PRELIMINARY INFOS

1) All changes to the draft protocol that we discussed and agreed upon during the meeting in Rome (Eg to avoid serology and how to deal with paediatric patients) have been already amended in the protocol attached to this email, so please refer to the protocol I have attached to THIS email and ignore the first one 2) Please answer all following questions BY THE 15th OF JANUARY 2014; Should you have any problem with questions, send me an email (f_tamarozzi@yahoo.com) or call me (0039 347 0501715). I will be unable to answer only on 27-28-29 December. 3) We all know that cystic echinococcosis should have a patient-tailored management, HOWEVER it is important in study settings (which are different from normal hospital settings) to be as more schematic as possible in the treatment algorithm. Small deviations from the algorithm will be of course possible at the discretion of the clinician in particular cases, but we need to have a reference scheme of treatment in the protocol 4) Please make amendments to the protocol with TRACKABLE changes or using the NEW COMMENT command of the Word sheet 5) Please, answer questions directly in THIS POWER POINT (you can continue to write after the question)

FOR SAMPLING
1. Population: is there any web site where we can find population (of each country) stratified by the smallest administrative unit (e.g., in Italy is the municipality that usually refers to each city/village of the country) and within the unit population is further stratified by age (single year) and gender. At this web address you can see what we can access in Italy (http://www.demo.istat.it/pop2013/index.html). Response: This data can be obtain from the National Statistic Centre 2. Endemic: do you have access to hospital records of patients with CE? Do you have information about the municipality where the cases were living? Do you have this data for more calendar years? It will be ideal to have cases of the last five years. Combination of data from sheep and hospital records could help on better defining the endemic areas Rasp: We consider that it will be better to use data available from Colentina Hospital, where the cases (including cases from Hospital Floreasca) are monitored. The surveillance system is haotic, discontinuu. According to data hospital, during 2008-2012, the counties of Buzau, Ialomita Teleorman and Calarasi, (except Bucharest) are associated with most of the cases Because of this we thing to choose from those districts: either to go to the same counties (Buzau, Ialomita, Teleorman) but find other villages and to get more accurate data in those counties. More than that, we can briefly evaluate in the same places the situation after 8-10 years, and additionally to estimate the follow up of the cases we discovered during the previous studies. Or, we can choose Dambovita and Calarasi counties, also located in SE of Romania.

FOR SAMPLING
1. Rural area: is there any web site or institution such as the national bureau of census that provides a specific definition of rural and that classifies the smallest administrative unit as predominantly rural? As an example see the following web site: http://www.reterurale.it/flex/cm/pages/ServeBLOB.php/L/IT/IDPagina/597 Response: The rural areas are defined according to the administrative rules (number of population, infrastructures, industry)- We think that we can obtain such data
2. Sheep: In this site (http://www.fao.org/AG/againfo/resources/en/glw/Density_maps/sheep_census2005.jpg) is available the sheep density per square kilometer in the world. In a previous publication by Fenicia (Vescio FM et al. Environmental correlates of Crimean-Congo haemorrhagic fever incidence in Bulgaria. BMC Public Health. 2012 Dec 27;12:1116. doi: 10.1186/1471-2458-12-1116. PubMed PMID: 23270399; PubMed Central PMCID:PMC3547815.) the density of goats and sheep by districts (more than a municipality and this means that at least for Bulgaria it is possible to classify area on the basis of sheep density. The FAO web site seems to suggest that we do not need specific local registries. However, we should verify if the density is based on farming or tracing. Response: probably the estimation of sheep/goats is incompleet. It will be probable possible to receive some data, and I supose that we can have a difference between the areal of human cases and sheep cases. What about the stray dogs? We have many and not registered...This can explain the high number of cases even in towns Can we avoid

FOR PROTOCOL -1
1) Fill TEAM ROSTER Scientific Investigators in page 2 of the Protocol for what concerns your Country (only reference people should be inserted, not every single technician, nurse ) 2) Fill TREATMENT ALLOCATION ALGORITHM (on the scheme of Table 1 paragraph 4.2 of the protocol) including management of complicated cysts 3) Fill STUDY PROCEDURES (on the scheme of Table 2 paragraph 5.1 of the protocol and paragraph 5.3 of the protocol) according to point 2) and including management of complicated cysts, type of scolicdal agent if used, length of albendazole treatment (e.g. for surgery or percutaneous, how many hours/days will you start before and how many days will you continue afterwards; for albendazole only treatment, if you do it, decide a fixed number of months this will last 3 months? 6 months?) 4) Detail particular risks of the procedures you will perform if they are not listed in paragraphs 5.6.2 and following paragraphs of the protocol (e.g. risks of chemical cholangitis if you will use scolecidal agents is not enlisted yet) and corrective measures

5) Detail particular inclusion/exclusion/withdrowal criteria to treatment if they are not enlisted or are not appropriate in paragraphs 4.2 and 4.3 and 4.5 of the protocol
6) Please indicate if the management of CL lesions detailed in Task 2 paragraph 3.1 of the protocol is ok for you or what you want to change

FOR PROTOCOL -2
1) Will you do Chest X ray to everybody found a with cystic echinococcosis during the ultrasound screening?

2) IF you have included ALBENDAZOLE for more than 1 month in any of the treatment schemes (e.g if an ABZ only treatment exists on your treatment scheme or if prophylactic ABZ after surgery/percutaneous procedures is longer that 1 month) please answer the following questions: - for patients that will have to be treated only with albendazole, will you bring them to your hospital for the Chest X Ray (if you are doing it) and for the liver enzymes/ blood cell counts or will you be able to arrange these things in their communities by local physicians (Adriano Casulli will tell me if you can PAY some local physician to take care of this follow-up; Also, remember that you will have to PAY all TRANSPORTATIONS for patients coming to your hospital) - Will you give all albendazole pills required for the whole length of treatment or how are you going to manage this albendazole? (again, remember that patients will not have to pay anything! My sugestion id for 3 months /patient and for the rest in Romania is 90% reduceduce, so we can support only 10 %, !! Is it possible? Adriano Casulli will try to have albendazoloe donated but this is not guaranteed)

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1) What is your preferred scheme of follow-up during albendazole treatment if this is longer than 1 month? (Example liver enzymes + complete blood count every month? At month 1, then month 3, then month 6? remember that if you cannot do it in the local communities the patient will have to come to your hospital) 2) What do you want to do with problem of pregnancy check during albendazole treatment? In Romania we will just ask the woman (by signing the informed consent form) to take care of avoiding pregnancy and to inform us if she becomes pregnant. Will this be ok in you Country as well?

3) Payment of transportation of patients to your hospital: decide how will you do (fixed vouchers? Reimbursement of real cost?)
4) Payment of local physicians if monthly follow-up or other services are requested (Adriano Casulli will enquiry on this point): do you forecast to need such payments?

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Some laboratory procedures WILL HAVE TO be done straight after sample collection (or anyway within 6h from the blood collection) for both Time-zero (screening) and FOLLOW-UP with ultrasound + blood taking EVERY 6 MONTHS. Moreover there are blood follow-ups while on albendazole (see points 1 and 2 of previous slide) SO there three options (option 1 will not have the need for lab material in the field while options 2 and 3 yes lab equipment needed is a centrifuge + one fridge + minus-20 freezer ; also small portable ones will be ok!) OPTION 1 All patients found with CE on ultrasound (and 100 controls per Country) will be asked to come to your hospital for the blood taking and other baseline procedures regardless of the treatment allocation (e.g. also those managed by Watch and Wait) this in my opinion will be ok for the follow-up but for baseline may be more tricky and no control will agree to come and we will also have to pay for their transportation OPTION 2 At Time-zero (screening) we can collect all blood we need in the field, and patients that will not have to come to the hospital (for example those allocated to Watch and wait or albendazole only) will receive the answer of blood tests and only after they may start any treatment if needed. Then follow-ups will be done in the hospital

OPTION 3 At Time-zero (screening) we will take blood only from volunteer controls and all patients will have to come to your hospital regardless of management allocation (I do not see any advantage in this option)

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1) Carmen Cretu asked to have a standard scanning approach (e.g supine or standing position of the patients?) and if possible to have the same team scanning at least during survey in the three countries. Please address these issues (consider that I will come at beginning of each survey to help with workflow and form filling, and I can be considered one of the ultrasonographers in the field)

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1) Name the Ethical Committee you will submit the project for approval. In this occasion, also check the deadline for submission of 2014 (and tell me) and ask whether they would need to approve also the use of the Registry that will be anyway hosted in Italy. In case they want to approve also this part, please tell me AS SOON AS POSSIBLE so I can ask the relevant documents to Patrizia Rossi 2) Name all hospital structures will treat patients within the project (example surgery departments, hospital wards). In this occasion, please take the opportunity to contact them if not yet done 3) INSURANCE: It is requested by the European Commission that all patients and personnel are insured. In Morocco we did not do it because the colleagues found out that because the procedures are not experimental then insurance for patients was not needed. For example, if a patient dies while on surgery, there will be no cover by the project. If this is also the case in your country, please SPECIFY these terms to me. Remember however the project will HAVE TO cover ALL COSTS of the patient (including any treatment of complications if related to the project procedures). If treatment costs are at least in part upon the National Health System in your contry, please ask in your hospital what should you do as you will bring many more CE cases than what the hospital will expect on average to receive For people working in the project, please let me know health and insurance procedures you will put in place (e.g. HBV vaccination? Procedures in case of needle accident? Professional responsibility while in the field?) or if these are included in the insurance of employees of the hospital and can therefore be extended also while on field work for the project