The protocol was amended to include the following: Page 3. Dr Ian Chau no longer Clinical Coordinator. Any clinical queries should now be directed to Prof. David Cunningham as stated in protocol. Section 6.3 Administration of Rituximab in both treatment arms Page 13. Data on the safe, fast infusion of Rituximab became available. Some hospital trusts are now using this method of administration of Rituximab. This has therefore been incorporated into the protocol.Section 6.6 Central Nervous System (CNS) Prophylaxis Page 14. In keeping with the DOH intrathecal guidance which states “It is not acceptable to inconvenience patients by asking them to attend on two occasions”, the protocol has been altered so that intrathecal methotrexate will be given on the same day as CHOP, once the intravenous cytotoxic drugs have been given. Section 14.2 Safety Reporting Page 28. Amendments to the safety reporting have been made to make it clear that expected toxicities with CHOP chemotherapy and Rituximab do not need to be reported as adverse events.Section 14.4 Indemnity and Compensation Page 29. As a legal requirement the role of the sponsor of the trial and definitions of negligent and non-negligent harm are now included in the protocol.Appendix 3 Patient Information Sheet Page 34. CT scans are performed at diagnosis, after 4 cycles and at end of treatment. They are also performed at 3 months and 1 year after treatment. It has been brought to our attention that this final CT scan at 1 year post treatment, although performed routinely in some centres, is not universal practice. Therefore for some patients this is an additional scan and information regarding the implications of this is now incorporated into the patient information sheet. Definitions of negligent and non-negligent harm are now also included in the patient information sheet. Appendix 6 Expected Toxicities. Typographical error - doxorubicin to replace doxycycline. Appendix 7 Trial Management Group -Cathy Burton added

The protocol was amended to include the addition of a sub-protocol to allow the collection of constitutional DNA from buccal smears. The costs associated with this sub-study (i.e. kits for collecting smears, postage and storage) will be met from a Translational Research in Clinical Trials grant provided by Cancer Research UK. This amendment also included the addition of a second sub-protocol which will prospectively evaluate the prognostic value of PET scanning after 2 cycles of RCHOP chemotherapy. This sub-study will be funded by a subvention from the Department of Health.

The Lymphoma Trials Office moved premises, so contact details were amended in the protocol.

The Patient Information Sheet and consent form for the Buccal Smear Substudy were rewritten to make it clearer to patients that this was an add-on to the main trial that they were already taking part in and that any DNA extracted from the samples given would be stored and used anonymously for future research projects. This was not clear in the previous versions, v2.0 of both forms were approved for use in this amendment.

The protocol and substudy protocol were amended to update a number of contact telephone numbers, fax numbers and email addresses. In addition, the protocol had the following amended: - Change length of study from 3 to 4 years (page 5) - Now states that CT scans should be done within 28 days pre-randomisation (page 9) - Stage IB addition into inclusion criteria (page 10) - Update stratification variables (page 11) - Remove request for consent form (page 11) - Reworded when CT scan should be done on 14 arm (page 23) - Complete rewriting of Safety Reporting (page 28) - PIS Replace CERES with CancerBACUP (page 38) - PIS Change of side effects (page 41) - Consent form - Change date and version number of PIS (page 46) - Change in expected toxicities (to fit in with PIS) (page 49) In addition, the substudy protocol had the following amended: - PIS Replace CERES with CancerBACUP (page 13) - Addition of Appendix 4. Stating PET centres involved (page 18)

This substantial amendment allowed for an extension to the R-CHOP 14 vs 21 study. This was in the form of a single arm registration phase, post the initial 1080 patients randomised into the study. This was designed to enable the PET sub study to recruit its full 200 patients. Only patients that can be recruited onto the PET substudy were consented onto the registration phase of R-CHOP 14 vs 21. On the 4th August 2008, 60 patients had been entered onto the PET substudy, so it was estimated 75 patients would be enrolled at the close of the randomisation section of the protocol. Therefore, it was expected that the registration phase was to be for a further 125 patients. The registration phase was single arm. This was initially R-CHOP 21 as this is the standard arm. When analysis of the 1080 patients was complete and the results are known treatment could change, this is laid out on pages 11 and 12 of the main protocol. This enabled the study to react to any change in standard treatment in the UK. Patients will be treated as per protocol. Both the R-CHOP and the PET protocol had a new Patient Information Sheet and consent form when the registration phase began, replacing the previous PISs and CFs post 1080 patients. The Trial Management Group felt that the PET sub-study is a decisive trial in answering how patients should be treated in the future, and we needed to be able to recruit the full number of patients set out in the protocol.

This substantial amendment allowed for the number of CHOP cycles in the control arm (R-CHOP 21) to be reduced from 8 to 6 cycles. The following documents were amended to reflect this change: 1. Protocol (version 6.0) 2. Patient Information Sheet for registration (version 5.0) 3. Consent Form for registration (version 5.0) 4. GP letter for registration (version 4.0) 5. PET sub-study Protocol (version 5.0) 6. PET sub-study Patient Information Sheet for registration (version 4.0) 7. PET sub-study Consent Form for registration (version 4.0) In addition, contact details were updated in both the protocol and sub-study protocol. There was also a new site added to the trial and changes in PI at two sites: NEW SITE: Dr Naheed Mir - The Lewisham Hospital NHS Trust CHANGE IN PIs: Dr Toby Nicholson (was Dr Gnanam Satchi) - Whiston Hospital Dr Humayun Ahmad (Dr Adrian Smith) – Queens Hospital, Burton-on-Trent

This amendment was primarily to amend an error in the GP letter. Version 4.0 of the GP letter referred to Version 4.0 (dated 30/03/2010) of the protocol. This is an error, and should read version 6.0 (dated 30/03/2010) of the protocol. This was corrected and version 4.1 was approved in this amendment. Also approved in this amendment, North Cheshire NHS Trust (Warrington Hospital & Halton Hospital, PI Dr Peter Clark) had not recruited any patients into the trial and requested that they were closed in order to archive. Hannah Farrant left the UCL CTC and was replaced by Jo Gambell, the REC was asked to update their contact details to reflect this.

This substantial amendment allowed for an additional assessment of the response by PET scan using new criteria. The response using this new criteria was compared with the original criteria. This substantial amendment also allowed for analysis of the effect of cell proliferation, as measured by MIB1. The protocol and substudy protocol were amended to reflect this.

This amendment was to correct an error in the GP letter. Version 4.0 of the GP letter referred to Version 4.0 (dated 30/03/2010) of the protocol. This was an error, and should have read version 6.0 (dated 30/03/2010) of the protocol. North Cheshire NHS Trust (Warrington Hospital & Halton Hospital) had not recruited any patients into the trial and requested that they could close in order to archive. Lastly, Hannah Farrant had left the Haematology Trials Group and was was replaced by Jo Gambell, so the REC were informed of a change in contact information for the trial.

This substantial amendment was made to provide clarification of the methods of pathology review. An additional paragraph was added to section 9.0 of the trial protocol to clarify the methods of pathology review already approved within this clinical trial. The contact details of the UCL Cancer Trials Centre were also updated on page 3.

This amendment was made to the trial protocol to allow trial data to be shared with the German High Grade Lymphoma Group and with the SEAL project, there was no scope to do this in the previously approved version. The entirety of ‘Section 18 – Data Sharing’ was new and reads as follows: “In accordance with Cancer Research UK data sharing policy which states that “Cancer Research UK is committed to ensuring that the data generated through its funding should be put to maximum use by the cancer research community and, whenever possible, is translated to deliver patient benefit. It is therefore our policy that all data generated as a result of our funding be considered for sharing and made as widely and freely accessible as possible whilst safeguarding intellectual property, the privacy of patients and confidential data.” All requests for data sharing will be considered by the Trial Management Group. If they approve the request data will provided in a confidential and secure manner i.e. no patient identifiable material will be sent and data will be sent in an encrypted format. As of February 2016 two requests to share data have been received. The first project is in collaboration with the German High Grade Lymphoma group and they have requested data from this trial to try to confirm that the outcome of treatment with rituximab differs between the sexes because the drug is metabolised differently in men and women. The second project (SEAL) is in collaboration with an international consortium and will explore whether progression-free survival can be used as a surrogate endpoint for overall survival in this patient population. The analysis for this project will be done in America and the results of the analysis will be made available to the pharmaceutical company, Celgene. Release of data for these projects was approved by London – Hampstead NRES committee. Any further requests for data will require separate ethical approval.”