Thrombosis, Venous
Conditions
Keywords
Pulmonary thromboembolism, contrast-enhanced MDCT, Deep Vein Thrombosis, Fondaparinux sodium
Brief summary
The primary objective of this study 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 symptomatic DVT 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
* Confirmed diagnosis of acute proximal DVT based on contrast-enhanced Multi detector-row CT (MDCT) (not more than 10 days after the onset of the symptoms of DVT) * Age:20 years * Gender: No restriction * 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
* Symptomatic PE * Requirement for surgical thrombectomy, catheter intervention and thrombolytic therapy for the current DVT * 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 * Anticoagulant therapy for at least 24 hours to treat the current episode prior to entry into the study * 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 * 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 * QT interval prolonged (QT interval corrected by Bazett's formula \[QTcB\] ≥450 msec; for patients with bundle branch block QTcB ≥480 msec) at screening * Documented hypersensitivity to contrast media * Use of any contraindicated drug that cannot be combined with the injection of contrast medium \[e.g., antihyperglycemics, such as biguanides (metformin hydrochloride, buformin hydrochloride)\] * 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 \[Fondaparinux Sodium; including the studies of Org31540/SR90107A (ex-project code)\] or previous exposure to the therapeutic dose 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 |
|---|---|---|
| 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 thrombosis \[DVT\]) was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic VTE (by Type) | From Day 1 to Day 90 (±7 days) | VTE (pulmonary thromboembolism \[PE\] and/or deep vein thrombosis \[DVT\]) was adjudicated blindly by the CIACE. |
| Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse Compared to Baseline | Baseline, single day between Day 5 and Day 10 (the day when the medication [FPX or UFH] was finished /discontinued) (±1 day) | Classifications of Improved, No change, or Worse were adjudicated blindly by the CIACE. |
| Total Perfusion Score at Baseline and Mean Change From Baseline at Day 5-10 | Baseline, single day between Day 5 and Day 10 (the day when the medication [FPX or UFH] was finished /discontinued) (±1 day) | Change from baseline was calculated as the score on the day medication was finished/discontinued (anywhere from Day 5 to Day 10) minus the baseline score. 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 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). |
| Percentage of Participants With a Bleeding Event | Initial treatment period (from the first dose of FPX/UFH to N days after the last dose of FPX/UFH; specified based on creatinine clearance [CLcr]; N=3, CLcr >=50 mL/min; N=4, 30 =< CLcr < 50 mL/min; N=9, CLcr < 30 mL/min). | Bleeding events (major bleeding \[clinically overt bleeding with fatality, location in a critical organ, a fall in hemoglobin \>=2 grams (g)/deciliter (dL), or a transfusion \>=2 units\]; minor bleeding \[clinically overt bleeding and not adjudicated as major bleeding\], and no 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 was 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 1.5-2.5 times control and was 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. | 9 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Need for prohibited drug (heparin) | 1 | 0 |
| Overall Study | Need to treat for lung cancer | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Fondaparinux Sodium (FPX) | Unfractionated Heparin (UFH) | Total |
|---|---|---|---|
| Age, Continuous | 64.5 years STANDARD_DEVIATION 19.7 | 76.1 years STANDARD_DEVIATION 12.2 | 67.3 years STANDARD_DEVIATION 18.7 |
| Number of Participants with the Indicated Body Weight >100 kg | 0 participants | 0 participants | 0 participants |
| Number of Participants with the Indicated Body Weight 50-100 kg | 20 participants | 6 participants | 26 participants |
| Number of Participants with the Indicated Body Weight <50 kg | 8 participants | 3 participants | 11 participants |
| Race/Ethnicity, Customized Asian-Japanese | 28 participants | 9 participants | 37 participants |
| Sex: Female, Male Female | 15 Participants | 9 Participants | 24 Participants |
| Sex: Female, Male Male | 13 Participants | 0 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 18 / 29 | 6 / 10 |
| serious Total, serious adverse events | 1 / 29 | 1 / 10 |
Outcome results
Primary
Percentage of Participants With Recurrent or New Symptomatic Venous Thromboembolism (VTE)
VTE (pulmonary thromboembolism \[PE\] and/or deep vein thrombosis \[DVT\]) 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 symptomatic deep vein thrombosis (DVT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fondaparinux Sodium (FPX) | Percentage of Participants With Recurrent or New Symptomatic Venous Thromboembolism (VTE) | 0 percentage of participants |
| Unfractionated Heparin (UFH) | Percentage of Participants With Recurrent or New Symptomatic Venous Thromboembolism (VTE) | 0 percentage of participants |
Secondary
Percentage of Participants With a Bleeding Event
Bleeding events (major bleeding \[clinically overt bleeding with fatality, location in a critical organ, a fall in hemoglobin \>=2 grams (g)/deciliter (dL), or a transfusion \>=2 units\]; minor bleeding \[clinically overt bleeding and not adjudicated as major bleeding\], and no bleeding) were adjudicated blindly by the Central Independent Adjudication Committee of Safety (CIACS).
Time frame: Initial treatment period (from the first dose of FPX/UFH to N days after the last dose of FPX/UFH; specified based on creatinine clearance [CLcr]; N=3, CLcr >=50 mL/min; N=4, 30 =< CLcr < 50 mL/min; N=9, CLcr < 30 mL/min).
Population: Safety Population: all participants who received at least one dose of medication (FPX or UFH).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux Sodium (FPX) | Percentage of Participants With a Bleeding Event | Minor bleeding only | 3.4 percentage of participants |
| Fondaparinux Sodium (FPX) | Percentage of Participants With a Bleeding Event | Major bleeding | 3.4 percentage of participants |
| Fondaparinux Sodium (FPX) | Percentage of Participants With a Bleeding Event | Any bleeding (major and/or minor bleedings) | 6.9 percentage of participants |
| Unfractionated Heparin (UFH) | Percentage of Participants With a Bleeding Event | Major bleeding | 0 percentage of participants |
| Unfractionated Heparin (UFH) | Percentage of Participants With a Bleeding Event | Minor bleeding only | 0 percentage of participants |
| Unfractionated Heparin (UFH) | Percentage of Participants With a Bleeding Event | Any bleeding (major and/or minor bleedings) | 0 percentage of participants |
Secondary
Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse Compared to Baseline
Classifications of Improved, No change, or Worse were adjudicated blindly by the CIACE.
Time frame: Baseline, single day between Day 5 and Day 10 (the day when the medication [FPX or UFH] was finished /discontinued) (±1 day)
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux Sodium (FPX) | Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse Compared to Baseline | Improved | 18.5 percentage of participants |
| Fondaparinux Sodium (FPX) | Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse Compared to Baseline | No Change | 81.5 percentage of participants |
| Fondaparinux Sodium (FPX) | Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse Compared to Baseline | Worse | 0 percentage of participants |
| Unfractionated Heparin (UFH) | Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse Compared to Baseline | Improved | 11.1 percentage of participants |
| Unfractionated Heparin (UFH) | Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse Compared to Baseline | No Change | 88.9 percentage of participants |
| Unfractionated Heparin (UFH) | Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse Compared to Baseline | Worse | 0 percentage of participants |
Secondary
Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic VTE (by Type)
VTE (pulmonary thromboembolism \[PE\] and/or deep vein thrombosis \[DVT\]) was adjudicated blindly by the CIACE.
Time frame: From Day 1 to Day 90 (±7 days)
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux Sodium (FPX) | Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic VTE (by Type) | (Symptomatic) Non-fatal PE | 0 percentage of participants |
| Fondaparinux Sodium (FPX) | Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic VTE (by Type) | Asymptomatic DVT only | 3.6 percentage of participants |
| Fondaparinux Sodium (FPX) | Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic VTE (by Type) | Symptomatic DVT only | 0 percentage of participants |
| Fondaparinux Sodium (FPX) | Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic VTE (by Type) | Asymptomatic PE | 0 percentage of participants |
| Fondaparinux Sodium (FPX) | Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic VTE (by Type) | (Symptomatic) Fatal PE | 0 percentage of participants |
| Unfractionated Heparin (UFH) | Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic VTE (by Type) | Asymptomatic PE | 0 percentage of participants |
| Unfractionated Heparin (UFH) | Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic VTE (by Type) | Symptomatic DVT only | 0 percentage of participants |
| Unfractionated Heparin (UFH) | Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic VTE (by Type) | (Symptomatic) Non-fatal PE | 0 percentage of participants |
| Unfractionated Heparin (UFH) | Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic VTE (by Type) | (Symptomatic) Fatal PE | 0 percentage of participants |
| Unfractionated Heparin (UFH) | Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic VTE (by Type) | Asymptomatic DVT only | 0 percentage of participants |
Secondary
Total Perfusion Score at Baseline and Mean Change From Baseline at Day 5-10
Change from baseline was calculated as the score on the day medication was finished/discontinued (anywhere from Day 5 to Day 10) minus the baseline score. 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 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, single day between Day 5 and Day 10 (the day when the medication [FPX or UFH] was finished /discontinued) (±1 day)
Population: FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fondaparinux Sodium (FPX) | Total Perfusion Score at Baseline and Mean Change From Baseline at Day 5-10 | Baseline | 0.944 points on a scale | Standard Deviation 0.087 |
| Fondaparinux Sodium (FPX) | Total Perfusion Score at Baseline and Mean Change From Baseline at Day 5-10 | Change from Baseline | 0.015 points on a scale | Standard Deviation 0.034 |
| Unfractionated Heparin (UFH) | Total Perfusion Score at Baseline and Mean Change From Baseline at Day 5-10 | Baseline | 0.959 points on a scale | Standard Deviation 0.048 |
| Unfractionated Heparin (UFH) | Total Perfusion Score at Baseline and Mean Change From Baseline at Day 5-10 | Change from Baseline | 0.004 points on a scale | Standard Deviation 0.011 |