Naproxen Versus Placebo as Adjunct Treatment of Cellulitis: A Randomized Controlled Trial (NVP)

Cellulitis is a painful bacterial skin infection commonly seen in Canadian emergency departments. Cellulitis has a negative impact on patients' quality of life and productivity. While this is a bacterial infection, there is evidence inflammation also contributes to the disabling symptoms of pain, redness and swelling. Some studies have suggested that a nonsteroidal anti-inflammatory drug (NSAID) such as naproxen in addition to antibiotics may control inflammation and speed recovery. However, these studies have had too few patients to tell if there is a true benefit.

The investigators are proposing a randomized controlled trial of patients with cellulitis to compare oral naproxen (500 mg twice daily) plus oral antibiotics versus placebo plus oral antibiotics. The investigators will compare the proportion of patients who have an early clinical response (reduction in area of redness ≥20% at 72 hours), cure, treatment failure, adverse events, and hospital admission.

If naproxen proves to be superior to placebo, this simple, low-cost intervention will speed time to recovery with less pain for patients, and may potentially reduce treatment failure and time missed from activities. The results of this trial will help inform future cellulitis treatment guidelines.

Study Overview

• Status: Not yet recruiting
• Conditions: Cellulitis; Infection; Skin Disease, Infectious; Skin and Soft Tissue Infections (SSTIs)
• Intervention / Treatment: Drug: enteric-coated naproxen; Drug: Cephalexin Tablets; Drug: Placebo

Detailed Description

Background and Importance: Cellulitis is a bacterial skin infection that is the 9th most common reason for an emergency department (ED) visit in Canada. This condition is treated with antibiotics; however, most people require rest and time off work due to the disabling symptoms of pain, redness and swelling. Cellulitis results in high healthcare costs and negatively impacts quality of life of affected persons. Although cellulitis is a bacterial infection, there is evidence that inflammation contributes to the symptoms of pain, redness and swelling. While antibiotics are the mainstay of treatment, adjunct non-steroidal anti-inflammatory drugs (NSAIDs) may control inflammation and speed time to recovery. The investigators conducted a meta-analysis which found that adjunct NSAIDs may improve early clinical response; however, these results must be interpreted with caution as the three available trials were small and underpowered. There is no consensus on whether NSAIDs are effective adjunct cellulitis treatments. A large, robust randomized controlled trial is required to evaluate the role of NSAIDs in treating cellulitis.

Goals/Research Aims: The investigators goal is to conduct a patient randomized controlled trial to determine whether naproxen (NSAID) improves outcomes among cellulitis patients receiving antibiotics.

Methods/Approaches/Expertise: Design: The investigators propose a double-blind randomized (1:1) trial of oral naproxen (500 mg twice daily) versus placebo as adjunct treatment to standard antibiotics for patients with cellulitis. Randomization will be stratified by site, age (<65 vs. ≥65 years), and infection location (lower limb vs. other). Setting: EDs of 3 large, tertiary care Canadian hospitals (Ottawa Hospital Civic and General campuses, Montfort Hospital). Subjects: Adults ≥18 years diagnosed with cellulitis and eligible for outpatient oral antibiotics. Interventions: a) Naproxen 500 mg orally twice daily for 7 days, b) placebo twice daily for 7 days. All participants will receive oral cephalexin antibiotic for 7 days. Both naproxen and placebo will be encased in identical capsules, prepared by an external pharmacy. Outcomes: In accordance with Food and Drug Administration recommendations, the primary outcome is early clinical response, defined as reduction of erythema ≥20% from baseline at 72 hours. Secondary outcomes include clinical cure, treatment failure, adverse events, intravenous antibiotic use, and unplanned hospitalization. Sample size: After accounting for 10% attrition, a total of 884 patients will be required to achieve 80% power to detect a 10% absolute increase in clinical response. Data Analysis: The primary analysis will be by intention to treat. The difference in the rate of early clinical response between the two treatment groups will be assessed using Poisson regression.

Expected Outcomes: The investigators have previously demonstrated feasibility by completing a double-blind pilot randomized trial involving ED adult patients with cellulitis comparing two doses of cephalexin antibiotic (N=69 patients enrolled over 6 months at two sites, demonstrating excellent recruitment and follow-up). If naproxen is found to be superior to placebo, this simple, low-cost intervention will speed time to recovery with less pain for patients, and may reduce treatment failure, intravenous antibiotic use, hospitalization, and time missed from work or school.

• Study Type: Interventional
• Enrollment (Estimated): 884
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Krishan Yadav, MD, MSc; Phone Number: 19489 613-798-5555; Email: kyadav@toh.ca
• Study Contact Backup: Name: Gabriel Sandino-Gold, BScHK; Phone Number: 17709 613-798-5555; Email: gsandino@ohri.ca

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1y 4E9
      • The Ottawa Hospital
      • Contact: Krishan Yadav; Phone Number: 613-798-5555; Email: kyadav@toh.ca
      • Contact: Gabriel Sandino-Gold; Email: gsandino@ohri.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• adults (age ≥18 years) diagnosed with cellulitis and determined by the treating physician to be eligible for outpatient treatment with oral cephalexin.

Exclusion Criteria:

• These are appropriate exclusions according to eligibility for treatment with naproxen in clinical practice, and we believe that relatively few patients will be excluded. We will exclude participants for any of the following reasons: (a) Age <18 years; (b) Patient already taking oral antibiotics or NSAIDs; (c) Treating physician decides IV antibiotics are required; (d) Skin abscess requiring incision and drainage; (e) Known prior skin or soft tissue infection secondary to methicillin-resistant Staphylococcus aureus (MRSA); (f) Cellulitis secondary to a human or animal bite; (g) Penetrating wound or water exposure resulting in cellulitis; (h) Surgical site infection; (i) Pregnancy or breastfeeding; (j) Prior gastric bypass surgery; (k) Patients on dual antiplatelet therapy; (l) Patients on warfarin, low molecular weight heparin, or direct oral anticoagulant therapy; (m) Severe uncontrolled heart failure, or coronary artery bypass grafting (CABG) surgery within 14 days prior to the index visit, or planned CABG surgery within 21 days following the index visit.; (n) History of gastric/duodenal ulcer or gastrointestinal bleeding in the past 12 months; (o) Known kidney impairment with an estimated glomerular filtration rate <30 mL/min documented on the electronic health record at any time within the past three months; (p) Known hyperkalemia documented on the electronic health record at any time within the past three months; (q) Liver cirrhosis; (r) Inflammatory bowel disease; (s) History of asthma, urticaria or allergic reactions after taking NSAIDs or aspirin; (t) Allergy to cephalosporins or history of anaphylaxis to penicillin; (u) Inability to provide informed consent.

Exclusion criteria (i) through (s) are known contraindications to NSAIDs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Naproxen + Cephalexin; seven-day medication package of naproxen 500 mg to be taken orally twice daily plus cephalexin antibiotic 500 mg four times daily.	Drug: enteric-coated naproxen; 500 mg naproxen PO BID for 7 days; Other Names: naproxen; naproxen EC; Drug: Cephalexin Tablets; 500 mg PO QID for 7 days; Other Names: Cephalexin
Active Comparator: Placebo + Cephalexin; seven-day medication package of placebo to be taken orally twice daily plus cephalexin antibiotic 500 mg four times daily.	Drug: Cephalexin Tablets; 500 mg PO QID for 7 days; Other Names: Cephalexin; Drug: Placebo; Placebo tablets PO BID x 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Early Clinical Response	Defined as a reduction in lesion size ≥20% compared to baseline	within 72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with medication adherence	with full adherence defined as patients who report taking all study medication over 7 days	7 days
Number of Participants with Oral antibiotic treatment failure	Defined as a change in antibiotic (change in class of oral antibiotic or step up to IV therapy) between 3-7 days due to worsening infection. Criteria for worsening infection: (1) New fever (temperature ≥38.0ºC) or persistent fever at follow-up; (2) Increasing area of erythema (in cm2) ≥20% from baseline; or (3) Increasing pain ≥2 points from baseline (using the Numeric Rating Scale).	between 3-7 days
Pain Measurement	Pain measured using the Numeric Rating Scale from 0 to 10	Evaluated at day 0, 3, 8 and 30
Number of Participants with an Antibiotic switch	Defined as an unplanned antibiotic change (change in class of oral antibiotic or step up to IV therapy) within 7 days that did not meet worsening infection criteria and treatment failure	Within 7 days
Number of Participants with Clinical Cure	Defined as absence of erythema, pain and fever	Evaluated at day 8 and 30
Recurrence	Number of patients that had a recurrence of infection at day 90, defined as development of a new skin and soft tissue infection (cellulitis or skin abscess) at the same or different anatomic site	Evaluated at day 90
Number of Participants with health-related quality of life	Measured using the EuroQoL-5D-5L39 instrument, evaluated at day 0 (index ED visit), 3, 8, 30 and 90.	90 days
Number of participants with unplanned visits to a healthcare provider for cellulitis	Visits to ED, family doctor or walk in clinic	90 days
Number of Participants with an Unplanned hospitalization for cellulitis	within 30 and 90 days.	90 days
Use of (i) acetaminophen; (ii) opioids; and (iii) corticosteroids	Reporting if there is use of acetaminophen, opioids or corticosteroids during the study period.	Evaluated at day 3, 8 and 30.

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: The Ottawa Hospital Academic Medical Association; l'Association Médicale Universitaire Montfort (AMUM)
• Investigators: Principal Investigator: Krishan Yadav, MD, MSc, Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2031

Study Registration Dates

• First Submitted: June 18, 2026
• First Submitted That Met QC Criteria: June 18, 2026
• First Posted (Actual): June 24, 2026

Study Record Updates

• Last Update Posted (Actual): June 24, 2026
• Last Update Submitted That Met QC Criteria: June 18, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Emergency Medicine; Infectious Diseases; oral antibiotics; naproxen; antibiotics; anti-inflammatories; Cellulitis; cephalexin
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Connective Tissue Diseases; Inflammation; Skin Diseases; Suppuration; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Infections; Communicable Diseases; Soft Tissue Infections; Cellulitis; Skin Diseases, Infectious; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Hydrocarbons, Cyclic; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Amides; beta-Lactams; Lactams; Cephalosporins; Thiazines; Naphthaleneacetic Acids; Naproxen; Cephalexin
• Other Study ID Numbers: 20260315-01T

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD requests can be submitted to the Investigator and will be reviewed on a case by case basis.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No