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

Study Description

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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

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	74 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Investigator, Outcomes Assessor)
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
Study Start Date :	October 2012
Estimated Primary Completion Date :	August 2018
Estimated Study Completion Date :	August 2018

Arms and Interventions

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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) as of 21 days before surgery. Dose may be adjusted based on platelet count monitoring (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 (2 g/kg, over 2 days) given 7 (+/-2) days prior to surgery and additional infusions given as needed until 7 days after surgical hemostasis is achieved.; Other Names: Intervenous Immunoglobulin; IgG

Outcome Measures

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Primary Outcome Measures :

1. Proportion of patients achieving the platelet count threshold before surgery and maintaining platelet counts within the target range without the use of ITP rescue treatment. [ Time Frame: For a the period of time from surgery until 7 days after surgical hemostasis is achieved (average duration is 7 days) ]
   Hemostasis will be assessed daily after surgery. The main outcome measure (platelet count above threshold) will be evaluated 7 days after hemostasis is achieved.

Secondary Outcome Measures :

1. Time to treatment failure [ Time Frame: During the period from surgery until 7 days after surgical hemostasis is acehieved ]
2. Bleeding [ Time Frame: During treatment and follow up (on average, 8 weeks from starting treatment) ]
3. Proportion of participants who undergo surgery as planned [ Time Frame: Measured at time of planned surgery (2 week for IVIG; 3 weeks for eltrombopag) ]
4. Treatment satisfaction assessment [ Time Frame: Assessed immediately before surgery (Day -2) and at 4 weeks (average for IVIG) or 5 weeks (average for eltrombopag). ]
   Treatment satisfaction assessed on Day -2 +/-1 day and once during follow up using the Treatment Satisfaction Questionnaire for Medications Score (which incorporates effectiveness, convenience, side effects, and overall satisfaction)
5. Use of blood transfusions [ Time Frame: During treatment and follow up (on average, 8 weeks from starting treatment) ]
   Platelet, red blood cells and plasma transfusions
6. Pre-surgery platelet count change from baseline [ Time Frame: Measured immediately before surgery (3 weeks, average for eltrombopag; 2 weeks, average for IVIG) ]
   Includes platelet change from baseline, proportion of pts who have a platelet count greater than 400x10exp9/L pre and post surgery, proportion of pts who have a platelet count less than 50x10exp9/L (minor surgery) or 100x10exp9/L (major surgery)
7. Total clinic and hospital days [ Time Frame: During treatment and follow up (on average, 8 weeks from starting treatment) ]
   Number of days participant spends at clinic appointments and number of days hospitalized
8. Venous thromboembolism and arterial thromboembolism [ Time Frame: During treatment and follow up (on average, 8 weeks from starting treatment) ]
   Rare known adverse event with eltrombopag
9. Adverse Events [ Time Frame: During treatment and follow up (on average, 8 weeks from starting treatment) ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
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

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Donald M Arnold, MD	905-521-2100 ext 76305	arnold@mcmaster.ca
Contact: Julie B Carruthers, MLT	905-525-9140 ext 22942	carrutj@mcmaster.ca

Locations

Canada, Alberta
University of Alberta Hospital	Recruiting
Edmonton, Alberta, Canada, T6G2G3
Contact: Loree Larratt, MD 780-407-7021 loree.larratt@ualberta.ca
Contact: Donna Perez 780-407-6090 Donna.Perez@albertahealthservices.ca
Principal Investigator: Loree Laratt, MD
Sub-Investigator: Irwindeep Sandhu, MD
Canada, British Columbia
Vancouver General Hospital	Terminated
Vancouver, British Columbia, Canada, V5Z1M9
Canada, Ontario
Hamilton Health Sciences	Recruiting
Hamilton, Ontario, Canada, L8N 3Z5
Contact: Donald M Arnold, MD 905-525-9140 ext 28603 arnold@mcmaster.ca
Contact: Erin Jamula, MSc 905-525-9140 ext 21845 jamulae@mcmaster.ca
Principal Investigator: Donald M Arnold, MD
London Health Sciences Center	Recruiting
London, Ontario, Canada, N6A5W9
Contact: Cyrus Hsia, MD 519-685-8500 ext 56060 cyrus.hsia@lhsc.on.ca
Contact: Laura Meraw 519-685-8500 ext 57135 Laura.Meraw@lhsc.on.ca
Principal Investigator: Cyrus Hsia, MD
Ottawa Hospital	Recruiting
Ottawa, Ontario, Canada, K1H8L6
Contact: Alan Tinmouth, MD 613-737-8899 ext 73914 Atinmouth@Ottawahospital.on.ca
Contact: Elizabeth Chatelain 613-737-8899 ext 71264 echatelain@ohri.ca
Principal Investigator: Alan Tinmouth, MD
Sunnybrook Hospital	Recruiting
Toronto, Ontario, Canada, M4N3M5
Contact: Yulia Lin, MD 416-480-6100 ext 2781 Yulia.Lin@sunnybrook.ca
Principal Investigator: Yulia Lin, MD
St.Micheal's Hospital	Recruiting
Toronto, Ontario, Canada, M5B1W8
Contact: Michelle Sholzberg, MD 416-864-6060 SholzbergM@smh.ca
Contact: Aziz Jiwajee 416-864-5354 JiwajeeA@smh.ca
Principal Investigator: Michelle Sholzberg, MD
Canada, Quebec
Hopital Maisonneuve-Rosemont	Recruiting
Montreal, Quebec, Canada, H1T2M4
Contact: Jeannine Kassis, MD 514-252-3404 jkassis.hmr@ssss.gouv.qc.ca
Contact: Julie Trinh Lu, B.Sc, DESS 514-252-3400 ext 3336 jtlu.hmr@ssss.gouv.qc.ca
Principal Investigator: Jeannine Kassis, MD
Jewish General Hospital	Recruiting
Montreal, Quebec, Canada, H3T1E2
Contact: Mark Blostein, MD 514-340-8214 mark.blostein@mgill.ca
Contact: Vivian Pananis 514-340-8222 ext 5982 vpananis@gmail.com
Principal Investigator: Mark Blostein, MD

Sponsors and Collaborators

McMaster University

GlaxoSmithKline

Hamilton Health Sciences Corporation

Novartis

Investigators

Principal Investigator:	Donald M Arnold, MD MSc	McMaster University

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Donald Arnold, Principal Investigator, McMaster University
ClinicalTrials.gov Identifier:	NCT01621204 History of Changes
Other Study ID Numbers:	M-EIBS-A-12
First Posted:	June 18, 2012
Last Update Posted:	April 7, 2017
Last Verified:	April 2017

Keywords provided by Donald Arnold, McMaster University:

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

Additional relevant MeSH terms:

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