Frequesntly Asked Questions (FAQs)
QUESTIONS
Q.1 Is EURAMOS 1 included in the National Research Register?Q.2 Is the Investigator Statement the same as the Form of Participation?
Q.3 Does submission to Ethics have to be done separately for paediatric and adult units?
Q.4 If two centres have the same PI do they have to fill out two investigator statements?
Q.5 Do the local pathologists and surgeons need to sign the Delegation Log?
Q.6 Is there a specific form for drug accountability
Q.7 If one data manager works at 2 sites, do 2 complete site files need to be kept and maintained separately?
Q.8 Since bone scans are one of the essential investigations in EURAMOS 1 protocol, will an ARSAC (Administration of Radioactive Substances Advisory Committee) licence need to be applied for?
Q.9 When is the next Investigators’ Meeting?
Q.10 If a data manager fills in part of an SAE form i.e. name, D.O.B etc, do they need to indicate this on the delegation log?
Q.11 Can completed CRFs be kept in the patient notes and referenced to the site file?
Q.12 Are patient diary cards compulsory?
Q.13 On the consent forms, who is the Researcher?
Q.14 Can research nurses consent patients for EURAMOS 1 or can only the clinicians do this?
Q.15 What is the procedure for registering new patients?
Q.16 Is it possible to register patients after chemotherapy treatment has started?
Q.17 When registering a patient, if there is some question about the possibility that the patient has lung metastases, should we hold on to the registration form until this has been confirmed or should we return the form straight away?
Q.18 What is the procedure for randomising patients?
Q.19 What is the procedure if a registered patient is not to be randomised?
Q.20 Can a patient be randomised using the local pathologist's assessment of the histological response?
Q.21 If a patient was not randomised but later went on to have thoractomy, does a Thoractomy form need to be completed?
Q.22 If a patient did not fill out the first Quality of Life questionnaire at week 5 of the protocol, is it still relevant to ask for further questionnaires to be completed?
Q.23 For patients who have consented to participate in the parallel Biological Study, when should blood samples be collected, how should the samples be stored and when will they be collected?
Q.24 When a patient is randomised to MAPifn, what is the procedure for requesting PegIntron supply?
Q.25 Is GCSF being supplied free of charge?
Q.26 Who is the contact at Chugai Pharma UK?
Q.27 At the end of their first session of Cisplatin and Doxorubicin, the patient was still suffering from nausea and vomiting and so was kept in hospital overnight and was discharged the following day. Should this be reported as a SAE?
Q.28 Is it acceptable if imaging takes place in more than one site?
Q.29 Do we need to confirm bone scan or plain radiograph suspected metastases on MR / biopsy?
Q.30 Should patients on EURAMOS 1 be given Septrin or anti-fungal prophylaxis?
Q.31 Could doxorubicin been administered as a daily bolus at the time point 1, 24, 48 hours instead of the 48-hour continuous infusion stated in the protocol?
Q.32 Is it possible to continue on trial without using dexrazoxane if left ventricular ejection fraction falls?
Q.33 Is carboxypeptidase mandatory in the case of delayed methotrexate elimination or methotrexate-related renal toxicity?
Q.34 Could different folinic asid rescue regiman be used than the one stated in the protocol?
Q.35 “Urinary electrolyte wasting” is one of the adverse events mentioned on the chemotherapy form. What does it refer to?
Q.36 How frequently should Glomerural Filtration Rate (GFR) be measured directly by radionuclide determination?
ANSWERS
Q.1 Is EURAMOS 1 included in the National Research Register?Yes
Q.2 Is the Investigator Statement the same as the Form of Participation?
Yes
Q.3 Does submission to Ethics have to be done separately for paediatric and adult units?
No, as long as they are on the same site and under the supervision of the same PI
Q.4 If two centres have the same PI do they have to fill out two investigator statements?
No, as long as the investigator statement makes it clear that it is for two centres
Q.5 Do the local pathologists and surgeons need to sign the Delegation Log?
No, as their involvement in the trial is no different to how they would normally treat the patient.
However, if they fill in any of the CRFs, such as pathology or surgery forms, they should sign the delegation log.
Q.6 Is there a specific form for drug accountability
No, drug accountability can take place as per normal local practice
Q.7 If one data manager works at 2 sites, do 2 complete site files need to be kept and maintained separately?
Either one or two site files can be maintained, as long as the data manager is able to retrieve all documents related to each site
Q.8 Since bone scans are one of the essential investigations in EURAMOS 1 protocol, will an ARSAC (Administration of Radioactive Substances Advisory Committee) licence need to be applied for?
This is a local decision based on standard local care.
However, for EURAMOS 1 we would not expect the centre to need to apply for a ARSAC license because the scans required are part of the standard routine clinical care for osteosarcoma patients.
Q.9 When is the next Investigators’ Meeting?
Investigators' meetings have previously taken place in London (June 2005), Glasgow (April 2006), Oslo, Norway (October, 2006) and most recently in Surrey (Jan 2008).
The next Investigators' meeting has not yet been confirmed.
Q.10 If a data manager fills in part of an SAE form i.e. name, D.O.B etc, do they need to indicate this on the delegation log?
No, as they will not be signing the form
Q.11 Can completed CRFs be kept in the patient notes and referenced to the site file?
Yes
Q.12 Are patient diary cards compulsory?
No
Q.13 On the consent forms, who is the Researcher?
Researcher refers to the Investigator.
The Consent form should be signed by an Investigator - that is any of the clinicians that have signed the Delegation of Responsibilities Log
Q.14 Can research nurses consent patients for EURAMOS 1 or can only the clinicians do this?
Research nurses can obtain the patients consent, but the Investigator must also sign the Consent form.
Q.15 What is the procedure for registering new patients?
To register a patient, please complete the registration form (form 1) before calling the MRC CTU registration/randomisation line on +44(0)207 670 4777.
Provided that the patient is eligible an identification number will be assigned.
The completed registration form should be returned to the MRC CTU within 7 days of registering the patient.
Q.16 Is it possible to register patients after chemotherapy treatment has started?
Patients must be registered within 30 days of diagnostic biopsy and before chemotherapy has taken place.
Please note that patients can be registered on the same day as the first cycle of chemotherapy begins.
Q.17 When registering a patient, if there is some question about the possibility that the patient has lung metastases, should we hold on to the registration form until this has been confirmed or should we return the form straight away?
Question 13 on the Registration form (form 1) should be answered '2' i.e. 'possible lung metastases' and the form returned immediately to the MRC Clinical Trials Unit.
Whether or not the patient had any lung metastases can be confirmed at the time of randomisation on the Randomisation Checklist (form 2), question 9.
Q.18 What is the procedure for randomising patients?
The patient’s histological response must be confirmed (by the review pathologist where possible) and the patient randomised within 35 days after definitive surgery.
The surgery form must be completed and returned to the MRC CTU before randomisation takes place, along with all pre-operative chemotherapy forms.
To randomise a patient, please complete all sections of the randomisation checklist (form 2) before calling the MRC CTU registration/randomisation line on +44 (0)207 670 4777.
Provided that the patient is eligible a treatment will be assigned. The completed randomisation form should be returned to the MRC CTU within 7 days of randomising the patient.
Q.19 What is the procedure if a registered patient is not to be randomised?
For patients who are not to be randomised, please complete the randomisation checklist (form 2) answering 'No' to question 12 and return the form to the MRC Clinical Trials Unit as soon as possible.
Q.20 Can a patient be randomised using the local pathologist's assessment of the histological response?
Where possible, please use the review pathologist's assessment.
However, if the review pathologist's assessment is not available within 35 days of surgery then the local pathologist's assessment can be used.
If you have not received confirmation of the patients histological response from the review pathologist, please contact the review pathologist prior to randomisation to check whether the assessment is available.
Q.21 If a patient was not randomised but later went on to have thoractomy, does a Thoractomy form need to be completed?
No, you do not need to complete the Thoracotomy form (form 9) for patients who are not randomised but later have thoracotomy.
Q.22 If a patient did not fill out the first Quality of Life questionnaire at week 5 of the protocol, is it still relevant to ask for further questionnaires to be completed?
The first questionnaire is not a true baseline questionnaire as it is completed after treatment begins therefore it is likely that the questionnaires will be used to look at how each patient was feeling at each individual time point rather than comparing across the time points.
Therefore, we should continue to collect as many questionnaires as possible regardless of whether the week 5 questionnaire was completed.
Q.23 For patients who have consented to participate in the parallel Biological Study, when should blood samples be collected, how should the samples be stored and when will they be collected?
A 10ml EDTA blood sample should be taken from the patient, BEFORE treatment begins.
DNA will be collected from the blood and so samples should be stored to allow for this, as per local practice.
It is not yet certain when the blood samples will be required and so samples should be stored until further notice.
Q.24 When a patient is randomised to MAPifn, what is the procedure for requesting PegIntron supply?
When a patient is randomised to MapInfo, the MRC CTU will automatically request the first three months of PegIntron supply for that patient from Schering Plough, which will be delivered to the hospital Pharmacy. A copy of the PegIntron request form will be forwarded to the hospital Pharmacist as confirmation that the drug has been ordered. It is then the responsibility of the hospital pharmacist to request subsequent PegIntron supply for that patient directly from Schering Plough. Guidelines on how to order subsequent supplies will be sent to the pharmacist and are also available on the EURAMOS website. The 'Drug Re-Request form' is available on the EURAMOS website (Participating Institutions/Pharmacy).
Q.25 Is GCSF being supplied free of charge?
The use of G-CSF (Human Granulocyte Colony Stimulating Factor) is recommended when chemotherapy induced myelosuppression leads to treatment delays.
There will be a 25% retrospective stock reimbursement for GranocyteTM (rHuG-CSF, lenogastrim) used within this study for patients treated within the protocol in the UK.
In the UK, Granocyte is manufactured by Chugai Pharma UK Limited and distributed by Aventis UK ( Tel. 07774 415571, Fax 0208 9875661).
For reimbursement, please complete a reimbursement form, available on the EURAMOS website (Participating Institutions/Pharmacy).
Q.26 Who is the contact at Chugai Pharma UK?
Mr David Eves: Tel. +44 (0)7774415571, email d.eves@chugai-pharm.co.uk
Q.27 At the end of their first session of Cisplatin and Doxorubicin, the patient was still suffering from nausea and vomiting and so was kept in hospital overnight and was discharged the following day. Should this be reported as a SAE?
This is defined as a SAE as it required hospitalization or prolongation of an existing hospitalization, however the EURAMOS 1 protocol (section 13.4) has defined some exceptions for SAE reporting: Hospitalisation for chemotherapy is not reported as an SAE.
In addition expected side effects of chemotherapy, which are listed in the product information, will not be reported on an SAE form for the purposes of this clinical trial unless in the opinion of the investigator they unexpectedly prolonged the hospitalization or required intensive care therapy.
Q.28 Is it acceptable if imaging takes place in more than one site?
Yes it is. However, reports of imaging should be kept in the patient’s notes
Q.29 Do we need to confirm bone scan or plain radiograph suspected metastases on MR / biopsy?
We would certainly recommend confirmation of suspected bone metastases either by MRI or biopsy as this has such a fundamental impact on treatment and prognosis.
This is referring to cases where one may see one or two suspected lesions on bone scan.
Q.30 Should patients on EURAMOS 1 be given Septrin or anti-fungal prophylaxis?
Concurrent use of methotrexate and Septrin (co-trimoxazole) decreases the renal excretion of Methotrexate. This may prolong the need for intravenous hydration, folinic acid rescue and hospitalisation and lead to increased methotrexate toxicity. Therefore Septrin should not be used. There is no need for anti-fungal prophylaxis.
Q.31 Could doxorubicin been administered as a daily bolus at the time point 1, 24, 48 hours instead of the 48-hour continuous infusion stated in the protocol?
There is increasing evidence that the mode of administration plays an important role for doxorubicin-induced cardiotoxicity and data indicate that bolus administration rather than continuous infusion appears to be an important risk factor.
In EURAMOS 1 it is mandatory to give doxorubicin as a 48 hour continuous iv infusion and therefore all patients should have a central line.
Q.32 Is it possible to continue on trial without using dexrazoxane if left ventricular ejection fraction falls?
Cumulative, dose-related anthracycline-induced cardiac toxicity is a serious, significant limiting side effect of its use.
Cardiac toxicity occurs in 1 to 2% of patients given a cumulative dose of <450mg/m2 and in 20 to 40% at doses >600mg/m2.
Children and adolescents appear to be particularly sensitive to cardiotoxic effects.
The degree of endomyocardial injury has been correlated with dose and schedule of administration.
Less severe injury is associated with lower cumulative dose, administration using a weekly schedule and administration using a continuous infusion.
As explained in Appendix A.5, dexrazoxane is converted intracellularly to a chelating agent that interferes with iron mediated free radical generation which is thought to be responsible, in part, for anthracycline-induced cardiomyopathy.
In EURAMOS 1, if a confirmed 10% fall within the normal range of left ventricular EF or FS occurs, our standard practice is to give dexrazoxane as instructed in the protocol section 9.1.8.4.6 and in Appendix A.5 and B.6.
Dexrazoxane is supplied in the UK under ""named patient basis"" by Chiron Biopharmaceuticals Limited, tel 0208 5804040.
It costs £124 (+ VAT) per 500mg.
It would be better to contact Chiron Biopharmaceuticals Limited before-hand to find out how many days are required for drug delivery for each individual site.
Q.33 Is carboxypeptidase mandatory in the case of delayed methotrexate elimination or methotrexate-related renal toxicity?
MTX is primarily cleared by renal excretion. Despite hyperhydration and urinary alkalinisation, MTX and its metabolites may precipitate in the renal tubules causing acute renal dysfunction.
This can be life-threatening, because it delays MTX excretion, thereby exacerbating other toxicities associated with MTX, especially myelosuppression, mucositis.
In a recent review of 3887 patients with osteosarcoma who received HD-MTX, almost 2% develop nephrotoxicity.
The mortality rate among those patients was 4.4%. Dialysis-based methods of MTX removal have limited effectiveness in removing MTX.
However, a single intravenous dose of 50 units/kg of carboxypeptidase results in the reduction of plasma MTX levels to the non-toxic range within minutes, without causing toxicity (Widermann B et al. High-Dose Methotrexate-induced nephrotoxicity in patients with osteosarcoma, Cancer 2004;100:2222-32).
Carboxypeptidase (Voraxaze™) is supplied in the UK under ""named patient basis"".
Further information, guidelines on administration, supplier details etc could be found in Appendix A.5.
Protherics plc, the manufacturer of Voraxaze™ (carboxypeptidase G2) has contracted with IDIS in the UK.
Registration with IDIS in advance of ordering is necessary to quickly process your request.
They deliver Voraxaze within 24 hrs of receipt of your order. It is supplied in packs of 2 vials containing 1000 IU per vial. The cost of 2 vial pack is £9440 + VAT.
This will effectively mean next day delivery and there will be a service during weekends and holidays (there may be an additional charge for this weekend service).
Contact telephone number for IDIS for information or order enquiries about Voraxaze: 01932 824 100.
Email contact during buisiness hours: enquiries@idispharma.com,
Out of hours emergency line: 01932 824 198.
Q.34 Could different folinic asid rescue regiman be used than the one stated in the protocol?
Different FAR doses result in different level of rescue.
It is important to follow similar practice for all patients.
The guidelines in B.6 should be followed for all EURAMOS 1 patients.
Q.35 “Urinary electrolyte wasting” is one of the adverse events mentioned on the chemotherapy form. What does it refer to?
Urinary electrolyte wasting (see EURAMOS 1 protocol: Appendix A.4, page 41) refers to the inability of the kidneys to excrete acid into the urine.
This condition is called renal tubular acidosis and can be triggered by several drugs, including chemotherapy drugs. It may also be hereditary (ie Fanconi's syndrome), triggered by an autoimmune disease, or caused by heavy metal poisoning diabetes, sickle cell disease or an obstruction in the urinary tract.
Resulting symptoms and metabolic abnormalities include:
a) high blood acidity, e.g. low bicarbonate
b) mild dehydration
c) low or high potassium blood levels (depending of the type of renal tubular acidosis)
d) fragile bones and bone pain
e) kidney stones due to calcium deposits in the kidneys
The grading of this AE is as follows:
grade 1: asymptomatic, intervention not indicated
grade 2: mild, reversible and manageable with replacement
grade 3: irreversible, requiring continued replacement
grade 4: not applicable
grade 5: not applicable
Management depends on the type of renal tubular acidosis. It usually involves oral sodium bicarbonate supplements. Potassium supplements may also be required.
If potassium blood levels are high they can usually be kept under control by restricting the potassium intake and, if necessary, taking diuretics.
Q.36 How frequently should Glomerural Filtration Rate (GFR) be measured directly by radionuclide determination?
The measurement of GFR is necessary prior to each chemotherapy course.
It can be calculated by estimation (see Appendix A.3 for suggested formulae) or direct measurement by radionuclide estimation.
This a suggested schedule for direct measurement of GFR:
MAP /MAPifn arm: pre treatment, pre cycle 3, 5 and at the end of MAP chemotherapy;
MAPIE arm: pre treatment, pre cycle 3, 6, 8 and at end of treatment.