Title: Low-dose Intravenous Immunoglobulin Treatment for Complex Regional Pain Syndrome (‘LIPS’) Randomised Controlled Trial.
Funder: Department of Health (England)

Abstract: Research design: Randomised double-blinded placebo controlled parallel trial with an open single- dose extension. Study Population: Adult patients with Complex Regional Pain Syndrome of 1-5 years duration and a pain intensity of >4 on an 11-point numeric rating scale (NRS). Excluded are patients with other significant chronic pains unstable medical conditions rare IVIG contraindications or who are pregnant or breastfeeding. Planned interventions: Patients are randomised (online block-randomisation with stratification to study site and pain intensity) to receive either 0.5g/kg intravenous immunoglobulin (IVIG) or an equal volume of placebo (0.1% Albumin in Normal Saline) with a second infusion three weeks later. After six weeks patients can choose to receive a one off dose of 0.5g/kg IVIG openly. Proposed outcome measures: Primary outcome: NRS 24h average pain intensity over 37 days (study days 6 - 42); secondary outcomes: pain interference and quality of life; additional exploratory outcomes including skin sensitivity. Assessment and long-term follow up: Daily for 10 weeks: pain intensity (average/worst) safety and sleep; at baseline 3 6 and 10 weeks: Brief Pain Inventory interference scales EQ5-D quality of life scale safety and exploratory assessments. Safety also in phone calls after infusions. Follow up after open infusion weekly for eight weeks. Proposed sample size: 108 patients (54 per arm) in 6 treatment centres. Assuming 5% statistical significance and 85% power we expect an effect of 1.2 NRS points pain score difference (calculations based on the t-test suggest that the treatment effect will have a standard error (SE) of 0.45; the use of 37 repeated measurements should lead to a lower SE - simulation results suggest 0.39). In our single-centre RCT the effect was 1.55 NRS point (95% CI: 1.29-1.82); the lower assumed effect reflects an expected more diverse study population. We assumed a common standard deviation of 2.2 a correlation between a patient’s measures of 0.7 (both from our prior trial) a 10% loss to follow up and 5% non-compliance. Statistical Analysis: Descriptive analysis to investigate the distribution of the primary outcome which will be analysed using a mixed model to establish whether the mean pain score differs between IVIG and placebo. Centres and pain intensity will be fixed effects. Intention to treat; participants without any primary outcome data will be omitted. No imputation is planned. Interim analysis for futility and safety after 54 participants. Number needed to treat will be calculated in a secondary analysis. Project timetables including recruitment rate: 44 months study duration from 01.04.2012. Milestones: (before study start: sponsor’s protocol sign off and ethics approval); by 01.05.12: MHRA and local R&D submission; by 15.08.12 sponsor contracts arrangements for pharmacies study working instructions; by 30.09.12: completion of staff training/trial runs study registration recruitment letters/e-mails to all UK pain centres first patients approached. Recruitment from 01.10.2012; expected recruitment rate one patient/9 days target check in bi-monthly intervals; last enrolment before 01.06.2015. Database lock 15.08.15. Study analysis unblinding and draft manuscript by 30.11.15.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INJURIES AND ACCIDENTS;NEUROLOGICAL