Clinical Trial Results:
A Phase 3b, Double-Blind, Multicenter, Randomised Study to Compare the Efficacy and Safety of Single Dose Dalbavancin to a Two Dose Regimen of Dalbavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infections
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Summary
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EudraCT number |
2014-000419-15 |
Trial protocol |
LV EE HU BG HR |
Global end of trial date |
11 Mar 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Oct 2018
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First version publication date |
19 Oct 2018
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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 |
DUR001-303
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02127970 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Allergan Pharmaceutical International Ltd
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Sponsor organisation address |
Clonshaugh Business & Technology Park, Coolock, Dublin,, Ireland, D17 E400
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Public contact |
Clinical Trials Registry Team, Allergan plc, 001 877‐277‐8566, IR-CTRegistration@Allergan.com
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Scientific contact |
Therapeutic Area Head, Allergan plc, 001 862-261-7000, IR-CTRegistration@Allergan.com
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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 |
11 Mar 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Mar 2015
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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 was to compare the efficacy of treatment with a single dose of dalbavancin 1500 mg to treatment with a two-dose regimen of dalbavancin (1000 mg on Day 1 followed by 500 mg on Day 8) in participants with known or suspected Gram-positive acute bacterial skin and skin structure infections (ABSSSI) at 48 to 72 hours after the initiation of treatment.
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Protection of trial subjects |
All study participants were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 Apr 2014
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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 |
United States: 318
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Country: Number of subjects enrolled |
Croatia: 4
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Country: Number of subjects enrolled |
Estonia: 13
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Country: Number of subjects enrolled |
Georgia: 31
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Country: Number of subjects enrolled |
Hungary: 3
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Country: Number of subjects enrolled |
Latvia: 63
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Country: Number of subjects enrolled |
Romania: 10
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Country: Number of subjects enrolled |
Russian Federation: 54
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Country: Number of subjects enrolled |
Serbia: 26
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Country: Number of subjects enrolled |
South Africa: 40
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Country: Number of subjects enrolled |
Ukraine: 136
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Worldwide total number of subjects |
698
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EEA total number of subjects |
93
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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) |
608
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From 65 to 84 years |
88
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85 years and over |
2
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 698 participants were randomly assigned in a 1:1 ratio to the following treatment groups: • Single-dose dalbavancin group, received a single dose of dalbavancin intravenous (IV) on Day 1, and a matching placebo IV on Day 8. • Two-dose dalbavancin group, received dalbavancin IV on Day 1 and Day 8. | ||||||||||||||||||||||||||||||
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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, Carer, Assessor | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Single-Dose Dalbavancin | ||||||||||||||||||||||||||||||
Arm description |
Single-dose of dalbavancin 1500 mg intravenous (IV) infusion over 30 minutes on Day 1 followed by dalbavancin-matching placebo IV infusion over 30 minutes on Day 8 for participants with creatinine clearance (CrCl) ≥30 mL/min or with CrCl <30 mL/min who were receiving regular hemodialysis or peritoneal dialysis. For participants with CrCl <30 mL/min who were not receiving regular hemodialysis or peritoneal dialysis, the dalbavancin dose was 1000 mg. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Dalbavancin
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Investigational medicinal product code |
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Other name |
DALVANCE®
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Participants randomised to the single-dose dalbavancin group were to receive a single dose of dalbavancin IV on Day 1 over 30 minutes as follows: 1500 mg for participants with CrCl ≥30 mL/min or with creatinine clearance (CrCl) <30 mL/min who were receiving regular hemodialysis or peritoneal dialysis. For participants with CrCl <30 mL/min who were not receiving regular hemodialysis or peritoneal dialysis, the dalbavancin dose was 1000 mg.
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Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Participants randomised to the single-dose dalbavancin group were to receive dalbavancin-matching placebo IV on Day 8 over 30 minutes.
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Arm title
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Two-Dose Dalbavancin | ||||||||||||||||||||||||||||||
Arm description |
Two-dose regimen of dalbavancin 1000 mg IV infusion over 30 minutes on Day 1 followed by 500 mg IV infusion over 30 minutes on Day 8 for participants with CrCl ≥30 mL/min or with CrCl <30 mL/min who were receiving regular hemodialysis or peritoneal dialysis. For participants with CrCl <30 mL/min who were not receiving regular hemodialysis or peritoneal dialysis, the dalbavancin doses were 750 mg on Day 1 and 375 mg on Day 8. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Dalbavancin
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Investigational medicinal product code |
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Other name |
DALVANCE®
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Participants randomised to the two-dose dalbavancin group were to receive dalbavancin IV over 30 minutes as follows: 1000 mg on Day 1 and 500 mg on Day 8 for participants with CrCl ≥30 mL/min or with CrCl <30 mL/min who were receiving regular hemodialysis or peritoneal dialysis. For participants with CrCl <30 mL/min who were not receiving regular hemodialysis or peritoneal dialysis, the dalbavancin doses were 750 mg on Day 1 and 375 mg on Day 8.
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Baseline characteristics reporting groups
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Reporting group title |
Single-Dose Dalbavancin
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Reporting group description |
Single-dose of dalbavancin 1500 mg intravenous (IV) infusion over 30 minutes on Day 1 followed by dalbavancin-matching placebo IV infusion over 30 minutes on Day 8 for participants with creatinine clearance (CrCl) ≥30 mL/min or with CrCl <30 mL/min who were receiving regular hemodialysis or peritoneal dialysis. For participants with CrCl <30 mL/min who were not receiving regular hemodialysis or peritoneal dialysis, the dalbavancin dose was 1000 mg. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Two-Dose Dalbavancin
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Reporting group description |
Two-dose regimen of dalbavancin 1000 mg IV infusion over 30 minutes on Day 1 followed by 500 mg IV infusion over 30 minutes on Day 8 for participants with CrCl ≥30 mL/min or with CrCl <30 mL/min who were receiving regular hemodialysis or peritoneal dialysis. For participants with CrCl <30 mL/min who were not receiving regular hemodialysis or peritoneal dialysis, the dalbavancin doses were 750 mg on Day 1 and 375 mg on Day 8. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Single-Dose Dalbavancin
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Reporting group description |
Single-dose of dalbavancin 1500 mg intravenous (IV) infusion over 30 minutes on Day 1 followed by dalbavancin-matching placebo IV infusion over 30 minutes on Day 8 for participants with creatinine clearance (CrCl) ≥30 mL/min or with CrCl <30 mL/min who were receiving regular hemodialysis or peritoneal dialysis. For participants with CrCl <30 mL/min who were not receiving regular hemodialysis or peritoneal dialysis, the dalbavancin dose was 1000 mg. | ||
Reporting group title |
Two-Dose Dalbavancin
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Reporting group description |
Two-dose regimen of dalbavancin 1000 mg IV infusion over 30 minutes on Day 1 followed by 500 mg IV infusion over 30 minutes on Day 8 for participants with CrCl ≥30 mL/min or with CrCl <30 mL/min who were receiving regular hemodialysis or peritoneal dialysis. For participants with CrCl <30 mL/min who were not receiving regular hemodialysis or peritoneal dialysis, the dalbavancin doses were 750 mg on Day 1 and 375 mg on Day 8. | ||
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End point title |
Percentage of Participants Who were Clinical Responders 48-72 Hours After the Initiation of Study Drug | ||||||||||||
End point description |
Clinical responder was defined as a participant who was alive and had received no rescue therapy for acute bacterial skin and skin structure infection (ABSSSI) prior to the 48-72 hour infection site assessment (if an antibiotic has been given for another reason, the participant will not be considered a non-responder for this reason); and examination of the participant’s ABSSSI lesion demonstrates a decrease of ≥ 20% in lesion area (calculated as the longest length multiplied by the longest perpendicular width) relative to the baseline measurement. ITT Population included all randomized participants regardless of whether or not they received study drug.
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End point type |
Primary
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End point timeframe |
Up to 48-72 hours after the initiation of study drug
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Statistical analysis title |
Single Dose Dalbavancin vs Two Dose Dalbavancin | ||||||||||||
Statistical analysis description |
For the difference in clinical responder rates (single-dose group minus two-dose group), the 95% CI was calculated using the Miettinen and Nurminen method without adjustment.
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Comparison groups |
Single-Dose Dalbavancin v Two-Dose Dalbavancin
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Number of subjects included in analysis |
698
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
Method |
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Parameter type |
Difference | ||||||||||||
Point estimate |
-2.9
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-8.5 | ||||||||||||
upper limit |
2.8 | ||||||||||||
| Notes [1] - The non-inferiority hypothesis test was to be a one-sided hypothesis test performed at the 2.5% level of significance. If the lower limit of the 95% CI for the difference in responder rates is greater than -10%, then the single-dose dalbavancin regimen was to be declared non-inferior to the two dose dalbavancin regimen. |
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End point title |
Percentage of Participants by Clinical Status at End of Treatment (EOT) and Final Visit (FV) | ||||||||||||||||||||||||||||||
End point description |
Clinical Success was defined as follows: For evaluation at EOT visit, lesion area must be decreased by ≥80% from baseline and at FV lesion area must be decreased by ≥90% from baseline; Temperature is ≤37.6°C; Local signs of tenderness to palpation and swelling/induration are no worse than mild; For evaluation at EOT visit, local signs of fluctuance and localized heat/warmth must be improved from baseline and no worse than mild, and at FV local signs of fluctuance and localized heat/warmth must be absent; for participants with a wound infection the severity of purulent drainage is improved and no worse than mild relative to baseline. Clinical Failure was defined as the opposite to success or if the participant died during the study period up to visit or received study therapy for ABSSSI beyond the protocol treatment period. Clinical status was Indeterminate if any of the data needed to determine clinical success or clinical failure were missing. ITT Population.
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End point type |
Secondary
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End point timeframe |
End of Treatment (Day 14-15 after the initiation of study drug) and Final Visit (28 ±2 days after the initiation of study drug)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Percentage of Participants by Clinical Status Based on Localized Fluctuance and Heat/Warmth at End of Treatment (EOT) | |||||||||||||||||||||
End point description |
Clinical Success was defined as localized fluctuance and heat/warmth that if present at Baseline must be improved and no worse than mild. Clinical Failure was defined as the opposite to success. Clinical status was Indeterminate if any of the data needed to determine clinical success or clinical failure were missing. ITT Population included all randomized participants regardless of whether or not they received study drug.
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End point type |
Other pre-specified
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End point timeframe |
EOT (Day 14-15)
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Percentage of Participants by Investigator Assessment of Clinical Outcome | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
A successful outcome was based on resolution or improvement of all signs and symptoms of the infection to such an extent that no further antibacterial treatment was given. An unsuccessful outcome was the opposite of successful. An Indeterminate outcome was defined as any of the data needed to determine a successful or unsuccessful outcome were missing. ITT Population included all randomized participants regardless of whether or not they received study drug. Number analysed is the number of participants with data available for analysis at the given time-point.
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End point type |
Other pre-specified
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End point timeframe |
Day 3-4, Day 8, EOT (Day 14-15) and Final Visit (Day 28 +/- 2 days)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Percentage of Participants Achieving Clinical Outcome of Success Based on Key Target Pathogen at Baseline | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
A successful outcome was based on resolution or improvement of all signs and symptoms of the infection to such an extent that no further antibacterial treatment was given. Microbiological Intent-to-treat (MicroITT) Population included all ITT participants who had at least 1 Gram-positive bacterial pathogen isolated at Baseline. Here, "n" is the number of participants with data available for analysis at the given time-point.
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End point type |
Other pre-specified
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End point timeframe |
Day 3-4 and EOT (Day 14-15)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Percentage of Participants With Complete Resolution of Local Signs of Infection | ||||||||||||||||||||||||
End point description |
Resolution of Local Signs of Infection that include absence of purulence/drainage, erythema, heat/localized warmth, pain/tenderness to palpation, fluctuance, and swelling/induration. ITT Population included all randomized participants regardless of whether or not they received study drug. Here, "n" is the number of participants with data available for analysis at the given time-point.
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End point type |
Other pre-specified
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End point timeframe |
Day 3-4, Day 8, EOT (Day 14-15) and Final Visit (Day 28 +/- 2 days)
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change From Baseline in Participant's Assessment of Pain | |||||||||||||||||||||||||||
End point description |
Using the Brief Pain Inventory Scale, participants rated their pain “right now” on a scale where: 0=no pain to 10=pain as bad as you can imagine. A negative change from Baseline indicated improvement. ITT Population included all randomized participants regardless of whether or not they received study drug. Number analysed is the number of participants with data available for analysis at the given time-point.
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End point type |
Other pre-specified
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End point timeframe |
Baseline (Day 0) to Day 3-4, Day 8, EOT (Day 14-15) and Final Visit (Day 28 + /- 2 days)
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Percentage of Participants by Resource Utilization Categories | |||||||||||||||||||||||||||
End point description |
Resource Utilization Categories included: Any additional visits (including urgent care), Any additional procedures, Any additional tests, Any home visits or nursing care and Any ER Visits. The percentage of participants in each category is reported. ITT Population included all randomized participants regardless of whether or not they received study drug. Number analysed is the number of participants with data available for analysis at the given time-point.
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End point type |
Other pre-specified
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End point timeframe |
Final Visit (Day 28 +/- 2 days)
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Percentage of Participants by Skin and Soft Tissue Infection-Convenience (SSTI-C) Questionnaire: Overall Satisfaction Response | |||||||||||||||||||||||||||
End point description |
The SSTI-C Questionnaire is an 11-item self-reported questionnaire that measures subjective experiences of the participant. One of the items assessed was overall satisfaction with treatment. Participants answered the question: “Overall, how satisfied were you with your antibiotic treatment?” using one of the following responses: Extremely satisfied, Moderately satisfied, Not at all satisfied, Slightly satisfied and Very satisfied. The percentage of participants in each category is reported. ITT Population included all randomized participants regardless of whether or not they received study drug. Number analysed is the number of participants with data available for analysis at the given time-point.
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End point type |
Other pre-specified
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End point timeframe |
EOT (Day 14-15)
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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 28 Days
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Adverse event reporting additional description |
The number of participants at risk for Serious Adverse Events and Adverse Events was based on the Safety Population that included all participants who received at least 1 dose of study treatment.
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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 |
Two-Dose Dalbavancin
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Reporting group description |
Two-dose regimen of dalbavancin 1000 mg IV infusion over 30 minutes on Day 1 followed by 500 mg IV infusion over 30 minutes on Day 8 for participants with CrCl ≥30 mL/min or with CrCl <30 mL/min who were receiving regular hemodialysis or peritoneal dialysis. For participants with CrCl <30 mL/min who were not receiving regular hemodialysis or peritoneal dialysis, the dalbavancin doses were 750 mg on Day 1 and 375 mg on Day 8. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Single-Dose Dalbavancin
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Reporting group description |
Single-dose of dalbavancin 1500 mg intravenous (IV) infusion over 30 minutes on Day 1 followed by dalbavancin-matching placebo IV infusion over 30 minutes on Day 8 for participants with creatinine clearance (CrCl) ≥30 mL/min or with CrCl <30 mL/min who were receiving regular hemodialysis or peritoneal dialysis. For participants with CrCl <30 mL/min who were not receiving regular hemodialysis or peritoneal dialysis, the dalbavancin dose was 1000 mg. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 occurred at a frequency of 5% or greater. |
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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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26 Mar 2014 |
1. A secondary objective was added to introduce a population PK study in order to compare the population PK profiles of a single dose of dalbavancin 1500 mg versus the two-dose regimen of dalbavancin (1000 mg on Day 1 followed by 500 mg on Day 8) in participants with ABSSSI and to estimate and compare the PK/PD relationship of each dose regimen. 2. Clinical laboratory tests were to be obtained at Baseline, Day 3-4 and at Day 14-15 or premature withdrawal instead of just baseline and Day 28. 3. Minor changes to the protocol included the option to dilute dalbavancin in glucose as well as dextrose, contact information for medical monitoring and safety purposes as well as clarification of statistical methodology. |
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24 Nov 2014 |
1. Clarification was made to the definition of rescue antibacterial therapy as related to the primary endpoint. 2. Clarification was provided related to the analysis populations for the secondary analyses. 3. The protocol sample size was changed from 410 participants to 698 based on the observed response rate at the interim analysis. |
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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 | |||
