Clinical trial NCT05852262: High-dose Cephalexin for Cellulitis (HI-DOCC)
Official title: High-dose Cephalexin for Cellulitis (HI-DOCC)
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE4
Conditions: Cellulitis
Keywords: Cellulitis
Cephalexin
Oral antibiotics
Treatment failure
Lead sponsor: Ottawa Hospital Research Institute
Sponsor class: OTHER
Collaborators: name: Network of Canadian Emergency Researchers (NCER)
name: The Ottawa Hospital Academic Medical Association
First posted: 2023-05-10
Enrollment: 446
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The Investigators will conduct a parallel arm double-blind randomized controlled trial.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants with Oral Antibiotic Treatment Failure
timeFrame: 7 days
Secondary outcomes:
measure: Number of Participants with clinical cure
timeFrame: evaluated at day 8 and day 30
measure: Number of Participants with clinical response
timeFrame: evaluated at days 3 and 8
measure: Number of Participants with unplanned visits to a healthcare provider for cellulitis
timeFrame: 30 days
measure: Number of Participants with unplanned hospitalization for cellulitis
timeFrame: 30 days
measure: Number of Participants with adverse events
timeFrame: 30 days
measure: Number of Participants with antibiotic intolerance
timeFrame: 7 days
measure: Number of Participants with antibiotic allergy
timeFrame: 7 days
measure: Number of Participants with medication adherence
timeFrame: 7 days
measure: Number of Participants with health-related quality of life
timeFrame: 30 days
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: South Health Campus
state: Alberta
city: Halifax
country: Canada
facility: Queen Elisabeth II Health Sciences Centre
state: Nova Scotia
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Sudbury
country: Canada
facility: Health Sciences North
state: Ontario
city: Thunder Bay
country: Canada
facility: Thunder Bay Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Sinai Health System
state: Ontario
city: Montréal
country: Canada
facility: Hôpital du Sacré-Cœur de Montréal
state: Quebec
city: Québec
country: Canada
facility: Enfant-Jésus Hospital
state: Quebec
Study officials:
affiliation: Ottawa Hospital Research Institute
name: Krishan Yadav, MD
role: PRINCIPAL_INVESTIGATOR
References: