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Extended Peri-operative Tinzaparin to Improve Disease-free Survival in Patients With Resectable Colorectal Cancer (PERIOP-01)

Primary Purpose

Adenocarcinoma of the Colon

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Tinzaparin
Tinzaparin
Sponsored by
Ottawa Hospital Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Adenocarcinoma of the Colon

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Diagnosis of pathologically-confirmed invasive adenocarcinoma of the colon or rectum
  2. Pre-operative work-up that reveals potential resectability (CT scan or MRI of the abdomen and pelvis) with resection planned within 6 weeks of date of randomization
  3. Pre-operative work-up that reveals no evidence of metastatic disease (CT scan or MRI of the abdomen and pelvis and chest X-ray (CXR) or CT scan of the chest)
  4. Age ≥18 years
  5. Hemoglobin ≥ 80g/L
  6. Able and willing to comply with study procedures and follow-up examinations contained within the written consent form.

Exclusion Criteria:

  1. Carcinoma only present in a completely excised polyp (i.e. no residual tumour evident in the colon)
  2. Prior VTE including deep vein thrombosis (DVT) or pulmonary embolism (PE)
  3. Requirement for full dose peri-operative anticoagulation

  4. Contraindication to heparin therapy

    1. history of heparin induced thrombocytopenia (HIT)
    2. platelet count of less than 100 x 109/L
    3. actively bleeding
    4. severe hypertension (SBP >200 and/or DBP >120) on more than one reading
    5. documented peptic ulcer within 6 weeks
    6. severe hepatic failure (INR >1.8)
    7. creatinine clearance of < 30 ml/min as calculated by the Cockcroft-Gault formula
    8. Other contraindication to anticoagulation
  5. Participating in another interventional trial that may result in co-intervention or contamination (to be determined by sponsor)
  6. History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within 5 years of the colorectal cancer diagnosis
  7. Pregnant or lactating
  8. Unable/unwilling to providing informed consent.

Sites / Locations

  • Ghent University Hospital
  • Hamilton Health Sciences Corporation
  • Kingston General Hospital
  • London Health Research Institute
  • The Ottawa Hospital
  • Montfort Hospital
  • Queensway Carleton Hospital
  • Sault Area Hospital
  • Health Sciences North
  • Humber River Hospital
  • Mount Sinai Hospital
  • North York General Hospital
  • St. Joseph's Health Centre
  • Sunnybrook Health Science Centre
  • Jewish General Hospital
  • CHRU Brest

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Extended peri-operative thromboprophylaxis

Standard thromboprophylaxis

Arm Description

The experimental arm will receive a subcutaneous injection of 4,500 IU of tinzaparin daily beginning at randomization and continued for 56 days following resection. There will be a minimum of one dose of pre-operative LMWH since it is not reasonable to delay surgery for the purpose of administering LMWH. The maximum duration of pre-operative LMWH will be 6 weeks.

The control arm will receive a daily subcutaneous injection of 4,500 IU of tinzaparin beginning with the first post-operative dose and continued for the duration of hospitalization.

Outcomes

Primary Outcome Measures

Disease Free Survival
Disease free survival is measured from the time of randomization until local disease recurrence, distant disease recurrence, a new primary colon cancer malignancy, other second primary cancer or death from any cause.

Secondary Outcome Measures

Overall Survival
Death from any cause
Venous Thromboembolism events
• VTE events defined as: a. Deep vein thrombosis: i. non-compressibility of any vein segment from the common femoral vein to the trifurcation of the popliteal vein on compressive ultrasonography ii.persistent intra-luminal filling defect of the iliac, common femoral, superficial femoral, popliteal, posterior tibial or peroneal veins on contrast venography b. Pulmonary embolism: i.high probability V/Q scan ii.positive pulmonary angiogram iii.spiral CT demonstrating intraluminal filling defect in a vessel larger than a segmental artery
Major surgical site bleeding events
• Major surgical site bleeding events defined as bleeding at the surgical site associated with: requirement for ≥4 units of packed red blood cells a drop in Hb of >40 g/L during the first post-op week bleeding requiring re-operation fatal bleeding
Major bleeding events (not including the surgical site)
• Major bleeding events (not including the surgical site) defined as: fatal bleeding, and/or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or, bleeding causing a fall in hemoglobin level of ≥20 g/L, or leading to transfusion of ≥2 units of whole blood or red cells.
• Clinically relevant bleeding events prior to surgery and during the • Clinically relevant bleeding events
Clinically relevant bleeding events prior to surgery and during the follow-up period will be defined as overt bleeding episodes not meeting the inclusion for major bleeding but associated with one of the following: medical intervention; an unscheduled contact with a physician; temporary cessation of anticoagulant treatment
Transfusion requirements
Transfusion requirements using the number of units transfused: Red blood cells Platelets (Adult dose) Frozen Plasma
Correlative endpoints
The correlative endpoints seek to evaluate the pro-metastatic mechanisms of surgery and the antimetastatic mechanisms of LMWH in subjects undergoing surgical resection for colon cancer.
Other post-operative (day 0 - day 28) complications
Other post-operative (day 0 - day 28) complications as defined using the modified Clavien Classification

Full Information

First Posted
October 18, 2011
Last Updated
May 14, 2021
Sponsor
Ottawa Hospital Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT01455831
Brief Title
Extended Peri-operative Tinzaparin to Improve Disease-free Survival in Patients With Resectable Colorectal Cancer
Acronym
PERIOP-01
Official Title
A Multicentre Randomized Controlled Trial of the Use of Extended Peri-Operative Low Molecular Weight Heparin to Improve Cancer Specific Survival Following Surgical Resection of Colorectal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
May 2021
Overall Recruitment Status
Completed
Study Start Date
September 2011 (undefined)
Primary Completion Date
December 31, 2020 (Actual)
Study Completion Date
February 1, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ottawa Hospital Research Institute

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The human body has a natural stress response to surgery, including the formation of blood clots. This response to surgery has been shown to increase metastases (the spread of cancer cells to other organs in the body). These metastases cannot be seen at the time of surgery but when they grow into new tumors, the cancer has recurred (come back). A blood thinner called "low molecular weight heparin" (LMWH) can suppress the development of metastases after surgery in animal experiments. The investigators want to see if giving patients with colorectal cancer the blood thinner, LMWH, around the time of surgery can decrease the chance of their cancer spreading to other organs (metastases) and coming back (recurrence). The investigators need 1075 patients to answer our scientific question. Patients who give informed consent will be randomly put into one of two groups, the experimental group and the control group. The patients in the control group will be treated with LMWH starting a few hours after surgery and every day until they leave the hospital. This is how most patients are treated after colon cancer surgery (standard care). The patients in the experimental group will be treated with LMWH for a longer period of time, starting on the day they agree to have surgery and continuing for two months after surgery. All the patients will be followed for at least three years after surgery to find out if their cancer has recurred (come back). If LMWH treatment around the time of surgery reduces the chance of recurrence in patients with colorectal cancer, it would improve the health and quality of life for these patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adenocarcinoma of the Colon

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
616 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Extended peri-operative thromboprophylaxis
Arm Type
Experimental
Arm Description
The experimental arm will receive a subcutaneous injection of 4,500 IU of tinzaparin daily beginning at randomization and continued for 56 days following resection. There will be a minimum of one dose of pre-operative LMWH since it is not reasonable to delay surgery for the purpose of administering LMWH. The maximum duration of pre-operative LMWH will be 6 weeks.
Arm Title
Standard thromboprophylaxis
Arm Type
Active Comparator
Arm Description
The control arm will receive a daily subcutaneous injection of 4,500 IU of tinzaparin beginning with the first post-operative dose and continued for the duration of hospitalization.
Intervention Type
Drug
Intervention Name(s)
Tinzaparin
Other Intervention Name(s)
Innohep
Intervention Description
The experimental arm will receive a subcutaneous injection of 4,500 IU of tinzaparin daily beginning at randomization and continued for 56 days following resection. There will be a minimum of one dose of pre-operative LMWH since it is not reasonable to delay surgery for the purpose of administering LMWH. The maximum duration of pre-operative LMWH will be 6 weeks.
Intervention Type
Drug
Intervention Name(s)
Tinzaparin
Other Intervention Name(s)
Innohep
Intervention Description
The control arm will receive a daily subcutaneous injection of 4,500 IU of tinzaparin beginning with the first post-operative dose and continued for the duration of hospitalization.
Primary Outcome Measure Information:
Title
Disease Free Survival
Description
Disease free survival is measured from the time of randomization until local disease recurrence, distant disease recurrence, a new primary colon cancer malignancy, other second primary cancer or death from any cause.
Time Frame
measured at 3 years
Secondary Outcome Measure Information:
Title
Overall Survival
Description
Death from any cause
Time Frame
measured at 5 years
Title
Venous Thromboembolism events
Description
• VTE events defined as: a. Deep vein thrombosis: i. non-compressibility of any vein segment from the common femoral vein to the trifurcation of the popliteal vein on compressive ultrasonography ii.persistent intra-luminal filling defect of the iliac, common femoral, superficial femoral, popliteal, posterior tibial or peroneal veins on contrast venography b. Pulmonary embolism: i.high probability V/Q scan ii.positive pulmonary angiogram iii.spiral CT demonstrating intraluminal filling defect in a vessel larger than a segmental artery
Time Frame
From randomization until 56 days post-surgery
Title
Major surgical site bleeding events
Description
• Major surgical site bleeding events defined as bleeding at the surgical site associated with: requirement for ≥4 units of packed red blood cells a drop in Hb of >40 g/L during the first post-op week bleeding requiring re-operation fatal bleeding
Time Frame
From randomization until 56 days post-surgery
Title
Major bleeding events (not including the surgical site)
Description
• Major bleeding events (not including the surgical site) defined as: fatal bleeding, and/or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or, bleeding causing a fall in hemoglobin level of ≥20 g/L, or leading to transfusion of ≥2 units of whole blood or red cells.
Time Frame
From randomization until 56 days post-surgery
Title
• Clinically relevant bleeding events prior to surgery and during the • Clinically relevant bleeding events
Description
Clinically relevant bleeding events prior to surgery and during the follow-up period will be defined as overt bleeding episodes not meeting the inclusion for major bleeding but associated with one of the following: medical intervention; an unscheduled contact with a physician; temporary cessation of anticoagulant treatment
Time Frame
From randomization to 56 days post-surgery
Title
Transfusion requirements
Description
Transfusion requirements using the number of units transfused: Red blood cells Platelets (Adult dose) Frozen Plasma
Time Frame
From randomization to 56 days post-surgery
Title
Correlative endpoints
Description
The correlative endpoints seek to evaluate the pro-metastatic mechanisms of surgery and the antimetastatic mechanisms of LMWH in subjects undergoing surgical resection for colon cancer.
Time Frame
5 years
Title
Other post-operative (day 0 - day 28) complications
Description
Other post-operative (day 0 - day 28) complications as defined using the modified Clavien Classification
Time Frame
Measured from Day 0 until day 28 post-operatively

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of pathologically-confirmed invasive adenocarcinoma of the colon or rectum Pre-operative work-up that reveals potential resectability (CT scan or MRI of the abdomen and pelvis) with resection planned within 6 weeks of date of randomization Pre-operative work-up that reveals no evidence of metastatic disease (CT scan or MRI of the abdomen and pelvis and chest X-ray (CXR) or CT scan of the chest) Age ≥18 years Hemoglobin ≥ 80g/L Able and willing to comply with study procedures and follow-up examinations contained within the written consent form. Exclusion Criteria: Carcinoma only present in a completely excised polyp (i.e. no residual tumour evident in the colon) Prior VTE including deep vein thrombosis (DVT) or pulmonary embolism (PE) Requirement for full dose peri-operative anticoagulation Contraindication to heparin therapy history of heparin induced thrombocytopenia (HIT) platelet count of less than 100 x 109/L actively bleeding severe hypertension (SBP >200 and/or DBP >120) on more than one reading documented peptic ulcer within 6 weeks severe hepatic failure (INR >1.8) creatinine clearance of < 30 ml/min as calculated by the Cockcroft-Gault formula Other contraindication to anticoagulation Participating in another interventional trial that may result in co-intervention or contamination (to be determined by sponsor) History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within 5 years of the colorectal cancer diagnosis Pregnant or lactating Unable/unwilling to providing informed consent.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marc Carrier, MD
Organizational Affiliation
Ottawa Hospital Research Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Rebecca Ann Auer, MD
Organizational Affiliation
Ottawa Hospital Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ghent University Hospital
City
Ghent
Country
Belgium
Facility Name
Hamilton Health Sciences Corporation
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8L 8E7
Country
Canada
Facility Name
Kingston General Hospital
City
Kingston
State/Province
Ontario
Country
Canada
Facility Name
London Health Research Institute
City
London
State/Province
Ontario
ZIP/Postal Code
N6C 2R5
Country
Canada
Facility Name
The Ottawa Hospital
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H 8L6
Country
Canada
Facility Name
Montfort Hospital
City
Ottawa
State/Province
Ontario
Country
Canada
Facility Name
Queensway Carleton Hospital
City
Ottawa
State/Province
Ontario
Country
Canada
Facility Name
Sault Area Hospital
City
Sault Ste. Marie
State/Province
Ontario
Country
Canada
Facility Name
Health Sciences North
City
Sudbury
State/Province
Ontario
Country
Canada
Facility Name
Humber River Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M3M 0B2
Country
Canada
Facility Name
Mount Sinai Hospital
City
Toronto
State/Province
Ontario
Country
Canada
Facility Name
North York General Hospital
City
Toronto
State/Province
Ontario
Country
Canada
Facility Name
St. Joseph's Health Centre
City
Toronto
State/Province
Ontario
Country
Canada
Facility Name
Sunnybrook Health Science Centre
City
Toronto
State/Province
Ontario
Country
Canada
Facility Name
Jewish General Hospital
City
Montreal
State/Province
Quebec
Country
Canada
Facility Name
CHRU Brest
City
Brest
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
36100263
Citation
Auer RC, Ott M, Karanicolas P, Brackstone MR, Ashamalla S, Weaver J, Tagalakis V, Boutros M, Stotland P, Marulanda AC, Moloo H, Jayaraman S, Patel S, Le Gal G, Spadafora S, MacLellan S, Trottier D, Jonker D, Asmis T, Mallick R, Pecarskie A, Ramsay T, Carrier M; PERIOP-01 investigators. Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial. BMJ. 2022 Sep 13;378:e071375. doi: 10.1136/bmj-2022-071375.
Results Reference
derived

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Extended Peri-operative Tinzaparin to Improve Disease-free Survival in Patients With Resectable Colorectal Cancer

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