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Table 1 Key Protocol Amendments since Trial registration

From: A randomised controlled trial of the clinical and cost-effectiveness of ultrasound-guided intra-articular corticosteroid and local anaesthetic injections: the hip injection trial (HIT) protocol

Protocol Section Original protocol Amended details Date of Amendment REC approval Rationale for amendment
Secondary objectives To explore reasons for non-participation in the study and perceptions of recruitment processes with aim of identifying any modifiable barriers to recruitment [To undertake only if recruitment less than anticipated at 3 month review] Objective removed May 2018 We could not to complete the qualitative objective - to explore reasons for non-adherence - due to low recruitment to this qualitative study of people who were eligible for the trial but unwilling to participate. Furthermore, we had identified key modifiable issues to facilitate method of recruitment relating to eligibility criteria (see below) and recruitment route (see ‘Progress of the trial’).
Inclusion Criteria Moderate-to-severe hip pain (a score of four or more on a 0–10 numeric rating scale (NRS)) on the day of assessment Moderate-to-severe hip pain (a score of four or more on a 0–10 numeric rating scale (NRS)) on average over the last 2 weeks and current hip pain rated as at least 1 out of 10 (on a 0–10 NRS) on the day of assessment September 2016 During the first 5 months of recruitment we observed that, due to the day-to day variability of osteoarthritis symptoms, a number of potential participants did not meet the eligibility criterion of pain of 4/10 on the day of assessment.
Exclusion Criteria Any contraindications to the use of 1% lidocaine hydrochloride as listed in Summary of Product Characteristics (SPC) e.g. complete heart block, hypovolaemia, Any contraindications to the use of 1% lidocaine hydrochloride as listed in Summary of Product Characteristics (SPC) e.g. complete heart block, hypovolaemia, porphyria September 2016 A review of the summary of product characteristics (SPC) for lidocaine hydrochloride revealed a new contraindication (porphyria). Porphyria was added to the exclusion criteria as part of an urgent safety measure and subsequent amendment.
  Receiving anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban or low molecular weight heparin) Receiving anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban or low molecular weight heparin), ritonavir or cobicistat January 2017 It was noted in the MHRA Drug Safety Update dated 14 December 2016 ‘Cobicistat, ritonavir and coadministration with a steroid: risk of systemic corticosteroid adverse effects’ that coadministration of corticosteroids, including intra-articular triamcinolone, with an HIV-treatment-boosting agent may increase the risk of corticosteroid side-effects including adrenal insufficiency, adrenal suppression and Cushing’s syndrome, due to a pharmacokinetic interaction. Receiving cobicistat or ritonavir were added to the exclusion criteria as part of an urgent safety measure and subsequent amendment.
Sample Size To address the primary objective, the analysis will be based on comparisons of participants’ ‘average’ follow-up pain NRS scores, based on a random effects linear repeated-measures model, with a ‘cluster’ size of 4 (denoting 4 follow-up assessments) and a postulated coefficient of 0.5. A sample size of 232 will provide 90% power (5% two-tailed significance) to detect a minimum difference of 1.5 points in mean pain NRS score (anticipated baseline SD of pain scores = 4.5 points; effect size of 0.33) between I1 and I2 across the 6-month follow-up period, allowing for total of 15% loss to follow-up. As our trial also evaluates I3 (against I1), we have three groups of interest and hence need 348 participants. To address the primary objective, the analysis will be based on comparisons of participants’ ‘average’ follow-up pain NRS scores, based on a random effects linear repeated-measures model, with four follow-ups and postulated correlations of 0.5 for repeat-measures and 0.2 for baseline-outcome. A sample size of 136 (68 per arm) provides 80% power (5% two-tailed significance) to detect a minimum difference of 1 point in mean pain NRS score (anticipated SD of about 2.5; effect size of 0.4) between I1 and I2 across the 6-month follow-up period, allowing for 15% loss to follow-up. As the trial also evaluates I3 (against I1), there are three groups of interest and hence 204 participants are needed. May 2018 The Data Monitoring Committee noted poor recruitment and suggested rerunning the sample size calculations to ensure the original sample size assumptions were still valid. The observed baseline standard deviation (SD) of the primary outcome based on data collected from participants recruited by this time point (n = 65) was 1.7 (and the SD for follow up scores was around 2.5) – i.e. much lower than the SD of 4.5 expected before the start of recruitment on which the original sample size calculation was based. The clinically important difference of 1.5 (originally stated) in the context of this baseline SD would be ‘large’ (effect size above 0.8). The clinically important difference of 1.5 was considered to be too large in relation to the lower expected SD. The clinically important difference for the NRS-pain scale has taken different values across studies; an absolute difference of 1 has been specified in some studies (which would relate to a “moderate” effect size (0.5) when the SD is around 2; or, 0.4 in relation to higher SD of 2.5 which is observed across follow up time points). Hence, we felt that a revised effect size of 0.4 is justifiable. Using this revised effect size of 0.4 and revised power of 80% (on the advice of the TSC), the sample size was amended as described, and was approved by the funder, TMC and DMC.
Recruitment period The monthly target for recruitment will be 20. A recruitment period of 18 months will therefore be required. An amended recruitment period of 29 months is required to meet the revised sample size (n = 204). The monthly target for recruitment has been adjusted from 20 to 10. May 2018 During the first 18 months of trial recruitment an average of 7 patients per month were recruited. Recruitment improved since greater emphasis has been placed on recruitment route 3 to an average of 10 per month. Recruitment period was recalculated based on observed recruitment and revised sample size.