The TIKI study: Treatment with or without IVIG in Kids with acute ITP.
|- candidate number||4607|
|- NTR Number||NTR1563|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||26-nov-2008|
|- Secondary IDs||08-162 METC UMCU|
|- Public Title||The TIKI study: Treatment with or without IVIG in Kids with acute ITP.
|- Scientific Title||Development of chronic disease in newly diagnosed Idiopathic Thrombocytopenic Purpura of Childhood. A randomized controlled study on the influence of treatment with intravenous gammaglobulin on the course of the disease.|
|- hypothesis||The primary objective is to investigate to what extent early IVIG treatment in children with newly diagnosed acute ITP reduces the risk of development of chronic disease. |
Secondary objectives are:
1. To estimate the alteration in the clinical parameters during the course of the disease, eg: bleeding score and time between onset of symptoms and recovery of platelet numbers.
2. To measure the difference between the health-related quality of life (HRQoL) in parents and patients with acute ITP who did and did not have IVIG and in those that do and do not develop chronic ITP.
3. To study biological parameters to learn more about the pathogenesis of ITP and of the working mechanism of IVIG.
|- Healt Condition(s) or Problem(s) studied||Idiopathic thrombocytopenic purpura (ITP), Immunoglobulin|
|- Inclusion criteria||General inclusion criteria:|
1. Children aged 3 months -16 years, presenting to a pediatrician with newly diagnosed acute ITP
2. Platelet count < 20 x 10 9 /L
3. Bleeding tendency < grade 4 (Buchanan)
4. No prior immunomodulating treatment within 4 weeks before diagnosis
5. Sufficient comprehension of the Dutch language
6. Signed informed consent by parents and/ or patients
|- Exclusion criteria||General exclusion criteria: |
1. Clinical features that are not compatible with the diagnosis of acute ITP, for example: presence of other auto-immune phenomena, organomegaly, other cytopenias besides thrombocytopenia or features susceptible for infectious disease like hepatitis, Epstein-Barr virus or HIV
2. Immunomodulating treatment (IVIG, corticosteroids) within 4 weeks before diagnosis
3. History of allergic reactions against human plasma, plasma products or intravenous immunoglobulin
4. Severe or life threatening bleeding at presentation: grade 4 or 5 (Buchanan)
5. A patient known with IgA deficiency with IgA antibodies
6. A patient known with renal insufficiency
7. Insufficient comprehension of the Dutch language
8. No informed consent
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||2 or more arms, randomized|
|- planned startdate ||1-jan-2009|
|- planned closingdate||1-jan-2013|
|- Target number of participants||300|
|- Interventions||The intervention consists of one dose of 0.8 g/kg bodyweight Nanogam ®, a liquid intravenous immunoglobulin, manufactured by Sanquin. |
Besides the primary intervention, quality of life questionnaires and laboratory studies will be performed.
|- Primary outcome||- Main study parameter is the percentage of patients developing chronic ITP, defined by a platelet count of < 150 x 10^9/l six months after diagnosis.|
|- Secondary outcome||- Clinical parameters during the course of the disease, eg: bleeding score graded according to the revised grading system developed by Buchanan, and time between onset of symptoms and recovery of platelet numbers. |
- Comparing the HRQoL in parents and patients with acute ITP who did and did not have IVIG and in those that do and do not develop chronic ITP.
- Estimation of variability of biological parameters of the immune system of the patient that are supposed to be involved in the differences in outcome between acute vs. chronic disease as well as between response on IVIG treatment vs. non response. These include:
A) the genetic polymorphisms of the activating and inhibiting IgG-Fc receptor and other inhibiting immune receptors.
B) Immunoglobulin glycosylation variability within the platelet auto antibodies and its changes during time, as well as the changes due to IVIG treatment.
C) Quantity and function of regulatory T cells.
|- Timepoints||At diagnosis, after 1 week, 1 month, 3 months, 6 months and 12 months.|
|- Trial web site||http://www.juliuscenter.com/tiki|
|- CONTACT FOR PUBLIC QUERIES|| K.M.J. Heitink-Pollé|
|- CONTACT for SCIENTIFIC QUERIES|| M.C.A. Bruin|
|- Sponsor/Initiator ||University Medical Center Utrecht (UMCU), Wilhelmina Children's Hospital (WKZ)|
(Source(s) of Monetary or Material Support)
|Wilhelmina Children's Hospital research fund, Landsteiner Foundation|
|- Publications||(1) Kuhne T. Investigation and management of newly diagnosed childhood idiopathic thrombocytopenic purpura: problems and proposed solutions. J Pediatr Hematol Oncol. 2003;25 Suppl 1:S24-S27.|
(2) Tarantino MD, Bolton-Maggs PH. Update on the management of immune thrombocytopenic purpura in children. Curr Opin Hematol. 2007;14:526-534.
(3) Blanchette VS, Luke B, Andrew M et al. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr. 1993;123:989-995.
(4) Bolton-Maggs P. Severe bleeding in idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol. 2003;25 Suppl 1:S47-S51.
(5) Bolton-Maggs PH, Moon I. Assessment of UK practice for management of acute childhood idiopathic thrombocytopenic purpura against published guidelines. Lancet. 1997;350:620-623.
(6) Rosthoj S, Hedlund-Treutiger I, Rajantie J et al. Duration and morbidity of newly diagnosed idiopathic thrombocytopenic purpura in children: A prospective Nordic study of an unselected cohort. J Pediatr. 2003;143:302-307.
(7) Zeller B, Rajantie J, Hedlund-Treutiger I et al. Childhood idiopathic thrombocytopenic purpura in the Nordic countries: epidemiology and predictors of chronic disease. Acta Paediatr. 2005;94:178-184.
(8) Sutor AH, Harms A, Kaufmehl K. Acute immune thrombocytopenia (ITP) in childhood: retrospective and prospective survey in Germany. Semin Thromb Hemost. 2001;27:253-267.
(9) Lilleyman J. Medical nemesis and childhood ITP. Br J Haematol. 2003;123:586-589.
(10) Blanchette VS, Price V. Childhood chronic immune thrombocytopenic purpura: unresolved issues. J Pediatr Hematol Oncol. 2003;25 Suppl 1:S28-S33.
(11) Buchanan GR. Bleeding signs in children with idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol. 2003;25 Suppl 1:S42-S46.
(12) Bruin M, Bierings M, Uiterwaal C et al. Platelet count, previous infection and FCGR2B genotype predict development of chronic disease in newly diagnosed idiopathic thrombocytopenia in childhood: results of a prospective study. Br J Haematol. 2004;127:561-567.
(13) Beck CE, Nathan PC, Parkin PC, Blanchette VS, Macarthur C. Corticosteroids versus intravenous immune globulin for the treatment of acute immune thrombocytopenic purpura in children: a systematic review and meta-analysis of randomized controlled trials. J Pediatr. 2005;147:521-527.
(14) Crow AR, Song S, Siragam V, Lazarus AH. Mechanisms of action of intravenous immunoglobulin in the treatment of immune thrombocytopenia. Pediatr Blood Cancer. 2006;47:710-713.
(15) Lazarus AH, Crow AR. Mechanism of action of IVIG and anti-D in ITP. Transfus Apher Sci. 2003;28:249-255.
(16) Clynes R. Protective mechanisms of IVIG. Curr Opin Immunol. 2007;19:646-651.
(17) Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science. 2006;313:670-673.
(18) Ephrem A, Chamat S, Miquel C et al. Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood. 2008;111:715-722.
(19) Breunis WB, van Mirre E, Bruin M et al. Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura. Blood. 2008;111:1029-1038.
(20) Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141-151.
(21) Bond A, Cooke A, Hay FC. Glycosylation of IgG, immune complexes and IgG subclasses in the MRL-lpr/lpr mouse model of rheumatoid arthritis. Eur J Immunol. 1990;20:2229-2233.
(22) Rademacher TW, Williams P, Dwek RA. Agalactosyl glycoforms of IgG autoantibodies are pathogenic. Proc Natl Acad Sci U S A. 1994;91:6123-6127.
(23) Matsumoto A, Shikata K, Takeuchi F, Kojima N, Mizuochi T. Autoantibody activity of IgG rheumatoid factor increases with decreasing levels of galactosylation and sialylation. J Biochem. 2000;128:621-628.
(24) Shinkawa T, Nakamura K, Yamane N et al. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem. 2003;278:3466-3473.
(25) Shields RL, Lai J, Keck R et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem. 2002;277:26733-26740.
(26) Okazaki A, Shoji-Hosaka E, Nakamura K et al. Fucose depletion from human IgG1 oligosaccharide enhances binding enthalpy and association rate between IgG1 and FcgammaRIIIa. J Mol Biol. 2004;336:1239-1249.
(27) Nimmerjahn F, Anthony RM, Ravetch JV. Agalactosylated IgG antibodies depend on cellular Fc receptors for in vivo activity. Proc Natl Acad Sci U S A. 2007;104:8433-8437.
(28) Liu B, Zhao H, Poon MC et al. Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura. Eur J Haematol. 2007;78:139-143.
(29) Yu J, Heck S, Patel V et al. Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura. Blood. 2008.
(30) Kessel A, Ammuri H, Peri R et al. Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol. 2007;179:5571-5575.
(31) Barnard D, Woloski M, Feeny D et al. Development of disease-specific health-related quality-of-life instruments for children with immune thrombocytopenic purpura and their parents. J Pediatr Hematol Oncol. 2003;25:56-62.
(32) Klaassen RJ, Blanchette VS, Barnard D et al. Validity, reliability, and responsiveness of a new measure of health-related quality of life in children with immune thrombocytopenic purpura: the Kids' ITP Tools. J Pediatr. 2007;150:510-5, 515.
(33) Bleeker WK, Teeling JL, Verhoeven AJ et al. Vasoactive side effects of intravenous immunoglobulin preparations in a rat model and their treatment with recombinant platelet-activating factor acetylhydrolase. Blood. 2000;95:1856-1861.
(34) Anderson D, Ali K, Blanchette V et al. Guidelines on the use of intravenous immune globulin for hematologic conditions. Transfus Med Rev. 2007;21:S9-56.
|- Brief summary||Rationale: |
Acute idiopathic thrombocytopenic purpura (ITP) in childhood is characterized by auto-immune destruction of platelets and a typical history of acute development of purpura and bruising in an otherwise healthy child. The incidence in The Netherlands is approximately 120-150 newly diagnosed children per year.
In The Netherlands, according to the current guidelines, the management of acute ITP in children consists mainly of careful observation. Only in case of severe bleeding, occurring in about 2-3% of all patients, treatment with corticosteroids or intravenous immunoglobulin (IVIG) has to be instituted. Most children with newly diagnosed ITP will recover within 6 months. Nevertheless, thrombocytopenia has a major influence on daily life activities, because all activities which carry a risk of causing severe bleeding have to be avoided. About 25% of the patients will remain thrombocytopenic after 6 months and thus are diagnosed with chronic ITP.
The incidence of bleeding correlates well with the duration of the thrombocytopenia and thus with chronic disease.
In a previous prospective observational study we found a significant reduction of relative risk of developing chronic disease in children treated with IVIG in the acute phase. These results are supported by data of the international ITP registry, a recent meta-analysis and research in mice.
The primary objective is to investigate to what extent early IVIG treatment in children with newly diagnosed acute ITP reduces the risk of development of chronic disease. Secondary objectives are:
1) To estimate the alteration in the clinical parameters during the course of the disease, eg: bleeding score and time between onset of symptoms and recovery of platelet numbers.
2) To measure the difference between the health-related quality of life (HRQoL) in parents and patients with acute ITP who did and did not have IVIG and in those that do and do not develop chronic ITP.
3) To study biological parameters to learn more about the pathogenesis of ITP and of the working mechanism of IVIG.
The study comprises a randomized controlled intervention study in which patients with newly diagnosed acute ITP will be randomized to receive either standard treatment, namely careful observation without medication, or intervention with IVIG treatment.
Children aged 3 months-16 years (according to the International ITP registry (ICIS) criteria) with newly diagnosed ITP presenting to a pediatrician without severe bleeding, and with platelets < 20 x 10^9/l and no prior immunomodulating treatment within 4 weeks before diagnosis.
Patients in the intervention arm will receive IVIG 0.8 g/kg once, within three days of diagnosis. Patients in the control arm will have careful observation and will only receive medication (IVIG, prednisone) in case of severe bleeding. In all patients clinical data and blood samples will be collected at diagnosis, 1 and 4 weeks and 3, 6 and 12 months after diagnosis. Questionnaires regarding quality of life will be obtained at the same time points.
Main study parameters/endpoints:
Primary outcome of the study is the development of chronic ITP, defined by a platelet count < 150 x10^9/L six months after presentation with thrombocytopenia. Secondary parameters are
1) bleeding score according to Buchanan,
2) time in weeks to reach recovery of platelets;
3) HRQoL in children with acute ITP and their parents
4) genetic polymorphisms of FcãR’s and other inhibiting immune-receptors;
5) Glycosylation patterns of anti-platelet-antibodies and the changes in these patterns during time;
6) Quantity and function of regulatory T cells.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients in the intervention arm of the study will receive IVIG. They will need an intravenous canule. The administration of IVIG carries only a minor risk of adverse reactions, of which headache is the most common. Secondly, IVIG is a human blood product, of which a minor risk of transmission of viruses that are not yet known to us cannot be excluded.
At time points 0, 1 week, 4 weeks, 3, 6 and 12 months all parents, and, from the age of seven years also patients, will be asked to fill out a questionnaire regarding HRQoL. At the same time points also a history and physical examination will be done and blood samples will be taken. This frequency of blood sampling and physical examination is not different from regular management of acute ITP. The volume of the blood samples for the study involves a total of 60-100 ml over a period of one year. This amount is so limited that adverse consequences for patients are not to be expected.
Acute ITP in children is a different disease than ITP in adults with regard to clinical course, as well as presumed etiology. The response to immunomodulating treatment also differs between children and adults with ITP. Therefore, to answer our questions, this study cannot be performed in an adult population.
|- Main changes (audit trail)|
|- RECORD||26-nov-2008 - 9-feb-2010|
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