Evaluation of Naproxen Sodium on Synovial Fluid Cytokine Levels and Clinical Outcomes in Knee Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Trial
- Trial ID
- 2023-505875-56-00
- Protocol
- KCT23/2022-ZOOM-IN
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the effect of **naproxen sodium** therapy on the synovial fluid concentration of **Interleukin-6 (IL-6)** after 14 days of treatment, compared to placebo, in patients with knee osteoarthritis. This is clinically relevant as IL-6 is a pro-inflammatory cytokine implicated in the pathophysiology of osteoarthritis, and its modulation could potentially alleviate symptoms and improve joint function.
Secondary objectives include assessing the effect of treatment on synovial fluid concentration of **TNF-α** and **IL-1β**, and evaluating the correlation between naproxen concentration in synovial fluid and cytokine concentrations (IL-6, TNF-α, IL-1β) after a 2-week treatment with naproxen sodium. The trial will also assess the impact of treatment on clinical outcomes such as pain, stiffness, physical function, and quality of life, as well as evaluate the synovial membrane penetration index of naproxen in patients with knee osteoarthritis.
Participants
The clinical trial focuses on **knee osteoarthritis** and involves both male and female participants aged 40 years and older. The study population includes individuals diagnosed with primary osteoarthritis, specifically those with disease severity classified as grade III or IV according to the Kellgren-Lawrence classification. Participants are required to have an average pain intensity of 6 or less in the affected knee joint over the last 24 hours, as measured by a numeric rating scale. Additionally, an ultrasound examination must confirm the presence of sufficient synovial fluid for withdrawal. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are expected to adhere to the trial protocol and have successfully undergone arthrocentesis with at least 1ml of synovial fluid obtained without visible blood. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the effects of **naproxen sodium** on synovial fluid cytokine concentrations and clinical outcomes in patients with knee osteoarthritis. This study is a randomized, double-blind, placebo-controlled, parallel, multicenter trial. The primary objective is to assess the effect of naproxen sodium therapy on the synovial fluid concentration of Interleukin-6 (IL-6) after 14 days of treatment compared to placebo. The trial is expected to commence recruitment on September 2, 2024, and conclude by February 28, 2025.
Participants will be randomly assigned to receive either **Nalgesin Forte** (550 mg film-coated tablets) or a placebo. The trial will involve several key visits: an initial screening visit, a baseline visit, follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be confirmed based on criteria such as age (≥40 years), diagnosis of primary osteoarthritis with a severity grade of III or IV, and the presence of synovial fluid in the knee joint. Successful arthrocentesis with at least 1 ml of synovial fluid is required at Visit 2.
The trial duration for each participant is approximately 14 days, with the possibility of early termination if adverse events occur or if the participant is unable to adhere to the trial protocol. The primary endpoint is the mean change from baseline in IL-6 concentration in synovial fluid after the treatment period. Secondary endpoints include changes in TNF-α and IL-1β concentrations, as well as various subscales of the KOOS score, which assess pain, symptoms, function, and quality of life. Correlations between naproxen concentration in synovial fluid and these endpoints will also be evaluated.
Treatment
The clinical trial involves the administration of **Nalgesin Forte**, a film-coated tablet containing **naproxen sodium** as the active ingredient. Each tablet contains 550 mg of naproxen sodium, and the medication is administered orally. The maximum daily dose is 1100 mg, with a total maximum dose of 22000 mg over a treatment period of 20 days. The pharmaceutical form is a film-coated tablet, and the product is manufactured by KRKA, D.D., Novo Mesto. The trial aims to evaluate the effects of naproxen sodium on synovial fluid cytokine levels and clinical outcomes in patients with knee osteoarthritis.
In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled trial. The placebo is designed to mimic the appearance of Nalgesin Forte but does not contain any active pharmaceutical ingredients. The placebo is administered in the same manner as the experimental drug to maintain blinding and ensure the integrity of the study results.
**Paracetamol Biofarm**, a 500 mg tablet, is included as an auxiliary treatment. This medication is administered orally, with a maximum daily dose of 4000 mg and a total maximum dose of 68000 mg over a 17-day period. Paracetamol is a well-known analgesic and antipyretic agent, and its inclusion in the study serves to provide standard-of-care therapy for pain management. The product is manufactured by BIOFARM SP. Z O.O. and is chemically derived.
Efficacy
The clinical trial aims to assess the efficacy of **naproxen sodium** therapy in patients with knee osteoarthritis by evaluating changes in specific biomarkers and clinical outcomes. The primary endpoint is the mean change from baseline in the concentration of Interleukin-6 (IL-6) in synovial fluid after a 2-week treatment period with naproxen compared to placebo. Secondary endpoints include the mean change from baseline in the concentrations of TNF-α and IL-1β in synovial fluid, as well as various subscales of the Knee injury and Osteoarthritis Outcome Score (KOOS), which assess pain, symptoms, function in daily living, function in sports and recreational activities, and quality of life.
Efficacy parameters will be measured and collected at baseline and after the 2-week treatment period. The analysis will involve comparing the changes in these parameters between the naproxen and placebo groups. The correlation between naproxen concentration in synovial fluid and the concentrations of cytokines (IL-1β, IL-6, and TNF-α) will also be evaluated, along with the correlation between naproxen concentration and the KOOS subscale scores. Additionally, the synovial membrane penetration index of naproxen will be determined. These assessments will provide comprehensive insights into the therapeutic effects of naproxen sodium in the context of knee osteoarthritis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Female or male patients, aged ≥40 years.
- Patients diagnosed with primary osteoarthritis with disease severity grade III or IV according to the Kellgren-Lawrence classification.
- Average intensity of pain in investigated knee joint ≤6 in last 24h on numeric rating scale (NRS).
- Ultrasound examination of investigated knee, that confirms presence of synovial fluid in sufficient amount for withdrawal of at least 1ml of synovial fluid.
- Patients who have been provided with information about the trial and have voluntarily signed the informed consent.
- Patients who have signed the consent for collection, analysis and processing of personal data, that will be collected during this clinical trial for the purpose of statistical analysis and final report of this clinical trial.
- Patients with ability to adhere to the trial protocol according to the investigator’s judgement.
- Successfull arthrocentesis of the investigated knee on Visit 2 with at least 1ml of obtained synovial fluid in which no visible blood is present.
Exclusion Criteria
- Active chronic painful conditions apart from osteoarthritis.
- History of surgical treatment of the investigated knee joint.
- Intra-articular treatment with corticosteroids or hyaluronic acid within 6 months prior to Visit 1.
- Current treatment or treatment within 3 months prior to Visit 1 with corticosteroids in any of pharmaceutical form or indomethacin.
- Rheumatoid arthritis based on physical examination and laboratory data.
- Hypersensitivity or intolerance to naproxen or paracetamol or any excipient of the Tested Investigational Medicinal Product (TIMP) or placebo, rescue medicine (RM) or to salicylates and other non–steroidal anti-inflammatory drug (NSAID) and anti-rheumatic drugs manifested as bronchial asthma, urticaria and rhinitis.
- Bleeding disorders (e.g., haemophilia or other blood clotting or haemostatic disorder, cerebrovascular bleeding within last 6 months).
- Disturbances of bone marrow function (e.g., after treatment with cytostatic medicinal products) or haematopoietic disorders.
- Medications that may interfere with pain perception or inflammation: all analgesics other than TIMP and RM, all antihistamines and corticosteroids in any of pharmaceutical form.
- Medications that could confound the evaluation of pain relief (anti-epileptics, benzodiazepines, pregabalin and antidepressants (Selective Serotonin Reuptake Inhibitors (SSRIs) are allowed if dose is stable for > 3 months before Visit 1).
- Medications that may increase the risk of nephrotoxicity: cyclosporin, tacrolimus.
- Medications that may increase the risk of bleeding such as: anticoagulants, antiplatelets (except low dose aspirin for cardioprotection), thrombolytics.
- Medications that may increase the risk of hepatotoxicity and hematoxicity: myelotoxic drugs.
- Medications whose plasma concentration will be affected: probenecid, methotrexate (reduced clearance), phenytoin, chloramphenicol.
- Known presence or history within the past 2 years of gastrointestinal ulcer, gastrointestinal bleeding, or gastrointestinal complaint related to previous NSAID treatment or congestive or atrophic gastritis.
- Inflammatory bowel disease.
- Any acute cardiovascular or cerebrovascular event within the last six months.
- Haemodynamically unstable heart failure after acute myocardial infarction, congestive heart failure, severe heart failure (NYHA class III and IV) or postoperative period of ≤ 3 months after coronary bypass grafting.
- Renal impairment (GFR <45 mL/min/1.73 m2) , progressive kidney disease, confirmed hyperkalemia (above max. reference value) that is clinically significant according to ivestigator's opinion.
- Severe liver problems such as cholestasis or biliary obstructive disorders or hepatic encephalopathy or severe hepatic impairment or hepatic encephalopathy or any other severe liver disease.
- Glucose-6-phosphate dehydrogenase deficiency, acute intermittent hepatic porphyria.
- Any serious acute disease with or without subsequent hospitalization within 30 days prior to Visit 1, such as: severe local or systemic infection, exacerbation or uncontrolled phase of a chronic disease, major trauma, major surgery (including planned major surgery during the trial involvement), COVID-19, as well as post-COVID-19/long COVID-19 syndromes diagnosed.
- Any serious clinical state that could affect patient safety, protocol compliance or treatment adherence, or have an impact on patient’s short-term survival rate, such as: advanced malignant disease or any other life-threatening illness, excessive chronic alcohol consumption (defined as ≥15 units per week for men or ≥8 units per week for women), heavy smoking (more than 20 cigarettes/day), medicine abuse or addiction, psychoactive substance abuse or addiction, chronic infection with HIV and/or HBV and/or HCV, uncontrolled seizures, uncontrolled psychiatric conditions.
- Significant anaemia with haemoglobin ≤80 g/L.
- Significant thrombocytopenia with platelet count less than < 50x109/L.
- Serum AST and/or ALT and/or total bilirubin of ≥3x ULN.
- Pregnancy or lactation.
- Female of childbearing potential without highly effective contraception (according to the Recommendations related to contraception and pregnancy testing in clinical trials ) or female planning to become pregnant during the trial.
- Patient is currently participating in another clinical trial or has participated in another clinical trial within 30 days prior to the Visit 1.
- Patient is a member of the research team and is actively involved in the trial conduct as such.
- Patient refuses to cooperate with the investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Not Recruiting | 02 Sept 2024 | 38 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Paracetamol Biofarm, 500 mg, tabletki | Other | TABLETKI | ORAL | 4000 | 17 | PRD7394343 |
Placebo - Nalgesin forte | Placebo | N/A | — | — | — | N/A |
Nalgesin Forte, 550 mg, tabletki powlekane | Test | TABLETKI POWLEKANE | ORAL | 1100 | 20 | PRD959742 |