NSAIDs for Knee Osteoarthritis

Overseen By Thomas J Schnitzer, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Northwestern University

Must not be taking: Oral anticoagulants, Heparin

Disqualifiers: NSAID allergy, GI bleed, Renal insufficiency, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of naproxen, a common pain reliever, for individuals with painful knee osteoarthritis. Participants will receive both naproxen and a placebo (a dummy pill) at different times to assess their impact on knee pain. It suits those with knee osteoarthritis who regularly experience moderate pain and use medication for knee pain at least four days a week. As a Phase 4 trial, this research aims to understand how the already FDA-approved treatment benefits more patients, offering participants a chance to contribute to broader knowledge about managing knee osteoarthritis.

Do I have to stop taking my current medications for the trial?

Yes, you must be willing to discontinue current medications taken for osteoarthritis pain to participate in the trial.

Will I have to stop taking my current medications?

Yes, you will need to stop taking your current medications for osteoarthritis pain to participate in this trial.

What is the safety track record for naproxen?

Research shows that naproxen, a common pain reliever, is generally safe for treating pain. Studies have found that people taking naproxen experienced more pain relief than those taking a placebo, which contains no active medicine. However, like all medications, it can have side effects. One study found that long-term use of naproxen might worsen knee osteoarthritis. Another analysis showed that NSAIDs, including naproxen, had a 29.8% higher chance of causing side effects, such as stomach upset or heart issues. Overall, naproxen is well-tolerated for short-term use, but it's important to be aware of potential risks with long-term use. Always consult a healthcare provider before starting any new treatment. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Most treatments for knee osteoarthritis, like ibuprofen and acetaminophen, primarily focus on pain relief without altering the progression of the condition. However, researchers are excited about naproxen because it belongs to the class of NSAIDs (nonsteroidal anti-inflammatory drugs), which not only provide pain relief but also reduce inflammation, potentially offering more comprehensive symptom management. Unlike some other treatments, naproxen is well-known for its longer-lasting effects, which means it may need to be taken less frequently, potentially improving patient adherence. This makes naproxen a promising option for people seeking both pain relief and reduced inflammation in managing knee osteoarthritis.

What is the effectiveness track record for naproxen in treating knee osteoarthritis?

Research has shown that naproxen, a common pain reliever, reduces pain and improves movement in people with osteoarthritis. In this trial, participants will receive both naproxen and a placebo in a cross-over design. One study found that participants experienced less pain and better physical function compared to those taking a placebo, with many rating the treatment as "good." Another study found that Aleve®, a brand of naproxen, provided significant pain relief, especially for those aged 65 and older. Overall, strong evidence supports naproxen's effectiveness in managing knee osteoarthritis. ^{1 2 3 4 6}

Who Is on the Research Team?

Thomas Schnitzer

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

This trial is for men and women over 40 with painful knee osteoarthritis, experiencing moderate pain levels. Participants must be willing to stop current OA pain medications, use birth control if applicable, maintain any non-drug therapies stable, and have access to a cellphone or computer for eDiary entries.

Inclusion Criteria

eDiary entries on at least 4 out 7 days per week during the observation period

I have been diagnosed with knee osteoarthritis.

I am over 40 years old.

Exclusion Criteria

My back pain is worse than my arthritis pain.

I have had a nerve ablation for knee pain.

I haven't had any biological injections in the affected area in the last year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a 4-period double-cross-over design with 2 weeks of treatment with either naproxen or placebo, followed by 2 weeks of washout, repeated 4 times

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Naproxen
• Placebo

Trial Overview The study tests the effectiveness of Naproxen (an NSAID) against a placebo in managing knee osteoarthritis pain. It's designed as a pilot with four periods where participants switch between treatments and placebos without knowing which they're receiving.

How Is the Trial Designed?

Group I: Cross-over Treatment: Initial treatment with placebo Experimental Treatment 2 Interventions

There will be a 4 period cross-over: 2 weeks of treatment with IP, followed by 2 weeks of washout, and this repeated 3 more times. Treatment will be such that all participants will receive 2 treatment periods with naproxen and 2 treatment periods with placebo. The order of treatment will be randomized and the treatment allocation and IP will be blinded.

Group II: Cross-over Treatment: Initial treatment with naproxen Experimental Treatment 2 Interventions

There will be a 4 period cross-over: 2 weeks of treatment with IP, followed by 2 weeks of washout, and this repeated 3 more times. Treatment will be such that all participants will receive 2 treatment periods with naproxen and 2 treatment periods with placebo. The order of treatment will be randomized and the treatment allocation and IP will be blinded.

Naproxen is already approved in United States, Canada, European Union, United Kingdom for the following indications:

Approved in United States as Naprosyn for:

• Painful knee osteoarthritis
• Arthritis
• Menstrual pain
• Muscle and joint inflammation
• Gout

Approved in United States as Aleve for:

• Pain relief
• Fever reduction
• Headache

Approved in Canada as Naprelan for:

• Painful knee osteoarthritis
• Arthritis
• Menstrual pain

Approved in European Union as Naprosyn for:

• Painful knee osteoarthritis
• Arthritis
• Menstrual pain
• Muscle and joint inflammation
• Gout

Approved in United Kingdom as Feminax Ultra for:

• Primary dysmenorrhoea

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

Published Research Related to This Trial

In a 12-week clinical trial involving 374 patients with active knee osteoarthritis, aceclofenac (100 mg twice daily) was found to be as effective as naproxen (500 mg twice daily) in reducing pain and improving knee function, with 76-86% of aceclofenac patients reporting pain reduction.

Aceclofenac demonstrated better tolerability than naproxen, with fewer adverse effects (12.6% vs. 16.3%), particularly in terms of gastrointestinal side effects, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aceclofenac is a well-tolerated alternative to naproxen in the treatment of osteoarthritis. Kornasoff, D., Frerick, H., Bowdler, J., et al.[2019]

In a study involving 347 patients with knee osteoarthritis, Naprelan (1,000 mg once daily) was found to be equally effective as Naprosyn (500 mg twice daily) in reducing symptoms, with both showing significant benefits over placebo after 12 weeks.

Naprelan had a better safety profile, as it did not show a significant increase in adverse events compared to placebo, while Naprosyn was associated with more drug-related adverse events, particularly gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of Naprelan and Naprosyn in the treatment of osteoarthritis of the knee. Schiff, MH.[2013]

In a study involving 367 Asian patients with knee osteoarthritis, celecoxib was found to be as effective as naproxen in reducing pain, with both treatments showing significant improvements compared to placebo.

Celecoxib demonstrated a better safety profile, with a lower incidence of treatment-related adverse events (13%) compared to naproxen (24%), indicating it is a well-tolerated option for managing knee OA in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nonsteroidal anti-inflammatory drugs in Asian patients with knee osteoarthritis: summary of a randomized, placebo-controlled study. Essex, MN., O'Connell, MA., Behar, R., et al.[2022]

In a study of 307 patients over 12 weeks, tenoxicam demonstrated a lower incidence of adverse events (29.0%) compared to ketoprofen (47.3%), indicating it may be a safer option for treating osteoarthritis.

Both tenoxicam and ketoprofen showed similar efficacy in managing osteoarthritis symptoms, with no significant differences in overall treatment outcomes, suggesting that tenoxicam offers a favorable balance of effectiveness and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised double-blind multicentre trial comparing tenoxicam and ketoprofen in osteoarthritis. Ejstrup, L., Knudsen, JV., Petersen, L.[2019]

In a clinical trial involving 600 patients with knee osteoarthritis, celecoxib (200 mg daily) was found to be as effective as diclofenac (150 mg daily) in relieving pain and symptoms, with both medications showing significant improvement compared to placebo.

Celecoxib demonstrated a superior safety profile, with fewer gastrointestinal side effects and no significant elevations in liver enzymes or reductions in hemoglobin levels, which were observed in patients taking diclofenac.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celecoxib versus diclofenac in the management of osteoarthritis of the knee. McKenna, F., Borenstein, D., Wendt, H., et al.[2022]

In a 6-month study involving 586 patients with knee osteoarthritis, celecoxib showed similar efficacy to naproxen, with 52.7% of celecoxib patients achieving a significant improvement in symptoms compared to 49.7% for naproxen.

Celecoxib was associated with significantly fewer gastrointestinal side effects, with only 4.1% of patients discontinuing treatment due to these issues, compared to 15.1% for those taking naproxen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of celecoxib versus naproxen in patients with osteoarthritis of the knee: a randomized, double-blind, double-dummy trial. Essex, MN., Bhadra, P., Sands, GH.[2022]

In a six-week study involving 85 patients with osteoarthritis, Flurbiprofen-SR 200 mg showed similar efficacy to Diclofenac Sodium-SR 100 mg, with no significant differences in treatment outcomes.

Both medications had comparable tolerability and safety profiles, as there were no significant differences in adverse events or treatment terminations between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-blind randomized controlled trial of flurbiprofen-SR (ANSAID-SR) and diclofenac sodium-SR (Voltaren-SR) in the treatment of osteoarthritis. Bellamy, N., Bensen, WG., Ford, PM., et al.[2013]

Topical NSAIDs are effective for treating knee and hand osteoarthritis as well as acute musculoskeletal pain, and they are recommended in various clinical guidelines due to their efficacy and safety profile.

These medications have fewer systemic side effects compared to oral NSAIDs, making them a preferable first option, especially for patients who cannot take oral NSAIDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Topical NSAIDs: ineffective or undervalued?] van Herwaarden, N., van den Elsen, GAH., de Jong, ICA., et al.[2021]

In a 53-week study involving 1,020 patients with knee osteoarthritis, both doses of naproxcinod (375 mg and 750 mg) showed significantly greater improvements in pain and function compared to placebo at 13 weeks.

Naproxcinod 750 mg was found to be as effective as naproxen 500 mg, indicating it is a viable alternative for treating osteoarthritis, and it was well tolerated with no significant safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of naproxcinod in patients with osteoarthritis of the knee: a 53-week prospective randomized multicenter study. Schnitzer, TJ., Hochberg, MC., Marrero, CE., et al.[2013]

In a study involving 444 patients with knee osteoarthritis, both naproxen sodium (660 mg and 440 mg for older patients) and ibuprofen (1200 mg) were found to significantly relieve pain compared to placebo, with naproxen showing a greater reduction in symptoms overall.

Naproxen sodium was particularly effective for night-time pain relief and improved all assessed symptoms compared to placebo, while both medications had similar safety profiles with no significant differences in adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the analgesic efficacy and safety of nonprescription doses of naproxen sodium and Ibuprofen in the treatment of osteoarthritis of the knee. Schiff, M., Minic, M.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8506236/

Effectiveness and safety of non-steroidal anti-inflammatory ... Etoricoxib 60 mg/day and diclofenac 150 mg/day seem to be the most effective oral NSAIDs for pain and function in patients with osteoarthritis.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29394869/

Analgesic efficacy and safety of non-prescription doses ... Results: Compared with placebo, there were significant improvements in pain and physical function with naproxen sodium (p < .05), and treatment was rated "good" ...

3. nature.com nature.com/articles/s41598-024-56665-3

Association of long-term use of non-steroidal anti ... At the 4-to-5-year follow-up, compared to non-users, long-term NSAID users had an increase in adjusted mean pain score of 3.95 (95% confidence ...

4. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0320379

Assessing the efficacy and safety of different nonsteroidal anti ... The NMA results showed that compared with the placebo, the WOMAC pain score in KOA patients significantly decreased after interventions with Etoricoxib, ...

5. aleve.com aleve.com/healthcare-professionals/efficacy-and-pain-guidelines/osteoarthritis-pain

Osteoarthritis Pain Studies and Guidelines Aleve® provided significant pain relief across all efficacy endpoints (P<0.05) · Aleve® also provided significantly greater pain relief§ for patients ≥65 years ...

6. rheumatologyadvisor.com rheumatologyadvisor.com/news/effectiveness-safety-of-nsaids-and-opioids-for-osteoarthritis-pain-determined-in-meta-analysis/

Effectiveness, Safety of NSAIDs and Opioids for ... In the safety analysis, oral NSAIDs and opioid interventions had 29.8% and 89.5% increased risk for any adverse event, respectively. Opioid and ...