Clinical Trial Results:
Phase 3 Study of IV to Oral 6-Day Tedizolid Phosphate Compared with 10-Day Comparator in Subjects 12 to <18 Years with cSSTI
Summary
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EudraCT number |
2014-004023-40 |
Trial protocol |
SI BG DE CZ LT LV ES PL Outside EU/EEA |
Global end of trial date |
17 Sep 2018
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Results information
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Results version number |
v2(current) |
This version publication date |
08 Nov 2019
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First version publication date |
23 Mar 2019
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Other versions |
v1 |
Version creation reason |
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 |
MK-1986-012
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02276482 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Cubist Protocol Number: TR701-122, Merck Protocol Number: MK-1986-012 | ||
Sponsors
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Sponsor organisation name |
Cubist Pharmaceuticals LLC
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Sponsor organisation address |
2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
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Public contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
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Scientific contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001379-PIP01-12 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
17 Sep 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
17 Sep 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
17 Sep 2018
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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 purpose of the study is to compare the safety of intravenous (IV) and/or oral 6-day 200 mg tedizolid phosphate with 10-day comparator in participants 12 to <18 years with complicated skin and soft tissue infection (cSSTI).
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Protection of trial subjects |
This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
The following additional measure defined for this individual study was in place for the protection of trial subjects: the investigator may discontinue study medication and initiate rescue medication for the treatment of a gram negative pathogen.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 Mar 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 |
Bulgaria: 29
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Country: Number of subjects enrolled |
Georgia: 38
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Country: Number of subjects enrolled |
Latvia: 9
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Country: Number of subjects enrolled |
Lithuania: 4
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Country: Number of subjects enrolled |
Poland: 4
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Country: Number of subjects enrolled |
Spain: 1
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Country: Number of subjects enrolled |
Ukraine: 9
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Country: Number of subjects enrolled |
United States: 10
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Country: Number of subjects enrolled |
South Africa: 16
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Worldwide total number of subjects |
120
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EEA total number of subjects |
47
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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) |
120
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
Participants included in the study were age 12 years to <18 years; had adequate venous access for intravenous (IV) administration of study drug for at least 24 hours (for participants receiving IV medication) and collection of protocol specified blood samples, and had cSSTI meeting at least 1 of the clinical syndrome definitions. | ||||||||||||||||||||||||
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 |
Single blind | ||||||||||||||||||||||||
Roles blinded |
Assessor [1] | ||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Tedizolid Phosphate | ||||||||||||||||||||||||
Arm description |
Tedizolid Phosphate IV and/or oral 200 mg once per day for 6 days. Participants with gram-negative wound infection may receive aztreonam (IV) and/or metronidazole (IV or oral). | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Tedizolid Phosphate
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Investigational medicinal product code |
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Other name |
TR701-122, MK-1986, SIVEXTRO®
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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 |
200 mg administered daily for 6 days
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Investigational medicinal product name |
Metronidazole
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Investigational medicinal product code |
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Other name |
Flagyl, Metro
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Pharmaceutical forms |
Injection, Tablet
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
Adjunctive metronidazole may be initiated on Day 1 or during the first 3 days of treatment if the participant is determined or suspected to have an infection with an anaerobic pathogen.
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Investigational medicinal product name |
Aztreonam
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Investigational medicinal product code |
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Other name |
Azactam, Cayston
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
In countries and/or sites where aztreonam is available, adjunctive aztreonam may be initiated on Day 1 or during the first 3 days of treatment if the participant is determined or suspected to have an infection with a gram-negative aerobic pathogen.
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Arm title
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Antibiotic comparator drug | ||||||||||||||||||||||||
Arm description |
IV and/or oral antibiotic comparator drug for 10 days. Participants with gram-negative wound infection may receive aztreonam (IV) and/or metronidazole (IV or oral). | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Antibiotic comparator includes the following: Vancomycin, Linezolid, Clindamycin, Flucloxacillin, Cefazolin, Cephalexin.
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Investigational medicinal product code |
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Other name |
Vancomycin: Vancocin, Firvanq, Lyphocin; Linezolid: Zyvox; Clindamycin: Cleocin; Cefazolin: Ancef, Kefzol; Cephalexin: Keflex, Zartan, Panixine, Biocef
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Pharmaceutical forms |
Infusion, Tablet, Capsule, Injection
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
Antibiotic comparator drug, IV and/or orally for 10 days.
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Investigational medicinal product name |
Metronidazole
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Investigational medicinal product code |
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Other name |
Flagyl, Metro
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Pharmaceutical forms |
Injection, Tablet
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
Adjunctive metronidazole may be initiated on Day 1 or during the first 3 days of treatment if the participant is determined or suspected to have an infection with an anaerobic pathogen.
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Investigational medicinal product name |
Aztreonam
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Investigational medicinal product code |
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Other name |
Azactam, Cayston
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
In countries and/or sites where aztreonam is available, adjunctive aztreonam may be initiated on Day 1 or during the first 3 days of treatment if the participant is determined or suspected to have an infection with an gram-negative aerobic pathogen.
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Notes [1] - The roles blinded appear inconsistent with a simple blinded trial. Justification: The assessor is blinded in this single-blind study. |
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Baseline characteristics reporting groups
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Reporting group title |
Tedizolid Phosphate
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Reporting group description |
Tedizolid Phosphate IV and/or oral 200 mg once per day for 6 days. Participants with gram-negative wound infection may receive aztreonam (IV) and/or metronidazole (IV or oral). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Antibiotic comparator drug
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Reporting group description |
IV and/or oral antibiotic comparator drug for 10 days. Participants with gram-negative wound infection may receive aztreonam (IV) and/or metronidazole (IV or oral). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Tedizolid Phosphate
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Reporting group description |
Tedizolid Phosphate IV and/or oral 200 mg once per day for 6 days. Participants with gram-negative wound infection may receive aztreonam (IV) and/or metronidazole (IV or oral). | ||
Reporting group title |
Antibiotic comparator drug
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Reporting group description |
IV and/or oral antibiotic comparator drug for 10 days. Participants with gram-negative wound infection may receive aztreonam (IV) and/or metronidazole (IV or oral). |
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End point title |
Number of Participants With Adverse Events on Tedizolid Phosphate and Comparator Drugs [1] | |||||||||
End point description |
An adverse event (AE) refers to a treatment-emergent adverse event (TE-AE). A TE-AE is any AE that newly appeared, increased in frequency, or worsened in severity following initiation of study drug. The analysis population consisted of all randomized participants who received at least one dose of study drug.
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End point type |
Primary
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End point timeframe |
Up to 40 days (including 30-day follow-up)
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analyses were planned for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Number of Participants with Investigator's Assessment Indicating Clinical Success at Test of Cure (TOC) Visit (Intent to Treat Analysis Set) | |||||||||
End point description |
Investigator’s assessment of clinical success is defined as (1) resolution or near resolution of most disease-specific signs and symptoms, (2) absence or near resolution of regional or systemic signs of infection (lymphadenopathy, fever, >10% immature neutrophils, abnormal white blood cell count), if present at baseline, and (3) no new signs, symptoms, or complications attributable to the infection under study so no further antibiotic therapy is required for the treatment of the primary lesion. The analysis population consisted of all randomized participants.
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End point type |
Secondary
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End point timeframe |
TOC Visit: 18-25 days after first drug infusion
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Statistical analysis title |
Between group comparison | |||||||||
Statistical analysis description |
The difference (Tedizolid minus Comparator group) in the clinical success rate and 95% confidence interval calculated using the unstratified method of Miettinen and Nurminen.
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Comparison groups |
Tedizolid Phosphate v Antibiotic comparator drug
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
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Method |
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Parameter type |
Difference in percentages | |||||||||
Point estimate |
3.6
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-6.3 | |||||||||
upper limit |
13.5 |
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End point title |
Number of Participants with Investigator's Assessment Indicating Clinical Success at TOC Visit (Clinically Evaluable-Test of Cure [CE-TOC] Analysis Set) | |||||||||
End point description |
Investigator’s assessment of clinical success is defined as (1) resolution or near resolution of most disease-specific signs and symptoms, (2) absence or near resolution of regional or systemic signs of infection (lymphadenopathy, fever, >10% immature neutrophils, abnormal white blood cell count), if present at baseline, and (3) no new signs, symptoms, or complications attributable to the infection under study so no further antibiotic therapy is required for the treatment of the primary lesion. The analysis population consisted of all randomized participants who received a full dose of study treatment and completed TOC.
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End point type |
Secondary
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End point timeframe |
TOC Visit: 18-25 days after first drug infusionn
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Statistical analysis title |
Between group comparison | |||||||||
Statistical analysis description |
The difference (Tedizolid minus Comparator group) in the clinical success rate and 95% confidence interval calculated using the unstratified method of Miettinen and Nurminen.
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Comparison groups |
Tedizolid Phosphate v Antibiotic comparator drug
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Number of subjects included in analysis |
114
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Analysis specification |
Pre-specified
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Analysis type |
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Method |
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Parameter type |
Difference in percentages | |||||||||
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 |
-3.4 | |||||||||
upper limit |
10.8 |
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End point title |
Number of Participants with Early Clinical Responses Measured by Lesion Reduction | |||||||||
End point description |
Early clinical response is defined as ≥20% reduction from baseline lesion area (defined as length multiplied by width of the erythema, edema, and/or induration [EEI]) at the 48-72 hour (hr) visit. The analysis population consisted of all randomized participants.
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End point type |
Secondary
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End point timeframe |
48-72 hr after first drug infusion
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Statistical analysis title |
Between group comparison | |||||||||
Statistical analysis description |
The difference (Tedizolid minus Comparator group) in the clinical success rate and 95% confidence interval calculated using the unstratified method of Miettinen and
Nurminen.
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Comparison groups |
Tedizolid Phosphate v Antibiotic comparator drug
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
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Method |
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Parameter type |
Difference in percentages | |||||||||
Point estimate |
-4.2
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-12.9 | |||||||||
upper limit |
4.4 |
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End point title |
Number of Participants with Investigator's Assessment Indicating Clinical Success at at End of Therapy (EOT) Visit (Intent to Treat Analysis Set) | |||||||||
End point description |
Investigator’s assessment of clinical success is defined as (1) resolution or near resolution of most disease specific signs and symptoms, (2) absence or near resolution of regional or systemic signs of infection (lymphadenopathy, fever, >10% immature neutrophils, abnormal white blood cell count), if present at baseline, and (3) no new signs, symptoms, or complications attributable to the infection under study so no further antibiotic therapy is required for the treatment of the primary lesion. The analysis population consisted of all randomized participants.
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End point type |
Secondary
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End point timeframe |
EOT Visit: up to 13 days after first drug infusion
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Statistical analysis title |
Between group comparison | |||||||||
Statistical analysis description |
The difference (Tedizolid minus Comparator group) in the clinical success rate and 95% confidence interval calculated using the unstratified method of Miettinen and Nurminen.
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Comparison groups |
Tedizolid Phosphate v Antibiotic comparator drug
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||
Method |
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Parameter type |
Difference in percentages | |||||||||
Point estimate |
0.2
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-7.4 | |||||||||
upper limit |
7.7 |
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End point title |
Number of Participants with Investigator's Assessment Indicating Clinical Success at EOT Visit (Clinically Evaluable-End of Therapy [CE-EOT] Analysis Set) | |||||||||
End point description |
Investigator’s assessment of clinical success is defined as (1) resolution or near resolution of most disease specific signs and symptoms, (2) absence or near resolution of regional or systemic signs of infection (lymphadenopathy, fever, >10% immature neutrophils, abnormal white blood cell count), if present at baseline, and (3) no new signs, symptoms, or complications attributable to the infection under study so no further antibiotic therapy is required for the treatment of the primary lesion. The analysis population consisted of all randomized participants received a full dose of study treatment and completed EOT.
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End point type |
Secondary
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End point timeframe |
EOT Visit: up to 13 days after first drug infusion
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Statistical analysis title |
Between group comparison | |||||||||
Statistical analysis description |
The difference (Tedizolid minus Comparator group) in the clinical success rate and 95% confidence interval calculated using the unstratified method of Miettinen and Nurminen.
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Comparison groups |
Tedizolid Phosphate v Antibiotic comparator drug
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Number of subjects included in analysis |
114
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||
Method |
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Parameter type |
Difference in percnetages | |||||||||
Point estimate |
0
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0 | |||||||||
upper limit |
0 |
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End point title |
Change from Baseline in Lesion Size | ||||||||||||||||||
End point description |
Lesion size is the area in cm^2 of erythema, edema or induration. A negative number corresponds to a decrease in lesion size. The analysis population consisted of all randomized participants who received a full dose of study treatment, had a baseline value and a TOC visit value (Days 18 to 25).
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End point type |
Other pre-specified
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End point timeframe |
Baseline and TOC visit (18 to 25 days after infusion)
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No statistical analyses for this end point |
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End point title |
Peak Plasma Concentration (Cmax) of Tedizolid | ||||||||||||
End point description |
The Cmax of tedizolid in plasma after the last dose was estimated based on population pharmacokinetic analysis of observed pharmacokinetic data. Blood samples were collected for pharmacokinetic analysis at specific time points. The analysis population consisted of all randomized participants who received a dose of tedizolid phosphate. Pharmacokinetic analysis was not performed with participants receiving antibiotic comparator drug.
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End point type |
Other pre-specified
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End point timeframe |
Day 1 at 5-80 minutes (min) and 4-12 hrs post-infusion or 2 samples collected between 4-12 hrs after oral dose, at least 60 min apart; at 48-72 hrs: within 60 min prior to administration and 4-12 hrs after administration; and anytime between Day 7 and 9
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No statistical analyses for this end point |
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End point title |
Area Under the Plasma Concentration Versus Time Curve Time 0 to 24 Hours (AUC0-24h) of Tedizolid | ||||||||||||
End point description |
AUC0-24h is a measure of the total tedizolid exposure in the plasma from the dose to 24 hours after last dose. AUC0-24h was estimated based on population pharmacokinetic analysis of observed pharmacokinetic data. Blood samples were collected for pharmacokinetic analysis at specific time points. The analysis population consisted of all randomized participants who received a dose of tedizolid phosphate. Pharmacokinetic analysis was not performed with participants receiving antibiotic comparator drug.
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End point type |
Other pre-specified
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End point timeframe |
Day 1 at 5-80 min and 4-12 hrs post-infusion or 2 samples collected between 4-12 hrs after oral dose, at least 60 min apart; at 48-72 hrs: within 60 min prior to administration and 4-12 hrs after administration; and anytime between Day 7 and 9
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No statistical analyses for this end point |
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Adverse events information [1]
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Timeframe for reporting adverse events |
Up to 40 days (including 30-day follow-up)
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
Antibiotic comparator drug
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Reporting group description |
IV and/or oral antibiotic comparator drug for 10 days. Participants with gram-negative wound infection may receive aztreonam (IV) and/or metronidazole (IV or oral). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tedizolid Phosphate
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Reporting group description |
Tedizolid Phosphate IV and/or oral 200 mg once per day for 6 days. Participants with gram-negative wound infection may receive aztreonam (IV) and/or metronidazole (IV or oral). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: No non-serious adverse events exceeded the 5% threshold for any treatment group. |
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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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04 Feb 2015 |
Amendment #1: primary reason for this amendment was to revise the study design, schedule of assessments, discontinuation of treatment, study drug, administration, sample collection, reporting of adverse events, and protocol deviations. |
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15 Apr 2016 |
Amendment #2: primary reason for this amendment was to revise the secondary objectives, overall study design, schedule of assessments, exclusion criteria, discontinuation of treatment, concomitant therapy rules, study drug, administration, reporting of adverse events, and handling of missing data. |
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27 Jun 2016 |
Amendment #3: primary reason for this amendment was to revise "IV to oral” therapy to “IV and/or oral" therapy, the inclusion/exclusion criteria, and sample collection assessment. |
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01 Feb 2017 |
Amendment #4: primary reason for this amendment was to revise the study design, study drug, safety samples, exclusion criteria, and discontinuation of treatment. |
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22 Jun 2017 |
Amendment #5: primary reason for this amendment was to revise the exclusion criteria and concomitant medications. |
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13 Jun 2018 |
Amendment #6: primary reason for this amendment was to revise the overall study design and the number of participants. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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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 |