LEAP: Study to Compare Lefamulin to Moxifloxacin (With or Without Linezolid) for the Treatment of Adults With Pneumonia

• Sponsor: Nabriva Therapeutics AG (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02559310
• Collaborator: (none)
• Enrollment: 551
• Locations: 99
• Arms: 2
• Duration (Months): 20
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study evaluates the safety and efficacy of lefamulin, a pleuromutilin, for the treatment of adults with moderate to severe community-acquired bacterial pneumonia.

Condition or Disease	Intervention/Treatment	Phase
Community Acquired Pneumonia	Drug: lefamulin; Drug: Moxifloxacin; Drug: Linezolid	Phase 3

Detailed Description

Lefamulin is a potent, semi-synthetic antibacterial belonging to a novel class known as the pleuromutilins. Both the intravenous (IV) and oral dosage forms of lefamulin are under investigation in this study. Lefamulin's in vitro antibacterial profile includes the most important bacterial pathogens causing respiratory tract infection (RTI). The antibacterial spectrum comprises S. pneumoniae, H. influenzae, M. catarrhalis, the atypical respiratory pathogens L. pneumophila, C. pneumoniae, and M. pneumoniae, S. aureus including MRSA and CA-MRSA, ß-haemolytic streptococci including S. pyogenes and S. agalactiae, and Enterococcus faecium including vancomycin-resistant enterococci (VRE). Moreover, as demonstrated in cross-resistance studies, lefamulin remains active against clinical isolates resistant to the following antimicrobial(s) (classes): macrolides, lincosamides, streptogramin B, oxazolidinones, tetracyclines, ß lactams, quinolones, trimethoprim-sulfametoxazole, mupirocin, and vancomycin.

Study Design

• Study Type: Interventional
• Actual Enrollment: 551 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy and Safety of Lefamulin (BC 3781) Versus Moxifloxacin (With or Without Adjunctive Linezolid) in Adults With Community-Acquired Bacterial Pneumonia
• Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Apr 1, 2017
• Actual Study Completion Date: May 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lefamulin Intravenous lefamulin with potential step-down to oral lefamulin	Drug: lefamulin; antibacterial agent; Other Names: BC-3781
Active Comparator: Moxifloxacin +/- Linezolid Intravenous moxifloxacin with potential step-down to oral moxifloxacin +/- linezolid	Drug: Moxifloxacin; antibacterial agent; Other Names: Avelox ; Drug: Linezolid; antibacterial agent; Other Names: Zyvox

Outcome Measures

Primary Outcome Measures

1. Early Clinical Response (ECR) [ECR was assessed 96 +/- 24 hours after the first dose of study drug.]

   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 (other than adjunctive linezolid, as allowed by the study protocol) for the treatment of CABP through the ECR assessment.

Secondary Outcome Measures

1. Investigator's Assessment of Clinical Response (IACR) [IACR was assessed at the Test-of-Cure visit; 5-10 days after the last dose of study drug.]

   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

2. Investigator's Assessment of Clinical Response (IACR) [IACR was assessed at the Test of Cure visit, 5 - 10 days after the last dose of study drug.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Be male or female at least 18 years of age.

2. Provide written informed consent and be willing and able to adhere to the study-specified procedures and restrictions.

3. Have an acute illness (7 days duration) with at least 3 of the following symptoms consistent with a lower respiratory tract infection (new or worsening):

• Dyspnea

• New or increased cough

• Purulent sputum production

• Chest pain due to pneumonia

1. Have at least 2 of the following vital sign abnormalities:

• Fever (body temperature >38.0°C (100.4°F) measured orally or equivalent temperature from an alternate body site) or hypothermia (body temperature <35.0°C (95.0°F) measured orally or equivalent temperature from an alternate body site)

• Hypotension (systolic blood pressure <90 mmHg)

• Tachycardia (heart rate >100 beats/min)

• Tachypnea (respiratory rate >20 breaths/min)

1. Have at least 1 other clinical sign or laboratory finding of CABP:

• Hypoxemia (i.e., O2 saturation <90% on room air or while receiving supplemental oxygen at subject's baseline requirement or PaO2 <60 mmHg)

• Auscultatory and/or percussion findings consistent with pneumonia (e.g., crackles, egophony, dullness)

• White blood cell (WBC) count >10,000 cells/mm3 or <4500 cells/mm3 or >15% immature neutrophils (bands) regardless of total WBC count

1. Have radiographically-documented pneumonia within 48 hours before enrollment (i.e., infiltrates in a lobar or multilobar distribution or diffuse opacities on chest x-ray or chest computed tomography scan consistent with acute bacterial pneumonia).

2. Have a Pneumonia Outcomes Research Team (PORT) Risk Class ≥III.

Exclusion Criteria:

1. Have received more than a single dose of a short-acting oral or IV antibacterial for CABP within 72 hours before randomization

2. Require concomitant systemic antibacterial therapy potentially effective against CABP pathogens

3. Have been hospitalized for 2 or more days within 90 days prior to the onset of symptoms or have resided in a nursing home or long-term healthcare facility within 30 days prior to the onset of symptoms. NOTE: Residence in an independent living facility is permitted.

4. Have confirmed or suspected CABP caused by a pathogen known to be resistant to any of the study drugs (e.g., Pseudomonas aeruginosa, any pathogen of the Enterobacteriaceae Family) or attributable to etiologies other than community acquired bacterial pathogens (e.g., ventilator associated pneumonia, hospital acquired bacterial pneumonia, bacterial aspiration pneumonia, Pneumocystis jiroveci pneumonia or other fungal pneumonia, viral or mycobacterial infection of the lung).

5. Have a noninfectious cause of pulmonary infiltrates (e.g., pulmonary embolism, chemical pneumonitis from aspiration, hypersensitivity pneumonia, congestive heart failure, bronchial obstruction, lung cancer, cystic fibrosis).

6. Have confirmed or suspected pleural empyema (does not include sterile parapneumonic effusions).

7. Require mechanical ventilation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site 1006	Hazard	Kentucky	United States	41701
2	Site 1008	Shreveport	Louisiana	United States	71103
3	Site 1005	Minneapolis	Minnesota	United States	55415
4	Site 1001	Butte	Montana	United States	59701
5	Site 1009	Akron	Ohio	United States	44309
6	Site 1002	Dayton	Ohio	United States	45402
7	Site 1004	Splendora	Texas	United States	77372
8	Site 3005	La Plata	Buenos Aires	Argentina	1900
9	Site 3006	Rosario	Santa Fe	Argentina	S2000CVB
10	Site 3004	Cordoba		Argentina	X5016KEH
11	Site 3003	Córdoba		Argentina	X5000EPU
12	Site 3007	Córdoba		Argentina	X5000JRD
13	Site 3001	Córdoba		Argentina	X5004CDT
14	Site 4003	Mostar		Bosnia and Herzegovina	88000
15	Site 4001	Tuzla		Bosnia and Herzegovina	75000
16	Site 4004	Zenica		Bosnia and Herzegovina	72000
17	Site 3104	Belo Horizonte	Minas Gerais	Brazil	30150-221
18	Site 3102	Passo Fundo	Rio Grande Do Sol	Brazil	99010-080
19	Site 3103	Campinas	Sao Paulo	Brazil	13059-900
20	Site 3101	Sao Paulo Do Rio Preto	Sao Paulo	Brazil	15090-000
21	Site 4105	Gabrovo		Bulgaria	5300
22	Site 4107	Lovech		Bulgaria	5500
23	Site 4112	Pernik		Bulgaria	2300
24	Site 4103	Ruse		Bulgaria	7002
25	Site 4108	Smolyan		Bulgaria	4700
26	Site 4102	Sofia		Bulgaria	1202
27	Site 4101	Sofia		Bulgaria	1233
28	Site 4106	Sofia		Bulgaria	1233
29	Site 4110	Sofia		Bulgaria	1606
30	Site 4111	Sofia		Bulgaria	1606
31	Site 4104	Veliko Tarnovo		Bulgaria	5000
32	Site 4109	Vidin		Bulgaria	3700
33	Site 4206	Tbilisi		Georgia	0101
34	Site 4204	Tbilisi		Georgia	0144
35	Site 4205	Tbilisi		Georgia	0144
36	Site 4201	Tbilisi		Georgia	0159
37	Site 4202	Tbilisi		Georgia	0186
38	Site 4305	Budapest		Hungary	1121
39	Site 4306	Csorna		Hungary	9300
40	Site 4304	Debrecen		Hungary	4043
41	Site 4302	Farkasgyepű		Hungary	8582
42	Site 4307	Miskolc		Hungary	3529
43	Site 4308	Miskolc		Hungary	3529
44	Site 4303	Törökbálint		Hungary	2045
45	Site 4403	Daugavpils		Latvia	LV-5417
46	Site 4401	Liepaja		Latvia	LV-3414
47	Site 4402	Riga		Latvia	LV-1038
48	Site 4603	Almelo	Overijssel	Netherlands	7609 PP
49	Site 4602	Helmond		Netherlands	5707 HA
50	Site 3205	Trujillo	La Libertad	Peru
51	Site 3202	Lima		Peru	Lima 18
52	Site 3204	Lima		Peru	Lima 1
53	Site 3201	Lima		Peru	Lima 29
54	Site 2005	Iloilo City		Philippines	5000
55	Site 2003	Manila City		Philippines	1000
56	Site 2004	Manila		Philippines	1012
57	Site 2002	Quezon City		Philippines	1100
58	Site 2001	Quezon City		Philippines	1114
59	Site 4703	Skierniewice	Lódzkie	Poland	96-100
60	Site 4704	Warszawa	Mazowieckie	Poland	02-097
61	Site 4701	Lódz		Poland	90-153
62	Site 4702	Wilkowice		Poland	43-365
63	Site 4802	Palazu Mare	Constanta	Romania	900002
64	Site 4801	Bucharest		Romania	21105
65	Site 4806	Bucharest		Romania	21105
66	Site 4810	Bucuresti		Romania	030303
67	Site 4811	Cluj-Napoca		Romania	040000
68	Site 4803	Craiova		Romania	200515
69	Site 4808	Craiova		Romania	200515
70	Site 4807	Timisoara		Romania	300310
71	Site 4809	Timisoara		Romania	300310
72	Site 4904	Chelyabinsk		Russian Federation	454021
73	Site 4902	Novosibirsk		Russian Federation	630102
74	Site 4906	Smolensk		Russian Federation	214019
75	Site 4903	St. Petersburg		Russian Federation	191163
76	Site 4901	St. Petersburg		Russian Federation	197706
77	Site 4905	Yaroslavl		Russian Federation	150062
78	Site 5003	Nis	Nišavski Okrug	Serbia	18204
79	Site 5002	Belgrade		Serbia	11000
80	Site 5004	Sremska Kamenica		Serbia	11080
81	Site 5001	Kragujevac	Šumadijski Okrug	Serbia	34000
82	Site 5103	Benoni	Gauteng	South Africa	1500
83	Site 5104	Pretoria	Gauteng	South Africa	181
84	Site 5105	Thabazimbi	Limpopo	South Africa	380
85	Site 5101	Middelburg	Mpumalanga	South Africa	1050
86	Site 5102	Krugersdorp		South Africa	1724
87	Site 2103	Nonthaburi		Thailand	10110
88	Site 5203	Chernivtsi	Chernivets'ka Oblast	Ukraine	58005
89	Site 5204	Ivano-Frankivsk	Ivano-Frankivs'ka Oblast	Ukraine	76018
90	Site 5201	Kharkiv	Kharkivs'ka Oblast	Ukraine	61124
91	Site 5209	Kherson	Khersons'ka Oblast	Ukraine	73000
92	Site 5211	Odesa	Odes'ka Oblast	Ukraine	65025
93	Site 5210	Zaporizhzhia	Zaporiz'ka Oblast	Ukraine	69118
94	Site 5202	Kyiv		Ukraine	01133
95	Site 5205	Kyiv		Ukraine	03680
96	Site 5207	Kyïv		Ukraine	03680
97	Site 5208	Sumy		Ukraine	40022
98	Site 5212	Zaporizhzhia		Ukraine	69035
99	Site 5206	Zhytomyr		Ukraine	10002

Sponsors and Collaborators

• Nabriva Therapeutics AG

Investigators

• Study Chair: Jennifer Schranz, MD, Nabriva Therapeutics

Study Documents (Full-Text)

• Statistical Analysis Plan - Aug 30, 2017
• Study Protocol - Mar 15, 2016

More Information

Publications

None provided.

• Responsible Party: Nabriva Therapeutics AG
• ClinicalTrials.gov Identifier: NCT02559310
• Other Study ID Numbers: NAB-BC-3781-3101
• First Posted: Sep 24, 2015
• Last Update Posted: Oct 23, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Nabriva Therapeutics AG: Pneumonia; CABP; CAP; Community acquired bacterial pneumonia
• Additional relevant MeSH terms: Pneumonia; Moxifloxacin; Linezolid; Lefamulin

Study Results

Participant Flow

Recruitment Details	The study was designed to enroll adults with CABP that was severe enough to require a minimum of at least 3 days of IV treatment. Subjects with a PORT score of III, IV and V were eligible. The first subject was randomized in February 2016 and the last subject was randomized in April 2017.
Pre-assignment Detail	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 IV study drug.

Arm/Group Title	Lefamulin	Moxifloxacin ± Linezolid
Arm/Group Description	Lefamulin 150 mg IV q12h with option to switch to 600 mg PO q12h after at least 6 doses of IV treatment. Linezolid placebo q12h was added at baseline for patients with suspected MRSA.	Moxifloxacin 400 mg IV q24h with option to switch to 400 mg PO q24h after at least 6 doses of IV treatment. Linezolid 600 mg IV q12h was added at baseline for patients with suspected MRSA.
Period Title: Overall Study
STARTED	276	275
COMPLETED	249	256
NOT COMPLETED	27	19

Baseline Characteristics

Arm/Group Title	Lefamulin	Moxifloxacin ± Linezolid	Total
Arm/Group Description	Lefamulin 150 mg IV q12h with option to switch to 600 mg PO q12h after at least 6 doses of IV treatment. Linezolid placebo q12h was added at baseline for patients with suspected MRSA.	Moxifloxacin 400 mg IV q24h with option to switch to 400 mg PO q24h after at least 6 doses of IV treatment. Linezolid 600 mg IV q12h was added at baseline for patients with suspected MRSA.	Total of all reporting groups
Overall Participants	276	275	551
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61 (16.31)	59.6 (14.86)	60.3 (15.61)
Sex: Female, Male (Count of Participants)
Female	170 61.6%	160 58.2%	330 59.9%
Male	106 38.4%	115 41.8%	221 40.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 2.9%	10 3.6%	18 3.3%
Not Hispanic or Latino	268 97.1%	265 96.4%	533 96.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.4%	1 0.2%
Asian	25 9.1%	20 7.3%	45 8.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	11 4%	12 4.4%	23 4.2%
White	239 86.6%	239 86.9%	478 86.8%
More than one race	1 0.4%	3 1.1%	4 0.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Argentina	3 1.1%	6 2.2%	9 1.6%
Romania	7 2.5%	4 1.5%	11 2%
Hungary	10 3.6%	13 4.7%	23 4.2%
United States	2 0.7%	1 0.4%	3 0.5%
Philippines	23 8.3%	17 6.2%	40 7.3%
Ukraine	55 19.9%	61 22.2%	116 21.1%
Thailand	0 0%	1 0.4%	1 0.2%
Russia	8 2.9%	13 4.7%	21 3.8%
Latvia	17 6.2%	11 4%	28 5.1%
Netherlands	1 0.4%	0 0%	1 0.2%
Brazil	0 0%	1 0.4%	1 0.2%
Poland	6 2.2%	1 0.4%	7 1.3%
South Africa	12 4.3%	15 5.5%	27 4.9%
Georgia	25 9.1%	29 10.5%	54 9.8%
Bulgaria	65 23.6%	58 21.1%	123 22.3%
Serbia	30 10.9%	27 9.8%	57 10.3%
Bosnia and Herzegovina	11 4%	14 5.1%	25 4.5%
Peru	1 0.4%	3 1.1%	4 0.7%
Pneumonia Outcomes Research Team (PORT) Risk Class (Count of Participants)
II	0 0%	1 0.4%	1 0.2%
III	196 71%	201 73.1%	397 72.1%
IV	76 27.5%	70 25.5%	146 26.5%
V	4 1.4%	3 1.1%	7 1.3%
CURB-65 Score (Count of Participants)
0	24 8.7%	33 12%	57 10.3%
1	130 47.1%	121 44%	251 45.6%
2	98 35.5%	97 35.3%	195 35.4%
3	22 8%	22 8%	44 8%
4	2 0.7%	2 0.7%	4 0.7%
American Thoracic Society (ATS) Minor Severity Criteria (Count of Participants)
Count of Participants [Participants]	54 19.6%	48 17.5%	102 18.5%
Systemic inflammatory response syndrome (SIRS) Criteria (Count of Participants)
Count of Participants [Participants]	268 97.1%	267 97.1%	535 97.1%
Bacteremic (Count of Participants)
Count of Participants [Participants]	7 2.5%	3 1.1%	10 1.8%
Received Single Dose Short Acting Systemic Antibacterial within 72 hrs of Randomization (Count of Participants)
Count of Participants [Participants]	66 23.9%	66 24%	132 24%
Renal Status (Count of Participants)
Severe Impairment (CrCl <30mL/min)	3 1.1%	3 1.1%	6 1.1%
Moderate Impairment (CrCl 30-<60mL/min)	61 22.1%	62 22.5%	123 22.3%
Mild Impairment (CrCl 60-<90mL/min)	89 32.2%	75 27.3%	164 29.8%
Normal Function (CrCl >=90mL/min)	121 43.8%	134 48.7%	255 46.3%
Missing renal status	2 0.7%	1 0.4%	3 0.5%

Outcome Measures

1. Primary Outcome

Title	Early Clinical Response (ECR)
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 (other than adjunctive linezolid, as allowed by the study protocol) for the treatment of CABP through the ECR assessment.
Time Frame	ECR was assessed 96 +/- 24 hours after the first dose of study drug.

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis Set: All randomized subjects

Arm/Group Title	Lefamulin	Moxifloxacin ± Linezolid
Arm/Group Description	Lefamulin 150 mg IV q12h with option to switch to 600 mg PO q12h after at least 6 doses of IV treatment. Linezolid placebo q12h was added at baseline for patients with suspected MRSA.	Moxifloxacin 400 mg IV q24h with option to switch to 400 mg PO q24h after at least 6 doses of IV treatment. Linezolid 600 mg IV q12h was added at baseline for patients with suspected MRSA.
Measure Participants	276	275
Responder	241 87.3%	248 90.2%
Non-Responder	29 10.5%	21 7.6%
Indeterminate	6 2.2%	6 2.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lefamulin, Moxifloxacin ± Linezolid
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority Margin = 12.5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference (Lef - Mox)
	Estimated Value	-2.9
	Confidence Interval	(2-Sided) 95%; -8.5 to 2.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in percentage of Responders for ECR (Lefamulin - Moxifloxacin). CI computed using continuity-corrected Z-statistic.

2. Secondary Outcome

Title	Investigator's Assessment of Clinical Response (IACR)
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; 5-10 days after the last dose of study drug.

Outcome Measure Data

Analysis Population Description

Modified ITT population: All randomized subjects who received any amount of study drug.

Arm/Group Title	Lefamulin	Moxifloxacin ± Linezolid
Arm/Group Description	Lefamulin 150 mg IV q12h with option to switch to 600 mg PO q12h after at least 6 doses of IV treatment. Linezolid placebo q12h was added at baseline for patients with suspected MRSA.	Moxifloxacin 400 mg IV q24h with option to switch to 400 mg PO q24h after at least 6 doses of IV treatment. Linezolid 600 mg IV q12h was added at baseline for patients with suspected MRSA.
Measure Participants	273	273
Success	223 80.8%	230 83.6%
Failure	43 15.6%	40 14.5%
Indeterminate	7 2.5%	3 1.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lefamulin, Moxifloxacin ± Linezolid
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority Margin = 10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference (Lef - Mox)
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -8.9 to 3.9
	Parameter Dispersion	Type: Value:
	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.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lefamulin
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-Inferiority Margin = 10%
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference (Lef - Mox)
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -9.2 to 4.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in percentage of Success for IACR at test of cure visit. CI computed using continuity-corrected Z-statistic.

3. Secondary Outcome

Title	Investigator's Assessment of Clinical Response (IACR)
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 - 10 days after the last dose of study drug.

Outcome Measure Data

Analysis Population Description

Clinically Evaluable population: Subset of ITT population having met additional pre-defined criteria.

Arm/Group Title	Lefamulin	Moxifloxacin ± Linezolid
Arm/Group Description	Lefamulin 150 mg IV q12h with option to switch to 600 mg PO q12h after at least 6 doses of IV treatment. Linezolid placebo q12h was added at baseline for patients with suspected MRSA.	Moxifloxacin 400 mg IV q24h with option to switch to 400 mg PO q24h after at least 6 doses of IV treatment. Linezolid 600 mg IV q12h was added at baseline for patients with suspected MRSA.
Measure Participants	236	245
Success	205 74.3%	219 79.6%
Failure	31 11.2%	26 9.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lefamulin, Moxifloxacin ± Linezolid
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-Inferiority Margin = 10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -8.4 to 3.4
	Parameter Dispersion	Type: Value:
	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.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lefamulin, Moxifloxacin ± Linezolid
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-Inferiority Margin = 10%
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference (Lef - Mox)
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -8.7 to 3.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in Percentage of Success for IACR at test of cure visit (Lefamulin - Moxifloxacin). CI computed using continuity-corrected Z-statistic

Adverse Events

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 ± Linezolid
Arm/Group Description	Lefamulin 150 mg IV q12h with option to switch to 600 mg PO q12h after at least 6 doses of IV treatment. Linezolid placebo q12h was added at baseline for patients with suspected MRSA.		Moxifloxacin 400 mg IV q24h with option to switch to 400 mg PO q24h after at least 6 doses of IV treatment. Linezolid 600 mg IV q12h was added at baseline for patients with suspected MRSA.
All Cause Mortality
	Lefamulin		Moxifloxacin ± Linezolid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/273 (2.2%)		5/273 (1.8%)
Serious Adverse Events
	Lefamulin		Moxifloxacin ± Linezolid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/273 (7%)		13/273 (4.8%)
Cardiac disorders
Acute Myocardial Infarction	0/273 (0%)		1/273 (0.4%)
Atrial Fibrillation	1/273 (0.4%)		0/273 (0%)
Cardiac Arrest	0/273 (0%)		1/273 (0.4%)
Cardiac Failure Congestive	1/273 (0.4%)		0/273 (0%)
Cardiogenic Shock	0/273 (0%)		1/273 (0.4%)
Myocardial Infarction	1/273 (0.4%)		0/273 (0%)
Myocardial Ischaemia	0/273 (0%)		1/273 (0.4%)
Ventricular Arrhythmia	1/273 (0.4%)		0/273 (0%)
Gastrointestinal disorders
Haematemesis	0/273 (0%)		1/273 (0.4%)
General disorders
Death	0/273 (0%)		1/273 (0.4%)
Injection Site Reaction	1/273 (0.4%)		0/273 (0%)
Infections and infestations
Infectious Pleural Effusion	1/273 (0.4%)		1/273 (0.4%)
Lung Abscess	0/273 (0%)		1/273 (0.4%)
Pneumonia	4/273 (1.5%)		1/273 (0.4%)
Pulmonary Tuberculosis	1/273 (0.4%)		1/273 (0.4%)
Sepsis	1/273 (0.4%)		0/273 (0%)
Urinary Tract Infection	1/273 (0.4%)		0/273 (0%)
Viral Pharyngitis	1/273 (0.4%)		0/273 (0%)
Investigations
Alanine Aminotransferase Increased	1/273 (0.4%)		0/273 (0%)
Liver Function Test Increased	1/273 (0.4%)		0/273 (0%)
Metabolism and nutrition disorders
Hypokalaemia	0/273 (0%)		1/273 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bronchial Carcinoma	0/273 (0%)		1/273 (0.4%)
Lung Neoplasm	1/273 (0.4%)		0/273 (0%)
Squamous Cell Carcinoma of Lung	1/273 (0.4%)		0/273 (0%)
Testicular Seminoma (Pure)	0/273 (0%)		1/273 (0.4%)
Nervous system disorders
Cerebrovascular Accident	0/273 (0%)		1/273 (0.4%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	0/273 (0%)		1/273 (0.4%)
Bronchial Disorder	1/273 (0.4%)		0/273 (0%)
Chronic Obstructive Pulmonary Disease	1/273 (0.4%)		0/273 (0%)
Pleurisy	1/273 (0.4%)		0/273 (0%)
Pulmonary Embolism	1/273 (0.4%)		1/273 (0.4%)
Pulmonary Necrosis	0/273 (0%)		1/273 (0.4%)
Skin and subcutaneous tissue disorders
Angioedema	0/273 (0%)		1/273 (0.4%)
Vascular disorders
Shock Haemorrhagic	0/273 (0%)		1/273 (0.4%)
Other (Not Including Serious) Adverse Events
	Lefamulin		Moxifloxacin ± Linezolid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/273 (14.3%)		46/273 (16.8%)
Gastrointestinal disorders
Nausea	8/273 (2.9%)		6/273 (2.2%)
Diarrhoea	2/273 (0.7%)		21/273 (7.7%)
General disorders
Infusion Site Pain	8/273 (2.9%)		0/273 (0%)
Infusion Site Phlebitis	6/273 (2.2%)		3/273 (1.1%)
Investigations
Alanine Aminotransferase Increased	4/273 (1.5%)		6/273 (2.2%)
Metabolism and nutrition disorders
Hypokalaemia	8/273 (2.9%)		6/273 (2.2%)
Psychiatric disorders
Insomnia	8/273 (2.9%)		5/273 (1.8%)
Vascular disorders
Hypertension	2/273 (0.7%)		6/273 (2.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.