We applying for the substantial amendment because in the original application the Active IMP, pentoxifylline 400mg prolonged release tablets (Trental), was to be sourced from Germany. Since then, our IMP supplier has informed us that the German product has become unavailable for export, so the IMP is now to be sourced from Portugal. Trental as marketed in Portugal has the Marketing Authorisation (registration) number 4600284 (packs of 60)

After careful consideration of the recent literature and the funding situation, we should like to remove the “experimental end-points” in the protocol. However, we shall still be consenting patients to have bloods stored for future research. For this reason, we will not change the number, volume or the frequency of the blood tests. As per original protocol, blood will be stored in a HTA approved tissue bank. If we decide to analysis of these stored blood samples at a future date, we shall submit a new study protocol and seek ethical approval prior to any analysis. We believe that there would be potential ethical issues if we were performed tests on patients that are no longer relevant given the current literature. We believe the scientific validity of the study will not be compromised as we are seeking consent for blood to be stored. These can be analysed for experimental end-points at a future date (subject to a different study protocol/ethic submission). Because the frequency and the amount of blood / intervention is unchanged, we have not felt it necessary to amend the Patient Information Sheet (remaining version 4-1 27th Nov 2012).

1. Changes to the inclusion crieteria: a. Removal of CRP > 5 as one of the inclusion crieteria b. Erythropoietin stimulating agent (ESA) dose has been changed to erythropoietin dose greater than or equal to 6000 iu equivalent of EPO (erythropoietin) per week or if ESA resistance index is greater than or equal to 6.5 iu /kg/wk/g Hb for equivalent EPO dose to maintain stable haemoglobin levels. This dose is similar to median ESA requirement for haemodialysis patients with arterio venous fistula as dialysis access in our unit. 2. Changes to FDG - PET / CT scan protocol : Following the review of initial 5 scans research team has changed the FDG-PET / CT protocol. The new protocol will provide sufficient data for secondary end point analysis. The duration of dynamic imaging for the PET scan has been changed from 0 to 50 minutes to 0 to 60 minutes. The initial protocol of whole body imaging at 60 min and 160 min has now been changed to single whole body imaging at 90 min. The number of venous blood samples during the dynamic imaging has also been reduced to total 11 samples ( total blood volume 33 mls per scan) from total 21 blood samples (total blood volume 63mls per scan). This change in imaging protocol had to be implemented before formal approval because there is better patient experience during the scan visit and reduced radiation exposure to patients with no compromise to the quality of data obtained. 3. Patient information sheet has also been modified based in view of change in FDG-PET/CT protocol. Total imaging time for FDG-PET/CT scan has been reduced to 2 hrs compared to 4 hrs previously.