The effects of 2-week long treatment with naproxen sodium (Nalgesin® Forte) on synovial fluid cytokine and naproxen concentration and clinical outcomes in patients with knee osteoarthritis – ZOOM-IN: A randomized, double-blind, placebo-controlled, parallel, multicentre clinical trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

KRKA tovarna zdravil d.d. Novo mesto

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

21 May 2025 → 17 Sep 2025

Decision date (initial)

2024-10-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To assess the effect of naproxen sodium therapy on the synovial fluid (SF) concentration of Interleukin-6 (IL-6), after 14 days of treatment in comparison to placebo in patients with knee osteoarthritis.

Secondary objectives 1

1. To assess the effect of treatment on SF concentration of TNF-α and IL-1β and to asses correlation between naproxen concentration in SF and cytokine (IL-6, TNF-α, IL-1β) concentrations in SF after after 2-week long treatment with naproxen sodium. Clinical trial will asses effect of treatment on clinical outcomes pain, stiffness, physical function and quality of life and asses the synovial membrane penetration index of naproxen in patients with knee osteoarthritis.

Conditions and MedDRA coding

Knee osteoarthritis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Female or male patients, aged ≥40 years.
2. Patients diagnosed with primary osteoarthritis with disease severity grade III or IV according to the Kellgren-Lawrence classification.
3. Average intensity of pain in investigated knee joint ≤6 in last 24h on numeric rating scale (NRS).
4. Ultrasound examination of investigated knee, that confirms presence of synovial fluid in sufficient amount for withdrawal of at least 1ml of synovial fluid.
5. Patients who have been provided with information about the trial and have voluntarily signed the informed consent.
6. 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.
7. Patients with ability to adhere to the trial protocol according to the investigator’s judgement.
8. 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 31

1. Active chronic painful conditions apart from osteoarthritis.
2. History of surgical treatment of the investigated knee joint.
3. Intra-articular treatment with corticosteroids or hyaluronic acid within 6 months prior to Visit 1.
4. Current treatment or treatment within 3 months prior to Visit 1 with corticosteroids in any of pharmaceutical form or indomethacin.
5. Rheumatoid arthritis based on physical examination and laboratory data.
6. 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.
7. Bleeding disorders (e.g., haemophilia or other blood clotting or haemostatic disorder, cerebrovascular bleeding within last 6 months).
8. Disturbances of bone marrow function (e.g., after treatment with cytostatic medicinal products) or haematopoietic disorders.
9. 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.
10. 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).
11. Medications that may increase the risk of nephrotoxicity: cyclosporin, tacrolimus.
12. Medications that may increase the risk of bleeding such as: anticoagulants, antiplatelets (except low dose aspirin for cardioprotection), thrombolytics.
13. Medications that may increase the risk of hepatotoxicity and hematoxicity: myelotoxic drugs.
14. Medications whose plasma concentration will be affected: probenecid, methotrexate (reduced clearance), phenytoin, chloramphenicol.
15. 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.
16. Inflammatory bowel disease.
17. Any acute cardiovascular or cerebrovascular event within the last six months.
18. 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.
19. 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.
20. 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.
21. Glucose-6-phosphate dehydrogenase deficiency, acute intermittent hepatic porphyria.
22. 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.
23. 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.
24. Significant anaemia with haemoglobin ≤80 g/L.
25. Significant thrombocytopenia with platelet count less than < 50x109/L.
26. Serum AST and/or ALT and/or total bilirubin of ≥3x ULN.
27. Pregnancy or lactation.
28. 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.
29. Patient is currently participating in another clinical trial or has participated in another clinical trial within 30 days prior to the Visit 1.
30. Patient is a member of the research team and is actively involved in the trial conduct as such.
31. Patient refuses to cooperate with the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Mean change from baseline in IL-6 concentration in SF after 2-week long treatment in study arm with naproxen compared to study arm with placebo.

Secondary endpoints 14

1. Mean change from baseline in TNF-α concentration in SF after 2-week long treatment in study arm with naproxen compared to study arm with placebo.
2. Mean change from baseline in IL-1β concentration in SF after 2-week long treatment in study arm with naproxen compared to study arm with placebo.
3. Mean change from baseline in pain subscale (P1-P9) KOOS score after 2-week long treatment in study arm with naproxen compared to study arm with placebo.
4. Mean change from baseline in symptoms subscale (S1-S7) KOOS score after 2-week long treatment in study arm with naproxen compared to study arm with placebo.
5. Mean change from baseline in function, daily living subscale (A1-A17) KOOS score after 2-week long treatment in study arm with naproxen compared to study arm with placebo.
6. Mean change from baseline in function, sports and recreational activities subscale (SP1-SP5) KOOS score after 2-week long treatment in study arm with naproxen compared to study arm with placebo.
7. Mean change from baseline in quality of life subscale (Q1-Q4) KOOS score after 2-week long treatment in study arm with naproxen compared to study arm with placebo
8. Correlation between naproxen concetration in SF and cytokine (IL-1β, IL-6 and TNF-α) concentrations in SF after 2-week long treatment in study arm with naproxen.
9. Correlation between naproxen concentration and pain subscale (P1-P9) KOOS score after 2-week long treatment in study arm with naproxen.
10. Correlation between naproxen concentration in SF and symptoms subscale (S1-S7) KOOS score after 2-week long treatment in study arm with naproxen.
11. Correlation between naproxen concentration in SF and function, daily living subscale (A1-A17) KOOS score after 2-week long treatment in study arm with naproxen.
12. Correlation between naproxen concentration in SF and function, sports and recreational activities subscale (SP1-SP5) KOOS score after 2-week long treatment in study arm with naproxen.
13. Correlation of naproxen concentration in SF and quality of life subscale (Q1-Q4) KOOS score after 2-week long treatment in study arm with naproxen.
14. Determination of synovial membrane penetration index of naproxen after 2-week long treatment in study arm with naproxen.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

KRKA tovarna zdravil d.d. Novo mesto

Sponsor organisation

KRKA tovarna zdravil d.d. Novo mesto

Address

Smarjeska Cesta 6

City

Novo Mesto

Postcode

8501

Country

Slovenia

Scientific contact point

Organisation

KRKA tovarna zdravil d.d. Novo mesto

Contact name

Breda Barbič-Žagar

Public contact point

Organisation

KRKA tovarna zdravil d.d. Novo mesto

Contact name

Breda Barbič-Žagar

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications