Clinical trial NCT05225805
Conditions: Cystic Fibrosis
Sponsor: Nabriva Therapeutics AG
Start date: 2022-03-01; Completion date: 2023-01-13
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is intended to assess the pharmacokinetic (PK) and safety of a single dose of IV and oral formulations of lefamulin in adults with cystic fibrosis (CF).

Detailed description:
Staphylococcus aureus is one of the most common causative pathogens associated with exacerbations of CF. Current treatment guidelines for the management of exacerbations of CF caused by S. aureus recommend the use of unapproved antibacterial agents. Further, many of the recommended treatments can only be administered via the IV route and/or have limitations due to safety and tolerability. Lefamulin is a novel, first-in-class, IV and oral pleuromutilin antimicrobial agent that has been demonstrated to be highly potent against S. aureus, including Methicillin-resistant Staphylococcus aureus (MRSA) and strains obtained from patients with CF. Cystic fibrosis patients have altered drug distribution and elimination kinetics for many antimicrobials relative to patients without CF. While the advent of Cystic fibrosis transmembrane conductance regulator (protein) (CFTR) modulators has resulted in improved lung function and had a positive impact on the quality of life of CF patients, limited data have been published describing the impact of the concomitant use of CFTR modulators and commonly used antibacterial agents.

Arms: arm 1: Group A will receive one dose of 150 mg lefamulin IV followed by one dose of 600 mg lefamulin oral arm 2: Group B will receive one dose of 600 mg lefamulin oral followed by one dose of 150 mg lefamulin IV
Interventions: intervention 1: Lefamulin
Intervention descriptions: intervention 1: Antibiotic

Protocol documents:
Prot_000.pdf: 
 
 
 
 
    
 
 
 
 
 
 
Official Title:  A Phase 1, Open-Label, Randomized, Crossover Study to Assess the Safety and 
Pharmacokinetics Following Single Doses of Oral and Intravenous Xenleta 
(Lefamulin) in Adult Patients With Cystic Fibrosis 
 
NCT Number: NCT05225805 
 
Applicant/MAH: Nabriva Therapeutics 
 
Version Date: 02 November 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
 
Nabriva Therapeutics 
NAB-BC-3781-1014 
 
Lefamulin 
02 November 2021 
1 
Confidential 
 
1. 
TITLE PAGE 
XENLETA® (LEFAMULIN) 
NAB-BC-3781-1014 
A PHASE 1, OPEN-LABEL, RANDOMIZED, CROSSOVER STUDY TO 
ASSESS THE SAFETY AND PHARMACOKINETICS FOLLOWING 
SINGLE DOSES OF ORAL AND INTRAVENOUS XENLETA® 
(LEFAMULIN) IN ADULT PATIENTS WITH CYSTIC FIBROSIS 
 
US IND 106594 
 
Protocol Status 
Version 
Date 
Original 
1.0 
02 November 2021 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained herein is the property of Nabriva Therapeutics Ireland Designated 
Activity Company (DAC) and may not be produced, published, or disclosed to others without the 
written authorization of Nabriva Therapeutics Ireland DAC. 


Clinical Study Protocol 
 
Nabriva Therapeutics 
NAB-BC-3781-1014 
 
Lefamulin 
02 November 2021 
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Confidential 
INVESTIGATOR SIGNATURE PAGE 
A Phase 1, Open-Label, Randomized, Crossover Study to Assess the Safety and 
Pharmacokinetics Following Single Doses of Oral and Intravenous XENLETA® 
(Lefamulin) in Adult Patients with Cystic Fibrosis 
Protocol NAB-BC-3781-1014 
In conducting this clinical study, I agree to be responsible for: 
• Ensuring that the clinical investigation is conducted according to the World Medical 
Association Declaration of Helsinki in its revised edition (Fortaleza, Brazil, October 
2013), the Good Clinical Practice (GCP) guidelines of the International Council for 
Harmonisation (ICH) (CPMP/ICH/135/95), the signed Form Food and Drug 
Administration (FDA) 1572 Statement of Investigator (applies to all studies 
conducted under a United States Investigational New Drug Application) and other 
applicable local and national laws and requirements. 
• Protecting the rights, safety, and welfare of patients under my care. 
• Maintaining control of the drugs under investigation. 
I also agree to conduct the study as detailed in the protocol and in accordance with Nabriva 
Therapeutics guidelines and all applicable government regulations. These guidelines and 
regulations include, but are not limited to: 
• Permission to allow Nabriva Therapeutics and regulatory agencies to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner, which 
ensures patient confidentiality. If I am notified that this study is to be inspected by a 
regulatory agency, I will notify Nabriva Therapeutics as soon as possible thereafter 
(no later than 1 week). 
• Submission of the proposed clinical investigation, including the protocol, the 
informed consent documents, and any other patient materials required for study 
conduct, to a duly constituted Institutional Review Board (IRB) for approval, and 
acquisition of written approval for each, before the use of the study drug. 
• Obtaining written informed consent only after ensuring that the patient, or his/her 
legal representative, is competent to make the decision, understands what is contained 
in the informed consent document, and is consenting voluntarily. Written informed 
consent will be obtained before administration of study drug or any non-routine 
study-related procedures; the document contains all the essential elements of consent 
and has been previously approved by the Sponsor and IRB. Reference of written 
informed consent will be provided in source documentation. 
• Submission of any protocol amendment to an accredited IRB. Institutional Review 
Board written approval must be obtained before implementation of any protocol 
amendment. 
• Adherence to the study protocol. Documentation and explanation of individual post-
enrollment protocol deviations will be recorded in the source documentation at the 
site and be provided to Nabriva Therapeutics. 


Clinical Study Protocol 
 
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NAB-BC-3781-1014 
 
Lefamulin 
02 November 2021 
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• Notification to Nabriva Therapeutics of all serious adverse events (SAEs), regardless 
of relationship to study drug, as specified in the protocol. Notification to the IRB of 
SAEs as specified in the protocol and as per the guidelines provided by the IRB. 
• Notification to the IRB of all unanticipated problems within the timeframe provided 
by the IRB. For the purposes of this study, unanticipated problems are defined as any 
incident, experience, or patient outcome that meets all of the following criteria: 
(1) unexpected; (2) related or possibly related to participation in the study; (3) and 
suggests that the research places patients or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known. 
• Provision of adequate study oversight by personally conducting or supervising the 
investigation, including, but not limited to: allotting sufficient time to properly 
conduct and complete the study within the agreed upon time period; having available 
an adequate number of qualified staff and adequate facilities for the expected duration 
of the study and to conduct the study properly and safely; and ensuring that all 
persons assisting with the study are adequately informed about the protocol and the 
investigational product(s) and are capable of performing their study-related duties and 
functions. Qualifications of individuals assigned responsibility for the administration 
of the investigational product will be compliant with state and local law or national 
regulations, as applicable. 
• Submission of timely progress reports to the IRB and Nabriva Therapeutics at 
appropriate intervals not to exceed 1 year and submission of a final report to the IRB 
within the timeframe set by the IRB, but not later than 3 months after the completion 
or termination of the clinical investigation. 
• Maintenance of accurate source records from which electronic case report forms 
(eCRFs) are completed as well as drug accountability records that show the receipt 
and disposition (on an overall and per patient basis) of all study drug(s) shipped to the 
Investigator by Nabriva Therapeutics. 
In addition, I agree to provide all the information requested in the eCRF presented to me by Nabriva 
Therapeutics by carefully following the completion guidelines provided as part of the eCRF. 
If I opt to terminate my participation in the study, the foregoing shall equally apply. 
 
 
Investigator’s Name (Please Print) 
 
 
 
 
Investigator’s Signature 
 
Date 


Clinical Study Protocol 
 
Nabriva Therapeutics 
NAB-BC-3781-1014 
 
Lefamulin 
02 November 2021 
4 
Confidential 
Sponsor-related Contact Details 
A Phase 1, Open-Label, Randomized, Crossover Study to Assess the Safety and 
Pharmacokinetics Following Single Doses of Oral and Intravenous XENLETA® 
(Lefamulin) in Adult Patients with Cystic Fibrosis 
Protocol NAB-BC-3781-1014 
Sponsor: 
Nabriva Therapeutics Ireland DAC 
Alexandra House, Office 225/227 
The Sweepstakes 
Ballsbridge 
Dublin 4 
D04 C7H2 
Republic of Ireland 
Sponsor’s Study Manager: 
, 
, Project and Alliance Management 
Sponsor’s Medical Officer: 
, MD, MBA, MPH 
Sponsor’s Selected CRO:  
 
 
 
Pharmacovigilance: 
PrimeVigilance 
Bioanalytical Laboratory: 
 
 
 
 
 
Pharmacokinetics and Statistical 
Analysis 
 
PI
PI
PI
PI
PI
PI


Clinical Study Protocol 
 
Nabriva Therapeutics 
NAB-BC-3781-1014 
 
Lefamulin 
02 November 2021 
5 
Confidential 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Nabriva Therapeutics 
Name of Investigational Product: 
XENLETA® (lefamulin) 
Name of Active Ingredient: 
Lefamulin (BC-3781) 
Title of Study:  
A Phase 1, Open-Label, Randomized, Crossover Study to Assess the Safety and Pharmacokinetics 
Following Single Doses of Oral and Intravenous XENLETA® (Lefamulin) in Adult Patients with 
Cystic Fibrosis 
Number of study centers: Approximately 6 
Principal Investigator:  
 
 
 
 
Studied period (years):  
Estimated date first patient enrolled: Jan 2022 
Estimated date last patient completed: Mar 2023 
Phase of development: 1 
 
Objectives:  
Primary: 
• 
To evaluate the pharmacokinetics (PK) of a 600-mg immediate-release (IR) tablet and 150-mg 
intravenous (IV) formulations of lefamulin in adult patients with cystic fibrosis (CF)  
Secondary: 
• 
To evaluate the safety and tolerability of lefamulin when administered as single oral or IV doses 
in adult patients with CF 
Endpoints:  
Primary: 
• 
Plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150-mg IV 
infusion and 600-mg IR tablet in patients with CF. 
Secondary: 
Descriptive summaries of the following: 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Laboratory assessments (chemistry and hematology)  
• 
Vital signs measurements 
• 
Electrocardiogram (ECG) parameters 
PI


Clinical Study Protocol 
 
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NAB-BC-3781-1014 
 
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02 November 2021 
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Methodology:  
This will be a single-cohort, open-label, randomized, 2-part, crossover study in patients receiving a 
single dose of lefamulin at 2 study periods 4 to 7 days apart. Lefamulin will be administered as a 
600-mg IR tablet orally in the fasted state and a 150-mg IV infusion in 250 mL citrate buffered saline 
over 1 hour. 
Number of patients (planned):  
Approximately 12 patients are planned to be enrolled. 
Diagnosis and main criteria for inclusion:  
Key inclusion criteria are as follows: 
1. Signed informed consent. 
2. Adult patients, ≥ 18 years of age. 
3. Genetic confirmation of CF diagnosis by a report from a genetic test, such as “F508 deletion 
detected.” 
4. Weight > 40 kgs. 
5. Forced expiration volume (FEV)1 > 40% predicted, as measured during the most recent 
evaluation. 
6. Mentally and physically able to participate in the study as determined by the Investigator, ie, 
clinically stable with no significant changes in health status within 28 days prior to, and 
including, Day 1. 
7. Vital signs within the following ranges: 
a. Tympanic temperature, < 38°C 
b. Systolic blood pressure, 90 to 160 mmHg 
c. Diastolic blood pressure, 50 to 90 mmHg 
d. Heart rate < 100 beats per minute at rest 
e. Respiration rate 12 to 20 breaths per minute 
f. Oxygen saturation to be documented. No selection criteria; supplemental oxygen use 
is acceptable. 
8. Negative beta-human chorionic gonadotropin (β-hCG) urine or serum pregnancy test for 
females of childbearing potential. 
9. Willing to commit to acceptable methods of contraception as defined in the protocol. 
Key exclusion criteria are as follows: 
1. Known history of chronic liver or biliary disease, Gilbert’s syndrome, or any of the following 
at Screening: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
> 2 x upper limit of normal (ULN), total bilirubin > 1.5 x ULN. 
2. Prolonged baseline corrected QT interval corrected according to Fridericia (QTcF) defined as 
> 440 ms (females) and > 430 ms (males). 
3. Family history or presence of prolonged QTc syndrome, Torsades de Pointes, or known 
conduction defects (eg, bundle branch block, atrioventricular block). 
4. Use of Orkambi® (lumacaftor/ivacaftor) within 28 days prior to Day 1. 
5. Use of cytochrome P450 (CYP)3A substrates that prolong the QT interval within 24 hours 
prior to Day 1. 


Clinical Study Protocol 
 
Nabriva Therapeutics 
NAB-BC-3781-1014 
 
Lefamulin 
02 November 2021 
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6. Use of strong and moderate CYP3A inducers or P-glycoprotein (P-gp) inducers within 28 
days prior to Day 1. 
7. Use of strong inhibitors of CYP3A4 within 24 hours prior to Day 1. 
8. Serum potassium level below the normal reference range at Screening. 
9. Known allergy to pleuromutilin class of antibiotic or any of the excipients of the lefamulin 
formulations. 
10. Consumption of grapefruit, grapefruit juice, grapefruit products, pomelo, or Seville oranges 
within 24 hours before Day 1. 
11. Use of vaporized nicotine or cannabidiol products, smoking (regularly or intermittently) more 
than 5 cigarettes (or equivalent) per day, or any use of tobacco other than in cigarettes or 
cigars within 28 days of Day 1. 
12. Positive blood test for hepatitis C, human immunodeficiency virus (HIV), or hepatitis B 
antigen or core antibody (indicating active infection). 
13. Positive test for drugs of abuse or alcohol at Screening or Day -1 that cannot be satisfactorily 
supported by medical history. 
14. Use of an investigational product within the 30 days prior to Day 1 (3 months prior to Day 1 
if the study drug was a new chemical entity). 
15. Difficulty swallowing tablets. 
16. Females who are pregnant or breastfeeding. 
17. Does not have suitable venous access for multiple venipuncture or cannulation. 
18. Any medical, psychological, cognitive, social, or legal conditions that, in the opinion of the 
Investigator, would interfere with the patient’s ability to give an informed consent and/or 
participate fully in the study. 
19. Any other reason, in the opinion of the Investigator, the patient is unsuitable to participate. 
Investigational product, dosage, and mode of administration:  
Study drug will be administered as follows to all patients after an overnight fast: 
• 
IV Treatment Period: Lefamulin 150 mg in 250 mL citrate buffered saline IV infusion over 
1 hour  
• 
Oral Treatment Period: Lefamulin as a 600-mg IR tablet in the fasted state. The oral treatment 
will be swallowed whole with 6 to 8 ounces of water at least 1 hour before or 2 hours after a 
meal. 
Duration of treatment:  
Total duration of study participation for each patient will be approximately 10 to 13 days (from 
Screening to Follow-up). 
Reference therapy, dosage, and mode of administration:  
None 
Criteria for evaluation: 
Pharmacokinetics: 
Blood samples will be taken for the measurement of PK parameters at the following time points in 
each part of the study: 
• 
Pre-dose; 30 min, and 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose. 


Clinical Study Protocol 
 
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NAB-BC-3781-1014 
 
Lefamulin 
02 November 2021 
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Sputum samples will be collected first thing in the morning on Day 1 (pre-dose), and spontaneous 
sputum samples may be collected through 24 hours post-dosing as often as the patient can provide a 
sample. The exact time of the sputum collection will be documented for determination of PK 
parameters of lefamulin in sputum. 
Safety: 
Safety will be evaluated with the following assessments:  
• 
Adverse events and concomitant medications will be monitored and recorded throughout the 
study. 
• 
Clinical chemistry and hematology assessments will be performed at Screening, Day -1, and 
24 hours post-dose; laboratory assessments will be conducted at Follow-up only if necessary. 
• 
Vital signs will be measured at Screening, pre-dose on Day 1, at 0.5 hours, 2 hours, and 24 hours 
post-dose; vital signs will be measured at Follow-up only if necessary. 
• 
Electrocardiograms will be performed at Screening, pre-dose on Day 1, and at 0.5 and 2 hours 
post-dose; ECGs will be performed at Follow-up only if necessary. 
• 
Physical examination will be performed at Screening, Day -1 and at 24 hours post-dose; physical 
examinations will be performed at Follow-up only if necessary. 
• 
Drugs of abuse and alcohol (breath test) Screening will be performed at Screening and Day -1. 
• 
After the first dosing period of the study, a Follow-up Visit will take place 4 to 7 days after the 
final dose of lefamulin. This visit will also serve as the Screening Visit for the second dosing 
period. After the second dosing period, a Follow-up phone call will take place 4 to 7 days after 
the final dose of lefamulin to ensure the ongoing wellbeing of the patients. If a patient reports any 
TEAEs which represent a cause for concern (as determined by the Investigator) he/she will be 
required to attend the clinic for a Follow-up assessment. This will be considered an unscheduled 
visit. 
Tolerability will be assessed by evaluation of the safety parameters and recorded adverse events.  
Statistical methods: 
Pharmacokinetics:  
Presentation of PK data will be descriptive in nature and will be presented by treatment.  
Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited 
to, the following PK parameters (defined in the protocol) in plasma for lefamulin and the metabolite 
BC-8041 in plasma when possible and appropriate: 
Tlag (oral dose only), Tmax, Cmax, AUC(0-last), AUC(0-24h), AUC(0-inf), AUC%extrap, lambda-z, t1/2, CL (IV 
dose only), CL/F (oral dose only), Vd (IV dose only), Vd/F (oral dose only), Vss (IV dose only), 
MRT, and (F). 
Safety:  
Safety and tolerability will be assessed by monitoring adverse events (AEs) and concomitant 
medications, clinical chemistry and hematology laboratory assessments, vital signs, ECG results, and 
physical examination findings. A complete description of the safety analysis variables will be 
presented in the Statistical Analysis Plan. 
 
 


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Table 1: 
Schedule of Assessments   
Study Procedure 
Screeninga 
IV Treatment Period and Oral Treatment Period 
Day -1b 
Day 1 
pre-
dosec 
Day 
1 
Day 1 Post-dose 
Follow-
upd 
0.5 h 
1 h 
1.5 h 
2 h 
4 h 
8 h 
12 h 
24 h 
Assessment window 
D -30 to -1 
─ 
─ 
─ 
± 5 m 
± 5 m 
± 10 m 
± 10 m 
± 30 m 
± 1 h 
± 1 h 
± 1 h 
4 to 7 
days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/medication history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination e 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsf 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
12-lead ECG 
X 
 
X 
 
Xg 
 
 
Xh 
 
 
 
 
 
Blood for chemistry, hematology, 
virology 
Xi 
X 
 
 
 
 
 
 
 
 
 
X 
 
Drugs and alcohol screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum or urine)j 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Sputum collectionk 
 
 
X 
     X 
 
Study drug administrationl 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Plasma for PK 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medications 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from CRUm 
 
 
 
 
 
 
 
 
 
 
 
X 
 


Clinical Study Protocol 
 
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NAB-BC-3781-1014 
 
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Table 1: 
Footnotes for Schedule of Assessments   (Continued) 
Abbreviations: AE  = adverse event CRU = clinical study unit; D = study day; ECG = electrocardiogram; h = hour(s); IV = intravenous; m = minute(s);  PK = pharmacokinetics 
a. Informed consent must be obtained before study specific-procedures are performed. However, assessments performed as part of standard of care within the screening period 
may be used to determine eligibility.  
b. After completion of all Day -1 assessments, patients who remain eligible per entry criteria will be admitted to the CRU. Day -1 assessments do not have to be repeated if 
Screening occurred within 72 hours. 
c. Day 1 pre-dose testing and sample collection should be performed within 2 hours before dosing. 
d. A Follow-up phone call will take place 4 to 7 days after the final dose. For any AEs or other issues of concern, investigators, at their discretion, may ask patients to return to 
the study site for an in-person visit (this would be considered an unscheduled visit). 
e. Complete physical examinations will be performed at Screening and Day -1; a focused physical examination will be performed on Day 1 at 24 hours. 
f. Systolic blood pressure, diastolic blood pressure, body temperature, heart rate, respiratory rate, oxygen saturation 
g. IV Treatment Period only (following IV dosing) 
h. Oral Treatment Period only (following oral dosing) 
i. Includes viral serology at Screening 
j. Follicle stimulating hormone (FSH) level will be determined for women who are  ≥ 1 year post-menopausal.  
k. Sputum should be collected first thing in the morning on Day 1 pre-dose, then collect as many sputum samples as possible. 
l. IV Treatment Period: IV dose infused over 1 hour (± 2 minutes); Oral Treatment Period : the oral treatment will be swallowed whole with 6 to 8 ounces of water at least 1 hour 
before or 2 hours after a meal. 
m. Patient may be discharged from the CRU after completion of all 24-hour procedures and Investigator determination that no additional safety monitoring is required. 
 


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Lefamulin 
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TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
CONFIDENTIALITY STATEMENT .............................................................................................1 
INVESTIGATOR SIGNATURE PAGE .........................................................................................2 
SPONSOR-RELATED CONTACT DETAILS ..............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF TABLES .........................................................................................................................14 
LIST OF FIGURES .......................................................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
3. 
INTRODUCTION ......................................................................................................17 
3.1. 
Cystic Fibrosis ............................................................................................................17 
3.2. 
Lefamulin ....................................................................................................................18 
3.3. 
Study and Dose Rationale ...........................................................................................19 
3.3.1. 
Study Rationale ...........................................................................................................19 
3.3.2. 
Dose Rationale ............................................................................................................19 
3.4. 
Risk Assessment .........................................................................................................20 
4. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................21 
4.1. 
Objectives ...................................................................................................................21 
4.1.1. 
Primary Objective .......................................................................................................21 
4.1.2. 
Secondary Objectives .................................................................................................21 
4.1.3. 
Exploratory Objective .................................................................................................21 
4.2. 
Endpoints ....................................................................................................................21 
4.2.1. 
Primary Endpoint ........................................................................................................21 
4.2.2. 
Secondary Endpoints ..................................................................................................22 
4.2.3. 
Exploratory Endpoint ..................................................................................................22 
5. 
INVESTIGATIONAL PLAN .....................................................................................23 
6. 
STUDY POPULATION .............................................................................................25 
6.1. 
Subject Inclusion Criteria ...........................................................................................25 
6.2. 
Subject Exclusion Criteria ..........................................................................................26 
7. 
STUDY DRUG ADMINISTRATION .......................................................................28 
7.1. 
Duration of Treatment ................................................................................................28 


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7.2. 
Timing of Dose and Dose Administration ..................................................................28 
7.3. 
Treatment Compliance ................................................................................................28 
7.4. 
Randomization ............................................................................................................28 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................29 
8.1. 
Medical/Surgical History ............................................................................................29 
8.2. 
Physical Examinations ................................................................................................29 
8.3. 
Vital Signs ..................................................................................................................29 
8.4. 
Clinical Laboratory Tests (Safety) ..............................................................................30 
8.5. 
Electrocardiograms .....................................................................................................30 
8.6. 
Pharmacokinetics ........................................................................................................31 
8.6.1. 
Plasma Sample Collection ..........................................................................................31 
8.6.2. 
Sputum Sample Collection .........................................................................................31 
8.7. 
Prior and Concomitant Medications ...........................................................................31 
8.7.1. 
Prior Medications ........................................................................................................31 
8.7.2. 
Concomitant Medications ...........................................................................................32 
8.8. 
Restrictions During the Study .....................................................................................32 
8.9. 
Discontinuation from Study Medication ....................................................................32 
8.10. 
Discontinuation from Study ........................................................................................33 
9. 
ADVERSE EVENTS..................................................................................................33 
9.1. 
Definition of Adverse Events .....................................................................................33 
9.2. 
Assessment of Severity (Intensity) .............................................................................34 
9.3. 
Assessment of Relationship to Study Drug ................................................................35 
9.4. 
Serious Adverse Events ..............................................................................................35 
9.5. 
Other Reportable Events .............................................................................................36 
10. 
DRUG SUPPLIES ......................................................................................................37 
10.1. 
Description of Drug Products .....................................................................................37 
10.2. 
Packaging and Labeling ..............................................................................................37 
10.3. 
Storage of Study Drugs ...............................................................................................37 
10.4. 
Product Accountability ...............................................................................................38 
10.5. 
Compliance .................................................................................................................38 
10.6. 
Treatment of Overdose ...............................................................................................38 
10.7. 
Occupational Safety ....................................................................................................38 
11. 
STATISTICAL ANALYSIS ......................................................................................39 


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11.1. 
Sample Size Determination ........................................................................................39 
11.2. 
Analysis Sets ...............................................................................................................39 
11.3. 
Variables for Analysis ................................................................................................39 
11.3.1. 
Pharmacokinetic Analysis Variables ..........................................................................39 
11.3.2. 
Safety Analysis Variables ...........................................................................................39 
11.4. 
Pharmacokinetic Analysis ..........................................................................................39 
11.5. 
Statistical Analysis ......................................................................................................39 
11.6. 
Safety Analysis ...........................................................................................................40 
12. 
STUDY MONITORING ............................................................................................40 
13. 
INSTITUTIONAL REVIEW BOARD APPROVAL ................................................40 
14. 
ETHICAL CONDUCT OF THE STUDY ..................................................................41 
15. 
INFORMED CONSENT ............................................................................................41 
16. 
QUALITY ASSURANCE/QUALITY CONTROL ...................................................41 
17. 
DATA HANDLING AND RECORD KEEPING ......................................................43 
17.1. 
Data Handling .............................................................................................................43 
17.2. 
Subject Confidentiality ...............................................................................................43 
17.3. 
Computer Systems ......................................................................................................43 
17.4. 
Data Entry ...................................................................................................................43 
17.5. 
Data Validation ...........................................................................................................43 
17.6. 
Record Keeping ..........................................................................................................44 
18. 
TERMINATION OF STUDY ....................................................................................44 
19. 
FINANCING AND INSURANCE .............................................................................44 
20. 
PUBLICATION POLICY ..........................................................................................46 
21. 
REFERENCES ...........................................................................................................47 
APPENDIX 1. CLINICAL LABORATORY TESTS (SAFETY)..............................................48 
APPENDIX 2. INTERACTING MEDICATIONS .....................................................................49 
 


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LIST OF TABLES 
Table 1: 
Schedule of Assessments ..............................................................................................9 
 
LIST OF FIGURES 
Figure 1: 
Prevalence of Respiratory Microorganisms by Age Cohort (2019) ...........................17 
Figure 2: 
Kaplan-Meier Estimates of Survival According to MRSA Status  
(N = 19,833 patients) ..................................................................................................18 
Figure 3: 
Study Design ...............................................................................................................23 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC%extrap 
Percentage of the area under the drug concentration curve due to extrapolation 
for infinity 
AUC0-12h 
Area under the drug concentration curve from time zero (0 h) to 12 h 
AUC0-24h 
Area under the drug concentration curve from time zero (0 h) to 24 h 
AUC0-inf 
Area under the drug concentration curve from time zero (0 h) to infinity 
AUC0-last 
Area under the drug concentration curve from time zero (0 h) to 24 h 
β-hCG 
beta-human chorionic gonadotropin 
CABP 
Community-acquired bacterial pneumonia 
CF 
Cystic fibrosis 
CFR 
Code of Federal Regulation 
CFTR 
Cystic fibrosis transmembrane conductance regulator (protein) 
CL 
Clearance, the apparent volume cleared for drug 
CL/F 
Total body clearance for extravascular administration 
Cmax 
Maximum observed plasma concentration 
CRF 
Case report form 
CRU 
Clinical research unit 
CV 
Coefficient of variation 
CYP3A 
Cytochrome P450 
DAC 
Designated Activity Company 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
F 
Oral bioavailability 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
h 
Hour; hours 
HBsAg 
Hepatitis B surface antigen 
HIPAA 
Health Insurance Portability and Accountability Act 


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Abbreviation 
Definition 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
ICH 
International Council for Harmonisation 
IR 
Immediate-release 
IRB 
Institutional Review Board 
IV 
Intravenous 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
lambda-z 
Individual estimate of the terminal elimination rate constant, calculated using 
log-linear regression of the terminal portions of the plasma concentration-
versus-time curves 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRSA 
Methicillin-resistant Staphylococcus aureus 
MRT 
Mean residence time 
N 
Number 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PTC 
Peptidyl transferase center 
q12h 
Every 12 hours 
QA 
Quality Assurance 
QTcF 
QT interval corrected according to Fridericia 
rRNA 
Ribosomal ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SUSAR 
Suspected unexpected serious adverse event 
t½ 
Apparent elimination half-life calculated as ln(2)/ke 
TEAE 
Treatment-emergent adverse event 
Tlag 
The finite time taken for a drug to appear in systemic circulation following 
extravascular administration 
tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
US 
United States 
Vd 
Volume of distribution 
Vd/F 
Volume of distribution corrected for bioavailability 
Vss 
Volume of distribution at steady state 
WHO 
World Health Organization 


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3. 
INTRODUCTION 
3.1. 
Cystic Fibrosis 
Cystic fibrosis (CF) is a genetic, autosomal recessive disease resulting from a mutation in a 
single gene on chromosome 7 that encodes the cystic fibrosis transmembrane conductance 
regulator (CFTR) protein (Katkin, 2020). The CFTR gene encodes for the CFTR protein, which 
is located in every mucus-producing organ of the body, including the lungs, liver, pancreas, and 
intestines, as well as sweat glands. Normally, the CFTR protein controls the movement of ions 
from inside the cell to outside the cell. In people with CF, the mutated gene causes the protein to 
not work properly, which, in turn, affects the movement of sodium and water. This causes thick, 
sticky mucus and blockages in the lungs and digestive system.  
Staphylococcus aureus is one of the most common airway pathogen in patients with CF 
(Figure 1). Airway infections are associated with progressive lung function decline and 
respiratory failure, which is the leading cause of mortality. Pulmonary exacerbations are 
aggressively managed with high health care utilization, requiring chronic treatment. Methicillin-
resistant S. aureus (MRSA) is also associated with poor survival in CF patients. In patients with 
respiratory tract cultures positive for MRSA, median survival time is 6.2 years less than for 
patients with negative MRSA cultures. Therefore, MRSA infection may be a modifiable risk 
factor for death in patients with CF (Figure 2). 
Figure 1: 
Prevalence of Respiratory Microorganisms by Age Cohort (2019) 
 
MRSA = methicillin-resistant Staphylococcus aureus 
Source: Cystic Fibrosis Foundation Patient Registry. Annual Data Report 2019.  
 


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Figure 2: 
Kaplan-Meier Estimates of Survival According to MRSA Status  
(N = 19,833 patients) 
 
MRSA = methicillin-resistant Staphylococcus aureus; y = year 
Source: Dasenbrook et al, 2010  
 
While a number of anti-staphylococcal antibiotics are marketed, several major limitations exist 
regarding their utility in the management of bacterial exacerbations in patients with CF: 1) no 
agent has been demonstrated to have an acceptable efficacy and safety profile to result in 
marketing authorization approval by the Food and Drug Administration (FDA), European 
Medicines Agency (EMA), or other health authority for the treatment of exacerbations of CF 
caused by S. aureus; 2) the agents possessing appreciable activity against MRSA require 
parenteral administration; 3) agents such as trimethoprim-sulfamethoxazole, clindamycin, 
doxy/minocycline, that can be administered orally do not possess consistent activity against 
MRSA and have significant safety and tolerability issues limiting their utility in CF patients.  
3.2. 
Lefamulin 
XENLETA® (lefamulin; BC-3781), is a novel, semi-synthetic, first-in-class pleuromutilin 
antibiotic for systemic use in humans. Pleuromutilin derivatives inhibit bacterial protein 
synthesis by a novel interaction with the peptidyl transferase center (PTC) in domain V of 23S 
ribosomal ribonucleic acid (rRNA) in the large ribosomal subunit. The unique binding site of the 
pleuromutilins in the highly conserved core of the ribosomal PTC confers a low propensity for 
the development of bacterial resistance, and a lack of cross-resistance with other antibiotic 
classes. A pleuromutilin has been approved for topical use in humans and oral pleuromutilins 
have been used in veterinary medicine for many years. 


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In August 2019, the United States (US) FDA approved lefamulin in the treatment of community-
acquired bacterial pneumonia (CABP) in adults 18 years of age and older caused by the 
following susceptible microorganisms: Streptococcus pneumoniae, Staphylococcus aureus 
(methicillin-susceptible isolates), Haemophilus influenzae, Legionella pneumophila, 
Mycoplasma pneumoniae, and Chlamydophila pneumoniae (Nabriva Therapeutics, Inc., 2021). 
While the number of patients in the CABP pivotal program with MRSA did not result in an 
indication statement that includes MRSA, lefamulin has been demonstrated to possess excellent 
activity against MRSA in in vitro and in vivo animal infection models. In addition, lefamulin was 
shown to have similar efficacy as compared with intravenous (IV) vancomycin in a Phase 2 
clinical study of the treatment of acute bacterial skin and skin structure infections in which 
approximately 69% of subjects had MRSA as the causative organism identified (Prince, 2013). 
For details on lefamulin nonclinical and clinical development programs, see the current version 
of the Investigator’s Brochure. 
3.3. 
Study and Dose Rationale 
Study NAB-BC-3781-1014 (hereafter referred to as Study 1014) is designed to evaluate the 
pharmacokinetics (PK) of a 600-mg immediate-release (IR) tablet and 150-mg IV formulations 
of lefamulin in adult patients with CF. 
3.3.1. 
Study Rationale 
Staphylococcus aureus is one of the most common causative pathogens associated with 
exacerbations of CF (Cystic Fibrosis Foundation, 2019). Current treatment guidelines for the 
management of exaccerbations of CF caused by S. aureus recommend the use of unapproved 
antibactertial agents. Further, many of the recommended treatments can only be administered via 
the IV route and/or have limitations due to safety and tolerability. Lefamulin is a novel, first-in-
class, IV and oral pleuromutilin antimicrobial agent that has been demonstrated to be highly 
potent against S. aureus, including MRSA and strains obtained from patients with CF (Nabriva 
Therapeutics, Inc., 2021; Sader, 2021). Cystic fibrosis patients have altered drug distribution and 
elimination kinetics for many antimicrobials relative to patients without CF. While the advent of 
CFTR modulaotrs has resulted in improved lung function and had a positive impact on the 
quality of life of CF patients, limited data have been published describing the impact of the 
conomittnat use of CFTR modulaotrs and commonly used antibacterial agents (Albright, 2020).  
This study is intended to assess the PK and safety of  a single dose of IV and oral formulations of 
lefamulin in adults with CF. 
3.3.2. 
Dose Rationale 
For treatment of adults with CABP, the recommended dosage regimen of lefamulin is as follows: 
• 150 mg every 12 hours (q12h) by IV infusion over 60 minutes for 5 to 7 days, or 
• 150 mg q12h by IV infusion over 60 minutes then switch to 600 mg orally 
q12h (at  the discretion of the physician) for 5 to 7 days total, or 
• 600 mg orally q12h for 5 days. 


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In this study, single doses of IV and oral lefamulin will be studied in CF patients; PK data from 
this study will be sufficient to compare exposure in these patients to the known exposure in non-
CF patients. The single doses to be evaluated in adults will be those recommended for treatment 
of CABP, ie, 150 mg IV or 600 mg orally. 
3.4. 
Risk Assessment 
Patients participating in this crossover study will receive lefamulin as a single 600-mg IR tablet 
and a 150-mg IV infusion in a crossover fashion for the purposes of PK and safety assessment. 
Consequently, patients participating in the study will be unlikely to derive any clinical benefit 
from exposure to lefamulin. 
In adult clinical studies conducted to date, lefamulin has been well tolerated when administered 
by the oral and IV routes (see Investigator’s Brochure, Section 5.2.1). Following oral dosing, 
gastrointestinal adverse events were most frequent (typically mild nausea, diarrhoea, or 
abdominal pain), without a clear correlation with dose level. Following IV dosing, the most 
frequently reported adverse events were administration site reactions. Analysis by dose showed 
that these events generally were more frequent at IV doses ≥ 150 mg. Thus, this study is 
expected to pose low risk to patients.  
To minimize potential risk to individuals in this study there are strict inclusion and exclusion 
criteria. Potential patients will be carefully screened by laboratory evaluations, medical history, 
physical examination, and by electrocardiogram (ECG) to exclude those patients who could be at 
increased risk. Participating patients will be monitored for safety and tolerability during each part 
of the study and through a Follow-up phone call which will take place 4 to 7 days after the last 
dose of lefamulin in the second dosing period of the study. 


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4. 
STUDY OBJECTIVES AND ENDPOINTS 
4.1. 
Objectives 
4.1.1. 
Primary Objective 
• To evaluate the PK of a 600-mg IR tablet and 150-mg IV formulations of lefamulin in 
adult patients with CF  
4.1.2. 
Secondary Objectives 
• To evaluate the safety and tolerability of lefamulin when administered as single oral 
or IV doses in adult patients with CF  
4.1.3. 
Exploratory Objective 
• To approximate the penetration of lefamulin into sputum in CF patients 
4.2. 
Endpoints 
4.2.1. 
Primary Endpoint 
Plasma PK of lefamulin and its main metabolite, BC-8041, following 150-mg IV infusion and 
600-mg IR tablet in patients with CF. 
Appropriate non-compartmental techniques will be used to obtain estimates, including but not 
limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 
when possible and appropriate:  
• Cmax: maximum observed plasma concentration 
• tmax: time to reach maximum plasma concentration of lefamulin following drug 
administration 
• AUC0-12h: area under the drug concentration curve from time zero (0 hour [h]) to 12 h 
• AUC0-24h: area under the drug concentration curve from time zero (0 h) to 24 h 
• AUC0-last: area under the drug concentration curve from time zero (0 h) to 24 h 
• AUC∞ area under the drug concentration curve from time zero (0 h) to infinity 
• t½: apparent elimination half-life calculated as ln(2)/ ke 
• CL: clearance (IV dose only) 
• CL/F: total body clearance (oral dose only) 
• Tlag (oral dose only): the finite time taken for a drug to appear in systemic circulation 
following extravascular administration 
• AUC%extrap: percentage of AUC due to extrapolation for infinity 


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• lambda-z: Individual estimate of the terminal elimination rate constant, calculated 
using log-linear regression of the terminal portions of the plasma concentration-
versus-time curves 
• Vd (IV dose only): volume of distribution  
• Vd/F (oral dose only): volume of distribution corrected for bioavailability  
• Vss (IV dose only): volume of distribution at steady state  
• MRT: mean residence time  
• F: oral bioavailability  
4.2.2. 
Secondary Endpoints 
• Descriptive summaries of the following: 
− Treatment-emergent adverse events (TEAEs) 
− Laboratory assessments (chemistry and hematology)  
− Vital signs measurements 
− Electrocardiogram parameters 
4.2.3. 
Exploratory Endpoint 
• To evaluate the concentration of lefamulin in sputum following 150-mg IV infusion 
and 600-mg IR tablet in adult patients with CF. 


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5. 
INVESTIGATIONAL PLAN 
This will be a single-cohort, open-label, randomized, 2-part, crossover study in patients with CF. 
In one dosing period, lefamulin will be administered as a 150 mg IV infusion in 250 mL citrate 
buffered saline over 1 hour. In the second dosing period, lefamulin will be administered as a 
600-mg IR tablet orally in the fasted state. Study periods will be separated by 4 to 7 days. The 
overall study design is depicted in Figure 3. 
Figure 3: 
Study Design 
 
Abbreviations: hr = hour; IR = immediate-release; IV = intravenous 
a For the first dosing period, the Follow-up Visit may be used as the Screening Visit for the second dosing period. 
For the second dosing period, a Follow-up phone call will take place 4 to 7 days post final dose. 
 
Twelve adult patients with CF are planned to be enrolled. Patients will be screened for study 
eligibility up to 30 days before the first dose of study drug in the first dosing period  (Day 1). For 
each period, eligible patients will remain at the clinical research unit (CRU) on Day -1 until 
collection of the 12-hour post-dose PK sample and safety assessments are completed. Patients 
will have the option to: 1) be discharged from the CRU after the 12-hour study procedures are 
completed; or 2) stay overnight in the CRU through the 24-hour study procedures. If a patient 
chooses to be discharged, he/she will be required to reurn to the CRU for the 24-hour study 
procedures to be completed. 


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After the first dosing period, a Follow-up Visit will be reassessed before each CRU admission. 
Patients will have a Follow-up phone call assessment take place 4 to 7 days after the final dose of 
lefamulin. This visit will also serve as the Screening Visit for the second dosing period. After the 
second dosing period, a Follow-up phone call will take place 4 to 7 days after the final dose of 
lefamulin to ensure the ongoing wellbeing of the patients.  
Following Screening, total duration of study participation for each patient will be approximately 
10 to 13 days (depending on the duration of the washout period).  


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6. 
STUDY POPULATION 
Patients ≥ 18 years of age with a confirmed diagnosis of CF receiving standard of care will be 
enrolled in this study. Prior to any study-related procedures being performed, written informed 
consent will be obtained from all patients.  
6.1. 
Subject Inclusion Criteria 
Potential patients must meet all of the following inclusion criteria to be eligible for participation 
in the study: 
1. Signed informed consent. 
2. Age ≥ 18 years of age. 
3. Genetic confirmation of CF diagnosis will be by a report from a genetic test, such as 
“F508 deletion detected.”   
4. Weight > 40 kgs. 
5. Forced expiration volume (FEV)1 > 40% predicted, as measured during the most recent 
evaluation. 
6. Mentally and physically able to participate in the study as determined by the Investigator, 
ie, clinically stable with no significant changes in health status within 28 days prior to, 
and including, Day 1. 
7. Vital signs within the following ranges: 
a. Tympanic temperature, < 38°C 
b. Systolic blood pressure, 90 to 160 mmHg 
c. Diastolic blood pressure, 50 to 90 mmHg 
d. Heart rate (HR) < 100 beats per minute at rest 
e. Respiration rate 12 to 20 breaths/min 
f. Oxygen saturation to be documented. No selection criteria; supplemental oxygen use 
is acceptable. 
8. Negative beta-human chorionic gonadotropin (β-hCG) urine or serum pregnancy test for 
females of childbearing potential. 
9. Willing to commit to acceptable methods of contraception as defined below. 
a. Female patients of childbearing potential must agree to use approved, highly effecive 
methods of contraception from the Screening Visit through the Follow-up Visit or 
phone call. These contraceptives include: true abstinence (when this is in line with the 
preferred and usual lifestyle of the patient), intrauterine devices with a failure rate of 
< 1%, or double barrier contraception (diaphragm with spermicide plus condom with 
spermicide). 
NOTE: A woman is assumed to be of childbearing potential unless one of the 
following criterion is met: 
− Underwent an acceptable method of surgical sterilization at least 6 months prior 
to the first dose. 


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− Has had amenorrhea for ≥ 12 months with follicle stimulating hormone (FSH) 
level > 40 mIU/mL. 
b. Male patients must agree to use either true abstinence (when this is in line with the 
preferred and usual lifestyle of the patient ) or double method of contraception (ie, 
condom with spermicide) from Screening through at least 90 days after the last dose 
of lefamulin. 
6.2. 
Subject Exclusion Criteria 
Potential patients meeting any of the following criteria will be excluded from the study: 
1. Known history of chronic liver or biliary disease, Gilbert’s syndrome, or or any of the 
following at Screening: aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) > 2 x upper limit of normal (ULN), total bilirubin > 1.5 x ULN. 
2. Prolonged baseline corrected QT interval corrected according to Fridericia (QTcF) 
defined as > 440 ms (females) and > 430 ms (males). 
3. Family history or presence of prolonged QT syndrome, Torsades de Pointe, or known 
conduction defects (eg, bundle branch block, atrioventricular block). 
4. Use of Orkambi® (lumacaftor/ivacaftor) within 28 days prior to Day 1. 
5. Use of cytochrome P450 (CYP)3A substrates that prolong the QT interval within 
24 hours prior to Day 1 (see Appendix 2). 
6. Use of strong and moderate CYP3A inducers or P-glycoprotein (P-gp) inducers within 
28 days prior to Day1 (see Appendix 2). 
7. Use of strong inhibitors of CYP3A4 within 24 hours prior to Day 1 as described in 
Appendix 2. 
8. Serum potassium levels below the normal reference range at Screening. 
9. Known allergy to pleuromutilin class of antibiotic or any of the excipients of the 
lefamulin formulations. 
10. Consumption of grapefruit, grapefruit juice, grapefruit products, pomelo, or Seville 
oranges within 24 hours before Day 1. 
11. Use of vaporized nicotine or cannabidiol products, smoking (regularly or intermittently) 
more than 5 cigarettes (or equivalent) per day, or any use of tobacco other than in 
cigarettes or cigars within 28 days of Day 1.  
12. Positive blood test for hepatitis C, human immunodeficiency virus (HIV), or hepatitis B 
antigen or core antibody (indicating active infection). 
13. Positive test for drugs of abuse or alcohol at Screening or Day -1 that cannot be supported 
by medical history  (eg, recent physician prescribed use of codeine). 
14. Use of an investigational product within the 30 days prior to Day 1 (3 months prior to 
Day 1 if the study drug was a new chemical entity).  
15. Difficulty swallowing tablets. 


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16. Females who are pregnant or breastfeeding. 
17. Does not have suitable venous access for multiple venipuncture or cannulation. 
18. Any medical, psychological, cognitive, social, or legal conditions that, in the opinion of 
the Investigator, would interfere with the patient’s ability to give an informed consent 
and/or participate fully in the study. 
19. Any other reason, in the opinion of the Investigator, the patient is unsuitable to 
participate. 


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7. 
STUDY DRUG ADMINISTRATION 
7.1. 
Duration of Treatment  
Each patient will receive a single dose of lefamulin at 2 study periods 4 to 7 days apart.  
7.2. 
Timing of Dose and Dose Administration 
Lefamulin will be administered as follows to all patients after an overnight fast: 
• IV Treatment Period: Lefamulin 150-mg in 250 mL citrate buffered saline IV 
infusion over 1 hour  
• Oral Treatment Period: Lefamulin as a 600-mg IR tablet in the fasted state. The oral 
treatment will be swallowed whole with 6 to 8 ounces of water at least 1 hour before 
or 2 hours after a meal. 
7.3. 
Treatment Compliance 
Study personnel will observe administration of each oral dose of lefamulin to each patient while 
at the investigative site. A mouth and hand check will be performed to ensure patients took the 
full dose provided. The study personnel will administer the IV infusion of lefamulin at the 
investigative site. 
The dose and date/time of the administration of the study drug will be recorded in the site source 
documents and in the appropriate sections of the electronic case report form (eCRF).  
7.4. 
Randomization 
Randomization will be accomplished by using a pre-prepared randomization scheme at each site 
and assigning patients to treatment, sequentially at the site, according to the site's randomization 
table. 
 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
A schedule of study assessments is provided in Table 1. Patients meeting all inclusion criteria 
and none of the exclusion criteria may be enrolled in the study after the nature and purpose of the 
protocol has been explained and written informed consent/assent has been voluntarily given by 
the patient or his/her legal representative, when appropriate.  
Consent must be obtained before any screening procedures are performed and before study drug 
administration. All study assessments and procedures as specified in this protocol will be 
performed by the Investigator or a qualified designee. 
Patients will be screened within 30 days before check-in to the CRU on Day -1. For patients who 
are screened (ie, those with signed written informed consent) but not enrolled, the reason for 
screening failure will be documented. If a patient is determined to be a screen failure, he/she can 
be rescreened once if the Investigator believes the patient will be eligible upon rescreening. 
8.1. 
Medical/Surgical History 
A medical and surgical history will be taken at Screening and on Day -1 of each Period. All 
medical history findings that have been present/active within 1 year before enrollment will be 
entered into the eCRF regardless of clinical relevance or presence at study start. Medical history 
findings that have been present within the 5 years before enrollment will be recorded if deemed 
clinically relevant by the Investigator to the conduct of the study. The medical history should 
include drug allergy history. 
8.2. 
Physical Examinations 
A complete physical examination (except for rectal and vaginal examinations) will be performed 
by the Investigator at Screening and upon check-in to the CRU on Day -1. At the other time 
points specified in Table 1, focused physical examinations will be performed according to 
standard institutional practices and must be documented in source documents. Clinically 
significant findings, as determined by the Investigator, will be documented in the eCRF as either 
medical history or adverse events. 
Body weight and height will be measured at Screening only. 
8.3. 
Vital Signs 
Systolic blood pressure (SBP), diastolic blood pressure (DBP), body temperature, HR, 
respiratory rate, and oxygen saturation measurements will be recorded at the time points 
specified in Table 1.  
Vital signs will be measured after patients have rested for at least 5 minutes in a sitting position. 
The position adopted by an individual patient should be consistent throughout the study. On 
Day 1 of each dosing period, pre-dose vital signs will be measured within 2 hours before each 
dose. If a patient has an abnormal value for SBP, DBP, or HR, the measurement may be repeated 
twice. If the second repeat measurement value does not qualify the patient, he or she is not 
eligible for that part of the study but may be reevaluated at a later time. 
Vital signs measurements should be repeated if clinically significant changes or machine errors 
occur during the course of the study.  


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Sitting BP and/or HR (as applicable) will be measured more frequently if warranted by the 
clinical condition of the patient. 
Vital signs will be measured using the same type of device throughout the study. Vital sign 
measurements will be recorded in the eCRF. Clinically relevant vital signs abnormalities meeting 
the definition of an adverse event (AE) must be recorded by the Investigator on the AE page of 
the eCRF. 
8.4. 
Clinical Laboratory Tests (Safety) 
Clinical chemistry and hematology assessments will be performed at the time points specified in 
Table 1. All safety laboratory tests performed during the study (Screening through Follow-up) 
will be analyzed at a local laboratory. Additional tests may be performed at the discretion of the 
Investigator if deemed clinically appropriate. A full list of the clinical laboratory tests that will be 
performed and analyzed can be found in Appendix 1. 
A serum or urine pregnancy test will be performed on all females of childbearing potential at the 
Screening and Day -1 Visits for each dosing period. A confirmatory FSH level will be 
determined at Screening for females who are ≥ 1 year post-menopausal. A FSH level 
> 40 mIU/mL indicates non-child bearing potential.  
Safety laboratory results outside the normal range will be evaluated by the Investigator as 
“clinically significant” or “not clinically significant.” Any clinically significant value that is not 
expected for this population should be repeated as necessary. 
If a patient has an abnormal laboratory value at check-in for either study period, the laboratory 
test may be repeated. If after the repeat measurement the value does not qualify the patient , the 
patient is not eligible for that part of the study. If the Investigator determines that the laboratory 
abnormality is likely to be transient and easily explained, the explanation will be documented 
and the patient may return once for re-evaluation after an appropriate time interval determined by 
the Principal Investigator at the time of the disqualifying laboratory result availability. Only a 
single re-evaluation will be accepted. 
8.5. 
Electrocardiograms 
A 12-lead ECG will be performed at the time points specified in Table 1 after the patient has 
been resting in a supine position for 10 minutes. The Day  1 pre-dose ECG must be reviewed by 
the Investigator or their designee before dosing to ensure that there are no clinically significant 
findings that would prevent dosing. Additional ECGs may be performed at the discretion of the 
Investigator or when clinically indicated. 
If a patient has an abnormal value ECG at Screening for either of the parts of the study, the ECG 
may be repeated twice. If after the second repeat measurement the value does not qualify the 
patient, he or she is not eligible for dosing. If the patient has prolongation of the QTc interval or 
any arrhythmia during the post-dose ECGs, no further lefamulin should be administered.   


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8.6. 
Pharmacokinetics 
8.6.1. 
Plasma Sample Collection  
Blood samples will be taken for the measurement of PK parameters at the following time points 
in each part of the study (Table 1): 
• Pre-dose; 30 min, and 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose. 
For details on sample collection, preparation, and shipment, refer to the study-specific 
Laboratory Manual supplied by the Sponsor. It is recommended that the blood samples are taken 
by a venipuncture or from a separate catheter, other than the catheter used for the infusion, to 
prevent any contamination of the PK blood samples with lefamulin from the infusion line and 
catheter. 
Plasma samples will be analyzed for concentrations of lefamulin and its metabolite BC-8041 
using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method at the 
bioanalytical laboratory.  
The maximum total blood volume collected in the study for safety and PK evaluations is 36 mL 
per patient. 
8.6.2. 
Sputum Sample Collection 
Spontaneous sputum samples will be collected first thing in the morning on Day 1 (pre-dose), 
and as many times as possible that the patient can provide a sample until 24 hours after dosing 
for PK analysis of lefamulin. The exact time of sputum production will be recorded so the post-
dose time can be determined precisely. 
Any spontaneous production of sputum during inpatient observation will also be collected and 
the time of collection documented. 
For details on sample collection, preparation, and shipment, refer to the study specific 
Laboratory Manual supplied by the Sponsor. 
Sputum samples will be analyzed for concentrations of lefamulin using a validated LC-MS/MS 
method at the bioanalytical laboratory. 
8.7. 
Prior and Concomitant Medications 
Prior and concomitant medications, including prescription medications, dietary supplements/ 
vitamins, and over-the-counter medications will be recorded in the eCRF throughout the study. 
Topical medications will be recorded only if used as treatment for an adverse event. At a 
minimum, the drug name (preferably generic), dose, frequency, indication, and the start and stop 
dates of administration should be recorded.  
Medications will be coded using the current version of the World Health Organization (WHO) 
Drug Dictionary. 
8.7.1. 
Prior Medications 
All medications taken within 14 days before Day -1 of the first treatment administration will be 
recorded in the eCRF. 


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8.7.2. 
Concomitant Medications 
All medications (other than study drug) taken from Day 1 through the Follow-up Visit after the 
second dosing period will be recorded in the eCRF, including any medications used to treat an 
adverse event. 
8.8. 
Restrictions During the Study 
The following restrictions apply to all patients. 
• No grapefruit, grapefruit juice, grapefruit products, pomelo, or Seville oranges from 
24 hours before Day 1 until discharge from CRU in each part of the study. 
• No excessive alcohol consumption (> 21 g alcohol per day for men and > 14 g 
alcohol per day for women) or use of alcohol from 48 hours before Day 1 until 
discharge from CRU in each part of the the study. 
• No use of vaporized nicotine or cannabidiol products, smoking (regularly or 
intermittently) more than 5 cigarettes (or equivalent) per day, or any use of tobacco 
other than in cigarettes or cigars within 28 days of Day 1 through discharge from the 
CRU. 
8.9. 
Discontinuation from Study Medication 
Patients are free to withdraw from study medication at any time for any reason. Patients may be 
withdrawn from study medication at the discretion of the Investigator at any time. If a patient is 
discontinued from study medication, the reason for discontinuation will be collected in the 
eCRF. 
A patient will be discontinued prematurely from the study medication for any of the following 
reasons: 
• Patient request 
• Lost to follow-up 
• Death 
• Physician decision (ie, assessment that it is not in the patient’s best interest to 
continue, or other reason)  
• Sponsor decision  
• Positive drug/alcohol test 
• Failure to meet eligibility criteria either part of the study 
If a patient is prematurely discontinued from study medication, the Investigator should obtain a 
PK sample if possible and perform all procedures scheduled for discharge from the unit. The 
patient will be contacted for a Follow-up phone call 4 to 7 days from the time he/she is 
discharged from the unit to ensure the ongoing wellbeing of the patient. If a patient reports any 
AEs which represent a cause for concern, he/she will be required to attend the clinic for a 
Follow-up assessment. This will be considered an unscheduled visit. Any patient withdrawn 
from study medication due to an adverse event or clinically significant abnormal laboratory test 


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result will be evaluated by the Investigator, or a monitoring physician, and will be treated and/or 
followed until the symptoms or values have either resolved or are assessed as stable by the 
Investigator. 
8.10. 
Discontinuation from Study 
Patients are free to withdraw from the study at any time for any reason. Patients may be 
withdrawn from the study at the discretion of the Investigator at any time. If a patient is 
discontinued from the study, the reason for discontinuation will be collected in the eCRF. 
A patient may be discontinued prematurely from the study for the following reasons: 
• Withdrawal of consent by patient  
• Adverse event 
• Pregnancy 
• Lost to follow-up 
• Death 
• Other (to be specified by the Investigator) 
If a patient is prematurely discontinued from the study, the Investigator should obtain a PK 
sample if possible and perform all procedures scheduled for discharge from the unit. The patient 
will be contacted for a Follow-up phone call 4 to 7 days from the time he/she is discharged from 
the unit to ensure the ongoing wellbeing of the patient. If a patient reports any AEs which 
represent a cause for concern, he/she will be required to attend the clinic for a Follow-up 
assessment. This will be considered an unscheduled visit. Any patient withdrawn from study 
medication due to an adverse event or clinically significant abnormal laboratory test result will 
be evaluated by the Investigator, or a monitoring physician, and will be treated and/or followed 
until the symptoms or values have either resolved or are assessed as stable by the Investigator. 
Every reasonable attempt should be made to retain patients in the study. If a patient does not 
report to the study site for a scheduled visit, study personnel will make 3 contact attempts: 
2 telephone contact attempts and, if these are unsuccessful, a certified letter will be sent to the 
patient. The patient will be considered lost to follow-up if: (1) upon receipt of delivery 
confirmation of the certified letter the patient does not contact the site; or (2) the certified letter is 
returned as undeliverable. 
9. 
ADVERSE EVENTS 
9.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the investigational medicinal 
product. 


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Any pre-existing conditions or signs and/or symptoms present in a patient before the start of the 
study (ie, before informed consent) should be recorded as medical/surgical history. Any medical 
occurrences that are new or worsened from the time of informed consent and up to and including 
the final visit must be reported as AEs. All AEs must be recorded regardless of causality. 
Patients will be monitored throughout the study for adverse reactions to the study medications 
and/or procedures at each study visit. Questions will be posed in a non-leading manner so as not 
to bias the response. In addition to questioning at specific time points, patients will be 
encouraged to spontaneously report any AEs. Any patient with an AE or clinically significant 
abnormal laboratory test result will be evaluated by the Investigator, or a monitoring physician, 
and will be treated and/or followed until the symptoms or values have resolved or are assessed as 
stable by the Investigator. A physician, either at the investigative site or at a nearby hospital 
emergency room, will administer treatment for any serious adverse events (SAEs). When 
appropriate, medical tests and examinations may be performed to ensure an AE has fully 
resolved. 
Adverse events will be collected throughout the study from the time a patient signs the informed 
consent through the Follow-up assessment after the second dosing period. Whenever possible, a 
specific disease or syndrome rather than individual associated signs and symptoms should be 
identified by the Investigator and recorded on the eCRF. However, if an observed or reported 
sign or symptom is not considered a component of a specific disease or syndrome by the 
Investigator, it should be recorded as a separate AE on the eCRF. 
The Investigator will evaluate and report the onset date/time, outcome and end date/time, 
severity (intensity), relationship to study drug, actions taken with study drug, whether event 
caused study discontinuation, whether concomitant or additional treatment was given, and 
determination of seriousness for each AE. 
Laboratory abnormalities will not be considered AEs unless they are associated with clinical 
signs and symptoms or require medical intervention. Clinically significant abnormal clinical 
laboratory findings, unless judged by the Investigator as more severe than expected for the 
patient’s condition, or that are present or detected at the start of the study and do not worsen, will 
not be reported as AEs. 
The Investigator will exercise medical and scientific judgment in deciding whether an abnormal 
clinical laboratory finding or other abnormal assessment is clinically significant. 
9.2. 
Assessment of Severity (Intensity) 
The following definitions for rating severity (intensity) will be used: 
• Mild: An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
• Moderate: An AE that is usually alleviated with specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but the 
patient is still able to function. 
• Severe: An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 


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9.3. 
Assessment of Relationship to Study Drug 
The Investigator will use his/her clinical judgment to explain each AE and determine its 
relationship, if any, to study drug treatment. Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the 
event to the study drug will be considered and investigated. The Investigator will also consult the 
Investigator’s Brochure in the determination of his/her assessment. Causality should be assessed 
using the following categories: 
• Not related: The event could readily be explained by factors not involving the study 
drug and a temporal relationship with the study drug did not exist.  
• Possibly Related: There was some temporal relationship between the event and the 
administration of the study drug and the event was unlikely to be explained by the 
patient’s medical condition or other therapies. 
• Probably Related: The temporal relationship between the event and the 
administration of the study drug was suggestive, and the event was less likely to be 
explained by the patient’s medical condition or other therapies.  
• Definitely Related: The event followed a reasonable temporal sequence from 
administration of the study drug, followed a known or suspected response pattern to 
the study drug, was confirmed by improvement upon stopping the study drug 
(dechallenge) and reappeared upon repeated exposure (rechallenge). (NOTE: this is 
not to be construed as requiring re-exposure of the patient, however, a category of 
definitely related could only be used when recurrence was observed.). 
9.4. 
Serious Adverse Events 
An SAE is any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening. NOTE: The term ‘life-threatening’ in the definition of “serious” 
refers to an event in which the patient was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it was 
more severe.  
• Results in persistent or significant disability/incapacity. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
NOTE: Hospitalizations, which are the result of elective or previously scheduled surgery for pre-
existing conditions, which have not worsened after entry into the study, should not be classified 
as SAEs. For example, admission for a previously scheduled ventral hernia repair would not be 
classified as an SAE; however, complication(s) resulting from a hospitalization for an elective or 
previously scheduled surgery that meet(s) serious criteria must be reported as SAE(s). 
• Is a congenital anomaly/birth defect. 
• Is an important medical event. 


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NOTE: Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention to prevent 1 of the other outcomes listed in the above definition. 
These should also be considered serious. Examples of such events are invasive or malignant 
cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
All SAEs occurring from the time of informed consent through completion of the Follow-up 
assessment after the second dosing period must be reported to Nabriva Therapeutics DAC or 
their representative within 24 hours of the knowledge of the occurrence (this refers to any AE 
that meets 1 or more of the aforementioned serious criteria). Reporting is done by completing the 
SAE form electronically in the Electronic Data Capture (EDC) system or paper SAE report form, 
whichever is applicable. The EDC system and/or paper report forms should be completed in as 
much detail as possible but lack of complete information should not delay the reporting of the 
SAE.  
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to Nabriva Therapeutics DAC, or their representative. 
However, it is very important that the Investigator always makes an assessment of causality for 
every event prior to transmission of the SAE report form to Nabriva Therapeutics DAC, or their 
representative. The Investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE report form accordingly. The causality assessment is 1 of the 
criteria used when determining regulatory reporting requirements. 
The Investigator will provide the assessment of causality per instructions on the SAE form in the 
eCRF. Serious AEs determined by the Investigator to be related to the study drug must be 
reported even if more than 30 days after the last administration of study drug have elapsed. In 
addition, the Sponsor will also assess causality of SAEs based on the information provided by 
the Investigator. 
All SAEs and suspected unexpected serious adverse events (SUSARs) will be reported by the 
Sponsor to the relevant competent authorities in accordance with the European Directive 
2001/20/EC, as applicable. 
Sponsor Safety Contact Information:  
 
, Drug Safety and 
Pharmacovigilance 
 
9.5. 
Other Reportable Events 
Certain events should be reported to the Sponsor as Other Reportable Events. These include the 
following: 
PI
PI
PI


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• Pregnancy exposure (a patient becomes pregnant while taking study drug) 
Patients who are pregnant at Screening and/or Day -1 are not permitted to participate 
in this study. Nabriva Therapeutics DAC or their representative must be notified of 
any female patient (or the partner of a male patient) who becomes pregnant during the 
study. Although pregnancy is not technically an AE, all pregnancies must be followed 
to conclusion to determine their outcome. This information is important for both drug 
safety and public health concerns. It is the responsibility of the Investigator or 
designee to report any pregnancy that occurs during this study to Nabriva 
Therapeutics DAC or their representative.  
• Lactation exposure (ie, the patient was taking study drug while nursing an infant) 
• Accidental exposure (someone other than the study patient was exposed to study 
drug) 
• Overdose (the patient received more than the prescribed dose of study drug within a 
given timeframe) 
• Other medication errors that potentially place patients at a greater risk of harm than 
was previously known or recognized (eg, study drug was administered by an incorrect 
route) 
10. 
DRUG SUPPLIES 
10.1. 
Description of Drug Products 
The active substance being investigated in this study is lefamulin (BC-3781), present in the drug 
product as the acetate salt (BC-3781.Ac). Physicochemical properties can be found in the 
Lefamulin Investigator’s Brochure. 
The IV drug product is supplied by the Sponsor in clear glass vials containing a sterile 
concentrate of the acetate salt of lefamulin (BC 3781.Ac) in normal saline. The content of one 
vial equals to 150 mg lefamulin free base. Lefamulin for IV use is constituted from one 
lefamulin 15 mL sterile concentrate vial into a sterile custom-manufactured 250 mL citrate 
buffered normal saline bag pH 5 for IV administration.  
Oral lefamulin is supplied by the Sponsor as 600 mg blue, oval, film-coated, immediate-release 
tablets printed with “LEF 600” on one side.  
Details of the qualitative and quantitative composition of lefamulin IV drug product and 
lefamulin 600-mg IR tablets are provided in the Lefamulin Investigator’s Brochure. 
10.2. 
Packaging and Labeling 
Lefamulin will be packaged and labeled in accordance with the applicable regulatory authority 
requirements. 
10.3. 
Storage of Study Drugs 
Access to all study drugs must be restricted to designated study personnel throughout the study. 


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The lefamulin IV drug product is supplied in clear glass vials. The shelf life of the lefamulin 
concentrate vials is 48 months at 2 to 8°C. Commercial supplies of citrate buffered normal saline 
will be used. 
The lefamulin 600-mg IR tablets will be supplied in a high-density polyethylene bottle with 
30 tablets per bottle. The shelf life of the IR tablets is at least 48 months at controlled room 
temperature (15°C to 25°C).  
Temperature excursions must be reported to the Sponsor. 
10.4. 
Product Accountability 
The Investigator is responsible for study drug accountability, reconciliation, and record 
maintenance. In accordance with all applicable regulatory requirements, the Investigator or 
designated study site personnel must maintain study drug accountability records throughout the 
course of the study. This person(s) will document the amount of study drug received from the 
supplier, the amounts dispensed to patients as well as lot numbers and expiration / retest date of 
study medications. At conclusion of the study, any unused study drug will be destroyed at the 
site after approval from the Sponsor. If no supplies remain, this will be recorded in the drug 
accountability section of the final monitoring report. 
10.5. 
Compliance 
Study personnel will supervise, observe, and record all study drug dosing of each patient while 
he/she is an inpatient at the CRU.  
10.6. 
Treatment of Overdose 
As study personnel are administering and documenting all doses in the study, the risk of 
overdose is considered to be low. 
No specific antidote to lefamulin is known. Any signs or symptoms of a possible overdose will 
be treated supportively. In the case of an emergency, standard emergency procedures will be 
employed. 
10.7. 
Occupational Safety 
Lefamulin is not expected to pose a significant occupational safety risk to site staff under normal 
conditions of use and administration. Material Safety Data Sheets describing occupational 
hazards and recommended handling precautions will be either provided to the Investigator, 
where this is required by local laws, or are available upon request from Nabriva Therapeutics. 
In line with good handling of chemical products, precautions are to be taken to avoid eye contact, 
and generating aerosols or mists. In the case of unintentional occupational exposure, any signs or 
symptoms should be treated appropriately, and the Sponsor notified. 


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11. 
STATISTICAL ANALYSIS 
11.1. 
Sample Size Determination 
Target enrollment for this study will be 12 patients.  
11.2. 
Analysis Sets 
• Safety analysis set: All patients who received any dose of lefamulin. 
• Pharmacokinetic analysis set: All patients who receive any dose of lefamulin and 
have an evaluable PK profile. 
11.3. 
Variables for Analysis 
11.3.1. 
Pharmacokinetic Analysis Variables 
Appropriate non-compartmental techniques will be used to obtain estimates, including but not 
limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 
when possible and appropriate: Tlag (oral dose only), Tmax, Cmax, AUC(0-last), AUC(0-24h), 
AUC(0-inf), AUC%extrap, lambda-z, t1/2, CL (IV dose only), CL/F (oral dose only), Vd (IV dose 
only), Vd/F (oral dose only), Vss (IV dose only), MRT, and (F). 
A complete description of the PK analysis variables will be presented in the Statistical Analysis 
Plan (SAP). 
11.3.2. 
Safety Analysis Variables 
Safety and tolerability will be assessed by monitoring AEs and concomitant medications, clinical 
chemistry and hematology laboratory assessments, vital signs, ECG results, and physical 
examination findings. A complete description of the safety analysis variables will be presented in 
the SAP. 
11.4. 
Pharmacokinetic Analysis 
Presentation of PK data will be descriptive in nature and will be presented by treatment. 
11.5. 
Statistical Analysis 
A separate SAP will be developed and approved before the final analyses. A complete 
description of the analyses will be provided in the SAP. 
Categorical data will be summarized with counts and percentages and continuous variables with 
N, mean, coefficient of variation (CV), median, standard deviation, and range. In addition, PK 
parameters will be summarized with the geometric mean and geometric CV.  
Further details of the statistical analysis will be provided in a study-specific SAP, which will 
include, but are not limited to: 
• Definition of analysis populations 
• Details of planned analysis of primary and secondary variables as well as safety 


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• Data handling conventions  
11.6. 
Safety Analysis 
Descriptive summaries and listings of individual patient safety data will be presented by 
treatment. 
Safety will be evaluated in the Safety Analysis Set by presenting summaries of AEs, routine 
clinical laboratory parameters, ECG results, and vital sign parameters by treatment. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Summary tables will be provided for all TEAEs. A TEAE is defined as an AE with 
a start date and time on or after study drug administration. The number and percentage of 
patients  with TEAEs will be tabulated by system organ class and MedDRA preferred term for 
each treatment and dose, and by severity and relationship to treatment.  
Treatment-emergent AEs leading to premature discontinuation from study and serious TEAEs 
will be presented in a table and/or a listing. 
Safety data including clinical laboratory parameters, ECG results and vital signs will be 
summarized by treatment and scheduled assessment. These summaries will also include change 
from baseline for each scheduled assessment by treatment.  
12. 
STUDY MONITORING 
All aspects of the study will be carefully monitored by the Sponsor’s authorized individuals, 
acting as agents of the Sponsor with respect to current Good Clinical Practice (GCP) and 
Standard Operating Procedures for compliance with applicable government regulations. These 
individuals will have access to all records necessary to ensure integrity of the data and will 
periodically review the progress of the study with the Principal Investigator. 
Frequent communication between the study site and the Sponsor is essential to ensure that the 
patient safety is monitored adequately. The Investigator will make safety assessments on an 
ongoing basis. The Sponsor’s medical monitor will review safety information from all study sites 
as it becomes available throughout the study. 
13. 
INSTITUTIONAL REVIEW BOARD APPROVAL 
The Principal Investigator agrees to provide the Institutional Review Board (IRB) with all 
appropriate material, including a copy of the informed consent. The study will not be initiated 
until the Investigator obtains written approval of the research plan (protocol) and the informed 
consent document from the appropriate IRB and copies of these documents are received by 
Nabriva Therapeutics. 
It is the Investigator’s responsibility to obtain IRB approval for all subsequent major changes to 
the protocol, in compliance with local law. Appropriate reports on the progress of this study will 
be made by the Investigator to the IRB and Sponsor in accordance with applicable government 
regulations and in agreement with policy established by the Sponsor. 


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14. 
ETHICAL CONDUCT OF THE STUDY 
This clinical study will be conducted in compliance with this protocol, the guidelines of the 
World Medical Association Declaration of Helsinki in its revised edition (Fortaleza, Brazil, 
October 2013), the guidelines of International Council on Harmonisation (ICH) GCP 
(CPMP/ICH/135/95), European Union (EU) Clinical Trials Directive 2001/20/EC, EU 
Commission Directive 2005/28/EC, and Code of Federal Regulation (CFR) Title 21, CFR Part 
50, 56 and 312, designated Standard Operating Procedures, and with local laws and regulations 
relevant to the use of new therapeutic agents in the country of conduct. 
15. 
INFORMED CONSENT 
The ICH has issued guidelines to provide protection for human patients in clinical investigations. 
The ICH Tripartite Guideline for Good Clinical Practice establishes the general requirements for 
informed consent. 
A properly executed, written informed consent in compliance with the terms of these guidelines 
shall be obtained from each patient before entering the study, or before performing any unusual 
or non-routine procedure in relation to the study. The purpose of the study, procedures to be 
carried out, and potential hazards will be described to each potential patient in non-technical 
terms. Patients will be required to read, voluntarily sign, and date an informed consent form 
summarizing the discussion at Screening, and will be assured that they may withdraw from the 
study at any time without jeopardizing their medical care. 
Patients will sign and date one copy of the informed consent form which will be photocopied. 
The copy will be retained by the patient and the original will be retained on file by the 
Investigator. The consent form must be approved by the appropriate IRB and Sponsor before 
study initiation at a study site. Any subsequent changes to the approved informed consent form 
must be reviewed and approved by the appropriate IRB and Sponsor before implementation. 
16. 
QUALITY ASSURANCE/QUALITY CONTROL 
Standard Operating Procedures belonging to Nabriva Therapeutic or designee(s) will be adhered 
to for all activities relevant to the quality of the study and are routinely monitored by the Quality 
Assurance (QA) Division. 
Data will undergo quality control checks before clinical database lock. Sponsor-designated, 
independent monitors will be responsible for the monitoring of the study and its data within the 
eCRFs. 
A QA audit of this study may be conducted by the Sponsor or Sponsor’s designee. The QA 
auditor will have access to all medical records, the Investigator’s study-related files and 
correspondence, and information in the informed consent documentation of this study. 
An inspection of this study may be conducted by a regulatory agency. The Investigator agrees to 
contact the Sponsor as soon as possible, but not later than within 1 week, upon notification of an 
inspection by a regulatory agency. The Investigator agrees to allow the Inspector direct access to 
all relevant documents and to allocate his/her time and that of study site personnel to the 


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Inspector to discuss findings in any relevant issues. The Investigator will allow Sponsor 
personnel to be present as an observer during a regulatory inspection, if requested. 


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17. 
DATA HANDLING AND RECORD KEEPING 
17.1. 
Data Handling 
Electronic case report forms are produced, stored electronically, and are available to the designated 
study team members. Each eCRF is reviewed and signed by the Investigator. The final signed case 
report forms (CRFs) are provided to the Sponsor in the format as decided upon by the Sponsor, as 
documented in the data management plan (if applicable). 
17.2. 
Subject Confidentiality 
Investigator and his/her staff will be required to manage patient data collected for the study in 
accordance with applicable laws and regulations on personal data protection. 
All US-based investigational sites and laboratories or entities providing support for this study, 
must, where applicable, comply with the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996. An investigational site that is not a Covered Entity as defined by HIPAA must 
provide documentation of this fact to Nabriva Therapeutics. 
After patients have consented to take part in the study their medical records and the data 
collected during the study will be reviewed by Nabriva Therapeutics or its representatives. These 
records and data may, in addition, be reviewed by the following: independent auditors who 
validate the data on behalf of Nabriva Therapeutics; third parties with whom Nabriva 
Therapeutics may develop, register or market lefamulin; national or local regulatory authorities 
and the IRBs that gave approval for this study to proceed. 
Patients will be known by a unique number; however, their date of birth can also be collected if 
not in contradiction with any requirements and used to assist Nabriva Therapeutics to verify the 
accuracy of the data, for example, that the laboratory results are assigned to the correct patient. 
The results of this study may be recorded and transferred to and used in other countries 
throughout the world, which may not afford the same level of protection that applies within the 
EU. The purpose of any such transfer would be to support regulatory submissions in other 
countries. 
17.3. 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
17.4. 
Data Entry 
Data must be recorded using the eCRF as the study is in progress. All study site personnel must 
log into the system using their secure user name and password in order to enter, review, or 
correct study data. These procedures must comply with the Title 21 CFR Part 11 for US sites and 
EU Directives 2001/20/EC and 2005/28/EC for EU sites. All passwords will be strictly 
confidential. 
17.5. 
Data Validation 
Validation checks will be performed as agreed to in the Data Validation Plan.  


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17.6. 
Record Keeping 
Raw data generated in connection with this study as well as an original copy of the final clinical 
study report, will be retained in archive until at least 5 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 5 years have elapsed since the formal discontinuation of 
clinical development of lefamulin. These documents will be retained for a longer period if 
required by the applicable regulatory requirements or by an agreement with the Sponsor. It is the 
responsibility of the Sponsor to inform the Investigator/Institution as to when these documents 
no longer need to be retained. 
As required under European Directive 2005/28/EC, Article 17, all ‘essential documents’ (as 
described in the ICH GCP Guidelines) must be retained by Nabriva Therapeutics and the 
Investigator for at least 5 years after the completion of the clinical study. Therefore, all studies, 
independent of where they were conducted in the world, must follow this requirement in the 
event a submission is ever made in the EU. These documents may be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement with 
Nabriva Therapeutics. It is the responsibility of Nabriva Therapeutics to inform the Investigator 
as to when these documents no longer need to be retained. The Investigator must obtain written 
permission from Nabriva Therapeutics before the destruction of any study document.  
The retention of investigator study records is an Investigator responsibility and Nabriva 
Therapeutics will neither arrange nor pay for this activity. Any transfer of ownership of the 
content of the clinical trial master file is the responsibility of the Investigator or site 
representative, and shall be documented. The new owner shall assume the responsibilities set 
forth in the applicable regulations. 
These records must be made available at reasonable times for inspection and duplication, if 
required, by a properly authorized representative of the US FDA in accordance with 21 CFR 
312.68 or other national or foreign regulatory authorities in accordance with regulatory 
requirements. 
18. 
TERMINATION OF STUDY 
The Sponsor reserves the right to discontinue this study at any time. 
19. 
FINANCING AND INSURANCE 
The costs necessary to perform the study will be agreed upon with each Investigator and will be 
documented in a separate financial agreement that will be signed by the Investigator and Nabriva 
Therapeutics (or designee), before the start of the study.  
The Investigator will be required to disclose any financial arrangement whereby the value of the 
compensation for conducting the study could be influenced by the results or outcome of the 
study. The following information will be collected: any significant payments of other sorts from 
Nabriva Therapeutics, (eg, money to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria); any proprietary interest in lefamulin; 
any significant equity interest in Nabriva Therapeutics as defined in 21 CFR 54 2(b). In 


Clinical Study Protocol 
 
Nabriva Therapeutics 
NAB-BC-3781-1014 
 
Lefamulin 
02 November 2021 
45 
Confidential 
consideration of participation in the study, Nabriva Therapeutics will pay the Investigator or 
nominated payee the sums set out in the payment schedule attached to the Investigator 
agreement.  


Clinical Study Protocol 
 
Nabriva Therapeutics 
NAB-BC-3781-1014 
 
Lefamulin 
02 November 2021 
46 
Confidential 
20. 
PUBLICATION POLICY 
It is intended that the results of the study may be published as scientific literature. Results may 
also be used in submissions to Regulatory Authorities. The following conditions are to protect 
commercial confidential materials (eg, patents, etc.), not to restrict publication. 
All information concerning lefamulin (such as patent applications, formulae, manufacturing 
processes, basic scientific data, or formulation information supplied to the Investigator by 
Nabriva Therapeutics and not previously published) is considered confidential by Nabriva 
Therapeutics and shall remain the sole property of Nabriva Therapeutics. The Investigator agrees 
not to use it for other purposes without Nabriva Therapeutics written consent. 
All manuscripts, abstracts or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by Nabriva Therapeutics in advance of submission. 
The review is aimed at protecting Nabriva Therapeutics proprietary information existing either at 
the date of the commencement of the study or generated during the study. 
The detailed obligations regarding the publication of any data shall be set out in the agreement 
between each Investigator and Nabriva Therapeutics. 


Clinical Study Protocol 
 
Nabriva Therapeutics 
NAB-BC-3781-1014 
 
Lefamulin 
02 November 2021 
47 
Confidential 
21. 
REFERENCES 
Albright JC, Houck AP, Pettit RS. Effects of CFTR modulators on pharmacokinetics of 
tobramycin during acute pulmonary exacerbations in the pediatric cystic fibrosis population. 
2020;55(10):2662-6. 
Cystic Fibrosis Foundation Patient Registry. Annual Data Report 2019. 
Dasenbrook EC, Checkley W, Merlo CA, et al. Association between respiratory tract methicillin-
resistant Staphylococcus aureus and survival in cystic fibrosis. JAMA. 2010 Jun 
16;303(23):2386-92. 
Katkin JP. Cystic fibrosis: Genetics and pathogenesis. Available at: 
https://www.uptodate.com/contents/cystic-fibrosis-genetics-and-
pathogenesis?search=cystic%20fibrosis&topicRef=110933&source=see_link#H1. Accessed on 
18 Sept 2021. 
Nabriva Therapeutics, Inc. XENLETA® Package Insert. 2021. Available at: 
https://www.xenleta.com/?gclid=CjwKCAjwos-
HBhB3EiwAe4xM9_1gYCcR2SPuVIqEEAP2t2r7NrCp8UlqOHDJYD9Xw2DulMmWQeuHJx
oCp5oQAvD_BwE. Accessed on 18 Sept 2021. 
Prince WT, Ivezic-Schoenfeld Z, Lell C, et al. Phase II clinical study of BC-3781, a 
pleuromutilin antibiotic, in treatment of patients with acute bacterial skin and skin structure 
infections. Antimicrob Agents Chemother. 2013;57(5):2087-94. 
Sader HS, Duncan LR, Doyle TB et al. Antimicrobial activity of ceftazidime/avibactam, 
ceftolozane/tazobactam and comparator agents against Pseudomonas aeruginosa from cystic 
fibrosis patients. JAC Antimicrob. Resist. 2021;3(3):dlab126. 


Clinical Study Protocol 
 
Nabriva Therapeutics 
NAB-BC-3781-1014 
 
Lefamulin 
02 November 2021 
48 
Confidential 
APPENDIX 1. CLINICAL LABORATORY TESTS (SAFETY) 
Hematology 
Red blood cell count 
White blood cell count 
Hematocrit 
Hemoglobin 
Platelet count 
Differential count 
Chemistry  
Blood urea nitrogen 
Creatinine 
Glucose 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Calcium  
Phosphorus 
Magnesium 
Aspartate aminotransferase 
Alanine aminotransferase 
Alkaline phosphatase 
Creatine phosphokinase 
Total bilirubin 
Albumin 
Total protein 
Other tests 
Pregnancy test (serum or urine) – women of childbearing potential 
Follicle stimulating hormone (at Screening) – women who are ≥ 1 year post-menopausal 
Viral serology (at Screening):  
• 
HCVAb Ab (if positive, qualitative HCV RNA to test for active infection) 
• 
Hepatitis B surface antigen (HBsAg) 
• 
HIV Ab/HIV p24 Ag 
Urine drug screen – including but not limited to amphetamines, barbiturates, benzodiazepines, cocaine, 
marijuana, methamphetamine, opioids, and phencyclidine (PCP) 
Alcohol urine/breath test 
 


Clinical Study Protocol 
 
Nabriva Therapeutics 
NAB-BC-3781-1014 
 
Lefamulin 
02 November 2021 
49 
Confidential 
APPENDIX 2. INTERACTING MEDICATIONS 
XENLETA is classified as a moderate CYP3A inhibitor with mild inhibition potential for 
CYP2C8, but no induction potential. When administered orally, XENLETA may increase the 
plasma concentrations of drugs that are primarily metabolized by CYP450 3A4. No interaction 
on P-gp or significant interactions with other drug transporters has been observed or predicted. 
XENLETA is a substrate to CYP3A. The table below provides examples of potential 
co- medications and is not intended to be an exhaustive list. 
XENLETA Injection 
  
  
Strong or moderate CYP3A 
inducers or P-gp inducers 
eg, lumacaftor, rifampicin, St. 
John´s wort (Hypericum 
perforatum), rifabutin, 
phenobarbital, carbamazepine, 
phenytoin, bosentan, efavirenz, 
primidone  
Avoid XENLETA  
Co-medication could 
significantly decrease lefamulin 
plasma concentration. 
Drugs associated with QT 
interval prolongation 
eg, moxifloxacin, disopyramide, 
doxepin, erythromycin, 
droperidol, salmeterol 
 
Avoid XENLETA 
Co-medication could cause QT-
interval prolongation 
XENLETA Tablets 
  
  
Strong or moderate CYP3A 
inducers or P-gp inducers 
eg, lumacaftor, rifampicin, St. 
John´s wort (Hypericum 
perforatum), rifabutin, 
phenobarbital, carbamazepine, 
phenytoin, bosentan, efavirenz, 
primidone  
Avoid XENLETA  
Co-medication could 
significantly decrease lefamulin 
plasma concentration.  
Strong CYP3A inhibitors or 
P-gp inhibitors  
eg, clarithromycin, diltiazem, 
grapefruit juice, itraconazole, 
ketoconazole, nefazodone, 
posaconazole, ritonavir-
containing regimens, 
voriconazole, telithromycin  
Avoid XENLETA 
Co-medication could 
significantly decrease lefamulin 
plasma concentration. 
significantly increase lefamulin 
plasma concentration. 
Moderate CYP3A inhibitors or 
P-gp inhibitors 
eg, fluconazole, zolpidem, 
ciprofloxacin, erythromycin 
  
Record time and dose of co-
medication. 
Could slightly increase 
lefamulin plasma concentration. 
Drugs associated with QT 
interval prolongation 
eg, moxifloxacin, disopyramide, 
doxepin, erythromycin, 
droperidol, salmeterol 
Avoid XENLETA 
Co-medication could cause QT-
interval prolongation 
CYP3A substrates that prolong 
the QT interval 
eg, pimozide, quinidine 
Avoid XENLETA 
Concomitant use is 
contraindicated. 
Sensitive CYP3A substrates or 
those that demonstrate a narrow 
therapeutic index  
eg, midazolam, tacrolimus, ergot 
alkaloids, colchicine, fentanyl, 
macrolide immunosuppressants 
Monitor for adverse reactions. 
No impact on plasma 
concentration of lefamulin. 
 

SAP_001.pdf: 
 
 
 
 
    
 
 
 
 
 
 
Official Title:  A Phase 1, Open-Label, Randomized, Crossover Study to Assess the Safety and 
Pharmacokinetics Following Single Doses of Oral and Intravenous Xenleta 
(Lefamulin) in Adult Patients With Cystic Fibrosis 
 
NCT Number: NCT05225805 
 
Applicant/MAH: Nabriva Therapeutics 
 
Version Date:  16 September 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROPRIETARY — © 2021 Rho, Inc. 
STATISTICAL ANALYSIS PLAN
STUDY TITLE: A PHASE 1, OPEN-LABEL, RANDOMIZED, 
CROSSOVER STUDY TO ASSESS THE SAFETY AND 
PHARMACOKINETICS FOLLOWING SINGLE DOSES OF ORAL AND 
INTRAVENOUS XENLETA® (LEFAMULIN) IN ADULT PATIENTS 
WITH CYSTIC FIBROSIS
PROTOCOL NUMBER: NAB-BC-3781-1014 (VERSION 1.0)
SHORT TITLE:
NAB-BC-3781-1014
NCT#:
NCT05225805
COMPOUND #: 
BC-3781 
CLIENT:
Nabriva Therapeutics
REGULATORY 
AGENCY 
IDENTIFIER 
NUMBER(S): 
US IND 106594
PREPARED BY: 
Rho
 
Minor Updates prior to Database lock:
EmpiriStat, Inc.
This document is confidential and proprietary to Nabriva Therapeutics.  This study is being conducted in 
compliance with good clinical practice, including the archiving of essential documents.  Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein will be 
reproduced, published, or otherwise disclosed without the prior written approval of Nabriva Therapeutics, except 
that this document may be disclosed to appropriate Institutional Review Boards under the condition that they keep 
the information confidential. 
 
PI
PI


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ACKNOWLEDGEMENT AND SIGNATURE SHEET 
Approved:
Approved:
 PhD
, Clinical Research and 
Development 
Nabriva Therapeutics
, PhD
Biostatistician (Consultant)
Signature and Date
Signature and Date
PI
PI
PI
PI
PI
PI


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VERSION HISTORY 
SAP Version 
Version Date 
Change(s) 
Rationale 
1.0
16SEP2022 
Not applicable. 
Original version. 


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TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS.......................................................................................7
2.
PURPOSE OF THE ANALYSES ................................................................................9
3.
PROTOCOL SUMMARY..........................................................................................10
3.1
Study Objectives.........................................................................................................10
3.2
Study Endpoints ..........................................................................................................10
3.3
Overall Study Design and Plan ...................................................................................10
3.4
Study Population.........................................................................................................10
3.5
Treatment Regimens...................................................................................................10
3.6
Sample Size Determination ........................................................................................11
4.
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..............................12
5.
ANALYSIS SAMPLES..............................................................................................14
6.
STUDY SUBJECTS ...................................................................................................15
6.1.
Disposition of Subjects ...............................................................................................15
6.2.
Demographic and Other Baseline Characteristics ......................................................16
6.3.
Prior and Concomitant Medications ...........................................................................16
6.4.
Medical History ..........................................................................................................17
7.
STUDY OPERATIONS .............................................................................................18
7.1.
Protocol Deviations ....................................................................................................18
7.2.
Randomization ............................................................................................................18
7.3.
Measures of Treatment Compliance ...........................................................................18
8.
ENDPOINT EVALUATION .....................................................................................19
8.1.
Overview of Efficacy Analysis Methods....................................................................19
8.1.1. 
Multicenter Studies.....................................................................................................19
8.1.2. 
Assessment Time Windows........................................................................................19
8.1.3. 
Timing of Analyses.....................................................................................................19
8.1.4. 
Multiple Comparisons/Multiplicity ............................................................................20
8.2.
Primary Endpoint ........................................................................................................20
8.2.1. 
Computation of the Primary Endpoint........................................................................21
8.2.2. 
Primary Analysis of the Primary Endpoint.................................................................22
8.3.
Secondary Endpoints ..................................................................................................22


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8.4.
Other Endpoints ..........................................................................................................22
8.5.
Examination of Subgroups .........................................................................................23
9.
SAFETY EVALUATION ..........................................................................................24
9.1.
Overview of Safety Analysis Methods .......................................................................24
9.2.
Extent of Exposure .....................................................................................................25
9.3.
Adverse Events ...........................................................................................................26
9.4.
Deaths, Serious Adverse Events, and Other Significant Adverse Events ..................28
9.5.
Clinical Laboratory Evaluation...................................................................................28
9.6.
Vital Signs, Physical Findings, and Other Observations Related to Safety ...............29
9.6.1. 
Vital Signs ..................................................................................................................29
9.6.2. 
Physical Examinations................................................................................................29
9.6.3. 
Other Safety Measures................................................................................................29
9.6.4. 
ECG ............................................................................................................................29
9.6.5. 
Concomitant medications ...........................................................................................30
10.
PHARMACOKINETIC EVALUATION...................................................................31
11.
OTHER ANALYSES .................................................................................................32
12.
INTERIM ANALYSES AND DATA MONITORING .............................................33
13.
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .....................34
14.
REFERENCES ...........................................................................................................35
15.
APPENDIX.................................................................................................................36
15.1.
Study Flow Chart........................................................................................................36
15.2.
Schedule of Events .....................................................................................................37


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LIST OF TABLES
Table 1: 
List of Abbreviations ....................................................................................................7


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1.
LIST OF ABBREVIATIONS
Table 1: 
List of Abbreviations
Abbreviation 
Term 
ADaM 
Analysis Data Model 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
AUC0-12hr 
area under the drug concentration curve from time zero (0 hour [hr]) to 12 hr 
AUC0-24hr 
area under the drug concentration curve from time zero (0 hr) to 24 hr 
AUC0-last
area under the drug concentration curve from time zero (0 hr) to 24 hr 
AUC  
area under the drug concentration curve from time zero (0 hr) to infinity 
AUC%extrap
percentage of AUC due to extrapolation for infinity 
BLQ 
below limit of quantification 
CF 
cystic fibrosis 
CL 
clearance 
CL/F 
total body clearance 
Cmax 
maximum observed plasma concentration 
CSR 
clinical study report 
CTMS 
clinical trial management system 
CV 
coefficient of variation 
ECG 
electrocardiogram
F 
oral bioavailability 
HBsAg 
Hepatitis B surface antigen 
HCVAb 
Hepatitis C antibody  
HIV Ab/HIV p24 Ag 
Human immunodeficiency virus 
hr 
hour 
ICH 
International Conference on Harmonisation 
IR
immediate-release 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
mean residence time 
NA 
not applicable 


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Abbreviation 
Term 
PK 
pharmacokinetic 
PT 
preferred term  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SfAS 
safety analysis set 
SOC 
system organ class 
t1/2
apparent elimination half-life
TEAE 
treatment-emergent adverse event
tlag
finite time taken for a drug to appear in systemic circulation following 
extravascular administration 
tmax 
time to reach maximum plasma concentration 
Vd 
volume of distribution 
Vd/F 
volume of distribution corrected for bioavailability 
Vss 
volume of distribution at steady state 
WHO 
World Health Organization 


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2.
PURPOSE OF THE ANALYSES
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the clinical study report (CSR) for Protocol NAB-BC-3781-1014.  
This document provides details on study populations, how the variables will be derived, how 
missing data will be handled and details on statistical methods to be used to analyze the 
pharmacokinetic (PK), efficacy, and safety data.  If additional analyses are required to 
supplement the planned analyses described in this SAP, they may be completed and will be 
identified in the CSR as post hoc.  Table, listing, and figure specifications are in separate 
documents. 
The SAP is based on International Conference on Harmonisation (ICH) guidelines E3 and E9 
(Statistical Principles for Clinical Trials). 
The SAP may evolve over time, for example, to reflect the requirements of protocol amendments 
or regulatory requests.  However, the final SAP must be finalized, approved by Nabriva 
Therapeutics, and placed on file before the clinical database is locked.  If differences occur 
between the analyses described in the SAP and the current protocol, those found in the SAP will 
assume primacy.  Deviations from the final approved SAP will be noted in the CSR. 
 


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3.
PROTOCOL SUMMARY
3.1 Study Objectives
Primary: To evaluate the pharmacokinetics (PK) of a 600-mg immediate-release (IR) tablet and 
150-mg intravenous (IV) formulation of lefamulin in adult patients with cystic fibrosis (CF).
Secondary: To evaluate the safety and tolerability of lefamulin when administered as single oral 
or IV doses in adult patients with CF.
Exploratory:  To approximate the penetration of lefamulin into sputum in CF patients.
3.2
Study Endpoints
Primary: Plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150-mg 
IV infusion and 600-mg IR tablet in patients with CF.
Secondary: Descriptive summaries of the following:
Treatment-emergent adverse events (TEAEs)
Laboratory assessments (chemistry and hematology)
Vital signs measurements
Electrocardiogram (ECG) parameters
Exploratory: To evaluate the concentration of lefamulin in sputum following 150-mg IV infusion 
and 600-mg IR tablet in adult patients with CF.
3.3
Overall Study Design and Plan
This will be a single-cohort, open-label, randomized, 2-part, crossover study in patients receiving 
a single dose of lefamulin at 2 study periods 4 to 7 days apart. Lefamulin will be administered as 
a 600-mg IR tablet orally in the fasted state and a 150-mg IV infusion in 250 mL citrate buffered 
saline over 1 hour.
3.4
Study Population
Patients 
18 years of age with a confirmed diagnosis of CF receiving standard of care will be
enrolled in this study. Prior to any study-related procedures being performed, written informed
consent will be obtained from all patients.
3.5
Treatment Regimens
Study drug will be administered as follows to all patients after an overnight fast:
IV Treatment Period: lefamulin 150 mg in 250 mL citrate buffered saline IV infusion 
over 1 hour
Oral Treatment Period: lefamulin as a 600-mg IR tablet in the fasted state. The oral 
treatment will be swallowed whole with 6 to 8 ounces of water at least 1 hour before or 2 
hours after a meal.
Stu
Stu
Stu
Stu
Stu


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Total duration of study participation for each patient will be approximately 10 to 13 days (from
Screening to Follow-up). 
3.6 
Sample Size Determination 
Target enrollment for this study will be 12 patients.


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4.
GENERAL ANALYSIS AND REPORTING CONVENTIONS
The following is a list of general analysis and reporting conventions to be applied for this study:
 Categorical variables will be summarized using counts (n) and percentages (%) and will 
be presented in the form n (%).  If a count is zero, no percentage will be shown.  To 
ensure completeness, summaries for categorical and discrete variables will include all 
categories, even if no subjects had a response for a particular category.  Missing data for 
categorical variables will have a ‘Missing’ category added at the end and the count will 
be presented with a percentage.  When counts are zero, the zero will be presented without 
a percentage.  Percentages for categorical variables will include the ‘Missing’ category. 
 Continuous variables will be summarized using number of subjects, arithmetic mean, 
median, standard deviation, minimum, and maximum.  In addition, PK summaries may 
include the coefficient of variation (CV), geometric mean and geometric CV.  The 
arithmetic mean, median, and geometric mean will be rounded and reported to 1 more 
digit than the precision of the original data.  The CV, geometric CV, and standard 
deviation will be rounded and reported to 2 more digits than the precision of the original 
data.  The minimum and maximum will be rounded and reported to the same level of 
precision as the original observations.  If any values are calculated to have more 
significant digits, then the value should be rounded so that it is the same level of 
precision as the original data.  The level of precision may be modified on specific 
displays based on clinical judgement. 
 Following SAS default rules, the median will be reported as the average of the two 
middle numbers if the dataset contains an even number of observations.
 No preliminary rounding should be performed; rounding should only occur after analysis.  
To round, consider the digit to right of last significant digit: if < 5 then round down, if 
>=5 then round up. 
 In general, listings will be displayed by subject and time of assessment (e.g., visit, time, 
and/or event) and will be sorted in the order that columns are displayed, starting with the 
first column on the left.  
 Dates in listings will be displayed as YYYY-MM-DD (e.g., 2022-02-11). 
 All analyses will be performed using the SAS System version 9.4 or later. 
 Page formatting for all tables, listings and figures will be as follows: 
o Page size = 47
o Line size = 134 
o Font = Courier 
o Font Size = 9
o Margin = 1.5 inch top, 1 inch bottom, left and right. 


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o
Displays should span fully from the left to right margin, with the white space 
distributed evenly. 
o Display headers will be formatted as:
Protocol: NAB-BC 3781-1014  
      Nabriva Therapeutics 
 
 
o Display footers will be formatted as: 
Program: ProgramName.sas
 
DDMMMYYY HH: MM
 
        Page x of y 
o Displays will be provided in .RTF and .PDF format.  Tables, figures, and listings 
will be stacked into three separate files and provided in .RTF and .PDF format.  If 
possible, a single stacked file including all displays will be provided in .RTF and 
.PDF format.    
If departures from these general conventions are present in the specific evaluations section of this 
SAP, then those conventions will take precedence over these general conventions. 


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5.
ANALYSIS SAMPLES
The following definitions will be used to derive the analysis sets for this study. 
 PK analysis set:  All subjects who receive any full or partial dose of lefamulin and have 
an evaluable PK profile (plasma concentrations adequate for the calculation of PK 
parameters).  The PK analysis set will be used for the PK analyses.  
 Safety analysis set (SfAS): All subjects who receive any full or partial dose of lefamulin.  
The SfAS will be used for the analysis of safety data.   
SfAS/PK analysis sets will be analyzed by actual treatment received, all screened/randomized 
subjects by randomized treatment.   The SfAS analyses will also include summaries overall.  For 
the disposition, demographic, medical history, and prior medications tabular summaries, subjects 
will be summarized according to their randomized treatment group sequence and overall.  
Laboratory plots will be presented by actual treatment group sequence. 
For tabular PK and SfAS summaries by treatment group, the denominator for percentages may 
vary by treatment group.  For the PK analyses, the number of subjects in the PK analysis set who 
received a full or partial dose and had an evaluable PK profile for the treatment being 
summarized will be used as the denominator.  For the SfAS analyses, the number of subjects in 
the SfAS who received a full or partial dose of the treatment being summarized will be used as 
the denominator.  Percentages for overall summaries in the SfAS analyses will use the number of 
subjects in the SfAS as the denominator.   
Select displays will use all screen failures, all subjects screened, or all subjects randomized as the 
analysis set. 
 


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6.
STUDY SUBJECTS
6.1.
Disposition of Subjects
The disposition of all screened subjects will be summarized by randomized treatment group 
sequence and overall.  Subjects who failed screening or who were not enrolled (randomized) will 
only be included in the overall column.  The following disposition information will be 
summarized: 
 The number of subjects screened (signed informed consent).  Subjects who re-screen will 
be counted once. 
 The number and percentage of subjects who failed screening and the reasons for failure 
(Did not meet criteria, Withdrew consent, Lost to follow-up, Other). 
 The number and percentage of subjects not randomized and the number and percentage 
of subjects randomized. 
 The number and percentage of subjects in each analysis set (PK, SfAS). 
 The number and percentage of subjects who completed the study. 
 The number and percentage of subjects who discontinued the study early and the reasons 
for withdrawal (Adverse event, Death, Lost to follow-up, Pregnancy, Withdrawal by 
subject, Other). 
 The number and percentage of subjects who discontinued the study early for reasons 
related to COVID-19 (Subject has confirmed COVID-19, Site discretion, Subject 
discretion, Unknown). 
 The number and percentage of subjects who discontinued IV treatment early and the 
primary reason for discontinuation (Adverse event, Death, Lost to follow-up, Withdrawal 
by subject, Physician decision, Positive drug/alcohol test, Prolongation of the QTc 
interval or any arrhythmia, Sponsor decision, Failure to meet eligibility criteria, Other). 
 The number and percentage of subjects who discontinued oral treatment early and the 
primary reason for discontinuation (Adverse event, Death, Lost to follow-up, Withdrawal 
by subject, Physician decision, Positive drug/alcohol test, Prolongation of the QTc 
interval or any arrhythmia, Sponsor decision, Failure to meet eligibility criteria, Other).. 
Percentages for the number of subjects who failed screening, the reasons for failure, the number 
of subjects not randomized, and the number of subjects randomized will be based on the number 
of subjects who signed informed consent.  Percentages for reasons for premature withdrawal 
from study treatment will be based on the number of subjects in the SfAS.  Percentages for all 
other rows will use the number of randomized subjects as the denominator.  All rows will be 
summarized by randomized treatment group sequence and overall. 
Subject disposition data for all subjects randomized will also be listed.  A separate listing of 
subjects who failed screening with the reason for screen failure will be provided. 


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A listing of all subjects affected by the COVID-19 pandemic (discontinued the study early or 
missed visits for reasons related to COVID-19) will be provided by site and subject for all 
screened subjects to document how the subject’s participation was impacted by COVID-19. 
6.2.
Demographic and Other Baseline Characteristics
Summary descriptive statistics for demographic and other baseline characteristics will be 
reported for the PK and SfAS analysis sets by randomized treatment group sequence and overall.  
Percentages will use the number of subjects in each analysis set as the denominator.  
Characteristics to be summarized include: 
 Demographic:  age, race, ethnicity, sex, and child bearing potential, if female. 
 Virology screening:  Hepatitis B virus surface antigen (HBsAg) result, Hepatitis C virus 
antibody (HCVAb) result, and Human immunodeficiency virus (HIV Ab/HIV p24 Ag) 
antibody result. 
 Vital signs: height, body weight, and body mass index (BMI) at screening. BMI will be 
computed as 
(
)
(
). 
Demographic data will also be listed for all screened subjects.  Cystic fibrosis diagnosis will be 
collected for randomized subjects and reported on the demographics listing.  Virology screening 
data will be listed for all randomized subjects.  Additional baseline characteristic data to be listed 
for all randomized subjects includes:
Pregnancy test results for women of childbearing potential.
-menopausal.
Drugs and alcohol screen.
6.3. 
Prior and Concomitant Medications 
Prior medications will include all medications that started and stopped prior to the day of the first 
administration of any study drug, IV or oral.  Concomitant medications will include all 
medications that started, or were continuing, during or after the first administration of any study 
drug, IV or oral.  Concomitant medications will be attributed to each treatment period as follows:
Treatment Period 1 Treatment (IV or Oral):  Concomitant medications will include all 
medications that started, or were continuing, during or after the first administration of study drug 
in treatment period 1 and prior to treatment period 2 study drug administration.  For subjects who 
did not receive treatment period 2 study drug (e.g., due to early study discontinuation), all 
concomitant medications recorded will be attributed to the treatment received in treatment period 
1. 
Treatment Period 2 Treatment (IV or Oral):  Concomitant medications will include all 
medications that started, or were continuing, during or after the first administration of study drug 
in treatment period 2.   


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Concomitant medications that started, or were continuing during or after treatment period 1, and 
continued into treatment period 2 will be attributed to both the treatment period 1 and 2 
treatments. 
Where necessary, imputed dates for defining concomitant medications will be used to attribute 
concomitant medications to each treatment group.  
The number and percentage of subjects using concomitant medications will be tabulated by 
World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) class and preferred 
term (PT) for all subjects in the SfAS by treatment group (actual treatment received) and overall.  
If a subject has more than one medication within an anatomic class within a treatment period, the 
subject will be counted only once in that anatomic class.  Similarly, if a subject has more than 
one medication that codes to the same PT within a treatment period, the subject will be counted 
only once for that PT.  Percentages for each treatment group and overall are described in Section 
5.  The tabular summary will be sorted in descending order based on the overall frequency.   
The number and percentage of subjects using prior medications will be tabulated by ATC class 
and PT for all subjects in the SfAS by randomized treatment sequence and overall  If a subject 
has more than one medication within an anatomic class, the subject will be counted only once in 
that anatomic class.  Similarly, if a subject has more than one medication that codes to the same 
PT, the subject will be counted only once for that PT.  Percentages for each randomized 
treatment sequence group overall are described in Section 5.  The tabular summary will be sorted 
in descending order based on the overall frequency.   
Prior and concomitant medication data will also be presented in a data listing for all randomized 
subjects. 
6.4. 
Medical History 
Medical history events will be classified by system organ class (SOC) and PT, according to a 
standardized thesaurus (Medical Dictionary for Regulatory Activities [MedDRA] version 25.0).  
Medical history events will be summarized by SOC and PT by randomized treatment sequence 
and overall for subjects in the SfAS.  The summaries will display the number and percentage of 
subjects experiencing any medical history event as well as the number and percentage of subjects 
with at least one medical history event in each SOC and PT.
Medical history data will also be listed for all randomized subjects.


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7.
STUDY OPERATIONS
7.1.
Protocol Deviations
All protocol deviations will be recorded in Rho’s clinical trial management system (CTMS).  
Prior to unblinding and database lock, the medical and study team will perform a blinded review 
of the protocol deviations to classify the protocol deviations as major or minor.   
Protocol deviations will be attributed to each treatment group as follows: 
Treatment Period 1 Treatment (IV or Oral) – All protocol deviations that started on or after 
treatment period 1 study drug administration and prior to treatment period 2 study drug 
administration.  For subjects who did not receive treatment period 2 study drug (e.g., due to early 
study discontinuation), all protocol deviations that started on or after treatment period 1 study 
drug administration will be attributed to the treatment received in treatment period 1. 
Treatment Period 2 Treatment (IV or Oral) – All protocol deviations that started on or after the 
treatment period 2 study drug administration.   
All subject-level protocol deviations will be summarized in tabular format by actual treatment 
group, including overall, and type of deviation for randomized subjects.  Protocol deviations that 
started prior to any study drug administration will be reported in the overall column only.  
Subject-level protocol deviations will also be reported in listings for randomized subjects.  The 
listings will include the subject ID, actual treatment group, date of the deviation, protocol 
deviation text, protocol deviation type, and classification of major or minor.  Any site-level 
deviations will also be listed. 
7.2. 
Randomization 
Subjects will be randomized 1:1 to one of two treatment group sequences (Oral – IV, IV – Oral, 
respectively.  Randomization will be accomplished by using a pre-prepared randomization 
scheme held by the sponsor, assigning subjects to treatment, sequentially across the study as 
subjects are enrolled.
7.3. 
Measures of Treatment Compliance 
The study drug administration listing is described in Section 9.2. 


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8.
ENDPOINT EVALUATION
8.1.
Overview of Efficacy Analysis Methods
8.1.1.
Multicenter Studies
Study subjects will be enrolled from multiple study sites in the United States.  For all analyses, 
study data will be analyzed and summarized as a whole, and no formal accommodation for site-
to-site variation will be made. 
8.1.2. 
Assessment Time Windows 
The following study visits are scheduled. 
Visit 
Visit Number
Visit Window
Screening 
1
Up to Day -30
Day -1 
2
Day -1
Period 1 Day 1
3
Day 1
Period 2 Day 1 (Also Period 1 Follow-up) 
4
Period 1 Day 1 + 4-7
Follow-up (Also Period 2 Follow-up)
5
Period 2 Day 1 + 4-7
The following Day 1 timepoints for Periods 1 and 2 are scheduled. 
Timepoint 
Timepoint Number 
Timepoint Window 
Pre-dose 
1 
Pre-dose  
0.5 hr Post-dose
2 
0.5 hr post dosing ± 5 min
1 hr Post-dose
3 
1 hr post dosing ± 5 min
1.5 hrs Post-dose
4 
1.5 hr post dosing ± 10 min
2 hrs Post-dose
5 
2 hr post dosing ± 10 min
4 hrs Post-dose
6 
4 hr post dosing ± 30 min
8 hrs Post-dose
7 
8 hr post dosing ± 1 hr 
12 hrs Post-dose
8 
12 hr post dosing ± 1 hr 
24 hrs Post-dose
9 
24 hr post dosing ± 1 hr 
Note: All timepoints are relative to post infusion start for both IV and oral treatment 
administration.
All scheduled visit data, including assessments performed outside of the assessment window will 
be summarized or graphed according to the planned nominal visits.  If the planned nominal visit 
is missing, the nearest unscheduled or early termination visit within the assessment window will 
be selected for inclusion in tables and figures and reported as the nominal visit.  All data, 
scheduled, unscheduled, and early termination, will be included in listings. 
8.1.3. 
Timing of Analyses 
Final CSR analyses will be performed after the study is completed and the clinical database is 
locked. 


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8.1.4. 
Multiple Comparisons/Multiplicity
Not applicable since treatment comparisons will not be performed. 
8.2. 
Primary Endpoint 
Plasma PK of lefamulin and its main metabolite, BC-8041, following 150-mg IV infusion and 
600-mg IR tablet in patients with CF. 
The following PK parameters in plasma for lefamulin and its metabolite BC-8041 will be 
estimated when possible and appropriate:
PK 
Parameter 
(unit)
Definition
Oral Dose
IV Dose
lefamulin
BC-
8041
lefamulin
BC-
8041
Cmax 
(mg/L) 
maximum observed plasma 
concentration 
Yes 
Yes 
Yes
Yes
Tmax (hr)
time to reach maximum plasma 
concentration of lefamulin following 
drug administration
Yes
Yes
Yes
Yes
AUC0-12hr
(mg hr/L)
area under the drug concentration 
curve from time zero (0 hr) to 12 hr
Yes 
Yes 
Yes
Yes
AUC0-24hr 
(mg hr/L)
area under the drug concentration 
curve from time zero (0 hr) to 24 hr
Yes 
Yes 
Yes
Yes
AUC0-last 
(mg hr/L)
area under the drug concentration 
curve from time zero (0 hr) to 24 hr
Yes 
Yes 
Yes
Yes
AUC (mg 
hr/L) 
area under the drug concentration 
curve from time zero (0 hr) to infinity 
Yes 
Yes 
Yes
Yes
t½ (hr) 
apparent elimination half-life 
calculated as ln(2)/ z
Yes 
Yes 
Yes
Yes
CL (L/hr)
clearance calculated as Dose/ AUC  
NA 
NA 
Yes
NA
CL/F 
(L/hr) 
total body clearance for extravascular 
administration calculated as Dose/
AUC
Yes 
NA 
NA
NA
Tlag (hr)
the finite time taken for a drug to 
appear in systemic circulation 
following extravascular administration
Yes
Yes
NA
Yes
AUC%extrap 
(%) 
percentage of AUC due to 
extrapolation for infinity 
Yes 
Yes 
Yes
Yes
lambda-z
z)
Individual estimate of the terminal 
elimination rate constant, calculated 
using log-linear regression of the 
terminal portions of the plasma 
concentration versus-time curves 
Yes 
Yes 
Yes
Yes
Vd (L) 
volume of distribution calculated as 
z*AUC )
NA 
NA 
Yes
NA


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PK 
Parameter 
(unit) 
Definition 
Oral Dose
IV Dose
lefamulin 
BC-
8041 lefamulin
BC-
8041
Vd/F (L) 
volume of distribution corrected for 
bioavailability calculated as 
z*AUC )
Yes 
NA 
NA
NA
Vss (L) 
volume of distribution at steady state 
NA 
NA 
Yes
NA
MRT (hr)
mean residence time
Yes
NA
Yes
NA
F (%)
oral bioavailability
Yes 
NA 
NA 
NA
Metabolite 
Ratio
AUC
of BC-8041/AUC
of 
lefamulin
NA
Yes
NA
Yes
NA = Not Applicable. 
8.2.1. 
Computation of the Primary Endpoint 
Plasma PK parameters for each subject will be estimated for lefamulin and its metabolite BC-
8041 over the sampling interval for each period using non-compartmental analysis (WinNonlin). 
In all PK parameter derivations, 0 will be substituted for concentrations that are below the limit 
of quantification (BLQ) of the assay.  Samples or intervals that are BLQ, but are between two 
samples or intervals with detectable concentrations will be excluded from the PK analysis. 
Cmax and Tmax will be determined by direct inspection of the concentration versus time data by 
WinNonlin.
AUC calculations will be performed using the linear/log trapezoidal rule.  AUC0-12hr will be 
calculated between t0hr and t12hr.  AUC0-24hr will be calculated between t0hr and t24hr.  AUC0-last
will be calculated between t0hr and the last measurable concentration.  AUC  will be calculated 
between t0hr and infinity.  The percentage of AUC
due to extrapolation for infinity will be 
calculated as: 
(( _
/(
_  )))/(
_
 ) 
where
_
/(
_ ) = (
_
_
)
Profiles where >20% of the AUC is extrapolated will be marked and excluded from summary 
statistics.   
The terminal 
z) will be calculated for all subjects using log-linear 
regression of the terminal portions of the plasma concentration versus-time curves.  A minimum 
of 3 points, not including Cmax, will be used for the regression analysis to determine
z.  The 
z will be selected using the Best Fit method in 
WinNonlin as the number of data points with the largest adjusted R2 value from regression.  
Elimination rate estimates with an adjusted R2 value of < 0.8 will be marked and excluded from 
summary statistics.
z is not reported, the values for t½, AUC , CL, CL/F, Vd, 
Vd/F or Vss will be considered noncalculable and not reported.    


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Oral bioavailability, F will be calculated as:
= ((
_
)/(
_
 ))
((
_
)/(
_
 ))
100 
8.2.2. 
Primary Analysis of the Primary Endpoint 
Summary descriptive statistics for the PK parameters for lefamulin and separately for its 
metabolite BC-8041 will be reported for the PK analysis set by actual treatment group.  For BC-
8041, AUC%extrap and z-related parameters will be estimated but not summarized.  No treatment 
comparisons are planned for the PK parameters.
Box and whisker plots for Cmax, AUC0-12h, AUC0-last
treatment group and overlaid with geometric means for subjects in the PK analysis set for 
lefamulin and separately for its metabolite BC-8041.  Additional box and whisker plots for other 
PK parameters may be presented as needed. 
Summary descriptive statistics for plasma concentration for lefamulin (mg/L) and separately for 
its metabolite BC-8041 (mg/L) will be reported for the PK analysis set by actual treatment group.  
Arithmetic mean (± arithmetic SD) concentration versus timepoint will be plotted on both the 
linear and semi-logarithmic scale for lefamulin and separately for its metabolite BC-8041 for 
subjects in the PK analysis set by actual treatment group.  The nominal sample timepoint will be 
used.  Individual concentration data versus timepoint will be plotted on both the linear and semi-
logarithmic scale for lefamulin and separately for its metabolite BC-8041 for each subject in the 
PK analysis set and the actual PK sampling time will be used. 
Pharmacokinetic parameter data for lefamulin and its metabolite BC-8041 will be listed for 
subjects in the PK analysis set.   Plasma concentration data for lefamulin and its metabolite BC-
8041 will be listed for subjects in the SfAS. 
8.3. 
Secondary Endpoints 
Descriptive summaries of the following by visit and timepoint for the SfAS by actual treatment 
group: 
Treatment-emergent adverse events (TEAEs) overall
Laboratory assessments (chemistry and hematology)
Vital signs measurements
Electrocardiogram parameters
8.4. 
Other Endpoints 
The exploratory endpoint is to evaluate the concentration of lefamulin in sputum following 150-
mg IV infusion and 600-mg IR tablet in adult patients with CF. Summary descriptive statistics 
for the concentration of lefamulin in sputum will be reported for the SfAS by actual treatment 
group and timepoint.  No treatment comparisons are planned. 


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8.5.
Examination of Subgroups
None planned. 


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9.
SAFETY EVALUATION
The evaluation of the safety and tolerability of lefamulin when administered as single oral and 
IV doses in adult patients with CF is the secondary objective of this study.  The endpoints 
described in Section 8.3 are part of the safety evaluation.  Descriptive summaries will be 
performed for the SfAS by actual treatment group and will include TEAEs, serious adverse 
events (SAEs), laboratory assessments (chemistry and hematology), vital signs, and ECG.  Study 
medication exposure, physical examination, and concomitant medications will also be included 
as part of the safety evaluation.  
9.1.
Overview of Safety Analysis Methods
For all safety endpoints, baseline will be defined separately for each treatment period as the last
non-missing value before the first study drug administration in the treatment period.  For 
laboratory values, baseline values for the second treatment period are scheduled to be collected 
at the last follow-up assessment for the first treatment period.  For vital signs and ECG, baseline 
values for each treatment period are scheduled to be collected at the Day 1 Pre-dose assessment 
for each treatment period.  
For all change from baseline analyses, change from baseline will be defined as the post-baseline 
measurement minus the baseline measurement.
For all shift from baseline analyses, percentages will be based on the number of subjects in each 
category at baseline. A ‘Missing’ category will be added for subjects missing post-baseline 
assessments and the count will be presented with a percentage.  When counts are zero, the zero 
will be presented without a percentage. 
Safety data will not be imputed, except for partial and missing dates, missing adverse event 
severity (intensity), and missing adverse event relationship to study drug.  Partial and missing 
dates will be imputed only for defining TEAEs and concomitant medications.  Imputed data will 
not be presented in data listings.
Partial dates will be imputed for the purposes of defining TEAEs and concomitant medications 
as follows:
For a missing start day where the month and year are present, the start day will be set to 
the first day of the month, unless the following two conditions are met: 
1. the first day of the month is before the first date of administration of study drug and 
the month and year are the same as the month and year of the first date of 
administration of study drug, and 
2. the end date is on or after the first date of administration of study drug or the end date 
is completely missing. 
If the two above conditions are met, the start day will be set to the day of administration 
of study drug.
For a missing start day and month where the year is present, the start day and month will 
be set to January 1st, unless 1) January 1st is before the first date of administration of 


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study drug and the year is the same as the year of the first date of administration of study 
drug, and 2) the end date is on or after the first date of administration of study drug or the 
end date is completely missing, in which case the start day and month will be set to that 
of the first date of administration of study drug.  
 For a missing end day where the month and year are present, the end day will be set to 
the last day of the month, unless the month and year are the same as the month and year 
of the last contact date for the subject, in which case the end day will be set to that of the 
subject's last contact date.  
 For a missing end day and month where the year is present, the end day and month will 
be set to the subject's last contact date, unless the year of the subject's last contact date is 
greater than the end year, in which case the end day and month will be set to December 
31st.  
 For an entirely missing start date (i.e., day, month, and year are missing), the start date 
will be set to the first date of administration of study drug unless the stop date is prior to 
the first date of administration of study drug, in which case the start date will be set to the 
stop date.  
 For an entirely missing stop date (i.e., day, month, and year are missing), the AE or 
medication will be treated as ongoing.  
Imputation for adverse events with missing severity (intensity) or relationship to study drug is 
described in Section 9.3.  Imputed values will be reported in summary tables, but will not be 
presented in listings. 
9.2. 
Extent of Exposure 
The following exposure data at Day 1 will be summarized by actual treatment group and overall 
for subjects in the SfAS.
 The number and percentage of subjects who received any treatment. 
For the oral treatment group only:
The number and percentage of subjects who took dose 1 hour before a meal or 2 hours 
after a meal.
For the IV treatment group only:
The number and percentage of subjects who received complete IV treatment.
The number and percentage of subjects with IV administration of study treatment 
interrupted.
The duration of IV treatment (minutes), summarized descriptively as a continuous 
variable.
The duration of the treatment interruption (minutes), summarized descriptively as a 
continuous variable.


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 The total amount of study treatment administered (mL), summarized descriptively as a 
continuous variable. 
The number and percentage of subjects who received study treatment in a different order than 
specified in the randomized treatment sequence will also be summarized in the overall column 
only. 
9.3.
Adverse Events
AEs will be collected throughout the study from the time a subject signs the informed consent 
through the follow-up assessment after the second dosing period.  All AEs will be classified by 
SOC and PT, according to a standardized thesaurus (Medical Dictionary for Regulatory 
Activities [MedDRA] version 25.0).  The severity (intensity) of AEs will be classified as Mild, 
Moderate and Severe as defined in Section 9.2 of the protocol.  Severity will also be classified 
using the National Cancer Institute’s (NCI’s) Common Toxicity Criteria for Adverse Events 
(CTCAE).  Summary tabulations for AE severity will be based on the protocol definitions and 
the CTCAE grading will be reported in listings. 
AEs with a start date and time on or after the date and time of the first study drug administration 
will be classified as TEAEs.  Events that started before first study drug administration and 
worsened in severity will also be classified as TEAEs.  Only TEAEs will be presented in 
summary tables by actual treatment group and overall for subjects in the SfAS.  All AEs will be 
listed for subjects in the SfAS with a flag indicating if the AE was treatment-emergent.  TEAEs 
will be attributed to each treatment group as follows: 
Treatment Period 1 Treatment (IV or Oral) – All TEAEs that started prior to treatment period 2 
study drug administration.  For subjects who did not receive treatment period 2 study drug (e.g., 
due to early study discontinuation), all TEAEs recorded will be attributed to the treatment 
received in treatment period 1. 
Treatment Period 2 Treatment (IV or Oral) – All TEAEs that started on or after the treatment 
period 2 study drug administration.  TEAEs that started during treatment period 1 and continued 
into treatment period 2 without worsening in severity in treatment period 2 will be attributed to 
the treatment period 1 treatment.   
TEAEs that started during treatment period 1 and continued into treatment period 2 with 
worsening in severity in treatment period 2would have had a new record created in the EDC
with the start date based on when the AE worsened.  The record with the start date during 
treatment period 1 will be attributed to treatment period 1 and the record with the start date 
during treatment period 2 will be attributed to treatment period 2. 
Where necessary, imputed dates for defining TEAEs will be used to attribute TEAEs to each 
treatment group.  
TEAEs will be summarized in an overall table by actual treatment group and overall for subjects 
in the SfAS and will include: 
 Total number of TEAEs 


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 Total number of TEAEs indicated as serious 
Total number of TEAEs related to study drug
The number and percentage of subjects with at least one TEAE
The number and percentage of subjects with at least one serious TEAE
The number and percentage of subjects with at least one TEAE related to study drug
 The number and percentage of subjects with at least one TEAE leading to study drug 
discontinuation
The number and percentage of subjects with at least one TEAE leading to death
 The number and percentage of subjects with TEAE with maximum severity of Mild (only 
counting the subject in the highest severity)
 The number and percentage of subjects with TEAE with maximum severity of Moderate 
(only counting the subject in the highest severity)
 The number and percentage of subjects with TEAE with maximum severity of Severe 
(only counting the subject in the highest severity)
 The number and percentage of subjects with Related TEAE with maximum severity of 
Mild (only counting the subject in the highest severity)
The number and percentage of subjects with Related TEAE with maximum severity of 
Moderate (only counting the subject in the highest severity) 
The number and percentage of subjects with Related TEAE with maximum severity of 
Severe (only counting the subject in the highest severity)
If a subject experiences the same AE on multiple occasions, the event will be counted once for 
each occurrence when reporting the number of TEAEs.  When reporting the number of subjects 
experiencing events, a subject will only be counted once.  Percentages will be based on the 
number of subjects in the SfAS by actual treatment group. 
TEAEs classified by MedDRA SOC and PT will be summarized by actual treatment group and 
overall.  The summaries will display the number and percentage of subjects experiencing any 
TEAE as well as the number and percentage of subjects with at least one TEAE in each SOC and 
PT for each of the following: 
All TEAEs 
Related TEAEs 
All TEAEs leading to study drug discontinuation 
TEAEs by maximum severity (intensity) 
TEAEs by maximum relationship to study drug 


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If a subject has more than one AE within a SOC, the subject will be counted only once in that 
SOC.  If a subject has more than one AE that codes to the same PT, the subject will be counted 
only once for that PT.  The tabular summaries will be sorted by descending frequency by SOC 
and PT for the overall incidence.
In the TEAEs by maximum severity and maximum relationship to study drug summaries, 
severity (intensity) will be rated as Mild, Moderate, or Severe based on the definitions in 
Protocol Section 9.2 and relationship to study drug will be scored as Definitely Related, Probably 
Related, Possibly Related or Not Related.  In the event that severity (intensity) or relationship 
data are missing, the study analysis will follow the assumption of maximum relationship or 
severity in the summary tables.  If a subject has more than one AE within a SOC or PT within a 
treatment period, the subject will be counted only once for that event under the maximum 
severity or most related category for the study drug.  The tabular summaries will be sorted by 
descending frequency by SOC and PT for the overall incidence. 
All AEs will be presented in data listings for all randomized subjects.   
9.4. 
Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
TEAEs resulting in death and serious TEAEs will be summarized by SOC and PT for subjects in 
the SfAS by actual treatment group and overall.  Rules for counting TEAEs are the same as those 
described in Section 9.3. 
All TEAEs resulting in death and serious TEAEs will be presented in data listings for all 
randomized subjects.  The listing of TEAEs resulting in death will also report the death date and 
cause of death. 
9.5. 
Clinical Laboratory Evaluation 
Clinical laboratory measurements to be summarized for the safety evaluation include the serum 
chemistry and hematology parameters listed in Protocol Appendix 1.  Laboratory normal range 
data will be collected at each site and stored in the Medidata Lab Administration Module and 
subsequently mapped to study data tabulation model (SDTM) and analysis data model (ADaM) 
datasets for use in analysis. Mayo clinic laboratory ranges will be used in the Medidata Lab 
Administration Module when laboratory normal range data are not available at a site. Mayo 
clinic laboratory ranges will be mapped to SDTM and ADaM datasets for use in analysis.
Numeric laboratory results will be classified as low, normal, or high based on the specific result 
falling below, within, or above the laboratory normal range, respectively.
For numeric laboratory results, descriptive statistics of laboratory values and the change from 
baseline of laboratory values at each visit and timepoint will be presented by actual treatment 
group and overall for subjects in the SfAS. The number and percentage of subjects with 
laboratory results classified as low, normal, or high will be summarized for each laboratory test 
by visit and timepoint, actual treatment group and overall for subjects in the SfAS.  Shift from 
baseline tables will also be produced for each laboratory test by visit and timepoint, actual 
treatment group and overall for subjects in the SfAS.   


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Numeric laboratory result data will also be plotted by subject over time (Planned timepoints: 
Screening, Day -1, Period 1 Day 1 24 hrs Post-dose, Period 2 Day 1 24 hrs Post-dose). For each 
test, data will be plotted as a spaghetti plot where each subject’s values will be plotted and 
connected by line segments, forming one line per subject.  The plots will be paginated by actual 
treatment group sequence within each test. 
Serum chemistry and hematology data, including the assessment for clinical significance, will be 
listed for all randomized subjects. 
9.6. 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
9.6.1. 
Vital Signs 
Descriptive statistics of numeric vital signs results and change from baseline of vital signs at 
each visit and timepoint will be presented by actual treatment group and overall for subjects in 
the SfAS.  Vital signs results will also be classified as Low, Normal, or High and summarized in 
shift tables from baseline to each post baseline visit and timepoint by actual treatment group and 
overall for subjects in the SfAS.  The following categories will be used to assess clinical 
relevance for vital signs data. 
Vital Sign
Low 
Normal
High
Systolic Blood Pressure (mmHg) 
<90 
90-160 
>160
Diastolic Blood Pressure (mmHg) 
<50 
50-90 
>90
Heart Rate (beats per minute) 
<60 
60-100 
>100
Respiration Rate (breaths per minute) 
<12 
12-20 
>20
Vital signs data will also be listed for all randomized subjects.
9.6.2. 
Physical Examinations 
Physical examination data will be listed for all randomized subjects. 
9.6.3. 
Other Safety Measures 
9.6.4. 
ECG
Descriptive statistics of numeric ECG results and change from baseline of ECG at each visit and 
timepoint will be presented by actual treatment group and overall for subjects in the SfAS.  ECG 
parameters to be summarized include heart rate, PR interval, QT interval (uncorrected), QTcF – 
Fridericia’s correction formula, QRS duration, and RR interval. 
ECG overall interpretation will be summarized in a shift table from baseline to each post 
baseline visit and timepoint by actual treatment group and overall for subjects in the SfAS.  
 


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ECG results will also be also be categorized based on the magnitude of QTcF and the change 
from baseline.  The number and percentage of subjects will be summarized for the following 
categories:   
Absolute QTcF 
 msec 
>480  and  
>500 msec
Post-Infusion change in QTcF 
< 30 msec
30 to 60 msec
> 30 msec
> 60 msec
Post-Infusion QTcF value >450msec and  
Change >30 msec 
Change >60 msec 
Post-Infusion QTcF value >500 msec and  
Change >30 msec 
Change >60 msec 
ECG data will also be listed for all randomized subjects. 
9.6.5. 
Concomitant medications
Concomitant medication summaries are described in Section 6.3. 


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10.
PHARMACOKINETIC EVALUATION
The pharmacokinetic evaluation for this study is specified in Section 8.2 of the SAP. 


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11.
OTHER ANALYSES
None.


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12.
INTERIM ANALYSES AND DATA MONITORING
Not applicable.


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13.
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL
None.


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14.
REFERENCES
None.


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15.
APPENDIX
15.1.
Study Flow Chart


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15.2.
Schedule of Events