title: Which and How Many Patients Should Be Included in Randomised Controlled Trials to Demonstrate the Efficacy of Biologics in Primary Sjögren's Syndrome?
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Rheumatology Department, CHU de la Cavale Blanche, Boulevard Tanguy Prigent, 29609, Brest, France; EA 2216, INSERM ESPRI, ERI29 Université Bretagne Occidentale, 29200, Brest, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Devauchelle-Pensec
authors.affiliation: Rheumatology Department, Strasbourg University Hospital, Strasbourg, France.
authors.forename: Jacques-Eric
authors.initials: JE
authors.lastname: Gottenberg
authors.affiliation: Rheumatology Department, CHU de la Cavale Blanche, Boulevard Tanguy Prigent, 29609, Brest, France; EA 2216, INSERM ESPRI, ERI29 Université Bretagne Occidentale, 29200, Brest, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Jousse-Joulin
authors.affiliation: Rheumatology Department, Hôtel-Dieu, CHU Nantes, 44093, Nantes Cedex 01, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Berthelot
authors.affiliation: Rheumatology Department, C.H.U. Hôpital Sud, 35000, Rennes, France.
authors.forename: Aleth
authors.initials: A
authors.lastname: Perdriger
authors.affiliation: Internal Medicine Department, Claude Huriez Hospital, Lille2 University, 59037, Lille Cedex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Hachulla
authors.affiliation: Internal Medicine Department, Claude Huriez Hospital, Lille2 University, 59037, Lille Cedex, France.
authors.forename: Pierre Yves
authors.initials: PY
authors.lastname: Hatron
authors.affiliation: Internal Medicine Department, Hôpital Cochin, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Puechal
authors.affiliation: Internal Medicine Department, Hôpital Cochin, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Le Guern
authors.affiliation: Rheumatology Department, Strasbourg University Hospital, Strasbourg, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Sibilia
authors.affiliation: Internal Medicine Department, Hôpital de la Conception, 147 Bd Baille, 13005, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Chiche
authors.affiliation: Rheumatology Department, C.H.R.U. d'Amiens, 76 230 Bois-Guillaume, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Goeb
authors.affiliation: Rheumatology Department, C.H.R.U. de Rouen, 76 230 Bois-Guillaume, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Vittecoq
authors.affiliation: Internal Medicine Department, Bobigny University Hospital, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Larroche
authors.affiliation: Internal Medicine Department, Limoges University Hospital, Limoges, France.
authors.forename: Anne Laure
authors.initials: AL
authors.lastname: Fauchais
authors.affiliation: Rheumatology Department, Ambroise Paré University Hospital, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Hayem
authors.affiliation: Immuno-Rhumatology Department, C.H.U. Lapeyronie, 34295 Montpellier, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Morel
authors.affiliation: Rheumatology Department, C.H. J. Monod, Montivilliers, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Zarnitsky
authors.affiliation: Rheumatology Department, Gabriel Montpied Teaching Hospital, Place H. Dunant, Clermont-Ferrand, 63000, France.
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Dubost
authors.affiliation: Rheumatology Department, Bichat Claude-Bernard Hospital, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieudé
authors.affiliation: EA 2216, INSERM ESPRI, ERI29 Université Bretagne Occidentale, 29200, Brest, France.
authors.forename: Jacques Olivier
authors.initials: JO
authors.lastname: Pers
authors.affiliation: Rheumatology Department, CHU de la Cavale Blanche, Boulevard Tanguy Prigent, 29609, Brest, France; EA 2216, INSERM ESPRI, ERI29 Université Bretagne Occidentale, 29200, Brest, France.
authors.forename: Divi
authors.initials: D
authors.lastname: Cornec
authors.affiliation: Rheumatology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), INSERM U1012, Université Paris-Sud, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.
authors.forename: Raphaele
authors.initials: R
authors.lastname: Seror
authors.affiliation: Rheumatology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), INSERM U1012, Université Paris-Sud, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Mariette
authors.affiliation: INSERM CIC 0502, CHU Brest, Brest, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Nowak
authors.affiliation: Rheumatology Department, CHU de la Cavale Blanche, Boulevard Tanguy Prigent, 29609, Brest, France; EA 2216, INSERM ESPRI, ERI29 Université Bretagne Occidentale, 29200, Brest, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Saraux
mesh_terms: D023381:Endpoint Determination / Q000379:methods*; D006801:Humans; D018579:Patient Selection; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000592:standards; D012859:Sjogren's Syndrome / Q000188:drug therapy* / Q000453:epidemiology