The Patient-Centered Trial Paradigm For Knee Osteoarthritis

By Katie Mowry, Ph.D., vice president, R&D, Organogenesis

Patient-centered trials that prioritize validated patient-reported outcomes (PROs) are essential for evaluating the real-world impact of new therapies. That’s especially true for those with knee osteoarthritis (OA), a degenerative joint disease affecting roughly 30 million Americans that is among the most common causes of adult disability. The burden is profound for patients with persistent pain, impaired function, and often reduced participation in the things they enjoy doing. For physicians and the health system, there are repeated patient encounters, escalating resource use and downstream surgical demand.

However, PROs introduce analytic and operational complexities that differ from those of more straightforward structural or radiographic metrics. And while that might be challenging, it’s essential that a trial’s design reflects patients’ true knee OA challenges to produce meaningful evidence for patients, clinicians, and policymakers.

Where Standard Of Care Falls Short

Most patients with knee OA navigate a lengthy nonsurgical pathway, often spanning a decade or more, seeking pain relief and preservation of function before moving to surgery.¹ Conservative measures include modification of activities, bracing, physical therapy, weight management, and pharmacologic options such as oral and topical NSAIDs, acetaminophen, and, in some cases, limited short-term use of opioids. Intra-articular interventions, including corticosteroid injections, hyaluronic acid viscosupplementation, and various orthobiologic approaches, are also utilized as patients fail to respond adequately to conservative interventions. However, analgesic benefits are usually modest and short-lived, with reported risk around repeated corticosteroid injections. The evidence for hyaluronic acid and platelet-rich plasma injections varies based on a number of factors, with treatment recommendations differing among guidelines. These limitations leave a substantial treatment gap for patients who need clinically meaningful pain reduction and functional improvement without the risks of long-term pharmaceuticals or who are not ready for surgery.

Radiographic severity is commonly classified using the Kellgren–Lawrence (KL) grading scale (0–4). For individuals who progress to KL-4, the most severe category, nonsurgical options frequently fail to provide adequate and sustained relief, leaving total knee arthroplasty (TKA) as the only viable option. Younger patients are known to face higher rates of residual symptoms, periprosthetic joint infection, and mechanical failure. For these patients, survivorship data suggest a substantial lifetime risk of at least one revision, based on 25-year survivorship data, and they are often advised to delay TKA as long as possible.^2,3 Many others either do not want major surgery or are not candidates for TKA because of medical frailty, obesity, age, activity level, or comorbidities. The result is a sizable population living with pain and functional impairment, with few treatment options and significant consequences for their quality of life and productivity.

Trials Must Reflect Patients’ Realities

There is a critical need for treatment innovations to address knee OA pain. Because patient experiences will vary among individuals, clinical trials should be designed around patients' outcomes and experiences, capturing pain improvements through validated PROs as the primary endpoint. Structural progression and radiographic grades are important, but pain has been reported to not correlate linearly with imaging findings.⁴ Capturing what patients feel and can do, and how that improves over time, requires validated measurement tools, such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), knee injury and osteoarthritis outcome score (KOOS), and visual analog scale (VAS). When trial endpoints are designed and anchored in the patient experience, studies better reflect clinical reality and inform decisions that matter to both patients and clinicians.

Trial designs for OA demand rigor, in part due to the varying and multifactorial nature of pain. For example, studies have shown intra-articular saline placebo injection can yield a statistically and clinically meaningful improvement in PROs up to six months after the injection in patients with knee OA.⁵ Placebo response, expectation effects, rescue analgesic use, daily fluctuations, and comorbid conditions can confound outcomes if not addressed prospectively. Robust design elements include adequate randomization and blinding, stratification by KL grade, frequent and standardized PRO assessments, endpoint strategies that integrate pain and function, and careful management of rescue medications. This level of rigor allows PROs to serve as dependable, clinically meaningful measures rather than anecdotal reports.

New Treatments Needed — But Only If They Address Patients’ Pain

Organogenesis is developing ReNu, a cryopreserved amniotic suspension allograft (ASA), for the management of symptoms associated with knee OA. The processing of ReNu is designed to preserve and deliver cells and matrix components rich in growth factors, cytokines, and anti-inflammatory factors native to the amniotic tissue. This type of regenerative therapy has the potential to provide symptom relief and sustain function to help patients maintain activity and delay the need for TKA, particularly for those with advanced disease who lack viable treatment alternatives. Importantly, the primary endpoint for two Phase 3 trials for patients with KL2 through KL4 evaluates the difference between the ReNu and saline control groups in the reduction of knee OA pain at six months, assessed by the WOMAC pain scale.

By designing studies that fit patients’ knee OA experience, representing the full spectrum of severity of diseases, and elevating patient outcomes including pain and function, the field can close the treatment gap and bring meaningful relief to patients. It is essential to elevate PROs wherever possible and continue to have those linked to the principal signal of therapeutic value in the development paradigm.

References:

1. Losina 2015.
2. J. T. Evans, R. W. Walker, J. P. Evans, A. W. Blom, A. Sayers, and M. R. Whitehouse, “How long does a knee replacement last? A systematic review and meta-analysis of case series and national registry reports with more than 15 years of follow-up,” The Lancet, vol. 393, no. 10172, 2019, doi: 10.1016/s0140-6736(18)32531-5.
3. J. Parvizi et al., “High level of residual symptoms in young patients after total knee arthroplasty knee,” in Clinical Orthopaedics and Related Research, 2014. doi: 10.1007/s11999-013-3229-7.
4. John Bedson, Peter R. Croft, “The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature.” BMC Musculoskeletal Disorders 2008 Sep 2;9:116.
5. Saltzman BM, Leroux T, Meyer MA, Basques BA, Chahal J, Bach BR Jr, Yanke AB, Cole BJ., “The Therapeutic Effect of Intra-articular Normal Saline Injections for Knee Osteoarthritis: A Meta-analysis of Evidence Level 1 Studies. The American Journal of Sports Medicine. 2017 Sep;45(11):2647-2653.

About The Author:

Katie Mowry, Ph.D., is the vice president, R&D, at Organogenesis.