Omadacycline versus moxifloxacin for community-acquired bacterial pneumonia (OPTIC-2): a phase 3b, randomised, double-blind, multicentre, controlled, noninferiority trial.

Background: Omadacycline is a first-in-class aminomethylcycline antibiotic approved to treat adults with community-acquired bacterial pneumonia (CABP). This trial was conducted as a postmarketing regulatory commitment to confirm the efficacy and safety of omadacycline. Methods: This phase 3b, randomised, double-blind, multicentre, noninferiority trial enrolled adults in Eastern Europe between February 2021 (first patient enrolled) and March 2024 (last patient follow-up visit) who had CABP (NCT04779242). Participants with Pneumonia Severity Index (PSI) class III or IV CABP were randomised 1:1 to omadacycline (100 mg IV every 12 h for two doses, then 100 mg IV QD) or moxifloxacin (400 mg IV QD), with an oral option after ≥2 days of treatment (omadacycline, 300 mg QD; or moxifloxacin, 400 mg QD), for a total of 7-10 days. Primary efficacy endpoint was early clinical response (ECR), assessed 72-120 h after first dose, with a noninferiority margin of 10%. Key secondary endpoint was investigator's assessment of clinical response at post-therapy evaluation (PTE), 5-10 days after last dose. Microbiological response was determined by subject and pathogen. Treatment-emergent adverse events (TEAEs) were reported through 30-37 days after first dose. Findings: Of 670 participants randomised (omadacycline, n = 336; moxifloxacin, n = 334), approximately half were aged >65 years, and 76% had PSI class III disease. Omadacycline was noninferior to moxifloxacin at ECR and PTE (ECR, 89.6% versus 87.7%, treatment difference [95% CI]: 1.9 [-3.0, 6.8]; PTE, 86.0% versus 87.7%, treatment difference [95% CI]: -1.7 [-6.9, 3.4]). Clinical success rates were consistently high across select pathogens: 74.4-100% for omadacycline, 75.0-97.4% for moxifloxacin. Omadacycline was generally safe and well tolerated. Most commonly reported TEAEs (≥2%) in the omadacycline and moxifloxacin groups, respectively, were headache (3.6%, 4.5%), AST increase (2.1%, 0%), insomnia (0.6%, 2.1%), and diarrhoea (0%, 3.0%). Interpretation: This trial demonstrates the safety and efficacy of omadacycline in CABP. Omadacycline offers a once-daily monotherapy oral and IV option to treat CABP, including in patients with comorbidities. Funding: This study was sponsored by Paratek Pharmaceuticals, Inc. This study described herein has been funded in whole or in part with federal funds from the U.S. Department of Health and Human Services (HHS), Administration for Strategic Preparedness and Response (ASPR), Biomedical Advanced Research and Development Authority (BARDA), under Contract No. 75A50120C00001. The contract and federal funding are not an endorsement of the study results, products, or company.