title: A multi-center, randomized, double blind placebo-controlled trial of estrogens to prevent Alzheimer's disease and loss of memory in women: design and baseline characteristics.
abstract: BACKGROUND
  Observational studies and small clinical trials suggested that hormone replacement therapy (HRT) decreases risk of cognitive loss and Alzheimer's disease (AD) in postmenopausal women and may have value in primary prevention.
  
  
  OBJECTIVE
  A clinical trial was designed to determine if HRT delays AD or memory loss. This report describes the rationale and original design of the trial and details extensive modifications that were required to respond to unanticipated findings that emerged from other studies during the course of the trial.
  
  
  METHODS
  The trial was designed as a multi-center, placebo-controlled primary prevention trial for women 65 years of age or older with a family history of dementia. Recruitment from local sites was supplemented by centralized efforts to use names of Medicare beneficiaries. Inclusion criteria included good general health and intact memory functioning. Participants were randomized to HRT or placebo in a 1:1 ratio. Assignment was stratified by hysterectomy status and site. The primary outcomes were incident AD and memory decline on neuropsychological testing.
  
  
  RESULTS
  Enrollment began in March 1998. In response to the Women's Health Initiative (WHI) May 2002 report of increased incidence of heart disease, stroke, pulmonary embolism, and breast cancer among women randomized to HRT, participants were re-consented with a revised consent form. Procedural modifications, including discontinuation of study medication and a modification of the planned primary outcome based on a final enrollment below the target enrollment (N = 477), were enacted in response to the subsequent WHI Memory Study report of increased risk of dementia and poorer cognitive function with HRT. The mean length of treatment exposure prior to discontinuation was 2.14 years. Participants' mean age at baseline was 72.8; mean education was 14.2 years. Minority participation was 19% and 34% had a hysterectomy. The study continues to follow these participants for a total of 5 years blind to the original medication assignment.
  
  
  CONCLUSIONS
  Results reported from the WHI during the course of this study mandated extensive procedural modifications, including discontinuing recruitment before completion and halting study medication. Alternative strategies for study redesign that were considered are discussed.
authors.affiliation: Mount Sinai School of Medicine, Department of Psychiatry, New York, NY, USA. mary.sano@mssm.edu
authors.forename: Mary
authors.initials: M
authors.lastname: Sano
authors.forename: Diane
authors.initials: D
authors.lastname: Jacobs
authors.forename: Howard
authors.initials: H
authors.lastname: Andrews
authors.forename: Karen
authors.initials: K
authors.lastname: Bell
authors.forename: Neill
authors.initials: N
authors.lastname: Graff-Radford
authors.forename: John
authors.initials: J
authors.lastname: Lucas
authors.forename: Peter
authors.initials: P
authors.lastname: Rabins
authors.forename: Karen
authors.initials: K
authors.lastname: Bolla
authors.forename: Wei-Yan
authors.initials: WY
authors.lastname: Tsai
authors.forename: Peter
authors.initials: P
authors.lastname: Cross
authors.forename: Karen
authors.initials: K
authors.lastname: Andrews
authors.forename: Rosann
authors.initials: R
authors.lastname: Costa
authors.lastname: Xiaodong Luo
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy / Q000517:prevention & control*; D004311:Double-Blind Method; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008569:Memory Disorders / Q000188:drug therapy / Q000517:prevention & control*
chemical_list: D004967:Estrogens