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

A Prospective Randomized Multicenter Study of Dalteparin Prophylaxis in High-Risk Ambulatory Cancer Patients

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00876915

Acronym

PHACS

Enrollment

218

Registered

2009-04-07

Start date

2009-07-31

Completion date

2014-12-31

Last updated

2015-11-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pulmonary Embolism, Venous Thromboembolism

Keywords

prevention of VTE and PE in high risk cancer patients

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.

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.

Interventions

DRUGdalteparin 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).

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Patients With Venous Thromboembolisms	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.
Percentage of Patients Who Experienced Clinically Significant Bleeding Events.	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

Measure	Time frame	Description
The Value of Human F12 at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients	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
The Value of Tissue Factor Pathway Inhibitor (TFPI) at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients	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
The Value of Tissue Factor (TF) at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients	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.
The Value of Thrombin Antithrombin (TAT) at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients	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
The Value of Factor VIIa (FVIIa) at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients	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
The Value of D-Dimer at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients	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

Countries

Canada, United States

Participant flow

Recruitment details

Participants screened for the study but deemed low or medium risk by Khorona scoring will be offered to consent to a one time baseline blood sample. These samples will be used as the control group to establish the value of TF as a predictive marker for VTE in ambulatory cancer patients as described in the Secondary Objectives.

Pre-assignment details

Participants who undergo a baseline US/CT scan and are found to have a DVT/PE will be considered a screen failure and will not be randomized and continue on in the study. In addition, if any of the screening criteria are not met, these subjects will be considered screen failures.

Participants by arm

Arm	Count
High Risk Randomized to Dalteparin Injection Patients will be assigned at random to receive prophylactic dalteparin injections 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).	50
High Risk Randomized to No Therapy No prophylactic therapy for VTE prevention given (Subjects just receiving standard of care)	48
Low Risk Ambulatory cancer patients deemed Low risk based on a Khorona score of 0-2	101
Total	199

Baseline characteristics

Characteristic	High Risk Randomized to Dalteparin Injection	High Risk Randomized to No Therapy	Low Risk	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	16 Participants	13 Participants	27 Participants	56 Participants
Age, Categorical Between 18 and 65 years	34 Participants	35 Participants	74 Participants	143 Participants
Age, Continuous	60 years STANDARD_DEVIATION 10	58 years STANDARD_DEVIATION 12	58 years STANDARD_DEVIATION 13	58 years STANDARD_DEVIATION 12
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	3 Participants	1 Participants	6 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	48 Participants	45 Participants	96 Participants	189 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	4 Participants	4 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants	2 Participants	0 Participants	4 Participants
Race (NIH/OMB) Asian	2 Participants	0 Participants	1 Participants	3 Participants
Race (NIH/OMB) Black or African American	7 Participants	8 Participants	9 Participants	24 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants	1 Participants	0 Participants	2 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	38 Participants	37 Participants	91 Participants	166 Participants
Region of Enrollment Canada	4 participants	3 participants	0 participants	7 participants
Region of Enrollment United States	46 participants	45 participants	101 participants	192 participants
Sex: Female, Male Female	21 Participants	24 Participants	41 Participants	86 Participants
Sex: Female, Male Male	29 Participants	24 Participants	60 Participants	113 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	39 / 50	43 / 48
serious Total, serious adverse events	26 / 50	18 / 48

Outcome results

Primary

Percentage of Patients Who Experienced Clinically Significant Bleeding Events.

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.

Time frame: 13 weeks

Arm	Measure	Value (NUMBER)
Dalteparin Injection	Percentage of Patients Who Experienced Clinically Significant Bleeding Events.	14 percentage of participants
No Therapy	Percentage of Patients Who Experienced Clinically Significant Bleeding Events.	2 percentage of participants

p-value: 0.025295% CI: [1.236, 131.632]stratified Cox

Primary

Percentage of Patients With Venous Thromboembolisms

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.

Time frame: 12 weeks

Arm	Measure	Value (NUMBER)
Dalteparin Injection	Percentage of Patients With Venous Thromboembolisms	12 percentage of participants
No Therapy	Percentage of Patients With Venous Thromboembolisms	21 percentage of participants

p-value: 0.479595% CI: [0.235, 1.89]stratified Cox

Secondary

The Value of D-Dimer at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients

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

Time frame: baseline value of D-Dimer