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. PURPOSE: 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. LIMITATIONS: 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.
RCT Entities:
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. PURPOSE: 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. LIMITATIONS: 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: M C Carlson; P P Zandi; B L Plassman; J T Tschanz; K A Welsh-Bohmer; D C Steffens; L A Bastian; K M Mehta; J C Breitner Journal: Neurology Date: 2001-12-26 Impact factor: 9.910
Authors: Sally E Shaywitz; Frederick Naftolin; Daniel Zelterman; Karen E Marchione; John M Holahan; Steven F Palter; Bennett A Shaywitz Journal: Menopause Date: 2003 Sep-Oct Impact factor: 2.953
Authors: Jacques E Rossouw; Garnet L Anderson; Ross L Prentice; Andrea Z LaCroix; Charles Kooperberg; Marcia L Stefanick; Rebecca D Jackson; Shirley A A Beresford; Barbara V Howard; Karen C Johnson; Jane Morley Kotchen; Judith Ockene Journal: JAMA Date: 2002-07-17 Impact factor: 56.272
Authors: Mark A Espeland; Stephen R Rapp; Sally A Shumaker; Robert Brunner; JoAnn E Manson; Barbara B Sherwin; Judith Hsia; Karen L Margolis; Patricia E Hogan; Robert Wallace; Maggie Dailey; Ruth Freeman; Jennifer Hays Journal: JAMA Date: 2004-06-23 Impact factor: 56.272
Authors: K Pun; C W Zhu; M T Kinsella; M Sewell; H Grossman; J Neugroschl; C Li; A Ardolino; N Velasco; M Sano Journal: J Prev Alzheimers Dis Date: 2021
Authors: Valentina Echeverria; Florencia Echeverria; George E Barreto; Javier Echeverría; Cristhian Mendoza Journal: Front Pharmacol Date: 2021-05-20 Impact factor: 5.810