Oral Omadacycline vs. Oral Linezolid for the Treatment of ABSSSI

• Sponsor: Paratek Pharmaceuticals Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02877927
• Collaborator: (none)
• Enrollment: 735
• Locations: 50
• Arms: 2
• Duration (Months): 10.2
• Patients Per Site: 14.7
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of omadacycline as compared to linezolid in the treatment of adults with acute bacterial skin and skin structure infections.

Condition or Disease	Intervention/Treatment	Phase
Bacterial Infections; Skin Structures and Soft Tissue Infections	Drug: Omadacycline; Drug: Linezolid	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 735 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Randomized, Double-Blind, Multi-Center Study to Compare the Safety and Efficacy of Oral Omadacycline to Oral Linezolid for Treating Adult Subjects With Acute Bacterial Skin and Skin Structure Infection (ABSSSI)
• Study Start Date: Aug 1, 2016
• Actual Primary Completion Date: May 26, 2017
• Actual Study Completion Date: Jun 6, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Omadacycline Omadacycline tablets	Drug: Omadacycline; po tablets
Active Comparator: Linezolid Linezolid tablets	Drug: Linezolid; po tablets; Other Names: Zyvox

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Early Clinical Response [Screening; 48 to 72 hours after the first dose of test article]

   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.

Secondary Outcome Measures

1. Number of Participants With the Indicated Investigator Assessment of Clinical Response in the mITT Population at the Post Therapy Evaluation (PTE) Visit [Screening; 7 to 14 days after the last day of therapy]

   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.

2. Number of Participants With the Indicated Investigator Assessment of Clinical Response in the Clinically Evaluable-Post Therapy Evaluation (CE-PTE) Population [Screening; 7 to 14 days after the last day of therapy]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients, ages 18 years or older who have signed the informed consent

• Has a qualifying skin and skin structure infection

• Female patients must not be pregnant at the time of enrollment

• Must agree to a reliable method of birth control during the study and for 30 days following the last dose of study drug

Exclusion Criteria:

• Infections where the outcome is strongly influenced by factors other than protocol-defined treatments and procedures, or that require antibacterial treatment for greater than 14 days

• Evidence of significant immunological disease

• Severe renal disease or requirement for dialysis

• Evidence of septic shock

• Has a history of hypersensitivity or allergic reaction to any tetracycline or to linezolid

• Has received an investigational drug within the past 30 days

• Women who are pregnant or nursing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site 620	Birmingham	Alabama	United States	35215
2	Site 642	Mobile	Alabama	United States	36608
3	Site 616	Anaheim	California	United States	92801
4	Site 601	Anaheim	California	United States	92804
5	Site 636	Bakersfield	California	United States	93301
6	Site 606	Buena Park	California	United States	90620
7	Site 604	Chula Vista	California	United States	91911
8	Site 659	Huntington Beach	California	United States	92647
9	Site 608	La Mesa	California	United States	91942
10	Site 618	Laguna Hills	California	United States	92653
11	Site 612	Long Beach	California	United States	90813
12	Site 648	Modesto	California	United States	95350
13	Site 610	Oceanside	California	United States	92056
14	Site 615	San Diego	California	United States	92114
15	Site 621	San Diego	California	United States	92119
16	Site 613	San Francisco	California	United States	94115
17	Site 603	Stockton	California	United States	95204
18	Site 650	Torrance	California	United States	90502
19	Site 646	Ventura	California	United States	93003
20	Site 614	DeLand	Florida	United States	32720
21	Site 655	Fort Myers	Florida	United States	33901
22	Site 656	Homestead	Florida	United States	33030
23	Site 640	Miami Lakes	Florida	United States	33016
24	Site 662	Miami Lakes	Florida	United States	33104
25	Site 631	Miami	Florida	United States	33015
26	Site 658	Miami	Florida	United States	33125
27	Site 654	Miami	Florida	United States	33134
28	Site 626	Miami	Florida	United States	33144
29	Site 637	Miami	Florida	United States	33144
30	Site 653	Miami	Florida	United States	33145
31	Site 641	Miami	Florida	United States	33175
32	Site 645	Miami	Florida	United States	33175
33	Site 609	Saint Cloud	Florida	United States	34769
34	Site 644	Council Bluffs	Iowa	United States	51503
35	Site 657	Boston	Massachusetts	United States	02115
36	Site 617	Saint Louis	Missouri	United States	63128
37	Site 602	Butte	Montana	United States	59701
38	Site 623	Las Vegas	Nevada	United States	89109
39	Site 630	Somers Point	New Jersey	United States	08244
40	Site 647	Jackson Heights	New York	United States	11372
41	Site 632	Mount Airy	North Carolina	United States	27030
42	Site 649	Toledo	Ohio	United States	43608
43	Site 607	Rapid City	South Dakota	United States	57702
44	Site 635	Jackson	Tennessee	United States	38305
45	Site 628	Smyrna	Tennessee	United States	37167
46	Site 633	Baytown	Texas	United States	77521
47	Site 605	Channelview	Texas	United States	77530
48	Site 625	Houston	Texas	United States	77008
49	Site 627	Houston	Texas	United States	77084
50	Site 634	Sugar Land	Texas	United States	77479

Sponsors and Collaborators

• Paratek Pharmaceuticals Inc

Investigators

• Study Director: Amy Manley, Senior Director, Clinical Operations

Study Documents (Full-Text)

• Study Protocol - Nov 22, 2016
• Statistical Analysis Plan - May 24, 2017

More Information

Publications

None provided.

• Responsible Party: Paratek Pharmaceuticals Inc
• ClinicalTrials.gov Identifier: NCT02877927
• Other Study ID Numbers: PTK0796-ABSI-16301
• First Posted: Aug 24, 2016
• Last Update Posted: Nov 30, 2018
• Last Verified: Nov 1, 2018

• Additional relevant MeSH terms: Infections; Communicable Diseases; Bacterial Infections; Soft Tissue Infections; Linezolid

Study Results

Participant Flow

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

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 Participants	368	367	735
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.8 (12.72)	44.5 (13.11)	43.7 (12.94)
Sex: Female, Male (Count of Participants)
Female	126 34.2%	147 40.1%	273 37.1%
Male	242 65.8%	220 59.9%	462 62.9%
Race (NIH/OMB) (Count of 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%	3 0.4%
Black or African American	22 6%	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%
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.
Measure Participants	360	360
Clinical success	315 85.6%	297 80.9%
Clinical failure	26 7.1%	32 8.7%
Indeterminate	19 5.2%	31 8.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Omadacycline, Linezolid
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	A non-inferiority margin of 10% was used for the analysis.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	treatment difference
	Estimated Value	5.0
	Confidence Interval	(2-Sided) 95%; -0.2 to 10.3
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	360	360
Clinical success	303 82.3%	291 79.3%
Clinical failure	12 3.3%	21 5.7%
Indeterminate	45 12.2%	48 13.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Omadacycline, Linezolid
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	A non-inferiority margin of 10% was used for the analysis.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	treatment difference
	Estimated Value	3.3
	Confidence Interval	(2-Sided) 95%; -2.2 to 8.9
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	284	292
Clinical success	278 75.5%	279 76%
Clinical failure	6 1.6%	13 3.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Omadacycline, Linezolid
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	A non-inferiority margin of 10% was used for the analysis.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	treatment difference
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; -0.6 to 5.6
	Parameter Dispersion	Type: Value:
	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 (%)	# Events	Affected / at Risk (%)	# Events
Total	0/368 (0%)		1/367 (0.3%)
Serious Adverse Events
	Omadacycline		Linezolid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/368 (1.4%)		5/367 (1.4%)
General disorders
Drug Withdrawal Syndrome	1/368 (0.3%)		0/367 (0%)
Death	0/368 (0%)		1/367 (0.3%)
Hepatobiliary disorders
Cholecystitis Acute	1/368 (0.3%)		0/367 (0%)
Infections and infestations
Wound Infection	1/368 (0.3%)		1/367 (0.3%)
Hepatitis C	1/368 (0.3%)		0/367 (0%)
Staphylococcal Bacteraemia	1/368 (0.3%)		0/367 (0%)
Subcutaneous Abscess	1/368 (0.3%)		0/367 (0%)
Sepsis	0/368 (0%)		2/367 (0.5%)
Cellulitis	0/368 (0%)		1/367 (0.3%)
Injury, poisoning and procedural complications
Overdose	1/368 (0.3%)		0/367 (0%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	1/368 (0.3%)		0/367 (0%)
Skin and subcutaneous tissue disorders
Angioedema	0/368 (0%)		1/367 (0.3%)
Other (Not Including Serious) Adverse Events
	Omadacycline		Linezolid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	166/368 (45.1%)		83/367 (22.6%)
Gastrointestinal disorders
Nausea	111/368 (30.2%)		28/367 (7.6%)
Vomiting	62/368 (16.8%)		11/367 (3%)
Diarrhea	15/368 (4.1%)		10/367 (2.7%)
Abdominal pain upper	10/368 (2.7%)		4/367 (1.1%)
Infections and infestations
Wound infection	21/368 (5.7%)		16/367 (4.4%)
Cellulitis	12/368 (3.3%)		8/367 (2.2%)
Subcutaneous abscess	5/368 (1.4%)		8/367 (2.2%)
Investigations
Alanine aminotransferase increased	19/368 (5.2%)		11/367 (3%)
Aspartate aminotransferase increased	17/368 (4.6%)		12/367 (3.3%)
Nervous system disorders
Headache	13/368 (3.5%)		8/367 (2.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.