International Immune Tolerance Study

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to see if a low-dose arm or a high dose-arm of immune tolerance is more effective in eliminating inhibitors in patients with hemophilia A.

Detailed Description
-----------------
Subjects will be randomized into a low-dose or high-dose immune tolerance regimen and this study will compare the success rates, the time to achieve tolerance,the complications and the cost of both regimens.It will also aim to identify predictors of successful immune tolerance.

Official Title
-----------------
An International Randomised Controlled Trial Of Immune Tolerance Induction

Conditions
-----------------
Hemophilia A With Inhibitors

Intervention / Treatment
-----------------
* Drug: Factor VIII concentrates
* Other: Low-dose treatment
* Other: High-dose treatment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Severe hemophilia A (FVIII level <1%). A maximum historical inhibitor titer of between 5 BU and 200 BU that must be confirmed once prior to the beginning of ITI. The inhibitor titer should be <10 BU at the start of ITI, confirmed once. The inhibitor must be present for <24 months when ITI begins. Maximum age of 7 at the start of ITI. Willingness to comply with the protocol. Exclusion Criteria: Moderate or mild hemophilia A (FVIII level >1%). Spontaneous disappearance of the inhibitor prior to ITI. Historical maximum inhibitor titer <5 BU or > 200 BU before starting ITI. Inhibitor titer > 10 BU at the start of ITI. Inhibitor present for more than 24 months before starting ITI. Systemic immunomodulatory drug therapy during immune tolerance e.g. corticosteroids (< 5 days every 2 months maximum dose 2 mg/kg or 60 mg/day), azathioprine, cyclophosphamide, high-dose immunoglobulin or the use of a protein A column or plasmapheresis. Age > 7 years at the start of ITI. Inability or unwillingness to comply with the protocol. Previous attempt at ITI.

Ages Eligible for Study
-----------------
Maximum Age: 7 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Low-dose treatment (50 FVIII u/kg three times a week). | Drug: Factor VIII concentrates<br>* To be determined at the discretion of the investigator.<br>Other: Low-dose treatment<br>* 50 FVIII u/kg three times a week.<br>|
| Active Comparator: 2<br>High-dose treatment (200 FVIII u/kg per day). | Drug: Factor VIII concentrates<br>* To be determined at the discretion of the investigator.<br>Other: High-dose treatment<br>* 200 FVIII u/kg per day.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success-rate and partial success-rate |  | Up to 69 months | 
| The time from the start of ITI to successful tolerance |  | Up to 33 months | 
| The comparative cost-effectiveness of the two treatment arms |  | Up to 69 months | 
| A comparative assessment of morbidity between the two treatment arms including: number of intercurrent bleeds, infections and number of hospital in-patient days. |  | Up to 69 months | 
| The inhibitor recurrence (relapse) rate in the first twelve months after successful ITI. |  | Up to 45 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The dose-regimen, success rate and time to ITI, |  | Up to 69 months | 
| The starting inhibitor titre, success rate and time to ITI, |  | Up to 69 months | 
| The peak historical inhibitor titre, success rate and time to ITI, |  | Up to 69 months | 
| The peak inhibitor titre after starting ITI, success rate and time to success, |  | Up to 69 months | 
| The age at the time of inhibitor detection, success-rate and time to success, |  | Up to 69 months | 
| The number of factor VIII treatment days between inhibitor detection and initiation of ITI, success of ITI. |  | Up to 69 months | 
| The type of concentrate used (von Willebrand factor-containing, monoclonal or recombinant), success rate and time to success, |  | Up to 69 months | 
| The effect of interim infections/immunisations, success rate and time to success, |  | Up to 69 months | 
| The effect of treatment interruption, success rate and time to success. |  | Up to 69 months |