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

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ClinicalTrials.gov Identifier: NCT01621204
Recruitment Status : Recruiting
First Posted : June 18, 2012
Last Update Posted : August 31, 2018
Sponsor:
Collaborators:
GlaxoSmithKline
Hamilton Health Sciences Corporation
Novartis
Information provided by (Responsible Party):
Donald Arnold, McMaster University

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 Type : Interventional  (Clinical Trial)
Estimated 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
Study Start Date : October 2012
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2019


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




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



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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01621204


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    llarratt@ualberta.ca   
Contact: Ovais Shaikh    780-407-6090    Ovais.Shaikh@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: Maisam Abouzeenni       Maisam.Abouzeenni@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@toh.ca   
Contact: Holly Carr       hcarr@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         
Netherlands
The Haga Hospital Not yet recruiting
The Hague, Netherlands
Contact: Sufia Amini    31 702102556    s.amini@hagaziekenhuis.nl   
Contact: Okke Eissen    31 702101844    o.eissen@hagaziekenhuis.nl   
Principal Investigator: Martin Schipperus, MD         
Sponsors and Collaborators
McMaster University
GlaxoSmithKline
Hamilton Health Sciences Corporation
Novartis
Investigators
Principal Investigator: Donald M Arnold, MD MSc McMaster University

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    Key Record Dates
Last Update Posted: August 31, 2018
Last Verified: August 2018

Keywords provided by Donald Arnold, McMaster University:
Thrombocytopenia
ITP
Platelets
Bleeding
Immune
Eltrombopag
IVIG

Additional relevant MeSH terms:
Thrombocytopenia
Purpura
Purpura, Thrombocytopenic
Purpura, Thrombocytopenic, Idiopathic
Blood Platelet Disorders
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