A Study of Dalteparin Prophylaxis in High-Risk Ambulatory Cancer Patients (PHACS)

• ClinicalTrials.gov Identifier: NCT00876915
• Recruitment Status: Terminated
• First Posted: April 7, 2009
• Results First Posted: October 12, 2015
• Last Update Posted: November 24, 2015
• Sponsor: University of Rochester
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Eisai Inc.
• Information provided by (Responsible Party): Charles Francis, University of Rochester

Study Description

Brief Summary:

Some cancer patients starting a new chemotherapy regimen are likely to develop blood clots, also known as venous thromboembolism (VTE). Blood clots can cause symptoms and can occasionally be life-threatening. The purpose of this study is to determine if a daily injection of a blood-thinner, dalteparin, for 12 weeks can safely and effectively reduce the frequency of blood clots. Dalteparin is currently approved for prevention of blood clots following surgery and in hospitalized patients but not specifically for cancer outpatients.

Condition or disease	Intervention/treatment	Phase
Venous Thromboembolism; Pulmonary Embolism	Drug: dalteparin injection	Phase 3

Detailed Description:

VTE is an increasingly frequent complication of cancer and anti-cancer therapies. It is associated with increased mortality and other significant adverse consequences. Risk factors for VTE in the cancer population have been identified, and multiple studies have also shown that VTE can be prevented in high-risk populations with the use of thromboprophylaxis. This study evaluated the safety and efficacy of prophylaxis in a high-risk subgroup of cancer patients identified by a validated risk model developed by us previously called the "Khorana Score." Correlative studies evaluated the value of tissue factor as a predictive biomarker of VTE. The purpose of this study was to conduct a prospective, randomized clinical trial comparing the safety and efficacy of prophylaxis with dalteparin to no treatment in reducing VTE in high-risk ambulatory cancer patients initiating chemotherapy and to establish the value of TF as a predictive marker for VTE in ambulatory cancer patients receiving chemotherapy.

PHACS was a randomized multi-center clinical trial. Eligible patients were enrolled and underwent baseline screening ultrasonography of the lower extremities to rule out pre-existing DVT and a chest CT scan to rule out PE. If negative, patients were then randomized to receive either dalteparin 5000 units subcutaneously daily or observation for a study period of 12 weeks. The first day of dalteparin prophylaxis coincided with the first day of initiation of a new systemic chemotherapy regimen. The patients were seen every 4 weeks (±1 week) at the time of regularly scheduled chemotherapy cycle visits for serial ultrasonography of lower extremities during study period (i.e. at 4, 8 and 12 weeks.) A chest CT scan was performed at 12 weeks. Compliance was measured by asking patients about missed doses at these 4-weekly visits as well as by asking patients to fill an injection diary.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 218 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Prospective Randomized Multicenter Study of Dalteparin Prophylaxis in High-Risk Ambulatory Cancer Patients
• Study Start Date: July 2009
• Actual Primary Completion Date: July 2014
• Actual Study Completion Date: December 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: High Risk for VTE recieving dalteparin; Patients assigned at random to receive prophylactic dalteparin injections	Drug: dalteparin injection; Potency is described in international anti-Xa units (IU). One unit (anti-Xa) of dalteparin sodium, average molecular weight 5,000, corresponds to the activity of one unit of the 1st International Standard for Low Molecular Weight Heparin (LMWH)with respect to inhibition of coagulation Factor Xa in plasma utilizing the chromogenic peptide substrate S-2765 (N-alpha-Benzyloxycarbonyl-D-arginyl-glycyl-arginine-pNA.2HCl).; Other Name: Fragmin
No Intervention: High Risk for VTE No therapy; No prophylactic therapy for VTE prevention given (Subjects receiving standard of care)
No Intervention: Low Risk for VTE; Used as a control for the secondary outcome of evaluating tissue factor in collected blood samples

Outcome Measures

Primary Outcome Measures :

1. Percentage of Patients With Venous Thromboembolisms [ Time Frame: 12 weeks ]
   The percentage of patients who developed a Venous thromboembolism were recorded within 12 weeks following randomization including all adjudicated occurrences of symptomatic DVT, PE and upper extremity thrombus as well as all asymptomatic DVT and PE detected by lower extremity ultrasonography and chest CT.
2. Percentage of Patients Who Experienced Clinically Significant Bleeding Events. [ Time Frame: 13 weeks ]
   The percentage of patients who experienced a clinically significant bleeding event were recorded (including major and clinically significant non-major bleeding) over 13 weeks (12 weeks of study and an additional week of observation). Major bleeding was defined as being clinically overt and satisfying one of the following: decrease in hemoglobin of 2.0 g/dL, leading to transfusion of 2 or more units of blood or packed red cells, occurring in a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial) or leading to death. Clinically significant non-major bleeding was defined as clinically overt, not meeting criteria for major bleeding and with one of the following characteristics: multiple-source, spontaneous hematoma > 25 cm², epistaxis > 5 mins, macroscopic hematuria not related to instrumentation, spontaneous rectal bleeding, gingival bleeding > 5 mins, hemoptysis, hematemesis or prolonged bleeding (> 5 minutes) after venipuncture.

Secondary Outcome Measures :

1. The Value of Tissue Factor (TF) at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients [ Time Frame: baseline value of tissue factor ]
   Blood samples were obtained to measure the value of Tissue Factor at baseline compared between high risk for VTE and low risk for VTE ambulatory cancer patients.
2. The Value of D-Dimer at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients [ Time Frame: baseline value of D-Dimer ]
   Blood samples were obtained to measure the value of D-Dimer at baseline compared between high risk for VTE and low risk for VTE ambulatory cancer patients
3. The Value of Human F12 at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients [ Time Frame: baseline value of Human F12 ]
   Blood samples were obtained to measure the value of Human F12 at baseline compared between high risk for VTE and low risk for VTE ambulatory cancer patients
4. The Value of Tissue Factor Pathway Inhibitor (TFPI) at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients [ Time Frame: baseline value of TFPI ]
   Blood samples were obtained to measure the value of TFPI at baseline compared between high risk for VTE and low risk for VTE ambulatory cancer patients
5. The Value of Factor VIIa (FVIIa) at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients [ Time Frame: baseline value of FVIIa ]
   Blood samples were obtained to measure the value of FVIIa at baseline compared between high risk for VTE and low risk for VTE ambulatory cancer patients
6. The Value of Thrombin Antithrombin (TAT) at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients [ Time Frame: baseline value of TAT ]
   Blood samples were obtained to measure the value of TAT at baseline compared between high risk for VTE and low risk for VTE ambulatory cancer patients

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• A histologic diagnosis of malignancy;
• At planned initiation of a new systemic chemotherapy regimen (including patients starting on first chemotherapy or patients previously treated but starting on a new regimen);
• A risk score for VTE ≥3 [assign score of 2 for very high risk sites of cancer (stomach, pancreas), score of 1 for high risk site (lung, lymphoma, gynecologic, bladder, testicular) and score of 0 for all other sites], hemoglobin <10 g/dL or planned use of erythropoiesis stimulating agents, platelet count ≥350,000/mm3, total leukocyte count > 11,000/mm3 or body mass index ≥ 35 kg/m2]. Any counts meeting criteria drawn within 2 weeks prior to enrollment are considered acceptable.
• Age 18 years or older
• Provide written, informed consent.

Exclusion Criteria:

• Active bleeding or at high risk of serious bleeding complication in the opinion of the investigator
• Diagnosis of primary brain tumor multiple myeloma, leukemia, or myelodysplastic syndrome
• Planned stem cell transplant
• Life expectancy < 6 months
• Known allergy to heparin or LMWH
• Patient or caregiver incapable of daily self-injection
• Acute or chronic renal insufficiency with creatinine clearance < 30 mL/min
• History of heparin-induced thrombocytopenia
• Allergy to contrast agents
• Pregnancy
• Need for anticoagulant therapy
• Platelet count < 75,000/mm3

Contacts and Locations

Locations

United States, California

University of California, Davis

Sacramento, California, United States, 95817

United States, New York

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263

Rochester General Hospital

Rochester, New York, United States, 14621

University of Rochester Medical Center

Rochester, New York, United States, 14642

United States, North Carolina

Duke University School of Medicine

Durham, North Carolina, United States, 27705

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

Canada, Ontario

Ottawa Hospital Research Institute (OHRI)

Ottawa, Ontario, Canada, K1H 8L6

Sponsors and Collaborators

University of Rochester

National Heart, Lung, and Blood Institute (NHLBI)

Eisai Inc.

Investigators

• Principal Investigator: Charles W. Francis, MD; Univeristy of Rochester Medical Center

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Rutjes AW, Porreca E, Candeloro M, Valeriani E, Di Nisio M. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev. 2020 Dec 18;12:CD008500. doi: 10.1002/14651858.CD008500.pub5.

Khorana AA, Francis CW, Kuderer NM, Carrier M, Ortel TL, Wun T, Rubens D, Hobbs S, Iyer R, Peterson D, Baran A, Kaproth-Joslin K, Lyman GH. Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: A randomized trial. Thromb Res. 2017 Mar;151:89-95. doi: 10.1016/j.thromres.2017.01.009. Epub 2017 Jan 26.

• Responsible Party: Charles Francis, Professor emeritus, University of Rochester
• ClinicalTrials.gov Identifier: NCT00876915
• Other Study ID Numbers: 25387; 1R01HL095109-01 ( U.S. NIH Grant/Contract )
• First Posted: April 7, 2009
• Results First Posted: October 12, 2015
• Last Update Posted: November 24, 2015
• Last Verified: October 2015

Keywords provided by Charles Francis, University of Rochester:

prevention of VTE and PE in high risk cancer patients

Additional relevant MeSH terms:

Pulmonary Embolism; Embolism; Thromboembolism; Venous Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases; Dalteparin; Tinzaparin; Heparin, Low-Molecular-Weight; Anticoagulants; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action