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Delafloxacin vs Vancomycin and Aztreonam for the Treatment of Acute Bacterial Skin and Skin Structure Infections

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ClinicalTrials.gov Identifier: NCT01984684
Recruitment Status : Completed
First Posted : November 15, 2013
Results First Posted : August 28, 2017
Last Update Posted : November 17, 2017
Sponsor:
Information provided by (Responsible Party):
Melinta Therapeutics, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Skin and Subcutaneous Tissue Bacterial Infections
Skin Structures and Soft Tissue Infections
Interventions Drug: delafloxacin
Drug: vancomycin
Drug: aztreonam
Enrollment 850

Recruitment Details  
Pre-assignment Details  
Arm/Group Title Delafloxacin Vancomycin Plus Aztreonam
Hide Arm/Group Description 300 mg IV Q12H for 6 doses, 450 mg oral tablet Q12H for a minimum of 10 up to a maximum of 28 doses total Vancomycin 15 mg/kg IV plus two grams Aztreonam every 12 hours for a minimum of 10 up to a maximum of 28 doses total
Period Title: Overall Study
Started 423 427
Completed 366 368
Not Completed 57 59
Reason Not Completed
Lost to Follow-up             25             24
Adverse Event             8             12
Withdrawal by Subject             9             9
Lack of Efficacy             3             6
Physician Decision             4             2
Protocol Violation             4             2
Death             0             1
Noncompliance with study drug             2             1
Subject incarcerated             1             0
Study drug not available at site             1             1
Subject had inadequate IV access             0             1
Arm/Group Title Delafloxacin Vancomycin Plus Aztreonam Total
Hide Arm/Group Description 300mg iv Q12H for 6 doses, 450mg oral tablet Q12H for a minimum of 10 up to a maximum of 28 doses total Vancomycin 15mg/kg iv plus two grams Aztreonam every 12 hours for a minimum of 10 up to a maximum of 28 doses total Total of all reporting groups
Overall Number of Baseline Participants 423 427 850
Hide Baseline Analysis Population Description
Intent-to-Treat (ITT) Population included all patients who were randomly assigned to treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 423 participants 427 participants 850 participants
51.2  (15.98) 50.2  (16.03) 50.7  (16.00)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 423 participants 427 participants 850 participants
<= 65 years
344
  81.3%
352
  82.4%
696
  81.9%
> 65 years
79
  18.7%
75
  17.6%
154
  18.1%
> 75 years
35
   8.3%
31
   7.3%
66
   7.8%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 423 participants 427 participants 850 participants
Female
161
  38.1%
151
  35.4%
312
  36.7%
Male
262
  61.9%
276
  64.6%
538
  63.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 423 participants 427 participants 850 participants
Hispanic or Latino
132
  31.2%
99
  23.2%
231
  27.2%
Not Hispanic or Latino
291
  68.8%
328
  76.8%
619
  72.8%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 423 participants 427 participants 850 participants
American Indian or Alaska Native
12
   2.8%
7
   1.6%
19
   2.2%
Asian
11
   2.6%
15
   3.5%
26
   3.1%
Native Hawaiian or Other Pacific Islander
2
   0.5%
2
   0.5%
4
   0.5%
Black or African American
13
   3.1%
18
   4.2%
31
   3.6%
White
348
  82.3%
355
  83.1%
703
  82.7%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
37
   8.7%
30
   7.0%
67
   7.9%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 423 participants 427 participants 850 participants
Europe
165
  39.0%
173
  40.5%
338
  39.8%
North America
202
  47.8%
196
  45.9%
398
  46.8%
Mexico
8
   1.9%
4
   0.9%
12
   1.4%
Brazil
0
   0.0%
5
   1.2%
5
   0.6%
Chile
1
   0.2%
1
   0.2%
2
   0.2%
Peru
34
   8.0%
29
   6.8%
63
   7.4%
South Korea
8
   1.9%
13
   3.0%
21
   2.5%
Taiwan
1
   0.2%
1
   0.2%
2
   0.2%
Argentina
4
   0.9%
5
   1.2%
9
   1.1%
BMI (Body Mass Index)  
Mean (Standard Deviation)
Unit of measure:  Kg/m2
Number Analyzed 423 participants 427 participants 850 participants
30.4  (7.44) 30.7  (7.54) 30.5  (7.49)
BMI category  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 423 participants 427 participants 850 participants
< 30 kg/m2
212
  50.1%
213
  49.9%
425
  50.0%
>= 30 kg/m2
211
  49.9%
214
  50.1%
425
  50.0%
Presence of diabetes  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 423 participants 427 participants 850 participants
53
  12.5%
54
  12.6%
107
  12.6%
1.Primary Outcome
Title Objective Response of ≥20% Reduction in Lesion Erythema Area Compared to Baseline at 48 to 72 Hours After Initiation of Treatment as Determined by Digital Measurements of the Leading Edge.
Hide Description A patient was considered a responder if s/he had a ≥20% reduction in size of the area of erythema associated with the baseline ABSSSI, as determined by digital planimetry of the leading edge and had none of the reasons for clinical failure; a patient was considered a non-responder (failure) if s/he had <20% reduction in size of the area of erythema associated with the baseline ABSSSI as determined by digital planimetry of the leading edge, or had major intervention such as another antibiotic or surgical intervention or died within 74 hours after initiation of study drug.
Time Frame 48 to 72 hrs after starting treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Delafloxacin Vancomycin Plus Aztreonam
Hide Arm/Group Description:
300mg iv Q12H for 6 doses, 450mg oral tablet Q12H for a minimum of 10 up to a maximum of 28 doses total
Vancomycin 15mg/kg iv plus two grams Aztreonam every 12 hours for a minimum of 10 up to a maximum of 28 doses total
Overall Number of Participants Analyzed 423 427
Measure Type: Count of Participants
Unit of Measure: Participants
Responder
354
  83.7%
344
  80.6%
Nonresponder
69
  16.3%
83
  19.4%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Delafloxacin, Vancomycin Plus Aztreonam
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments A 2-sided 95% confidence interval (CI) for noninferiority testing was computed based on the difference in responder rates for vancomycin + aztreonam and delafloxacin at the primary endpoint. If the upper limit (UL) of the CI was less than 0.10, delafloxacin would be considered noninferior to vancomycin + aztreonam.
Method of Estimation Estimation Parameter Difference in Responder Rates
Estimated Value 3.1
Confidence Interval (2-Sided) 95%
-2.0 to 8.3
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Investigator-assessed Response of Signs and Symptoms of Infection at the Follow up Visit (European Medicines Agency [EMA] Primary Endpoint)
Hide Description

A patient was considered a Cure if all baseline signs and symptoms of ABSSSI had resolved; if some symptoms remained, but the patient was improved to the extent that no additional antibiotic treatment was necessary, the response was Improved. A patient was considered a Failure for any of the following reasons: nonstudy antibacterial drug therapy was required because of lack of efficacy after at least 4 doses of study drug or for a treatment-related AE; study antibacterial drug therapy was required for longer than 28 doses; and/or unplanned surgical intervention was needed after study entry except for limited bedside debridement and standard wound care. Improved and Indeterminate responses were considered failures in the primary analysis.

A sensitivity analysis was also performed, in which the assigned responses were Success (Cure + Improved) or Failure (Failure + Indeterminate/Missing).

Time Frame Study Day 14 ± 1
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Delafloxacin Vancomycin Plus Aztreonam
Hide Arm/Group Description:
300mg iv Q12H for 6 doses, 450mg oral tablet Q12H for a minimum of 10 up to a maximum of 28 doses total
Vancomycin 15mg/kg iv plus two grams Aztreonam every 12 hours for a minimum of 10 up to a maximum of 28 doses total
Overall Number of Participants Analyzed 423 427
Measure Type: Count of Participants
Unit of Measure: Participants
Cure
244
  57.7%
255
  59.7%
Improved
125
  29.6%
107
  25.1%
Failure
17
   4.0%
21
   4.9%
Indeterminate/Missing
37
   8.7%
44
  10.3%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Delafloxacin, Vancomycin Plus Aztreonam
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Analysis of the investigator's assessment of response of signs and symptoms of infection (cure only) was performed using the Miettinen-Nurminen method without stratification for the ITT analysis set.
Method of Estimation Estimation Parameter Difference in Cure Rates
Estimated Value -2.0
Confidence Interval (2-Sided) 95%
-8.6 to 4.6
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Investigator-assessed Response of Signs and Symptoms of Infection at the Late Follow-up Visit
Hide Description

A patient was considered a Cure if all baseline signs and symptoms of ABSSSI had resolved; if some symptoms remained, but the patient was improved to the extent that no additional antibiotic treatment was necessary, the response was Improved. A patient was considered a Failure for any of the following reasons: nonstudy antibacterial drug therapy was required because of lack of efficacy after at least 4 doses of study drug or for a treatment-related AE; study antibacterial drug therapy was required for longer than 28 doses; and/or unplanned surgical intervention was needed after study entry except for limited bedside debridement and standard wound care. Improved and Indeterminate responses were considered failures in the primary analysis.

A sensitivity analysis was also performed, in which the assigned responses were Success (Cure + Improved) or Failure (Failure + Indeterminate/Missing).

Time Frame Study Day 21 to 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Delafloxacin Vancomycin Plus Aztreonam
Hide Arm/Group Description:
300mg iv Q12H for 6 doses, 450mg oral tablet Q12H for a minimum of 10 up to a maximum of 28 doses total
Vancomycin 15mg/kg iv plus two grams Aztreonam every 12 hours for a minimum of 10 up to a maximum of 28 doses total
Overall Number of Participants Analyzed 423 427
Measure Type: Count of Participants
Unit of Measure: Participants
Cure
287
  67.8%
303
  71.0%
Improved
66
  15.6%
48
  11.2%
Failure
21
   5.0%
24
   5.6%
Indeterminate/Missing
49
  11.6%
52
  12.2%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Delafloxacin, Vancomycin Plus Aztreonam
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Analysis of the investigator's assessment of response (cure only) at the Late Follow-up Visit was assessed using the Miettinen-Nurminen method without stratification.
Method of Estimation Estimation Parameter Difference in Cure Rates
Estimated Value -3.1
Confidence Interval (2-Sided) 95%
-9.3 to 3.1
Estimation Comments [Not Specified]
Time Frame Adverse event data were collected from the time the patient signed informed consent through the follow-up telephone contact 30 (+3) days after the last dose of study drug (up to 48 days).
Adverse Event Reporting Description AE data are only included for the safety population which included all patients in the ITT population who received at least 1 dose of study drug.
 
Arm/Group Title Delafloxacin Vancomycin Plus Aztreonam
Hide Arm/Group Description 300mg iv Q12H for 6 doses, 450mg oral tablet Q12H for a minimum of 10 up to a maximum of 28 doses total Vancomycin 15mg/kg iv plus two grams Aztreonam every 12 hours for a minimum of 10 up to a maximum of 28 doses total
All-Cause Mortality
Delafloxacin Vancomycin Plus Aztreonam
Affected / at Risk (%) Affected / at Risk (%)
Total   0/417 (0.00%)   2/425 (0.47%) 
Show Serious Adverse Events Hide Serious Adverse Events
Delafloxacin Vancomycin Plus Aztreonam
Affected / at Risk (%) Affected / at Risk (%)
Total   16/417 (3.84%)   17/425 (4.00%) 
Cardiac disorders     
Myocardial infarction * 1  0/417 (0.00%)  1/425 (0.24%) 
Gastrointestinal disorders     
Colitis * 1  0/417 (0.00%)  1/425 (0.24%) 
Intestinal ischemia * 1  0/417 (0.00%)  1/425 (0.24%) 
Nausea * 1  0/417 (0.00%)  1/425 (0.24%) 
General disorders     
Pyrexia * 1  0/417 (0.00%)  1/425 (0.24%) 
Systemic inflammatory response symdrome * 1  0/417 (0.00%)  1/425 (0.24%) 
Infections and infestations     
Abscess limb * 1  1/417 (0.24%)  0/425 (0.00%) 
Arthritis bacterial * 1  0/417 (0.00%)  1/425 (0.24%) 
Cellulitis * 1  1/417 (0.24%)  3/425 (0.71%) 
Erysipelas * 1  0/417 (0.00%)  1/425 (0.24%) 
Infection * 1  1/417 (0.24%)  1/425 (0.24%) 
Osteomyelitis * 1  1/417 (0.24%)  0/425 (0.00%) 
Pneumonia * 1  1/417 (0.24%)  1/425 (0.24%) 
Skin infection * 1  4/417 (0.96%)  0/425 (0.00%) 
Injury, poisoning and procedural complications     
Clavicle fracture * 1  0/417 (0.00%)  1/425 (0.24%) 
Laceration * 1  0/417 (0.00%)  1/425 (0.24%) 
Subdural hematoma * 1  1/417 (0.24%)  1/425 (0.24%) 
Toxicity to various agents * 1  1/417 (0.24%)  0/425 (0.00%) 
Wound * 1  0/417 (0.00%)  2/425 (0.47%) 
Investigations     
ALT increased * 1  1/417 (0.24%)  0/425 (0.00%) 
AST increased * 1  1/417 (0.24%)  0/425 (0.00%) 
Musculoskeletal and connective tissue disorders     
Rheumatoid arthritis * 1  0/417 (0.00%)  1/425 (0.24%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Adenocarcinoma of the colon * 1  1/417 (0.24%)  0/425 (0.00%) 
Neoplasm malignant * 1  0/417 (0.00%)  1/425 (0.24%) 
Psychiatric disorders     
Schizophrenia * 1  0/417 (0.00%)  1/425 (0.24%) 
Suicidal ideation * 1  0/417 (0.00%)  1/425 (0.24%) 
Renal and urinary disorders     
Renal failure * 1  0/417 (0.00%)  2/425 (0.47%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure * 1  1/417 (0.24%)  0/425 (0.00%) 
Pulmonary embolism * 1  2/417 (0.48%)  0/425 (0.00%) 
Skin and subcutaneous tissue disorders     
Dermatitis * 1  0/417 (0.00%)  1/425 (0.24%) 
Rash * 1  0/417 (0.00%)  1/425 (0.24%) 
Urticaria * 1  1/417 (0.24%)  0/425 (0.00%) 
1
Term from vocabulary, MedDRA (16.1)
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Delafloxacin Vancomycin Plus Aztreonam
Affected / at Risk (%) Affected / at Risk (%)
Total   55/417 (13.19%)   32/425 (7.53%) 
Gastrointestinal disorders     
Diarrhea * 1  32/417 (7.67%)  14/425 (3.29%) 
Nausea * 1  32/417 (7.67%)  19/425 (4.47%) 
1
Term from vocabulary, MedDRA (16.1)
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Melinta has the right to first publication of results, which would be made in conjunction with the PIs from all appropriate sites. Thereafter, PIs may publish results provided the PI submits the proposed publication to Melinta for review at least 60 days prior to the date of the proposed publication. Melinta may remove any information that is considered confidential and/or proprietary. If a publication is not submitted within 12 months of study conclusion, the PI may publish results.
Results Point of Contact
Name/Title: Sue Cammarata (Chief Medical Officer)
Organization: Melinta Therapeutics, Inc.
Phone: 1-844-MELINTA (1-844-635-4682)
Responsible Party: Melinta Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT01984684     History of Changes
Other Study ID Numbers: RX-3341-303
First Submitted: November 8, 2013
First Posted: November 15, 2013
Results First Submitted: July 26, 2017
Results First Posted: August 28, 2017
Last Update Posted: November 17, 2017