Investigation of the role of articular ultrasonography in rheumatoid arthritis early phase clinical trials
Author(s)
Seymour, Matthew Wadham
Type
Thesis or dissertation
Abstract
Objective
To investigate the utility of ultrasonographic measures of synovitis in rheumatoid arthritis (RA) early phase clinical trials.
Methods
Study 1 contained a double-blind, placebo and comparator controlled two-centre study to investigate the effect of 28 days repeat daily oral dosing of 60 mg of an inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. 50 subjects (DAS28≥4.0) were randomized into 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial vascularity was assessed in the transverse plane over the dorsum of all 10 metacarpophalangeal joints (MCPJs) by ultrasonography and measured quantitatively as power Doppler area (PDA). Study 2 was a randomized, double-blind, parallel group, placebo controlled two-centre study to assess the effects of oral prednisone (15 mg once daily) on DAS28(CRP) and ultrasonographic measures of MCPJ synovitis (quantitative and qualitative assessments of synovial vascularity and thickness measured in the longitudinal and transverse planes over the dorsum) in 18 subjects (10 placebo and 8 prednisone) with RA (DAS28≥3.2) over 2 weeks; endpoints measured on Day 1 (baseline), Day 2, Day 8 and Day 15.
Results
Study 1: At Day 28, there was a 55% decrease in PDA for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003). Study 2: In the prednisone group significant treatment effects were observed at all time points for a variety of US endpoints (largest effect size=1.82) but only at Day 15 for DAS28(CRP) (effect size=0.95, P=0.032). The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of ultrasound measures.
Conclusion
Ultrasonography of MCPJs could be utilized in early phase RA clinical trials to reduce patient numbers and trial length.
Key words:
Rheumatoid Arthritis
Ultrasound
Power Doppler Ultrasound
Gray-Scale Ultrasound
Corticosteroid
Prednisolone
Prednisone
GW274150
iNOS (inducible nitric oxide synthase)
Metacarpophalangeal Joints
Synovitis
To investigate the utility of ultrasonographic measures of synovitis in rheumatoid arthritis (RA) early phase clinical trials.
Methods
Study 1 contained a double-blind, placebo and comparator controlled two-centre study to investigate the effect of 28 days repeat daily oral dosing of 60 mg of an inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. 50 subjects (DAS28≥4.0) were randomized into 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial vascularity was assessed in the transverse plane over the dorsum of all 10 metacarpophalangeal joints (MCPJs) by ultrasonography and measured quantitatively as power Doppler area (PDA). Study 2 was a randomized, double-blind, parallel group, placebo controlled two-centre study to assess the effects of oral prednisone (15 mg once daily) on DAS28(CRP) and ultrasonographic measures of MCPJ synovitis (quantitative and qualitative assessments of synovial vascularity and thickness measured in the longitudinal and transverse planes over the dorsum) in 18 subjects (10 placebo and 8 prednisone) with RA (DAS28≥3.2) over 2 weeks; endpoints measured on Day 1 (baseline), Day 2, Day 8 and Day 15.
Results
Study 1: At Day 28, there was a 55% decrease in PDA for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003). Study 2: In the prednisone group significant treatment effects were observed at all time points for a variety of US endpoints (largest effect size=1.82) but only at Day 15 for DAS28(CRP) (effect size=0.95, P=0.032). The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of ultrasound measures.
Conclusion
Ultrasonography of MCPJs could be utilized in early phase RA clinical trials to reduce patient numbers and trial length.
Key words:
Rheumatoid Arthritis
Ultrasound
Power Doppler Ultrasound
Gray-Scale Ultrasound
Corticosteroid
Prednisolone
Prednisone
GW274150
iNOS (inducible nitric oxide synthase)
Metacarpophalangeal Joints
Synovitis
Date Issued
2011-10
Date Awarded
2012-04
Advisor
Taylor, Peter
Publisher Department
Medicine: Kennedy Institute of Rheumatology
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Medicine (Research) MD (Res)