A Randomized Study of IVIG vs. IVIG With High Dose Methylprednisolone in Childhood ITP.

• The rapidity of rise in Platelet Count [ Time Frame: The first 24 hours following the administration of therapy ] [ Designated as safety issue: No ]
• Time taken to reach a Platelet Count of less than or equal to 20, less than or equal to 30, and less than or equal to 50 x 10^9/L. [ Time Frame: Time frame determined by outcome ] [ Designated as safety issue: No ]

• The rapidity of rise in PC over the first 24 hours following the administration of therapy.
• Time taken to reach a PC of  20,  30, and  50 x 109/L.
• Primary outcome:

• Frequency of response to therapy at different time points [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Days to PC falling to < 20 x 109/L [ Time Frame: Time frame determined by outcome ] [ Designated as safety issue: No ]
• Adverse Effects of therapy [ Time Frame: 1 week ] [ Designated as safety issue: No ]
• Quality of life changes over time and between the treatment groups [ Time Frame: 6 months ] [ Designated as safety issue: No ]

• Secondary Outcomes:
• Frequency of response to therapy at different time points: Patients will be labeled as having;
• i) complete response (CR) if they obtain a PC > 150 x 109/L
• ii) partial response (PR) if they obtain a PC between 50 and 150 x 109/L
• iii) minimal response (MR) if they obtain a PC between 20 and 50 x 109/L and at least twice the baseline PC
• iv) non-response (NR) - All other situations will be classified as non-response.
• Days to PC falling to < 20 x 109/L
• Bleeding Risk as evaluated by Bleeding scores

Childhood immune thrombocytopenia purpura (ITP) is a disorder characterized by the production of antibodies against platelets, resulting in enhanced destruction of platelets. Most children with ITP present with low platelet counts (PC) but minimal bleeding. Very rarely a child may present with a severe life-threatening bleed, such as a bleed in the head. In this case it is very important that the PC be raised as quickly as possible. The combination of corticosteroids and intravenous gammaglobulin (IVIG) is commonly used in the management of such severe bleeding in children with ITP to quickly raise the PC and yet this treatment combination has not been tested against using IVIG alone. If it is shown that the combination of these agents does result in a quicker rise in PC then when using IVIG alone would support the use of this combination therapy in emergency situations.

As we can not ethically conduct this study in patients with life-threatening bleeds, we plan to study patients with ITP and PC less than 20 X 109/L, but without life threatening bleeding. Eligible patients will be randomized to one of these 2 regimens (IVIG + placebo or IVIG + IV corticosteroids). The study is designed as a double-blind trial, where the patient or the treating physician will not be aware of the regimen that a patient is randomized to. PC's will be measured as a surrogate measure of bleeding risk; bleeding scores (a score generated by observing patients for bleeding symptoms) will be used to grade bleeding severity, and adverse effects to treatment will be monitored by the means of questionnaires throughout the study.

Rarely children with immune thrombocytopenia purpura (ITP) can present with severe or life-threatening bleeding. In these cases it is very important that the platelet count be raised as quickly as possible. Several studies have shown that IVIG and corticosteroids on their own can raise platelet counts, but few studies have examined how the combination of IVIG and corticosteroids compares to IVIG alone in raising platelet counts in childhood ITP. Yet despite the lack of conclusive evidence to indicate that steroids given together with IVIG is more effective, this combination treatment is often given when children present with a life-threatening bleed, e.g. intracranial bleed. In addition to presumed greater effectiveness of giving the two agents together there is also evidence to show that the combination of IVIG with steroids may have other beneficial effects, in addition to greater effectiveness at raising platelet counts. This can include reducing side effects of IVIG.

We propose to compare the effectiveness of the combination of IVIG with corticosteroids to IVIG alone in raising platelet counts in children with ITP and a platelet count less than 20 x 109/L. Patient will be eligible only if they in conjunction with their treating physician have decided to be treated with IVIG. In this way they will require an intravenous regardless of study participation. The primary outcome is the rise in platelet count as reflected by the platelet count at 24 hours.

Hypothesis:

IVMP and IVIG, administered together, will

1. increase the PC faster, and
2. minimize the adverse effects of IVIG, and
3. lead to a more sustained increase in PC (longer time before needing retreatment) If it is shown that the combination of these agents does result in a quicker rise in PC, this would support and justify the use of the combination therapy in emergency situations.

Study Proposal and Methods:

We propose to prospectively evaluate 2 treatment regimens in patients with childhood ITP:

Regimen A: Placebo followed by IVIG 1 g/kg (Gamunex® Immune Globulin Intravenous [Human], 10%; Bayer)* x 1 dose Regimen B: Combination therapy (IV MP (Solu-Medrol®, Upjohn) 30 mg/kg (max. 1 g) over 30 min followed by IVIG 1 g/kg (Gamunex® Immune Globulin Intravenous [Human], 10%; Bayer)* x 1 dose

*Gamunex will be given according to manufacturer's guidelines. Gamunex has been demonstrated to be safely and effectively administered by means of a rapid infusion protocol whereby it can be given over a period of 2 hours (although in some cases it needs to be given at a slower rate over a longer period of time).

• Drug: Methylprednisolone and Intravenous Immune Globulin
  Combination therapy (IV MP (Solu-Medrol®, Upjohn) 30 mg/kg (max. 1 g) over 1 hour followed by IVIG 1 g/kg (Gamunex Immune Globulin Intravenous [Human], 10%; Bayer)* x 1 dose
• Drug: Methylprednisolone and Intravenous Immune Globulin
  Placebo followed by IVIG 1 g/kg (Gamunex Immune Globulin Intravenous [Human], 10%; Bayer)* x 1 dose

• Active Comparator: 1
  Intervention: Drug: Methylprednisolone and Intravenous Immune Globulin
• Experimental: 2
  Intervention: Drug: Methylprednisolone and Intravenous Immune Globulin

Inclusion Criteria:

• ages 1-17 yr. followed at participating centers
• diagnosed with primary ITP
• present with a PC < 20 x 10^9/L
• patient and attending physician have decided on treatment of ITP

Exclusion Criteria:

• initial presentation with ITP
• splenectomy
• life-threatening hemorrhage e.g. proven or suspected intracranial hemorrhage (ICH), major gastrointestinal hemorrhage with cardiorespiratory decompensation
• organ-threatening hemorrhage e.g. hemorrhage into the eye
• contraindication to IVIG ( renal disease with creatinine > x 2 upper list of normal )
• contraindication of IV methylprednisolone ( diabetes mellitus, hypertension, peptic ulceration )
• prior failure to attain a PC level over 50 X 109 within 2 weeks of treatment with IVIG of 0.8 to 1 g/kg or IV methyl-prednisolone (max 1 gram ) within 6 months prior to study entry
• co-existing situations that could affect platelet response to therapy e.g. sepsis, fever > 38.5°C ( orally or equivalent), splenomegaly (spleen tip > 2 cm below costal margin), Disseminated Intravascular Coagulation (DIC) - defined by a fibrinogen level < 1.0 g/dL and elevated D-dimer levels, surgery
• pregnancy (a mandatory urine pregnancy test will be obtained on all post-pubescent female patients). Such patients can only be eligible once the urine pregnancy test results are confirmed to be negative.