Oral Omadacycline vs. Oral Linezolid for the Treatment of ABSSSI

• ClinicalTrials.gov Identifier: NCT02877927
• Recruitment Status: Completed
• First Posted: August 24, 2016
• Results First Posted: November 30, 2018
• Last Update Posted: November 30, 2018
• Sponsor: Paratek Pharmaceuticals Inc
• Information provided by (Responsible Party): Paratek Pharmaceuticals Inc

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Bacterial Infections; Skin Structures and Soft Tissue Infections
• Interventions: Drug: Omadacycline; Drug: Linezolid
• Enrollment: 735

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Omadacycline	Linezolid
Arm/Group Description	Participants received omadacycline 450 milligrams (mg) orally every 24 hours (q24h) for 2 doses, followed by 300 mg orally q24h. The total treatment duration was 7 to 14 days. Participants received active omadacycline tablets and over-encapsulated linezolid placebo tablets.	Participants received linezolid 600 mg orally every 12 hours (q12h). The total treatment duration was 7 to 14 days. Participants received omadacycline placebo tablets and over-encapsulated active linezolid tablets.
Period Title: Overall Study
Started	368	367
Completed	314	310
Not Completed	54	57
Reason Not Completed
Adverse Event	1	0
Lost to Follow-up	37	38
Withdrawal by Subject	11	12
Physician Decision	0	1
Missed EOT/PTE Visit	5	6

Baseline Characteristics

Arm/Group Title		Omadacycline	Linezolid	Total
Arm/Group Description		Participants received omadacycline 450 milligrams (mg) orally every 24 hours (q24h) for 2 doses, followed by 300 mg orally q24h. The total treatment duration was 7 to 14 days. Participants received active omadacycline tablets and over-encapsulated linezolid placebo tablets.	Participants received linezolid 600 mg orally every 12 hours (q12h). The total treatment duration was 7 to 14 days. Participants received omadacycline placebo tablets and over-encapsulated active linezolid tablets.	Total of all reporting groups
Overall Number of Baseline Participants		368	367	735
Baseline Analysis Population Description		Safety Population: all randomized participants who received test article
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	368 participants	367 participants	735 participants
		42.8 (12.72)	44.5 (13.11)	43.7 (12.94)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	368 participants	367 participants	735 participants
	Female	126 34.2%	147 40.1%	273 37.1%
	Male	242 65.8%	220 59.9%	462 62.9%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	368 participants	367 participants	735 participants
	American Indian or Alaska Native	7 1.9%	3 0.8%	10 1.4%
	Asian	3 0.8%	5 1.4%	8 1.1%
	Native Hawaiian or Other Pacific Islander	3 0.8%	0 0.0%	3 0.4%
	Black or African American	22 6.0%	13 3.5%	35 4.8%
	White	327 88.9%	341 92.9%	668 90.9%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	6 1.6%	5 1.4%	11 1.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Early Clinical Response
Description	Early clinical response is defined as clinical success, which is categorized as survival with at least a 20% reduction of acute bacterial skin and skin structure infection (ABSSSI) primary lesion size compared to Screening measurements, without receiving any rescue antibacterial therapy. An indeterminate classification is used for a response that could not be adequately inferred because the participant was not assessed because they withdrew consent, were lost to follow-up, or other specified reason.
Time Frame	Screening; 48 to 72 hours after the first dose of test article

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: all randomized participants without a baseline sole Gram-negative ABSSSI pathogen

Arm/Group Title	Omadacycline	Linezolid
Arm/Group Description:	Participants received omadacycline 450 milligrams (mg) orally every 24 hours (q24h) for 2 doses, followed by 300 mg orally q24h. The total treatment duration was 7 to 14 days. Participants received active omadacycline tablets and over-encapsulated linezolid placebo tablets.	Participants received linezolid 600 mg orally every 12 hours (q12h). The total treatment duration was 7 to 14 days. Participants received omadacycline placebo tablets and over-encapsulated active linezolid tablets.
Overall Number of Participants Analyzed	360	360
Measure Type: Count of Participants; Unit of Measure: Participants
Clinical success	315 87.5%	297 82.5%
Clinical failure	26 7.2%	32 8.9%
Indeterminate	19 5.3%	31 8.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Omadacycline, Linezolid
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	A non-inferiority margin of 10% was used for the analysis.
Method of Estimation	Estimation Parameter	treatment difference
	Estimated Value	5.0
	Confidence Interval	(2-Sided) 95%; -0.2 to 10.3
	Estimation Comments	The 95% confidence interval was constructed based on the Miettinen and Nurminen method without stratification. Treatment difference for a response of clinical success was calculated as omadacycline minus linezolid.

2. Secondary Outcome

Title	Number of Participants With the Indicated Investigator Assessment of Clinical Response in the mITT Population at the Post Therapy Evaluation (PTE) Visit
Description	At the PTE Visit the investigator indicated one of the following outcomes relating to the primary infection under study: Clinical Success: participant was alive; infection was sufficiently resolved such that further antibacterial therapy was not needed. Participants may have had some residual changes related to infection requiring ancillary treatment. Clinical Failure was defined as meeting any of the following criteria: infection required additional treatment with alternative antibacterial therapy; participant received antibacterial therapy between the End-of-Treatment (EOT) Visit and the PTE Visit that may have been effective for the infection under study for a different infection from the one under study; unplanned major surgical intervention for the infection under study between the EOT and PTE Visits; participant died before evaluation; other specified reason. Indeterminate The clinical response to test article could not be adequately inferred.
Time Frame	Screening; 7 to 14 days after the last day of therapy

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	Omadacycline	Linezolid
Arm/Group Description:	Participants received omadacycline 450 milligrams (mg) orally every 24 hours (q24h) for 2 doses, followed by 300 mg orally q24h. The total treatment duration was 7 to 14 days. Participants received active omadacycline tablets and over-encapsulated linezolid placebo tablets.	Participants received linezolid 600 mg orally every 12 hours (q12h). The total treatment duration was 7 to 14 days. Participants received omadacycline placebo tablets and over-encapsulated active linezolid tablets.
Overall Number of Participants Analyzed	360	360
Measure Type: Count of Participants; Unit of Measure: Participants
Clinical success	303 84.2%	291 80.8%
Clinical failure	12 3.3%	21 5.8%
Indeterminate	45 12.5%	48 13.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Omadacycline, Linezolid
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	A non-inferiority margin of 10% was used for the analysis.
Method of Estimation	Estimation Parameter	treatment difference
	Estimated Value	3.3
	Confidence Interval	(2-Sided) 95%; -2.2 to 8.9
	Estimation Comments	The 95% confidence interval was constructed based on the Miettinen and Nurminen method without stratification. Treatment difference for a response of clinical success was calculated as omadacycline minus linezolid.

3. Secondary Outcome

Title	Number of Participants With the Indicated Investigator Assessment of Clinical Response in the Clinically Evaluable-Post Therapy Evaluation (CE-PTE) Population
Description	At the PTE Visit the investigator indicated one of the following outcomes relating to the primary infection under study: Clinical Success: participant was alive; infection was sufficiently resolved such that further antibacterial therapy was not needed. Participants may have had some residual changes related to infection requiring ancillary treatment. Clinical Failure was defined as meeting any of the following criteria: infection required additional treatment with alternative antibacterial therapy; participant received antibacterial therapy between the EOT Visit and the PTE Visit that may have been effective for the infection under study for a different infection from the one under study; unplanned major surgical intervention for the infection under study between the EOT and PTE Visits; participant died before evaluation; other specified reason.
Time Frame	Screening; 7 to 14 days after the last day of therapy

Outcome Measure Data

Analysis Population Description

CE-PTE Population: all participants in the mITT Population meeting additional pre-defined criteria

Arm/Group Title	Omadacycline	Linezolid
Arm/Group Description:	Participants received omadacycline 450 milligrams (mg) orally every 24 hours (q24h) for 2 doses, followed by 300 mg orally q24h. The total treatment duration was 7 to 14 days. Participants received active omadacycline tablets and over-encapsulated linezolid placebo tablets.	Participants received linezolid 600 mg orally every 12 hours (q12h). The total treatment duration was 7 to 14 days. Participants received omadacycline placebo tablets and over-encapsulated active linezolid tablets.
Overall Number of Participants Analyzed	284	292
Measure Type: Count of Participants; Unit of Measure: Participants
Clinical success	278 97.9%	279 95.5%
Clinical failure	6 2.1%	13 4.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Omadacycline, Linezolid
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	A non-inferiority margin of 10% was used for the analysis.
Method of Estimation	Estimation Parameter	treatment difference
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; -0.6 to 5.6
	Estimation Comments	The 95% confidence interval was constructed based on the Miettinen and Nurminen method without stratification. Treatment difference for a response of clinical success was calculated as omadacycline minus linezolid.

Adverse Events

Time Frame	Adverse events were assessed from the signing of Informed Consent Form to the time of the Final Follow-up assessment (up to 30 to 37 days after the first dose of test article).
Adverse Event Reporting Description	Adverse events are reported for members of the Safety Population, comprised of all randomized participants who received test article (either active or placebo). Treatment-emergent adverse events, defined as events occurring after the first dose of active test article, are reported.
Arm/Group Title	Omadacycline	Linezolid
Arm/Group Description	Participants received omadacycline 450 milligrams (mg) orally every 24 hours (q24h) for 2 doses, followed by 300 mg orally q24h. The total treatment duration was 7 to 14 days. Participants received active omadacycline tablets and over-encapsulated linezolid placebo tablets.	Participants received linezolid 600 mg orally every 12 hours (q12h). The total treatment duration was 7 to 14 days. Participants received omadacycline placebo tablets and over-encapsulated active linezolid tablets.
All-Cause Mortality
	Omadacycline	Linezolid
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/368 (0.00%)	1/367 (0.27%)
Serious Adverse Events
	Omadacycline	Linezolid
	Affected / at Risk (%)	Affected / at Risk (%)
Total	5/368 (1.36%)	5/367 (1.36%)
General disorders
Drug Withdrawal Syndrome * 1	1/368 (0.27%)	0/367 (0.00%)
Death * 1	0/368 (0.00%)	1/367 (0.27%)
Hepatobiliary disorders
Cholecystitis Acute * 1	1/368 (0.27%)	0/367 (0.00%)
Infections and infestations
Wound Infection * 1	1/368 (0.27%)	1/367 (0.27%)
Hepatitis C * 1	1/368 (0.27%)	0/367 (0.00%)
Staphylococcal Bacteraemia * 1	1/368 (0.27%)	0/367 (0.00%)
Subcutaneous Abscess * 1	1/368 (0.27%)	0/367 (0.00%)
Sepsis * 1	0/368 (0.00%)	2/367 (0.54%)
Cellulitis * 1	0/368 (0.00%)	1/367 (0.27%)
Injury, poisoning and procedural complications
Overdose * 1	1/368 (0.27%)	0/367 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure * 1	1/368 (0.27%)	0/367 (0.00%)
Skin and subcutaneous tissue disorders
Angioedema * 1	0/368 (0.00%)	1/367 (0.27%)
1 Term from vocabulary, MedDRA 17.1; * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Omadacycline	Linezolid
	Affected / at Risk (%)	Affected / at Risk (%)
Total	166/368 (45.11%)	83/367 (22.62%)
Gastrointestinal disorders
Nausea * 1	111/368 (30.16%)	28/367 (7.63%)
Vomiting * 1	62/368 (16.85%)	11/367 (3.00%)
Diarrhea * 1	15/368 (4.08%)	10/367 (2.72%)
Abdominal pain upper * 1	10/368 (2.72%)	4/367 (1.09%)
Infections and infestations
Wound infection * 1	21/368 (5.71%)	16/367 (4.36%)
Cellulitis * 1	12/368 (3.26%)	8/367 (2.18%)
Subcutaneous abscess * 1	5/368 (1.36%)	8/367 (2.18%)
Investigations
Alanine aminotransferase increased * 1	19/368 (5.16%)	11/367 (3.00%)
Aspartate aminotransferase increased * 1	17/368 (4.62%)	12/367 (3.27%)
Nervous system disorders
Headache * 1	13/368 (3.53%)	8/367 (2.18%)
1 Term from vocabulary, MedDRA 17.1; * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The only disclosure restriction on the Principal Investigator is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days from the time submitted to the sponsor for review. The sponsor can request changes to the communication and require the removal of confidential information.

Results Point of Contact

• Name/Title: Dr. Paul McGovern; Vice President, Clinical Affairs
• Organization: Paratek Pharmaceuticals, Inc.
• Phone: 484-751-4935
• EMail: Paul.Mcgovern@paratekpharma.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vacalis S, Brunton S, Gindi J. Omadacycline in Skin Infections and Pneumonia: A Review of the Evidence. J Fam Pract. 2022 Jun;71(5 Suppl):S10-S21. doi: 10.12788/jfp.0424.

Pai MP, Wilcox MH, Chitra S, McGovern PC. Safety and efficacy of omadacycline by BMI categories and diabetes history in two Phase III randomized studies of patients with acute bacterial skin and skin structure infections. J Antimicrob Chemother. 2021 Apr 13;76(5):1315-1322. doi: 10.1093/jac/dkaa558.

Cornely OA, File TM Jr, Garrity-Ryan L, Chitra S, Noble R, McGovern PC. Safety and efficacy of omadacycline for treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections in patients with mild-to-moderate renal impairment. Int J Antimicrob Agents. 2021 Feb;57(2):106263. doi: 10.1016/j.ijantimicag.2020.106263. Epub 2020 Dec 14.

O'Riordan W, Cardenas C, Shin E, Sirbu A, Garrity-Ryan L, Das AF, Eckburg PB, Manley A, Steenbergen JN, Tzanis E, McGovern PC, Loh E; OASIS-2 Investigators. Once-daily oral omadacycline versus twice-daily oral linezolid for acute bacterial skin and skin structure infections (OASIS-2): a phase 3, double-blind, multicentre, randomised, controlled, non-inferiority trial. Lancet Infect Dis. 2019 Oct;19(10):1080-1090. doi: 10.1016/S1473-3099(19)30275-0. Epub 2019 Aug 29.

Abrahamian FM, Sakoulas G, Tzanis E, Manley A, Steenbergen J, Das AF, Eckburg PB, McGovern PC. Omadacycline for Acute Bacterial Skin and Skin Structure Infections. Clin Infect Dis. 2019 Aug 1;69(Suppl 1):S23-S32. doi: 10.1093/cid/ciz396.

• Responsible Party: Paratek Pharmaceuticals Inc
• ClinicalTrials.gov Identifier: NCT02877927
• Other Study ID Numbers: PTK0796-ABSI-16301
• First Submitted: August 15, 2016
• First Posted: August 24, 2016
• Results First Submitted: November 2, 2018
• Results First Posted: November 30, 2018
• Last Update Posted: November 30, 2018