The efficacy of Duloxetine and exercise compared to exercise alone in patients with knee osteoarthritis: a 12-week, randomized, double- blinded, parallel trial. AB. Gomes, A. Schlesinger 1 , D. Hackner 2 , D. Uemac 3 *, D. Garcia Choza 4 , D. Nunes, F. Bernoit Peña, G. Negrão de Figueiredo 5 , H. Paredes Martínez de Arredondo, K. Geroula, L. Zhang, MF. Luiz 6 , M. Rodrigues, M. Al-Muhannadi, M. Mansour 7 , PR. Fortes 8 , P. Giglio, R. Obadia, R. Diaz, S. Nakane, S. Hort 9 , T. Almeida 10 *Corresponding author: Deise Uema. Bayer SA and Dresden International University. Rua Cancioneiro de Évora, 255 Santo Amaro – Prédio E1 - 1º andar 04708-010 São Paulo - SP – Brasil. Email: deiseu@gmail.com Rest of author’s affiliation at the end of the manuscript. Received December 15, 2017; accepted July 17, 2018; published July 05, 2019. Abstract: Introduction: Osteoarthritis (OA) is an irreversible disease that affects the population worldwide, directly impacting patients’ quality of life, work capacity and daily activities. Nowadays the standard conservative therapy for OA consists of exercise and adjunctive medication, however drug arsenal for management of pain is very limited. Duloxetine is an effective treatment for chronic pain, and we hypothesized that Duloxetine would have a synergistic effect with exercise, improving pain in addition to mood symptoms when compared to exercise alone. Methods: This is going to be 12-week multicentre, double-blind, placebo-controlled, randomized trial that will evaluate pain improvement in patients with radiologically confirmed knee OA and moderate to severe OA in WOMAC pain subscale score treated with Duloxetine + exercise in comparison to Placebo + exercise. During the study period, besides Duloxetine/placebo intake, patients will be asked to perform a set of exercises three times a week (one supervised session at the site; two home-based sessions with the assistance of a program in Wii and Better Knee App in Apple Watch). Outcomes: It is expected that patients receiving Duloxetine+exercise will have a 40% improvement in pain (assessed through WOMAC score) compared to placebo+exercise group. Secondary outcomes include impact in quality of life (i.e. EQ-5D-5L questionnaire: mobility, self-care, usual activities, pain/discomfort, anxiety/depression), and frequency of use of rescue drugs for pain. Exploratory endpoints will include the rate of adherence to study interventions and rate of treatment discontinuation. Final analysis of outcomes will be performed once all patients have reached week 13 and data collection is closed. If our hypothesis is confirmed, Duloxetine can turn into another effective option for management of OA pain, possibly delaying and/or avoiding surgery in this population and reducing healthcare related costs. Keywords: Knee osteoarthritis, Duloxetine, WOMAC score, Double-blind, Placebo control, Better Knee App. DOI: http://dx.doi.org/10.21801/ppcrj.2019.51.2 INTRODUCTION Osteoarthritis (OA) is a prevalent chronic musculoskeletal disorder affecting the population worldwide, predominantly the elderly (WHO, 2007). It is included in the World Health Organization's (WHO) list of chronic rheumatic conditions with the greatest impact on society (Laupattarakasem et al., 2008). Studies have found a prevalence ranging from 15.4% to 19.6% (Kim et al., 2014; Allena & Golightly, 2015) for symptomatic knee OA in individuals over 60 years of age and it is estimated that by 2050, 40 million will be severely disabled (WHO, 2017). A common symptom of OA is pain due to loss of bone joint function. This is result of an early fragmentation of the cartilage surface, variable crystal deposition, remodeling and violation of the tidemark by blood vessels Study Design Vol. 5, No. 1 / Jan-Jun 2019 /p. 08-13/ PPCR Journal