Toward designing human intervention studies to prevent osteoarthritis after knee injury: A report from an interdisciplinary OARSI 2023 workshop

Jackie L Whittaker; Raneem Kalsoum; James Bilzon; Philip G Conaghan; Kay Crossley; George R Dodge; Alan Getgood; Xiaojuan Li; Elena Losina; Deborah J Mason; Brian Pietrosimone; May Arna Risberg; Frank Roemer; David Felson; Adam G Culvenor; Duncan Meuffels; Nicole Gerwin; Lee S Simon; L Stefan Lohmander; Martin Englund; Fiona E Watt

doi:10.1016/j.ocarto.2024.100449

Toward designing human intervention studies to prevent osteoarthritis after knee injury: A report from an interdisciplinary OARSI 2023 workshop

Osteoarthr Cartil Open. 2024 Feb 23;6(2):100449. doi: 10.1016/j.ocarto.2024.100449. eCollection 2024 Jun.

Authors

Jackie L Whittaker^{1

2}, Raneem Kalsoum³, James Bilzon^{4

5}, Philip G Conaghan^{6

7}, Kay Crossley⁸, George R Dodge^{9

10}, Alan Getgood¹¹, Xiaojuan Li^{12

13}, Elena Losina^{14

15}, Deborah J Mason¹⁶, Brian Pietrosimone¹⁷, May Arna Risberg^{18

19}, Frank Roemer^{20

21}, David Felson²², Adam G Culvenor⁸, Duncan Meuffels²³, Nicole Gerwin²⁴, Lee S Simon²⁵, L Stefan Lohmander²⁶, Martin Englund²⁷, Fiona E Watt^{3

28}

Affiliations

¹ Department of Physical Therapy, University of British Columbia, Vancouver, Canada.
² Arthritis Research Canada, Vancouver, Canada.
³ Department of Immunology and Inflammation, Imperial College London, London, UK.
⁴ Department for Health, University of Bath, Bath, UK.
⁵ Centre for Sport, Exercise and Osteoarthritis Research Versus Arthritis, UK.
⁶ Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
⁷ NIHR Leeds Biomedical Research Centre, Leeds, UK.
⁸ La Trobe Sport and Exercise Medicine Research Centre, School of Allied Health, Human Services and Sport, La Trobe University, Melbourne, Australia.
⁹ Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Mechano Therapeutics LLC, Philadelphia, PA, USA.
¹¹ Division of Orthopedic Surgery, Bone and Joint Institute, Fowler Kennedy Sport Medicine Clinic, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
¹² Program of Advanced Musculoskeletal Imaging (PAMI), Cleveland Clinic, OH, USA.
¹³ Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, OH, USA.
¹⁴ Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, USA.
¹⁵ Department of Orthopedic Surgery, Harvard Medical School, Boston, USA.
¹⁶ Biomechanics and Bioengineering Research Centre Versus Arthritis, School of Biosciences, Cardiff University, Cardiff, UK.
¹⁷ Department of Exercise and Sport Science, University of North Carolina, USA.
¹⁸ Norwegian School Sport Sciences, Oslo, Norway.
¹⁹ Division of Orthopedic Surgery, Oslo University Hospital, Oslo, Norway.
²⁰ Department of Radiology, Universitätsklinikum Erlangen & Friedrich- Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
²¹ Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA.
²² Section of Rheumatology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
²³ Orthopedic and Sport Medicine Department, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
²⁴ Novartis BioMedical Research, Basel, Switzerland.
²⁵ SDG LLC, Cambridge, MA, USA.
²⁶ Department of Clinical Sciences Lund, Orthopaedics, Lund University, Lund, Sweden.
²⁷ Department of Clinical Sciences Lund, Orthopaedics, Clinical Epidemiology Unit, Lund University, Lund, Sweden.
²⁸ Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, University of Oxford, UK.

Abstract

Objective: The global impact of osteoarthritis is growing. Currently no disease modifying osteoarthritis drugs/therapies exist, increasing the need for preventative strategies. Knee injuries have a high prevalence, distinct onset, and strong independent association with post-traumatic osteoarthritis (PTOA). Numerous groups are embarking upon research that will culminate in clinical trials to assess the effect of interventions to prevent knee PTOA despite challenges and lack of consensus about trial design in this population. Our objectives were to improve awareness of knee PTOA prevention trial design and discuss state-of-the art methods to address the unique opportunities and challenges of these studies.

Design: An international interdisciplinary group developed a workshop, hosted at the 2023 Osteoarthritis Research Society International Congress. Here we summarize the workshop content and outputs, with the goal of moving the field of PTOA prevention trial design forward.

Results: Workshop highlights included discussions about target population (considering risk, homogeneity, and possibility of modifying osteoarthritis outcome); target treatment (considering delivery, timing, feasibility and effectiveness); comparators (usual care, placebo), and primary symptomatic outcomes considering surrogates and the importance of knee function and symptoms other than pain to this population.

Conclusions: Opportunities to test multimodal PTOA prevention interventions across preclinical models and clinical trials exist. As improving symptomatic outcomes aligns with patient and regulator priorities, co-primary symptomatic (single or aggregate/multidimensional outcome considering function and symptoms beyond pain) and structural/physiological outcomes may be appropriate for these trials. To ensure PTOA prevention trials are relevant and acceptable to all stakeholders, future research should address critical knowledge gaps and challenges.

Keywords: Knee; Osteoarthritis; Post-traumatic osteoarthritis; Prevention; Randomised controlled trials; Trial design.