TY - JOUR
T1 - Intravenous pegylated liposomal prednisolone outperforms intramuscular methylprednisolone in treating rheumatoid arthritis flares
T2 - A randomized controlled clinical trial
AU - Metselaar, Josbert M.
AU - Middelink, Leonie M.
AU - Wortel, Cornelis H.
AU - Bos, Reinhard
AU - van Laar, Jacob M.
AU - Vonkeman, Harald E.
AU - Westhovens, Rene
AU - Lammers, Twan
AU - Yao, Siu Long
AU - Kothekar, Mudgal
AU - Raut, Atul
AU - Bijlsma, Johannes W.J.
N1 - Funding Information:
This work was financially supported by SUN Pharma and Enceladus Pharmaceuticals BV . J.M. Metselaar and T. Lammers acknowledge grant support by the European Research Council ( ERC CoG 864121 : Meta-Targeting) and the German Research Foundation (DFG: GRK 2375 (Project number: 331065168); SFB1066 ; LA2937/4-1 ). The authors kindly acknowledge the following investigators who also recruited patients : M. Starmans, E. Griep, M. Nurmohamed, N. Jahangier, G. Bruijns, M. Vis, P. van Riel, P. Carron, Dr. J. Margaux, K. De Vlam, Prof. Durez, Prof Bentin.
Publisher Copyright:
© 2021
PY - 2022/1
Y1 - 2022/1
N2 - Glucocorticoids (GCs) are potent anti-inflammatory drugs but their use is limited by systemic exposure leading to toxicity. Targeted GC delivery to sites of inflammation via encapsulation in long-circulating liposomes may improve the therapeutic index. We performed a randomized, double-blind, active-controlled, multi-center study in which intravenously (i.v.) administered pegylated liposomal prednisolone sodium phosphate (Nanocort) was compared to equipotent intramuscular (i.m.) methylprednisolone acetate (Depo-Medrol®; i.e. a current standards-of-care for treating flares in rheumatoid arthritis patients). We enrolled 172 patients with active arthritis who met all eligibility criteria, eventually resulting in 150 patients randomized in three groups: (1) Nanocort 75 mg i.v. infusion plus i.m. saline injection; (2) Nanocort 150 mg i.v. infusion plus i.m. saline injection; and (3) Depo-Medrol® 120 mg i.m. injection plus i.v. saline infusion. Dosing in each group occurred at baseline and on day 15 (week 2). Study visits occurred at week 1, 2, 3, 4, 6, 8 and 12, to assess both efficacy and safety. The primary endpoint was the “European League Against Rheumatism” (EULAR) responder rate at week 1. Safety was determined by the occurrence of adverse events during treatment and 12 weeks of follow-up. Treatment with Nanocort was found to be superior to Depo-Medrol® in terms of EULAR response at week 1, with p-values of 0.007 (good response) and 0.018 (moderate response). Treatments were well tolerated with a comparable pattern of adverse events in the three treatment groups. However, the Nanocort groups had a higher incidence of hypersensitivity reactions during liposome infusion. Our results show that liposomal Nanocort is more effective than Depo-Medrol® in treating patients with rheumatoid arthritis flares and has similar safety. This is the first clinical study in a large patient population showing that i.v. administered targeted drug delivery with a nanomedicine formulation improves the therapeutic index of glucocorticoids.
AB - Glucocorticoids (GCs) are potent anti-inflammatory drugs but their use is limited by systemic exposure leading to toxicity. Targeted GC delivery to sites of inflammation via encapsulation in long-circulating liposomes may improve the therapeutic index. We performed a randomized, double-blind, active-controlled, multi-center study in which intravenously (i.v.) administered pegylated liposomal prednisolone sodium phosphate (Nanocort) was compared to equipotent intramuscular (i.m.) methylprednisolone acetate (Depo-Medrol®; i.e. a current standards-of-care for treating flares in rheumatoid arthritis patients). We enrolled 172 patients with active arthritis who met all eligibility criteria, eventually resulting in 150 patients randomized in three groups: (1) Nanocort 75 mg i.v. infusion plus i.m. saline injection; (2) Nanocort 150 mg i.v. infusion plus i.m. saline injection; and (3) Depo-Medrol® 120 mg i.m. injection plus i.v. saline infusion. Dosing in each group occurred at baseline and on day 15 (week 2). Study visits occurred at week 1, 2, 3, 4, 6, 8 and 12, to assess both efficacy and safety. The primary endpoint was the “European League Against Rheumatism” (EULAR) responder rate at week 1. Safety was determined by the occurrence of adverse events during treatment and 12 weeks of follow-up. Treatment with Nanocort was found to be superior to Depo-Medrol® in terms of EULAR response at week 1, with p-values of 0.007 (good response) and 0.018 (moderate response). Treatments were well tolerated with a comparable pattern of adverse events in the three treatment groups. However, the Nanocort groups had a higher incidence of hypersensitivity reactions during liposome infusion. Our results show that liposomal Nanocort is more effective than Depo-Medrol® in treating patients with rheumatoid arthritis flares and has similar safety. This is the first clinical study in a large patient population showing that i.v. administered targeted drug delivery with a nanomedicine formulation improves the therapeutic index of glucocorticoids.
KW - n/a OA procedure
KW - Glucocorticoids
KW - Long-circulating liposomes
KW - Rheumatoid arthritis
KW - Targeted drug delivery
KW - Enhanced permeability and retention
UR - http://www.scopus.com/inward/record.url?scp=85121730341&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2021.12.007
DO - 10.1016/j.jconrel.2021.12.007
M3 - Article
AN - SCOPUS:85121730341
SN - 0168-3659
VL - 341
SP - 548
EP - 554
JO - Journal of controlled release
JF - Journal of controlled release
ER -