Perioperative Eltrombopag in Patients With Inherited Thrombocytopenia

NCT ID: NCT03638817

Last Updated: 2024-08-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-08-02
• Study Completion Date: 2023-06-27

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.

Conditions

Thrombocytopenia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Eltrombopag

Group Type: EXPERIMENTAL

Eltrombopag

Intervention Type: DRUG

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

Interventions

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

Intervention Type: DRUG

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.

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

French network for inherited hemorragic diseases

UNKNOWN

Sponsor Role: collaborator

National Reference Centre for Platelet Pathologies

UNKNOWN

Sponsor Role: collaborator

University Hospital, Toulouse

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Pierre SIE, Prof.

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Toulouse

Locations

Angers Hospital

Angers, , France

Bensancon Hospital

Besançon, , France

Bordeaux Hospital

Bordeaux, , France

Caen Hospital

Caen, , France

Clermont-Ferrand Hospital

Clermont-Ferrand, , France

Dijon Hospital

Dijon, , France

Lille Hospital

Lille, , France

Hospices Civils Lyon

Lyon, , France

Marseille Hospital

Marseille, , France

Montpellier Hospital

Montpellier, , France

Nancy Hospital

Nancy, , France

Nantes Hospital

Nantes, , France

Cochin Hospital

Paris, , France

Hopital Europeen G Pompidou

Paris, , France

Kremlin Bicetre Hospital

Paris, , France

Necker Hospital

Paris, , France

Robert Debré Hospital

Paris, , France

Trousseau Hospital

Paris, , France

Poitiers Hospital

Poitiers, , France

Reims Hospital

Reims, , France

Rennes Hospital

Rennes, , France

Rouen Hospital

Rouen, , France

Strasbourg Hospital

Strasbourg, , France

university hospital Toulouse

Toulouse, , France

Tours Hospital

Tours, , France

Countries

France

References

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.

Reference Type: BACKGROUND

PMID: 20844233 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23636669 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22398565 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26224646 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23940247 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27276516 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28845713 (View on PubMed)

Other Identifiers

2017-004489-88

Identifier Type: OTHER

Identifier Source: secondary_id

RC31/16/8913

Identifier Type: -

Identifier Source: org_study_id