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Active Comparator-Controlled Study to Assess Safety and Efficacy of ISIS-FXIRx in Total Knee Arthroplasty

Primary Purpose

Venous Thromboembolism

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ISIS-FXIRx Dose #2
ISIS-FXIRx Dose #3
Enoxaparin
Sponsored by
Ionis Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Venous Thromboembolism focused on measuring total knee arthroplasty, Prophylaxis

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Give written informed consent
  • Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal. Males must be surgically sterile, abstinent, or if engaged in sexual relations of child-bearing potential, must use contraception
  • Undergoing elective, primary unilateral total knee arthroplasty

Exclusion Criteria:

  • Body weight <50 kg
  • Patients at increased risk of bleeding. History of intracranial or intraocular bleeding. History of gastrointestinal and/or endoscopically verified ulcer disease within the past year.
  • History of excessive intra- or direct post operative bleeding or a traumatic spinal or epidural anesthesia
  • Brain, spinal, or ophthalmologic surgery within the past 3 months
  • History of clinically significant liver disease in the past year

  • Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values

    • aPTT or PT or INR >ULN
    • Factor IX activity <LLN
    • Factor VIII activity, vWF antigen or Ristocetin cofactor activity <0.5 U/mL
    • FXI activity <0.3 U/mL
    • Urine protein or blood persistently positive by dipstick. In the event of positive test results, eligibility may be confirmed with urine microscopy or 24 hour urine protein measurement as applicable
    • ALT or AST >1.5 x ULN
    • Total bilirubin >ULN
    • Platelet count <150,000 (or history of thrombocytopenia)
  • Hypersensitivity to enoxaparin
  • Anticipated concomitant use of anticoagulants/antiplatelet agents or the NSAID nimesulide that may affect study outcome or any other drug influencing coagulation (except low dose aspirin and short acting NSAIDs with a half-life <20 hours) at least 7 days before surgery or during treatment with ISIS Rx.
  • Anticipated use of indwelling intrathecal or epidural catheters
  • Anemia at Screening
  • Have any other conditions which could interfere with the patient participating in or completing the study

Sites / Locations

  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site
  • Isis Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

ISIS-FXIRx Dose 2

ISIS-FXIRx Dose 3

Enoxaparin

Arm Description

Group B: ISIS-FXIRx Dose #2

Group C: ISIS-FXIRx Dose #3

Enoxaparin (40mg)

Outcomes

Primary Outcome Measures

Primary efficacy outcome
Composite of asymptomatic DVT (via bilateral venography), and symptomatic VTE, fatal PE, and unexplained death.

Secondary Outcome Measures

Secondary efficacy outcome
All DVTs and PEs up to 4 weeks after bilateral venography

Full Information

First Posted
October 4, 2012
Last Updated
August 25, 2014
Sponsor
Ionis Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01713361
Brief Title
Active Comparator-Controlled Study to Assess Safety and Efficacy of ISIS-FXIRx in Total Knee Arthroplasty
Official Title
An Open-label, Randomized, Active Comparator-Controlled, Adaptive Parallel-group Phase 2 Study to Assess the Safety and Efficacy of Multiple Doses of ISIS 416858 Administered Subcutaneously to Patients Undergoing Total Knee Arthroplasty
Study Type
Interventional

2. Study Status

Record Verification Date
August 2014
Overall Recruitment Status
Completed
Study Start Date
October 2012 (undefined)
Primary Completion Date
May 2014 (Actual)
Study Completion Date
August 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ionis Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is: To assess the safety and efficacy profile of ISIS-FXIRx, including incidence of bleeding and VTE, in patients undergoing total knee arthroplasty. To compare the efficacy and safety profile of ISIS-FXIRx in patients who achieve less than or equal to 0.2 U/mL FXI activity levels to that of enoxaparin.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Venous Thromboembolism
Keywords
total knee arthroplasty, Prophylaxis

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
315 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ISIS-FXIRx Dose 2
Arm Type
Experimental
Arm Description
Group B: ISIS-FXIRx Dose #2
Arm Title
ISIS-FXIRx Dose 3
Arm Type
Experimental
Arm Description
Group C: ISIS-FXIRx Dose #3
Arm Title
Enoxaparin
Arm Type
Active Comparator
Arm Description
Enoxaparin (40mg)
Intervention Type
Drug
Intervention Name(s)
ISIS-FXIRx Dose #2
Other Intervention Name(s)
ISIS-FXIRx
Intervention Description
Group B: ISIS-FXIRx dose #2 subcutaneously administered 7 times prior to total knee arthroplasty, and 2 times after surgery.
Intervention Type
Drug
Intervention Name(s)
ISIS-FXIRx Dose #3
Other Intervention Name(s)
ISIS-FXIRx
Intervention Description
Group C: ISIS-FXIRx dose #3 subcutaneously administered 7 times prior to total knee arthroplasty, and 2 times after surgery.
Intervention Type
Drug
Intervention Name(s)
Enoxaparin
Other Intervention Name(s)
Lovenox, Clexane
Intervention Description
Enoxaparin (40mg) will be administered by subcutaneous injection the evening prior to total knee arthroplasty (optionally), 6 to 8 hours after surgery, followed by daily injections for at least 8 additional days post surgery (a total of at least 9 consecutive days). [Except for Canadian region, in which the subcutaneous injection of enoxaparin the evening prior to total knee arthroplasty is expected, resulting in a total of at least 10 consecutive days of enoxaparin.]
Primary Outcome Measure Information:
Title
Primary efficacy outcome
Description
Composite of asymptomatic DVT (via bilateral venography), and symptomatic VTE, fatal PE, and unexplained death.
Time Frame
up to 12 days post-surgery
Secondary Outcome Measure Information:
Title
Secondary efficacy outcome
Description
All DVTs and PEs up to 4 weeks after bilateral venography
Time Frame
1st dose to up to Day 76

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Give written informed consent Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal. Males must be surgically sterile, abstinent, or if engaged in sexual relations of child-bearing potential, must use contraception Undergoing elective, primary unilateral total knee arthroplasty Exclusion Criteria: Body weight <50 kg Patients at increased risk of bleeding. History of intracranial or intraocular bleeding. History of gastrointestinal and/or endoscopically verified ulcer disease within the past year. History of excessive intra- or direct post operative bleeding or a traumatic spinal or epidural anesthesia Brain, spinal, or ophthalmologic surgery within the past 3 months History of clinically significant liver disease in the past year Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values aPTT or PT or INR >ULN Factor IX activity <LLN Factor VIII activity, vWF antigen or Ristocetin cofactor activity <0.5 U/mL FXI activity <0.3 U/mL Urine protein or blood persistently positive by dipstick. In the event of positive test results, eligibility may be confirmed with urine microscopy or 24 hour urine protein measurement as applicable ALT or AST >1.5 x ULN Total bilirubin >ULN Platelet count <150,000 (or history of thrombocytopenia) Hypersensitivity to enoxaparin Anticipated concomitant use of anticoagulants/antiplatelet agents or the NSAID nimesulide that may affect study outcome or any other drug influencing coagulation (except low dose aspirin and short acting NSAIDs with a half-life <20 hours) at least 7 days before surgery or during treatment with ISIS Rx. Anticipated use of indwelling intrathecal or epidural catheters Anemia at Screening Have any other conditions which could interfere with the patient participating in or completing the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sanjay Bhanot, MD, PhD
Organizational Affiliation
VP, Clinical Development, Isis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Isis Investigational Site
City
Plovdiv
ZIP/Postal Code
4002
Country
Bulgaria
Facility Name
Isis Investigational Site
City
Rousse
ZIP/Postal Code
7002
Country
Bulgaria
Facility Name
Isis Investigational Site
City
Sofia
ZIP/Postal Code
1527
Country
Bulgaria
Facility Name
Isis Investigational Site
City
Ajax
State/Province
Ontario
ZIP/Postal Code
LIS 2J4
Country
Canada
Facility Name
Isis Investigational Site
City
Oshawa
State/Province
Ontario
ZIP/Postal Code
LIG 2B9
Country
Canada
Facility Name
Isis Investigational Site
City
Adazi
ZIP/Postal Code
LV 2164
Country
Latvia
Facility Name
Isis Investigational Site
City
Riga
ZIP/Postal Code
LV 1004
Country
Latvia
Facility Name
Isis Investigational Site
City
Valmiera
ZIP/Postal Code
LV4201
Country
Latvia
Facility Name
Isis Investigational Site
City
Chelyabinsk
ZIP/Postal Code
454026
Country
Russian Federation
Facility Name
Isis Investigational Site
City
Orenburg
ZIP/Postal Code
460000
Country
Russian Federation
Facility Name
Isis Investigational Site
City
Saint Petersburg
ZIP/Postal Code
193312
Country
Russian Federation
Facility Name
Isis Investigational Site
City
Saint Petersburg
ZIP/Postal Code
194291
Country
Russian Federation
Facility Name
Isis Investigational Site
City
Saint Petersburg
ZIP/Postal Code
194354
Country
Russian Federation
Facility Name
Isis Investigational Site
City
Samara
ZIP/Postal Code
443095
Country
Russian Federation
Facility Name
Isis Investigational Site
City
Yaroslavl
ZIP/Postal Code
150047
Country
Russian Federation
Facility Name
Isis Investigational Site
City
Cherkassy
ZIP/Postal Code
18009
Country
Ukraine
Facility Name
Isis Investigational Site
City
Ivano-Frankivsk
ZIP/Postal Code
76000
Country
Ukraine
Facility Name
Isis Investigational Site
City
Kharkiv
ZIP/Postal Code
61024
Country
Ukraine
Facility Name
Isis Investigational Site
City
Kyiv
ZIP/Postal Code
01107
Country
Ukraine
Facility Name
Isis Investigational Site
City
Odessa
ZIP/Postal Code
65025
Country
Ukraine
Facility Name
Isis Investigational Site
City
Sevastopol
ZIP/Postal Code
99018
Country
Ukraine

12. IPD Sharing Statement

Citations:
PubMed Identifier
25482425
Citation
Buller HR, Bethune C, Bhanot S, Gailani D, Monia BP, Raskob GE, Segers A, Verhamme P, Weitz JI; FXI-ASO TKA Investigators. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015 Jan 15;372(3):232-40. doi: 10.1056/NEJMoa1405760. Epub 2014 Dec 7.
Results Reference
derived

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Active Comparator-Controlled Study to Assess Safety and Efficacy of ISIS-FXIRx in Total Knee Arthroplasty

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