Following initial application to the MHRA, a change was requested by the ethics committee to the protocol in order to obtain approval. It was requested that a statement was added so that it was clear that in the event of pregnancy, the patient must stop trial treatment. The protocol was therefore updated to version 2.0 and a change made to the patient information sheet to clarify patients must stop study treatment in the event of pregnancy.

Cycle 1 now optional- Update to protocol, PIS and GP letter to reflect change Update to exclusion criteria- the following exclusion criteria: Complex cytogenetics: Two or more abnormalities detected by FISH and/or conventional cytogenetics. We initially excluded patients with complex cytogenetics based on the fact that the disease is less likely to be dependent on the microenvironment in this cohort. However, it transpires that the first two patients screened with clinically very stable disease, previously thought to be good candidates for this trial had complex cytogenetics. Therefore, we now believe that we misjudged the affect that this exclusion criterion would have on patient selection, and as it is leading to the exclusion of otherwise suitable candidates we no longer feel that it is an appropriate selection condition. The Patient Information Sheet has been updated to clarify that the first of the three labelling cycles is now optional. More detail has been added to explain which are compulsory parts of the study and which parts are optional. Also, a schema has also been added to help the patient visualise the treatment schedule and understand what the trial will involve for them. In addition, we have clarified the section relating to patient samples. This is to highlight that although no new samples will be taken from a patient if they withdraw from the study, samples previously taken will be retained for future ethically approved projects. Correction of typo to PIS and Consent Form post acceptance

New day 56 sample- The protocol has been updated to include a further sample at the end of each cycle. In practical terms this means drawing an extra 1ml of blood when the patient attends clinic on Day 0 for cycle 1 and for cycle 2 and an extra 5ml of blood at an extra visit on day 56 of cycle 2. These samples will be used to assess if the patient has any remaining labelled CLL cells circulating in their system. These results will then be used to reset the baseline for each cycle and to obtain a final reading of cell death at the end of the three cycles. A new patient document has been produced, the Release of Medical Information Form. The purpose of this document is to provide a means of obtaining consent for monitoring pregnancies that occur in trial patients or the partners of trial patients. This form is being implemented only as a precaution in case pregnancy does occur, pregnancies are not expected in this trial and when entering the trial patients consent to use two forms of contraception whilst on the trial and for three months after they stop the trial medication to prevent pregnancy occurring.

The SmPC was previously combined with Neoral Oral Solution. The SmPC for all ciclosporin products has been harmonised throughout Europe. All sections of the SmPC have been updated. As the update has included a change to the Undesirable Effects section, section 7.5 of the Protocol has been updated accordingly. In addition, section 7.3.2 and 7.4.1 have been updated to reflect changes to the sample processing that are required to introduce new sites to the trial. Southampton Hospital were unable to process samples locally so these samples will now be frozen locally and collected in batches before being processed centrally at King's College London. Finally, the trial contact list has been updated to reflect new staff members working on the trial at the CRCTU. PIS and RSI amended to reflect changes.