High-dose Cephalexin for Cellulitis (HI-DOCC) (HI-DOCC)

Cellulitis is a common condition diagnosed and managed in the ED that carries significant burden on healthcare systems globally. Cellulitis is the 8th most common reason patients present to an ED in Canada. Among middle-aged patients (45-64 years) it is the 5th most common reason to visit an ED. This disease is responsible for significant healthcare system burden due to high hospitalization rates and subsequent costs. The Investigators conducted a health records review at two large urban EDs in Ottawa, and found that 29.6% of patients with cellulitis are admitted to hospital. In a separate study, The investigators found that the mean cost of care to hospitalize cellulitis patients for IV antibiotics was $10,145 CDN.

Study Overview

• Status: Recruiting
• Conditions: Cellulitis
• Intervention / Treatment: Drug: Cephalexin; Drug: Cephalexin

Detailed Description

Background Non-purulent cellulitis is a bacterial skin and soft tissue infection of the subcutaneous tissue. Group A streptococcus (Streptococcus pyogenes), beta-hemolytic streptococci and methicillin-susceptible Staphylococcus aureus are the most common bacteria causing non-purulent cellulitis. Patients typically present to the emergency department (ED) with pain, redness, swelling and induration (skin hardening due to inflammation) of the affected skin. A minority of patients may have fever or tachycardia. The diagnosis of cellulitis is clinical. Once the diagnosis is made, antibiotic treatment is initiated. The emergency physician must select the appropriate agent, oral versus intravenous (IV) route, dose, frequency and duration.

Rationale For ED adult patients with cellulitis, how does high-dose (1000 mg QID) cephalexin compare with standard-dose (500 mg QID) cephalexin with respect to antibiotic treatment failure, adverse events and health service utilization (i.e., need for IV antibiotics, unscheduled return ED visits and hospitalization)? Hypotheses (superiority): Treatment with high-dose cephalexin will lead to lower rates of oral antibiotic treatment failure than using standard-dose cephalexin.

Methods:

Study Design & Setting The investigators will conduct a multicentre, parallel-arm double-blind, individually randomized trial comparing high-dose (1000 mg) cephalexin to standard-dose (500 mg) cephalexin to treat ED adult patients with cellulitis. This is a superiority trial. The trial will be conducted at 8 Canadian EDs. A total sample size of 446 patients (223 per group) will be required.

Study Population Inclusion Criteria The Investigators will include adults (age ≥18 years) diagnosed with non-purulent cellulitis and determined by the treating emergency physician to be eligible for outpatient oral antibiotics.

Trial Intervention The study interventions are two accepted doses of oral cephalexin. The interventions will begin following randomization.

1. High-dose cephalexin. Patients randomized to this arm will receive a seven-day medication package of cephalexin 1000 mg (two 500 mg tablets per dose) to be taken four times daily. A duration of seven days was selected as this was the most common prescription duration in a survey of Canadian emergency physicians.32 The antibiotic pills will be provided in a dosette organized by dose and day.
2. Standard-dose cephalexin. Patients randomized to this arm will receive a seven-day medication package of cephalexin 500 mg (one 500 mg tablet and one placebo tablet per dose) to be taken four times daily.
3. Blinding. Both cephalexin and placebo will be encased in identical capsules, prepared and packaged independently by an external pharmacy. The patients, treating physician and research team (including outcome adjudicators) will be blinded.

Primary Outcome: Oral Antibiotic Treatment Failure The primary outcome is outpatient oral antibiotic treatment failure, defined as a change in antibiotic (change in class of oral antibiotic or step up to IV therapy) within 7 days due to worsening infection.

Secondary Outcomes

1. Clinical cure, defined as absence of treatment failure criteria, evaluated at day 8 and 30
2. Clinical response, defined as a reduction in lesion size ≥20% compared to baseline, evaluated at the day 3 and day 8 follow-up assessments
3. Unplanned visits to a healthcare provider (ED, family doctor) within 30 days
4. Unplanned hospitalization within 30 days.
5. Adverse events will be classified as serious or other and will be assessed at day 30 follow up. Serious adverse events will include anaphylaxis to study medication, development of Clostridium difficile colitis or unexpected deaths related to the infection or treatment. Other adverse events include nausea, vomiting, diarrhea, abdominal pain and rash.
6. Antibiotic intolerance, defined as change in treatment due to adverse events.
7. Antibiotic allergy, defined as change in treatment due to skin, respiratory, cardiovascular, or gastrointestinal symptoms requiring treatment with an antihistamine and/or epinephrine.
8. Medication adherence, with full adherence defined as patients who report taking all study medication over 7 days
9. Health-related quality of life measured using the EuroQoL-5D-5L36 instrument

IMPORTANCE Cellulitis is a common cause of ED visits, and many patients are hospitalized. Current evidence is lacking regarding the optimal management of cellulitis. If high-dose cephalexin is found to be superior to standard-dose cephalexin, this will change practice, with the potential to reduce unnecessary IV antibiotic use, hospitalization, and costs. The results will help inform future skin and soft tissue infection treatment guidelines.

• Study Type: Interventional
• Enrollment (Estimated): 446
• Phase: Phase 4

Contacts and Locations

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

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Not yet recruiting
      • Foothills Medical Centre
      • Contact: Andrew McRae, MD; Email: amcrae@ucalgary.ca
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Not yet recruiting
      • Queen Elisabeth II Health Sciences Centre
      • Contact: Sam Campbell, MD; Phone Number: 902-494-2255
      • Contact: Megi Nallbani; Email: megi.nallbani@nshealth.ca
  • Ontario
    • Kingston, Ontario, Canada
      • Not yet recruiting
      • Kingston Health Sciences Centre
      • Contact: Kerstin de Wit, MD; Phone Number: 613-548-2368; Email: Kerstin.dewit@queensu.ca
    • London, Ontario, Canada
      • Not yet recruiting
      • London Health Sciences Centre
      • Contact: Justin Yan, MD; Email: justin.yan@lhsc.on.ca
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Recruiting
      • The Ottawa Hospital
      • Contact: Krishan Yadav; Phone Number: 613-798-5555; Email: kyadav@toh.ca
      • Contact: Gabriel Sandino-Gold; Email: gsandino@ohri.ca
    • Sudbury, Ontario, Canada, P3E 2H2
      • Not yet recruiting
      • Health Sciences North
      • Contact: Robert Ohle, MD; Email: robert.ohle@gmail.com
    • Thunder Bay, Ontario, Canada
      • Not yet recruiting
      • Thunder Bay Health Sciences Centre
      • Contact: David Savage, MD; Email: dsavage@nosm.ca
    • Toronto, Ontario, Canada
      • Not yet recruiting
      • Sinai Health System
      • Contact: Bjug Borgundvaag, MD; Email: bjug.borgundvaag@sinaihealthsystem.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Adults (age ≥18 years) diagnosed with non-purulent cellulitis and determined by the treating emergency physician to be eligible for outpatient oral antibiotics.

Exclusion Criteria:

1. Age <18 years;
2. Patient already taking oral antibiotics;
3. Treating physician decides IV antibiotics are required;
4. Abscess requiring an incision and drainage procedure;
5. Known prior cellulitis secondary to methicillin-resistant Staphylococcus aureus (MRSA);
6. Cellulitis secondary to a human or animal bite wound;
7. Penetrating wound or water exposure resulting in cellulitis;
8. Surgical site infection;
9. Patient found at a follow up visit to have an alternative, non-infectious etiology (e.g., deep vein thrombosis);
10. bilateral symptoms (e.g., both legs involved);
11. Malignancy and currently being treated with chemotherapy;
12. Solid organ or bone marrow transplant recipient;
13. Renal impairment with an estimated glomerular filtration rate <30 mL/min documented on the health record at any time within the past three months;
14. Allergy to cephalosporins or history of anaphylaxis to penicillin;
15. Inability to provide informed consent

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High Dose Cephalexin; The intervention is high-dose cephalexin (1000mg PO QID) for seven days	Drug: Cephalexin; 1000 mg PO QID for 7 days; Other Names: High-dose cephalexin; Drug: Cephalexin; 500 mg PO QID plus oral placebo for 7 days; Other Names: Standard-dose cephalexin
Active Comparator: Standard Dose Cephalexin; The comparator is standard-dose cephalexin (500mg PO QID) plus oral placebo for seven days	Drug: Cephalexin; 1000 mg PO QID for 7 days; Other Names: High-dose cephalexin; Drug: Cephalexin; 500 mg PO QID plus oral placebo for 7 days; Other Names: Standard-dose cephalexin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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) within 7 days due to worsening infection. Any of the following meet criteria for worsening infection (at day 3 or 8 follow-up): (1) New fever (temperature ≥38.0C) 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).	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with clinical cure	defined as absence of pain, erythema, and fever	evaluated at day 8 and day 30
Number of Participants with clinical response	defined as a reduction in lesion size ≥20% compared to baseline	evaluated at days 3 and 8
Number of Participants with unplanned visits to a healthcare provider for cellulitis		30 days
Number of Participants with unplanned hospitalization for cellulitis		30 days
Number of Participants with adverse events	classified as serious or other and will be assessed at day 30 follow up. Serious adverse events will include anaphylaxis to study medication, development of Clostridium difficile colitis or unexpected deaths related to the infection or treatment. Other adverse events include nausea, vomiting, diarrhea, abdominal pain and rash.	30 days
Number of Participants with antibiotic intolerance	defined as change in treatment due to adverse events	7 days
Number of Participants with antibiotic allergy	defined as change in treatment due to skin, respiratory, cardiovascular, or gastrointestinal symptoms requiring treatment with an antihistamine and/or epinephrine.	7 days
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 health-related quality of life	Measured using EuroQol-5D-5L instrument at index visit and all follow-ups (days 3,8 and 30)	30 days

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: The Ottawa Hospital Academic Medical Association; Network of Canadian Emergency Researchers (NCER)
• Investigators: Principal Investigator: Krishan Yadav, MD, Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2023
• Primary Completion (Estimated): August 31, 2025
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: May 1, 2023
• First Submitted That Met QC Criteria: May 1, 2023
• First Posted (Actual): May 10, 2023

Study Record Updates

• Last Update Posted (Actual): March 21, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Cellulitis; Treatment failure; Cephalexin; Oral antibiotics
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Inflammation; Connective Tissue Diseases; Skin Diseases, Infectious; Suppuration; Cellulitis; Anti-Infective Agents; Anti-Bacterial Agents; Cephalexin
• Other Study ID Numbers: 20230205-01T

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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