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

• ClinicalTrials.gov Identifier: NCT02559310
• Recruitment Status: Completed
• First Posted: September 24, 2015
• Results First Posted: October 23, 2019
• Last Update Posted: October 23, 2019
• Sponsor: Nabriva Therapeutics AG
• 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; Drug: Linezolid
• Enrollment: 551

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 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 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
Reason Not Completed
Death	4	3
Lost to Follow-up	5	3
Physician Decision	2	1
Withdrawal by Subject	13	9
Sponsor Decision	0	1
Randomized but not treated	3	2

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 Number of Baseline Participants		276	275	551
Baseline Analysis Population Description		Intent-to-Treat (ITT) Analysis Set
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	276 participants	275 participants	551 participants
		61 (16.31)	59.6 (14.86)	60.3 (15.61)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	276 participants	275 participants	551 participants
	Female	170 61.6%	160 58.2%	330 59.9%
	Male	106 38.4%	115 41.8%	221 40.1%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	276 participants	275 participants	551 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%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	276 participants	275 participants	551 participants
	American Indian or Alaska Native	0 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%	0 0.0%
	Black or African American	11 4.0%	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%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	276 participants	275 participants	551 participants
Argentina		3	6	9
Romania		7	4	11
Hungary		10	13	23
United States		2	1	3
Philippines		23	17	40
Ukraine		55	61	116
Thailand		0	1	1
Russia		8	13	21
Latvia		17	11	28
Netherlands		1	0	1
Brazil		0	1	1
Poland		6	1	7
South Africa		12	15	27
Georgia		25	29	54
Bulgaria		65	58	123
Serbia		30	27	57
Bosnia and Herzegovina		11	14	25
Peru		1	3	4
Pneumonia Outcomes Research Team (PORT) Risk Class [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	276 participants	275 participants	551 participants
	II	0 0.0%	1 0.4%	1 0.2%
	III	196 71.0%	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%
		[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	276 participants	275 participants	551 participants
	0	24 8.7%	33 12.0%	57 10.3%
	1	130 47.1%	121 44.0%	251 45.6%
	2	98 35.5%	97 35.3%	195 35.4%
	3	22 8.0%	22 8.0%	44 8.0%
	4	2 0.7%	2 0.7%	4 0.7%
		[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	276 participants	275 participants	551 participants
		54 19.6%	48 17.5%	102 18.5%
		[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	276 participants	275 participants	551 participants
		268 97.1%	267 97.1%	535 97.1%
		[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	276 participants	275 participants	551 participants
		7 2.5%	3 1.1%	10 1.8%
Received Single Dose Short Acting Systemic Antibacterial within 72 hrs of Randomization; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	276 participants	275 participants	551 participants
		66 23.9%	66 24.0%	132 24.0%
Renal Status; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	276 participants	275 participants	551 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.
Overall Number of Participants Analyzed	276	275
Measure Type: Count of Participants; Unit of Measure: Participants
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	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority Margin = 12.5%.
Method of Estimation	Estimation Parameter	Treatment Difference (Lef - Mox)
	Estimated Value	-2.9
	Confidence Interval	(2-Sided) 95%; -8.5 to 2.8
	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.
Overall Number of Participants Analyzed	273	273
Measure Type: Count of Participants; Unit of Measure: Participants
Success	223 81.7%	230 84.2%
Failure	43 15.8%	40 14.7%
Indeterminate	7 2.6%	3 1.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lefamulin, Moxifloxacin ± Linezolid
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority Margin = 10%.
Method of Estimation	Estimation Parameter	Treatment Difference (Lef - Mox)
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -8.9 to 3.9
	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	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	Non-Inferiority Margin = 10%
Method of Estimation	Estimation Parameter	Treatment Difference (Lef - Mox)
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -9.2 to 4.1
	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.
Overall Number of Participants Analyzed	236	245
Measure Type: Count of Participants; Unit of Measure: Participants
Success	205 86.9%	219 89.4%
Failure	31 13.1%	26 10.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lefamulin, Moxifloxacin ± Linezolid
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	Non-Inferiority Margin = 10%.
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -8.4 to 3.4
	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	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	Non-Inferiority Margin = 10%
Method of Estimation	Estimation Parameter	Treatment Difference (Lef - Mox)
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -8.7 to 3.7
	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 (%)	Affected / at Risk (%)
Total	6/273 (2.20%)	5/273 (1.83%)
Serious Adverse Events
	Lefamulin	Moxifloxacin ± Linezolid
	Affected / at Risk (%)	Affected / at Risk (%)
Total	19/273 (6.96%)	13/273 (4.76%)
Cardiac disorders
Acute Myocardial Infarction † 1	0/273 (0.00%)	1/273 (0.37%)
Atrial Fibrillation † 1	1/273 (0.37%)	0/273 (0.00%)
Cardiac Arrest † 1	0/273 (0.00%)	1/273 (0.37%)
Cardiac Failure Congestive † 1	1/273 (0.37%)	0/273 (0.00%)
Cardiogenic Shock † 1	0/273 (0.00%)	1/273 (0.37%)
Myocardial Infarction † 1	1/273 (0.37%)	0/273 (0.00%)
Myocardial Ischaemia † 1	0/273 (0.00%)	1/273 (0.37%)
Ventricular Arrhythmia † 1	1/273 (0.37%)	0/273 (0.00%)
Gastrointestinal disorders
Haematemesis † 1	0/273 (0.00%)	1/273 (0.37%)
General disorders
Death † 1	0/273 (0.00%)	1/273 (0.37%)
Injection Site Reaction † 1	1/273 (0.37%)	0/273 (0.00%)
Infections and infestations
Infectious Pleural Effusion † 1	1/273 (0.37%)	1/273 (0.37%)
Lung Abscess † 1	0/273 (0.00%)	1/273 (0.37%)
Pneumonia † 1	4/273 (1.47%)	1/273 (0.37%)
Pulmonary Tuberculosis † 1	1/273 (0.37%)	1/273 (0.37%)
Sepsis † 1	1/273 (0.37%)	0/273 (0.00%)
Urinary Tract Infection † 1	1/273 (0.37%)	0/273 (0.00%)
Viral Pharyngitis † 1	1/273 (0.37%)	0/273 (0.00%)
Investigations
Alanine Aminotransferase Increased † 1	1/273 (0.37%)	0/273 (0.00%)
Liver Function Test Increased † 1	1/273 (0.37%)	0/273 (0.00%)
Metabolism and nutrition disorders
Hypokalaemia † 1	0/273 (0.00%)	1/273 (0.37%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bronchial Carcinoma † 1	0/273 (0.00%)	1/273 (0.37%)
Lung Neoplasm † 1	1/273 (0.37%)	0/273 (0.00%)
Squamous Cell Carcinoma of Lung † 1	1/273 (0.37%)	0/273 (0.00%)
Testicular Seminoma (Pure) † 1	0/273 (0.00%)	1/273 (0.37%)
Nervous system disorders
Cerebrovascular Accident † 1	0/273 (0.00%)	1/273 (0.37%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure † 1	0/273 (0.00%)	1/273 (0.37%)
Bronchial Disorder † 1	1/273 (0.37%)	0/273 (0.00%)
Chronic Obstructive Pulmonary Disease † 1	1/273 (0.37%)	0/273 (0.00%)
Pleurisy † 1	1/273 (0.37%)	0/273 (0.00%)
Pulmonary Embolism † 1	1/273 (0.37%)	1/273 (0.37%)
Pulmonary Necrosis † 1	0/273 (0.00%)	1/273 (0.37%)
Skin and subcutaneous tissue disorders
Angioedema † 1	0/273 (0.00%)	1/273 (0.37%)
Vascular disorders
Shock Haemorrhagic † 1	0/273 (0.00%)	1/273 (0.37%)
1 Term from vocabulary, MedDRA, Version 20.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Lefamulin	Moxifloxacin ± Linezolid
	Affected / at Risk (%)	Affected / at Risk (%)
Total	39/273 (14.29%)	46/273 (16.85%)
Gastrointestinal disorders
Nausea † 1	8/273 (2.93%)	6/273 (2.20%)
Diarrhoea † 1	2/273 (0.73%)	21/273 (7.69%)
General disorders
Infusion Site Pain † 1	8/273 (2.93%)	0/273 (0.00%)
Infusion Site Phlebitis † 1	6/273 (2.20%)	3/273 (1.10%)
Investigations
Alanine Aminotransferase Increased † 1	4/273 (1.47%)	6/273 (2.20%)
Metabolism and nutrition disorders
Hypokalaemia † 1	8/273 (2.93%)	6/273 (2.20%)
Psychiatric disorders
Insomnia † 1	8/273 (2.93%)	5/273 (1.83%)
Vascular disorders
Hypertension † 1	2/273 (0.73%)	6/273 (2.20%)
1 Term from vocabulary, MedDRA, Version 20.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Jennifer Schranz, MD, Chief Medical Officer
• Organization: Nabriva Therapeutics US, Inc.
• Phone: 610-981-2842
• EMail: jennifer.schranz@nabriva.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

File TM Jr, Alexander E, Goldberg L, Das AF, Sandrock C, Paukner S, Moran GJ. Lefamulin efficacy and safety in a pooled phase 3 clinical trial population with community-acquired bacterial pneumonia and common clinical comorbidities. BMC Pulm Med. 2021 May 8;21(1):154. doi: 10.1186/s12890-021-01472-z.

File TM, Goldberg L, Das A, Sweeney C, Saviski J, Gelone SP, Seltzer E, Paukner S, Wicha WW, Talbot GH, Gasink LB. Efficacy and Safety of Intravenous-to-oral Lefamulin, a Pleuromutilin Antibiotic, for the Treatment of Community-acquired Bacterial Pneumonia: The Phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) Trial. Clin Infect Dis. 2019 Nov 13;69(11):1856-1867. doi: 10.1093/cid/ciz090. Erratum In: Clin Infect Dis. 2020 May 23;70(11):2459.

• Responsible Party: Nabriva Therapeutics AG
• ClinicalTrials.gov Identifier: NCT02559310
• Other Study ID Numbers: NAB-BC-3781-3101
• First Submitted: September 22, 2015
• First Posted: September 24, 2015
• Results First Submitted: August 28, 2019
• Results First Posted: October 23, 2019
• Last Update Posted: October 23, 2019