Clinical trial NCT03638817: Perioperative Eltrombopag in Patients With Inherited Thrombocytopenia
Official title: Evaluation of Perioperative Eltrombopag for the Management of Elective Surgery and Invasive Acts in Patients With Inherited Thrombocytopenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Thrombocytopenia
Keywords: Inherited thrombocytopenias (IT)
Platelet concentrates (PC)
Eltrombopag
Surgery
Invasive acts
Perioperative
Rare disease
Thrombopoietin mimetic
Lead sponsor: University Hospital, Toulouse
Sponsor class: OTHER
Collaborators: name: French network for inherited hemorragic diseases
name: National Reference Centre for Platelet Pathologies
First posted: 2018-08-20
Enrollment: 13
Sex: ALL
Minimum age (years): 6
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Perioperative management by eltrombopag in inherited thrombocytopenia
timeFrame: up to 4 weeks after completion of treatment
Secondary outcomes:
measure: Adverse events
timeFrame: up to 4 weeks after completion of treatment
measure: Excessive bleeding
timeFrame: up to 4 weeks after completion of treatment
measure: Vascular thrombosis
timeFrame: up to 4 weeks after completion of treatment
measure: Doses of eltrombopag on-treatment
timeFrame: 2 and 4 weeks after the beginning of the treatment
measure: Platelet kinetics
timeFrame: up to 4 weeks after completion of treatment
measure: Platelet size
timeFrame: Inclusion and before the procedure
measure: Baseline of Serum Thrombopoietin
timeFrame: Inclusion visit
Other outcomes:
Locations:
city: Angers
country: France
facility: Angers Hospital
city: Besançon
country: France
facility: Bensancon Hospital
city: Bordeaux
country: France
facility: Bordeaux Hospital
city: Caen
country: France
facility: Caen Hospital
city: Clermont-Ferrand
country: France
facility: Clermont-Ferrand Hospital
city: Dijon
country: France
facility: Dijon Hospital
city: Lille
country: France
facility: Lille Hospital
city: Lyon
country: France
facility: Hospices Civils Lyon
city: Marseille
country: France
facility: Marseille Hospital
city: Montpellier
country: France
facility: Montpellier Hospital
city: Nancy
country: France
facility: Nancy Hospital
city: Nantes
country: France
facility: Nantes Hospital
city: Paris
country: France
facility: Cochin Hospital
city: Paris
country: France
facility: Hopital Europeen G Pompidou
city: Paris
country: France
facility: Kremlin Bicetre Hospital
city: Paris
country: France
facility: Necker Hospital
city: Paris
country: France
facility: Robert Debré Hospital
city: Paris
country: France
facility: Trousseau Hospital
city: Poitiers
country: France
facility: Poitiers Hospital
city: Reims
country: France
facility: Reims Hospital
city: Rennes
country: France
facility: Rennes Hospital
city: Rouen
country: France
facility: Rouen Hospital
city: Strasbourg
country: France
facility: Strasbourg Hospital
city: Toulouse
country: France
facility: university hospital Toulouse
city: Tours
country: France
facility: Tours Hospital
Study officials:
affiliation: University Hospital, Toulouse
name: Pierre SIE, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pecci A, Gresele P, Klersy C, Savoia A, Noris P, Fierro T, Bozzi V, Mezzasoma AM, Melazzini F, Balduini CL. Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. Blood. 2010 Dec 23;116(26):5832-7. doi: 10.1182/blood-2010-08-304725. Epub 2010 Sep 15.
citation: Pecci A. Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists. Int J Hematol. 2013 Jul;98(1):34-47. doi: 10.1007/s12185-013-1351-7. Epub 2013 May 1.
citation: Pecci A, Barozzi S, d'Amico S, Balduini CL. Short-term eltrombopag for surgical preparation of a patient with inherited thrombocytopenia deriving from MYH9 mutation. Thromb Haemost. 2012 Jun;107(6):1188-9. doi: 10.1160/TH12-01-0005. Epub 2012 Mar 8. No abstract available.
citation: Gerrits AJ, Leven EA, Frelinger AL 3rd, Brigstocke SL, Berny-Lang MA, Mitchell WB, Revel-Vilk S, Tamary H, Carmichael SL, Barnard MR, Michelson AD, Bussel JB. Effects of eltrombopag on platelet count and platelet activation in Wiskott-Aldrich syndrome/X-linked thrombocytopenia. Blood. 2015 Sep 10;126(11):1367-78. doi: 10.1182/blood-2014-09-602573. Epub 2015 Jul 29.
citation: Favier R, Feriel J, Favier M, Denoyelle F, Martignetti JA. First successful use of eltrombopag before surgery in a child with MYH9-related thrombocytopenia. Pediatrics. 2013 Sep;132(3):e793-5. doi: 10.1542/peds.2012-3807. Epub 2013 Aug 12.
citation: Fiore M, Saut N, Alessi MC, Viallard JF. Successful use of eltrombopag for surgical preparation in a patient with ANKRD26-related thrombocytopenia. Platelets. 2016 Dec;27(8):828-829. doi: 10.1080/09537104.2016.1190446. Epub 2016 Jun 8. No abstract available.
citation: Zhang J, Liang Y, Ai Y, Xie J, Li Y, Zheng W. Thrombopoietin-receptor agonists for children with immune thrombocytopenia: a systematic review. Expert Opin Pharmacother. 2017 Oct;18(15):1543-1551. doi: 10.1080/14656566.2017.1373091. Epub 2017 Sep 4.