Registry II remains open for follow-up data (24 months) only.

If you are interested in participating in an ICIS project, please sign up for the PARC-ITP registry.

Important information for investigators of Registry II:
If you are a physician participating in Registry II and you are interested in participating in the PARC-ITP registry, please continue to send in the follow-up forms of Registry II patients for 24 months. All newly diagnosed ITP patients may be registered prospectively in the PARC-ITP database, which means that some centers will possibly be submitting patient data to both registries, until the follow-ups of Registry II are completed. No data of the same patient should be entered to both Registry II and PARC-ITP. New centers are encouraged to participate in the PARC-ITP registry.

Registry II (since 2002, ongoing for follow-ups)

Frequency, Severity and Timing of Major Hemorrhage in Children with Immune Thrombocytopenic Purpura:
A Study of the Intercontinental Cooperative ITP Study Group


Study Protocol

Principal Investigator:

THE INTERCONTINENTAL COOPERATIVE ITP STUDY GROUP

Data Management:

Thomas Kühne & Caroline Martin, Basel
University Children's Hospital
P.O. Box
CH-4005 Basel, Switzerland
Phone: +41-61-685-6565 Fax: +41-61-685-6566
E-mail: Thomas Kühne
E-mail: Caroline Martin

Web Page:

www.itpbasel.ch

Study Coordinators:

George R. Buchanan, M.D.
The University of Texas
Southwestern Medical Center at Dallas
5323 Harry Hines Boulevard
Dallas, Texas, 75235-9063, USA
Phone: +1-214-648-8594 Fax: +1-214-648-3122
E-mail: George R. Buchanan, M.D.

Thomas Kühne, M.D.
University Children's Hospital Basel, Switzerland
Postfach
CH-4005 Basel, Switzerland
Phone: +41-61-685-6565 Fax: +41-61-685-6566
E-mail: Thomas Kuehne

Victor Blanchette, MA, MB, BChir, FRCPFRCP(C)
The Hospital for Sick Children, Toronto
555 University Avenue
Toronto, Ontario
Canada, M5G 1X8
Phone: +1-416-813-5852  Fax: +1-416-813-5327
E-mail: Victor Blanchette

Sara Vesely, Ph.D.
University of Oklahoma Health Sciences Center
Department of Biostatistics and Epidemiology
801 NE 13th Street, Room 303
Oklahoma City, Oklahoma 73104, USA
Phone: +1-405-271-2229 x 48069
Fax: +1-405-271-2068
E-mail: Sara Vesely

John Wu, M.D.
Department of Pediatrics
B.C.'s Children's Hospital
4480 Oak Street
Vancouver, B.C., V6H 3V4 Canada
Fax: +1-604-875-2890
E-mail: John Wu

Statistician:

W. Berchtold, Ph.D.
University of Applied Sciences of Aargau, Brugg, Switzerland

Hypothesis

Major hemorrhage (internally or from mucosal surfaces) is uncommon in children with immune thrombocytopenic purpura and is only rarely encountered during the first four weeks after diagnosis and initial therapy.

Objectives

The objectives of this multi-center international registry study
(also called Registry II) are as follows:

  • To determine the frequency, severity, and location of major hemorrhage in children with newly-diagnosed ITP, (1) at the time of diagnosis, (2) during the first four weeks following diagnosis after the initial diagnostic studies and treatment, and (3) subsequently for up to two years following diagnosis. Major hemorrhage is defined as intracranial or other overt internal or mucous membrane bleeding which results in anemia or which requires local treatment (nasal packing,estrogen/progestin,etc.) to stop hemorrhage.
  • To determine demographic, disease-related,and treatment-related factors that correlate with the risk of major hemorrhage in children with ITP.
  • To obtain further information regarding the demographics of childhood ITP and the diagnostic and therapeutic management decisions made by treating physicians, extending and refining the results obtained from Registry I.
  • To lay the framework for future prospective randomized controlled clinical trials of therapeutic intervention in childrenwith ITP.

Background

Rationale for Registry II

The majority of children with ITP do not exhibit major hemorrhage (profuse mucous membrane or intracranial bleeding) at diagnosis. Yet, such children are generally treated with corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin in order to raise the platelet count with the aim of preventing such major hemorrhage (1,2). A rise in platelet count has been viewed as a surrogate measure of successful treatment. However, no data show that initial drug treatment for children with minor or no bleeding actually prevents major hemorrhage, and the cost and adverse side effects of drug therapy have been problematic (3). The best means of determining whether drug treatment should be administered to newly-diagnosed children with ITP without major hemorrhage, with the goal of preventing such bleeding, is to conduct randomized clinical trials. Such studies should compare different treatments or compare observation alone to drug treatment. However, study design has been difficult because of the infrequency of major hemorrhage and uncertain definition of therapeutic endpoints (other than surrogate use of the platelet count). It is recognized that intracranial hemorrhage cannot be used as an outcome measure in randomized trials given its extremely rare occurrence (approximately 1 in 500 to 1 in 1,000 patients) (4,5). However, if clinically significant bleeding from the mucous membranes or in other internal sites were also considered as an adverse outcome, then controlled clinical trials might be feasible. Yet, the actual frequency of such major hemorrhage in children with ITP is unknown. Prior reports assessing extent of hemorrhage have focused primarily on patients at time of diagnosis (2,6). What must be determined is the percentage of children without major hemorrhage at presentation who (following initial observation or drug therapy) develop severe bleeding subsequently. In this registry study a four-week (28-day) period following diagnosis and initial therapy has been chosen as the primary interval during which the frequency of new major hemorrhage will be assessed, for it is generally felt that serious bleeding is most likely to occur within the first month (6), and initial treatment aimed at preventing hemorrhage is most frequently administered during this time. We will also request information regarding major hemorrhagic events occurring subsequently in patients who remain thrombocytopenic during the two years of follow-up.

The Intercontinental Cooperative ITP Study Group and Registry I

The Intercontinental Cooperative ITP Study Group was established in Basel, Switzerland by Drs. Paul Imbach and Thomas Kühne in the mid-1990’s with the aim of fostering communication and collaboration among specialists world-wide engaged in patient care and research involving childhood idiopathic thrombocytopenic purpura (ITP). The study group’s first successful effort was the conduct of a registry (termed Registry I) aimed at capturing information regarding presenting manifestations of ITP, initial management (with regard to bone marrow aspirate, hospitalization, and drug therapy) and outcome. The Registry I results, which will soon be presented at several international meetings and submitted for publication (7), are extremely interesting. Over 2,000 children with ITP from 149 institutions in 42 countries were enrolled, and six-month follow-up data have been obtained thus far in 1,285 (63%) of them. Novel information regarding current ITP management practices and the demographics of the disease have been elucidated as a result of Registry I. Moreover, the Intercontinental Cooperative ITP Study Group has gained credibility by other means, including conduct of an annual meeting of participants at the American Society of Hematology meeting, a periodic newsletter, and an informative website (www.unibas.ch/itpbasel). This current protocol (which will be called Registry II) will again employ a registry format to gain additional information about childhood ITP. First, efforts will be made to greatly increase the number of participating investigators and institutions enrolling their ITP patients on the Registry. This will be implemented by using numerous mechanisms to inform the world-wide pediatric hematology community about the Registry’s existence and about the Intercontinental ITP Study Group’s interest in increasing participation, especially from large centers that see many ITP patients. This new project, summarized in the current protocol, aims to expand upon Registry I by focusing on specific bleeding manifestations of childhood ITP, with the ultimate aim of embarking upon one or more randomized trials involving newly-diagnosed patients.

Patient eligibility

Inclusion criteria

  • Age between 4 months and 20 years.
  • Newly established diagnosis of ITP.
  • Isolated thrombocytopenia with no clinically apparent associated
  • conditions or other causes of thrombocytopenia, e.g. systemic
  • lupus erythematosus.
  • Informed consent.

Exclusion criteria

  • none

Study design & instructions for completing Form

While most attention has focused on platelet count as the important outcome determinant in children with ITP, other measures are relevant as well, in particular the location, severity, and timing of hemorrhage. The purpose of Registry II will be to accumulate prospective data on approximately 1,000 additional children (statistical consideration for this number is provided in section 7.0) with newly diagnosed ITP regarding sites of hemorrhage, severity of mucosal bleeding (reflected by hemoglobin concentration and need for red cell transfusion), specific therapy given, and hospitalizations. Little information is available in the literature regarding onset of serious new hemorrhage following diagnosis (3,6). Having data regarding the percentage of children with ITP who bleed during the first four weeks following (but not at the time of) diagnosis will be useful in designing subsequent prospective intervention studies aimed at preventing such bleeding. Sample size in future randomized trials cannot be determined unless the incidence of the adverse outcome measure – in this case major hemorrhage – is known.

  • Written approval of this study by the local Ethics Committee or Institutional Review Board (IRB) of each participating center will be required before the first patient can be enrolled (see attached model consent form). In most cases it is expected that IRB’s will require written informed consent from the parents of each child with ITP enrolled on Registry II.
  • Patients will be enrolled from participating centers whose investigators agree in writing (see attached "Investigator’s Participation Form") to attempt to register every one of their new ITP patients. The commitment form must be submitted before enrolling the first patient. Participating investigators will also be required to maintain and submit every six months a sequential log (see attached "Log of All New ITP Patients") of all new ITP patients (that lacks specific identification of patients) irrespective of whether or not parents’ consent is granted to participate in the registry.
  • Efforts will be made to encourage participation from medium-sized to large centers from as many countries as possible, including centers that did not participate in Registry I. It is anticipated that at least 20 centers will participate, aiming to enroll 5 to 50 patients each during a two-year period of study.
  • Initial Form
    The Initial Form will collect data on each patient for the first 28 days following diagnosis. It is to be submitted within one week after Day 28. There are Diagnosis Information and a Day 28 Information sections of the form. Some instructions for completing the forms are outlined below.
  • Diagnosis Information
    The date of diagnosis (Item 4) is defined as the first day that the child is documented as having thrombocytopenia, whether at the investigator’s institution or prior to the child’s referral there. Initial Treatment (Item 9) is that therapy (if any) administered at the time of (or within 24 hours of) the patient’s diagnosis. When treatment is administered more than 24 hours after diagnosis it should not be included on the Diagnosis Information portion of the form. The intent is to capture data regarding treatment given at the time of diagnosis only.

    Item 10 under Diagnosis Information refers to the bleeding manifestations noted upon presentation, i.e., at time of diagnosis before any therapy is given. Bleeding signs and/or symptoms occurring later (following presentation and initial therapy) are not to be included here.

    The overall severity and bleeding symptoms in each patient will be judged by the investigator (Item 11) at presentation and subsequently using the scale employed by Bolton-Maggs and Moon (2). The 4-week, 6-month, 12-month, and 24-month measurements should reflect the most serious bleeding observed during the previous 4 weeks (but not including the first 24 hours following diagnosis), 5 months, 6 months, and 12 months respectively. Bleeding severity is classified as follows:

    – Mild no bleeding at all or bruising, petechiae, occasional mild epistaxis with very little or no interference with daily living.

    – Moderate more severe skin manifestations with some mucosal lesions and more troublesome epistaxis or menorrhagia.

    – Severe bleeding episodes (epistaxis, melena, menorrhagia and/or intracranial hemorrhage) requiring hospital admission and/or blood transfusions – i.e., symptoms interfering seriously with quality of life.

    Day 28 Information. The Day 28 Information portion of the form (Items 12-18) is completed four weeks following diagnosis. The intent is to obtain information about bleeding location, severity of hemorrhage (reflected by the lowest hemoglobin concentration and need for red cell transfusion during the 28 days after diagnosis) and response to therapy (reflected by the highest platelet count recorded during the first 28 days following diagnosis). Response to items 15 and 16 should reflect transfusions given to treat new bleeding occurring between 24 hours and 28 days after diagnosis. RBC or platelet transfusions given at time of diagnosis are recorded in Item 9.

  • 6-Month Form
    The 6-month Form is to be submitted approximately six months (no less than 5 nor greater than 7 months) following diagnosis. The intent is to obtain follow-up data regarding platelet count, treatment, hospitalization, and bleeding manifestations which occurred since the 28 days following diagnosis.
  • 12-Month Form
    The 12-month form is to be submitted approximately twelve months (no less than 11 nor greater than 13 months) following diagnosis. The intent is to obtain follow-up data regarding platelet count, treatment, hospitalization, and bleeding manifestations in those patients who remained thrombocytopenic at 6 months.
  • 24-Month Form
    The 24-month form is to be submitted approximately twenty-four months (no less than 22 nor greater than 26 months) following diagnosis. The intent is to obtain follow-up data regarding platelet count, treatment, hospitalization, and bleeding manifestations in those patients who remained thrombocytopenic at 12 months.
  • Intracranial Hemorrhage
    Patients who have intracranial hemorrhage at diagnosis or at any time during follow-up will be of special interest. Participating investigators will be asked to submit additional data on these patients, including events antecedent to the intracranial hemorrhage, further details about bleeding in other sites, imaging studies used to diagnose intracranial hemorrhage, treatment modalities administered, and outcome. A detailed summary of these patients’ clinical course should be submitted in narrative fashion to the Data Center in Basel.
  • Data Submission All data are to be submitted by FAX or electronically to the Intercontinental Cooperative ITP Study Group office in Basel.

Statistical considerations

A sample size of approximately 1000 will allow us to meet the objectives described above. With a sample size of 1000 we can estimate the proportion (or mean) of variables of interest with a reasonable amount of accuracy in the overall cohort as well as treatment subgroups (we approximate there would be about 300 in each of the following treatment groups: no treatment, IVIG, steroids and 100 others). A sample size of 1000 will allow us to determine with 95% confidence the proportion of patients who have a major hemorrhage within approximately 1-2% on either side (e.g., if the point estimate from sample is 2.0% we can be 95% confident the true population proportion is between 1.1 and 2.9%).

Descriptive statistics including 95% confidence will be calculated on all relevant variables. Hypothesis tests, including chi-square tests, t-tests, analysis of variance, and other applicable procedures will be used for planning a subsequent randomized clinical trial. Chi-square analysis will be used to determine if there are differences between the proportion of patients by treatment group who have a major hemorrhage. If there are differences of 5% or more between groups, a sample size of 1000 is sufficient.

Ethical considerations

The declaration of Helsinki and its subsequent amendments shall be the accepted basis for the ethical conduct of the clinical investigation. It shall be applied by all parties involved and at every step in the clinical investigation from the first recognition of the need and justification to the publication of results.

The protocol will be approved by the Intercontinental Cooperative ITP Study Group, and by the local, regional or national ethical committees/institutional review boards. All changes to the protocol must be reviewed and approved prior to implementation.

Informed consent
All patients will be informed of the aims of the study. The patients will be informed as to the strict confidentiality of their patient data, but that their anonymized medical records may be reviewed for trial purposes by authorized individuals other than the treating physicians. The information that is given to the patient shall be in language understandable to the patient. An example of a patient informed consent statement is added as appendix 11.7 to this protocol and may be translated into the relevant language. Documented informed consent must be obtained for all patients included in the study before they are registered to the administrative office in Basel, Switzerland. This must be done in accordance with the national and local regulatory requirements.

Patient confidentiality
The investigator must ensure that patient anonymity is maintained. On the case report forms (initial form and follow-up forms) or other documents, patients should be identified by their initials and a study number only. Documents which are not for submission (e.g. signed informed consent form) should be kept in strict confidence by the investigator.

Study administration

  • Study administration office
  • All study administrative procedures are coordinated and conducted by the study administration office in Basel, Switzerland. These include: collection of registration forms, data collection and management, call for follow-up data. All questions concerning the data processing aspects of this study should be addressed to the study administrator (Mrs. Caroline Martin), or to the study coordinator (Thomas Kühne, MD).

  • Finances
  • The promoter of the study is the Intercontinental Cooperative ITP Study Group (Secretary: Thomas Kühne, MD, Basel, Switzerland). The study is supported financially by Novartis AG (Basel, Switzerland).

  • Participating Centers
  • A participating center can be any institution with expertise in the diagnosis and management of children with ITP. Participating centers need to enroll at least 5 patients in 2 years.

  • Publication procedures
  • The Intercontinental Cooperative ITP Study Group will establish a writing committee including the study coordinators and the study statistician. Results will be published under the auspice of the Intercontinental Cooperative ITP Study Group.


Search & Find

For information please contact

Caroline Martin
E-mail: itpbasel(at)unibas.ch

this study is granted by