A Trial of Eltrombopag or Intravenous Immune Globulin Before Surgery for Immune Thrombocytopenia Patients

• ClinicalTrials.gov Identifier: NCT01621204
• Recruitment Status: Completed
• First Posted: June 18, 2012
• Last Update Posted: September 9, 2020
• Sponsor: McMaster University
• Collaborators: GlaxoSmithKline; Hamilton Health Sciences Corporation; Novartis
• Information provided by (Responsible Party): Donald Arnold, McMaster University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Immune Thrombocytopenic Purpura	Drug: Eltrombopag; Drug: IVIG infusion	Phase 3

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 74 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• 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
• Actual Study Start Date: October 2012
• Actual Primary Completion Date: June 2019
• Actual Study Completion Date: August 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Eltrombopag; 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.	Drug: Eltrombopag; Participants are started on 50mg daily oral pill (or 25mg daily for patients of East Asian descent) 21 days before surgery. Dose may be adjusted based on subsequent platelet counts (minimum 25mg; maximum 75mg).; Other Name: Revolade
Active Comparator: IVIG infusion; Intravenous immunoglobulin (IVIG) is used to rapidly increase platelet counts in ITP patients. IVIG is associated with a transient platelet count response in approximately 80% of patients, which occurs within 2 - 4 days. It is commonly used to improve platelet count numbers prior to surgery for patients with ITP.	Drug: IVIG infusion; IVIG infusion (1-2 g/kg) given 7 (+/-2) days prior to surgery; with an additional infusion allowed within one week of achievement of surgical hemostasis, if needed; Other Names: Intravenous Immunoglobulin; IgG

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: For a the period of time from the final pre-operative visit until 7 days after surgical hemostasis is achieved ]
   Threshold is a platelet count of 50 x 10^9/L for minor surgery and 100 x 10^9/L for major surgery.

Secondary Outcome Measures :

1. Time to treatment failure [ Time Frame: During the period from the final pre-operative visit until 7 days after surgical hemostasis is achieved ]
   Time to the occurrence of a platelet count level below the designated threshold, or the administration of rescue treatment
2. Surgical delays or cancellations [ Time Frame: Measured at time of planned surgery ]
   Proportion of patients with surgical delays or cancellations
3. Bleeding [ Time Frame: During treatment and follow up (on average, 8 weeks from starting treatment) ]
   Graded as per the ITP bleeding score
4. Thrombocytosis [ Time Frame: During treatment and follow up (on average, 8 weeks from starting treatment) ]
   Platelet count >400 x 10^9/L
5. Blood product transfusions [ Time Frame: During treatment and follow up (on average, 8 weeks from starting treatment) ]
   Proportion of patients requiring platelet, red blood cells and plasma transfusions
6. Rescue treatment [ Time Frame: During the period from the final pre-operative visit until 7 days after surgical hemostasis is achieved ]
   New ITP treatment (typically platelet transfusions, high dose IVIG or high dose corticosteroids) or an increased dose of existing ITP treatment administered to increase platelet counts above threshold
7. Platelet count change over time [ Time Frame: During treatment and follow up (on average, 8 weeks from starting treatment) ]
   Trend of all platelet count measurements in the trial
8. Patient satisfaction with treatment [ Time Frame: Immediately before surgery (final pre-op visit) and 7 days (+/- 2 days) after surgical hemostasis is achieved ]
   Assessed using the Treatment Satisfaction Questionnaire for Medications Score vII (which incorporates effectiveness, convenience, side effects, and overall satisfaction)
9. Hospitalizations [ Time Frame: During treatment and follow up (on average, 8 weeks from starting treatment) ]
   Unanticipated admissions to hospital or prolongation of hospitalization
10. Thrombosis [ Time Frame: During treatment and follow up (on average, 8 weeks from starting treatment) ]
    Symptomatic thrombotic events confirmed with diagnostic imaging
11. Adverse Events [ Time Frame: During treatment and follow up (on average, 8 weeks from starting treatment) ]
    Defined using the Common Terminology Criteria for Adverse Events v3.0

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Canada, Alberta

University of Alberta Hospital

Edmonton, Alberta, Canada, T6G2G3

Canada, British Columbia

Vancouver General Hospital

Vancouver, British Columbia, Canada, V5Z1M9

Canada, Ontario

Hamilton Health Sciences

Hamilton, Ontario, Canada, L8N 3Z5

London Health Sciences Center

London, Ontario, Canada, N6A5W9

Ottawa Hospital

Ottawa, Ontario, Canada, K1H8L6

Sunnybrook Hospital

Toronto, Ontario, Canada, M4N3M5

St.Micheal's Hospital

Toronto, Ontario, Canada, M5B1W8

Canada, Quebec

Hopital Maisonneuve-Rosemont

Montreal, Quebec, Canada, H1T2M4

Jewish General Hospital

Montreal, Quebec, Canada, H3T1E2

Netherlands

The Haga Hospital

The Hague, Netherlands

Sponsors and Collaborators

McMaster University

GlaxoSmithKline

Hamilton Health Sciences Corporation

Novartis

Investigators

• Principal Investigator: Donald M Arnold, MD MSc; McMaster University

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Donald Arnold, Principal Investigator, McMaster University
• ClinicalTrials.gov Identifier: NCT01621204
• Other Study ID Numbers: M-EIBS-A-12
• First Posted: June 18, 2012
• Last Update Posted: September 9, 2020
• Last Verified: September 2020

Keywords provided by Donald Arnold, McMaster University:

Thrombocytopenia; ITP; Platelets; Bleeding; Immune; Eltrombopag; IVIG

Additional relevant MeSH terms:

Thrombocytopenia; Purpura; Purpura, Thrombocytopenic, Idiopathic; Purpura, Thrombocytopenic; Blood Platelet Disorders; Hematologic Diseases; Blood Coagulation Disorders; Hemorrhage; Pathologic Processes; Skin Manifestations; Thrombotic Microangiopathies; Hemorrhagic Disorders; Autoimmune Diseases; Immune System Diseases; Immunoglobulins; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin; Immunologic Factors; Physiological Effects of Drugs