TINzaparin Prophylaxis in Patients With Metastatic Colorectal Cancer

NCT05625932 | Completed Phase 3

• 2 other identifiers: GIT-PRo-2022-022022-001534-11
• Study Type: interventional
• Target: 232
• Locations: 1 country
• Sites: 35

Brief 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. 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.

Conditions

Colorectal Cancer Metastatic; Thromboembolism

Keywords

LMWH; Prophylaxis; Thromboembolic event; Colorectal cancer

Outcome Measures

Primary Outcomes (1)

• 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

  Throughout the study period, approximately 6 months per patient

Secondary Outcomes (33)

• Incidence of symptomatic non-fatal PE

  Throughout the study period, approximately 6 months per patient

• Incidence of sllDVT

  Throughout the study period, approximately 6 months per patient

• Incidence of sueDVT

  Throughout the study period, approximately 6 months per patient

• Incidence of incidentally diagnosed PE or proximal DVT

  Throughout the study period, approximately 6 months per patient

• Incidence of symptomatic central venous catheter thromboembolism

  Throughout the study period, approximately 6 months per patient

Study Arms (2)

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.

Drug: Tinzaparin

Interventions

Tinzaparin DRUG

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.

Also known as: Innohep

Experimental arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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:
• 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.

Sponsors & Collaborators

• Galician Research Group on Digestive Tumors: lead
• LEO Pharma: collaborator

Study Sites (35)

Hospital Clínico Universitario de Santiago CHUS

Santiago de Compostela, A Coruña, 15706, Spain

Location

Hospital Público Verge dels Lliris

Alcoy, Alicante, 03804, Spain

Location

Hospital Universitario Son Espases

Palma de Mallorca, Balearic Islands, 07120, Spain

Location

ICO (Institut Català d'Oncologia) de Badalona

Badalona, Barcelona, 08916, Spain

Location

Institut Català d'Oncologia L'Hospitalet

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

Location

Consorcio Corporación Sanitaria Parc Taulí

Sabadell, Barcelona, 08208, Spain

Location

Hospital Universitario Marqués de Valdecilla

Santander, Cantabria, 39008, Spain

Location

Hospital General La Mancha Centro

Alcázar de San Juan, Ciudad Real, 13600, Spain

Location

Hospital Univ. de Jerez de la Frontera

Jerez de la Frontera, Cádiz, 11407, Spain

Location

Hospital Universitario Príncipe de Asturias (HUPA) de Alcalá de Henares

Alcalá de Henares, Madrid, 28805, Spain

Location

Hospital Universitario De Móstoles

Móstoles, Madrid, 28935, Spain

Location

Hospital Infanta Cristina (Parla)

Parla, Madrid, 28981, Spain

Location

Hospital Universitario Infanta Elena

Valdemoro, Madrid, 28342, Spain

Location

Hospital Costa del Sol de Marbella

Marbella, Málaga, 29603, Spain

Location

Hospital Obispo Polanco De Teruel

Teruel, Terul, 44002, Spain

Location

Complejo Hospitalario Universitario de A Coruña (CHUAC)

A Coruña, 15006, Spain

Location

Centro Oncológico de Galicia (A coruña)

A Coruña, 15009, Spain

Location

Complejo Hospitalario Universitario de Ferrol ( Arquitecto Macide)

A Coruña, 15405, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08025, Spain

Location

Hospital Clinic Barcelona

Barcelona, 08036, Spain

Location

Hospital General Virgen de la Luz de Cuenca

Cuenca, 16002, Spain

Location

Hospital Universitario Arnau de Vilanova de Lleida

Lleida, 25198, Spain

Location

Hospital Universitario Lucus Augusti

Lugo, 27003, Spain

Location

Hospital Clinico San Carlos

Madrid, 28040, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital General Universitario Morales Meseguer

Murcia, 30008, Spain

Location

Complejo Hospitalario Universitario De Ourense

Ourense, 32005, Spain

Location

Complejo Hospitalario Universitario de Pontevedra

Pontevedra, 36071, Spain

Location

Complejo Asistencial Universitario De Salamanca

Salamanca, 37007, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, 41013, Spain

Location

Hospital General Universitario de Toledo

Toledo, 45007, Spain

Location

Hospital General Universitario de Valencia

Valencia, 46014, Spain

Location

Hospital Ribera Povisa

Vigo, 36211, Spain

Location

Complejo Hospitalario Universitario de Vigo (Álvaro Cunqueiro)

Vigo, 36312, Spain

Location

Complejo Asistencial de Zamora

Zamora, 49022, Spain

Location

Related Publications (1)

• 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.

  PMID: 41249955 DERIVED

MeSH Terms

Conditions

Thromboembolism; Colorectal Neoplasms

Interventions

Tinzaparin

Condition Hierarchy (Ancestors)

Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Heparin, Low-Molecular-Weight; Heparin; Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Officials

• Mercedes Salgado, M.D. Ph.D.

  Complexo Hospitalario Universitario de Ourense (Galicia)

  STUDY CHAIR

• Andrés Muñoz, M.D. Ph.D.

  Hospital Universitario Gregorio Marañón (Madrid)

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Two-arm, randomized, non-placebo controlled, open-label

Study Record Dates

• First Submitted: November 15, 2022
• First Posted: November 23, 2022
• Study Start: March 2, 2023
• Primary Completion: June 4, 2025
• Study Completion: June 4, 2025
• Last Updated: August 22, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

ES (35)