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Study to Compare Lefamulin to Moxifloxacin for the Treatment of Adults With Pneumonia (LEAP2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02813694
Recruitment Status : Completed
First Posted : June 27, 2016
Results First Posted : October 23, 2019
Last Update Posted : October 23, 2019
Sponsor:
Information provided by (Responsible Party):
Nabriva Therapeutics AG

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Community Acquired Pneumonia
Interventions Drug: lefamulin
Drug: Moxifloxacin
Enrollment 738
Recruitment Details The study was designed to enroll adults with CABP for which oral antibacterial therapy was appropriate. Subjects with PORT score of II, III and IV were eligible. The first subject was randomized in August 2016 and the last subject was randomized in December 2017
Pre-assignment Details Subjects who met inclusion criteria and did not meet exclusion criteria were randomly assigned to a treatment group. Administration of study drug was expected to occur as soon as possible after the diagnosis of CABP with all Screening/baseline assessments expected to be completed within 24 hours before the first dose of study drug.
Arm/Group Title Lefamulin Moxifloxacin
Hide Arm/Group Description oral lefamulin, 600mg oral moxifloxacin, 400mg
Period Title: Overall Study
Started 370 [1] 368 [1]
Completed [2] 353 354 [2]
Not Completed 17 14
Reason Not Completed
Physician Decision             0             1
Withdrawal by Subject             10             9
Lost to Follow-up             1             1
Death             3             3
Randomized- did not receive study drug             2             0
Patient hospitalized             1             0
[1]
Intent to Treat Analysis Set
[2]
Completed Study (Late Follow Up Assessment)
Arm/Group Title Lefamulin Moxifloxacin Total
Hide Arm/Group Description oral lefamulin, 600mg oral moxifloxacin, 400mg Total of all reporting groups
Overall Number of Baseline Participants 370 368 738
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 370 participants 368 participants 738 participants
57.4  (16.4) 57.7  (16.2) 57.5  (16.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 370 participants 368 participants 738 participants
Female
163
  44.1%
188
  51.1%
351
  47.6%
Male
207
  55.9%
180
  48.9%
387
  52.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 370 participants 368 participants 738 participants
Hispanic or Latino
45
  12.2%
38
  10.3%
83
  11.2%
Not Hispanic or Latino
325
  87.8%
330
  89.7%
655
  88.8%
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 370 participants 368 participants 738 participants
American Indian or Alaska Native
24
   6.5%
17
   4.6%
41
   5.6%
Asian
49
  13.2%
53
  14.4%
102
  13.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
19
   5.1%
22
   6.0%
41
   5.6%
White
274
  74.1%
270
  73.4%
544
  73.7%
More than one race
4
   1.1%
6
   1.6%
10
   1.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 370 participants 368 participants 738 participants
Argentina 6 7 13
Romania 11 7 18
Hungary 13 15 28
United States 11 12 23
Philippines 35 36 71
Ukraine 65 63 128
Russia 31 24 55
Spain 0 1 1
South Korea 12 14 26
Latvia 3 0 3
Taiwan 0 1 1
Poland 4 3 7
Mexico 1 3 4
South Africa 21 34 55
Georgia 22 19 41
Bulgaria 38 42 80
Chile 2 2 4
Serbia 66 63 129
Peru 29 22 51
Renal Status  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 370 participants 368 participants 738 participants
Severe impairment (CrCl <30 mL/min)
4
   1.1%
3
   0.8%
7
   0.9%
Moderate impairment (CrCl 30 to <60 mL/min)
64
  17.3%
70
  19.0%
134
  18.2%
Mild impairment (CrCl 60 to <90 mL/min)
112
  30.3%
117
  31.8%
229
  31.0%
Normal function (CrCl >/= 90 mL/min)
190
  51.4%
178
  48.4%
368
  49.9%
Pneumonia Outcomes Research Team (PORT) Risk Class   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 370 participants 368 participants 738 participants
I
1
   0.3%
2
   0.5%
3
   0.4%
II
183
  49.5%
189
  51.4%
372
  50.4%
III
145
  39.2%
133
  36.1%
278
  37.7%
IV
40
  10.8%
42
  11.4%
82
  11.1%
V
1
   0.3%
2
   0.5%
3
   0.4%
[1]
Measure Description: PORT Risk Class is a clinical prediction rule used to calculate risk of morbidity and mortality among patients presenting with community-acquired pneumonia taking into consideration age, history of comorbid conditions, physical examination findings, and laboratory or radiographic results. PORT Risk Class I is a PORT score of 0-50, II is 51-70, III is 71-90, IV is 91-130 and V is >130 with higher risk class indicating higher risk of morbidity and mortality.
CURB-65 Score   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 370 participants 368 participants 738 participants
0
87
  23.5%
80
  21.7%
167
  22.6%
1
197
  53.2%
196
  53.3%
393
  53.3%
2
74
  20.0%
77
  20.9%
151
  20.5%
3
12
   3.2%
13
   3.5%
25
   3.4%
4
0
   0.0%
2
   0.5%
2
   0.3%
5
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: CURB-65 is a clinical tool used to predict mortality in patients with community acquired pneumonia. The risk of death at 30 days increases as the score increases; a score of 0 indicates the lowest risk of death and a score of 5 indicates the highest risk of death. Defined as confusion of new onset, BUN >19 mg/dL, respiratory rate ≥30 breaths/min, systolic blood pressure <90 mm Hg or diastolic blood pressure ≤60 mm Hg, and age ≥65 years.
American Thoracic Society (ATS) Minor Severity Criteria   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 370 participants 368 participants 738 participants
31
   8.4%
37
  10.1%
68
   9.2%
[1]
Measure Description: ATS minor criteria are used to indicate severe community acquired pneumonia and suggests the need for intensive care unit (ICU) level care. Defined as presence of 3 or more of the following 9 criteria at baseline: respiratory rate of 30 breaths/min or greater, oxygen saturation less than 90% or PaO2 less than 60mmHg, blood urea nitrogen level of 20mg/dL or greater, white blood cell count less than 4,000/mm3, confusion, multilobar infiltrates, platelet level less than 100,000 cells/mm3, temperature lower than 36 °C, or systolic blood pressure less than 90mmHg.
Systemic inflammatory response syndrome (SIRS) Criteria   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 370 participants 368 participants 738 participants
353
  95.4%
342
  92.9%
695
  94.2%
[1]
Measure Description: SIRS is used to define a clinical response to a nonspecific insult of either infectious or noninfectious origin. SIRS is defined as a subject meeting at least 2 or more of the following: Fever of more than 38C (100.4F) or less than 36C (96.8F); heart rate greater than 90 beats/min; respiratory rate greater than 20 breaths/min or PaCO2 less than 32 mm Hg; abnormal white blood cell count (greater than 12,000/microL or less than 4,000/microL or greater than 10% immature band forms)
Bacteremic  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 370 participants 368 participants 738 participants
6
   1.6%
9
   2.4%
15
   2.0%
Received Single Dose Short-Acting Antibacterial within 72 hrs of Randomization  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 370 participants 368 participants 738 participants
77
  20.8%
72
  19.6%
149
  20.2%
1.Primary Outcome
Title Early Clinical Response (ECR)
Hide Description ECR was defined as survival with improvement in at least 2 signs and symptoms of CABP (relative to baseline), no worsening of any CABP sign or symptom, and no use of concomitant antibiotics for the treatment of CABP through the ECR assessment
Time Frame 96 hours +/- 24 hours after first dose of study drug
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: All randomized subjects
Arm/Group Title Lefamulin Moxifloxacin
Hide Arm/Group Description:
oral lefamulin, 600mg
oral moxifloxacin, 400mg
Overall Number of Participants Analyzed 370 368
Measure Type: Count of Participants
Unit of Measure: Participants
Responder
336
  90.8%
334
  90.8%
Non-responder
29
   7.8%
31
   8.4%
Indeterminate
5
   1.4%
3
   0.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lefamulin, Moxifloxacin
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments non-inferiority margin= 10%
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-4.4 to 4.5
Estimation Comments Difference in percentage of Responders for ECR (Lefamulin - Moxifloxacin). Confidence interval computed using continuity-corrected Z-statistic
2.Secondary Outcome
Title Investigator's Assessment of Clinical Response (IACR)
Hide Description IACR was defined as resolution or improvement of a subject's clinical signs and symptoms such that no additional antibacterial therapy was administered for the treatment of the current episode of CABP
Time Frame IACR was assessed at the Test-of-Cure Visit; 5 to 10 days after last dose of study drug
Hide Outcome Measure Data
Hide Analysis Population Description
Modified ITT population: All randomized subjects who received any amount of study drug
Arm/Group Title Lefamulin Moxifloxacin
Hide Arm/Group Description:
oral lefamulin, 600mg
oral moxifloxacin, 400mg
Overall Number of Participants Analyzed 368 368
Measure Type: Count of Participants
Unit of Measure: Participants
Success
322
  87.5%
328
  89.1%
Failure
44
  12.0%
32
   8.7%
Indeterminate
2
   0.5%
8
   2.2%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lefamulin, Moxifloxacin
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments non-inferiority margin = 10%
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -1.6
Confidence Interval (2-Sided) 95%
-6.3 to 3.1
Estimation Comments Difference in Percentage of Success for IACR at test of cure visit (Lefamulin - Moxifloxacin). CI computed via Miettinen-Nurminen method, adjusted for prior antibiotic use [Y vs. N] and PORT risk class [III vs. IV/V], using CMH stratum weights.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Lefamulin, Moxifloxacin
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments non-inferiority margain = 10%
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -1.6
Confidence Interval (2-Sided) 95%
-6.5 to 3.3
Estimation Comments Difference in percentage of Success for IACR at test of cure visit. Confidence interval computed using a continuity-corrected Z-test.
3.Secondary Outcome
Title Investigator's Assessment of Clinical Response (IACR)
Hide Description IACR was defined as resolution or improvement of a subject's clinical signs and symptoms such that no additional antibacterial therapy was administered for the treatment of the current episode of CABP
Time Frame IACR was assessed at the Test-of-Cure Visit; 5 to 10 days after last dose of study drug
Hide Outcome Measure Data
Hide Analysis Population Description
Clinically Evaluable population: Subset of ITT population having met additional pre-defined criteria.
Arm/Group Title Lefamulin Moxifloxacin
Hide Arm/Group Description:
oral lefamulin, 600mg
oral moxifloxacin, 400mg
Overall Number of Participants Analyzed 330 326
Measure Type: Count of Participants
Unit of Measure: Participants
Success
296
  89.7%
305
  93.6%
Failure
34
  10.3%
21
   6.4%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lefamulin, Moxifloxacin
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments non-inferiority margain = 10%
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -3.9
Confidence Interval (2-Sided) 95%
-8.2 to 0.5
Estimation Comments Difference in percentage of success for IACR at test of cure visit (Lefamulin - Moxifloxacin). CI computed via Miettinen-Nurminen method, adjusted for prior antibiotic use [Y vs. N]; PORT risk class [III vs. IV/V], using CMH stratum weights.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Lefamulin, Moxifloxacin
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments non-inferiority margin = 10%
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -3.9
Confidence Interval (2-Sided) 95%
-8.4 to 0.7
Estimation Comments Difference in Percentage of Success for IACR at test of cure visit (Lefamulin - Moxifloxacin). Confidence interval computed using continuity-corrected Z-statistic.
Time Frame Adverse events were recorded from the time of informed consent through the completion of the Test-of-Cure (TOC) Visit (i.e., 5-10 days after the last dose of study drug). Serious adverse events were recorded from the time of informed consent to the Late Follow-Up Visit (approximately 30 days after the first dose of study drug).
Adverse Event Reporting Description Adverse events are reported for randomized subjects who received at least one dose of study drug (Safety Population). Treatment-emergent adverse events, defined as events occurring after the first dose of study drug, are reported. Adverse events were recorded whether or not they were considered to be study drug related.
 
Arm/Group Title Lefamulin Moxifloxacin
Hide Arm/Group Description oral lefamulin, 600mg oral moxifloxacin, 400mg
All-Cause Mortality
Lefamulin Moxifloxacin
Affected / at Risk (%) Affected / at Risk (%)
Total   5/368 (1.36%)   3/368 (0.82%) 
Hide Serious Adverse Events
Lefamulin Moxifloxacin
Affected / at Risk (%) Affected / at Risk (%)
Total   17/368 (4.62%)   18/368 (4.89%) 
Blood and lymphatic system disorders     
Anaemia  1  0/368 (0.00%)  1/368 (0.27%) 
Cardiac disorders     
Acute Myocardial Infarction  1  1/368 (0.27%)  2/368 (0.54%) 
Atrial Fibrillation  1  1/368 (0.27%)  0/368 (0.00%) 
Myocardial Infarction  1  1/368 (0.27%)  0/368 (0.00%) 
Gastrointestinal disorders     
Inguinal Hernia Strangulated  1  0/368 (0.00%)  1/368 (0.27%) 
General disorders     
Death  1  0/368 (0.00%)  1/368 (0.27%) 
Hepatobiliary disorders     
Cholecystitis Acute  1  0/368 (0.00%)  1/368 (0.27%) 
Infections and infestations     
Empyema  1  1/368 (0.27%)  0/368 (0.00%) 
Endocarditis  1  1/368 (0.27%)  0/368 (0.00%) 
Lung Abscess  1  1/368 (0.27%)  2/368 (0.54%) 
Pneumonia  1  4/368 (1.09%)  1/368 (0.27%) 
Pneumonia Bacterial  1  1/368 (0.27%)  0/368 (0.00%) 
Tuberculous Pleurisy  1  0/368 (0.00%)  1/368 (0.27%) 
Urinary Tract Infection  1  1/368 (0.27%)  1/368 (0.27%) 
Investigations     
Hepatic Enzyme Increased  1  0/368 (0.00%)  1/368 (0.27%) 
Nuclear Magnetic Resonance Imaging Brain Abnormal  1  1/368 (0.27%)  0/368 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Acute Myeloid Leukaemia  1  1/368 (0.27%)  0/368 (0.00%) 
Renal Cancer  1  1/368 (0.27%)  0/368 (0.00%) 
Small Cell Lung Cancer  1  0/368 (0.00%)  1/368 (0.27%) 
Squamous Cell Carcinoma of Lung  1  0/368 (0.00%)  1/368 (0.27%) 
Nervous system disorders     
Cerebral Infarction  1  0/368 (0.00%)  1/368 (0.27%) 
Cerebrovascular Accident  1  0/368 (0.00%)  1/368 (0.27%) 
Embolic Stroke  1  0/368 (0.00%)  1/368 (0.27%) 
Respiratory, thoracic and mediastinal disorders     
Acute Respiratory Distress Syndrome  1  2/368 (0.54%)  0/368 (0.00%) 
Acute Respiratory Failure  1  1/368 (0.27%)  0/368 (0.00%) 
Pulmonary Oedema  1  1/368 (0.27%)  0/368 (0.00%) 
Respiratory Failure  1  0/368 (0.00%)  1/368 (0.27%) 
Skin and subcutaneous tissue disorders     
Angioedema  1  0/368 (0.00%)  1/368 (0.27%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Lefamulin Moxifloxacin
Affected / at Risk (%) Affected / at Risk (%)
Total   61/368 (16.58%)   12/368 (3.26%) 
Gastrointestinal disorders     
Diarrhoea  1  45/368 (12.23%)  4/368 (1.09%) 
Nausea  1  19/368 (5.16%)  7/368 (1.90%) 
Vomiting  1  12/368 (3.26%)  3/368 (0.82%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by 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.
All data from the study is confidential information. Sponsor has the right to publish first. Thereafter, PI may publish data from the study, but PI must submit the publication to Sponsor for review at least 60 days prior to publication. Sponsor may remove any confidential and/or proprietary information. If Sponsor's publication is not submitted within 12 months after the study, or if Sponsor decides not to publish, PI may publish the data, subject to Sponsor's rights in the agreement.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Jennifer Schranz, M.D., Chief Medical Officer
Organization: Nabriva Therapeutics US, Inc
Phone: 610 981 2842
EMail: jennifer.schranz@nabriva.com
Layout table for additonal information
Responsible Party: Nabriva Therapeutics AG
ClinicalTrials.gov Identifier: NCT02813694    
Other Study ID Numbers: NAB-BC-3781-3102
First Submitted: June 20, 2016
First Posted: June 27, 2016
Results First Submitted: August 28, 2019
Results First Posted: October 23, 2019
Last Update Posted: October 23, 2019