title: Randomized controlled trials: who fails run-in?
abstract: Early identification of participants at risk of run-in failure (RIF) may present opportunities to improve trial efficiency and generalizability.
  
  
  
  We conducted a partial factorial-design, randomized, controlled trial of calcium and vitamin D to prevent colorectal adenoma recurrence at 11 centers in the United States. At baseline, participants completed two self-administered questionnaires (SAQs) and a questionnaire administered by staff. Participants in the full factorial randomization (calcium, vitamin D, both, or neither) received a placebo during a 3-month single-blinded run-in; women electing to take calcium enrolled in a two-group randomization (calcium with vitamin D, or calcium alone) and received calcium during the run-in. Using logistic regression models, we examined baseline factors associated with RIF in three subgroups: men (N = 1606) and women (N = 301) in the full factorial randomization and women in the two-group randomization (N = 666).
  
  
  
  Overall, 314/2573 (12 %) participants failed run-in; 211 (67 %) took fewer than 80 % of their tablets (poor adherence), and 103 (33 %) withdrew or were uncooperative. In multivariable models, 8- to 13-fold variation was seen by study center in odds of RIF risk in the two largest groups. In men, RIF decreased with age (adjusted odds ratio [OR] per 5 years 0.85 [95 % confidence interval, CI; 0.76-0.96]) and was associated with being single (OR 1.65 [95 % CI; 1.10-2.47]), not graduating from high school (OR 2.77 [95 % CI; 1.58-4.85]), and missing SAQ data (OR 1.97 [1.40-2.76]). Among women, RIF was associated primarily with health-related factors; RIF risk was lower with higher physical health score (OR 0.73 [95 % CI; 0.62-0.86]) and baseline multivitamin use (OR 0.44 [95 % CI; 0.26-0.75]). Women in the 5-year colonoscopy surveillance interval were at greater risk of RIF than those with 3-year follow-up (OR 1.91 [95 % CI; 1.08-3.37]), and the number of prescription medicines taken was also positively correlated with RIF (p = 0.03). Perceived toxicities during run-in were associated with 12- to 29-fold significantly increased odds of RIF.
  
  
  
  There were few common baseline predictors of run-in failure in the three randomization groups. However, heterogeneity in run-in failure associated with study center, and missing SAQ data reflect potential opportunities for intervention to improve trial efficiency and retention.
  
  
  
  ClinicalTrials.gov: NCT00153816 . Registered September 2005.
authors.affiliation: Department of Epidemiology, Geisel School of Medicine at Dartmouth, HB 7927, Dartmouth-Hitchcock Medical Center 1 Medical Center Drive, Lebanon, NH, 03756, USA.
authors.forename: Judy R
authors.initials: JR
authors.lastname: Rees
authors.affiliation: Department of Epidemiology, Geisel School of Medicine at Dartmouth, HB 7927, Dartmouth-Hitchcock Medical Center 1 Medical Center Drive, Lebanon, NH, 03756, USA.
authors.forename: Leila A
authors.initials: LA
authors.lastname: Mott
authors.affiliation: Department of Epidemiology, Geisel School of Medicine at Dartmouth, HB 7927, Dartmouth-Hitchcock Medical Center 1 Medical Center Drive, Lebanon, NH, 03756, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Barry
authors.affiliation: Department of Epidemiology, Geisel School of Medicine at Dartmouth, HB 7927, Dartmouth-Hitchcock Medical Center 1 Medical Center Drive, Lebanon, NH, 03756, USA.|Department of Medicine, University of North Carolina School of Medicine, CB #7555, 4160-A Bioinformatics Bldg., 130 Mason Farm Rd, Chapel Hill, NC, 27599, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Figueiredo
authors.affiliation: Department of Medicine, VA Medical Center, White River Junction, VT and Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Robertson
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Bresalier
authors.affiliation: Department of Epidemiology, Geisel School of Medicine at Dartmouth, HB 7927, Dartmouth-Hitchcock Medical Center 1 Medical Center Drive, Lebanon, NH, 03756, USA. janet.peacock@kcl.ac.uk.|Division of Health and Social Care Research, King's College London, London, UK and NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College, London, UK. janet.peacock@kcl.ac.uk.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Peacock
mesh_terms: D000368:Aged; D002118:Calcium / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D019587:Dietary Supplements; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D014807:Vitamin D / Q000008:administration & dosage*
chemical_list: D014807:Vitamin D; D002118:Calcium
keywords: Adherence; Generalizability; Randomized controlled trials; Run-in