Thrombosis, Venous
Conditions
Keywords
superficial vein thrombosis, superficial thrombophlebitis, fondaparinux, deep vein thrombosis, venous thromboembolism treatment, thrombosis
Brief summary
To evaluate fondaparinux 2.5mg subcutaneously once daily for 45 days in the treatment of acute (recent) superficial thrombophlebitis.
Detailed description
Comparison of ARIXTRA™ in lower LImb Superficial Thrombophlebitis with placebo (CALISTO). An International, Multicentre, Randomised, Double-blind, Placebo-controlled, Two-parallel Group, Phase III Study to Evaluate the Efficacy and Safety of ARIXTRA (2.5 mg subcutaneously) for the Treatment of Patients with Acute Symptomatic Isolated Superficial Thrombophlebitis of the Lower Limbs to prevent Thromboembolic Complications
Interventions
DRUGFondaparinux 2.5mg or placebo
Fondaparinux 2.5mg or matching placebo subcutaneously once daily up to day 45 day
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Acute symptomatic superficial thrombophlebitis of the lower limbs at least 5 cm long diagnosed by compression ultrasound.
Exclusion criteria
* Superficial thrombophlebitis that is within 3 cm from the sapheno-femoral junction, * deep vein thrombosis on ultrasound exam, deep vein thrombosis or pulmonary embolism within last 6 months, treatment for cancer during last 6 months, * anticoagulant medication for more than 48 hours prior to inclusion, * need for oral non-steroidal anti-inflammatory drugs during the study, significant bleeding event during past month, * major surgery within last 3 months, low platelet count (below 100×109/L), * kidney disease (Calculated creatinine clearance \< 30 mL/min), woman of child-bearing potential not using reliable contraceptive method
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least on Event of Venous Thromboembolism (VTE) and/or Death From Any Cause Recorded up to Day 47 | Baseline to Day 47 | VTE was defined as a composite of symptomatic deep-vein thrombosis (DVT), symptomatic pulmonary embolism (PE), symptomatic extension of superficial vein thrombosis (SVT), or symptomatic recurrence of SVT. All VTEs were confirmed by objective tests and then adjudicated by an independent central adjudication committee (CAC), whose members were blinded to treatment assignment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least One Event of Venous Thromboembolism (VTE) and/or Death From Any Cause Recorded up to Day 77 | Baseline to Day 77 | VTE was defined as a composite of symptomatic deep-vein thrombosis (DVT), symptomatic pulmonary embolism (PE), symptomatic extension of superficial vein thrombosis (SVT), or symptomatic recurrence of SVT. All VTEs were confirmed by objective tests and then adjudicated by an independent central adjudication committee (CAC), whose members were blinded to treatment assignment. |
| Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Days 47 and 77 | VTE was defined as a composite of symptomatic DVT; symptomatic PE; symptomatic extension of SVT, defined as downstream progression of the initial SVT by at least 2 cm and to within \<=3 cm from the sapheno-femoral junction; or symptomatic recurrence of SVT, defined as a new episode in any other superficial venous location, meeting the following criteria: the new SVT was in a different superficial vein and not directly contiguous upstream with the index SVT, or it was in the same superficial vein but clearly distinct from the index SVT with an open venous segment of at least 10 cm in length. |
| Number of Participants Who Required Surgery to Treat Superficial Vein Thrombosis Recurrence at Days 47 and 77 | Days 47 and 77 | The number of participants requiring surgery was measured. |
| Number of Adjudicated Non-Major Bleeding Events at Days 47 and 77 | Days 47 (or last dose plus 4 days) and 77 | Clinically relevant non-major bleeding was defined as clinically relevant bleeding that did not qualify as major but satisfied a priori criteria, and/or any bleeding that resulted in clinical consequences for a participant. The revision of the Day 47 time point was to account for participants with treatment duration longer than 45 days. Adverse events were evaluated On-Treatment, defined as from randomization up to the last injection +4 days. |
| Number of Any Adjudicated Bleeding Events at Days 47 and 77 | Days 47 (or last dose plus 4 days) and 77 | The sum of adjudicated major bleeds, non-major clinically relevant bleeds, and minor bleeds was calculated. Minor bleeding was defined as other clinically overt bleeding events that did not meet the criteria for major or clinically relevant non-major bleeding. The revision of the Day 47 time point was to account for participants with treatment duration longer than 45 days. Adverse events were evaluated On-Treatment, defined as from randomization up to the last injection +4 days. |
| Number of Adjudicated Major Bleeding Events and Deaths at Days 47 and 77 | Days 47 (or last dose plus 4 days) and 77 | Major bleeding was defined as bleeding that was fatal and/or (1) in a critical area/organ (e.g., intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome); (2) associated with a fall in hemoglobin \>=20 g/L (1.24 mmol/L); (3) led to a transfusion of \>=2 units of packed red blood cells/whole blood. The revision of the Day 47 time point was to account for participants with treatment duration longer than 45 days. Adverse events were evaluated On-Treatment, defined as from randomization up to the last injection +4 days. |
Countries
Bulgaria, Czechia, Estonia, France, Germany, Greece, Hungary, Israel, Italy, Latvia, Netherlands, Poland, Russia, Slovakia, Spain, Switzerland, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fondaparinux 2.5 mg Fondaparinux 2.5 milligrams (mg) administered subcutaneously (SC) once daily for 45 days | 1,502 |
| Placebo Matching placebo | 1,500 |
| Total | 3,002 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Did Not Meet Eligibility Criteria | 1 | 0 |
| Overall Study | Lost to Follow-up | 4 | 5 |
| Overall Study | Noncompliance | 2 | 1 |
| Overall Study | Other | 3 | 4 |
| Overall Study | Physician Decision | 0 | 4 |
| Overall Study | Withdrawal by Subject | 9 | 18 |
Baseline characteristics
| Characteristic | Fondaparinux 2.5 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 57.1 years STANDARD_DEVIATION 13.29 | 56.9 years STANDARD_DEVIATION 13.56 | 57.0 years STANDARD_DEVIATION 13.43 |
| Race/Ethnicity, Customized African American Heritage | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Arabic/North African Heritage | 15 participants | 4 participants | 19 participants |
| Race/Ethnicity, Customized Asian/South Asian Heritage | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Missing | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Mixed Race | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White, European Heritage | 1485 participants | 1492 participants | 2977 participants |
| Sex: Female, Male Female | 974 Participants | 944 Participants | 1918 Participants |
| Sex: Female, Male Male | 528 Participants | 556 Participants | 1084 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 95 / 1,499 | 79 / 1,488 |
| serious Total, serious adverse events | 10 / 1,499 | 16 / 1,488 |
Outcome results
Primary
Number of Participants With at Least on Event of Venous Thromboembolism (VTE) and/or Death From Any Cause Recorded up to Day 47
VTE was defined as a composite of symptomatic deep-vein thrombosis (DVT), symptomatic pulmonary embolism (PE), symptomatic extension of superficial vein thrombosis (SVT), or symptomatic recurrence of SVT. All VTEs were confirmed by objective tests and then adjudicated by an independent central adjudication committee (CAC), whose members were blinded to treatment assignment.
Time frame: Baseline to Day 47
Population: Intent-to-Treat (ITT) Population: all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fondaparinux 2.5 mg | Number of Participants With at Least on Event of Venous Thromboembolism (VTE) and/or Death From Any Cause Recorded up to Day 47 | 13 participants |
| Placebo | Number of Participants With at Least on Event of Venous Thromboembolism (VTE) and/or Death From Any Cause Recorded up to Day 47 | 88 participants |
p-value: <0.00195% CI: [0.08, 0.26]Fisher Exact
Secondary
Number of Adjudicated Major Bleeding Events and Deaths at Days 47 and 77
Major bleeding was defined as bleeding that was fatal and/or (1) in a critical area/organ (e.g., intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome); (2) associated with a fall in hemoglobin \>=20 g/L (1.24 mmol/L); (3) led to a transfusion of \>=2 units of packed red blood cells/whole blood. The revision of the Day 47 time point was to account for participants with treatment duration longer than 45 days. Adverse events were evaluated On-Treatment, defined as from randomization up to the last injection +4 days.
Time frame: Days 47 (or last dose plus 4 days) and 77
Population: As-Treated Population: randomized participants who received at least one dose of study treatment, as actually received
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux 2.5 mg | Number of Adjudicated Major Bleeding Events and Deaths at Days 47 and 77 | Major bleeding events, Day 47 | 1 events |
| Fondaparinux 2.5 mg | Number of Adjudicated Major Bleeding Events and Deaths at Days 47 and 77 | Deaths, Day 47 | 2 events |
| Fondaparinux 2.5 mg | Number of Adjudicated Major Bleeding Events and Deaths at Days 47 and 77 | Major bleeding events, Day 77 | 1 events |
| Fondaparinux 2.5 mg | Number of Adjudicated Major Bleeding Events and Deaths at Days 47 and 77 | Deaths, Day 77 | 2 events |
| Placebo | Number of Adjudicated Major Bleeding Events and Deaths at Days 47 and 77 | Deaths, Day 77 | 1 events |
| Placebo | Number of Adjudicated Major Bleeding Events and Deaths at Days 47 and 77 | Major bleeding events, Day 47 | 1 events |
| Placebo | Number of Adjudicated Major Bleeding Events and Deaths at Days 47 and 77 | Major bleeding events, Day 77 | 1 events |
| Placebo | Number of Adjudicated Major Bleeding Events and Deaths at Days 47 and 77 | Deaths, Day 47 | 1 events |
Secondary
Number of Adjudicated Non-Major Bleeding Events at Days 47 and 77
Clinically relevant non-major bleeding was defined as clinically relevant bleeding that did not qualify as major but satisfied a priori criteria, and/or any bleeding that resulted in clinical consequences for a participant. The revision of the Day 47 time point was to account for participants with treatment duration longer than 45 days. Adverse events were evaluated On-Treatment, defined as from randomization up to the last injection +4 days.
Time frame: Days 47 (or last dose plus 4 days) and 77
Population: As-Treated Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux 2.5 mg | Number of Adjudicated Non-Major Bleeding Events at Days 47 and 77 | Day 47 | 5 events |
| Fondaparinux 2.5 mg | Number of Adjudicated Non-Major Bleeding Events at Days 47 and 77 | Day 77 | 6 events |
| Placebo | Number of Adjudicated Non-Major Bleeding Events at Days 47 and 77 | Day 47 | 8 events |
| Placebo | Number of Adjudicated Non-Major Bleeding Events at Days 47 and 77 | Day 77 | 9 events |
Secondary
Number of Any Adjudicated Bleeding Events at Days 47 and 77
The sum of adjudicated major bleeds, non-major clinically relevant bleeds, and minor bleeds was calculated. Minor bleeding was defined as other clinically overt bleeding events that did not meet the criteria for major or clinically relevant non-major bleeding. The revision of the Day 47 time point was to account for participants with treatment duration longer than 45 days. Adverse events were evaluated On-Treatment, defined as from randomization up to the last injection +4 days.
Time frame: Days 47 (or last dose plus 4 days) and 77
Population: As-Treated Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux 2.5 mg | Number of Any Adjudicated Bleeding Events at Days 47 and 77 | Day 47 | 15 events |
| Fondaparinux 2.5 mg | Number of Any Adjudicated Bleeding Events at Days 47 and 77 | Day 77 | 16 events |
| Placebo | Number of Any Adjudicated Bleeding Events at Days 47 and 77 | Day 47 | 14 events |
| Placebo | Number of Any Adjudicated Bleeding Events at Days 47 and 77 | Day 77 | 15 events |
Secondary
Number of Participants Who Required Surgery to Treat Superficial Vein Thrombosis Recurrence at Days 47 and 77
The number of participants requiring surgery was measured.
Time frame: Days 47 and 77
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux 2.5 mg | Number of Participants Who Required Surgery to Treat Superficial Vein Thrombosis Recurrence at Days 47 and 77 | Day 47 | 11 participants |
| Fondaparinux 2.5 mg | Number of Participants Who Required Surgery to Treat Superficial Vein Thrombosis Recurrence at Days 47 and 77 | Day 77 | 15 participants |
| Placebo | Number of Participants Who Required Surgery to Treat Superficial Vein Thrombosis Recurrence at Days 47 and 77 | Day 47 | 57 participants |
| Placebo | Number of Participants Who Required Surgery to Treat Superficial Vein Thrombosis Recurrence at Days 47 and 77 | Day 77 | 61 participants |
Secondary
Number of Participants With at Least One Event of Venous Thromboembolism (VTE) and/or Death From Any Cause Recorded up to Day 77
VTE was defined as a composite of symptomatic deep-vein thrombosis (DVT), symptomatic pulmonary embolism (PE), symptomatic extension of superficial vein thrombosis (SVT), or symptomatic recurrence of SVT. All VTEs were confirmed by objective tests and then adjudicated by an independent central adjudication committee (CAC), whose members were blinded to treatment assignment.
Time frame: Baseline to Day 77
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fondaparinux 2.5 mg | Number of Participants With at Least One Event of Venous Thromboembolism (VTE) and/or Death From Any Cause Recorded up to Day 77 | 18 participants |
| Placebo | Number of Participants With at Least One Event of Venous Thromboembolism (VTE) and/or Death From Any Cause Recorded up to Day 77 | 94 participants |
p-value: <0.00195% CI: [0.12, 0.32]Fisher Exact
Secondary
Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77
VTE was defined as a composite of symptomatic DVT; symptomatic PE; symptomatic extension of SVT, defined as downstream progression of the initial SVT by at least 2 cm and to within \<=3 cm from the sapheno-femoral junction; or symptomatic recurrence of SVT, defined as a new episode in any other superficial venous location, meeting the following criteria: the new SVT was in a different superficial vein and not directly contiguous upstream with the index SVT, or it was in the same superficial vein but clearly distinct from the index SVT with an open venous segment of at least 10 cm in length.
Time frame: Days 47 and 77
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux 2.5 mg | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic DVT, D 47 | 3 participants |
| Fondaparinux 2.5 mg | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic PE, D 47 | 0 participants |
| Fondaparinux 2.5 mg | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Death, D 77 | 2 participants |
| Fondaparinux 2.5 mg | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic recurrence of SVT, D 47 | 5 participants |
| Fondaparinux 2.5 mg | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic PE, D 77 | 0 participants |
| Fondaparinux 2.5 mg | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Death, D 47 | 2 participants |
| Fondaparinux 2.5 mg | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic DVT, D 77 | 4 participants |
| Fondaparinux 2.5 mg | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Participants with at least one event, D 77 | 18 participants |
| Fondaparinux 2.5 mg | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic recurrence of SVT, D 77 | 8 participants |
| Fondaparinux 2.5 mg | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic extension of SVT, D 47 | 4 participants |
| Fondaparinux 2.5 mg | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic extension of SVT, D 77 | 5 participants |
| Fondaparinux 2.5 mg | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Participants with at least one event, D 47 | 13 participants |
| Placebo | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic extension of SVT, D 77 | 54 participants |
| Placebo | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Participants with at least one event, D 47 | 88 participants |
| Placebo | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Death, D 47 | 1 participants |
| Placebo | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic PE, D 47 | 5 participants |
| Placebo | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic DVT, D 47 | 18 participants |
| Placebo | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic recurrence of SVT, D 47 | 24 participants |
| Placebo | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic extension of SVT, D 47 | 51 participants |
| Placebo | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Participants with at least one event, D 77 | 94 participants |
| Placebo | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Death, D 77 | 1 participants |
| Placebo | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic PE, D 77 | 6 participants |
| Placebo | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic DVT, D 77 | 19 participants |
| Placebo | Number of Participants With at Least One Occurrence of Each Adjudicated Component of the Primary Efficacy Endpoint at Days (D) 47 and 77 | Symptomatic recurrence of SVT, D 77 | 26 participants |