title: A MULTICENTER, LONGITUDINAL, INTERVENTIONAL, DOUBLE BLIND RANDOMIZED CLINICAL TRIAL IN HEMATOPOIETIC CELL TRANSPLANT RECIPIENTS RESIDING IN REMOTE AREAS: LESSONS LEARNED FROM THE LATE CYTOMEGALOVIRUS PREVENTION TRIAL.
abstract: OBJECTIVE
  The logistics of conducting double-blinded phase III clinical trials with participants residing in remote locations are complex. Here we describe the implementation of an interventional trial for the prevention of late cytomegalovirus (CMV) disease in hematopoietic cell transplantation (HCT) subjects in a long-term follow-up environment.
  
  
  METHODS
  A total of 184 subjects at risk for late CMV disease surviving 80 days following allogeneic HCT were randomized to receive six months of valganciclovir or placebo. Subjects were followed through day 270 post-transplant at their local physician's office within the United States. Anti-viral treatment interventions were based on CMV DNAemia as measured by polymerase chain reaction (PCR) (>1000 copies/mL) and granulocyte colony stimulating factor (G-CSF) was prescribed for neutropenia (absolute neutrophil count (ANC <1.0 × 109cells/L). Blood samples for viral testing and safety monitoring were shipped to a central laboratory by overnight carrier. Real-time communication was established between the coordinating center and study sites, primary care physicians, and study participants to facilitate starting, stopping and dose adjustments of antiviral drugs and G-CSF. The time required to make these interventions was analyzed.
  
  
  RESULTS
  Of the 4169 scheduled blood specimens, 3832 (92%) were received and analyzed; the majority (97%) arriving at the central site within 2 days. Among subjects with positive CMV DNAemia (N=46), over 50% received open label antiviral medication within one day. The median time to start G-CSF for neutropenia was <1 day after posting of laboratory results (range 0-6; N=38). Study drug dose adjustments for abnormal renal function were implemented 203 times; within one day for 48% of cases and within 2 days for 80% of cases.
  
  
  CONCLUSIONS
  Complex randomized, double-blind, multicenter interventional trials with treatment decisions made at a central coordinating site can be conducted safely and effectively according to Good Clinical Practice (GCP) guidelines over a large geographic area.
authors.affiliation: Vaccine and Infectious Disease, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Kimball
authors.affiliation: Vaccine and Infectious Disease, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Terry
authors.initials: T
authors.lastname: Stevens-Ayers
authors.affiliation: Vaccine and Infectious Disease, Fred Hutchinson Cancer Research Center, Seattle, Washington; Medicine, University of Washington, Seattle, Washington.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Green
authors.affiliation: Clinical Research Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Hu
authors.initials: H
authors.lastname: Xie
authors.affiliation: Clinical Research Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington; Medicine, University of Washington, Seattle, Washington.
authors.forename: Mary E D
authors.initials: ME
authors.lastname: Flowers
authors.affiliation: Vaccine and Infectious Disease, Fred Hutchinson Cancer Research Center, Seattle, Washington; Virology Division, University of Washington, Seattle, Washington; Department of Laboratory Medicine, University of Washington, Seattle, Washington.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Jerome
authors.affiliation: Clinical Research Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Renee
authors.initials: R
authors.lastname: LeBlanc
authors.affiliation: Clinical Research Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Christi
authors.initials: C
authors.lastname: Dahlgren
authors.affiliation: Chimerix Inc., Durham, NC.
authors.forename: W Garrett
authors.initials: WG
authors.lastname: Nichols
authors.affiliation: Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Roy F
authors.initials: RF
authors.lastname: Chemaly
authors.affiliation: Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: G
authors.initials: G
authors.lastname: Papanicolaou
authors.affiliation: Vaccine and Infectious Disease, Fred Hutchinson Cancer Research Center, Seattle, Washington; Clinical Research Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington; Medicine, University of Washington, Seattle, Washington.
authors.forename: Michael
authors.initials: M
authors.lastname: Boeckh
keywords: Anti-viral treatment; Cytomegalovirus; Good Clinical Practice