Embolism, Pulmonary
Conditions
Keywords
Fondaparinux sodium, contrast-enhanced MDCT, Deep Vein Thrombosis, Pulmonary thromboembolism
Brief summary
The primary objective is to evaluate the efficacy (as measured by the rate of recurrent symptomatic Venous Thromboembolism \[VTE\] (i.e., Pulmonary thromboembolism \[PE\] and Deep Vein Thrombosis \[DVT\])) and safety of GSK576428 as the initial treatment in subjects with acute PE in an open-label design.
Interventions
The dose of Fondaparinux will be determined based on a subject's body weight (\<50 kg, 5 mg; 50 to 100 kg, 7.5 mg; \>100 kg, 10 mg) and administered once daily by subcutaneous (SC) injection.
UFH therapy will be started on Day 1 while adjusting activated partial thromboplastin time (aPTT) to maintain aPTT 1.5 to 2.5 times control.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects with a confirmed diagnosis (by Multi detector-row CT \[MDCT\]) of acute symptomatic PE who are hemodynamically stable (i.e., the condition where anticoagulant therapy alone are indicated) (the time from onset should be no longer than 5 days, and subjects with or without symptomatic DVT are eligible) * Age: \>=20 years * Gender: No restriction Female subjects must either be of non-childbearing potential (post-menopausal \>1 year, hysterectomy, or sterilization), or of childbearing potential, has a negative pregnancy test at screening, and agree to use contraception throughout the study period. * Hospitalization status: Subjects who are able to stay at the hospital at least during the initial treatment period. * Written informed consent from the subject him/herself or his/her legally acceptable representative. Written informed consent from the subject's legally acceptable representative must be obtained if the subject is incapable of giving consent.
Exclusion criteria
* Shock or hemodynamic instability\*. \*: Defined as shock or decreased blood pressure (systolic blood pressure \<90 mmHg or \>=40 mmHg) lasting for at least 15 minutes and does not represent hemodynamically unstable conditions due to newly emergent arrhythmia, dehydration or sepsis. * Right cardiac function failure detected by echocardiography at screening. * Requirement for surgical thrombectomy, catheter intervention and thrombolytic therapy for the current PE. * Subjects (for example, with free-floating thrombus in the femoral vein or ilium by MDCT at screening) for whom insertion of inferior vena cava filter is indicated or subjects in whom inferior vena cava filter is present. * Prior to entry into the study, therapeutic dosage of anticoagulants for more than 24 hours to treat the current episode. * Active, clinically significant bleeding * Thrombocytopenia (platelet count \<10×10⁴/µL at screening) * Concurrent conditions with bleeding risk (e.g., ulcer of the gastrointestinal tract, diverticulitis of the gastrointestinal tract, colitis, acute bacterial endocarditis, severe hypertension\*, or severe diabetes) or bleeding tendency. \*: systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg * Severe hepatic disorder * Known hypersensitivity to heparin, low-molecular-weight heparin (LMWH) or warfarin * Previous history of cerebral hemorrhage * Brain, spinal, or ophthalmological surgery within 3 months prior to entry into this study * Previous history of Heparin-induced thrombocytopenia * Patients for whom anticoagulant therapy is contraindicated or who cannot be taken off anticoagulant therapy due to coexistent condition (e.g. prosthetic heart valve implant). * Severe renal disorder (serum creatinine \>2.0 mg/dL \[180 µmol/L\] at screening) in a well hydrated subject * Documented hypersensitivity to contrast media * Use of any contraindicated drug that cannot be combined with the injection of contrast medium \[e.g., antihyperglycemic metformin hydrochloride (Glycoran®, Melbin®)\] * Participation in any other therapeutic drug study or a clinical study within 6 months prior to entry into this study * Previous participation in a study of GSK576428 * Drug or alcohol abuse * Systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg * Recent surgery within 3 days prior to entry into the study * Life expectancy \<3 months * Pregnant women, nursing mothers, women who may be pregnant, or women contemplating pregnancy during the study period * Others whom the investigator or subinvestigator considers not eligible for the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants With Recurrent or New Symptomatic Venous Thromboembolism (VTE) | From Day 1 to Day 90 (±7 days) | VTE (pulmonary thromboembolism \[PE\] and/or deep vein thromboembolism \[DVT\]) was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type) | From Day 1 to Day 90 (±7 days) | VTE (pulmonary thromboembolism \[PE\] and/or deep vein thromboembolism \[DVT\]) was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE). |
| The Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse | Baseline, Days 5-10 (the day when the medication [FPX or UFH] was finished /discontinued) (+/-1) | Improved, No change, or Worse was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE). Each category is adjudicated by comparison with the perfusion score at baseline by the CIACE. |
| Total Perfusion Score at Baseline and Mean Change From Baseline at Days 5-10 | Baseline, Days 5-10 (the day when the medication [FPX or UFH] was finished /discontinued) (+/-1) | The perfusion score (0: no perfusion; 0.25, 0.5, 0.75, 1: normal) in each of the six lobes of the lung was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE). Total perfusion score (r) was calculated as: r = (0.25 x right lower lobe) + (0.12 x right middle lobe) + (0.18 x right upper lobe) + (0.20 x left lower lobe) + (0.12 x lingula) + (0.13 x left upper lobe). |
| The Percentage of Participants With a Bleeding Event | FPX or UFH treatment period (Days 5-10, on average) | Bleeding events (major bleeding \[clinically overt bleeding with: fatality, location in critical organ, a fall in hemoglobin \>=2 g/dL, or a transfusion \>=2 units\], minor bleeding \[clinically overt bleeding and not adjudicated as major bleeding\]) were adjudicated blindly by the Central Independent Adjudication Committee of Safety (CIACS). |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fondaparinux Sodium (FPX) The dose of FPX was determined based on a participant's body weight (\<50 kg, 5 mg; 50 to 100 kg, 7.5 mg; \>100 kg, 10 mg) and administered once daily by subcutaneous (SC) injection for 5-10 days as a general rule. Concomitant warfarin therapy (administered no later than 72 hours after the first dose of FPX) was continued up to Day 90 (±7) at a dose adjusted to maintain the prothrombin time international normalized ratio (PT-INR) between 1.5 and 3.0. | 28 |
| Unfractionated Heparin (UFH) The dose of UFH was adjusted to maintain activated partial thromboplastin time (aPTT) at 1.5 to 2.5 times control and administered by intravenous (IV) drip bolus injection followed by IV infusion for 5-10 days as a general rule. Concomitant warfarin therapy (administered no later than 72 hours after the first dose of UFH) was continued up to Day 90 (±7) at a dose adjusted to maintain the PT-INR between 1.5 and 3.0. | 10 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 |
| Overall Study | Prostate Cancer Treatment before Trial | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Fondaparinux Sodium (FPX) | Unfractionated Heparin (UFH) | Total |
|---|---|---|---|
| Age, Continuous | 68.5 years STANDARD_DEVIATION 11.4 | 62.6 years STANDARD_DEVIATION 14.1 | 67.0 years STANDARD_DEVIATION 12.2 |
| Body weight 50-100 kg | 23 kilograms (kg) | 9 kilograms (kg) | 32 kilograms (kg) |
| Body weight <50 kg | 5 kilograms (kg) | 1 kilograms (kg) | 6 kilograms (kg) |
| Gender Female | 13 Participants | 7 Participants | 20 Participants |
| Gender Male | 15 Participants | 3 Participants | 18 Participants |
| Race/Ethnicity, Customized Asian-Japanese | 28 participants | 10 participants | 38 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 31 | 8 / 10 |
| serious Total, serious adverse events | 1 / 31 | 0 / 10 |
Outcome results
Primary
The Percentage of Participants With Recurrent or New Symptomatic Venous Thromboembolism (VTE)
VTE (pulmonary thromboembolism \[PE\] and/or deep vein thromboembolism \[DVT\]) was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE).
Time frame: From Day 1 to Day 90 (±7 days)
Population: Full Analysis Set (FAS): all participants receiving at least one dose of medication (FPX or UFH) who had efficacy data and had a confirmed diagnosis of acute pulmonary thromboembolism (PE)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fondaparinux Sodium (FPX) | The Percentage of Participants With Recurrent or New Symptomatic Venous Thromboembolism (VTE) | 0 percentage of participants |
| Unfractionated Heparin (UFH) | The Percentage of Participants With Recurrent or New Symptomatic Venous Thromboembolism (VTE) | 0 percentage of participants |
Secondary
The Percentage of Participants With a Bleeding Event
Bleeding events (major bleeding \[clinically overt bleeding with: fatality, location in critical organ, a fall in hemoglobin \>=2 g/dL, or a transfusion \>=2 units\], minor bleeding \[clinically overt bleeding and not adjudicated as major bleeding\]) were adjudicated blindly by the Central Independent Adjudication Committee of Safety (CIACS).
Time frame: FPX or UFH treatment period (Days 5-10, on average)
Population: Safety population: all participants who received at least one dose of medication (FPX or UFH).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux Sodium (FPX) | The Percentage of Participants With a Bleeding Event | Minor bleeding | 9.7 percentage of participants |
| Fondaparinux Sodium (FPX) | The Percentage of Participants With a Bleeding Event | Any bleeding (major and/or minor bleeding) | 9.7 percentage of participants |
| Fondaparinux Sodium (FPX) | The Percentage of Participants With a Bleeding Event | Major bleeding only | 0 percentage of participants |
| Unfractionated Heparin (UFH) | The Percentage of Participants With a Bleeding Event | Minor bleeding | 0 percentage of participants |
| Unfractionated Heparin (UFH) | The Percentage of Participants With a Bleeding Event | Any bleeding (major and/or minor bleeding) | 0 percentage of participants |
| Unfractionated Heparin (UFH) | The Percentage of Participants With a Bleeding Event | Major bleeding only | 0 percentage of participants |
Secondary
The Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse
Improved, No change, or Worse was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE). Each category is adjudicated by comparison with the perfusion score at baseline by the CIACE.
Time frame: Baseline, Days 5-10 (the day when the medication [FPX or UFH] was finished /discontinued) (+/-1)
Population: Full Analysis Set (FAS): all participants receiving at least one dose of medication (FPX or UFH) who had efficacy data and had a confirmed diagnosis of acute pulmonary thromboembolism (PE)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux Sodium (FPX) | The Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse | Improved | 78.6 percentage of participants |
| Fondaparinux Sodium (FPX) | The Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse | No change | 21.4 percentage of participants |
| Fondaparinux Sodium (FPX) | The Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse | Worse | 0 percentage of participants |
| Unfractionated Heparin (UFH) | The Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse | Improved | 90.0 percentage of participants |
| Unfractionated Heparin (UFH) | The Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse | No change | 10.0 percentage of participants |
| Unfractionated Heparin (UFH) | The Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse | Worse | 0 percentage of participants |
Secondary
The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type)
VTE (pulmonary thromboembolism \[PE\] and/or deep vein thromboembolism \[DVT\]) was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE).
Time frame: From Day 1 to Day 90 (±7 days)
Population: Full Analysis Set (FAS): all participants receiving at least one dose of medication (FPX or UFH) who had efficacy data and had a confirmed diagnosis of acute pulmonary thromboembolism (PE)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux Sodium (FPX) | The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type) | Symptomatic DVT only | 0 percentage of participants |
| Fondaparinux Sodium (FPX) | The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type) | (Symptomatic) Non-fatal PE | 0 percentage of participants |
| Fondaparinux Sodium (FPX) | The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type) | Asymptomatic DVT only | 0 percentage of participants |
| Fondaparinux Sodium (FPX) | The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type) | Asymptomatic PE | 0 percentage of participants |
| Fondaparinux Sodium (FPX) | The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type) | (Symptomatic) Fatal PE | 0 percentage of participants |
| Unfractionated Heparin (UFH) | The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type) | (Symptomatic) Fatal PE | 0 percentage of participants |
| Unfractionated Heparin (UFH) | The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type) | Symptomatic DVT only | 0 percentage of participants |
| Unfractionated Heparin (UFH) | The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type) | Asymptomatic PE | 0 percentage of participants |
| Unfractionated Heparin (UFH) | The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type) | (Symptomatic) Non-fatal PE | 0 percentage of participants |
| Unfractionated Heparin (UFH) | The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type) | Asymptomatic DVT only | 0 percentage of participants |
Secondary
Total Perfusion Score at Baseline and Mean Change From Baseline at Days 5-10
The perfusion score (0: no perfusion; 0.25, 0.5, 0.75, 1: normal) in each of the six lobes of the lung was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE). Total perfusion score (r) was calculated as: r = (0.25 x right lower lobe) + (0.12 x right middle lobe) + (0.18 x right upper lobe) + (0.20 x left lower lobe) + (0.12 x lingula) + (0.13 x left upper lobe).
Time frame: Baseline, Days 5-10 (the day when the medication [FPX or UFH] was finished /discontinued) (+/-1)
Population: Full Analysis Set (FAS): all participants receiving at least one dose of medication (FPX or UFH) who had efficacy data and had a confirmed diagnosis of acute pulmonary thromboembolism (PE)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fondaparinux Sodium (FPX) | Total Perfusion Score at Baseline and Mean Change From Baseline at Days 5-10 | Change from baseline, Days 5-10 (+/-1) | 0.101 points on a scale | Standard Deviation 0.079 |
| Fondaparinux Sodium (FPX) | Total Perfusion Score at Baseline and Mean Change From Baseline at Days 5-10 | Baseline | 0.654 points on a scale | Standard Deviation 0.141 |
| Unfractionated Heparin (UFH) | Total Perfusion Score at Baseline and Mean Change From Baseline at Days 5-10 | Baseline | 0.586 points on a scale | Standard Deviation 0.237 |
| Unfractionated Heparin (UFH) | Total Perfusion Score at Baseline and Mean Change From Baseline at Days 5-10 | Change from baseline, Days 5-10 (+/-1) | 0.185 points on a scale | Standard Deviation 0.148 |