Clinical trial NCT01713361: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Venous Thromboembolism
Keywords: total knee arthroplasty
Prophylaxis
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2012-10-24
Enrollment: 315
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


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

Primary outcomes:
measure: Primary efficacy outcome
timeFrame: up to 12 days post-surgery
Secondary outcomes:
measure: Secondary efficacy outcome
timeFrame: 1st dose to up to Day 76
Other outcomes:
Locations:
city: Plovdiv
country: Bulgaria
facility: Isis Investigational Site
city: Rousse
country: Bulgaria
facility: Isis Investigational Site
city: Sofia
country: Bulgaria
facility: Isis Investigational Site
city: Ajax
country: Canada
facility: Isis Investigational Site
state: Ontario
city: Oshawa
country: Canada
facility: Isis Investigational Site
state: Ontario
city: Adazi
country: Latvia
facility: Isis Investigational Site
city: Riga
country: Latvia
facility: Isis Investigational Site
city: Valmiera
country: Latvia
facility: Isis Investigational Site
city: Chelyabinsk
country: Russian Federation
facility: Isis Investigational Site
city: Orenburg
country: Russian Federation
facility: Isis Investigational Site
city: Saint Petersburg
country: Russian Federation
facility: Isis Investigational Site
city: Saint Petersburg
country: Russian Federation
facility: Isis Investigational Site
city: Saint Petersburg
country: Russian Federation
facility: Isis Investigational Site
city: Samara
country: Russian Federation
facility: Isis Investigational Site
city: Yaroslavl
country: Russian Federation
facility: Isis Investigational Site
city: Cherkassy
country: Ukraine
facility: Isis Investigational Site
city: Ivano-Frankivsk
country: Ukraine
facility: Isis Investigational Site
city: Kharkiv
country: Ukraine
facility: Isis Investigational Site
city: Kyiv
country: Ukraine
facility: Isis Investigational Site
city: Odessa
country: Ukraine
facility: Isis Investigational Site
city: Sevastopol
country: Ukraine
facility: Isis Investigational Site
Study officials:
affiliation: VP, Clinical Development, Isis Pharmaceuticals
name: Sanjay Bhanot, MD, PhD
role: STUDY_DIRECTOR
References:
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.