Amendment 01 added an exclusion criterion of ankle oedema, to assist in the exclusion of potential participants who may have had cardiovascular disease. Additionally, this amendment dispensed with the original protocol requirement for a general physical examination to be conducted prior to entry. As potential participants were to have a musculoskeletal examination by a study metrologist, it was felt that additional examination was unnecessary, also added stratification of patients to treatment depending on a classification of OA or non-OA according to an initial X-ray review. This was to ensure an even distribution of OA and non-OA patients across the groups without waiting for a detailed review, and documented a change of analytical laboratory conducting the haematology, biochemistry and urinalysis. This was required because the original laboratory was unable to supply evidence of GLP accreditation. No patients were enrolled in the study until after amendment 01 had been approved.

Amendment 02 changed the primary safety endpoint to the incidence of moderate and severe AEs regardless of the relationship to assigned treatment, as opposed to those classed as being possibly, probably or definitely related to treatment, also clarified the inclusion criterion relating to frequency of knee pain experienced by potential participants, to state that they must have experienced pain on at least four of seven days preceding the screening visit, added to the exclusion criteria any past history of GI bleeding.It also excluded patients taking methotrexate (at the request of Nottinghamshire Primary Care Trust), patients taking warfarin and other anticoagulants (at the request of the FDA), with the exception of those taking low dose aspirin who had been stable for 30 days prior to taking the 1st dose of study medication, added additional urinary pregnancy tests for female subjects, to be conducted at the Week 7, Week 13 assessments. Initially it was intended that patient medication packs would be dispensed on each of the Baseline, Day 10 and Week 7 visits. However, it was decided that patients would be issued with all their study medication at the baseline visit, and this was documented, changed the planned analysis definition of full analysis dataset, from those who took at least one dose of study medication, had at least one post-baseline assessment, to those who took at least one dose of study medication, regardless of whether a post-baseline assessment was available. The original protocol specified that high and low dose combinations would be compared to paracetamol alone, revised the statistical section to state that the combinations would also be compared to ibuprofen alone.It further made provision for the use of additional supportive analyses using baseline observation carried forward as one of the strategies for dealing with missing data. These change was requested by the FDA. No patients were enrolled into the study before amendment 02 was approved.

Amendment 03 added to the recruitment methods used for the study. Originally, patients were to be enrolled through General Practices in Nottinghamshire. This amendment allowed for additional recruitment through advertisements in local newspapers, magazines, posters and on local radio. It also allowed for recruitment through General Practices in the additional counties of Derbyshire, Staffordshire and Leicestershire. These changes were initiated by the Sponsor as recruitment was falling behind target and it was felt necessary to increase the population from which recruitment was made. It was later decided that it was not necessary to use General Practices in Derbyshire, Staffordshire and Leicestershire and hence Primary Care Trust approval in these counties was not sought, also changed the inclusion criterion requiring patients to experience knee pain of between 30 and 80mm on a VAS whilst walking on a flat surface, to cover the same level of pain but which occurred during any 1 or more of walking on a flat surface, or going up and down stairs, or at night while in bed, or while sitting or lying or while standing upright. This change was initiated by both the Investigator and the Sponsor as it was deemed that a positive response in any of these circumstances was indicative of knee pain and would enhance both the recruitment potential and the applicability of the data to the general population. This Amendment implemented when 233 patients had been randomised to the study.

Amendment 04 added seven Synexus sites to the study, in order to aid recruitment. It allowed for patients recruited by Synexus to have their assessment visits take place at the sites, with no home visits being made for these patients. This change was initiated by the Sponsor to address recruitment difficulties. Amendment 04 was implemented when 548 patients had been screened and 408 had been randomised.