Clinical trial NCT01621204: A Trial of Eltrombopag or Intravenous Immune Globulin Before Surgery for Immune Thrombocytopenia Patients
Official title: Treatment of thromBocytopenia With EltRombopag or Intravenous Immune Globulin (IVIG) Before and DurING Invasive Procedures in Patients With Immune ThrombocytoPenia- BRIDGING ITP Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Immune Thrombocytopenic Purpura
Keywords: Thrombocytopenia
ITP
Platelets
Bleeding
Immune
Eltrombopag
IVIG
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
name: Hamilton Health Sciences Corporation
name: Novartis
First posted: 2012-06-18
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: This is a study to investigate if eltrombopag can be used instead of Intravenous Immune Globulin (IVIG) in patients with ITP, to adequately raise their platelet count when they undergo minor or major surgery. Eltrombopag is a daily, oral pill approved for treatment of ITP. IVIG is a blood product frequently used to treat ITP. Patients with ITP who need surgery have to get treatment to increase their platelet count. IVIG is commonly used for this purpose but eltrombopag may be more effective and convenient for patients.

Detailed description: Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disease characterized by the presence of platelet autoantibodies, low platelet counts and an increased risk of bleeding. TPO receptor agonists which stimulate platelet production have been shown to be remarkably effective in ITP. Their use as a short-term means of elevating platelet counts in preparation for surgical procedures has not yet been adequately evaluated.

Many patients with moderate to severe ITP (platelet count less than 50 x 10exp9/L) have stable platelet counts and do not bleed; however, when surgeries or invasive procedures become necessary, additional treatment is often required to increase the platelet count to achieve adequate hemostasis. Although specific guidelines for surgical platelet count thresholds in ITP are lacking, platelet transfusion guidelines recommend a platelet count of 50 - 100 x10exp9/L for the vast majority of surgical procedure; 50x10exp9/L is a typical threshold for minor surgeries like tooth extractions and endoscopies; and 100x10exp9/L is used for major surgery like cardiac surgery or neurosurgery.

Commonly, intravenous immunoglobulin (IVIG) is used to rapidly increase platelet counts in ITP patients before an invasive procedure. IVIG is associated with a transient platelet count response in approximately 80% of patients, which occurs within 2 - 4 days. In most patients, platelet counts remain elevated for approximately 4 weeks, allowing enough time to complete the procedure and for adequate post-operative hemostasis. However, IVIG is a resource-intensive and expensive blood product associated with frequent side effects.

Eltrombopag is a small molecule, non-peptide thrombopoietin (TPO) receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. TPO receptor agonists are an effective new class of medications that are non-immunogenic agonists of the TPO receptor (c-Mpl) and work by increasing platelet production in ITP patients. In randomized controlled trials, eltrombopag maintenance therapy has been shown to raise the platelet count in 60 - 80% of ITP patients and platelet counts generally remain elevated as long as the drug is continued. Time to response is 1 - 2 weeks with minimal need for dose titration. Side effects of eltrombopag observed in clinical studies included elevation of liver enzymes (approximately 10% of patients). The risk of thrombosis and bone marrow reticulin formation remain uncertain.

The investigators propose a randomized controlled trial (RCT) involving 74 patients (across approximately 8 centers) in Canada. This study will evaluate the efficacy and safety of eltrombopag bridging therapy compared with IVIG bridging therapy in adult patients with ITP who require surgery. This study will also evaluate bleeding, adverse events and patient-reported treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication (TSQM). Patients will be stratified according to centre and surgery type (major vs. minor).

Eligibility criteria: Inclusion Criteria:

* Primary or secondary ITP;
* Platelet count below surgical platelet count threshold (50 x10\^9/L for minor surgery; 100 x 10\^9/L for major surgery);
* 18 years of age or older;
* On stable doses of concomitant ITP medications (i.e the dose administered has not changed) or no ITP medication for at least 2 weeks;
* At least 3-weeks lead time available between randomization and scheduled surgery;
* IVIG and Eltrombopag are acceptable ITP treatment options for this patient;
* Able to provide informed consent.

Exclusion Criteria:

* Pregnancy or breastfeeding;
* Treatment with IVIG within the last 2 weeks;
* Treatment with a thrombopoietin receptor agonist (eltrombopag or romiplostim) within the last 4 weeks;
* AST, ALT above 2X upper limit of normal;
* Bilirubin above 1.5X upper limit of normal in the absence of clinically benign liver disorder (eg. Gilberts syndrome);
* Deep vein thrombosis, myocardial infarction, thrombotic stroke or arterial thrombosis in the last 12 months;
* History of bone marrow reticulin or fibrosis;
* Known liver cirrhosis;
* Active malignancy (defined as requiring treatment or palliation within the last 6 months);
* Any additional laboratory test result, health related illness or other diagnosis which, in the opinion of the treating physician, may put the subject's health or safety at risk.

Primary outcomes:
measure: Achievement of a platelet count level that is above the platelet count threshold for surgery preoperatively and that is maintained above the threshold during the post-hemostasis period without the use of rescue treatment
timeFrame: For a the period of time from the final pre-operative visit until 7 days after surgical hemostasis is achieved
Secondary outcomes:
measure: Time to treatment failure
timeFrame: During the period from the final pre-operative visit until 7 days after surgical hemostasis is achieved
measure: Surgical delays or cancellations
timeFrame: Measured at time of planned surgery
measure: Bleeding
timeFrame: During treatment and follow up (on average, 8 weeks from starting treatment)
measure: Thrombocytosis
timeFrame: During treatment and follow up (on average, 8 weeks from starting treatment)
measure: Blood product transfusions
timeFrame: During treatment and follow up (on average, 8 weeks from starting treatment)
measure: Rescue treatment
timeFrame: During the period from the final pre-operative visit until 7 days after surgical hemostasis is achieved
measure: Platelet count change over time
timeFrame: During treatment and follow up (on average, 8 weeks from starting treatment)
measure: Patient satisfaction with treatment
timeFrame: Immediately before surgery (final pre-op visit) and 7 days (+/- 2 days) after surgical hemostasis is achieved
measure: Hospitalizations
timeFrame: During treatment and follow up (on average, 8 weeks from starting treatment)
measure: Thrombosis
timeFrame: During treatment and follow up (on average, 8 weeks from starting treatment)
measure: Adverse Events
timeFrame: During treatment and follow up (on average, 8 weeks from starting treatment)
Other outcomes:
Locations:
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Hamilton
country: Canada
facility: Hamilton Health Sciences
state: Ontario
city: London
country: Canada
facility: London Health Sciences Center
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Hospital
state: Ontario
city: Toronto
country: Canada
facility: St.Micheal's Hospital
state: Ontario
city: Montreal
country: Canada
facility: Hopital Maisonneuve-Rosemont
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: The Hague
country: Netherlands
facility: The Haga Hospital
Study officials:
affiliation: McMaster University
name: Donald M Arnold, MD MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Arnold DM, Heddle NM, Cook RJ, Hsia C, Blostein M, Jamula E, Sholzberg M, Lin Y, Kassis J, Larratt L, Tinmouth A, Amini S, Schipperus M, Lim W, Vishnu P, Warner M, Carruthers J, Li N, Lane S, Kelton JG. Perioperative oral eltrombopag versus intravenous immunoglobulin in patients with immune thrombocytopenia: a non-inferiority, multicentre, randomised trial. Lancet Haematol. 2020 Sep;7(9):e640-e648. doi: 10.1016/S2352-3026(20)30227-1.
citation: Arnold DM, Jamula E, Heddle NM, Cook RJ, Hsia C, Sholzberg M, Lin Y, Kassis J, Blostein M, Larratt L, Amini S, Schipperus M, Carruthers J, Lane SJ, Li N, Kelton JG. Peri-Operative Eltrombopag or Immune Globulin for Patients with Immune Thrombocytopaenia (The Bridging ITP Trial): Methods and Rationale. Thromb Haemost. 2019 Mar;119(3):500-507. doi: 10.1055/s-0038-1677531. Epub 2019 Jan 27.