Thromboembolism
Conditions
Keywords
Xa factor, VTE, MOSLL, pentasaccharide
Brief summary
This study is requested by PMDA to confirm the efficacy and the safety for HFS.
Interventions
DRUGFondaparinux
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients undergoing hip fracture surgery within 10 days following the time of fracture of the hip (proximal femur) (or following the time of fracture estimated from trauma).
Exclusion criteria
* Active, clinically significant bleeding (excluding drainage).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Major Bleeding During Treatment Period | From the first study drug injection up to Day 17 | Rate (%) was defined as number of events divided by the number of participants evaluated multiplied by 100. Signs and symptoms suggestive of venous thromboembolic events (VTE) included, but were not limited to lower extremity deep vein thrombosis (DVT): erythema, warmth, pain, swelling, tenderness and pulmonary embolism (PE): pleuritic chest pain, dyspnea, cough, hemoptysis, syncope, light-headedness/dizziness, tachypnea, and tachycardia. Intended treatment period started 24±2 hours after surgical closure. Venogram was obtained not later than 2 calendar days after the last study drug administration (between Day 11 and 17). These events were adjudicated by the Central Independent Adjudication Committee of Efficacy (CIACE). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of DVT During Treatment Period | Up to Day 17 | Rate (%) was defined as number of events divided by the number of patients evaluated multiplied by 100. Signs and symptoms suggestive of VTE included, but were not limited to lower extremity DVT: erythema, warmth, pain, swelling, tenderness. Intended treatment period started 24±2 hours after surgical closure. Venogram was obtained not later than 2 calendar days after the last study drug administration (between Day 11 and 17). These events were adjudicated by the CIACE. It was evaluated from the first study drug injection up to Day 17 or to first venogram, whichever occurred first. |
| Rate of Proximal DVT During Treatment Period | Up to Day 17 | Rate (%) was defined as number of events divided by the number of participants evaluated multiplied by 100. Signs and symptoms suggestive of VTE included, but were not limited to lower extremity DVT: erythema, warmth, pain, swelling, tenderness. Intended treatment period started 24±2 hours after surgical closure. Venogram was obtained not later than 2 calendar days after the last study drug administration (between Day 11 and 17). These events were adjudicated by the CIACE. It was evaluated from the first study drug injection up to Day 17 or to first venogram, whichever occurred first. |
| Rate of Distal Only DVT During Treatment Period | Up to Day 17 | Rate (%) was defined as number of events divided by the number of participants evaluated multiplied by 100. Signs and symptoms suggestive of VTE included, but were not limited to lower extremity DVT: erythema, warmth, pain, swelling, tenderness. Intended treatment period started 24±2 hours after surgical closure. Venogram was obtained not later than 2 calendar days after the last study drug administration (between Day 11 and 17). These events were adjudicated by the CIACE. It was evaluated from the first study drug injection up to Day 17 or to first venogram, whichever occurred first. |
| Number of Participants With Major Bleeding During Treatment Period | From the first study drug injection up to 2 days after the last study drug injection (approximately up to Day 17) | Major bleeding events were defined as clinically unusual bleeding meeting any of the following criteria: fatal bleeding, bleeding including retroperitoneal and intracranial bleeding or bleeding into a critical organ (eye, adrenal gland, pericardium, spine), reoperation due to bleeding/hematoma at the operative site, bleeding leading to a hemoglobin (Hb) fall \>=2 grams per deciliter (g/dL, 1.6 millimoles per liter \[mmol/L\]) within 48 hour of the bleed, bleeding that required a transfusion of red blood cell or whole blood derived from \>=900 millilters (mL) of whole blood within 48 hours of the bleed (excluding the autologous transfusion except for the treatment of bleeding adverse event (AE) and bleeding leading to the bleeding index (BI) \>=2. Major bleeding events were adjudicated by the Central Independent Adjudication Committee of Safety (CIACS). |
| Rate of PE During Treatment Period | Up to Day 17 | Rate (%) was defined as number of events divided by the number of participants evaluated multiplied by 100. Signs and symptoms suggestive of VTE included, but were not limited to lower extremity PE: pleuritic chest pain, dyspnea, cough, hemoptysis, syncope, light-headedness/dizziness, tachypnea, and tachycardia. Intended treatment period started 24±2 hours after surgical closure. Venogram was obtained not later than 2 calendar days after the last study drug administration (between Day 11 and 17). These events were adjudicated by the CIACE. It was evaluated from the first study drug injection up to Day 17 or to first venogram, whichever occurred first. |
| Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death | From the first study drug injection up to 2 days after the last study drug injection (approximately up to Day 17) | An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition. |
| Number of Transfused Participants | From the first study drug injection up to 2 days after the last study drug injection (approximately up to Day 17) | Blood product transfusions consisted of packed red blood cells or fresh frozen plasma or both. This was done between Day 2 and 2 calendar days after the last injection. |
| Summary of Units Transfused | From the first study drug injection up to 2 days after the last study drug injection (approximately up to Day 17) | Blood product transfusions consisted of packed red blood cells or fresh frozen plasma or both. This was done between Day 2 and 2 calendar days after the last injection. |
| Rate of Symptomatic DVT | Up to Day 17 | Rate (%) was defined as number of events divided by the number of participants evaluated multiplied by 100. Signs and symptoms suggestive of VTE included, but were not limited to lower extremity DVT: erythema, warmth, pain, swelling, tenderness. Intended treatment period started 24±2 hours after surgical closure. Venogram was obtained not later than 2 calendar days after the last study drug administration (between Day 11 and 17). These events were adjudicated by the CIACE. It was evaluated from the first study drug injection up to Day 17 or to first venogram, whichever occurred first. |
| Number of Participants With Minor Bleeding and Any Bleeding (Major and/or Minor Bleeding) | From the first study drug injection up to 2 days after the last study drug injection (approximately up to Day 17) | Minor bleeding and any bleeding (major and/or minor bleeding) events were adjudicated by the CIACS. Minor bleeding was defined as clinically overt bleeding not meeting the criteria for major bleeding and considered more than expected in the clinical context. Any bleeding (major and/or minor bleeding) could be recorded may be major and/or minor. |
Participant flow
Recruitment details
Total of 48 participants undergoing major orthopedic surgery of the lower limb such as hip fracture surgery, knee replacement surgery and hip replacement surgery were enrolled from 16 February 2006 to 26 October 2006 at 9 centers in Japan. The safety population consisted of 48 participants and full analysis set consisted of 37 participants.
Participants by arm
| Arm | Count |
|---|---|
| Fondaparinux Sodium 2.5 mg s.c. Participants received fondaparinux sodium 2.5 mg by s.c. injection for 14 days between Day 2 to Day 11-15. The first injection of the study drug was given 24 ± 2 hours after surgical closure. From Day 3 onwards, the injection of the study drug was given at about the same time every day as far as possible (but more than 12 hours after the first dose on Day 2). | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Other | 3 |
Baseline characteristics
| Characteristic | Fondaparinux Sodium 2.5 mg s.c. |
|---|---|
| Age, Continuous | 76.6 Years STANDARD_DEVIATION 14.4 |
| Region of Enrollment Japan | 48 Participants |
| Sex: Female, Male Female | 40 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 48 |
| other Total, other adverse events | 37 / 48 |
| serious Total, serious adverse events | 2 / 48 |
Outcome results
Primary
Rate of Major Bleeding During Treatment Period
Rate (%) was defined as number of events divided by the number of participants evaluated multiplied by 100. Signs and symptoms suggestive of venous thromboembolic events (VTE) included, but were not limited to lower extremity deep vein thrombosis (DVT): erythema, warmth, pain, swelling, tenderness and pulmonary embolism (PE): pleuritic chest pain, dyspnea, cough, hemoptysis, syncope, light-headedness/dizziness, tachypnea, and tachycardia. Intended treatment period started 24±2 hours after surgical closure. Venogram was obtained not later than 2 calendar days after the last study drug administration (between Day 11 and 17). These events were adjudicated by the Central Independent Adjudication Committee of Efficacy (CIACE).
Time frame: From the first study drug injection up to Day 17
Population: Full analysis set used which consisted of all participants who were assigned to study drug with the exception of those who did not receive study drug at all and those with no valid efficacy data (example no evaluable venogram).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fondaparinux Sodium 2.5 mg s.c. | Rate of Major Bleeding During Treatment Period | 21.6 % of normalized events per participant |
Secondary
Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death
An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.
Time frame: From the first study drug injection up to 2 days after the last study drug injection (approximately up to Day 17)
Population: Safety population used.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fondaparinux Sodium 2.5 mg s.c. | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death | Any AE | 37 Participants |
| Fondaparinux Sodium 2.5 mg s.c. | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death | Any SAE | 2 Participants |
| Fondaparinux Sodium 2.5 mg s.c. | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death | Death | 0 Participants |
Secondary
Number of Participants With Major Bleeding During Treatment Period
Major bleeding events were defined as clinically unusual bleeding meeting any of the following criteria: fatal bleeding, bleeding including retroperitoneal and intracranial bleeding or bleeding into a critical organ (eye, adrenal gland, pericardium, spine), reoperation due to bleeding/hematoma at the operative site, bleeding leading to a hemoglobin (Hb) fall \>=2 grams per deciliter (g/dL, 1.6 millimoles per liter \[mmol/L\]) within 48 hour of the bleed, bleeding that required a transfusion of red blood cell or whole blood derived from \>=900 millilters (mL) of whole blood within 48 hours of the bleed (excluding the autologous transfusion except for the treatment of bleeding adverse event (AE) and bleeding leading to the bleeding index (BI) \>=2. Major bleeding events were adjudicated by the Central Independent Adjudication Committee of Safety (CIACS).
Time frame: From the first study drug injection up to 2 days after the last study drug injection (approximately up to Day 17)
Population: Safety population used.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fondaparinux Sodium 2.5 mg s.c. | Number of Participants With Major Bleeding During Treatment Period | 0 Participants |
Secondary
Number of Participants With Minor Bleeding and Any Bleeding (Major and/or Minor Bleeding)
Minor bleeding and any bleeding (major and/or minor bleeding) events were adjudicated by the CIACS. Minor bleeding was defined as clinically overt bleeding not meeting the criteria for major bleeding and considered more than expected in the clinical context. Any bleeding (major and/or minor bleeding) could be recorded may be major and/or minor.
Time frame: From the first study drug injection up to 2 days after the last study drug injection (approximately up to Day 17)
Population: Safety population used.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fondaparinux Sodium 2.5 mg s.c. | Number of Participants With Minor Bleeding and Any Bleeding (Major and/or Minor Bleeding) | Minor Bleeding | 0 Participants |
| Fondaparinux Sodium 2.5 mg s.c. | Number of Participants With Minor Bleeding and Any Bleeding (Major and/or Minor Bleeding) | Any Bleeding | 0 Participants |
Secondary
Number of Transfused Participants
Blood product transfusions consisted of packed red blood cells or fresh frozen plasma or both. This was done between Day 2 and 2 calendar days after the last injection.
Time frame: From the first study drug injection up to 2 days after the last study drug injection (approximately up to Day 17)
Population: Safety population used.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fondaparinux Sodium 2.5 mg s.c. | Number of Transfused Participants | 1 Participants |
Secondary
Rate of Distal Only DVT During Treatment Period
Rate (%) was defined as number of events divided by the number of participants evaluated multiplied by 100. Signs and symptoms suggestive of VTE included, but were not limited to lower extremity DVT: erythema, warmth, pain, swelling, tenderness. Intended treatment period started 24±2 hours after surgical closure. Venogram was obtained not later than 2 calendar days after the last study drug administration (between Day 11 and 17). These events were adjudicated by the CIACE. It was evaluated from the first study drug injection up to Day 17 or to first venogram, whichever occurred first.
Time frame: Up to Day 17
Population: Efficacy evaluable participants used. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fondaparinux Sodium 2.5 mg s.c. | Rate of Distal Only DVT During Treatment Period | 21.6 % of normalized events per participant |
Secondary
Rate of DVT During Treatment Period
Rate (%) was defined as number of events divided by the number of patients evaluated multiplied by 100. Signs and symptoms suggestive of VTE included, but were not limited to lower extremity DVT: erythema, warmth, pain, swelling, tenderness. Intended treatment period started 24±2 hours after surgical closure. Venogram was obtained not later than 2 calendar days after the last study drug administration (between Day 11 and 17). These events were adjudicated by the CIACE. It was evaluated from the first study drug injection up to Day 17 or to first venogram, whichever occurred first.
Time frame: Up to Day 17
Population: Efficacy evaluable participants used consisted of a subpopulation of safety population who were judged to be evaluable for all DVT and proximal DVT or distal only DVT by the site of occurrence (total/side of operation/opposite side of operation/both sides). Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fondaparinux Sodium 2.5 mg s.c. | Rate of DVT During Treatment Period | 21.6 % of normalized events per participant |
Secondary
Rate of PE During Treatment Period
Rate (%) was defined as number of events divided by the number of participants evaluated multiplied by 100. Signs and symptoms suggestive of VTE included, but were not limited to lower extremity PE: pleuritic chest pain, dyspnea, cough, hemoptysis, syncope, light-headedness/dizziness, tachypnea, and tachycardia. Intended treatment period started 24±2 hours after surgical closure. Venogram was obtained not later than 2 calendar days after the last study drug administration (between Day 11 and 17). These events were adjudicated by the CIACE. It was evaluated from the first study drug injection up to Day 17 or to first venogram, whichever occurred first.
Time frame: Up to Day 17
Population: Safety population used which consisted of all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fondaparinux Sodium 2.5 mg s.c. | Rate of PE During Treatment Period | 0 % of normalized events per participant |
Secondary
Rate of Proximal DVT During Treatment Period
Rate (%) was defined as number of events divided by the number of participants evaluated multiplied by 100. Signs and symptoms suggestive of VTE included, but were not limited to lower extremity DVT: erythema, warmth, pain, swelling, tenderness. Intended treatment period started 24±2 hours after surgical closure. Venogram was obtained not later than 2 calendar days after the last study drug administration (between Day 11 and 17). These events were adjudicated by the CIACE. It was evaluated from the first study drug injection up to Day 17 or to first venogram, whichever occurred first.
Time frame: Up to Day 17
Population: Efficacy evaluable participants used. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fondaparinux Sodium 2.5 mg s.c. | Rate of Proximal DVT During Treatment Period | 2.6 % of normalized events per participant |
Secondary
Rate of Symptomatic DVT
Rate (%) was defined as number of events divided by the number of participants evaluated multiplied by 100. Signs and symptoms suggestive of VTE included, but were not limited to lower extremity DVT: erythema, warmth, pain, swelling, tenderness. Intended treatment period started 24±2 hours after surgical closure. Venogram was obtained not later than 2 calendar days after the last study drug administration (between Day 11 and 17). These events were adjudicated by the CIACE. It was evaluated from the first study drug injection up to Day 17 or to first venogram, whichever occurred first.
Time frame: Up to Day 17
Population: Safety population used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fondaparinux Sodium 2.5 mg s.c. | Rate of Symptomatic DVT | 0 % of normalized events per participant |
Secondary
Summary of Units Transfused
Blood product transfusions consisted of packed red blood cells or fresh frozen plasma or both. This was done between Day 2 and 2 calendar days after the last injection.
Time frame: From the first study drug injection up to 2 days after the last study drug injection (approximately up to Day 17)
Population: Safety population used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fondaparinux Sodium 2.5 mg s.c. | Summary of Units Transfused | 280 mL |