Clinical Trial Results:
A Phase 3 Randomized, Double-Blind, Multi-Center Study to Compare the Safety and Efficacy of Omadacycline IV/PO to Linezolid IV/PO for Treating Adult Subjects with Acute Bacterial Skin and Skin Structure Infection (ABSSSI)
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Summary
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EudraCT number |
2013-003644-23 |
Trial protocol |
LV HU ES PL GR HR |
Global end of trial date |
04 May 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Jul 2017
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First version publication date |
09 Jul 2017
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
PTK0796-ABSI-1108
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02378480 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Paratek Pharma LLC
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Sponsor organisation address |
75 Park Plaza, Boston, United States, MA, 02116
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Public contact |
Head of Research and Development, Paratek Pharma LLC, +1 617275-0040 ,
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Scientific contact |
Head of Research and Development, Paratek Pharma LLC, +1 617275-0040 ,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
24 Apr 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
04 May 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
04 May 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study is to demonstrate that omadacycline 100 mg iv every 12 hours (q12h) for 2 doses, followed by 100 mg iv every 24 hours (q24h)/300 mg po q24h is non-inferior to linezolid 600 mg iv q12h/600 mg po q12h in the treatment of adults with ABSSSI known or suspected to be due to Gram-positive pathogens
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Protection of trial subjects |
The switching from i.v. to p.o. treatment, the first dose of p.o. therapy should begin in the morning, approximately 12 hours after the last iv dose, to ensure the subjects continued to receive uninterrupted daily therapy.
To facilitate study enrollment at all times of the day infusion times were adjusted up to ± 2 hours per infusion interval until the desired administration schedule was achieved.
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Background therapy |
- | ||
Evidence for comparator |
The comparator drug, linezolid, is approved worldwide for the treatment of ABSSSI caused by Gram positive pathogens and has an acceptable and well defined safety profile. Linezolid can be administered iv and po and has regulatory approval for the treatment of ABSSSI caused by Gram positive pathogens including MRSA. | ||
Actual start date of recruitment |
22 Jun 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 6
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Country: Number of subjects enrolled |
Romania: 49
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Country: Number of subjects enrolled |
Croatia: 18
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Country: Number of subjects enrolled |
Bulgaria: 49
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Country: Number of subjects enrolled |
Greece: 8
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Country: Number of subjects enrolled |
Hungary: 12
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Country: Number of subjects enrolled |
Latvia: 31
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Country: Number of subjects enrolled |
United States: 415
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Country: Number of subjects enrolled |
South Africa: 2
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Country: Number of subjects enrolled |
Peru: 9
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Country: Number of subjects enrolled |
Turkey: 1
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Country: Number of subjects enrolled |
Ukraine: 55
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Worldwide total number of subjects |
655
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EEA total number of subjects |
173
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
580
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From 65 to 84 years |
67
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85 years and over |
8
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Recruitment
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Recruitment details |
The study is designed to enrolled adult patients with ABSSSI that was known or suspected to be due to a Gram positive pathogen(s). Subject randomization was stratified across treatment groups by type of infection (wound infection, cellulitis/erysipelas, and major abscess) and geographic region. | |||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects who met inclusion criteria and did not meet exclusion criteria were randomly assigned to a treatment group, and received their first dose of test article within 4 hours after randomization. All subjects were expected to present with ABSSSI severe enough to require a minimum of at least 3 days of i.v. treatment. | |||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Treatment period 1 (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||||||||||||||||||||
Blinding implementation details |
Treatment phase (both iv and po) of the study was double blind and double-dummy.
In an effort to maintain blinding, each site employed shrouding of the iv bag and iv lines used for infusion of test article. To maintain double-blinding, subjects on both arms received the same number of tablets (3 tablets in the morning [1 of which was over-encapsulated] and 1 over encapsulated tablet in the evening).
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Omadacycline | |||||||||||||||||||||||||||||||||
Arm description |
Investigational therapy: omadacycline 100 mg i.v. q12h (2 doses), followed by 100 mg iv q24h (starting 24 hours after first dose), with the option to switch to 300 mg p.o. q24h after a minimum of 3 days (6 doses) of i.v. treatment, thus 6 overall IV doses because of the blinding. For subjects assigned to OMC, they received 4 active doses plus 2 placebo doses to keep the blinded. Total treatment duration of 7 to 14 days. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Omadacycline
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for infusion, Tablet
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
2 doses of Omadacycline (100 mg) iv every 12 hours, followed by 100 mg iv every 24 hours, with the option to switch 300 mg po every 24 hours.
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Arm title
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Linezolid | |||||||||||||||||||||||||||||||||
Arm description |
Reference therapy: linezolid, 600 mg iv q12h with the option to switch to 600 mg po q12h after a minimum of 3 days (6 doses) of iv treatment. Total treatment duration of 7 to 14 days. | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Linezolid
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet, Infusion
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
600 mg Linezolid iv every 12 hours with the option to switch to 600 mg po every 12 hours.
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Baseline characteristics reporting groups
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Reporting group title |
Treatment period 1
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Intent-to-Treat Population
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The intent-to-treat (ITT) population consisted of all randomized subjects regardless of whether or not the subject received test article. A total of 655 subjects were randomized (329 subjects in the omadacycline group and 326 subjects in the linezolid group) in the study.
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Subject analysis set title |
Safety population
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The safety population consisted of all randomized subjects who received test article. All safety analyses were conducted in this analysis set.
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Subject analysis set title |
mITT
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Subject analysis set type |
Modified intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The mITT population consisted of all randomized subjects without a baseline sole Gram negative ABSSSI pathogen.
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End points reporting groups
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Reporting group title |
Omadacycline
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Reporting group description |
Investigational therapy: omadacycline 100 mg i.v. q12h (2 doses), followed by 100 mg iv q24h (starting 24 hours after first dose), with the option to switch to 300 mg p.o. q24h after a minimum of 3 days (6 doses) of i.v. treatment, thus 6 overall IV doses because of the blinding. For subjects assigned to OMC, they received 4 active doses plus 2 placebo doses to keep the blinded. Total treatment duration of 7 to 14 days. | ||
Reporting group title |
Linezolid
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Reporting group description |
Reference therapy: linezolid, 600 mg iv q12h with the option to switch to 600 mg po q12h after a minimum of 3 days (6 doses) of iv treatment. Total treatment duration of 7 to 14 days. | ||
Subject analysis set title |
Intent-to-Treat Population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The intent-to-treat (ITT) population consisted of all randomized subjects regardless of whether or not the subject received test article. A total of 655 subjects were randomized (329 subjects in the omadacycline group and 326 subjects in the linezolid group) in the study.
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Subject analysis set title |
Safety population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety population consisted of all randomized subjects who received test article. All safety analyses were conducted in this analysis set.
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Subject analysis set title |
mITT
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
The mITT population consisted of all randomized subjects without a baseline sole Gram negative ABSSSI pathogen.
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End point title |
Overall Clinical Response at PTE Visit Based on Investigator Assessments | ||||||||||||||||||||||||
End point description |
Overall clinical response at Post Treatment Evaluation was based on the investigator assessment at the EOT and Post Treatment Evaluation visits. Clinical success at the Early clinical Response (ECR) assessment was defined as reduction of the size of the primary lesion ≥ 20% compared to Screening measurement.
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End point type |
Primary
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End point timeframe |
Post Treatment Evaluation (PTE) visit was conducted 7 to 14 days after the subject’s last day of therapy. The total duration of test article therapy (iv plus po) for all subjects was at least 7 days and no more than 14 days.
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Statistical analysis title |
SAS Version 9.3 (or higher) | ||||||||||||||||||||||||
Statistical analysis description |
Descriptive statistics, including the numbers and percentages for categorical variables, and the numbers, means, standard deviations (SD), medians, minimums, and maximums for continuous variables were provided. All comparisons were for omadacycline versus linezolid.
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Comparison groups |
Omadacycline v Linezolid
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Number of subjects included in analysis |
627
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||||||||||||||
Method |
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Parameter type |
Median difference (net) | ||||||||||||||||||||||||
Point estimate |
2.5
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Confidence interval |
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95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-3.2 | ||||||||||||||||||||||||
upper limit |
8.2 | ||||||||||||||||||||||||
Variability estimate |
Standard deviation
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| Notes [1] - The study was designed to show non-inferiority in the primary efficacy outcome as clinical response at PTE was based on the investigator assessment at the EOT and PTE visits. An non inferiority margin of 10% was used for the analysis in the mITT population. To test the null hypothesis, a 2-sided 95% confidence interval (CI) was constructed based on the Miettinen and Nurminen method without stratification. |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events were assessed from the signing of ICF to the time of the Final Follow-up assessment.
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Adverse event reporting additional description |
Safety assessments included clinical review of reported adverse events, serious AEs (SAEs).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
Omadacycline
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Reporting group description |
Investigational therapy: omadacycline 100 mg iv q12h (2 doses), followed by 100 mg iv q24h (starting 24 hours after first dose), with the option to switch to 300 mg po q24h after a minimum of 3 days (6 doses) of iv treatment. For subjects assigned to OMC, they received 4 active doses plus 2 placebo doses to keep the blinded. Total treatment duration of 7 to 14 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Linezolid
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Reporting group description |
Reference therapy: linezolid, 600 mg iv q12h with the option to switch to 600 mg po q12h after a minimum of 3 days (6 doses) of iv treatment. Total treatment duration of 7 to 14 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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27 Oct 2015 |
Protocol amendment 1 (dated 27 Oct 2015 and labeled as version 2).
All Screening evaluations, with the exception of the blood culture, should be completed within 24 hours prior to randomization. The blood culture should be completed within 24 hours of the first dose of test article.
Monoamine oxidase inhibitors were prohibited from 14 days prior to Screening through the Final Follow-up assessment.
Antacids and/or multivitamins containing multivalent cations (eg, aluminum, magnesium, calcium, bismuth, iron, or zinc) are restricted during oral treatment.
The Screening lesion size measurement must be collected within 4 hours prior to randomization.
Subjects should receive their first dose of test article within 4 hours after randomization. The first oral test article dose must be administered in the morning.
If bacteria are isolated from baseline blood cultures, repeat blood cultures should be collected on the day that the positive blood culture is detected. If subsequent blood cultures are also positive, repeat the blood culture as necessary until negative cultures are obtained.
Additional clarification regarding the storage, dispensation, reconciliation, and monitoring of oral test article supplies was included to ensure blinding was maintained.
Up to 4 blood samples for PK analysis were collected between Days 1 and 7.
At the PTE visit, an infections site specimen for culture and Gram stain should be obtained for subjects who were clinical failures.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
