Application of the OMERACT Filter to Measures of Core Outcome Domains in Recent Clinical Studies of Acute Gout

William J. Taylor; David Redden; Nicola Dalbeth; H. Ralph Schumacher; N. Lawrence Edwards; Lee S. Simon; Markus R. John; Margaret N. Essex; Douglas J. Watson; Robert Evans; Keith Rome; Jasvinder A. Singh

doi:10.3899/jrheum.131245

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Table 1.

Data sources for validation data related to measures of 5 acute gout domains.

Source	n	Inclusion	Treatment Groups	Publication (reference)
Merck Sharp & Dohme	150	Onset within 48 h, 1977 ARA criteria, at least moderate pain	Etoricoxib, indomethacin	(7)
Pfizer	402	Onset within 48 h, 1977 ARA criteria, at least moderate pain	Celecoxib 50, 400/200, 800/400, indomethacin	(8)
Regeneron	225	Onset within 48 h, 1977 ARA criteria, at least moderate pain	Indomethacin, rilonacept and indomethacin, rilonacept	Not published [NCT00855920]
Novartis (2 replicate studies)	424	Onset of acute flare within 5 days, 1977 ARA criteria, at least 3 flares within prior 12 mo, pain at least 50 mm on 100 mm VAS	Canakinumab 150 mg SQ, triamcinolone 40 mg IM	(2)^*
Auckland University of Technology	20	Observational study, acute gout flare at baseline, 1977 ARA criteria	Not applicable	(3)

↵* Not published prior to data analyses and presentation but now published; dataset provided to investigators was a 90% random subsample of the main study dataset (n = 456). ARA: American Rheumatology Association; VAS: visual analog scale.

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Table 2.

Instruments available for each data source.

Source	Pain	Disability	Joint Swelling/tenderness	Patient Global
Merck Sharp & Dohme	Likert 0–4	NA	Likert 0–3^*	Response to treatment (Likert 0–4 point)
Pfizer	Likert 0–4	NA	Likert 0–3^*	Response to treatment (Likert 0–4 point)
Regeneron	Likert 0–4, NRS 0–10	Activity limitations, NRS 0–10 (from WPAI:SHP v2.0)	NA^†	No measure^† available
Novartis	Likert 0–4, VAS 0–100	HAQ-DI	Likert 0–3^*	Response to treatment (Likert 0–4 point)
Auckland University of Technology	VAS 0–100	HAQ-II	Swollen and tender joint count	VAS 0–100

↵* Index joint assessed by a physician;
↵† Likert 0–3 grade for joint tenderness and swelling was used in the actual trial but those data were not available for the current analysis. NA: no measure available; HAQ-II: Health Assessment Questionnaire version II; HAQ-DI: Health Assessment Questionnaire Disability Index; VAS: visual analog scale; WPAI:SHP: Worker Productivity and Activity Impairment Index (Specific Health Problem)⁹; NRS: numeric rating scale.

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Table 3.

Construct validity showing Spearman correlation coefficients for each measure.

Source Measure	Pain (VAS or NRS)	Joint Tenderness	Joint Swelling	Activity Limitations^*	Patient Global^‡
MSD
Pain (Likert)	NA	0.34	0.18	NA	NA
Joint tenderness			0.25	NA	NA
Joint swelling				NA	NA
Activity limitations					NA
Pfizer
Pain (Likert)	NA	0.36	0.18	NA	NA
Joint tenderness			0.37	NA	NA
Joint swelling				NA	NA
Activity limitations					NA
Regeneron
Pain (Likert)	0.75	NA	NA	0.31	NA
Pain (NRS)		NA	NA	0.39	NA
Joint tenderness			NA	NA	NA
Joint swelling				NA	NA
Activity limitations					NA
Novartis
Pain (VAS)	0.55	0.13	0.19	0.58	0.72
Pain (Likert)		0.15	0.17	0.58	0.70
Joint tenderness			0.46	0.18	0.56
Joint swelling				0.25	0.47
Activity limitations					0.50
AUT
Pain VAS	NA	NA	NA	0.66	0.73
Joint tenderness			NA	NA	NA
Joint swelling				NA	NA
Activity limitations^†					0.73

↵* Activity limitations measured by single 0–10 NRS in Regeneron data, HAQ-II in AUT data, and HAQ-DI in Novartis data.
↵† In addition the HAQ-II correlated highly with measures of specific foot function in this dataset.
↵‡ Changes in each measure were correlated with patient global because the patient global represented perception of change (except for the AUT dataset). NA: measure not available in the dataset; AUT: Auckland University of Technology; VAS: visual analog scale; NRS: numeric rating scale; MSD: Merck Sharp & Dohme Corp.

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Table 4.

Indices of discrimination.

Measure	Source	Within Group (pooled)		Between Group
Measure	Source	Effect Size	^† GEE, Wald Chi-square	KW Statistic	^† GEE, Wald Chi-square
Pain (Likert)	MSD^, Pfizer, Regeneron, Novartis^	2.32	NA	NA	NA
		2.72	816, p < 0.001	17.6, p = 0.001	16.8, p = 0.001
		1.20	NA	26.7, p < 0.001	NA
		2.84	446.8, p < 0.001	NA	NA
Pain (VAS)	AUT^, Novartis^	1.58	NA	NA	NA
Pain (VAS)	AUT^, Novartis^	4.46	602.2, p < 0.001	NA	NA
Pain (NRS)	Regeneron	1.62	NA	26.6, p < 0.001	NA
Joint tenderness	MSD^, Pfizer, Regeneron, Novartis^, AUT^*	3.2	NA	NA	NA
		2.5	542, p < 0.001	1.7, p = 0.67	12, p = 0.01
		NA	NA	NA	NA
		2.25	598, p < 0.001	NA	NA
		NA	NA	NA	NA
Joint swelling	MSD^, Pfizer, Regeneron, Novartis^, AUT^*	2.9	NA	NA	NA
		2.3	561, p < 0.001	2.2, p = 0.54	4.0, p = 0.26
		NA	NA	NA	NA
		2.5	523, p < 0.001	NA	NA
		NA	NA	NA	NA
Activity limitations	MSD^, Pfizer, Regeneron, Novartis^, AUT^*	NA	NA	NA	NA
		NA	NA	NA	NA
		0.81	NA	5.4, p = 0.067	NA^§
		1.04	159, p < 0.001	NA	NA
		1.72	NA	NA	NA
Patient global	MSD^, Pfizer^†, Regeneron, Novartis^, AUT^{^*^¶}	NA^‡	NA	NA	NA
		NA^‡	NA	5.5, p = 0.14	NA^§
		NA	NA	NA	NA
		NA^‡	NA	NA	NA
		1.46	NA	NA	NA

↵* MSD: Merck Sharp & Dohme Corp. Treatment allocation not available or not relevant therefore between-group discrimination was not assessable.
↵† Repeated measures GEE with ordinal regression performed in Pfizer and Novartis datasets;
↵‡ No baseline measure since it assessed response to treatment;
↵§ Not measured at multiple timepoints;
↵¶ PGA measured with 100 mm visual analog scale for current status (all other studies used global response to treatment). NA: not available or not applicable; GEE: generalized estimating equations; NRS: numeric rating scale; AUT: Auckland University of Technology; PGA: patient global assessment.

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Table 5.

Floor (percentage of participants at minimum possible value) and ceiling (percentage of participants at maximum possible value) effects.

Measure	Source	Floor (%)		Ceiling (%)
Measure	Source	Baseline	Final^*	Baseline	Final^*
Pain (Likert)	MSD, Pfizer, Regeneron, Novartis	0	42	21.7	1.8
		0	35.4	17.7	0.8
		0	11.6	11.1	4.0
		0.24	28.25	12.59	1.25
Pain (VAS)	AUT^†, Novartis	0	33.3	5	0
Pain (VAS)	AUT^†, Novartis	0	14.4	2.1	0
Pain (NRS)	Regeneron	0	11.6	9.3	4.9
Joint tenderness	MSD, Pfizer, Regeneron, Novartis, AUT^†	0	50.0	57.5	3.0
		0.5	44.1	39.1	4.7
		NA	NA	NA	NA
		0.71	55.1	43.4	2.64
		NA	NA	NA	NA
Joint swelling	MSD, Pfizer, Regeneron, Novartis, AUT^†	0	52.1	56.0	5.4
		2.2	47.2	27.1	4.5
		NA	NA	NA	NA
		1.4	63.7	35.1	2.2
		NA	NA	NA	NA
Disability^‡	MSD, Pfizer, Regeneron, Novartis, AUT^†	NA	NA	NA	NA
		NA	NA	NA	NA
		11.7	33.2	8.1	3.5
		5.63	46.19	0.43	0
		0	0	0	16.7
Patient Global Assessment^¶	MSD, Pfizer, Regeneron, Novartis, AUT^†	NA	4.5	NA	26.4
		NA	2.8	NA	40.1
		NA	NA	NA	NA
		NA	2.1	NA	39.1
		0	0	5	0

↵* Refers to Day 5 unless mentioned specifically;
↵† Final value at 6 to 8 wks;
↵‡ Measured by Health Assessment Questionnaire version II in AUT, Health Assessment Questionnaire Disability Index in Novartis, Worker Productivity and Activity Impairment Index 0–10 in Regeneron;
↵¶ Final value at Day 9 for Pfizer and Novartis. NA: measure not available; VAS: visual analog scale; NRS: numeric rating scale; AUT: Auckland University of Technology; HAQ-II: Health Assessment Questionnaire version II; HAQ-DI: Health Assessment Questionnaire Disability Index; WPAI:SHP: Worker Productivity and Activity Impairment Index (Specific Health Problem)⁹; MSD: Merck Sharp & Dohme Corp.

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Table 6.

Indices of test-retest reliability, smallest detectable difference (SDD) and minimal important difference (MID).

			ICC	SEM	SDD	MID
Pain (Likert)	MSD	Between day 2 and 5	0.56	0.51	1.41	1
	MSD	Between day 5 and 8	0.80	0.42	1.17	2
	Pfizer^*	Between 2 and 4 h	0.81	0.39	1.08
		Between 2 and 8 h	0.72	0.50	1.39
		Between 2 and 12 h	0.60	0.62	1.72
	Pfizer^†	Between day 1 and 9	0.07	0.76	2.1	2
		Between day 2 and 9	0.15	0.76	2.1	2
		Between day 5 and 9	0.59	0.54	1.50	2
	Novartis	Baseline to 7 days postdose	0.35	0.85	2.36	1.0
		24 h postdose to 7 days	0.55	0.64	1.77
		48 h postdose to 7 days	0.71	0.49	1.36
Pain (VAS)	Novartis	Baseline to 7 days postdose	0.35	3.66	10.15	19
		24 h postdose to 7 days	0.57	2.93	8.12
		48 h postdose to 7 days	0.76	2.23	6.18
Joint tenderness	MSD	Between day 2 and day 5	0.50	0.46	1.28	2
	MSD	Between day 5 and day 8	0.79	0.34	0.94	1
	Pfizer	Between Day 1 and 9	0.06	0.66	1.8	2
	Pfizer	Between Day 5 and 9	0.11	0.59	1.6	2
	Novartis	Baseline to 7 days postdose	0.0^**	1.06	2.93	1.0
		24 h postdose to 7 days	0.50	0.54	1.51
		48 h postdose to 7 days	0.49	0.54	1.50
		72 h postdose to 7 days	0.49	0.54	1.50
Joint swelling	MSD	Between day 2 and day 5	0.48	0.53	1.47	1
	MSD	Between day 5 and day 8	0.77	0.43	1.18	1
	Pfizer	Between Day 1 and 9	0.13	0.64	1.8	1
	Pfizer	Between Day 5 and 9	0.37	0.73	2.0	1
	Novartis	Baseline to 7 days	0.0	1.07	2.97	1
		24 h postdose to 7 days	0.44	0.65	1.80
		48 h postdose to 7 days	0.44	0.65	1.79
		72 h postdose to 7 days	0.44	0.65	1.79
Activity limitations	Novartis		0.55	0.45	1.25	0.5

↵* Pain assessed as “current” level of pain;
↵† pain assessed as “over the last 24 h;”
↵** Statistical software indicated that estimation of a negative variance parameter was attempted. MSD: Merck Sharp & Dohme Corp.; VAS: visual analog scale; ICC: intraclass correlation; SEM: standard error of measurement.