Andreas Goebel, MD, PhD; Jatinder Bisla, BSc; Roy Carganillo, RN; Bernhard Frank, MD; Rima Gupta, BSc (Pharm); Joanna Kelly, MSc; Candy McCabe, PhD; Caroline Murphy, MSc; Nick Padfield, MD; Ceri Phillips, PhD; Mark Sanders, MD; Mick Serpell, MD; Nick Shenker, MD, PhD; Karim Shoukrey, MD; Lynne Wyatt, BSc; Gareth Ambler, PhD
Note: The corresponding author and the trial statistician had full access to all the data in the study, and the corresponding author was responsible for the final submission of the publication.
Acknowledgment: The authors thank all participants of the LIPS study. They are indebted to all research teams, patient identification centers, and referring hospitals. The authors also thank Mairi James for her contributions to the article; Prof. Guenter Sprotte (Würzburg, Germany) for his contribution to the trial design; Shakeel Herwitker, Aseptic Manufacturing Pharmacy Unit at Royal Liverpool and Broadgreen Hospital, for assisting with the trial design; David Pang (London) and Sumit Gulati and Claire Cole (Liverpool), for support with recruitment; Prof. Roberto Perez, University of Amsterdam, for sharing the limb temperature protocol; Dr. Amanda Williams, University College London, for support with the patient-determined measures; Dr. Helen Poole for support with the psychological outcome measures; Oliver Pressey and Ekwujuru Ejibe at King's Clinical Trials Unit (KCTU) for data and study management and support; Oliver Gupta at Modepharma for investigational medicinal product planning support; and Rita Fitzpatrick at ESMS Global for emergency code break services.
Grant Support: By the Efficacy and Mechanism Evaluation Program, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership (reference 11/14/33), and the Pain Relief Foundation Liverpool. Biotest United Kingdom Limited provided the active study medication at no cost. This study was also supported by the United Kingdom Clinical Research Collaboration–registered KCTU at King's Health Partners, which is partly funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley National Health Service (NHS) Foundation Trust and King's College London, and the NIHR Evaluation, Trials and Studies Coordinating Centre.
Disclosures: Dr. Goebel reports grants and nonfinancial support from Biotest during the conduct of the study and personal fees from Biotest and Axsome Therapeutics outside the submitted work. Dr. McCabe reports grants from MRC during the conduct of the study. Dr. Serpell reports grants from MRC/NIHR during the conduct of the study and personal fees from Astellas, Grünenthal, Mundipharma, and Pfizer outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-0509.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: See Supplement 1. There were no additional substantial amendments between publication and the end of the trial. Statistical code and data set: Available from Dr. Goebel (e-mail, email@example.com).
Requests for Single Reprints: Andreas Goebel, MD, PhD, Pain Research Institute, Institute of Translational Medicine, University of Liverpool, Clinical Sciences Centre, Liverpool L9 7LJ, United Kingdom; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Goebel: Pain Research Institute, Institute of Translational Medicine, University of Liverpool, Clinical Sciences Centre, Liverpool L9 7LJ, United Kingdom.
Mr. Bisla, Ms. Kelly, and Ms. Murphy: King's Clinical Trials Unit, PO64, M2.06, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, London SE5 8AF, United Kingdom.
Mr. Carganillo and Dr. Padfield: Pain Management and Neuromodulation Centre, Guy's and St Thomas' Hospital, London SE1 7EH, United Kingdom.
Dr. Frank and Ms. Wyatt: The Walton Centre NHS Foundation Trust, Lower Lane, Liverpool L9 7LJ, United Kingdom.
Ms. Gupta: Modepharma Limited, 114 Barnfield Wood Road, Beckenham BR3 6SX, United Kingdom.
Dr. Serpell: Queen Elizabeth University Hospital, Glasgow Clinical Research Facility, AFF1345 Govan Road, Glasgow G51 4TF, United Kingdom.
Dr. McCabe: University West of England, Bristol and Royal United Hospitals NHS Foundation Trust, Bath Somerset BA1 1RL, United Kingdom.
Dr. Phillips: College of Human and Health Sciences, Swansea University, Singelton Park, Swansea SA2 8PP, United Kingdom.
Dr. Sanders: Norfolk and Norwich University NHS Trust, Colney Lane, Norwich NR4 7UY, United Kingdom.
Dr. Shenker: Department of Rheumatology, Cambridge University Hospitals, Hills Road, Cambridge CB2 0QQ, United Kingdom.
Dr. Shoukrey: University Hospitals of Leicester NHS Trust, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, United Kingdom.
Dr. Ambler: Statistical Science, 1-19 Torrington Place, University College London, London WC1E 7HB, United Kingdom.
Author Contributions: Conception and design: A. Goebel, J. Kelly, C. McCabe, C. Murphy, C. Phillips, N. Shenker, G. Ambler.
Analysis and interpretation of the data: A. Goebel, C. Phillips, M. Serpell, G. Ambler.
Drafting of the article: A. Goebel, J. Bisla, B. Frank, J. Kelly, C. McCabe, C. Murphy, N. Padfield, C. Phillips, M. Serpell, N. Shenker, K. Shoukrey, G. Ambler.
Critical revision for important intellectual content: A. Goebel, J. Bisla, B. Frank, J. Kelly, C. McCabe, C. Murphy, M. Serpell, G. Ambler.
Final approval of the article: A. Goebel, J. Bisla, R. Carganillo, B. Frank, R. Gupta, J. Kelly, C. McCabe, C. Murphy, N. Padfield, C. Phillips, M. Sanders, M. Serpell, N. Shenker, K. Shoukrey, L. Wyatt, G. Ambler.
Provision of study materials or patients: A. Goebel, R. Carganillo, B. Frank, J. Kelly, C. McCabe, C. Murphy, M. Serpell, N. Shenker.
Statistical expertise: G. Ambler.
Obtaining of funding: A. Goebel, J. Kelly, C. McCabe, C. Murphy, N. Shenker, G. Ambler.
Administrative, technical, or logistic support: A. Goebel, J. Bisla, R. Gupta, J. Kelly, C. Murphy, N. Shenker, L. Wyatt.
Collection and assembly of data: J. Bisla, R. Carganillo, J. Kelly, C. McCabe, C. Murphy, M. Sanders, M. Serpell, N. Shenker, K. Shoukrey, L. Wyatt.
Two small trials suggest that low-dose intravenous immunoglobulin (IVIg) may improve the symptoms of complex regional pain syndrome (CRPS), a rare posttraumatic pain condition.
To confirm the efficacy of low-dose IVIg compared with placebo in reducing pain during a 6-week period in adult patients who had CRPS from 1 to 5 years.
1:1 parallel, randomized, placebo-controlled, multicenter trial for 6 weeks, with an optional 6-week open extension. Patients were randomly assigned to 1 of 2 study groups between 27 August 2013 and 28 October 2015; the last patient completed follow-up on 21 March 2016. Patients, providers, researchers, and outcome assessors were blinded to treatment assignment. (ISRCTN42179756)
7 secondary and tertiary care pain management centers in the United Kingdom.
111 patients with moderate or severe CRPS of 1 to 5 years' duration.
IVIg, 0.5 g/kg of body weight, or visually indistinguishable placebo of 0.1% albumin in saline on days 1 and 22 after randomization.
The primary outcome was 24-hour average pain intensity, measured daily between days 6 and 42, on an 11-point (0- to 10-point) rating scale. Secondary outcomes were pain interference and quality of life.
The primary analysis sample consisted of 108 eligible patients, 103 of whom had outcome data. Mean (average) pain scores were 6.9 points (SD, 1.5) for placebo and 7.2 points (SD, 1.3) for IVIg. The adjusted difference in means was 0.27 (95% CI, −0.25 to 0.80; P = 0.30), which excluded the prespecified, clinically important difference of −1.2. No statistically significant differences in secondary outcomes were found between the groups. In the open extension, 12 of the 67 patients (18%) who received 2 IVIg infusions had pain reduction of at least 2 points compared with their baseline score. Two patients in the blinded phase (1 in the placebo and 1 in the IVIg group) and 4 in the open IVIg phase had serious events.
Results do not apply to patients who have had CRPS for less than 1 year or more than 5 years and do not extend to full-dose treatment (for example, 2 g/kg). The study was inadequately powered to detect subgroup effects.
Low-dose immunoglobulin treatment for 6 weeks was not effective in relieving pain in patients with moderate to severe CRPS of 1 to 5 years' duration.
Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Program, Pain Relief Foundation, and Biotest United Kingdom.
CONSORT (Consolidated Standards of Reporting Trials) flow diagram of the LIPS (Low-Dose Immunoglobulin in Long-Standing Complex Regional Pain Syndrome) trial.
IVIg = intravenous immunoglobulin.
Table 1. Baseline Characteristics of Patients in the Primary Analysis Sample*
Table 2. Success of Blinding*
Average pain score for each day, by trial group (days 1 to 84).
Values on the y-axis reflect average 24-h scores of pain intensity on the numeric rating scale (0 = “no pain,” 10 = “pain as bad as you can imagine”). Patient numbers for the placebo and IVIg groups, respectively, by time point, are as follows: screening, n = 56 and 52; day 1, n = 49 and 44; day 6, n = 53 and 48; day 22, n = 48 and 45; day 43, n = 46 and 39; and day 84, n = 35 and 27. Screening started a maximum of 21 days before randomization (randomization = day 0). The primary efficacy analysis does not include 5 patients without outcome data. The dashed vertical line marks the end of the parallel, blinded trial. IVIg = intravenous immunoglobulin.
Table 3. Harms Reported During the Blinded Phase of the Study*
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Goebel A, Bisla J, Carganillo R, Frank B, Gupta R, Kelly J, et al. Low-Dose Intravenous Immunoglobulin Treatment for Long-Standing Complex Regional Pain Syndrome: A Randomized Trial. Ann Intern Med. [Epub ahead of print 12 September 2017]167:476–483. doi: 10.7326/M17-0509
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Published: Ann Intern Med. 2017;167(7):476-483.
Published at www.annals.org on 12 September 2017
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