Low-dose Intravenous Immunoglobulin Treatment for Complex Regional Pain Syndrome (‘LIPS’) Randomised Controlled Trial.

Lead Research Organisation: University of Liverpool

Abstract

Complex Regional Pain Syndrome (CRPS) arises after injury to a limb. Patients experience ongoing, severe pain, out of proportion to the injury. The pain can eventually get better. However, unfortunately in every 7th patient (15%) the pain is unrelenting even after one year. If the pain lasts that long it is less likely to get better later. The quality of life of these patients is very poor. They cannot use the affected limb, and only a few can return to work. Unfortunately, we do not know why CRPS occurs. There are currently few treatments, and for many patients no treatment works.We propose to test a new treatment. We have recently shown in a small study, that a drug called intravenous immunoglobulin (IVIG) can profoundly reduce pain from CRPS. IVIG had only few side effects. IVIG treats the immune system. Our study only had 13 participants. We now wish to find out with more confidence whether IVIG is indeed effective, and how effective it is. This information is needed so that IVIG-treatment can be pursued for patients both in the NHS and abroad. In order to find out, we propose to conduct a trial to compare IVIG treatment with a dummy drug. The research will be carried out in 6 UK Pain Management Centres, over 44 months, starting from 2012. Patients (108 participants) will receive either IVIG, or a dummy drug (salty water) through an infusion into their vein. They will not know which they receive. After three weeks they will receive a repeat infusion of the same. Participants record their daily average pain into pain diaries for 10 weeks. In order to find out whether IVIG is effective, we will compare the daily pain intensity recorded by those who had received IVIG with that in the group after the dummy drug. We expect that the average pain intensity after IVIG is lower than that after the dummy drug. Further, that about a quarter of patients in the IVIG group, but only few in the dummy drug group will feel strong pain relief. After 6 weeks, we will offer all participants a one-off infusion of IVIG. During the study we will also test the participants' skin sensitivity. The skin tests will help us to find out whether IVIG can reduce pain to touch, a bothersome symptom which many patients feel. Participants will not be able to automatically receive the drug after the end of the trial, because IVIG is not approved for CRPS; we will tell patients about this before study start. The lead applicant and co-applicants are recognized experts in CRPS. The lead applicant and additional team members have already conducted trials with IVIG, and are leading in this research field. The trial costs (excluding the drug, which will be given by a company free of charge) are £889,457 (£35.000 of this will be contributed by a charity). These funds are needed to pay staff who will run the trial, pay those costs which would be incurred by the participants NHS treatment in any case (£241,812 NHS costs), and other expenses such as patient and investigator travel, training, drug preparation and blinding.

Technical Summary

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.
 
Description European Medicines Agency (EMA) Scientific Advisory Group on CRPS development following vaccindations
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
URL http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/11/news_detail_002428.js...
 
Description Parliament Debate
Geographic Reach National 
Policy Influence Type Citation in other policy documents
Impact The 2013 CRPS debate has led to a better recognition of CRPS by the UK government. The LIPS trial was cited by the Minister as evidence for UK government commitment to this health condition.
URL http://www.parliamentlive.tv/main/Player.aspx?meetingId=13533
 
Description 2016 Pain Call
Amount £90,000 (GBP)
Organisation Arthritis Research UK 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2017 
End 03/2020
 
Description Pain Relief Foundation
Amount £81,000 (GBP)
Organisation Pain Relief Foundation 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 02/2016 
End 02/2019
 
Description Cambridge whole-genome sequencing 
Organisation Biotest AG
Country Germany, Federal Republic of 
Sector Private 
PI Contribution We will provide samples from well-characterized patients with a rare neuropathic pain condition, i.e. all consenting patients who previously participated in the LIPS trial, for whole genome sequencing (max n=111). Update 28.02.2017 - this project has be closed. It was not possible to recruit our patients due to the recent national R&D submission rearrangements leading to a backlog with applications. Although the Cambridge team had put in an amendment to their ethics and R&D permissions, this amendment was not approved before the funding for that project from their side had run out. We have instead now engaged with a different team, also located in Cambridge, and this is described in a separate entry.
Collaborator Contribution NIHR Cambridge BioResource will perform whole genome sequencing on our patient samples. Biotest (Industry) will provide funds for patient travel to our center, required to ascertain the samples; the Biotest interest is that we may find predictive factors for a positive IVIG-response from LIPS data analysis
Impact No output (see ablove)
Start Year 2016
 
Description Cambridge whole-genome sequencing 
Organisation National Institute for Health Research
Department National Institute for Health Research (NIHR) BioResource
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We will provide samples from well-characterized patients with a rare neuropathic pain condition, i.e. all consenting patients who previously participated in the LIPS trial, for whole genome sequencing (max n=111). Update 28.02.2017 - this project has be closed. It was not possible to recruit our patients due to the recent national R&D submission rearrangements leading to a backlog with applications. Although the Cambridge team had put in an amendment to their ethics and R&D permissions, this amendment was not approved before the funding for that project from their side had run out. We have instead now engaged with a different team, also located in Cambridge, and this is described in a separate entry.
Collaborator Contribution NIHR Cambridge BioResource will perform whole genome sequencing on our patient samples. Biotest (Industry) will provide funds for patient travel to our center, required to ascertain the samples; the Biotest interest is that we may find predictive factors for a positive IVIG-response from LIPS data analysis
Impact No output (see ablove)
Start Year 2016
 
Description Confirmation of hits in CRPS 
Organisation Biotest AG
Country Germany, Federal Republic of 
Sector Private 
PI Contribution We have discussed the protocol and direction for this project. We have consequently established as a PIC site and have identified suitable patients, including well-phenotyped patients from the LIPS trial, which were then contacted by the Cambridge partner, and have since sent saliva samples for DNA extraction.
Collaborator Contribution Provision of recruitment kits, then all sample kits.
Impact The first samples are currently being analyzed. This part of the project is expected to be complete by summer 2017, dependent on results further progress will then be discussed. The collaboration is multi-disciplinary, between us, the Cambridge team, and the Biotest AG.
Start Year 2016
 
Description Confirmation of hits in CRPS 
Organisation University of Cambridge
Department Department of Chemistry
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We have discussed the protocol and direction for this project. We have consequently established as a PIC site and have identified suitable patients, including well-phenotyped patients from the LIPS trial, which were then contacted by the Cambridge partner, and have since sent saliva samples for DNA extraction.
Collaborator Contribution Provision of recruitment kits, then all sample kits.
Impact The first samples are currently being analyzed. This part of the project is expected to be complete by summer 2017, dependent on results further progress will then be discussed. The collaboration is multi-disciplinary, between us, the Cambridge team, and the Biotest AG.
Start Year 2016
 
Description Passive Transfer of CRPS-IgG 
Organisation Stanford University
Department Department of Energy Resources Engineering
Country United States of America 
Sector Academic/University 
PI Contribution We have provided serum samples from well-characterized LIPS participants, for the Stanford group to use in their rodent model.
Collaborator Contribution The Standford group will test the effects of serum components in the tibial fracture model, and related results to outcomes from the transfer of serum from patients with early CRPS. The LIPS trial has allowed us to gather a well defined cohort of patients who have this quite rare condition, along with these patients' serum samples.
Impact No output yet
Start Year 2016
 
Description Bath CRPS Patient Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact I was invited to give a plenary presentation at the UK CRPS Patient Conference organized by CRPSUK. I summarized recent research on the condition worldwide; the topic of immune modulation treatment including our LIPS IVIG study played a prominent role. The apparent response of patients with longstanding CRPS to immune treatment is of particular interest to them, because it suggests that this condition is sustained by an active disease process, even after many years, rather than being a functional functional brain abnormality as is often suggested. The conference was attended by about 80-120 patients from throughout the UK. Apparently this topic is now being intensely discussed in social media though I have no data on that.
Year(s) Of Engagement Activity 2015
URL https://crps-uk.org/event/2015-conference/?instance_id=15
 
Description Webinar for the Canadian Institute for Pain and Disability 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact This was a 1h Webinar about CRPS, which included the LIPS trial, and as with many of these activities my invitation may have been triggered as I am known to lead that trial. The CIRPD does not publish download data, and I don't know about impact. From speaking with the organisers it appears that webinar contents are typically downloaded/viewed by a few hundred people.
Year(s) Of Engagement Activity 2015
URL http://www.cirpd.org/Webinars/Pages/Webinar.aspx?wbID=75