ELPOT: Perioperative Eltrombopag in Patients With Inherited Thrombocytopenia

Sponsor

University Hospital, Toulouse (Other)

Overall Status

Recruiting

CT.gov ID

NCT03638817

Collaborator

French network for inherited hemorragic diseases (Other), National Reference Centre for Platelet Pathologies (Other)

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patient Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The objective of the study is to estimate the response to eltrombopag based on platelet count increase above a safety level of 80 G/L and lack of requirement for pre-, per- and post-operative administration of platelet concentrates (PC) for performing elective invasive acts at mild or high bleeding risk,in selected patients with inherited thrombocytopenia (IT).

Condition or Disease	Intervention/Treatment	Phase
Thrombocytopenia	Drug: Eltrombopag	Phase 2

Detailed Description

The hypothesis of the trial is that preoperative treatment by a thrombopoietin mimetic (eltrombopag) will be effective and safe and will avoid requirement of PC administration in a majority of IT patients Eltrombopag is a thrombopoietin mimetic available orally, not licenced for the treatment of IT. Preliminary data in short series of IT patients indicate that eltrombopag, at the doses used in primary immune thrombocytopenia, increases the platelet counts after 2-4 weeks of treatment and reduces spontaneous bleeding in a significant proportion of subjects. The tolerance of short-term treatment is good. The experience of eltrombopag for the management of perioperative thrombocytopenia in IT is anecdotic. Avoiding the administration of platelet concentrates in these patients, especially children, would represent a direct benefit by preventing adverse reactions to transfusion of blood products and human leukocyte antigen (HLA) immunisation.

Eltrombopag will be prescribed after the inclusion visit at the standard dose of 50 mg/day with dose adjustment on the platelet count (+/- 25 mg) after 2 weeks, for a maximum of 4 weeks before the invasive procedure. If the predefined safety level of platelet count required for the procedure is reached, the treatment will be discontinued and the patient operated without prophylactic administration of PC. In case of bleeding of undetermined cause per-and post-operatively, rescue PC will be given.

Clinical and biological follow-up will be performed until the end-of-study visit, 4 weeks after the intake of the last tablet of eltrombopag.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

25 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Evaluation of Perioperative Eltrombopag for the Management of Elective Surgery and Invasive Acts in Patients With Inherited Thrombocytopenia

Actual Study Start Date :

Aug 2, 2019

Anticipated Primary Completion Date :

Aug 1, 2022

Anticipated Study Completion Date :

Aug 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eltrombopag	Drug: Eltrombopag Eltrombopag will be prescribed at doses recommended in primary immune thrombocytopenia (50, 25 or 75 mg), starting 4 weeks before the procedure and stopped 2 days before. PC will be administrated prophylactically if the platelet count is < 80 G/L or per/post-operatively in case of bleeding of undetermined cause. Antifibrinolytics will be authorized and low molecular weight heparin prescribed if indicated for the prophylaxis of postoperative venous thrombosis according to the standard dose and duration, , irrespective of the platelet count

Arm

Intervention/Treatment

Experimental: Eltrombopag

Drug: Eltrombopag

Eltrombopag will be prescribed at doses recommended in primary immune thrombocytopenia (50, 25 or 75 mg), starting 4 weeks before the procedure and stopped 2 days before. PC will be administrated prophylactically if the platelet count is < 80 G/L or per/post-operatively in case of bleeding of undetermined cause. Antifibrinolytics will be authorized and low molecular weight heparin prescribed if indicated for the prophylaxis of postoperative venous thrombosis according to the standard dose and duration, , irrespective of the platelet count

Outcome Measures

Primary Outcome Measures

Perioperative management by eltrombopag in inherited thrombocytopenia [up to 4 weeks after completion of treatment]
The response to Eltrombopag is a composite criteria including the level of platelet count 2 days before the procedure and the requirement of PC administration at any time in the study period. The "study period" is running from the start of treatment (inclusion visit) to 4 weeks after completion of treatment. A platelet count remaining below 80 G/L preoperatively, whether or not eltrombopag was taken, is a criterion of failure of treatment.

Secondary Outcome Measures

Adverse events [up to 4 weeks after completion of treatment]
Adverse events and adverse reactions occurring at any time during the study period will be collected. Adverse events may be clinical and biological (especially liver function tests).
Excessive bleeding [up to 4 weeks after completion of treatment]
Excessive or unusual bleeding occurring at any time during the study period are major adverse events. An independent event adjudication committee (EAC) will review all bleeding events.
Vascular thrombosis [up to 4 weeks after completion of treatment]
Symptomatic thrombosis (venous or arterial) occurring at any time during the study period will be diagnosed by appropriate objective methods and reviewed by the EAC.
Doses of eltrombopag on-treatment [2 and 4 weeks after the beginning of the treatment]
The total doses of eltrombopag given in the preoperative period will be recorded, as the dose and duration of treatment required to obtained the safety level
Platelet kinetics [up to 4 weeks after completion of treatment]
Serial blood sampling during the study period will be performed for measuring the rise of platelet count on-treatment and its decline after completion of treatment.
Platelet size [Inclusion and before the procedure]
Mean platelet volume will be measured by flow cytometry.on blood samples obtained for platelet counts at inclusion, during hospitalisation and end-of study visit
Baseline of Serum Thrombopoietin [Inclusion visit]
Serum thrombopoietin will be measured once, at the inclusion visit.

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Symptomatic patients with bleeding history and chronic thrombocytopenia with strong presumption of constitutional origin on the basis of
the identified mutation and/or
a combination of the following criteria: familial antecedent with Mendelian transmission, duration of thrombocytopenia, suggestive syndromic presentation, and evidence against primary or secondary immune thrombocytopenia, especially absence of immunologic markers and failure of previous conventional or immunosuppressive therapies.
Averaged platelet counts during the last five years below the safety level required for the procedure.
Scheduled (>4 weeks) surgery or invasive procedure with anticipated risk of bleeding: e.g. needle biopsy of solid organ (liver, kidney….etc.), interventional endoscopy, major surgeries, or surgery without possibility of mechanical control of haemostasis (e.g. tonsillectomy). Written informed consent of the patient or his (her) parents or tutors (patients < 18 yrs).

Patients included in the French national registry of rare platelet disorders

Patient with social insurance coverage

Exclusion Criteria:

questionable constitutional origin;
definite platelet dysfunction associated to thrombocytopenia (eg: gray platelet syndrome, NBEAL2 and related gene mutations, homozygous Bernard-Soulier Syndrome);
thrombocytopenia with predisposition to hematologic malignancies (e.g; RUNX1, ETV6 or ANKRD26 gene mutations).
amegakaryocytic thrombocytopenia resulting from mutations in the thrombopoietin (TPO) TPO-Mpl receptor, supposed, by definition, to be hardly responsive to receptor agonists.
questionable requirement of prophylactic PC transfusions;
procedure usually associated with platelet consumption requiring transfusions of PC (e.g.: cardiac surgery), making difficult the evaluation of success or failure;
procedures at risk of bleeding with immediate vital or functional consequences (e.g.: intra cranial surgery);
personal history of arterial or venous thromboembolic events or known familial thrombophilia;
association with another acquired or constitutional hemorrhagic diathesis;
chronic hepatitis, cirrhosis, with moderate to severe liver failure (Child-Pugh score ≥5);
previous or concurrent myeloid malignancy, including myelodysplastic syndrome;
alanine aminotransferase (ALT) or bilirubin levels 2 times the upper limit of normal (ULN);
altered renal function (creatinin clearance <30 ml/min);
pregnancy (negative test required before inclusion in fertile women) or lactating women;
refusal of safe contraception;
ocular lenses opacity;
hypersensitivity to eltrombopag or one of excipients;
previous participation to the present study;
current treatment with antiplatelet drugs, anticoagulants or direct acting antiviral agents approved for treatment of chronic hepatitis C infection;
psychiatric, social or behavioral condition judged to be non-compatible with the respect of the protocol, including good observance of treatment and compliance to follow-up;
adult protected by the law.

Contacts and Locations

Locations

	Site	City	Country
1	Angers Hospital	Angers	France
2	Bensancon Hospital	Besançon	France
3	Bordeaux Hospital	Bordeaux	France
4	Caen Hospital	Caen	France
5	Clermont-Ferrand Hospital	Clermont-Ferrand	France
6	Dijon Hospital	Dijon	France
7	Lille Hospital	Lille	France
8	Hospices Civils Lyon	Lyon	France
9	Marseille Hospital	Marseille	France
10	Montpellier Hospital	Montpellier	France
11	Nancy Hospital	Nancy	France
12	Nantes Hospital	Nantes	France
13	Cochin Hospital	Paris	France
14	Hopital Europeen G Pompidou	Paris	France
15	Kremlin Bicetre Hospital	Paris	France
16	Necker Hospital	Paris	France
17	Robert Debré Hospital	Paris	France
18	Trousseau Hospital	Paris	France
19	Poitiers Hospital	Poitiers	France
20	Reims Hospital	Reims	France
21	Rennes Hospital	Rennes	France
22	Rouen Hospital	Rouen	France
23	Strasbourg Hospital	Strasbourg	France
24	university hospital Toulouse	Toulouse	France
25	Tours Hospital	Tours	France