Colorectal Cancer MetastaticPhase 3PROTINCOLNCT05625932
TINzaparin Prophylaxis in Patients With Metastatic Colorectal Cancer
A Phase 3 study testing Tinzaparin in people with Colorectal Cancer Metastatic and Thromboembolism, run by Galician Research Group on Digestive Tumors at 35 sites in Spain.
Trial summary
Patients with metastatic colorectal cancer (mCRC) who are scheduled to receive systemic cancer therapy have an increased risk for venous thromboembolic (VTE) events compared with the general population. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colorectal Cancer Metastatic, Thromboembolism
- What is being tested?
- Tinzaparin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 232 participants
- Where
- 35 sitesSpain
- Study dates
- 2 Mar 2023to 4 Jun 2025
- Phase
- Phase 3
- Are there results?
- None posted in the registry
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
Who may be able to join
- Male or female subjects with age ≥ 18 years.
- Written informed consent.
- Patients with a histologically confirmed diagnosis of stage IV colon or rectal adenocarcinoma (mCRC).
- Locally assessed BRAF and RAS genomic alterations available during screening.
- Beginning of the first line of treatment for metastatic disease with chemotherapy +/- targeted therapy (i.e. antiangiogenic, anti-EGFR, encorafenib-cetuximab doublet) or immunotherapy.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
- Life expectancy >6 months.
Who cannot join
- Contraindication to tinzaparin, or other heparins:
- Allergy (or hypersensitivity) to heparin, tinzaparin, other LMWHs, or pork products.
- History or presence of heparin-induced (type II) thrombocytopenia.
- Have or have had an epidural catheter or a traumatic spinal puncture within the previous 7 days.
- Prothrombin time (PT) (International normalized ratio [INR] >1.5 for any reason) or aPTT >2 times control value.
- Active major bleeding or conditions predisposing to major bleeding. a major bleeding is defined as one that meets one of the following three criteria:
Show all 26Show fewer
- occurring in a critical area or organ (for example, intracranial, intra-spinal, intraocular, retroperitoneal, intra-articular or pericardial, intrauterine or intramuscular with compartment syndrome),
- causing a decrease in hemoglobin levels of 2 g/l (1.24 mmol/l) or more, or that requires a transfusion of two or more units of whole blood or packed red blood cells.
- Lesions or conditions at increased risk of clinically significant bleeding, including:
- Previously diagnosed/treated VTE ≤ 28 days prior to randomization.
- Active ulcer disease.
- Diagnosed cerebral metastases.
- Stroke within the prior 6 months.
- History of central nervous system (CNS) or intraocular bleeding.
- Requirement of other anticoagulant therapy, dual antiplatelet therapy, daily non-steroidal anti-inflammatory drugs, or other medications known to increase the risk of bleeding.
- Note: A daily dose of ≤100 mg of aspirin and single agent clopidogrel are permitted
- Acute or chronic renal insufficiency with Creatinine clearance < 30 ml / min.
- Platelet count < 80.000 /ml at the time of inclusion.
- Severe liver insufficiency as defined by clinical manifestations of ascites, cirrhosis, encephalopathy and/or jaundice and/or biochemical abnormalities in liver function tests including:
- elevated levels of total bilirubin (> 2 times the upper limit normal [ULN]),
- elevated liver transaminases (> 2 times the ULN; > 5 in case of hepatic metastasis).
- Participating in another study of an investigational agent at the time of enrollment. Note: Use of an experimental regimen of an approved product is not cause for exclusion.
- Patients who weigh < 50 Kg.
- Women of childbearing potential (WOCBP), must provide a negative serum or urine pregnancy test at screening. Women breastfeeding are not eligible.
- Note: A pregnancy test is performed on WOCBP as per standard of care for patients undergoing anticancer treatments.
- Any underlying medical or psychiatric disorder, which, in the opinion of the investigator, makes the administration of tinzaparin unsafe or interferes with the informed consent process or trial procedures.
Trial locations and contacts
35 sites in 1 country.
35 sites in 1 country
Spain35 sites
Complejo Hospitalario Universitario de A Coruña (CHUAC)
A Coruña, 15006
Centro Oncológico de Galicia (A coruña)
A Coruña, 15009
Complejo Hospitalario Universitario de Ferrol ( Arquitecto Macide)
A Coruña, 15405
Hospital Universitario Príncipe de Asturias (HUPA) de Alcalá de Henares
Alcalá de Henares, Madrid, 28805
Hospital General La Mancha Centro
Alcázar de San Juan, Ciudad Real, 13600
Hospital Público Verge dels Lliris
Alcoy, Alicante, 03804
ICO (Institut Català d'Oncologia) de Badalona
Badalona, Barcelona, 08916
Hospital de la Santa Creu i Sant Pau
Barcelona, 08025
Hospital Clinic Barcelona
Barcelona, 08036
Hospital General Virgen de la Luz de Cuenca
Cuenca, 16002
Hospital Univ. de Jerez de la Frontera
Jerez de la Frontera, Cádiz, 11407
Institut Català d'Oncologia L'Hospitalet
L'Hospitalet de Llobregat, Barcelona, 08908
Hospital Universitario Arnau de Vilanova de Lleida
Lleida, 25198
Hospital Universitario Lucus Augusti
Lugo, 27003
Hospital Clinico San Carlos
Madrid, 28040
Hospital Universitario 12 de Octubre
Madrid, 28041
Hospital Costa del Sol de Marbella
Marbella, Málaga, 29603
Hospital Universitario De Móstoles
Móstoles, Madrid, 28935
Hospital General Universitario Morales Meseguer
Murcia, 30008
Complejo Hospitalario Universitario De Ourense
Ourense, 32005
Hospital Universitario Son Espases
Palma de Mallorca, Balearic Islands, 07120
Hospital Infanta Cristina (Parla)
Parla, Madrid, 28981
Complejo Hospitalario Universitario de Pontevedra
Pontevedra, 36071
Consorcio Corporación Sanitaria Parc Taulí
Sabadell, Barcelona, 08208
Complejo Asistencial Universitario De Salamanca
Salamanca, 37007
Hospital Universitario Marqués de Valdecilla
Santander, Cantabria, 39008
Hospital Clínico Universitario de Santiago CHUS
Santiago de Compostela, A Coruña, 15706
Hospital Universitario Virgen del Rocio
Seville, 41013
Hospital Obispo Polanco De Teruel
Teruel, Terul, 44002
Hospital General Universitario de Toledo
Toledo, 45007
Hospital Universitario Infanta Elena
Valdemoro, Madrid, 28342
Hospital General Universitario de Valencia
Valencia, 46014
Hospital Ribera Povisa
Vigo, 36211
Complejo Hospitalario Universitario de Vigo (Álvaro Cunqueiro)
Vigo, 36312
Complejo Asistencial de Zamora
Zamora, 49022
About this study
Official title: Prophylaxis of Venous Thromboembolic Disease With Low Molecular Weight (LMWH) (TINzaparin) in Patients With Metastatic Colorectal Cancer Who Start the First Line of Treatment.
Patients with metastatic colorectal cancer (mCRC) who are scheduled to receive systemic cancer therapy have an increased risk for venous thromboembolic (VTE) events compared with the general population.
PROTINCOL is a randomized, open label, non placebo-controlled, low intervention, and phase III clinical trial that will recruit patients with mCRC. The study hypothesizes that prophylaxis with Tinzaparin could prevent the appearance of symptomatic and incidental VTE.
Read more
All patients will receive the first-line anticancer treatment deemed more appropriate according to the physician criteria. Enrolled patients are randomized in a 1:1 ratio (stratifying by BRAF/RAS, resection of primary tumor, and anti-angiogenic first-line treatment) to: control arm (no interventions related to VTE risk and no placebo) or experimental arm (prophylactic Tinzaparin at a fixed dose of 4500 IU/day in patients with up to 80kg, 6000 IU/day for those between 80-100 kg, or 8000 IU/day for those >100kg). Treatment is scheduled for a maximum period of 4 months. Treatment could be stopped earlier in case of unacceptable toxicity, patient consent withdrawal, physician criteria or end of study. Patients will undergo tumor and VTE assessments according to standard clinical practice.
The main objective of the study is to evaluate the efficacy of tinzaparin for the prevention of symptomatic or incidental VTE events. Secondary objectives include the associations between VTE events and tumor characteristics (i.e. laterality, RAS/BRAF mutations) or management (i.e. surgery or treatment with anti-angiogenic or anti-EGFR agents), cancer-specific survival outcomes, safety, the incidence of bleeding events, and patient-reported quality of life. The trial includes also a translational exploratory analysis to assess the predictive value of risk assessment models and genetic risk scores, their evolution through the study and microsatellite instability or other biomarkers.
Read the detailed description
This research study is a prospective, randomized, open label (PROBE), non placebo-controlled, and phase III clinical trial; Investigator Initiated Study (IIS). The study has been considered a low-interventional clinical trial.
The trial will compare the efficacy and safety of tinzaparin with a watch and wait strategy for primary prophylaxis of symptomatic or incidental VTE in adult men and women, 18 years of age and older, with metastatic colorectal cancer who are scheduled to initiate systemic cancer therapy as a component of their standard of care anticancer regimen.
The study consists of 3 periods: a 4-week screening period, a 4 months treatment period and post-treatment follow-up period until the end of treatment (EOT) visit, scheduled 2 months after the last dose of tinzaparin or 6 months from the first dose of tinzaparin (whichever occurs latest). The duration of participation in the study for each subject is approximately 6 months. Further long-term phone follow-up to monitor for progression and survival could be carried out at the end of study. Tumor follow-up assessments will adhere to the standard clinical practice within each site.
All patients will receive the first-line anticancer treatment deemed more appropriate according to the physician criteria and current guideline recommendations. Patients in both groups will receive supportive care as per local practice. No formal recommendations will be issued by the study protocol regarding cancer treatment and supportive care, but the drugs used will be recorded in the clinical report form. Constitutive use of anticoagulant drugs will be prohibited during the treatment period.
Enrolled patients are randomized in a 1:1 ratio to the control arm, or the experimental arm:
Control arm: A watch and wait strategy will be used. There is no placebo. Since no reference treatment is available for long-term VTE prophylaxis in patients with cancer, patients in the control group will not receive VTE prophylaxis outside the hospital and will receive anticancer treatment and supportive care as per local practice. No formal recommendations will be issued by the study protocol regarding cancer treatment and supportive care, but the drugs used will be recorded in the clinical report form (CRF). Patients in the control group will receive antithrombotic prophylaxis as per local practice during hospitalizations. Any use of LMWH will be recorded in the CRF.
Experimental arm: Patients will receive prophylaxis tinzaparin at a fixed dose daily for 4 months.
The primary objective is to evaluate the efficacy of 4-months prophylaxis with tinzaparin for the prevention of symptomatic or incidental VTE events. Secondary efficacy objectives include the VTE incidence in specific subpopulations (stratification according to the laterality of the primary tumor, first-line treatment with anti-EGFR or antiangiogenics, and mutational status).
Safety of tinzaparin will be evaluated by means of relevant adverse events, incidence of bleedings according to International Society of Thrombosis and Hemostasis (ISTH) criteria, and patient-reported quality of life. Bleeding events will be evaluated locally by the investigator and centrally by a blinded committee.
- Conditions
- Colorectal Cancer Metastatic, Thromboembolism
- Being tested
- Tinzaparin
- Keywords
- LMWH, Prophylaxis, Thromboembolic event, Colorectal cancer
- Medical subject headings
- Thromboembolism, Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TinzaparinDrug
Also called Innohep
Patients < 80 kg will receive a fixed dose of 4500 IU daily. Patients between 80-100 kg will receive a fixed dose of 6000 IU daily. Patients > 100 kg will receive a fixed dose of 8000 IU daily.
| Study group | Role | What they receive |
|---|---|---|
| Control Arm | No intervention | Those patients allocated in the control arm will receive no interventions related to VTE risk. No placebo will be administered to avoid discomfort of these patients who are already under treatment for their cancer. |
| Experimental arm | Experimental | Those patients allocated to the experimental arm will receive prophylactic Tinzaparin at a fixed dose according to their weight:
Patients < 80 kg will receive a fixed dose of 4500 IU daily. Patients between 80-100 kg will receive a fixed dose of 6000 IU daily. Patients > 100 kg will receive a fixed dose of 8000 IU daily.
Accordingly, the effective dose of tinzaparin is estimated to be in the range of 56-90 IU/kg. Tinzaparin dose will be adjusted according to the dose levels specified above in patients who experience changes in body weight greater than 10% during treatment period. Receives: Drug: Tinzaparin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of any VTE
The primary efficacy endpoint is the cumulative incidence (percentage of patients) of any VTE event including:
Symptomatic non-fatal pulmonary thromboembolism (PE). Symptomatic lower-limb deep vein thromboembolism (sllDVT). Symptomatic upper extremity deep vein thromboembolism (sueDVT). Incidentally diagnosed PE or proximal DVT. Symptomatic central venous catheter thromboembolism. Incidentally visceral vein thrombosis (iVVT). Symptomatic visceral vein thrombosis (sVVT). VTE-related deaths
Measured: Throughout the study period, approximately 6 months per patient
Secondary outcomes (33)
Incidence of symptomatic non-fatal PE
Percentage of patients experiencing the event during the observation period (6 months)
Measured: Throughout the study period, approximately 6 months per patient
Incidence of sllDVT
Percentage of patients experiencing the event during the observation period (6 months)
Measured: Throughout the study period, approximately 6 months per patient
Incidence of sueDVT
Percentage of patients experiencing the event during the observation period (6 months)
Measured: Throughout the study period, approximately 6 months per patient
Incidence of incidentally diagnosed PE or proximal DVT
Percentage of patients experiencing the event during the observation period (6 months)
Measured: Throughout the study period, approximately 6 months per patient
Incidence of symptomatic central venous catheter thromboembolism
Percentage of patients experiencing the event during the observation period (6 months)
Measured: Throughout the study period, approximately 6 months per patient
Incidence of iVVT
Percentage of patients experiencing the event during the observation period (6 months)
Measured: Throughout the study period, approximately 6 months per patient
Incidence of sVVT
Percentage of patients experiencing the event during the observation period (6 months)
Measured: Throughout the study period, approximately 6 months per patient
Incidence of VTE-related deaths
Percentage of patients experiencing the event during the observation period (6 months)
Measured: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in BRAF/RAS mutated patients
Percentage of patients experiencing confirmed VTE events in patients with BRAF / RAS tumor genomic mutations vs native BRAF / RAS tumors.
Measured: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in resected or not resected patients
Percentage of patients experiencing confirmed VTE events in patients with primary tumor resection vs not resection.
Measured: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in patients with antiangiogenic therapy
Percentage of patients experiencing confirmed VTE events in patients on antiangiogenic treatment
Measured: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in patients with anti-EGFR therapy
Percentage of patients experiencing confirmed VTE events in patients on anti-EGFR treatment
Measured: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in patients according to tumor laterality
Percentage of patients experiencing confirmed VTE events in patients with right-side / transverse primary tumor vs left-side primary tumor.
Measured: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in patients according to progression (PD)
Percentage of patients experiencing confirmed VTE events in patients with PD according to usual clinical practice determined by the treating physician during treatment with tinzaparin
Measured: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in patients according genetic risk scores
Percentage of patients experiencing confirmed VTE events in patients according to their genetic risk score
Measured: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in patients according to blood type
Percentage of patients experiencing confirmed VTE events in patients according to their blood type
Measured: Throughout the study period, approximately 6 months per patient
Incidence of arterial thromboembolic events (ATE)
Percentage of patients experiencing ATE
Measured: Throughout the study period, approximately 6 months per patient
Thrombosis-free survival (TFS)
Defined as the time elapsed from the first dose of study treatment to the diagnosis of thrombotic event, or death from any cause, whichever occurs first
Measured: Throughout the study period, approximately 6 months per patient
Event-free survival (EFS)
Events are defined as the endpoint of mortality, major bleeding and VTE. EFS is defined as the time elapsed from the first dose of study treatment to the diagnosis of VTE event, major bleeding event, or death by any cause, whichever occurs first
Measured: Throughout the study period, approximately 6 months per patient
Progression-free survival (PFS)
Defined as the time elapsed from the first dose of study treatment to progression determined by the treating physician according to local standard clinical practice, or death from any cause, whichever occurs first
Measured: Throughout the study period, approximately 6 months per patient
Overall survival (OS)
Defined as the time elapsed from the first dose of study treatment until death from any cause
Measured: Throughout the study period, approximately 6 months per patient
Mortality rate
Percentage of patients who died through the study
Measured: Throughout the study period, approximately 2 years
Incidence of relevant adverse events (AE)
Percentage of patients who experience grade 3-5 according to CTCAE version 5.0
Measured: Throughout the study period, approximately 2 years
Incidence of treatment-related AEs (TRAEs)
Percentage of patients who experience TRAEs
Measured: Throughout the study period, approximately 2 years
Incidence of major bleeding (MB) events
Percentage of patients who experience MB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment
Measured: Throughout the study period, approximately 6 months per patient
Incidence of Clinically relevant non-major bleeding (CRNMB)
Percentage of patients who experience CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment
Measured: Throughout the study period, approximately 6 months per patient
Quality of life score
Patients reported outcomes through the EORTC quality of life questionnaire (QLQ)-C30 questionnaire. QLQ-C30 scale is a 28 items that are scored on a 4-point response scale. All scale scores are linearly converted to range from 0 to 100. For the functioning scales and global QOL higher scores indicate better functioning.
Measured: Throughout the study period, approximately 6 months per patient
Incidence of bleeding events in BRAF/RAS mutated patients
Percentage of patients who experienced a MB or CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment. Results will be reported according to BRAF/RAS mutational statu
Measured: Throughout the study period, approximately 6 months per patient
Incidence of bleeding events according to surgery
Percentage of patients who experienced a MB or CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment. Results will be reported according to previous surgery of the primary tumor
Measured: Throughout the study period, approximately 6 months per patient
Incidence of bleeding events according to antiangiogenic therapy
Percentage of patients who experienced a MB or CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment. Results will be reported according to first-line antiangiogenic agents treatment
Measured: Throughout the study period, approximately 6 months per patient
Incidence of bleeding events according to anti-EGFR therapy
Percentage of patients who experienced a MB or CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment. Results will be reported according to first-line anti-EGFR treatment
Measured: Throughout the study period, approximately 6 months per patient
Incidence of bleeding events according to tumor laterality
Percentage of patients who experienced a MB or CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment. Results will be reported in patients with right-sided or transversal vs. left-sided primary tumor
Measured: Throughout the study period, approximately 6 months per patient
Incidence of bleeding events according to genetic risk
Percentage of patients who experienced a MB or CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment. Results will be reported in patients according to their genetic risk score
Measured: Throughout the study period, approximately 6 months per patient
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Nov 2022
- Study start2 Mar 2023
- Primary completion4 Jun 2025
- Study completion4 Jun 2025
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 Colorectal Cancer MetastaticStudies 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
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Two-arm, randomized, non-placebo controlled, open-label
- Masking
- None (open label)
- Enrolment
- 232 participants (actual)
Sponsor and investigators
- Lead sponsor
- Galician Research Group on Digestive Tumors
- Sponsor type
- University, hospital or other
- Collaborators
- LEO Pharma
- Responsible party
- Sponsor
- Investigators
- Mercedes Salgado, M.D. Ph.D., Study chair, Complexo Hospitalario Universitario de Ourense (Galicia)Andrés Muñoz, M.D. Ph.D., Study chair, Hospital Universitario Gregorio Marañón (Madrid)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05625932
- Sponsor's protocol ID
- GIT-PRo-2022-02
- Other IDs
- 2022-001534-11
- Acronym
- PROTINCOL
- Status last verified
- Aug 2025
- First submitted
- 15 Nov 2022
- Last updated
- 22 Aug 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Anonymized individual participant data (IPD) may be available upon request if it is within the same scope approved by the participants when they gave their written informed consent to participate
Publications
Salgado M, de la Camara-Gomez J, Garcia-Escobar I, Alvarez-Llosa RC, Gonzalez-Villarroel P, Garay DF, Pampols-Felip M, Guillot-Morales M, Pelegrin-Mateo FJ, Jimenez-Orozco E, Sastre J, de Castro EM, Coma E, Bouzas LP, Ferrer-Perez AI, Momprade-Olive E, Cousillas-Castineiras A, Covela-Rua M, Rojas M, Querol R, Diaz LR, Merino M, Gil M, Sanchez-Canovas M, Elias T, Marrupe-Gonzalez D, Sanchez-Gil B, Carmona-Campos M, Garcia-Ferron M, Soria JM, Munoz A. Tinzaparin for the prevention of thromboembolic events in ambulatory patients with metastatic colorectal cancer receiving first line treatment: a randomised, clinical trial design. BMC Cancer. 2025 Nov 17;25(1):1773. doi: 10.1186/s12885-025-14620-z.
PubMed 41249955
Study at a glance
From the registry record, last updated by the sponsor on 22 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prophylaxis of Venous Thromboembolic Disease With Low Molecular Weight (LMWH) (TINzaparin) in Patients With Metastatic Colorectal Cancer Who Start the First Line of Treatment.
- ClinicalTrials.gov ID
- NCT05625932
- Acronym / sponsor ID
- PROTINCOL / GIT-PRo-2022-02
- Conditions
- Colorectal Cancer Metastatic, Thromboembolism
- Keywords
- LMWH, Prophylaxis, Thromboembolic event, Colorectal cancer
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 232 participants (actual)
- Lead sponsor
- Galician Research Group on Digestive TumorsUniversity, hospital or other
- Collaborators
- LEO Pharma
- Study start
- 2 Mar 2023 (actual)
- Primary completion
- 4 Jun 2025 (actual)
- Study completion
- 4 Jun 2025 (actual)
- First posted
- 23 Nov 2022 (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.
Patients with metastatic colorectal cancer (mCRC) who are scheduled to receive systemic cancer therapy have an increased risk for venous thromboembolic (VTE) events compared with the general population.
PROTINCOL is a randomized, open label, non placebo-controlled, low intervention, and phase III clinical trial that will recruit patients with mCRC. The study hypothesizes that prophylaxis with Tinzaparin could prevent the appearance of symptomatic and incidental VTE.
All patients will receive the first-line anticancer treatment deemed more appropriate according to the physician criteria. Enrolled patients are randomized in a 1:1 ratio (stratifying by BRAF/RAS, resection of primary tumor, and anti-angiogenic first-line treatment) to: control arm (no interventions related to VTE risk and no placebo) or experimental arm (prophylactic Tinzaparin at a fixed dose of 4500 IU/day in patients with up to 80kg, 6000 IU/day for those between 80-100 kg, or 8000 IU/day for those >100kg). Treatment is scheduled for a maximum period of 4 months. Treatment could be stopped earlier in case of unacceptable toxicity, patient consent withdrawal, physician criteria or end of study. Patients will undergo tumor and VTE assessments according to standard clinical practice.
The main objective of the study is to evaluate the efficacy of tinzaparin for the prevention of symptomatic or incidental VTE events. Secondary objectives include the associations between VTE events and tumor characteristics (i.e. laterality, RAS/BRAF mutations) or management (i.e. surgery or treatment with anti-angiogenic or anti-EGFR agents), cancer-specific survival outcomes, safety, the incidence of bleeding events, and patient-reported quality of life. The trial includes also a translational exploratory analysis to assess the predictive value of risk assessment models and genetic risk scores, their evolution through the study and microsatellite instability or other biomarkers.
Detailed description
This research study is a prospective, randomized, open label (PROBE), non placebo-controlled, and phase III clinical trial; Investigator Initiated Study (IIS). The study has been considered a low-interventional clinical trial.
The trial will compare the efficacy and safety of tinzaparin with a watch and wait strategy for primary prophylaxis of symptomatic or incidental VTE in adult men and women, 18 years of age and older, with metastatic colorectal cancer who are scheduled to initiate systemic cancer therapy as a component of their standard of care anticancer regimen.
The study consists of 3 periods: a 4-week screening period, a 4 months treatment period and post-treatment follow-up period until the end of treatment (EOT) visit, scheduled 2 months after the last dose of tinzaparin or 6 months from the first dose of tinzaparin (whichever occurs latest). The duration of participation in the study for each subject is approximately 6 months. Further long-term phone follow-up to monitor for progression and survival could be carried out at the end of study. Tumor follow-up assessments will adhere to the standard clinical practice within each site.
All patients will receive the first-line anticancer treatment deemed more appropriate according to the physician criteria and current guideline recommendations. Patients in both groups will receive supportive care as per local practice. No formal recommendations will be issued by the study protocol regarding cancer treatment and supportive care, but the drugs used will be recorded in the clinical report form. Constitutive use of anticoagulant drugs will be prohibited during the treatment period.
Enrolled patients are randomized in a 1:1 ratio to the control arm, or the experimental arm:
Control arm: A watch and wait strategy will be used. There is no placebo. Since no reference treatment is available for long-term VTE prophylaxis in patients with cancer, patients in the control group will not receive VTE prophylaxis outside the hospital and will receive anticancer treatment and supportive care as per local practice. No formal recommendations will be issued by the study protocol regarding cancer treatment and supportive care, but the drugs used will be recorded in the clinical report form (CRF). Patients in the control group will receive antithrombotic prophylaxis as per local practice during hospitalizations. Any use of LMWH will be recorded in the CRF.
Experimental arm: Patients will receive prophylaxis tinzaparin at a fixed dose daily for 4 months.
The primary objective is to evaluate the efficacy of 4-months prophylaxis with tinzaparin for the prevention of symptomatic or incidental VTE events. Secondary efficacy objectives include the VTE incidence in specific subpopulations (stratification according to the laterality of the primary tumor, first-line treatment with anti-EGFR or antiangiogenics, and mutational status).
Safety of tinzaparin will be evaluated by means of relevant adverse events, incidence of bleedings according to International Society of Thrombosis and Hemostasis (ISTH) criteria, and patient-reported quality of life. Bleeding events will be evaluated locally by the investigator and centrally by a blinded committee.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Two-arm, randomized, non-placebo controlled, open-label
| Arm | Type | Receives |
|---|---|---|
| Control Arm | No intervention | –Those patients allocated in the control arm will receive no interventions related to VTE risk. No placebo will be administered to avoid discomfort of these patients who are already under treatment for their cancer. |
| Experimental arm | Experimental | Drug: TinzaparinThose patients allocated to the experimental arm will receive prophylactic Tinzaparin at a fixed dose according to their weight: Patients < 80 kg will receive a fixed dose of 4500 IU daily. Patients between 80-100 kg will receive a fixed dose of 6000 IU daily. Patients > 100 kg will receive a fixed dose of 8000 IU daily. Accordingly, the effective dose of tinzaparin is estimated to be in the range of 56-90 IU/kg. Tinzaparin dose will be adjusted according to the dose levels specified above in patients who experience changes in body weight greater than 10% during treatment period. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Male or female subjects with age ≥ 18 years.
- Written informed consent.
- Patients with a histologically confirmed diagnosis of stage IV colon or rectal adenocarcinoma (mCRC).
- Locally assessed BRAF and RAS genomic alterations available during screening.
- Beginning of the first line of treatment for metastatic disease with chemotherapy +/- targeted therapy (i.e. antiangiogenic, anti-EGFR, encorafenib-cetuximab doublet) or immunotherapy.
Key exclusion criteria (26 listed)
- Contraindication to tinzaparin, or other heparins:
- Prothrombin time (PT) (International normalized ratio [INR] >1.5 for any reason) or aPTT >2 times control value.
- Active major bleeding or conditions predisposing to major bleeding. a major bleeding is defined as one that meets one of the following three criteria:
- Lesions or conditions at increased risk of clinically significant bleeding, including:
- Requirement of other anticoagulant therapy, dual antiplatelet therapy, daily non-steroidal anti-inflammatory drugs, or other medications known to increase the risk of bleeding.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TinzaparinAlso: InnohepPatients < 80 kg will receive a fixed dose of 4500 IU daily. Patients between 80-100 kg will receive a fixed dose of 6000 IU daily. Patients > 100 kg will receive a fixed dose of 8000 IU daily. | Drug | Experimental arm |
Primary outcome
Incidence of any VTE
Time frame: Throughout the study period, approximately 6 months per patient
The primary efficacy endpoint is the cumulative incidence (percentage of patients) of any VTE event including: Symptomatic non-fatal pulmonary thromboembolism (PE). Symptomatic lower-limb deep vein thromboembolism (sllDVT). Symptomatic upper extremity deep vein thromboembolism (sueDVT). Incidentally diagnosed PE or proximal DVT. Symptomatic central venous catheter thromboembolism. Incidentally visceral vein thrombosis (iVVT). Symptomatic visceral vein thrombosis (sVVT). VTE-related deaths
33 secondary outcomes
Incidence of symptomatic non-fatal PE
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of sllDVT
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of sueDVT
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of incidentally diagnosed PE or proximal DVT
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of symptomatic central venous catheter thromboembolism
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of iVVT
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of sVVT
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of VTE-related deaths
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in BRAF/RAS mutated patients
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in resected or not resected patients
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in patients with antiangiogenic therapy
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in patients with anti-EGFR therapy
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in patients according to tumor laterality
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in patients according to progression (PD)
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in patients according genetic risk scores
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of confirmed VTE events in patients according to blood type
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of arterial thromboembolic events (ATE)
Time frame: Throughout the study period, approximately 6 months per patient
Thrombosis-free survival (TFS)
Time frame: Throughout the study period, approximately 6 months per patient
Event-free survival (EFS)
Time frame: Throughout the study period, approximately 6 months per patient
Progression-free survival (PFS)
Time frame: Throughout the study period, approximately 6 months per patient
Overall survival (OS)
Time frame: Throughout the study period, approximately 6 months per patient
Mortality rate
Time frame: Throughout the study period, approximately 2 years
Incidence of relevant adverse events (AE)
Time frame: Throughout the study period, approximately 2 years
Incidence of treatment-related AEs (TRAEs)
Time frame: Throughout the study period, approximately 2 years
Incidence of major bleeding (MB) events
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of Clinically relevant non-major bleeding (CRNMB)
Time frame: Throughout the study period, approximately 6 months per patient
Quality of life score
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of bleeding events in BRAF/RAS mutated patients
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of bleeding events according to surgery
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of bleeding events according to antiangiogenic therapy
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of bleeding events according to anti-EGFR therapy
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of bleeding events according to tumor laterality
Time frame: Throughout the study period, approximately 6 months per patient
Incidence of bleeding events according to genetic risk
Time frame: Throughout the study period, approximately 6 months per patient
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Aug 2025.
- Derived from this study: PubMed 41249955Salgado M, de la Camara-Gomez J, Garcia-Escobar I, Alvarez-Llosa RC, Gonzalez-Villarroel P, Garay DF, Pampols-Felip M, Guillot-Morales M, Pelegrin-Mateo FJ, Jimenez-Orozco E, Sastre J, de Castro EM, Coma E, Bouzas LP, Ferrer-Perez AI, Momprade-Olive E, Cousillas-Castineiras A, Covela-Rua M, Rojas M, Querol R, Diaz LR, Merino M, Gil M, Sanchez-Canovas M, Elias T, Marrupe-Gonzalez D, Sanchez-Gil B, Carmona-Campos M, Garcia-Ferron M, Soria JM, Munoz A. Tinzaparin for the prevention of thromboembolic events in ambulatory patients with metastatic colorectal cancer receiving first line treatment: a randomised, clinical trial design. BMC Cancer. 2025 Nov 17;25(1):1773. doi: 10.1186/s12885-025-14620-z.
- Individual participant dataSharing planned: No. Anonymized individual participant data (IPD) may be available upon request if it is within the same scope approved by the participants when they gave their written informed consent to participate
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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. This study is not recruiting at the moment.
Mercedes Salgado, M.D. Ph.D. study chair
Complexo Hospitalario Universitario de Ourense (Galicia)
Andrés Muñoz, M.D. Ph.D. study chair
Hospital Universitario Gregorio Marañón (Madrid)
35 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Tinzaparin in people with Colorectal Cancer Metastatic and Thromboembolism, run by Galician Research Group on Digestive Tumors at 35 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 7 inclusion and 26 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: finished, as of the sponsor's last update on 22 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 35 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.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of any VTE (time frame: Throughout the study period, approximately 6 months per patient). 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 NCT05625932, 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 22 Aug 2025.