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Which and How Many Patients Should Be Included in Randomised Controlled Trials to
Demonstrate the Efficacy of Biologics in Primary Sjögren s Syndrome?
#MMPMID26368934
Devauchelle-Pensec V
; Gottenberg JE
; Jousse-Joulin S
; Berthelot JM
; Perdriger A
; Hachulla E
; Hatron PY
; Puechal X
; Le Guern V
; Sibilia J
; Chiche L
; Goeb V
; Vittecoq O
; Larroche C
; Fauchais AL
; Hayem G
; Morel J
; Zarnitsky C
; Dubost JJ
; Dieudé P
; Pers JO
; Cornec D
; Seror R
; Mariette X
; Nowak E
; Saraux A
PLoS One
2015[]; 10
(9
): e0133907
PMID26368934
show ga
OBJECTIVE: The goal of this study was to determine how the choice of the primary
endpoint influenced sample size estimates in randomised controlled trials (RCTs)
of treatments for primary Sjögren's syndrome (pSS). METHODS: We reviewed all
studies evaluating biotechnological therapies in pSS to identify their inclusion
criteria and primary endpoints. Then, in a large cohort (ASSESS), we determined
the proportion of patients who would be included in RCTs using various inclusion
criteria sets. Finally, we used the population of a large randomised therapeutic
trial in pSS (TEARS) to assess the impact of various primary objectives and
endpoints on estimated sample sizes. These analyses were performed only for the
endpoints indicating greater efficacy of rituximab compared to the placebo.
RESULTS: We identified 18 studies. The most common inclusion criteria were short
disease duration; systemic involvement; high mean visual analogue scale (VAS)
scores for dryness, pain, and fatigue; and biological evidence of activity. In
the ASSESS cohort, 35 percent of patients had recent-onset disease (lower than 4
years), 68 percent systemic manifestations, 68 percent high scores on two of
three VASs, and 52 percent biological evidence of activity. The primary endpoints
associated with the smallest sample sizes (nlower than 200) were a VAS dryness
score improvement higher to 20 mm by week 24 or variable improvements (10, 20, or
30 mm) in fatigue VAS by week 6 or 16. For patients with systemic manifestations,
the ESSDAI change may be the most logical endpoint, as it reflects all domains of
disease activity. However, the ESSDAI did not improve significantly with
rituximab therapy in the TEARS study. Ultrasound score improvement produced the
smallest sample size estimate in the TEARS study. CONCLUSION: This study provides
valuable information for designing future RCTs on the basis of previously
published studies. Previous RCTs used inclusion criteria that selected a small
part of the entire pSS population. The endpoint was usually based on VASs
assessing patient complaints. In contrast to VAS dryness cut-offs, VAS fatigue
cut-offs did not affect estimated sample sizes. SGUS improvement produced the
smallest estimated sample size. Further studies are required to validate
standardised SGUS modalities and assessment criteria. Thus, researchers should
strive to develop a composite primary endpoint and to determine its best cut-off
and assessment time point.
|Endpoint Determination/*methods
[MESH]
|Humans
[MESH]
|Patient Selection
[MESH]
|Randomized Controlled Trials as Topic/*methods/standards
[MESH]
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