Efficacy for SIVEXTRO
Efficacy in phase 3 clinical trials
SIVEXTRO was evaluated in 2 randomized controlled noninferiority phase 3 trials in patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI):
- ESTABLISH 1 trial in adults: All-oral course of SIVEXTRO vs linezolid (n=667)
- ESTABLISH 2 trial in patients ≥12: IV/oral switch of SIVEXTRO vs linezolid (n=666)
ESTABLISH 1 ABSSSI trial
SIVEXTRO delivered efficacy with a short, 6-day course of treatment
(a) Intent-to-treat (ITT) population.
Noninferiority for the primary endpoint was concluded if the lower limit of the 95% confidence interval was greater than –10%. The treatment difference (95% confidence interval) was 0.1 (–6.1, 6.2) for the primary endpoint and –0.5 (–5.8, 4.9) for the secondary endpoint.1
ESTABLISH 2 ABSSSI trial
SIVEXTRO delivered efficacy with a short, 6-day course of treatment
(a) Intent-to-treat (ITT) population.
Noninferiority for the primary endpoint was concluded if the lower limit of the 95% confidence interval was greater than -10%. The treatment difference (95% confidence interval) was 2.6 (-3.0, 8.2) for the primary endpoint and 0.3 (-4.8, 5.3) for the secondary endpoint.2
ABSSSI patients
Trials included ABSSSI patients with significant lesions,1,2 such as
- Cellulitis/erysipelas
- Major cutaneous abscess
- Wound infection
Patients evaluated had infection surrounded by erythema with a minimum total lesion surface area of at least 75 cm2, which were suspected or documented to be associated with a Gram-positive pathogen.1,2
Patients also exhibited at least 1 of the following regional or systemic signs of infection1:
- Lymphadenopathy, fever, white blood cell count ≥ 10,000 cells/mm3, or <4,000 cells/mm3, or >10% immature neutrophils
The median infection area for patients treated with SIVEXTRO was 188 cm2 in ESTABLISH 1 and 231 cm2 in ESTABLISH 2.
Trial design
Both randomized, multicenter, multinational, double-blind, noninferiority ESTABLISH trials compared SIVEXTRO 200 mg once daily for 6 days to linezolid 600 mg every 12 hours for 10 days in adults. Patients with cellulitis/erysipelas, major cutaneous abscess, or wound infection were enrolled in the trials. Patients with wound infections could have received aztreonam and/or metronidazole as adjunctive therapy for Gram-negative bacterial coverage, if needed. In the ESTABLISH 2 trial, patients taking SIVEXTRO received at least 1 day of IV treatment.
For the secondary endpoint of post-therapy evaluation, clinical success was defined as resolution or near resolution of disease-specific signs and symptoms, absence or near resolution of systemic signs of infection if present at baseline (lymphadenopathy, fever, >10% immature neutrophils, abnormal white blood cell count), and no further antibiotic treatment required for the treatment of the primary ABSSSI lesion.
Pediatric patients
The safety and efficacy of SIVEXTRO in pediatric patients 12 to <18 years of age were investigated in a randomized, single blind, active-controlled trial of 120 patients with clinically documented ABSSSI (91 receiving tedizolid, 29 receiving comparator). Patients were randomized in a 3:1 ratio with stratification by geographic region to receive SIVEXTRO IV and/or oral therapy, dosed 200 mg once daily for 6 days, or comparator IV and/or oral therapy, dosed over 10 days. Comparator therapy was selected by the investigator from a list of 5 IV and 4 oral comparators per local standard of care. The most frequently used comparators were cefazolin (11 patients) and vancomycin (8 patients).
The primary objective was to evaluate the safety and tolerability of SIVEXTRO. The trial was not powered for comparative inferential efficacy analysis. Clinical response at the test of cure visit (Day 18-25) was assessed by a blinded investigator in the ITT population (all randomized patients). Clinical successes were required to have resolution or near resolution of all related signs and symptoms such that no further antibacterial therapy was needed. Early clinical response, defined as at least a 20% reduction in lesion size at 48-72 hours after start of treatment, was also assessed in the ITT population.
Clinical success at test of cure was 96.7% (88/91) in the tedizolid group and 93.1% (27/29) in the comparator group (difference 3.6%, 95% CI: -6.3, 13.5). Early clinical response at 48-72 hours was 92.3% (84/91) in the tedizolid group and 96.6% (28/29) in the comparator group (difference -4.2%, 95% CI: -12.9, 4.4).
References:
1. Prokocimer P, De Anda C, Fang E, Mehra P, Das A. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections. The ESTABLISH-1 randomized trial. JAMA. 2013;309(6):559-569.
2. Moran GJ, Fang E, Corey GR, Das AF, De Anda C, Prokocimer P. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2 ): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2014;14(8):696-705.