IMMUNE TOLERANCE STUDY GROUP:
Issue 2. March 2004
ITI Study enters Second Year:
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As the ITI study enters its second year further centres and countries continue to obtain ethical approval for the study and patient recruitment is steadily increasing. 29 patients are currently registered in the study and a number of others are considering study entry at the present time. Four patients have achieved tolerance and only one patient failed. The majority of patients remain in the early stages of tolerance induction or are waiting for their inhibitor to decline below !0 BU prior to randomisation.
Enthusiasm for the study remains at a high level, though we would welcome even more widespread participation
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RECRUITMENT AND PROGRESS: Charles Hay and Janet Goldstone.
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Progress of Study
As of March 2004 there are 63 centres in 20 countries which have ethical approval for the ITI study and are ready to enroll patients.
There have been 29 patients recruited into the study up to date, with another 4-6 eligible patients awaiting clinical/parental decisions as to whether they will be registered in the study.
3 patients have been withdrawn from the study: 1 Health Authority refused to finance high-dose therapy, 1 parent withdrew consent, 1 patient was not randomised within 12 months. There has been one failure of ITI – this patient has now also been withdrawn.
Of the 25 patients currently on study,4 are in the pre-ITI phase awaiting a fall in inhibitor titre to below 10 iu/l. Of the 21 patients who have begun ITI, 7 have negative inhibitors and are close to achieving tolerance after a median of 9 months on study. 3 patients have been withdrawn from the study: 1 Health Authority refused to finance high-dose therapy, 1 parent withdrew consent, 1 patient was not randomised within 12 months. There has been one failure of ITI – this patient has also been withdrawn.
Of the 25 patients currently on study,4 are in the pre-ITI phase awaiting a fall in inhibitor titre to below 10 iu/l. Of the 21 patients who have begun ITI, 7 have negative inhibitors and are close to achieving tolerance after a median of 9 months on study.
The patients recruited so far have been from the following countries:
Australia / 2Belgium / 2
Canada / 7
Italy / 2
Israel / 2
Japan / 2
Netherlands / 1
UK / 4
USA / 7
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Progress on ITI:-
Data Collection and Safety Issues
Eligible Patients
n Patients should be recruited when they develop an inhibitor and data collected until <10 BU, when they are randomised.
n Patients should not be recruited only when they are ready for randomisation.
n There is a tendency to follow the patients until their inhibitor falls and only recruit at that point.
Data Entry
The timely collection of data is of vital importance in maintaining the integrity of the study. The study cannot be effectively monitored if we do not have access to the data. In order to facilitate this, a system of automatic e-mail reminders to the participating centres has been set up.
This reminds centres when their data is due to be entered and also e-mails them at intervals when data entry is overdue. This system, together with some direct follow up from the co-ordinating centre in Manchester is proving to be effective.
The reporting of adverse events, however, is proving harder to monitor as we are completely reliant on the vigilance of each individual centre in ensuring that all events are reported.
Can we please stress that all adverse events must be entered as soon as possible ( in the case of serious adverse events within 48 hours) in the electronic CRF. This data is monitored in Manchester (New York for US centres) and also by the Data Safety Committee (DSC). Please do not wait until the monthly data is due for entry.
It is the responsibility of the DSC to judge whether or not an adverse event is classed as serious.(There is no SAE form in the CRF). If there is a serious adverse event in the opinion of the DSC, then it is the responsibility of the Centre Investigator to report this to their ethical committee (IRB) and to provide the DSC with follow up information.
Please remember that all hospitalisations are by definition SAE’s
If there are any problem with reporting adverse events in the electronic CRF then please contact Manchester immediately.
n Patients should be recruited when they develop an inhibitor and data collected until <10 BU, when they are randomised.
n Patients should not be recruited only when they are ready for randomisation.
n There is a tendency to follow the patients until their inhibitor falls and only recruit at that point.
n We will shortly be e-mailing all participating centres monthly to ask if they have any new inhibitor patients and to enquire about non-recruitment. We need basic data on all patients presenting to participating centres so that we can analyse possible recruitment bias.
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THE ITI STUDY IN THE USA:
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EXCELLENT PROGRESS MADE
From Donna DiMichele
The study has been open in the US since July 2002. Enthusiasm and participation has been excellent! Currently 27 US HTCs have final ethical (IRB) approval with at least 6 other centers in the process of protocol submission. To date, twenty-nine subjects have been enrolled in the study worldwide. Seven US subjects have been enrolled and randomised. One subject has failed IT. The study data on US subjects is included in Dr Hay’s ITI study progress report in the newsletter. We continue to thank all ongoing new and potential investigators for their interest and precious collaboration!
PROTOCOL ALERTS
For any centers initiating or renewing their institutional protocol IRB approvals, please note that the latest version of the US-specific ITI protocol is Amendment 2; dated April 07, 2003. This amendment includes the amended protocol, amended sample consent, US-specific logistical details for each step of the study including a procedure manual, and the Data Safety Monitoring Committee guidelines. Please be sure that the correct version of the protocol has been or is being submitted for ethical approval. If you do not have this version, please let us know.
Please immediately advise Ilene Goldberg the US study co-ordinator of any changes in study contact information at your sites. Remember to fax all initial IRB approvals and renewals as well as consents to Ilene (212-746-8986). As always, please contact Donna DiMichele () or Ilene Goldberg (; 212-746-3463) for any and all study-related questions. (contact details also included on newsletter back page)
* PROTOCOL CLARIFICATIONS
· Bleeds that do not require hospitalisation should continue to be reported on the Intercurrent Bleeding screen (form), but are NOT to be reported as Adverse Events.
When subjects first achieve a normal FVIII recovery, they should return within 1 month for a follow-up hematocrit, inhibitor titer, recovery and half-life study. Subsequently they need only return every 3 months for the identical laboratory evaluation. Monthly inhibitor titers need not be performed during this phase of the study. [This was always the study intent but not clearly stated within the text of the protocol (pg 26 of US protocol)] Please also note that during this phase of the study, when subjects are requiring every 3 month visits, corresponding interim data should still be recorded on the Monthly FVIII Usage/Inhibitor Record but for the actual 3 month period. Data need not be entered monthly.
RESEARCH CONTRACTS
Although there were initial delays in processing institutional research contracts, international study coordinator, Janet Goldstone, and the Manchester team have succeeded in negotiating a streamlined submission process with their R&D department. This required clarification of the Hospital Trust’s liability between the indemnifier, Chubb, and the contracting institution. As A reminder, please note that the study reimburses investigators at a rate of 2000.00 $US per study subject enroled (indirect costs included). However, a limited additional subsidy for IRB fees can also be negotiated on a case by case basis. Please continue to initiate all research contract negotiations directly with Janet Goldstone in Manchester (contact details on back page). However, do not hesitate to contact Donna DiMichele for any assistance you require with research and contract –specific funding issues.
US STUDY ORGANISATION
· The US Steering group confers every 1-2 months on the status of the study in the US. This group includes Drs Tom Abshire, Nadia Ewing, Keith Hoots and Tom Kisker.
· The US Data and Sample Co-ordinating Centre is managed by Barbara Kroner () at the Research Triangle Institute (301-230-4674). Thus far, each centre has used the electronic CRF, by which data is directly back to the Manchester UK fileserver. RTI will start to play a bigger role in US data clarification and facilitation of timely and accurate data entry.
· The study pharmacy co-ordinator for the management of supplemental factor on the high dose arm is Marisela Trujillo () at the Gulf States Pharmacy (713-500-8375). Good news- clotting factor continues to be in great supply and, so far, all product-specific requests have been honoured without difficulty. We wish to again thank our industry collaborators for their ongoing timely and generous collaboration with this part of the study.
THE FIRST ITI COMPANION STUDY BEGINS IN THE US
In late 2003, Dr. Art Thompson initiated a companion study to the ITI protocol. Independently funded and in collaboration with Dr Johannes Oldenburg in Europe,, Dr Thompson’s study investigates the influence of hemophilia genotype on ITI outcome. All participating ITI centers are invited and encouraged to also participate in this companion study. Currently, 4 US centers have already obtained separate IRB approval for this study. Several others are in the active submission process. Please note that Dr Thompson’s research budget does not include funds for additional subject enrolment and IRB fees. Consequently each center will need to be firm with your Research and Contracts office on this point, while continuing to emphasise the low anticipated enrolment, the investigator-initiated nature of this study, as well as its scientific importance to the main study. We apologise for any and all time and effort that this will involve on the part of each center! Please know that we are continuing to explore the possibility of being able to process this protocol as an extensive amendment to the main study and will keep you posted on our progress.
For more information about Dr Thompson’s companion study, please contact Charles Cooper, RN at
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Electronic CRF Update
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Dr Rob Hollingsworth writes: -
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With increased usage of the electronic c.r.f. we are beginning to find ways in which we can improve the site to help make it easier for centres to enter their data whilst also improving compliance with the protocol.
One of the areas we have made a number of modifications is Adverse Event reporting. We have now included guidance on incident report forms and will shortly be introducing automatic linking of adverse event forms to incident report forms. It is essential that we receive timely and complete reporting of all adverse events.
There has been a lot of work on data validation to reduce erroneous entries and cater for higher than expected levels. We have encountered some patients whose inhibitors have risen to over 1000 whilst on ITI. This has meant us adjusting the c.r.f. validation limits to allow these entries. Extra validation on date entry has been introduced as there have been some occurrences of dates after the current date being entered by mistake. Some centres have been entering FVIII Recovery Data as percentages instead of the expected IU/ml therefore validation has been put into place to prevent this.
We have also made changes to the c.r.f. to improve its flexibility. Centres can now choose not to randomize their pre-ITI patient immediately after their second inhibitor of <10. The system will allow them to randomize the patient at a later date provided they are still within protocol guidelines. Also there is now the ability to report adverse events and incident reports as they happen rather than once per month. Other areas of improvement are the ability to enter a number of different products for each intercurrent bleed and also multiple symptoms for catheter infections.
ITI Study email contact addresses are a critical piece of information that must be correct in order for automated email alerts to function correctly. The c.r.f. will now force centres to enter a valid email address if they have not already done so. To add to this we will shortly be conducted a review of existing centre email addresses to ensure they are still valid.
Behind the scenes we have introduced data management and issue chasing systems to help us better manage data flow into the ITI Study Database. These systems are helping us monitor whether centres are up to date with data entry. This will become increasingly important as patient numbers increase.
Finally we have begun to improve the content of the ITI Study Home Page, please take a look and pass on any comments and suggestions you may have:
WWW.ITISTUDY.COM
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Stop Press
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The electronic CRF is equipped to send e-mails automatically to the Data Safety Monitoring Committee when adverse events are reported and to send reminders to investigators when data is overdue and to inform the principal investigators of new randomizations and all other significant events. It recently became apparent, however that many of these e-mails were not getting through. An extensive investigation revealed changes in the settings of one of the transit fileservers in the University of Manchester and a syntax error introduced by an outside contractor in a similar server in our hospital. These two changes were effectively blocking auto-e-mails but not normal e-mail traffic. This has now been fixed and so our auto-e-mails should resume.