Clinical Trial Results:
A Phase 3 Randomized, Double-Blind, Multicenter Study Comparing the Efficacy and Safety of Intravenous to Oral 6-Day TR-701 Free Acid and Intravenous to Oral 10-Day Linezolid for the Treatment of Acute Bacterial Skin and Skin Structure Infections
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Summary
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EudraCT number |
2011-002860-26 |
Trial protocol |
DE ES |
Global end of trial date |
10 Jan 2013
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Results information
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Results version number |
v3(current) |
This version publication date |
09 Feb 2019
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First version publication date |
02 Aug 2015
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Other versions |
v1 , v2 |
Version creation reason |
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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 |
1986-010
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01421511 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Trius Therapeutics, Inc.
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Sponsor organisation address |
6310 Nancy Ridge Drive, Suite 101, San Diego, United States, 92121
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Public contact |
Medical Director, Trius Therapeutics, Inc., +1 858 452 0370 249,
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Scientific contact |
Medical Director, Trius Therapeutics, Inc., +1 858 452 0370 241,
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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 |
28 Oct 2013
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
10 Jan 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Jan 2013
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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 is to determine the non-inferiority (NI) in the rate of the Investigator’s assessment of clinical success of intravenous (IV) to oral 6-day TR-701 free acid (FA) treatment compared with that of IV to oral 10-day linezolid treatment at the Post-therapy Evaluation (PTE) Visit (7 to 14 days after the End of Therapy [EOT] Visit) in the Intent-to-Treat (ITT) and Clinically Evaluable at PTE (CE-PTE) Analysis Sets.
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Protection of trial subjects |
The Data and Safety Monitoring Board (DSMB) reviewed safety data at 2 time points (when approximately 33% and 67% of the patients were randomized and completed the Late Follow-up Visit). At both meetings, the DSMB concluded that the study could continue without modification. Subjects were free to withdraw from the study at any time and could be discontinued from the study at the request of the Investigator or sponsor. This study was conducted in accordance with current United States (US) Food and Drug Administration (FDA) clinical trial regulations and guidelines, International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, the European Union Directive 2001/20/EC for clinical trials conducted in the European Union, and the institutional review board (IRB)/independent ethics committee (IEC)/ Research Ethics Board (REB), and local legal requirements.
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Background therapy |
For subjects with wound infections only, aztreonam and/or metronidazole could be added, if needed. | ||
Evidence for comparator |
Zyvox® (linezolid) is the only oral agent approved for methicillin-resistant Staphylococcus aureus (MRSA) activity. Linezolid has approximately 100% bioavailability, good efficacy, and an acceptable safety profile. | ||
Actual start date of recruitment |
19 Sep 2011
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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: 10
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Country: Number of subjects enrolled |
Spain: 2
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
United States: 314
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Country: Number of subjects enrolled |
Argentina: 26
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Country: Number of subjects enrolled |
Russian Federation: 208
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Country: Number of subjects enrolled |
South Africa: 94
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Country: Number of subjects enrolled |
Australia: 5
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Country: Number of subjects enrolled |
New Zealand: 4
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Worldwide total number of subjects |
666
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EEA total number of subjects |
15
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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) |
2
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Adults (18-64 years) |
588
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From 65 to 84 years |
70
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85 years and over |
6
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Eligible subjects signed an informed consent form and were to meet all of the inclusion and none of the exclusion criteria prior to be randomized in this study. Randomization was done via an interactive web system in a 1:1 ratio. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (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 |
The sponsor, Investigator, study staff participating in direct patient care or clinical evaluations, and subjects were blinded to treatment assignment until all subjects had completed the study and the database was locked. A double-dummy approach was chosen with placebo unique to each active treatment (placebo for TR-701 FA and placebo for linezolid for both IV and oral formulations) to maintain the treatment blind.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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TR-701 FA 200 mg | ||||||||||||||||||||||||||||||
Arm description |
Subjects were to be randomized to receive TR-701 FA 200 milligrams (mg) once daily for 6 days, followed by 4 days of placebo treatment. Subjects received 3 infusions or 3 tablets of study treatment (1 active dose and 2 double dummy placebo doses) daily. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
TR-701 FA
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Investigational medicinal product code |
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Other name |
Tedizolid Phosphate, tedizolid
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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 |
Subjects were dosed for 10 days. Subjects could have received IV therapy for the entire treatment duration. After Dose 1 and Dose 2 (after study day 1), subjects could be switched from IV to oral study drug at the investigator's discretion provided clinical criteria were met. All infusions were to be 60±10 minutes. Oral administration was twice daily.
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Arm title
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Linezolid 600 mg | ||||||||||||||||||||||||||||||
Arm description |
Subjects were to be randomized to receive IV to oral linezolid 600 mg every 12 hours for 10 days. Subjects received 3 infusions or 3 tablets of study treatment (2 active doses and 1 double dummy placebo dose) daily. | ||||||||||||||||||||||||||||||
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 |
Infusion, Tablet
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
Subjects were dosed for 10 days. Subjects could have received IV therapy for the entire treatment duration. After Dose 1 and Dose 2 (after study day 1), subjects could be switched from IV to oral study drug at the investigator's discretion provided clinical criteria were met. All infusions were to be 60±10 minutes. Oral administration was twice daily.
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Baseline characteristics reporting groups
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Reporting group title |
TR-701 FA 200 mg
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Reporting group description |
Subjects were to be randomized to receive TR-701 FA 200 milligrams (mg) once daily for 6 days, followed by 4 days of placebo treatment. Subjects received 3 infusions or 3 tablets of study treatment (1 active dose and 2 double dummy placebo doses) daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Linezolid 600 mg
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Reporting group description |
Subjects were to be randomized to receive IV to oral linezolid 600 mg every 12 hours for 10 days. Subjects received 3 infusions or 3 tablets of study treatment (2 active doses and 1 double dummy placebo dose) daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
TR-701 FA 200 mg
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Reporting group description |
Subjects were to be randomized to receive TR-701 FA 200 milligrams (mg) once daily for 6 days, followed by 4 days of placebo treatment. Subjects received 3 infusions or 3 tablets of study treatment (1 active dose and 2 double dummy placebo doses) daily. | ||
Reporting group title |
Linezolid 600 mg
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Reporting group description |
Subjects were to be randomized to receive IV to oral linezolid 600 mg every 12 hours for 10 days. Subjects received 3 infusions or 3 tablets of study treatment (2 active doses and 1 double dummy placebo dose) daily. | ||
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End point title |
Investigator’s Assessment of Clinical Success at the Post Treatment Evaluation Visit - ITT | |||||||||
End point description |
Clinical success defined as resolution/near resolution of disease specific signs and symptoms, absence/near resolution of baseline systemic signs of infection, and no further antibiotic therapy required for treatment of primary acute bacterial skin and skin structure infection (ABSSSI) lesion. A count of responders: subjects classified by the investigator as clinical successes. The analysis population is the ITT analysis set including data from all randomized subjects.
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End point type |
Primary
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End point timeframe |
Post-Treatment Evaluation (7-14 days after the End of Therapy)
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Statistical analysis title |
Analysis for Clinical Success at PTE - ITT | |||||||||
Statistical analysis description |
Non-inferiority test of the Risk difference which corresponds to the tedizolid (TR-701 FA) responder rate minus the linezolid responder rate.
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Comparison groups |
TR-701 FA 200 mg v Linezolid 600 mg
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Number of subjects included in analysis |
666
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | |||||||||
Method |
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Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
0.3
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-4.8 | |||||||||
upper limit |
5.1 | |||||||||
| Notes [1] - A two-sided 95% CI was calculated for the observed differences in the clinical success rates at the PTE Visit (after the infusion of study drug) using the method of Miettinen and Nurminen with adjustment for clinical syndrome and geographical region. Non-inferiority was concluded if the lower limit of the 95% CI was greater than -10%. |
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End point title |
Investigator’s Assessment of Clinical Success at the Post Treatment Evaluation Visit – CE-PTE | |||||||||
End point description |
Clinical success defined as resolution/near resolution of disease specific signs and symptoms, absence/near resolution of baseline systemic signs of infection, and no further antibiotic therapy required for treatment of primary ABSSSI lesion. A count of responders: subjects classified by the investigator as clinical successes. The analysis population is the clinically evaluable at PTE (CE-PTE) analysis set including data from all randomized subjects receiving minimal study therapy, completed EOT and PTE Investigator's assessments, no concomitant systemic antibiotic therapy through PTE, and no confounding events or factors.
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End point type |
Primary
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End point timeframe |
Post-Treatment Evaluation (7-14 days after the End of Therapy)
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Statistical analysis title |
Analysis for Clinical Success at PTE - CE-PTE | |||||||||
Statistical analysis description |
Non-inferiority test of the Risk difference which corresponds to the tedizolid (TR-701 FA) responder rate minus the linezolid responder rate.
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Comparison groups |
TR-701 FA 200 mg v Linezolid 600 mg
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Number of subjects included in analysis |
570
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [2] | |||||||||
Method |
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Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
-3.7
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-8 | |||||||||
upper limit |
0 | |||||||||
| Notes [2] - A two-sided 95% CI was calculated for the observed differences in the clinical success rates at the PTE Visit (after the infusion of study drug) using the method of Miettinen and Nurminen with adjustment for clinical syndrome and geographical region. Non-inferiority was concluded if the lower limit of the 95% CI was greater than -10%. |
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End point title |
The Early Clinical Response Rate - ITT | |||||||||
End point description |
A count of responders: subjects with no increase in lesion surface area from baseline. The analysis population is the ITT analysis set including data from all randomized subjects.
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End point type |
Secondary
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End point timeframe |
48-72 hours after first dose of study drug
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Statistical analysis title |
Analysis for The Early Clinical Response - ITT | |||||||||
Statistical analysis description |
Non-inferiority test of the Risk difference which corresponds to the tedizolid (TR-701 FA) responder rate minus the linezolid responder rate.
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Comparison groups |
TR-701 FA 200 mg v Linezolid 600 mg
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Number of subjects included in analysis |
666
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [3] | |||||||||
Method |
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Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
2.6
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-3 | |||||||||
upper limit |
8.2 | |||||||||
| Notes [3] - A two-sided 95% Confidence Interval (CI) was calculated for the observed differences in the early clinical response rates at 48 to 72 Hours after the first infusion of study drug using the method of Miettinen and Nurminen without stratification. Non-inferiority was concluded if the lower limit of the 95% CI was greater than -10%. |
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End point title |
Clinical Response at the End of Therapy Visit - ITT | |||||||||
End point description |
A count of responders: subjects with no increase in lesion surface area from baseline. The analysis population is the ITT analysis set including data from all randomized subjects.
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End point type |
Secondary
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End point timeframe |
Day 11 after first dose of study drug
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Statistical analysis title |
Analysis for Clinical Response at the EOT - ITT | |||||||||
Statistical analysis description |
Risk difference which corresponds to the tedizolid (TR-701 FA) responder rate minus the linezolid responder rate.
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Comparison groups |
TR-701 FA 200 mg v Linezolid 600 mg
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Number of subjects included in analysis |
666
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Analysis specification |
Pre-specified
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Analysis type |
other [4] | |||||||||
Method |
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Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
-1
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-6.1 | |||||||||
upper limit |
4.1 | |||||||||
| Notes [4] - A two-sided 95% CI was calculated for the observed differences in the clinical response rates at 11 Days after the first infusion of study drug using the method of Miettinen and Nurminen without stratification. |
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End point title |
Investigator’s Assessment of Clinical Response at the 48-72 Hour Visit- ITT | |||||||||
End point description |
A count of responders: subjects with clinical improvement defined as improvement in overall clinical status. The analysis population is the ITT analysis set including data from all randomized subjects.
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End point type |
Secondary
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End point timeframe |
48-72 hours after first dose of study drug
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Statistical analysis title |
Analysis for Clinical Response at 48-72 hours -ITT | |||||||||
Statistical analysis description |
Risk difference which corresponds to the tedizolid (TR-701 FA) responder rate minus the linezolid responder rate.
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Comparison groups |
TR-701 FA 200 mg v Linezolid 600 mg
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Number of subjects included in analysis |
666
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Analysis specification |
Pre-specified
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Analysis type |
other [5] | |||||||||
Method |
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Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
1.2
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-3.3 | |||||||||
upper limit |
5.5 | |||||||||
| Notes [5] - A two-sided 95% CI was calculated for the observed differences in the clinical response rates at 48-72 hours after first infusion of study drug using the method of Miettinen and Nurminen without stratification. |
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End point title |
Investigator’s Assessment of Clinical Response at the Day 7 Visit- ITT | |||||||||
End point description |
A count of responders: subjects with clinical improvement defined as improvement in overall clinical status. The analysis population is the ITT analysis set including data from all randomized subjects.
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End point type |
Secondary
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End point timeframe |
Day 7 after first dose of study drug
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Statistical analysis title |
Analysis for Clinical Response at Day 7 -ITT | |||||||||
Statistical analysis description |
Risk difference which corresponds to the tedizolid (TR-701 FA) responder rate minus the linezolid responder rate.
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Comparison groups |
TR-701 FA 200 mg v Linezolid 600 mg
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Number of subjects included in analysis |
666
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Analysis specification |
Pre-specified
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Analysis type |
other [6] | |||||||||
Method |
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Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
0.9
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-3.2 | |||||||||
upper limit |
4.9 | |||||||||
| Notes [6] - A two-sided 95% CI was calculated for the observed differences in the clinical response rates at 7 Days after the first infusion of study drug using the method of Miettinen and Nurminen without stratification. |
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End point title |
Investigator’s Assessment of Clinical Response at the EOT Visit-CE-EOT | |||||||||
End point description |
A count of responders: subjects classified by the investigator as clinical successes. The analysis population is the clinically evaluable at PTE (CE-EOT) analysis set including data from all randomized subjects receiving minimal study therapy, completed EOT Investigator's assessment, no concomitant systemic antibiotic therapy through EOT, and no confounding events or factors.
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End point type |
Secondary
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End point timeframe |
Day 11 after first dose of study drug
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Statistical analysis title |
Analysis for Clinical Response at EOT –CE-EOT | |||||||||
Statistical analysis description |
Risk difference which corresponds to the tedizolid (TR-701 FA) responder rate minus the linezolid responder rate.
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Comparison groups |
TR-701 FA 200 mg v Linezolid 600 mg
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Number of subjects included in analysis |
589
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Analysis specification |
Pre-specified
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Analysis type |
other [7] | |||||||||
Method |
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Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
-2
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-5.7 | |||||||||
upper limit |
1.2 | |||||||||
| Notes [7] - A two-sided 95% CI was calculated for the observed differences in the clinical response rates at 11 Days after the first infusion of study drug using the method of Miettinen and Nurminen without stratification. |
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End point title |
Clinical Response at the End of Therapy Visit - CE-EOTUS | |||||||||
End point description |
A count of responders: subjects with no increase in lesion surface area from baseline. The analysis population is the clinically evaluable at EOT using programmatic assessment of response, a United States FDA objective (CE-EOTUS) analysis set including data from all randomized subjects receiving minimal study therapy, completed EOT Investigator's assessment, no concomitant systemic antibiotic therapy through EOT, and no confounding events or factors.
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End point type |
Secondary
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End point timeframe |
Day 11 after first dose of study drug
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Statistical analysis title |
Analysis for Clinical Response at EOT - CE-EOTUS | |||||||||
Statistical analysis description |
Risk difference which corresponds to the tedizolid (TR-701 FA) responder rate minus the linezolid responder rate.
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Comparison groups |
TR-701 FA 200 mg v Linezolid 600 mg
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Number of subjects included in analysis |
603
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Analysis specification |
Pre-specified
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Analysis type |
other [8] | |||||||||
Method |
||||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
-4.1
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Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
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lower limit |
-8.8 | |||||||||
upper limit |
0.3 | |||||||||
| Notes [8] - A two-sided 95% CI was calculated for the observed differences in the clinical response rates at 11 Days after the first infusion of study drug using the method of Miettinen and Nurminen without stratification. |
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End point title |
Change From Baseline in Patient-reported Pain via the Total Faces Rating Scale, by Study Visit - ITT | ||||||||||||||||||||||||
End point description |
The mean change in total faces rating scale (FRS) is presented by Study Visit. The assessment was made at 6 time points. One visit per subject on Day 2 and Day 3, only 1 visit total for Days 4-6, only 1 visit total for Days 7-9, only 1 visit total for Days 10-13, and 1 visit after Day 14. Data displayed for Day 2, Day 4-6, Day 7-9, and Day 10-13. Baseline is the last assessment made before first dose of study drug. The FRS is a 10 point scale where 0 is no pain, 4 is hurts little more, and 10 is the worst pain “you can imagine”. The analysis population is the ITT analysis set including data from all randomized subjects.
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End point type |
Secondary
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End point timeframe |
Multiple: Day 2, Day 4-6, Day 7-9, Day 10-13
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Collected from signing of the ICF through the late follow-up visit (up to 38 days)
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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 |
13.1
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Reporting groups
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Reporting group title |
TR-701 FA 200 mg
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Reporting group description |
Subjects were to be randomized to receive TR-701 FA 200 mg once daily for 6 days, followed by 4 days of placebo treatment. Subjects received 3 infusions or 3 tablets of study treatment (1 active dose and 2 double dummy placebo doses) daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Linezolid 600 mg
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Reporting group description |
Subjects were to be randomized to receive IV to oral linezolid 600 mg every 12 hours for 10 days. Subjects received 3 infusions or 3 tablets of study treatment (2 active doses and 1 double dummy placebo dose) daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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17 Oct 2012 |
Protocol Amendment 6 changed the definition of responder in the primary efficacy endpoint to a ≥20% reduction in lesion area and no fever component. Protocol Amendment 6 was reviewed by the US FDA and agreement that the Special Protocol Assessment was still intact. |
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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. | |||
| Analyses for this study were conducted using 2 statistical plans, 1 for the US FDA and 1 for the EMA, to address differing guidance on the development of antibacterials. These differences are reflected in the EudraCT and clinicaltrials.gov records. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/25421472 |
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