title: Nonspecific adverse events in knee osteoarthritis clinical trials: a systematic review.
abstract: BACKGROUND
  Adverse events (AEs) derived from nonspecific activity of treatments can impair the validity of trials, and even make it difficult to identify specific AEs associated with treatments. To better understand these nonspecific AEs, we investigated the AEs in placebo groups by using knee osteoarthritis clinical trials.
  
  
  METHODS
  Randomized, placebo-controlled, knee osteoarthritis trials were identified by searching electronic databases. We determined the rate of patients with AEs and the rate of dropouts caused by AEs in the active and placebo groups. Furthermore, we calculated the rate of patients for individual AEs in the placebo groups. Finally, we performed secondary analyses to identify the factors associated with these rates.
  
  
  RESULTS
  Overall, 272 papers reporting 281 trials were included in the analysis. The rates of patients with AEs were 31.8% in the active groups and 27.4% in the placebo groups. The rate of the placebo groups accounted for 86.2% of the rate of the active groups. The rates of dropouts caused by AEs were 5.2% in the active groups and 4.8% in the placebo groups. The rate of the placebo groups accounted for 92.3% of the rate of the active groups. AEs in the placebo groups included a number of clinical conditions, with elevated alanine aminotransferase (0.59%; 95% CI: 0.46 to 0.77) being the most common objective outcome and headache (4.48%; 95% CI: 4.20 to 4.79) being the most frequent subjective outcome. The rate of patients with AEs and the rate of dropouts caused by AEs were associated with the treatment type, delivery route, and study design.
  
  
  CONCLUSIONS
  The nonspecific AEs substantially accounted for the development of AEs in the active groups and included conditions involving the entire body.
authors.affiliation: Honam Research Center, Medifarm Hospital, Suncheon, Republic of Korea; Department of Oriental Medicine, Medifarm Hospital, Suncheon, Republic of Korea.
authors.forename: Yun Hyung
authors.initials: YH
authors.lastname: Koog
authors.affiliation: Honam Research Center, Medifarm Hospital, Suncheon, Republic of Korea; Department of Rehabilitation, Medifarm Hospital, Suncheon, Republic of Korea.
authors.forename: Jin Su
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Honam Research Center, Medifarm Hospital, Suncheon, Republic of Korea.
authors.forename: Hyungsun
authors.initials: H
authors.lastname: Wi
mesh_terms: D016208:Databases, Factual; D006261:Headache / Q000209:etiology* / Q000628:therapy*; D006801:Humans; D020370:Osteoarthritis, Knee / Q000150:complications* / Q000628:therapy*; D016032:Randomized Controlled Trials as Topic