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

Venous Thromboembolism Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01713361
• Other study ID #: ISIS 416858-CS3
• Status: Completed
• Phase: Phase 2
• First received: October 4, 2012
• Last updated: August 25, 2014
• Start date: October 2012
• Est. completion date: August 2014

Study information

• Verified date: August 2014
• Source: Ionis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health CanadaRussia: Ministry of Health of the Russian FederationUkraine: Ministry of HealthLatvia: State Agency of MedicinesBulgaria: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 315
• Est. completion date: August 2014
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Thromboembolism
• Venous Thromboembolism

Intervention

Drug:
• ISIS-FXIRx Dose #2
Group B: ISIS-FXIRx dose #2 subcutaneously administered 7 times prior to total knee arthroplasty, and 2 times after surgery.
• ISIS-FXIRx Dose #3
Group C: ISIS-FXIRx dose #3 subcutaneously administered 7 times prior to total knee arthroplasty, and 2 times after surgery.
• Enoxaparin
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.]

Locations

Country	Name	City	State
Bulgaria	Isis Investigational Site	Plovdiv
Bulgaria	Isis Investigational Site	Rousse
Bulgaria	Isis Investigational Site	Sofia
Canada	Isis Investigational Site	Ajax	Ontario
Canada	Isis Investigational Site	Oshawa	Ontario
Latvia	Isis Investigational Site	Adazi
Latvia	Isis Investigational Site	Riga
Latvia	Isis Investigational Site	Valmiera
Russian Federation	Isis Investigational Site	Chelyabinsk
Russian Federation	Isis Investigational Site	Orenburg
Russian Federation	Isis Investigational Site	Saint Petersburg
Russian Federation	Isis Investigational Site	Saint Petersburg
Russian Federation	Isis Investigational Site	Saint Petersburg
Russian Federation	Isis Investigational Site	Samara
Russian Federation	Isis Investigational Site	Yaroslavl
Ukraine	Isis Investigational Site	Cherkassy
Ukraine	Isis Investigational Site	Ivano-Frankivsk
Ukraine	Isis Investigational Site	Kharkiv
Ukraine	Isis Investigational Site	Kyiv
Ukraine	Isis Investigational Site	Odessa
Ukraine	Isis Investigational Site	Sevastopol

Sponsors (1)

Lead Sponsor	Collaborator
Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

Bulgaria,  Canada,  Latvia,  Russian Federation,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary efficacy outcome	Composite of asymptomatic DVT (via bilateral venography), and symptomatic VTE, fatal PE, and unexplained death.	up to 12 days post-surgery	Yes
Secondary	Secondary efficacy outcome	All DVTs and PEs up to 4 weeks after bilateral venography	1st dose to up to Day 76	Yes