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The API-CALF Study: Apixaban to Treat Calf Vein Thrombosis (API-CALF)

Primary Purpose

Deep Vein Thrombosis

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Apixaban 2.5 MG Oral Tablet [ELIQUIS]
Sponsored by
University Hospital, Geneva
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Deep Vein Thrombosis focused on measuring Isolated distal deep vein thrombosis, Anticoagulation, Direct oral anticoagulants

Eligibility Criteria

18 Years - 120 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Consecutive patients with acute (symptoms <10 days) symptomatic iDDVT diagnosed on leg CUS who have none of the following exclusion criteria and who provided informed consent to participate. Diagnosis of iDDVT is made in the presence of an incompressible distal deep vein (deep calf vein (posterior tibial, anterior tibial or peroneal veins) or muscular vein (soleal or gastrocnemius veins)).

Exclusion Criteria:

  • Age < 18 years
  • Ipsi or contralateral Proximal DVT
  • Distal DVT involving the tibio-peroneal trunk (i.e. calf trifurcation)
  • DVT occurring while on anticoagulation (started ≥48hours before DVT diagnosis); However, inpatients that developed their iDDVT while on prophylactic anticoagulation are eligible if their expected date of discharge is <6 days post randomization.
  • Clinically suspected PE (patient eligible if PE ruled out with objective tests)
  • Active cancer, receiving cancer treatment or cured for < 6 months
  • Indication for long-term therapeutic anticoagulation (e.g. atrial fibrillation, mechanical heart valve…)
  • Thrombocytopenia (platelet count <100 g/l)
  • Severe renal impairment (creatinine clearance <30 ml/min)
  • Liver disease (including Child-Pugh Class B and C) associated with coagulopathy
  • Pregnant or breast-feeding woman
  • Body weight >120kg or <40 kg
  • Ongoing active bleeding or condition at high risk of bleeding with anticoagulation (e.g. peptic ulcer…)
  • Treatment with daily NSAIDs (aspirin ≤160 mg/day or clopidogrel ≤75 mg day permitted)
  • Allergy to Apixaban
  • Use of concomitant drugs that significantly interact with Apixaban: strong inhibitors of P-gp and CYP3A4 or strong inducers of CYP3A4
  • Treatment with anticoagulants at therapeutic dose >2 days after DVT diagnosis
  • Life expectancy < 1 year
  • Enrolled in another clinical trial within previous 30 days
  • Inability or refusal to provide informed consent

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Active Comparator

    Arm Label

    Experimental

    Standard

    Arm Description

    After a conventional course of 7 days of Apixaban 10mg BID, Apixaban 2.5mg BID during 3 months.

    After a conventional course of 7 days of Apixaban 10 mg BID, Apixaban 5 mg BID during 3 months.

    Outcomes

    Primary Outcome Measures

    Rate of i) symptomatic VTE; ii) major bleeding and clinically relevant non major bleeding (CRNMB); iii) VTE and bleeding related death.
    The primary outcome is a composite of rate of i) symptomatic VTE (includes iDDVT involving a new distal deep vein, proximal DVT or PE; ii) major bleeding and clinically relevant non major bleeding (CRNMB); iii) VTE and bleeding related death.

    Secondary Outcome Measures

    Individual components of the composite endpoint at 3 months and 1 year - Generic and venous disease-specific QOL scores at 1 year - Patient's compliance with treatment at 3 months - Serious adverse events during follow-up - PTS as measured at 1 year
    as above
    Generic and venous disease-specific QOL scores at 1 year
    QOL score
    Patient's observance with treatment at 3 months
    Observance of the patient
    Serious adverse events during follow-up
    Adverse events
    PTS as measured at 1 year
    Post thrombotic syndrome assessed with the Villalta scale

    Full Information

    First Posted
    July 7, 2021
    Last Updated
    July 22, 2021
    Sponsor
    University Hospital, Geneva
    Collaborators
    Sunnybrook Health Sciences Centre
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04981327
    Brief Title
    The API-CALF Study: Apixaban to Treat Calf Vein Thrombosis
    Acronym
    API-CALF
    Official Title
    The API-CALF Study: Apixaban to Treat Calf Vein Thrombosis
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2021
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    September 1, 2022 (Anticipated)
    Primary Completion Date
    August 31, 2026 (Anticipated)
    Study Completion Date
    August 31, 2027 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    University Hospital, Geneva
    Collaborators
    Sunnybrook Health Sciences Centre

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No

    5. Study Description

    Brief Summary
    Isolated distal DVT (iDDVT) is the most frequent clinical presentation of VTE and is associated with a significant morbidity and risks of long-term complications. Data from clinical trials highlighted that patients with iDDVT might require some level of AC treatment. However, the optimal anticoagulant intensity is uncertain, and it is plausible that the best benefit/risk ratio for AC might be achieved with lower intensity doses rather than therapeutic doses. The principal research question of the Apixaban to treat calf vein thrombosis (API-CALF) study is to determine whether, after a conventional course of 7 days of Apixaban 10mg BID, Apixaban 2.5mg BID (experimental arm) is non inferior to Apixaban 5 mg BID (standard arm) in preventing VTE recurrence and bleeding in patients with iDDVT. Patients will be treated with Apixaban for a total of 3 months. In that perspective we will conduct an international multicentre open-label assessor-blinded study
    Detailed Description
    Isolated distal deep vein thrombosis (iDDVT) is an infra-popliteal DVT, without concomitant proximal DVT and without pulmonary embolism (PE). Until recently, few large studies have focused on iDDVT, and the clinical significance and therapeutic management of iDDVT was mostly based on expert opinion and "gestalt" rather than on strong scientific data. iDDVT is the most frequent presentation of venous thromboembolic disease (VTE). Indeed, in the large French, multicentre, observational, OPTIMEV study, where all patients with suspected DVT underwent systematic whole leg compression ultrasound (CUS) exploration, iDDVT represented 56% of all DVTs. A similar high proportion of distal DVT among DVT (52.1%) was reported in Johnson's meta-analysis. The risk of proximal extension of iDDVT to the proximal veins is substantial. In an extensive review of the literature published 15 years ago, the investigators reported that the risk of proximal extension of iDDVT, whether treated or left untreated, ranged from 0-44%, underlining the heterogeneity of the available data. Data from the CALTHRO study and CACTUS trial and extrapolation of data from management studies comparing the safety of serial proximal CUS vs. whole leg CUS for DVT diagnosis suggest that the rate of extension of untreated iDDVT to proximal deep veins was ~ 10% and up to 28% in high-risk populations, such as patients with cancer (3, 7-9). This 10% average risk of proximal extension is far above the usual 2% cut-off for an acceptable false-negative rate for negative findings in DVT diagnostic strategies. Hence, from a strict natural history standpoint, clinical significance of iDDVT is no longer in question. In summary, iDDVT is the most frequent clinical presentation of VTE and patients with iDDVT are at significant risk of proximal extension and of adverse outcomes both in the short and in the long-term. Management of iDDVT is one of the most debated issue in the field of VTE. Thus, in all trials that validated the use of DOAC, distal location of DVT was an exclusion criterion. While the American society of Hematology (ASH) guidelines do not comment on iDDVT specific treatment, the American college of chest physicians (ACCP) guidelines state that only 'high risk' distal DVT should be systematically treated with anticoagulation. Non high risk iDDVT could benefit from surveillance by repeated CUS. However, in the international CACTUS study, the investigators observed that a primary reason for refusal of participation and failure to fulfil recruitment was that patients and their treating physicians refused that iDDVT be left untreated. In routine clinical practice, data from observational registries showed that the majority iDDVT are treated with full dose of anticoagulants: 97% of iDDVT in the French OPTIMEV study, 98% in the Italian MASTER registry and 99% in the international RIETE registry. These therapeutic attitudes reflect physicians' beliefs (and patients' preference) that anticoagulation is important in case of iDDVT. For proximal DVT and PE, "therapeutic" doses of anticoagulants are prescribed as use of lower doses was associated with an unacceptably high VTE risk. In contrast, for superficial vein thrombosis (SVT), "prophylactic" doses (fondaparinux 2.5mg or rivaroxaban 10 mg daily) were shown to be very effective and associated with a very low bleeding risk. Regarding iDDVT, risk of VTE recurrence and effectiveness of different dose regimen of anticoagulation are less clear and literature suggests that it could depend on patients' characteristics . Based on literature review, main risk factors for VTE extension/recurrence include cancer, calf trifurcation involvement, previous VTE, unprovoked character of DVT or presence of a permanent risk factor, and multiple vein distal vein thromboses. In the CACTUS study, at 3 months, the proportion of extension to proximal deep veins in the therapeutic anticoagulation arm was lower than in the placebo arm (3.3% vs. 6.2% at 3 months; p=NS), but the risk of significant bleeding was significantly higher (4.1% vs. 0.0%)(3). Namely, in CACTUS, the benefit of therapeutic anticoagulation in terms of VTE risk reduction was offset by the excess in risk of bleeding. In summary, iDDVT is the most frequent clinical presentation of VTE and is associated with a significant morbidity and risks of long-term complications. Data from clinical trials highlighted that patients with iDDVT might require some level of AC treatment. However, the optimal anticoagulant intensity is uncertain, and it is plausible that the best benefit/risk ratio for AC might be achieved with lower intensity doses rather than therapeutic doses. The principal research question of the Apixaban to treat calf vein thrombosis (API-CALF) study is to determine whether, after a conventional course of 7 days of Apixaban 10mg BID, Apixaban 2.5mg BID (experimental arm) is non inferior to Apixaban 5 mg BID (standard arm) in preventing VTE recurrence and bleeding in patients with iDDVT. Patients will be treated with Apixaban for a total of 3 months. In that perspective we will conduct an international multicentre open-label assessor-blinded study

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Deep Vein Thrombosis
    Keywords
    Isolated distal deep vein thrombosis, Anticoagulation, Direct oral anticoagulants

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    Outcomes Assessor
    Masking Description
    Strategies to protect against bias include randomization with allocation concealment, enrolling consecutive patients. Patients will be advised to not disclose to study personnel during follow-up to which arm they were randomized to. Adjudicators will be blinded from treatment allocation group, and we will use standardized, validated measures to diagnose DVT, PE, PTS, and bleeding. We plan to allow phone follow-up to limit the risk of lost to follow-up and the impact on patients' in person consultation of a COVID wave during the course of the study.
    Allocation
    Randomized
    Enrollment
    1300 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Experimental
    Arm Type
    Experimental
    Arm Description
    After a conventional course of 7 days of Apixaban 10mg BID, Apixaban 2.5mg BID during 3 months.
    Arm Title
    Standard
    Arm Type
    Active Comparator
    Arm Description
    After a conventional course of 7 days of Apixaban 10 mg BID, Apixaban 5 mg BID during 3 months.
    Intervention Type
    Drug
    Intervention Name(s)
    Apixaban 2.5 MG Oral Tablet [ELIQUIS]
    Other Intervention Name(s)
    Apixaban 5 MG Oral Tablet
    Intervention Description
    Apixaban 5 MG BID versus Apixaban 2.5 MG BID
    Primary Outcome Measure Information:
    Title
    Rate of i) symptomatic VTE; ii) major bleeding and clinically relevant non major bleeding (CRNMB); iii) VTE and bleeding related death.
    Description
    The primary outcome is a composite of rate of i) symptomatic VTE (includes iDDVT involving a new distal deep vein, proximal DVT or PE; ii) major bleeding and clinically relevant non major bleeding (CRNMB); iii) VTE and bleeding related death.
    Time Frame
    1 year
    Secondary Outcome Measure Information:
    Title
    Individual components of the composite endpoint at 3 months and 1 year - Generic and venous disease-specific QOL scores at 1 year - Patient's compliance with treatment at 3 months - Serious adverse events during follow-up - PTS as measured at 1 year
    Description
    as above
    Time Frame
    1 year
    Title
    Generic and venous disease-specific QOL scores at 1 year
    Description
    QOL score
    Time Frame
    1 year
    Title
    Patient's observance with treatment at 3 months
    Description
    Observance of the patient
    Time Frame
    3 months
    Title
    Serious adverse events during follow-up
    Description
    Adverse events
    Time Frame
    1 year
    Title
    PTS as measured at 1 year
    Description
    Post thrombotic syndrome assessed with the Villalta scale
    Time Frame
    1 year

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    120 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Consecutive patients with acute (symptoms <10 days) symptomatic iDDVT diagnosed on leg CUS who have none of the following exclusion criteria and who provided informed consent to participate. Diagnosis of iDDVT is made in the presence of an incompressible distal deep vein (deep calf vein (posterior tibial, anterior tibial or peroneal veins) or muscular vein (soleal or gastrocnemius veins)). Exclusion Criteria: Age < 18 years Ipsi or contralateral Proximal DVT Distal DVT involving the tibio-peroneal trunk (i.e. calf trifurcation) DVT occurring while on anticoagulation (started ≥48hours before DVT diagnosis); However, inpatients that developed their iDDVT while on prophylactic anticoagulation are eligible if their expected date of discharge is <6 days post randomization. Clinically suspected PE (patient eligible if PE ruled out with objective tests) Active cancer, receiving cancer treatment or cured for < 6 months Indication for long-term therapeutic anticoagulation (e.g. atrial fibrillation, mechanical heart valve…) Thrombocytopenia (platelet count <100 g/l) Severe renal impairment (creatinine clearance <30 ml/min) Liver disease (including Child-Pugh Class B and C) associated with coagulopathy Pregnant or breast-feeding woman Body weight >120kg or <40 kg Ongoing active bleeding or condition at high risk of bleeding with anticoagulation (e.g. peptic ulcer…) Treatment with daily NSAIDs (aspirin ≤160 mg/day or clopidogrel ≤75 mg day permitted) Allergy to Apixaban Use of concomitant drugs that significantly interact with Apixaban: strong inhibitors of P-gp and CYP3A4 or strong inducers of CYP3A4 Treatment with anticoagulants at therapeutic dose >2 days after DVT diagnosis Life expectancy < 1 year Enrolled in another clinical trial within previous 30 days Inability or refusal to provide informed consent
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Jean-Philippe Galanaud, MD, PhD
    Phone
    001
    Email
    Jean-Philippe.Galanaud@sunnybrook.ca
    First Name & Middle Initial & Last Name or Official Title & Degree
    Marc Righini, MD
    Phone
    +41223729294
    Email
    marc.righini@hcuge.ch
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Jean-Philippe Galanaud, MD, PhD
    Organizational Affiliation
    Sunnybrook Health Sciences Centre and University of Toronto, Toronto, Canada
    Official's Role
    Principal Investigator
    First Name & Middle Initial & Last Name & Degree
    Marc Righini, MD
    Organizational Affiliation
    Geneva University Hospital, Switzerland
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    IPD Sharing Plan Description
    Individual research subjects' data cannot legally nor ethically be made available to non authorised people (HRA, cf. §7). According to the research subjects' informed consent, only the sponsor, the investigation team, reviewers, auditors and inspection authorities are entitled to access such data.
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    The API-CALF Study: Apixaban to Treat Calf Vein Thrombosis

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