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

Sponsor

McMaster University (Other)

Overall Status

Completed

CT.gov ID

NCT01621204

Collaborator

GlaxoSmithKline (Industry), Hamilton Health Sciences Corporation (Other), Novartis (Industry)

Enrollment

Locations

Arms

Actual Duration (Months)

7.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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

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 :

Oct 1, 2012

Actual Primary Completion Date :

Jun 1, 2019

Actual Study Completion Date :

Aug 1, 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 Names: 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

Arm

Intervention/Treatment

Experimental: Eltrombopag

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 Names:

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

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 [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

Time to treatment failure [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
Surgical delays or cancellations [Measured at time of planned surgery]
Proportion of patients with surgical delays or cancellations
Bleeding [During treatment and follow up (on average, 8 weeks from starting treatment)]
Graded as per the ITP bleeding score
Thrombocytosis [During treatment and follow up (on average, 8 weeks from starting treatment)]
Platelet count >400 x 10^9/L
Blood product transfusions [During treatment and follow up (on average, 8 weeks from starting treatment)]
Proportion of patients requiring platelet, red blood cells and plasma transfusions
Rescue treatment [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
Platelet count change over time [During treatment and follow up (on average, 8 weeks from starting treatment)]
Trend of all platelet count measurements in the trial
Patient satisfaction with treatment [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)
Hospitalizations [During treatment and follow up (on average, 8 weeks from starting treatment)]
Unanticipated admissions to hospital or prolongation of hospitalization
Thrombosis [During treatment and follow up (on average, 8 weeks from starting treatment)]
Symptomatic thrombotic events confirmed with diagnostic imaging
Adverse Events [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

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	State	Country	Postal Code
1	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G2G3
2	Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z1M9
3	Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
4	London Health Sciences Center	London	Ontario	Canada	N6A5W9
5	Ottawa Hospital	Ottawa	Ontario	Canada	K1H8L6
6	Sunnybrook Hospital	Toronto	Ontario	Canada	M4N3M5
7	St.Micheal's Hospital	Toronto	Ontario	Canada	M5B1W8
8	Hopital Maisonneuve-Rosemont	Montreal	Quebec	Canada	H1T2M4
9	Jewish General Hospital	Montreal	Quebec	Canada	H3T1E2
10	The Haga Hospital	The Hague		Netherlands