- Occult Cancer, Venous thromboembolism, Machine learning, Prediction model, External validation, CLOVER score
- Medical subject headings
- Venous Thromboembolism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Prospective VTE Cohort | Adults with objectively confirmed symptomatic venous thromboembolism (deep vein thrombosis and/or pulmonary embolism) consecutively enrolled from December 2025 to December 2027 in participating hospitals. All participants will undergo routine clinical evaluation, laboratory testing, and cancer screening according to standard practice. The CLOVER score will be calculated at baseline using the web-based tool (CLOVER-Web). |
What is being measured
The primary outcome is the main question the study is designed to answer.
Detection of occult cancer within 24 months
Proportion of participants with a histologically confirmed diagnosis of occult cancer identified between 1 and 24 months after the index venous thromboembolism (VTE) event. Occult cancer is defined as a new cancer diagnosis not clinically evident at the time of VTE diagnosis
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Dec 2025
- Study start1 Dec 2025
- Primary completion31 Dec 2028 (estimated)
- Study completion31 Dec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Venous Thromboembolism (VTE)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 500 participants (estimated)
- Target duration
- 2 Years
Sponsor and investigators
- Lead sponsor
- Infanta Leonor University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Fundación para la Investigación e Innovación Biomédica del Hospital Universitario Infanta Leonor
- Responsible party
- Principal investigator, Anabel Franco Moreno, Infanta Leonor University Hospital
- Investigators
- Anabel Franco-Moreno, MD, PhD, Principal investigator, Hospital Universitario Infanta LeonorFranco-Moreno, MD, PhD, Principal investigator, Hospital Universitario Infanta Leonor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07310693
- Sponsor's protocol ID
- CLOVER_validation
- Acronym
- CLOVER
- Status last verified
- Dec 2025
- First submitted
- 8 Dec 2025
- Last updated
- 30 Dec 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-identified individual participant data (IPD) will be shared, including baseline characteristics, clinical variables, imaging results, and outcomes related to occult cancer detection. Data will be made available to qualified investigators upon reasonable request and after signing a data sharing agreement ensuring confidentiality and appropriate use. IPD will be available beginning 12 months after study completion and will remain accessible for 5 years. Access to IPD will be granted to qualified researchers with a methodologically sound research proposal. Requests must be submitted to the study's coordinating center and will be evaluated by the principal investigators. A data use agreement will be required before any data transfer. Data will be hosted on the HORUS-ML secure research platform (restricted access).
Publications
Franco-Moreno A, Madronal-Cerezo E, de Ancos-Aracil CL, Farfan-Sedano AI, Munoz-Rivas N, Bascunana Morejon-Giron J, Ruiz-Giardin JM, Alvarez-Rodriguez F, Prada-Alonso J, Gala-Garcia Y, Casado-Suela MA, Bustamante-Fermosel A, Alfaro-Fernandez N, Torres-Macho J; CLOVER Research Group. Development of a Predictive Model of Occult Cancer After a Venous Thromboembolism Event Using Machine Learning: The CLOVER Study. Medicina (Kaunas). 2024 Dec 27;61(1):18. doi: 10.3390/medicina61010018.
PubMed 39859000
Study at a glance
From the registry record, last updated by the sponsor on 30 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- External Validation of a Predictive Model for Occult Cancer Risk in Patients With Venous Thromboembolism Developed Using Machine Learning
- ClinicalTrials.gov ID
- NCT07310693
- Acronym / sponsor ID
- CLOVER / CLOVER_validation
- Conditions
- Venous Thromboembolism (VTE), Occult Cancer
- Keywords
- Occult Cancer, Venous thromboembolism, Machine learning, Prediction model, External validation, CLOVER score
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 500 participants (estimated)
- Lead sponsor
- Infanta Leonor University HospitalUniversity, hospital or other
- Collaborators
- Fundación para la Investigación e Innovación Biomédica del Hospital Universitario Infanta Leonor
- Study start
- 1 Dec 2025 (actual)
- Primary completion
- 31 Dec 2028 (estimated)
- Study completion
- 31 Dec 2028 (estimated)
- First posted
- 30 Dec 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study aims to externally validate the CLOVER score, a machine learning-based predictive model designed to identify patients with venous thromboembolism (VTE) who are at increased risk of having an occult cancer. The study includes a retrospective cohort of patients with acute symptomatic VTE diagnosed between 2000 and 2022, and a prospective cohort of consecutively recruited patients from December 2025 to December 2027. The CLOVER model will be applied to all participants, and its ability to discriminate between patients with and without occult cancer will be evaluated. The study also assesses clinicians' satisfaction with the web-based tool (CLOVER-Web) developed to facilitate the use of the score in clinical practice.
Detailed description
This study aims to externally validate the CLOVER score, a machine learning-based predictive model designed to identify patients with venous thromboembolism (VTE) who are at increased risk of having an occult cancer. The study combines a retrospective and a prospective cohort.
Retrospective cohort:
Patients aged ≥18 years with objectively confirmed symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism (PE) diagnosed between January 1, 2000, and August 31, 2022, in participating hospitals across Spain will be included. Patients from centers involved in the model derivation (Hospital Universitario Infanta Leonor and Hospital Universitario de Fuenlabrada) will be excluded. Cases are defined as patients with a histologically confirmed cancer diagnosis occurring between 1 and 24 months after the index VTE event. Controls are defined as patients without a cancer diagnosis during the same period. All variables required for the CLOVER model (age, D-dimer, systolic blood pressure, ALT, hemoglobin, creatinine, total cholesterol, platelet count, triglycerides, leukocyte count, weight, chronic lung disease, heart rate, sex, and previous VTE recurrence) will be extracted from electronic health records using a standardized data collection form. The CLOVER model will be applied to each patient to assess its discrimination for cancer prediction in the retrospective cohort.
Prospective cohort:
From December 1, 2025, to December 31, 2027, consecutive adult patients with objectively confirmed symptomatic VTE will be recruited in participating hospitals. All patients will undergo a standard clinical evaluation including medical history, physical examination, basic laboratory testing (complete blood count and biochemistry), chest X-ray, and age- and sex-appropriate cancer screening tests according to clinical practice guidelines. The CLOVER score will be calculated at the time of VTE diagnosis using a dedicated web-based tool (CLOVER-Web). Patients will be classified as "low risk" or "high risk" based on the optimal F1-score threshold (0.487), corresponding to a sensitivity of 51%, specificity of 95%, PPV of 46%, and NPV of 96%. All participants will be followed for at least two years to determine whether an occult cancer is diagnosed. Further diagnostic testing for suspected cancer will be performed at the discretion of the treating physician, regardless of CLOVER result.
Model performance and bias assessment:
The external validation will evaluate model discrimination using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the area under the ROC curve (AUC). Additional analyses will assess potential prediction bias across demographic and clinical subgroups (e.g., age, sex, comorbidities). Model calibration and temporal performance will also be reviewed, with predefined procedures for identifying deviations from expected behavior. Weekly reports during the prospective phase will alert investigators to performance drift or potential implementation issues in the web-based tool.
Clinician satisfaction:
A secondary objective is to evaluate clinician satisfaction with the CLOVER-Web tool. An online questionnaire specifically designed for this study will be administered to participating clinicians to assess usability, clarity, and clinical utility.
Ethical considerations:
The study follows the Declaration of Helsinki and Spanish regulations on biomedical research and data protection. Retrospective data collection will request exemption from informed consent due to the use of anonymized clinical information. Prospective participants will provide written or electronic informed consent. All data will be pseudonymized and stored securely.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 2 Years
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Prospective VTE Cohort | – | –Adults with objectively confirmed symptomatic venous thromboembolism (deep vein thrombosis and/or pulmonary embolism) consecutively enrolled from December 2025 to December 2027 in participating hospitals. All participants will undergo routine clinical evaluation, laboratory testing, and cancer screening according to standard practice. The CLOVER score will be calculated at baseline using the web-based tool (CLOVER-Web). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Adults (≥18 years) with objectively confirmed symptomatic venous thromboembolism (deep vein thrombosis or pulmonary embolism) who are consecutively recruited in participating hospitals in Spain. All participants undergo routine clinical evaluation, laboratory testing, and age- and sex-appropriate cancer screening according to standard practice. The population represents real-world patients with new-onset VTE without known or suspected cancer at baseline.
Key inclusion criteria (3 listed)
- Age ≥18 years.
- Objectively confirmed acute symptomatic venous thromboembolism (deep vein thrombosis and/or pulmonary embolism).
- Ability to provide written or electronic informed consent.
Key exclusion criteria (3 listed)
- Suspicion of cancer during the initial diagnostic evaluation for VTE.
- Participation in another interventional study that may interfere with outcomes.
- Inability or refusal to provide informed consent.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Detection of occult cancer within 24 months
Time frame: 24 months
Proportion of participants with a histologically confirmed diagnosis of occult cancer identified between 1 and 24 months after the index venous thromboembolism (VTE) event. Occult cancer is defined as a new cancer diagnosis not clinically evident at the time of VTE diagnosis
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Dec 2025.
- Background: PubMed 39859000Franco-Moreno A, Madronal-Cerezo E, de Ancos-Aracil CL, Farfan-Sedano AI, Munoz-Rivas N, Bascunana Morejon-Giron J, Ruiz-Giardin JM, Alvarez-Rodriguez F, Prada-Alonso J, Gala-Garcia Y, Casado-Suela MA, Bustamante-Fermosel A, Alfaro-Fernandez N, Torres-Macho J; CLOVER Research Group. Development of a Predictive Model of Occult Cancer After a Venous Thromboembolism Event Using Machine Learning: The CLOVER Study. Medicina (Kaunas). 2024 Dec 27;61(1):18. doi: 10.3390/medicina61010018.
- Individual participant dataSharing planned: Yes. De-identified individual participant data (IPD) will be shared, including baseline characteristics, clinical variables, imaging results, and outcomes related to occult cancer detection. Data will be made available to qualified investigators upon reasonable request and after signing a data sharing agreement ensuring confidentiality and appropriate use. IPD will be available beginning 12 months after study completion and will remain accessible for 5 years. Access to IPD will be granted to qualified researchers with a methodologically sound research proposal. Requests must be submitted to the study's coordinating center and will be evaluated by the principal investigators. A data use agreement will be required before any data transfer. Data will be hosted on the HORUS-ML secure research platform (restricted access).
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Anabel Franco-Moreno, MD, PhD principal investigator
Hospital Universitario Infanta Leonor
Franco-Moreno, MD, PhD principal investigator
Hospital Universitario Infanta Leonor
12 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Venous Thromboembolism (VTE) and Occult Cancer, run by Infanta Leonor University Hospital at 12 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 30 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Anabel Franco Moreno, MD, PhD (+34686102661, afranco278@hotmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Detection of occult cancer within 24 months (time frame: 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07310693, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Dec 2025.