Randomized Clinical Trial Evaluating
Transdermal Ibuprofen for Moderate to Severe
Knee Osteoarthritis
Authors: Varadi Dr. Gyula 
Published: March 2021

Background: Osteoarthritis is a common condition, typically treated with orally administered analgesics
and non-steroidal anti-inflammatory drugs (NSAIDs). Chronic administration of NSAIDs, serotoninnorepinephrine reuptake inhibitors (SNRIs, i.e., duloxetine), and opioid medications (i.e., tramadole) is
regularly associated with multiple, serious side effects, in part due to the route of administration. Transdermal
delivery of NSAIDs, such as ibuprofen, represents a potentially alternative treatment for this inflammatory
pain condition with a better therapeutic profile.
Objective: Investigate the safety and efficacy of a novel transdermal ibuprofen formulation (VALE®-
ibuprofen) containing 10% ibuprofen, compared to a placebo in a randomized, double-blinded clinical trial,
for clinical improvement in patients with moderate to severe painful osteoarthritis of the knee.
Study Design: A randomized, placebo-controlled, double blind, multi-center Phase 2 clinical trial.
Setting: An academic medical center, and private rheumatology and interventional pain management
practices in Massachusetts and in Switzerland.
Methods: The Phase 2 clinical study included patients with primary osteoarthritis in a single knee joint
with a progression level of moderate to severe based in part on a grade II or III designation according to the
Kellgren and Lawrence classification system. Patients received the corresponding, randomly assigned study
formulation (VALE-ibuprofen or placebo) for application to the target knee at a dose of 2.0 grams of drug
product (200 mg ibuprofen) twice daily for 14 days. The evaluation of the efficacy of the treatments utilized
the widely accepted methods of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis
Index and the Visual Analog Scale (VAS) scores for the patients.
Results: The results indicate that the transdermal VALE-ibuprofen formulation was very well tolerated from
a safety perspective during the 2-week trial and also produced significant, positive clinical improvements
superior to the placebo in all clinical endpoints tested. In particular, the WOMACTotal and WOMACPhysical
Functioning, for the VALE-ibuprofen, were superior compared to the placebo (P = 0.0283 and P = 0.0201,
respectively). Other clinical endpoints including the WOMACPain, WOMACStiffness, and VASResting scores were
superior to those obtained from the placebo group, trending towards statistical significance compared
to placebo (P = 0.0811, 0.1103, and 0.0785, respectively). Based on the Patient and Physician Global
Impression of Change survey, patient satisfaction slightly improved across both groups; however, no
statistical significance was detectable as compared to the baseline.
Limitations: The sample size of 64 subjects in the final data analysis and the lack of including an orally
administered drug group are limitations of this study.
Conclusions: The use of transdermal VALE-ibuprofen has beneficial clinical effects on the pain levels
experienced in some patients with moderate to severe osteoarthritis of the knee as measured by the
WOMAC Osteoarthritis Indices for stiffness, pain, physical function, and total. Visual Analog Scales (VAS)
tests, VASMotion and VASWeight-bearing, again while appeared superior to placebo, were not statistically different
from placebo.
Clinical Trial Registration: NCT01496326
Key words: Ibuprofen, transdermal treatment, VALE-ibuprofen, knee osteoarthritis, Visual Analog Scale,
WOMAC score