title: The use of group sequential, information-based sample size re-estimation in the design of the PRIMO study of chronic kidney disease.
abstract: BACKGROUND
  Chronic kidney disease is associated with a marked increase in risk for left ventricular hypertrophy and cardiovascular mortality compared with the general population. Therapy with vitamin D receptor activators has been linked with reduced mortality in chronic kidney disease and an improvement in left ventricular hypertrophy in animal studies.
  
  
  OBJECTIVE
  PRIMO (Paricalcitol capsules benefits in Renal failure Induced cardia MOrbidity) is a multinational, multicenter randomized controlled trial to assess the effects of paricalcitol (a selective vitamin D receptor activator) on mild to moderate left ventricular hypertrophy in patients with chronic kidney disease.
  
  
  METHODS
  Subjects with mild-moderate chronic kidney disease are randomized to paricalcitol or placebo after confirming left ventricular hypertrophy using a cardiac echocardiogram. Cardiac magnetic resonance imaging is then used to assess left ventricular mass index at baseline, 24 and 48 weeks, which is the primary efficacy endpoint of the study. Because of limited prior data to estimate sample size, a maximum information group sequential design with sample size re-estimation is implemented to allow sample size adjustment based on the nuisance parameter estimated using the interim data. An interim efficacy analysis is planned at a pre-specified time point conditioned on the status of enrollment. The decision to increase sample size depends on the observed treatment effect. A repeated measures analysis model, using available data at Week 24 and 48 with a backup model of an ANCOVA analyzing change from baseline to the final nonmissing observation, are pre-specified to evaluate the treatment effect. Gamma-family of spending function is employed to control family-wise Type I error rate as stopping for success is planned in the interim efficacy analysis.
  
  
  CONCLUSIONS
  If enrollment is slower than anticipated, the smaller sample size used in the interim efficacy analysis and the greater percent of missing week 48 data might decrease the parameter estimation accuracy, either for the nuisance parameter or for the treatment effect, which might in turn affect the interim decision-making.
  
  
  CONCLUSIONS
  The application of combining a group sequential design with a sample-size re-estimation in clinical trial design has the potential to improve efficiency and to increase the probability of trial success while ensuring integrity of the study.
authors.affiliation: Abbott Laboratories, Abbott Park, IL, USA. yili.pritchett@aboott.com
authors.forename: Yili
authors.initials: Y
authors.lastname: Pritchett
authors.forename: Yannis
authors.initials: Y
authors.lastname: Jemiai
authors.forename: Yuchiao
authors.initials: Y
authors.lastname: Chang
authors.forename: Ishir
authors.initials: I
authors.lastname: Bhan
authors.forename: Rajiv
authors.initials: R
authors.lastname: Agarwal
authors.forename: Carmine
authors.initials: C
authors.lastname: Zoccali
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.forename: Donald
authors.initials: D
authors.lastname: Lloyd-Jones
authors.forename: Jorge B
authors.initials: JB
authors.lastname: Cannata-Andía
authors.forename: Taylor
authors.initials: T
authors.lastname: Thompson
authors.forename: Evan
authors.initials: E
authors.lastname: Appelbaum
authors.forename: Paul
authors.initials: P
authors.lastname: Audhya
authors.forename: Dennis
authors.initials: D
authors.lastname: Andress
authors.forename: Wuyan
authors.initials: W
authors.lastname: Zhang
authors.forename: Scott
authors.initials: S
authors.lastname: Solomon
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Manning
authors.forename: Ravi
authors.initials: R
authors.lastname: Thadhani
mesh_terms: D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D003627:Data Interpretation, Statistical; D004872:Ergocalciferols / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy*; D007676:Kidney Failure, Chronic / Q000150:complications*; D008297:Male; D018167:Receptors, Calcitriol / Q000819:agonists; D018401:Sample Size; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D050071:Bone Density Conservation Agents; D004872:Ergocalciferols; D018167:Receptors, Calcitriol; C084656:paricalcitol