1. Collection of blood for Bio-bank at three and six months The protocol (Study Flow chart) was amended to reflect blood sampling for the bio-bank at 3 and 6 months. 2. Patient Information Sheet was amended to reflect the changes to the blood sampling component.

Amendment to Patient Information Sheet – has been amended on at the request of the Sponsor to include more detailed information about the risk of developing the very rare condition, Progressive Multifocal Leukoencephalopathy. Following documents were enclosed with the amendment: • Final ORBIT Patient Information Sheet V2, 16/12/2009 with changes highlighted • Final ORBIT Patient Information Sheet V3, 6/01/2010

Amendment to study requirement – collection of additional 30mls of blood at baseline, 3 and 6 months for epigenetic analyses in 50 patients. The protocol was changed on Page 15 to reflect this. The PIS was amended on page 3 to reflect the above. Following documents were enclosed with the amendment: • Protocol V2.1 dated 03/02/2010 with changes highlighted • PIS V3.2 dated 11/02/2010 with changes highlighted

Removal of existing sites: • Perth Royal Infirmary • Victoria Infirmary Glasgow • Dumfries & Galloway Royal Infirmary Additional site added: • University of Newcastle Change of PI at existing sites: • Aberdeen • Ayr Hospital

1. Temporary halt. A temporary halt to the study was needed to allow the Sponsor to review the merit of the study following a substantial update of the Rituximab SmPC; as a result of EMA not granting approval. As a result a change to the Patient Information Sheet was also required. The temporary halt was submitted to both Ethics and MHRA. 2. Change to PIS V.3.5. The following was included into new PIS V3.5: “Are there any risks involved in taking part? In Europe, the European Medicines Agency (EMA) is responsible for assessing the risks and benefits of drugs. At the moment, it has decided that in routine clinical practice, patients with rheumatoid arthritis who have failed to respond to second line drugs should be treated with anti-TNF drugs (rather than rituximab). This is because there is uncertainty about whether rituximab is as safe and effective as anti-TNF therapy – in technical terms; the EMA says ‘the benefit-risk balance of switching directly to rituximab is at present not settled.’ However, the EMA has decided that rituximab is a safe and effective treatment for patients with rheumatoid arthritis who have failed to respond to anti-TNF therapy. No research has been done to directly compare the risks and benefits of rituximab and anti-TNF therapy. It is possible that rituximab is better, as good; or worse than anti-TNF therapy, and this study will help to find this out.”

Uplift of temporary halt

Addition of sites, the following sites have been added: • Poole Hospital NHS Trust • Ipswich Hospital NHS Trust • Plymouth Hospitals NHS Trust • South Devon Healthcare NHS Foundation Trust • West Suffolk Hospitals NHS Trust • University Hospitals Coventry and Warwickshire NHS Trust • Royal Devon and Exeter NHS Trust • Betsi Cadwaladr University Health Board • Royal Cornwall Hospitals Trust • South London Healthcare NHS Trust • Barking, Havering & Redbridge University Hospitals NHS Trust, Queens Hospital and King George Hospital • University Hospital of Wales. • Basildon and Thurrock University Hospital NHS Trust • West Herts Hospital NHS Trust • The Countess of Chester Hospital NHS Foundation Trust Protocol – clarification and minor amendments. New protocol – Protocol V2.2 dated 25/04/2011 Change of Sponsorship – Addition of University as co-sponsor.

Amendment to Patient Information Sheet: (PIS V4.0 dated 22/06/2012). Included: “As with all therapies for arthritis, very serious side effects can occur rarely with either anti-TNF or Rituximab. For instance, some patients treated with Rituximab have developed allergic reactions, which rarely have proved have proved fatal. Similarly, some patients treated with anti-TNF therapy have developed severe infections that rarely have proved fatal.”

Change of co-sponsorship agreement: the University of Glasgow will now act as co-Sponsor for the above study.

1. Addition of sites: • Salisbury NHS Foundation Trust • The Royal Wolverhampton Hospitals NHS Trust • University Hospitals Leicester • Oxford University Hospitals NHS Trust • Southend University Hospitals NHS Foundation Trust • Trafford Healthcare NHS Trust • University Hospitals of Morecambe Bay NHS Foundation Trust • Mid Staffordshire NHS Foundation Trust • The Pennine Acute Hospitals NHS Trust • Kettering General Hospital NHS Foundation Trust • Hairmyres Hospital – NHS Lanarkshire Change of PI: • Change of PI at Countess of Chester Hospital NHS Foundation Trust. • Change of PI at Raigmore Hospital , Inverness. • Change PI Hertfordshire. 2. Change to protocol: • point of clarification. New protocol Version 2.3 -01/10/2012 Exclusion criterion: “Current inflammatory joint disease or autoimmune disease other then RA”, changed to “Current inflammatory joint disease or autoimmune rheumatic disease other then RA” • Use of blood urine samples for future use 3. Change to Reference Safety Information

Extension request to the study.

Update to Reference Safety Information