title: Safety and patient response as indicated by biomarker changes to binding immunoglobulin protein in the phase I/IIA RAGULA clinical trial in rheumatoid arthritis.
abstract: OBJECTIVE
  Binding immunoglobulin protein (BiP) is a human endoplasmic reticulum-resident stress protein. In pre-clinical studies it has anti-inflammatory properties due to the induction of regulatory cells. This randomized placebo-controlled, dose ascending double blind phase I/IIA trial of BiP in patients with active RA, who had failed accepted therapies, had the primary objective of safety. Potential efficacy was measured by DAS28-ESR and changes in biomarkers.
  
  
  METHODS
  Twenty-four patients with active RA who had failed one or more DMARDs were sequentially assigned to three groups each of eight patients randomly allocated to receive placebo (two patients) or BiP (six patients), 1, 5 or 15 mg. Patients received a single i.v. infusion over 1 h and were observed as inpatients overnight. A 12-week follow-up for clinical, rheumatological and laboratory assessments for safety, efficacy (DAS28-ESR) and biomarker analysis was performed.
  
  
  RESULTS
  No infusion reactions or serious adverse drug reactions were noted. Adverse events were evenly distributed between placebo and BiP groups with no BiP-related toxicities. Haematological, renal and metabolic parameters showed no drug-related toxicities. Remission was only achieved by patients in the 5 and 15 mg groups, and not patients who received placebo or 1 mg BiP. Good DAS28-ESR responses were achieved in all treatment groups. The BiP responding patients showed significantly lower serum concentrations of CRP, 2 weeks post-infusion compared with pre-infusion levels, and of VEGF and IL-8 from the placebo group.
  
  
  CONCLUSIONS
  BiP (⩽15 mg) is safe in patients with active RA. Some patients had clinical and biological improvements in RA activity. BiP merits further study.
  
  
  BACKGROUND
  ISRCTN registry, http://isrctn.com, ISRCTN22288225 and EudraCT, https://eudract.ema.europa.eu, 2011-005831-19.
authors: Department of Rheumatology, Guys and St Thomas' NHS Foundation Trust Hospital.
authors: Bruce
authors: B
authors: Kirkham
authors: Department of Rheumatology, Guys and St Thomas' NHS Foundation Trust Hospital.
authors: Khaldoun
authors: K
authors: Chaabo
authors: Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, King's College London.
authors: Christopher
authors: C
authors: Hall
authors: Department of Rheumatology, Guys and St Thomas' NHS Foundation Trust Hospital.
authors: Toby
authors: T
authors: Garrood
authors: Quintiles Clinical Trials Unit.
authors: Timothy
authors: T
authors: Mant
authors: Quintiles Clinical Trials Unit.
authors: Elizabeth
authors: E
authors: Allen
authors: Department of Rheumatology, Guys and St Thomas' NHS Foundation Trust Hospital.
authors: Alexandra
authors: A
authors: Vincent
authors: Department of Primary Care and Public Health Sciences, King's College London, London, UK.
authors: Joana C
authors: JC
authors: Vasconcelos
authors: Department of Primary Care and Public Health Sciences, King's College London, London, UK.
authors: Andrew T
authors: AT
authors: Prevost
authors: Department of Rheumatology, Guys and St Thomas' NHS Foundation Trust Hospital gabriel.panayi@kcl.ac.uk.|Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, King's College London.
authors: Gabriel S
authors: GS
authors: Panayi
authors: Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, King's College London.
authors: Valerie M
authors: VM
authors: Corrigall
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001688:Biological Products / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D016209:Interleukin-8 / Q000378:metabolism; D008222:Lymphokines / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D012074:Remission Induction; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D001688:Biological Products; D015415:Biomarkers; D016209:Interleukin-8; D008222:Lymphokines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C013059:immunoglobulin-binding factors
keywords: BiP; CRP; IL-8; VEGF; changes in biomarkers; efficacy; first-in-human trial; prolonged activity; regulatory cells; safety