Conditions: Mycobacterium Infections, Nontuberculous Mycobacterium Abscessus Infection Nontuberculous Mycobacterial Lung Disease Nontuberculous Mycobacterial Pulmonary Infection
Keywords: Nontuberculous Mycobacteria (NTM) Mycobacterium abscessus complex (MABc) NTM pulmonary disease NTM lung disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 66
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy, safety and tolerability of oral omadacycline as compared to placebo in the treatment of adults with Nontuberculous Mycobacterial (NTM) pulmonary disease caused by Mycobacterium abscessus complex (MABc)

Detailed description:
The total duration of subject participation in the study is approximately 5 months which includes a total duration of study treatment for approximately 3 months (84 days). Eligible participants will be randomized 1.5:1 to receive 3 months of treatment with either omadacycline or placebo (monotherapy). The study will use a double-dummy design in order to maintain the study blinding.

Arms:
arm 1: omadacycline 150 mg tablets (x 2) administered orally, once daily, q24h arm 2: Placebo tablets resembling omadacycline (x 2) administered once daily, q24h

Interventions: intervention 1: Omadacycline Oral Tablet intervention 2: Placebo
Intervention descriptions: intervention 1: omadacycline 300 mg orally, once daily (150 mg tablets x 2) intervention 2: placebo tablets resembling omadacycline orally, once daily (x 2 tablets)

Protocol document:
Prot_000.pdf: 


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SYNOPSIS  
Sponsor: 
Paratek Pharmaceuticals, Inc.  
 
Name of Finished Product: 
Omadacycline tablet, 150 mg 
Name of Active Ingredient: 
Omadacycline tosylate  
Study Title:  
A Phase 2, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Multi-Center 
Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Omadacycline in Adult 
Subjects with Nontuberculous Mycobacterial (NTM) Pulmonary Disease Caused by 
Mycobacterium abscessus Complex (MABc) 
Study Number: 
PTK0796-NTM-20203 
Study Phase:  2 
Study Rationale: 
Omadacycline is an aminomethylcycline, a tetracycline class antibiotic, for intravenous or 
oral administration. Intravenous NUZYRA® (omadacycline) and oral NUZYRA tablets 
have been approved by the United States (US) Food and Drug Administration (FDA) for 
the treatment of adult patients with community-acquired bacterial pneumonia and acute 
bacterial skin and skin structure infections caused by susceptible microorganisms. 
More than 140 nontuberculous mycobacterial (NTM) species have been identified, with 
more than half of the NTM pulmonary infections in the US associated with Mycobacterium 
avium complex (MAC) (Prevots 2010; Spaulding 2017). Mycobacterium abscessus 
complex (MABc) is the second most common NTM grouping causing human disease in 
the US, comprising about 10% of all NTM pulmonary infections across various study sites 
(Prevots 2015). In 2010, the number of national cases of NTM pulmonary infections was 
estimated as 86,244 (Strollo 2015). More recently in 2019, the number of NTM pulmonary 
cases was estimated to be as high as 115,000 nationally (Insmed Presentation 2021). The 
annual prevalence of NTM pulmonary infections in the US in 2015 was estimated as 11.7 
per 100,000, representing a 7.5% annual increase from 2008 (Winthrop 2020).  
Infections caused by MABc are notoriously difficult to treat due to intrinsic resistance to 
many classes of antibiotics. Few oral antibiotics demonstrate in vitro activity against 
MABc, making long-term treatment extremely difficult. Currently there are no 
FDA-approved treatments for pulmonary disease caused by MABc. Current treatment 
options (off-label treatments) are typically lengthy and require complex, multi-drug 




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(PROMIS Short Form v1.0 – 
Fatigue 7a Daily) 
 Patient Global Impression of 
Change (PGI-C) 
 Patient Global Impression of 
Severity (PGI-S) 
 Clinical Global Impression – 
Severity of Illness (CGI-S) 
 Clinical Global Impression – 
Global Improvement Scale (CGI-I) 
 No new symptom (ie, symptom not 
present at baseline) with severity 
worse than mild 
To evaluate the microbiological response 
of omadacycline in adult subjects with 
NTM pulmonary disease caused by MABc 
 Decrease in quantitative sputum 
culture at Day 84 
 Time to growth in liquid medium 
only 
 Time to first negative sputum 
culture 
 
Study Design: 
This is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group, multi-
center study in adults with NTM pulmonary disease caused by MABc. 
 
 
Following a Screening period of up to 56 days (8 weeks) prior to dosing, eligible subjects 
will be randomized (1.5:1) to receive either 300 mg once daily oral omadacycline 
monotherapy or matching placebo.  
Subjects will attend monthly visits during the approximately 84 day (3-month) 
double-blind treatment period and will complete a 14-day safety tele-visit as well as a 
safety follow-up call approximately 30 days after their last dose of test article. 
 


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Approximate Duration of the Study: 
Following an estimated recruitment period of approximately 24 months, the total duration 
of subject participation in the study is approximately 5 months which includes a total 
duration of study treatment for approximately 3 months (84 days). 
Study Population:  
Approximately 75 subjects (45 omadacycline and 30 placebo) will be enrolled at up to 
20 sites. Subjects will be randomized (1.5:1) to receive either omadacycline or placebo. 
Subjects will be stratified according to their use of prior antibiotics for treatment of MABc 
NTM infection (received prior treatment vs. no prior treatment). 
Main Criteria for Inclusion: 
Subjects must meet all of the following criteria at Screening and/or Baseline to be eligible 
to participate in the study: 
1. Written and signed informed consent must be obtained before any protocol-specific 
assessment is performed. 
2. Male and female subjects age 18 years or older. 
3. Diagnosed MABc pulmonary disease as per Infectious Diseases Society of 
America/American Thoracic Society guidelines criteria. Subjects must have: 
 At least 2 of the following NTM-infection symptoms at Screening and Baseline:  
 Chronic cough, coughing up blood (hemoptysis), wheezing, chest pain, frequent 
throat clearing, phlegm or sputum production, shortness of breath, fatigue, 
fever, night sweats, poor appetite, and/or weight loss. 
 At least 1 positive pulmonary culture for MABc in the 6 months prior to Screening, 
and 1 positive culture at Screening (note: prior culture and screening cultures must 
be at least 30 days apart). 
 Radiographic evidence of MABc infection via computed tomography (CT) scan of 
the chest within 3 months prior to Screening with findings consistent with NTM 
pulmonary disease. If no CT scan obtained within previous 3 months, one should 
be performed at Screening to confirm eligibility.  
4. Based on the clinical assessment of the investigator, guideline-directed antibiotic 
therapy for treatment of MABc will not be required within the next 3 months, and a 
delay, in order for the subject to participate in a placebo-controlled clinical trial, is 
considered reasonable and clinically acceptable.  
5. Be able to produce approximately 5 mL of sputum via spontaneous expectoration or be 
willing to undergo sputum induction to produce approximately 5 mL of sputum for 
microbiological evaluation.  
6. Females must have a negative serum pregnancy test and agree to use a highly effective 
form of birth control (eg, abstinence, oral contraceptive, intrauterine device, or barrier 
contraception [eg, condom], tubal ligation, hysterectomy, bilateral oophorectomy, 
postmenopausal or vasectomized partner) from Screening through study completion. 


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Males (if sexually active) must agree to use a highly effective method of birth control 
with female partner(s) from Screening through study completion. 
7. Able and willing to adhere with the requirements and restrictions of the study. 
 
Main Criteria for Exclusion: 
Subjects meeting any of the following criteria at Screening and/or Pre-dose will be 
excluded from participation in the study: 
1. Pregnant or nursing (breastfeeding) women. 
2. Has received antibiotic treatment within 6 months prior to Screening for MABc or 
MAC.  
3. Has received systemic or inhaled antibiotic therapy (other than chronic macrolide 
therapy) within 4 weeks prior to Screening. 
4. Is experiencing an exacerbation of an infection with a non-Mycobacterium species (eg, 
Pseudomonas aeruginosa) that the investigator considers clinically relevant.  
5. Has any of the following medical conditions: 
 Active pulmonary malignancy (primary or metastatic), or any type of malignancy 
requiring chemotherapy or radiation within 1 year prior to Screening.  
 Active allergic bronchopulmonary mycosis, or any other condition requiring 
chronic treatment with systemic corticosteroids (ie, prednisone dose ≥ 15 mg/day 
for a period of ≥ 4 consecutive weeks above this level) within 90 days prior to 
Screening. 
 Radiologic evidence of cavitary disease.  
 Known active pulmonary tuberculosis.  
 Cystic fibrosis.  
 History of lung transplantation. 
 Another advanced lung disease with a known percent predicted forced expiratory 
volume in 1 second < 30%.  
 Disseminated, extra-pulmonary NTM disease. 
6. Screening calculated creatinine clearance < 30 mL/minute, using the Cockcroft-Gault 
equation, requirement for any form of dialysis (eg, hemodialysis, peritoneal dialysis), 
or other evidence of severe renal disease. 
7. Has any of the following at Screening: 
 Alanine aminotransferase or aspartate aminotransferase ≥ 3 × upper limit of 
normal.  
 Total bilirubin > 1.5 × upper limit of normal. 
 Suspected or confirmed clinical evidence of end-stage liver disease (eg, ascites, 
hepatic encephalopathy). 
8. History of having experienced unstable cardiac disease (eg, unstable angina, 
myocardial infarction, acute congestive heart failure, unstable cardiac arrhythmia, etc.) 
within the 3 months prior to Screening. 


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9. Significant immunological disease determined by any of the following: 
 Current or anticipated neutropenia defined as < 500 neutrophils/mm3. 
 Known infection with human immunodeficiency virus (HIV). 
10. History of hypersensitivity or allergic reaction (eg, anaphylaxis, urticaria, other 
significant reaction) to any tetracycline (eg, minocycline, doxycycline, tigecycline, or 
omadacycline). 
11. Has been previously treated with omadacycline. 
12. History of pseudotumor cerebri, or prior (within 2 weeks prior to Screening) or planned 
concomitant use of isotretinoin.  
13. Systemic treatment with disease-modifying antirheumatic agents, corticosteroids 
(equivalent to prednisone dose ≥ 15 mg/day for a period of ≥ 4 consecutive weeks 
above this level) or immunosuppressive agents in the 90 days prior to Screening. 
14. Has current evidence of active pancreatitis. 
15. Evidence or history of any other clinically significant medical condition or planned 
medical intervention that may, in the opinion of the investigator, pose a significant 
safety risk, impair study participation, impact the subject’s ability to undergo the 
required study procedures or ability to complete the expected course of study 
treatment.  
16. Any surgical or medical condition that, in the opinion of the investigator, might 
significantly alter the absorption, distribution, metabolism, or excretion of drugs. 
17. Inability to fast for 4 hours prior to dosing and/or 2 hours after dosing. 
18. Per discretion of the investigator, subject is not expected to survive the duration of the 
study. 
 
Test Article, Dose, and Mode of Administration:  
 300 mg oral omadacycline (2 × 150 mg tablets administered once daily, q24h) 
 Placebo tablets resembling omadacycline (2 tablets administered once daily, q24h) 
 
All doses should be taken in a fasted state. Fasting is defined as no food, antacids or 
multivitamins containing multivalent cations (eg, aluminum, magnesium, calcium, 
bismuth, iron, or zinc), or drink except water for at least 4 hours before dosing. After 
dosing, no food or drink (except water) is permitted for 2 hours and no dairy products, 
antacids or multivitamins containing multivalent cations (eg, aluminum, magnesium, 
calcium, bismuth, iron, or zinc) for 4 hours. 
Duration of Treatment:  
The total duration of blinded treatment is approximately 3 months (84 days). 


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Efficacy Assessments: 
 Subject-reported NTM-pulmonary infection symptoms using a 4-point scale 
(absent, mild, moderate, severe)  
 Quantitative sputum culture 
 Patient-reported outcomes and quality of life measures: 
 QOL-B 
 SGRQ 
 PROMIS Short Form v1.0 – Fatigue 7a Daily 
 PGI-C 
 PGI-S 
 CGI-S 
 CGI-I 
 
Safety Assessments: 
Safety and tolerability will be assessed by monitoring the following: 
 AEs and SAEs 
 Physical examinations 
 Vital signs (body weight, body temperature, blood pressure, heart rate) 
 Laboratory tests (hematology and serum chemistry) 
 ECGs 
 CT scan 
 
Pharmacokinetic Assessments: 
Not applicable. 
 
STATISTICAL METHODS: 
A Statistical Analysis Plan (SAP) will be prepared and finalized before database lock and 
analyses of data. Summary data will be tabulated and presented by treatment group. 
Sample Size Determination:  
As the study is exploratory with respect to determination of efficacy, the sample size 
determination is provided to better ensure sufficient subjects are enrolled to provide an 
initial assessment of efficacy rather than test a specific hypothesis. With a randomization 
ratio of 1.5:1, a sample size of 75 subjects (45 omadacycline and 30 placebo) will provide 
approximately 80% power to detect an absolute treatment difference of 30% in clinical 
response rate at Day 84, based on clinical response rates of 15% and 45% in the placebo 
and omadacycline treatment groups respectively, using a Mantel-Haenszel test with 
2-sided alpha level of 0.05. 


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Analysis Sets:  
The following subject analysis sets have been defined: 
 Intent-to-treat (ITT) Analysis Set includes all randomized subjects. 
 Per-Protocol Analysis Set includes all randomized subjects who received at least 
1 dose of test article and completed the study without major protocol deviations 
that affect the assessment of efficacy. 
 Safety Analysis Set includes all subjects who received at least 1 dose of test article. 
 
Safety Assessments:   
All safety data will be analyzed in the Safety Analysis Set. Adverse events will be coded 
using the Medical Dictionary of Regulatory Activities. The incidence of 
treatment-emergent adverse events will be presented by system organ class (SOC) and 
preferred term (PT); by SOC, PT, and relationship to test article; and by SOC, PT, and 
severity. Serious AEs and treatment-emergent adverse events that lead to discontinuation 
of the test article will also be presented by SOC and PT. Descriptive statistics for clinical 
laboratory test results, vital signs, and ECG parameters, including change from baseline, 
will be presented by timepoint collected and for the overall most abnormal post-baseline 
value (for clinical laboratory results and vital signs). Incidences of potentially clinically 
significant clinical laboratory results, vital signs, and ECG parameters, as defined in the 
SAP, will also be summarized by timepoint collected and the overall most abnormal 
post-baseline value (for clinical laboratory results and vital signs). 
Efficacy Assessments: 
The study is exploratory with respect to efficacy determination. Efficacy will be evaluated 
based on endpoints defined by subject-reported NTM symptoms, subject-reported 
outcomes and quality of life measures, and microbiologic assessment. Additional 
endpoints to assess efficacy will be defined in the SAP. Nominal p-values are provided as 
descriptive statistics. 
Clinical response at Day 84 will be defined as (1) improvement in severity of at least 50% 
of symptoms present at baseline and (2) improvement in severity of at least 50% of 
symptoms present at baseline and no deterioration in severity of symptoms present at 
baseline. Subjects who receive alternative antibiotic therapy for treatment of the NTM 
infection, withdraw consent, and/or die before reaching Day 84 will be considered as not 
achieving clinical response. For both definitions, the number and percentage of subjects 
with a clinical response and no clinical response will be summarized by treatment group in 
the ITT Analysis Set. Exact 2-sided 95% confidence intervals for the point estimates of the 
clinical response rates in each treatment group will be determined using the 
Clopper-Pearson method. The odds ratio (omadacycline /placebo) and p-value will be 
calculated using Cochran-Mantel-Haenszel test, stratified by prior antibiotic use. 
Secondary efficacy endpoints based on patient-reported outcomes and quality of life 
assessments and microbiologic assessments will also be analyzed to provide supportive 
evidence of efficacy. 


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Data Monitoring Committee: 
No data monitoring committee planned for this study. 


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TABLE OF CONTENTS 
SYNOPSIS .....................................................................................................................2 
TABLE OF CONTENTS .............................................................................................11 
LIST OF APPENDICES ..............................................................................................14 
LIST OF TABLES .......................................................................................................14 
LIST OF FIGURES .....................................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................15 
1 
DISCLOSURE STATEMENT .............................................................................17 
2 
CONTACTS .........................................................................................................18 
2.1 
Emergency Contacts ........................................................................................18 
2.2 
Additional Contacts .........................................................................................18 
3 
INTRODUCTION ................................................................................................19 
3.1 
Nontuberculous Mycobacterial Pulmonary Disease ........................................19 
3.2 
Omadacycline ..................................................................................................19 
3.3 
Properties of Omadacycline that Address the Unmet Treatment Need for 
M. abscessus Complex Pulmonary Infection ................................................20 
4 
STUDY OBJECTIVES AND ENDPOINTS ........................................................21 
5 
INVESTIGATIONAL PLAN ...............................................................................23 
5.1 
Overall Study Description ................................................................................23 
5.2 
Rationale for Study Design ..............................................................................23 
5.3 
Approximate Duration of Study .......................................................................24 
5.4 
Approximate Number of Subjects ...................................................................24 
6 
STUDY POPULATION SELECTION ................................................................25 
6.1 
Study Population ..............................................................................................25 
6.2 
Inclusion Criteria .............................................................................................25 
6.3 
Exclusion Criteria ............................................................................................26 
6.4 
Screen Failures .................................................................................................27 
7 
STUDY TREATMENT(S) ...................................................................................28 
7.1 
Treatments Administered .................................................................................28 
7.2 
Identity of the Investigational Product:  Omadacycline ..................................28 
7.3 
Dose Selection Rationale .................................................................................29 
7.4 
Description of Treatments ................................................................................30 
7.5 
Test Article Administration .............................................................................30 
7.5.1 
Oral Administration of Test Article ...........................................................30 
7.6 
Dose Adjustments and Interruptions of Test Article .......................................30 
7.7 
Method of Assigning Patients to Treatment Groups ........................................30 
7.7.1 
Subject Numbering ....................................................................................31 
7.8 
Dispensing Test Article....................................................................................31 
7.9 
Blinding............................................................................................................31 
7.10 
Emergency Unblinding of Treatment Assignment ..........................................32 


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7.11 
Prior and Concomitant Therapy .......................................................................32 
7.12 
Prohibited Therapy ...........................................................................................33 
7.13 
Permitted Treatments .......................................................................................33 
7.14 
Treatment Compliance .....................................................................................33 
7.15 
Packaging and Labeling ...................................................................................34 
7.16 
Storage and Accountability ..............................................................................34 
7.17 
Investigational Product Retention at Study Site ..............................................34 
8 
STUDY PROCEDURES ......................................................................................35 
8.1 
Informed Consent.............................................................................................35 
8.2 
Subject Demographics/Other Baseline Characteristics ...................................35 
8.3 
Medical History ...............................................................................................35 
8.4 
Physical Examination.......................................................................................35 
8.5 
Vital Signs ........................................................................................................36 
8.6 
Height, Weight and Body Mass Index .............................................................36 
8.7 
Electrocardiogram ............................................................................................36 
8.8 
Computed Tomography Scan – Chest .............................................................36 
8.9 
Clinical Laboratory Tests .................................................................................37 
8.9.1 
Central Safety Laboratory Parameters .......................................................37 
8.9.2 
Local Safety Laboratory Parameters ..........................................................37 
8.10 
Sputum Collection For Microbiology ..............................................................38 
8.11 
Serum and Plasma Collection for Biomarkers (optional) ................................38 
8.12 
NTM Symptom Assessment Questionnaire .....................................................39 
8.13 
Other Patient-Reported Outcomes and Clinician-Assessed Outcomes ...........39 
8.13.1 
Quality of Life – Bronchiectasis ................................................................39 
8.13.2 
St. Georges Respiratory Questionnaire ......................................................39 
8.13.3 
Patient-Reported Outcomes Measurement Information System Short Form 
v1.0 – Fatigue 7a Daily .............................................................................40 
8.13.4 
Patient Clinical Impression of Severity .....................................................40 
8.13.5 
Patient Clinical Impression of Change ......................................................40 
8.13.6 
Clinical Global Impression – Severity of Illness .......................................40 
8.13.7 
Clinical Global Impression – Improvement ...............................................40 
8.14 
Adverse Events ................................................................................................40 
8.15 
Serious Adverse Events ...................................................................................41 
8.16 
Other Reportable Information ..........................................................................42 
8.17 
Overdose ..........................................................................................................42 
8.18 
Medication Errors ............................................................................................42 
8.19 
Recording and Reporting .................................................................................43 
8.19.1 
Serious Adverse Event Reporting ..............................................................43 
8.19.2 
Assessment of Relatedness ........................................................................43 
8.19.3 
Assessment of Severity ..............................................................................44 
8.19.4 
Laboratory Findings ...................................................................................44 


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8.19.5 
Worsening or Progression of Disease Under Study ...................................44 
8.19.6 
Pregnancies ................................................................................................44 
8.20 
Concomitant Medication Assessments ............................................................45 
8.21 
Subject Discontinuation or Withdrawal ...........................................................45 
9 
STUDY ACTIVITIES ..........................................................................................46 
9.1 
Screening Period ..............................................................................................46 
9.2 
Double-blind Treatment Period .......................................................................46 
9.3 
Follow-up Period .............................................................................................46 
9.3.1 
30-Day Safety Follow-up Call ...................................................................46 
10  STUDY SUSPENSION, TERMINATION, AND COMPLETION .....................47 
10.1 
Study Completion and Post-study Test Article ................................................47 
10.2 
Study Suspension or Termination ....................................................................47 
11  QUALITY CONTROL AND ASSURANCE ......................................................48 
12  PLANNED STATISTICAL METHODS .............................................................49 
12.1 
General Considerations ....................................................................................49 
12.2 
Determination of Sample Size .........................................................................49 
12.3 
Analysis Populations ........................................................................................49 
12.4 
Demographics, Baseline Characteristics, and Subject Disposition .................50 
12.5 
Efficacy Endpoint(s) ........................................................................................50 
12.5.1 
Primary Efficacy Endpoints .......................................................................50 
12.5.2 
Secondary Efficacy Endpoints ...................................................................50 
12.5.2.1 
Patient-Reported Outcomes and Quality of Life .................................50 
12.5.2.2 
Microbiological Response ...................................................................52 
12.6 
Safety Endpoint(s) ...........................................................................................52 
12.7 
Data Monitoring Committee ............................................................................52 
13  ADMINISTRATIVE CONSIDERATIONS ........................................................53 
13.1 
Investigators and Study Administrative Structure ...........................................53 
13.2 
Institutional Review Board or Independent Ethics Committee Approval .......53 
13.3 
Ethical Conduct of the Study ...........................................................................53 
13.4 
Patient Information and Consent .....................................................................53 
13.5 
Direct Access, Data Handling, and Record Keeping .......................................54 
13.5.1 
Investigator ................................................................................................54 
13.5.2 
Sponsor ......................................................................................................54 
13.6 
Protocol Adherence ..........................................................................................54 
13.6.1 
Violations/Deviations ................................................................................54 
13.6.2 
Protocol Amendments ................................................................................54 
13.7 
Subject Injury ...................................................................................................55 
13.8 
Pre-study Documentation.................................................................................55 
13.9 
Retention of Data .............................................................................................56 
13.10  Publication and Disclosure Policy ...................................................................56 
14  REFERENCE LIST ..............................................................................................57 


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LIST OF APPENDICES  
 
Schedule of Assessments .................................................................................59 
 
Equations and Conversion Factors...................................................................62 
 
Sputum Induction Guidelines ..........................................................................63 
 
NTM Symptom Questionnaires .......................................................................65 
 
Sponsor Signature ............................................................................................67 
 
Investigator’s Signature ...................................................................................68 
 
LIST OF TABLES  
Table 1. 
Clinical Laboratory Tests (Central) .................................................................37 
 
LIST OF FIGURES  
Figure 1. 
Study Design Schema ......................................................................................23 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
BSSSI 
acute bacterial skin and skin structure infections 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATCC 
American Type Culture Collection 
AUC0-24 
area under the concentration-time curve from time zero to 24 hours 
AUC 
area under the concentration-time curve 
β-hCG 
serum β-human chorionic gonadotropin 
CABP 
community-acquired bacterial pneumonia 
CGI-I 
Clinical Global Impression – Global Improvement Scale 
CGI-S 
Clinical Global Impression – Severity of Illness 
CI 
confidence interval  
CSA 
clinical study agreement 
CT 
computed tomography 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 
iv 
intravenous 
IxRS 
interactive voice/web response system 
LS 
least squares 
MABc 
Mycobacterium abscessus complex 


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MAC 
Mycobacterium avium complex 
MIC 
minimum inhibitory concentration 
NTM 
nontuberculous mycobacterial 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PI 
principal investigator 
PK 
pharmacokinetics 
PRO 
patient-reported outcomes 
PROMIS Short 
Form v1.0 – 
Fatigue 7a Daily 
Patient-Reported Outcomes Measurement Information System Short 
Form v1.0 – Fatigue 7a Daily 
PT 
preferred term 
q24h 
every 24 hours 
QOL-B 
Quality of Life – Bronchiectasis 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis Software 
SE 
standard error 
SGRQ 
St. Georges Respiratory Questionnaire 
SOC 
system organ class 
US 
United States 


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1 DISCLOSURE STATEMENT  
Restricted Distribution of Documents 
This document contains information that is confidential and proprietary to the sponsor. This 
information is being provided to you solely for the purpose of evaluating and/or conducting a 
clinical study for the sponsor. You may disclose the contents of this document only to study 
personnel under your supervision, Institutional Review Boards (IRBs)/Independent Ethics 
Committees (IECs)/Research Ethics Boards (REBs), or duly authorized representatives of 
regulatory agencies for this purpose under the condition that they maintain confidentiality. 
The contents of this document may not be used in any other clinical study, disclosed to any 
other person or entity, and/or published without the prior written permission of the sponsor. 
The foregoing shall not apply to disclosure required by any regulations; however, you will 
give prompt notice to the sponsor of any such disclosure. All other nonpublic information 
provided by the sponsor and any information that may be added to this document also is 
confidential and proprietary to the sponsor and must be kept in confidence in the same 
manner as the contents of this document. 


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2 CONTACTS  
2.1 
Emergency Contacts  
Name/Title: 
 
 
 
 
 
 
, MD 
Global Medical Monitor 
Phone (during business hours): 
 
Phone (after business hours):  
 
E-mail (not for emergencies):  
 
2.2 
Additional Contacts  
SAE contact information: 
E-Mail: 
 
 
 
 
 
 
 
clinicalsafety@propharmagroup.com 


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3 INTRODUCTION  
3.1 
Nontuberculous Mycobacterial Pulmonary Disease  
More than 140 nontuberculous mycobacterial (NTM) species have been identified, with more 
than half of the NTM pulmonary infections in the United States (US) associated with 
Mycobacterium avium complex (MAC) (Prevots 2010; Spaulding 2017). Mycobacterium 
abscessus complex (MABc) is the second most common NTM grouping causing human 
disease in the US, comprising about 10% of all NTM pulmonary infections across various 
study sites (Prevots 2015). In 2010, the number of national cases of NTM pulmonary 
infections was estimated as 86,244 (Strollo 2015). More recently in 2019, the number of 
NTM pulmonary cases was estimated to be as high as 115,000 nationally (Insmed 
Presentation 2021). The annual prevalence of NTM pulmonary infections in the US in 2015 
was estimated as 11.7 per 100,000, representing a 7.5% annual increase from 2008 
(Winthrop 2020).  
Infections caused by MABc are notoriously difficult to treat due to intrinsic resistance to 
many classes of antibiotics. Few oral antibiotics demonstrate in vitro activity against MABc, 
making long-term treatment extremely difficult. Currently there are no Food and Drug 
Administration (FDA)-approved treatments for pulmonary disease caused by MABc. Current 
treatment options (off-label treatments) are typically lengthy and require complex, multidrug 
regimens (Strnad 2018). M. abscessus isolates display in vitro resistance to most oral 
antibiotics and are generally susceptible to a limited number of parenteral agents. Previous 
guidelines recommend using a multidrug regimen including ≥ 2 of these antibiotics to which 
the organism is susceptible in vitro. Recent work suggests a lack of consensus among treating 
physicians, with a variety of regimens employed against this organism ranging from 2 to 5 
drugs in the initial phases of therapy (Daley 2020). 
Most of the antibiotics recommended for the treatment of MABc pulmonary infection have 
safety and tolerability profiles that are not conducive to an extended treatment course. 
Current treatment regimens are frequently associated with serious adverse effects and poor 
patient adherence contributing to poor clinical outcomes. With these current treatment 
challenges, expert NTM clinicians and patient advocacy groups have emphasized the urgent 
need for developing new antibiotics for the treatment of NTM infections. Ideally, these 
antibiotics would have potent in vitro activity and a high barrier to the emergence of 
resistance. A favorable safety and tolerability profile and the availability of an oral 
formulation both take on added importance because of the anticipated prolonged treatment 
duration. An antibiotic with these properties has the potential to improve both microbiologic 
and patient quality of life outcomes in patients with MABc pulmonary disease. 
Therefore, a clear unmet need exists for an effective and safe antibiotic that is well-tolerated 
and can be administered orally. Omadacycline has the potential to fill this unmet need. 
3.2 
Omadacycline  
The investigational product, omadacycline (formerly named PTK 0796), is the first member 
of the aminomethylcycline class of antibiotics, which are semisynthetic derivatives of the 


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tetracycline class. As a class, tetracyclines have been in use for approximately 70 years. They 
are well-tolerated and have proven effective in the treatment of a variety of bacterial 
infections. Intravenous NUZYRA (omadacycline) and oral NUZYRA tablets have been 
approved by the US FDA for the treatment of adult patients with community-acquired 
bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) 
caused by susceptible microorganisms. 
While data from the completed nonclinical program supports dosing up to 90 days, this is the 
first clinical trial that will administer study dosing of omadacycline beyond 14 days of 
therapy. Current-use data indicate that omadacycline is being used for chronic dosing without 
any safety signal identified, through Paratek’s post-marketing pharmacovigilance program 
and published cases studies. Review of post-marketing off-label use reports did not reveal 
any trends or recommended updates to the current reference safety information. As of 
January 2021, 5 case series have been published that together report experience on 
19 patients with NTM infections, predominately M. abscesses (Frizzell 2020; Gill 2019; 
Minhas 2019; Morrisette 2021; Pearson 2020). Patients were treated with oral omadacycline 
for periods ranging from 4 weeks to 20.6 months, all but one as part of a multidrug regimen. 
Omadacycline was overall safe and well-tolerated. Clinical success was reported in 
16 patients. Reported events were consistent with the established safety profile and are not 
unexpected. These real-world observational reports of treatment with omadacycline for NTM 
provide support to progress to a randomized controlled trial setting, including long-term 
dosing. 
Please refer to the current version of the Investigator’s Brochure for additional information 
on omadacycline. 
3.3 
Properties of Omadacycline that Address the Unmet Treatment Need for 
M. abscessus Complex Pulmonary Infection  
Omadacycline has several key characteristics that may prove beneficial to patients with 
MABc pulmonary infection: 
 Potent in vitro activity versus M. abscessus complex subspecies  
 No antagonism in vitro when tested in combination with other antimicrobials 
commonly used to treat M. abscessus infections 
 Demonstrated efficacy in a mouse model of M. abscessus pulmonary infection 
 Favorable pharmacokinetics (PK) and dosing regimen  
 Extensive penetration into lung tissue compartments including epithelial lining 
fluid and alveolar macrophages  
 Half-life of 17 hours supports once-daily dosing  
 No dosing adjustments are required for age, weight, race, sex, renal or hepatic 
impairment   
 Established safety profile in pre-clinical studies and Phase 3 clinical trials conducted 
in CABP and ABSSSI populations (up to 14 days of dosing) 
 Does not prolong the QTc interval 






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5 INVESTIGATIONAL PLAN  
5.1 
Overall Study Description  
This is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group, multi-center 
study in adults with NTM pulmonary disease caused by MABc. The study design is shown in 
Figure 1. 
Figure 1. Study Design Schema 
 
 
 
Following a Screening period of up to 56 days (8 weeks) prior to dosing, eligible subjects 
will be randomized (1.5:1) to receive either 300 mg once daily oral omadacycline 
monotherapy or matching placebo. Subjects will be stratified according to their use of prior 
antibiotics for treatment of MABc NTM infection (received prior treatment vs. no prior 
treatment). 
Subjects will attend monthly visits during the approximately 84 day (3-month) double-blind 
treatment period. In addition, subjects will complete a 14-day safety tele-visit as well as a 
safety follow-up call approximately 30 days after their last dose of test article. Total duration 
of subject participation is approximately 5 months.  
Refer to the Schedule of Assessments for a complete summary of subject visits and 
assessments.  
5.2 
Rationale for Study Design  
This study is intended to assess the safety and efficacy of omadacycline in addition to non-
pharmacologic standard of care in NTM subjects caused by MABc. Non-pharmacologic 
measures, including patient education, airway clearance technique, inspiratory muscle 
training, and exercise training, are considered the first line of therapy in these subjects and 
will be permitted during the study (Lan 2020). A 3-month, monotherapy, placebo-controlled 
study design will allow the best assessment of omadacycline without any confounding 


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influence of other antibiotic treatments and will provide valuable, controlled data as well as 
adequate time to observe a treatment effect. 
5.3 
Approximate Duration of Study  
The study is expected to be clinically complete in approximately 28 months. 
5.4 
Approximate Number of Subjects  
Approximately 75 subjects (45 omadacycline and 30 placebo) will be enrolled at 
approximately 20 sites within the US. 


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6 STUDY POPULATION SELECTION  
Each subject must participate in the informed consent process and sign and date an 
IRB/IEC/REB-approved informed consent form (ICF) before any procedures specified in this 
protocol are performed. 
6.1 
Study Population  
This study will evaluate adult subjects with NTM pulmonary disease caused by MABc.  
6.2 
Inclusion Criteria  
Subjects must meet all of the following criteria at Screening and/or Baseline to be eligible to 
participate in the study: 
1. Written and signed informed consent must be obtained before any protocol-specific 
assessment is performed. 
2. Male and female subjects age 18 years or older. 
3. Diagnosed MABc pulmonary disease as per Infectious Diseases Society of 
America/American Thoracic Society guidelines criteria. Subjects must have: 
 At least 2 of the following NTM-infection symptoms at Screening and Baseline:  
 Chronic cough, coughing up blood (hemoptysis), wheezing, chest pain, frequent 
throat clearing, phlegm or sputum production, shortness of breath, fatigue, fever, 
night sweats, poor appetite, and/or weight loss 
 At least 1 positive pulmonary culture for MABc in the 6 months prior to Screening 
and 1 positive culture at Screening (note: prior culture and screening cultures must be 
at least 30 days apart). 
 Radiographic evidence of MABc infection via computed tomography (CT) scan of 
the chest within 3 months prior to Screening with findings consistent with NTM 
pulmonary disease. If no CT scan obtained within previous 3 months, one should be 
performed at Screening to confirm eligibility.  
4. Based on the clinical assessment of the investigator, guideline-directed antibiotic therapy 
for treatment of MABc will not be required within the next 3 months, and a delay, in 
order for the subject to participate in a placebo-controlled clinical trial, is considered 
reasonable and clinically acceptable.  
5. Be able to produce approximately 5 mL of sputum via spontaneous expectoration or be 
willing to undergo sputum induction to produce approximately 5 mL of sputum for 
microbiological evaluation. 
6. Females must have a negative serum pregnancy test and agree to use a highly effective 
form of birth control (eg, abstinence, oral contraceptive, intrauterine device, or barrier 
contraception [eg, condom], tubal ligation, hysterectomy, bilateral oophorectomy, 
postmenopausal or vasectomized partner) from Screening through study completion. 
Males (if sexually active) must agree to use a highly effective method of birth control 
with female partner(s) from Screening through study completion. 


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7. Able and willing to adhere with the requirements and restrictions of the study. 
 
6.3 
Exclusion Criteria  
Subjects meeting any of the following criteria at Screening and/or Baseline will be excluded 
from participation in the study: 
1. Pregnant or nursing (breastfeeding) women. 
2. Has received antibiotic treatment within 6 months prior to Screening for MABc or MAC. 
3. Has received systemic or inhaled antibiotic therapy (other than chronic macrolide 
therapy) within 4 weeks prior to Screening. 
4. Is experiencing an exacerbation of an infection with a non-Mycobacterium species (eg, 
Pseudomonas aeruginosa) that the investigator considers clinically relevant.  
5. Has any of the following medical conditions: 
 Active pulmonary malignancy (primary or metastatic), or any type of malignancy 
requiring chemotherapy or radiation within 1 year prior to Screening.  
 Active allergic bronchopulmonary mycosis, or any other condition requiring chronic 
treatment with systemic corticosteroids (ie, prednisone dose ≥ 15 mg/day for a period 
of ≥ 4 consecutive weeks above this level; see Appendix 2) within 90 days prior to 
Screening. 
 Radiologic evidence of cavitary disease.  
 Known active pulmonary tuberculosis.  
 Cystic fibrosis.  
 History of lung transplantation.  
 Another advanced lung disease with a known percent predicted forced expiratory 
volume in 1 second < 30%.  
 Disseminated or extra-pulmonary NTM disease. 
6. Screening calculated creatinine clearance < 30 mL/minute, using the Cockcroft-Gault 
equation (Appendix 2), requirement for any form of dialysis (eg, hemodialysis, peritoneal 
dialysis), or other evidence of severe renal disease. 
7. Has any of the following at Screening: 
 Alanine aminotransferase or aspartate aminotransferase ≥ 3 × upper limit of normal.  
 Total bilirubin > 1.5 × upper limit of normal. 
 Suspected or confirmed clinical evidence of end-stage liver disease (eg, ascites, 
hepatic encephalopathy). 
8. History of having experienced unstable cardiac disease (eg, unstable angina, myocardial 
infarction, acute congestive heart failure, unstable cardiac arrhythmia, etc.) within the 
3 months prior to Screening. 
9. Significant immunological disease determined by any of the following: 
 Current or anticipated neutropenia defined as < 500 neutrophils/mm3. 
 Known infection with human immunodeficiency virus (HIV). 


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10. History of hypersensitivity or allergic reaction (eg, anaphylaxis, urticaria, other 
significant reaction) to any tetracycline (eg, minocycline, doxycycline, tigecycline, or 
omadacycline). 
11. Has been previously treated with omadacycline. 
12. History of pseudotumor cerebri, or prior (within 2 weeks prior to Screening) or planned 
concomitant use of isotretinoin.  
13. Systemic treatment with disease-modifying antirheumatic agents, corticosteroids 
(equivalent to prednisone dose ≥ 15 mg/day for a period of ≥ 4 consecutive weeks above 
this level) or immunosuppressive agents in the 90 days prior to Screening. 
14. Has current evidence of active pancreatitis. 
15. Evidence or history of any other clinically significant medical condition or planned 
medical intervention that may, in the opinion of the investigator, pose a significant safety 
risk, impair study participation, impact the subject’s ability to undergo the required study 
procedures or ability to complete the expected course of study treatment.  
16. Any surgical or medical condition that, in the opinion of the investigator, might 
significantly alter the absorption, distribution, metabolism, or excretion of drugs. 
17. Inability to fast for 4 hours prior to dosing and/or 2 hours after dosing. 
18. Per discretion of the investigator, subject is not expected to survive the duration of the 
study. 
 
6.4 
Screen Failures  
Subjects who sign the ICF but withdraw or are withdrawn from the study before random 
assignment to double-blind treatment are defined as screen failures. All screen failures 
should be recorded on the subject master list. Limited information including reason for 
screen failure will be recorded on the electronic case report form (eCRF) or interactive 
voice/web response system (IxRS) system for screen failures. Screen failure subjects may be 
re-screened at the discretion of the investigator and in consultation with the medical monitor 
as needed. Any subject who discontinues participation or is withdrawn before receiving a 
treatment assignment, and who is re-screened at a later time will be assigned a new subject 
number and recorded as re-screened. 


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7 STUDY TREATMENT(S)  
7.1 
Treatments Administered  
Test articles will be supplied by Paratek Pharmaceuticals, Inc. (the sponsor). Test articles will 
be labeled according to regulations. 
The test articles should be administered only to subjects who have provided informed 
consent and who meet all of the inclusion criteria and none of the exclusion criteria. Once the 
test article has been assigned to a subject, it must not be reassigned to another subject. 
Following a Screening period of up to 56 days (8 weeks), eligible subjects will be randomly 
assigned to receive 300 mg oral omadacycline or matching placebo tablets. 
7.2 
Identity of the Investigational Product:  Omadacycline  
Oral Formulation (Omadacycline) 
Name 
Omadacycline Tablet, 150 mg 
 
Placebo 
Name 
Placebo tablets 
Excipients 
Lactose monohydrate, microcrystalline cellulose, sodium stearyl fumarate 
How supplied 
Tablets are packaged in an alu/alu 6-count (2 × 3) foil blister. Secondary packaging will 
consist of fold-over, child-resistant blister cards (2 blisters per card) and patient kits 
containing 6 blister cards (72 tablets per patient kit) 
Storage 
Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C 
to 30°C (59°F to 86°F) (see USP Controlled Room Temperature) 
Preparation and 
handling 
No special requirements 
Administration 
Please see Section 7.5  
 


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7.3 
Dose Selection Rationale  
The dosing regimen of omadacycline selected for this study is based on the demonstration of 
efficacy in a mouse model of M. abscessus pulmonary infection, as well as the totality of 
nonclinical and clinical experience to date, including in vitro antibacterial activity, PK 
characteristics, and the overall safety and tolerability profile of the FDA-approved dosing 
regimens for treatment of CABP and ABSSSI. 
In a nonclinical C3HeB/FeJ mouse model of M. abscessus pulmonary infection, 
omadacycline efficacy was demonstrated using the dose best representing the human 
equivalent exposure ie, area under the concentration-time curve (AUC) of the human 300 mg 
oral dose. The C3HeB/FeJ mouse was previously demonstrated to provide utility as a mouse 
model of M. abscessus pulmonary infection for antibacterial studies (Maggioncalda 2020; 
Story-Roller 2019). Administration of a corticosteroid (dexamethasone) allows for initial 
proliferation of and subsequent sustained M. abscessus pulmonary infection and pathology 
following infection via an aerosolized route. 
As detailed in the Investigator’s Brochure, the steady state AUC (hr*µg/mL) for the 300 mg 
oral dose is 11.156, while the steady state free AUC (hr*µg/mL) of the 300 mg oral dose is 
8.92 (adjustment for free fraction by 20% human plasma protein binding; on file at Paratek). 
Therefore, a mouse dose was selected to represent a steady state free AUC (hr*µg/mL) of 
approximately 9. 
Omadacycline PK parameters in C3HeB/FeJ mice were determined after subcutaneous 
administration of omadacycline doses of 7.5, 15 and 30 mg/kg in order to calculate the 
appropriate mouse dose to study in the efficacy model. Following determination of key PK 
parameters, adjustment for free fraction in mice (33.9% mouse plasma protein binding; data 
on file at Paratek), and graphical assessment of the mouse free area under the concentration-
time curve from time zero to 24 hours (AUC0-24) (hr*µg/mL) versus mouse doses studied, the 
resulting linear equation was utilized to calculate the appropriate mouse dose. Specifically, 
the data demonstrated that a mouse subcutaneous dose of approximately 15 mg/kg every 
24 hours (q24h) best represents a human AUC0-24 (hr* µg/mL) of 9 (on file at Paratek). 
The American Type Culture Collection (ATCC) reference strain M. abscessus 19977 
(omadacycline minimum inhibitory concentration [MIC] values of 0.25 to 0.5 µg/mL) and 
the clinical isolate M9501 (omadacycline MIC value of 0.25 µg/mL) were evaluated in the 
mouse model of efficacy (MIC data on file at Paratek). Mice were infected via aerosolization 
and treatment was initiated 1-week post-infection. Mice were treated with either 
omadacycline (15 mg/kg q24h), imipenem (200 mg/kg every 12 hours; positive control) or 
vehicle (phosphate buffered saline; q24h) for 4 weeks and the bacterial burden in the lungs 
was evaluated at various timepoints (0, 1 week, 2 weeks, and 4 weeks) throughout the study. 
Efficacy was determined as a reduction in lung bacterial burden compared to vehicle 
controls. 
M. abscessus lung burden in the vehicle control group increased throughout the course of 
infection as expected. In the positive control group (imipenem treatment), M. abscessus lung 
burden decreased gradually over the duration of the study. For mice infected with the 


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reference strain ATCC 19977, at the final timepoint of 4 weeks of treatment, omadacycline 
produced >3 log10 reduction in total lung colony forming units compared to mice in the 
vehicle control group. Similarly, omadacycline treatment reduced lung burden of the clinical 
strain M9501 by 2 log10 at the conclusion of 4 weeks of treatment.  
Therefore, based on the demonstration of omadacycline efficacy in the mouse model of M. 
abscessus pulmonary infection at the equivalent human steady state free AUC (hr*µg/mL) of 
approximately 9, the 300 mg oral dose will be evaluated in this human clinical study. 
Phase 3 clinical trials in CABP and ABSSSI have demonstrated that omadacycline has an 
acceptable safety profile. Additionally, the 300 mg oral dose being used in this study has 
been approved by the FDA for these indications.  
7.4 
Description of Treatments  
Subjects will be randomized (1.5:1) to 1 of the following treatment groups: 
 Group 1: 300 mg oral omadacycline (2 × 150 mg tablets administered once daily, 
q24h) 
 Group 2: Placebo tablets resembling omadacycline (2 tablets administered once daily, 
q24h) 
7.5 
Test Article Administration  
7.5.1 
Oral Administration of Test Article  
All doses of oral test article should be taken with water once daily, at approximately the same 
time of day. 
All doses should be taken in a fasted state. Fasting is defined as no food, antacids or 
multivitamins containing multivalent cations (eg, aluminum, magnesium, calcium, bismuth, 
iron, or zinc) or drink except water for at least 4 hours before dosing. After dosing, no food 
or drink (except water) is permitted for 2 hours and no dairy products, antacids or 
multivitamins containing multivalent cations (eg, aluminum, magnesium, calcium, bismuth, 
iron, or zinc) for 4 hours. 
7.6 
Dose Adjustments and Interruptions of Test Article  
No dose adjustments or planned interruptions of test article will be permitted during this 
study. 
7.7 
Method of Assigning Patients to Treatment Groups  
All eligible subjects will be randomized via an IxRS that assigns them to the treatment group 
in a 1.5 to 1 ratio (omadacycline: placebo). The site delegate will contact the IxRS after 
confirming that the subject fulfills all the inclusion criteria and has none of the exclusion 
criteria. The IxRS will assign a test article to the subject based on a computer-generated 


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randomization schedule. The randomization will be a blocked randomization sequence 
stratified by prior antibiotic use for treatment of MABc NTM infection (prior antibiotic use 
and no prior antibiotic use) as defined in the IxRS specifications. Subjects randomized into 
the study will be assigned the treatment corresponding to the next available number from the 
computer-generated randomization schedule. The subject is considered randomized when the 
IxRS provides the test article assignment, regardless of whether the subject actually receives 
any test article. 
7.7.1 
Subject Numbering  
Upon the subject signing the informed consent, site personnel should enter the subject in the 
IxRS, and the subject will be assigned a unique subject number. Subjects who have been 
pre-screened but who do not sign an ICF will not be assigned a subject number. A subject 
who discontinues participation or is withdrawn before receiving a treatment assignment, and 
who is re-screened at a later time will be assigned a new subject number and recorded as 
re-screened. Re-screening is at the discretion of the investigator and in consultation with the 
medical monitor. The investigator will maintain a subject master list to document every 
subject who has signed an ICF using the subject number assigned by the IxRS. A copy of this 
list should be retained in the investigator’s study files.  
7.8 
Dispensing Test Article  
Each study site will be supplied by the sponsor with the test article. Oral test article supplies 
are completely blinded, and blinded study personnel can conduct storage, dispensation, and 
reconciliation. The IxRS will assign the test article kit to be given to the subject. 
Oral test article will be supplied to the sites in labelled, blinded kits that contain 6 blister 
cards (12 tablets per card, 72 tablets per kit) of omadacycline (150 mg) tablets or matching 
placebo tablets. Each kit contains enough test article for 4 weeks of test article administration 
between visits. At each visit when test article is dispensed (Baseline, Day 28, Day 56), study 
personnel will access the IxRS and be assigned a test article kit to be given to the subject. 
The study coordinator/staff will instruct the subject on the use of oral test article. 
7.9 
Blinding  
The investigator and sponsor will be blinded to treatment group assignments throughout the 
study. The sponsor designee (eg, clinical supply manager, IxRS vendor, etc.) will have a 
designated randomization administrator who will maintain the randomization codes in 
accordance with standard operating procedures to ensure the blind is properly maintained and 
that only sponsor personnel who require knowledge of treatment assignments will be 
unblinded (eg, staff involved in maintaining the randomization codes). 
Randomization data are kept strictly confidential until the time of database lock and 
unblinding at the end of the study. Unblinded treatment assignments will be provided to 
study sites after the study has concluded. 


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All test articles will be supplied in identical packaging thereby maintaining the blinding for 
all site staff and subjects. 
Unblinding by site personnel is only to occur in the case of subject emergencies (see 
Section 7.10, below).  
7.10 Emergency Unblinding of Treatment Assignment  
Emergency unblinding should only be undertaken when it is essential to treat the subject 
safely and efficaciously. Most often, test article discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study subject who presents with an 
emergency condition. It is encouraged for the investigator, when contemplating unblinding, 
to contact the sponsor or sponsor’s designated medical monitor or designee to confirm the 
need to unblind, prior to unblinding (see Section 2 for contact information). However, if 
required, the investigator can unblind without consulting the medical monitor. 
Emergency code breaks are performed using the IxRS. When the investigator contacts the 
system to unblind a subject, he/she must provide the requested subject identifying 
information and confirm the necessity to unblind the subject. The investigator will then 
receive details of the drug treatment for the specified subject and a fax or e-mail confirming 
that the treatment assignment of the subject was unblinded. The system will automatically 
inform the sponsor’s monitor and the sponsor that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place at their site to 
allow access to the IxRS code break information in case of emergency. The investigator will 
inform the subject how to contact his/her backup in cases of emergency when he/she is 
unavailable. 
All steps outlined above will be followed, including contacting the medical monitor as soon 
as possible and not more than 24 hours afterwards. It will be the responsibility of all study 
personnel to ensure that, except for the above procedure, investigator blinding is maintained 
until after study completion. 
7.11 Prior and Concomitant Therapy  
 All antibiotics administered for the subject’s MABc or MAC infection within 2 years 
prior to the date of informed consent will be recorded in the eCRF. 
 All significant non-pharmacological therapies related to MABc infection including 
patient education, airway clearance technique, inspiratory muscle training, and 
exercise training administered from 30 days prior to date of informed consent, and 
administered throughout the duration of the study through the 30-day follow-up 
period, will be recorded in the eCRF. 
 All pharmacological therapies (regardless of indication) that have been administered 
from 7 days prior to the date of informed consent and administered throughout the 
duration of the study through the 30-day follow-up period, will be recorded in the 
eCRF. 


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 All significant non-pharmacological therapies not related to MABc infection 
administered from 7 days prior to date of informed consent, and administered 
throughout the duration of the study through the 30-day follow-up period, will be 
recorded in the eCRF. 
 
7.12 Prohibited Therapy  
The following therapies (including timeframe for exclusion) are prohibited: 
 Antibiotic treatment for MABc or MAC infection (including systemic or inhaled 
antibiotics) within 6 months prior to Screening and through Day 84/end of treatment 
(EOT) visit 
 Systemic or inhaled antibiotic therapy (other than chronic macrolide therapy) within 
4 weeks prior to Screening and through Day 84/EOT visit 
 Systemic treatment with disease-modifying antirheumatic agents, corticosteroids 
(equivalent to prednisone dose ≥ 15 mg/day for a period of ≥ consecutive 4 weeks 
above this level) or immunosuppressive agents within 90 days prior to Screening and 
through Day 84/EOT visit 
 Use of isotretinoin within 2 weeks prior to Screening and through Day 84/EOT visit 
 Subjects will be instructed to avoid taking antacids and multivitamins containing 
multivalent cations (eg, aluminum, magnesium, calcium, bismuth, iron, or zinc) for 
4 hours before and within 4 hours after oral doses  
 
7.13 Permitted Treatments  
All other treatments not specified as prohibited are permitted during the study. Subjects 
requiring additional or alternative therapy for their MABc NTM pulmonary disease will be 
discontinued from test article. Further treatment for their infection is at the discretion of the 
investigator or the subject’s health care provider and will be considered as a concomitant 
medication. 
Subjects should be encouraged to contact site personnel before starting any new treatment. 
7.14 Treatment Compliance  
Subjects will record daily test article dosing information in a paper diary. Study personnel at 
the site should monitor oral test article compliance at each study visit by comparing the 
returned test article with the dosing information reported by the subject. Compliance and any 
unresolved discrepancies will be documented in the source document and on the drug 
inventory record. The test article eCRF should reflect the reconciled dosing information 
provided by the subject. 


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7.15 Packaging and Labeling  
The investigational test article, omadacycline, and the placebo will be packaged by the 
sponsor and supplied to the investigator.  
7.16 Storage and Accountability  
Test article must be received at the study site by a designated person, acknowledged in the 
IxRS, handled and stored safely and properly, and kept in a secured location to which only 
the investigator and designated staff have access. Upon receipt, the test article should be 
stored according to the instructions specified on the drug labels. Storage conditions must be 
adequately monitored, and appropriate temperature logs maintained as source data. 
The designated study personnel must maintain an accurate record of the shipment and 
dispensing of test articles. Test article supplies are completely blinded. Subjects will be asked 
to return all unused test article and packaging at each visit and at the end of the study, last 
study visit or at the time of test article discontinuation. Monitoring of oral test article 
accountability will be performed by the field monitor during site visits and at the completion 
of the study. 
7.17 Investigational Product Retention at Study Site  
At the conclusion of the study, and as appropriate during the course of the study, with 
instruction and approval from the sponsor, the designated study personnel will destroy on site 
as permitted by local site operating procedures, or return all unused test articles, packaging, 
and drug labels. Test articles can only be returned or destroyed after the sponsor has 
performed accountability. Destruction/return of all test article will be documented and 
maintained in the site files. 


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8 STUDY PROCEDURES  
Written, signed, and dated informed consent will be obtained before any study-related 
procedures have been performed. Upon signing the informed consent, the subject will be 
assigned a study subject number. Subjects who have been pre-screened but who do not sign 
an ICF will not be assigned a subject number. The investigator will maintain a subject master 
list to document every subject who has signed an ICF using the subject number assigned by 
the IxRS. A copy of this list should be retained in the investigator’s study files.  
A study Schedule of Assessments is provided in Appendix 1. 
8.1 
Informed Consent  
The investigator will provide for the protection of the subjects by following all applicable 
regulations. These regulations are available upon request from the sponsor. The ICF must be 
reviewed by the sponsor and approved by the IRB/IEC/REB. 
Before any procedures specified in the protocol are performed, a subject must: 
 Be informed of all pertinent aspects of the study and all elements of informed consent  
 Be given time to ask questions and time to consider the decision to participate 
 Voluntarily agree to participate in the study 
 Sign and date an IRB/IEC/REB-approved ICF 
 
Subjects will also have the option to provide consent for collection of serum and plasma for 
biomarkers. This is not required for subject eligibility and participation (See Section 8.11). 
8.2 
Subject Demographics/Other Baseline Characteristics  
Subject demographic and baseline characteristic data to be collected on all subjects include 
date of birth (per local regulations), gender, and race/ethnicity. 
8.3 
Medical History  
The investigator will perform a comprehensive history at the Screening visit. Significant 
medical history (at any time) and any medical history within the past 6 months including 
ongoing medical conditions at the time of signing of the ICF will be recorded. 
Where possible, diagnoses are to be recorded. Any event or change in the subject’s condition 
or health status occurring after signing the ICF will be reported as an AE. 
8.4 
Physical Examination  
At Screening and Day 84/EOT, a full physical examination will include the examination of 
general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, and vascular and neurological systems. 


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Information for all physical examinations must be included in the source documentation at 
the study site. Relevant findings that are present prior to the start of test article must be 
included in the relevant medical history/current medical conditions screen on the subject’s 
eCRF. New clinically significant findings made after the start of test article which meet the 
definition of an AE must be recorded as an AE in the subject’s eCRF. 
8.5 
Vital Signs  
Vital signs including blood pressure, heart rate, body temperature, and pulse oximetry will be 
measured at the timepoints as specified in Appendix 1. 
The subject’s vital signs should be captured after at least 5 minutes (+ 5 minutes) of rest 
while in a non-standing position (supine or sitting). Subsequent vital sign measurements 
should be captured in the same non-standing position. 
8.6 
Height, Weight and Body Mass Index  
Height and body weight should be obtained with the subject’s shoes off and recorded in the 
eCRF at the timepoints as specified in Appendix 1. Body mass index will be automatically 
calculated upon entry of height and weight in the eCRF. 
8.7 
Electrocardiogram  
A standard 12-lead ECG should be obtained using site equipment. The ECG will be obtained 
after the subject has been in a semi-recumbent position for approximately 10 minutes at the 
Screening and Day 84/EOT Visit. Reading and interpretation of the ECG will be performed 
locally by the investigator, and hard copies of the reports retained in the files. 
8.8 
Computed Tomography Scan – Chest  
Computed tomography scans of the chest will be performed using site equipment or local 
radiology facility. High resolution CT scan is preferred, if available. The CT scan will be 
interpreted by appropriately qualified personnel who are certified or licensed to interpret 
chest radiographs according to applicable regional requirements, reviewed by the investigator 
or qualified personnel and the conclusions of this review will be the basis for subject 
inclusion. The review report should be included in the source documents. 
Sites may utilize results of a chest CT scan performed within 3 months prior to Screening to 
determine eligibility (radiographic evidence of MABc infection). If no CT scan was obtained 
within the 3 months prior to Screening, a CT scan will be required at Screening. A follow-up 
chest CT scan will also be performed at the Day 84/EOT visit. 


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8.9 
Clinical Laboratory Tests  
8.9.1 
Central Safety Laboratory Parameters  
A Central Laboratory will be used for safety analysis of all specimens collected. Details on 
the collection tubes and containers, shipment of samples and reporting of results by the 
Central Laboratory are provided to investigators in the Central Laboratory Manual.  
The total volume of blood collected from each subject will be approximately 10.5 mL 
(2 teaspoons) per visit, or approximately 42 mL (3 tablespoons) over the course of the study. 
Clinical laboratory tests for safety will include the following:  
Table 1. 
Clinical Laboratory Tests (Central) 
Hematology: 
 
Hematocrit (Hct) 
 
Hemoglobin (Hgb) 
 
Mean corpuscular hemoglobin (MCH) 
 
Mean corpuscular hemoglobin 
concentration (MCHC) 
 
Mean corpuscular volume (MCV) 
 
Platelet count 
 
Red blood cell (RBC) count  
 
White blood cell (WBC) count with 
differential 
Coagulation: 
 
Prothrombin time international normalized 
ration (INR) 
Pregnancy (all female subjects): 
 
Serum β-human chorionic gonadotropin 
(β-HCG) 
Serum Chemistry: 
 
Alkaline phosphatase (ALP) 
 
Alanine aminotransferase (ALT) 
 
Aspartate aminotransferase (AST) 
 
Blood urea nitrogen (BUN) 
 
Calcium (Ca) 
 
Carbon dioxide (CO2) 
 
Chloride (Cl) 
 
Creatinine 
 
Creatine phosphokinase (CK) 
 
Gamma-glutamyl transpeptidase (GGT) 
 
Glucose 
 
Lipase 
 
Magnesium 
 
Phosphorus (P) 
 
Potassium (K) 
 
Sodium (Na) 
 
Total bilirubin 
 
8.9.2 
Local Safety Laboratory Parameters  
All female subjects will have a local urine or serum pregnancy test at the site during 
Screening and at the Baseline Visit (just prior to randomization). Urine pregnancy test kits 
will be provided by the sponsor through the Central Laboratory. If a positive urine or serum 
pregnancy test result is obtained at the site during Screening or at the Baseline Visit, the 
subject is not to be randomized. 
A serum sample for serum β-human chorionic gonadotropin (β-hCG) testing will be collected 
and sent to the Central Laboratory for confirmation of the local urine or serum pregnancy test 
results. If a positive β-hCG result is reported by the Central Laboratory after a subject is 
enrolled, test article administration should be discontinued. 


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8.10 Sputum Collection For Microbiology  
A Central Specialty Microbiology Laboratory will be used for analysis of all sputum 
specimens. Details on the collection supplies, shipment of samples and reporting of results 
are provided to investigators in the Central Laboratory Manual.  
Pre-dose expectorated or induced sputum specimens (approximately 5 mL) will be collected 
at all timepoints as indicated in Appendix 1. To improve the probability of obtaining a good 
sputum specimen, at least 2 and preferably 3 spontaneously expectorated sputum samples 
will be obtained from subjects at each timepoint. During Screening, samples will be collected 
after the subject signs the informed consent. For all subsequent visits, sputum samples should 
be collected on 2 to 3 consecutive days (when possible), just prior to, and up through the day 
of the scheduled visit.  
If a subject is unable to produce sputum spontaneously and independently, sputum induction 
may be performed by appropriately qualified site staff to obtain one induced sputum 
specimen. Please refer to Appendix 3. If a subject is still unable to produce sputum despite 
reasonable efforts at any visit post-Baseline, this will be considered as a negative culture 
result at that timepoint. Sterile, leak proof, non-wax, disposable plastic containers will be 
used to collect specimens. Detailed instructions will be provided by site staff to subjects on 
how to collect and handle samples aseptically to avoid contamination. Subjects will also be 
instructed to keep sputum samples refrigerated, not frozen, until ready to transport to the site. 
Upon receipt at the site, samples should be kept refrigerated until ready to ship to the central 
specialty microbiology lab. Shipping should occur within approximately 2 days of receipt 
from subject to avoid overgrowth by contaminating normal flora. No fixative or preservatives 
are to be used with sputum samples. Detailed instructions for collecting, processing, and 
shipping sputum specimens will be provided in the Central Laboratory Manual. 
The Central Specialty Microbiology Lab will process the sputum specimens. Acid fast bacilli 
smear testing from sputum will be performed on all specimens received. Specimens will be 
further cultured in both solid and liquid media and identification of genus and species will be 
performed, to the subspecies level for M. abscessus. Results confirming M. abscessus 
infection will be used to verify subject eligibility during Screening. 
In vitro susceptibility testing of antimicrobial drugs that may be used to treat M. abscessus 
pulmonary infection will be performed, and molecular characterization for select drug 
resistance markers will be performed. Susceptibility results will not be reported to site 
personnel during the study. 
8.11 Serum and Plasma Collection for Biomarkers (optional)  
Serum and plasma for biomarkers will be collected and stored at a central laboratory for 
future use for all subjects who provide consent for this optional portion of the study.  
Samples may be stored for a period of up to 2 years after the completion (termination) of the 
study, or longer, to see if there may be indicators associated with NTM lung infections and 


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for other exploratory analyses. Genetic testing or analysis will not be performed on any 
samples collected.  
8.12 NTM Symptom Assessment Questionnaire  
The NTM Symptom Assessment Questionnaire is a tool created by Paratek to evaluate 
efficacy based on individual subject assessment of symptoms. It is a self-administered 
questionnaire that evaluates a list of 12 common NTM symptoms, asking subjects if they 
have experienced each symptom within the past 7 days. Responses are provided using a 
4-point scale (absent, mild, moderate, severe) and should reflect the subject’s perceived 
overall impression of their symptoms over the past 7 days. This questionnaire is completed 
by the subject without interpretation of the subject’s response by a clinician or site staff. 
In addition, at Screening, subjects will be asked to list up to 3 of their most bothersome 
symptoms.  
The NTM Symptom Assessment Questionnaire will be completed at Screening, 
Baseline/Day 1 (prior to first dose of test article), and the Day 28, Day 56, and Day 84/EOT 
Visits. Responses at Screening and Baseline/Day 1 will be used to determine eligibility. 
8.13 Other Patient-Reported Outcomes and Clinician-Assessed Outcomes  
Patient-reported outcomes are being utilized in this study to help understand and assess the 
subject’s health, quality of life or functional status associated with the disease under study 
and treatment received. The PROs are completed by the subject without interpretation of the 
subject’s response by a clinician or site staff but should be reviewed for completeness and to 
assess potential AE information. 
All PROs described below will be completed the Day 28, Day 56, and Day 84/EOT visits. In 
addition, the QOL-B, SGRQ, and PROMIS Fatigue will be collected at Day 1/Baseline visit 
(prior to first dose of test article). 
8.13.1 
Quality of Life – Bronchiectasis  
The QOL-B is a self-administered, patient-reported outcome measure assessing symptoms, 
functioning and health-related quality of life for patients with non-cystic fibrosis 
bronchiectasis using a series of 37 questions.  
8.13.2 
St. Georges Respiratory Questionnaire  
The SGRQ is a self-administered questionnaire that assesses health-related quality of life in 
subjects with chronic pulmonary disease by evaluating 3 health domains:  
 symptoms (distress caused by respiratory symptoms) 
 activity (effects of disturbances to mobility and physical activity) 
 impacts (the effect of disease on factors such as employment, personal control of 
one’s health, and need for medication)  


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8.13.3 
Patient-Reported Outcomes Measurement Information System Short Form 
v1.0 – Fatigue 7a Daily  
The PROMIS Fatigue is a self-administered questionnaire that assesses fatigue and its impact 
on physical, mental, and social activities. The fatigue short form is universal rather than 
disease-specific and assesses fatigue over the past 7 days. 
8.13.4 
Patient Clinical Impression of Severity  
The PGI-S is a self-administered, single question assessed using a 7-point scale that measures 
a subject’s perception of disease severity. 
8.13.5 
Patient Clinical Impression of Change  
The PGI-C is a self-administered, single question assessed using a 7-point scale that 
measures a subject’s perceived change in clinical status and overall improvement. 
8.13.6 
Clinical Global Impression – Severity of Illness  
The CGI-S is administered by an experienced clinician who is familiar with the disease under 
study. The CGI-S is a 1-item observer-rated scale that rates illness severity based upon 
observed and reported symptoms, behavior, and function over the past seven days. 
8.13.7 
Clinical Global Impression – Improvement  
The CGI-I is administered by an experienced clinician who is familiar with the disease under 
study and who can make an expert judgment about the total picture of the subject at each 
visit. The CGI-I is a 1-item observer-rated scale that rates total subject improvement 
compared to baseline and whether or not, per clinical judgment, it is due entirely to drug 
treatment.  
8.14 Adverse Events  
An AE is any untoward, undesired, or unplanned event in the form of signs, symptoms, 
disease, or laboratory or physiologic observations occurring in a person given a test article or 
in a clinical study. The event does not need to be causally related to the test article or clinical 
study. An AE includes, but is not limited to, the following: 
 Any clinically significant worsening of a preexisting condition. 
 An AE occurring from overdose of a test article, whether accidental or intentional. 
Overdose is a dose greater than that specified in the protocol. 
 An AE occurring from abuse (eg, use for nonclinical reasons) of a test article. 
 An AE that has been associated with the discontinuation of the use of a test article. 
 


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8.15 Serious Adverse Events  
An SAE is an AE that: 
 Results in death. 
 Is life-threatening (see below). 
 Requires hospitalization or prolongation of an existing hospitalization (see below). 
 Results in a persistent or significant disability or incapacity (see below). 
 Results in a congenital anomaly or birth defect. 
 Additionally, important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered SAEs when, based on 
appropriate medical judgment, the event may jeopardize the subject and may require 
medical or surgical intervention to prevent any one of the outcomes listed above in 
this definition. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 
An AE is considered “life-threatening” if, in the view of the investigator or sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an AE that, had 
it occurred in a more severe form, might have caused death. For example, hepatitis that 
resolved without evidence of hepatic failure would not be considered life-threatening, even 
though hepatitis of a more severe nature can be fatal. Similarly, an allergic reaction resulting 
in angioedema of the face would not be life-threatening, even though angioedema of the 
larynx, allergic bronchospasm, or anaphylaxis can be fatal. 
Hospitalization is official admission to a hospital. Hospitalization or prolongation of a 
hospitalization constitutes criteria for an AE to be serious; however, it is not in itself 
considered an SAE. In the absence of an AE, a hospitalization or prolongation of a 
hospitalization should not be reported as an SAE by the participating investigator. This is the 
case in the following situations: 
 The hospitalization or prolongation of hospitalization is needed for a procedure 
required by the protocol. 
 The hospitalization or prolongation of hospitalization is part of a routine procedure 
followed by the center (eg, stent removal after surgery). This should be recorded in 
the study file. 
 A hospitalization for a preexisting condition that has not worsened.  
 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
If there is any doubt about whether the information constitutes an SAE, the information is 
treated as an SAE. 


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8.16 Other Reportable Information  
Certain information, although not considered an SAE, must be recorded, reported, and 
followed up as indicated for an SAE. This includes: 
 Pregnancy exposure to a test article:  If a pregnancy is confirmed, use of the test 
article must be discontinued immediately. Information about pregnancy exposure 
includes the entire course of pregnancy and delivery, and perinatal and neonatal 
outcomes, even if there are no abnormal findings. Both maternal and paternal 
exposures are considered other reportable information. For exposure involving the 
female partner of a male subject, the necessary information must be collected from 
the subject, while respecting the confidentiality of the partner. 
 Lactation exposure to a test article with or without an AE. 
 Overdose of a test article as specified in this protocol with or without an AE. 
 Inadvertent or accidental exposure to a test article with or without an AE. 
 
8.17 Overdose  
Any administration of omadacycline of greater than 600 mg within a 24-hour period will be 
an overdose, regardless of whether the overdose is intentional or accidental. It is a reportable 
event and the sponsor must be notified within 1 business day. 
The physician managing the overdose may order any test he/she thinks is necessary to 
manage the subject properly. 
8.18 Medication Errors  
Medication errors are the result of administration or consumption of the wrong product, by 
the wrong subject, at the wrong time, and/or by the wrong administration route, due to human 
error. 
Medication errors include, but are not limited to, the following: 
 The administration and/or consumption of test article that has not been assigned to the 
subject 
 Administration of expired test article 
 
All AEs and SAEs must be handled as specified in this protocol whether or not they are 
associated with a medication error. A medication error associated with an SAE (including 
overdose, inadvertent exposure, and/or accidental exposure) will be reported with the SAE on 
the SAE Report Form. All other medication errors will be reported by e-mailing the Clinical 
Test Article Error Incident Report Form to clinicalsafety@propharmagroup.com. 


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8.19 Recording and Reporting  
A subject’s AEs and SAEs will be recorded and reported from the signing of the ICF to the 
time of the Follow-up assessment. The investigator must instruct the subject to report AEs 
and SAEs during this time period. Reports of death after the last study contact with the 
subject will be reported to the sponsor and additional information relative to the cause of 
death will be sought and documented. 
All AEs and SAEs must be recorded on source documents. All AEs and SAEs for subjects 
who receive a treatment assignment will be recorded in the eCRFs. 
The investigator must follow up as medically necessary on all AEs and SAEs until the events 
have subsided, the condition has returned to Baseline, or in case of permanent impairment, 
until the condition stabilizes. 
Adverse events should be based on the signs or symptoms detected during the physical 
examination and on clinical evaluation of the subject. In addition to the information obtained 
from those sources, the subject should be asked the following nonspecific question:  “How 
have you been feeling since your last visit?” Whenever possible, AEs should be reported as a 
diagnosis rather than individual signs and symptoms. If a definitive diagnosis is not possible, 
the individual signs and symptoms should be recorded using standard medical terminology. 
If an AE requires a surgical or diagnostic procedure, the illness leading to the procedure 
should be recorded as the AE, not the procedure itself. 
Death should be recorded in the eCRF as an outcome of an AE. Any unanticipated risks to 
the subjects must be reported promptly to the IRB/IEC/REB.  
8.19.1 
Serious Adverse Event Reporting  
All SAEs and follow-up information must be reported within 1 business day or 24 hours as 
required by local regulations by emailing a completed SAE Report to the email address 
below.  
E-Mail: 
8.19.2 
Assessment of Relatedness  
The investigator will assess causality (ie, whether there is a reasonable possibility that test 
article caused the event) for all AEs and SAEs. The relationship will be characterized using 
the following classification: 
 Not Related:  This relationship suggests that there is no association between test 
article and the reported event. The event can be explained by other factors such as an 
underlying medical condition, concomitant therapy, or accident, and no plausible 
temporal or biologic relationship exists between test article and the event. 
 Related:  This relationship suggests that a definite causal relationship exists between 
test article administration and the AE, or there is a reasonable possibility that the 


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event was caused by the test article, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not 
appear to explain the event. 
Adverse events and SAEs also will be assessed for their potential relationship to the protocol. 
A protocol-related AE is one that is not related to the test article but is considered by the 
investigator or the medical monitor (or designee) to be related to the research conditions, ie, 
related to the fact that a subject is participating in the study. For example, a protocol-related 
AE may be an untoward event related to a medical procedure required by the protocol. 
8.19.3 
Assessment of Severity  
The severity (or intensity) of an AE will be classified using the following criteria: 
 Mild:  These events are usually transient, require minimal or no treatment, and do not 
interfere with the subject’s daily activities. 
 Moderate:  These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with normal 
functioning but pose no significant or permanent risk of harm. 
 Severe:  These events interrupt a subject’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually incapacitating. 
 
Changes in the severity of an AE should be documented as a new event to allow an 
assessment of the duration of the event at each level of intensity to be performed. 
8.19.4 
Laboratory Findings  
Protocol-defined safety laboratory test results will be analyzed as part of specific laboratory 
safety analyses. Additional laboratory test results at other timepoints may be available to the 
investigator as part of standard clinical practice. Throughout the study, laboratory-related 
abnormalities should be recorded as AEs only if considered clinically significant, outside the 
range of expected values given the subject’s Baseline assessments and clinical course, and 
not known to be part of another AE diagnosis. 
8.19.5 
Worsening or Progression of Disease Under Study  
Worsening or progression of NTM pulmonary disease caused by Mycobacterium abscessus 
including worsening of baseline symptoms, should not be recorded as an AE unless the 
worsening/progression also meets the criteria for a serious AE (in which case the event also 
should be reported as an SAE). If worsening or progression of disease under study requires 
additional antibiotic therapy, subject will be discontinued from test article and this reason for 
discontinuation will be recorded in the eCRF.  
8.19.6 
Pregnancies  
To ensure subject safety, each pregnancy in a subject on test article must be reported to the 
sponsor within 1 business day of learning of its occurrence. Test article should be 
discontinued immediately, and the pregnancy should be followed up to determine outcome, 


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including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the sponsor. Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the test article of any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report 
Form. 
8.20 Concomitant Medication Assessments  
The investigator should instruct the subject to notify the study site about any new 
medications they take after the start of the test article. 
All prescription medications, over-the-counter drugs, and recreational drugs taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, 
must be recorded in the eCRF. Medication entries should be specific to trade name, the single 
dose and unit, the frequency and route of administration, the start and discontinuation dates 
or indication that the medication continues, and the reason for therapy.  
8.21 Subject Discontinuation or Withdrawal  
Reasons why a subject may discontinue or be withdrawn from the study include, but are not 
limited to, AE, worsening of disease under study, lost to follow up, withdrawal by subject, 
physician decision, death, and other (specify reason eg, subject non-compliance or study 
termination by the sponsor). Subjects may voluntarily withdraw from the study for any 
reason at any time. Subjects are considered withdrawn from the study if they state an 
intention to withdraw, or fail to return for visits, or become lost to follow up for any other 
reason. In the event a subject is lost to follow-up, every possible effort should be made to 
contact the subject and determine the reason for discontinuation as local law permits. The 
due diligence measures taken must be documented in the subject’s source documents. If 
premature withdrawal from the study occurs, the investigator should determine the primary 
reason for a subject’s premature withdrawal from the study and record the date and primary 
reason on the eCRF. Subjects who discontinue study treatment prematurely should complete 
the EOT visit and Safety Follow-up assessment, if possible (see Schedule of Assessments – 
Appendix 1). Exceptions to this include subjects who withdraw consent or are considered lost 
to follow-up after appropriate due diligence measures have been taken. 
Site personnel must also contact the IxRS to register the subject’s discontinuation from test 
article. 
For subjects who are lost to follow up, the investigator should show “due diligence” by 
documenting in the source documents the steps taken to contact the subject (eg, dates of 
telephone calls, registered letters, etc). 


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9 STUDY ACTIVITIES  
9.1 
Screening Period  
Screening procedures (as detailed in Appendix 1) may begin once informed consent is 
obtained and will be used to establish subject eligibility and baseline characteristics for each 
subject. The Screening period for this study is up to 8 weeks to allow sufficient time for 
collection and analysis of sputum specimens. Subjects may be randomized as soon as all 
screening procedures have been performed and results have been received to verify eligibility 
criteria. 
9.2 
Double-blind Treatment Period  
The double-blind treatment period is approximately 3 months (84 days) in duration. Subjects 
who meet all of the inclusion criteria and none of the exclusion criteria may be randomized. 
In-clinic visits will occur at Baseline/Day 1, Day 28 (± 3 days), Day 56 (± 3 days), and 
Day 84/EOT (+ 5 days /- 2 days). 
A tele-visit (phone call or virtual) will occur at Day 14 (± 2 days) to assess safety via review 
of AEs and concomitant medications.  
9.3 
Follow-up Period  
9.3.1 
30-Day Safety Follow-up Call  
The Follow-up assessment should be conducted 30 to 37 days following the subject’s last 
dose of test article to assess safety via review of AEs and concomitant medications. This 
evaluation should also be conducted for any prematurely withdrawn subject except for 
subjects who withdraw consent or are lost to follow up. The Follow-up assessment may be 
conducted via telephone or at the investigator’s discretion, the safety follow-up can be an 
office visit. 
 


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10 STUDY SUSPENSION, TERMINATION, AND COMPLETION  
10.1 Study Completion and Post-study Test Article  
A subject will have successfully completed the study after the planned test article regimen 
has been administered, and all assessments and visits have been performed up through the 
final Follow-up assessment. The study will be completed when the last subject has either 
discontinued or completed the Follow-up assessment. 
No long-term follow up of subjects is planned, with the exception of pregnancies, as 
described in Section 8.19.6, and SAEs described in Section 8.15. 
Sites will be notified by either the sponsor or IxRS to stop enrollment when the desired 
number of treated subjects have been enrolled. Subjects already consented, but not yet 
randomized, will be allowed to continue screening procedures. 
Upon study completion, the investigator will provide the sponsor, IRB/IEC/REB, and 
regulatory agency with final reports and summaries as required by regulations. The 
investigator must submit a written report to the sponsor and the IRB/IEC/REB within 
3 months after the completion or termination of the study. 
10.2 Study Suspension or Termination  
The sponsor may suspend or terminate the study or part of the study at any time for any 
reason. Should termination be necessary, subjects should be seen as soon as possible and 
treated as described in Section 8.21 for prematurely withdrawn subjects. The investigator 
may be informed of additional procedures to be followed to ensure that adequate 
consideration is given to the protection of the subject’s interests. The investigator will be 
responsible for informing IRBs and/or Ethics Committees of the early termination of the 
study. 
If the investigator suspends or prematurely terminates their participation in the study, the 
investigator will promptly inform the sponsor and the IRB/IEC/REB and provide them with a 
detailed written explanation. Subjects should be seen as soon as possible and treated as 
described in Section 8.21 for prematurely withdrawn subjects. The investigator will also 
return all test articles, containers, and other study materials to the sponsor. 


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11 QUALITY CONTROL AND ASSURANCE  
The sponsor performs quality control and assurance checks on all clinical studies that it 
sponsors. Before enrolling any subjects in this study, sponsor personnel and the investigator 
review the protocol, the Investigator’s Brochure, the case report forms and instructions for 
their completion, the procedure for obtaining informed consent, and the procedure for 
reporting AEs and SAEs. A qualified representative of the sponsor monitors the conduct of 
the study by visiting the site and/or by contacting the site by telephone and e-mail. During 
these site visits/meetings, information recorded in the case report forms is verified against 
source documents. 


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12 PLANNED STATISTICAL METHODS  
12.1 General Considerations  
All analyses of data for this study will comply with International Council on Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use 
(ICH-E9) and the sponsor’s guidance documents and standards. Statistical analyses will be 
performed using Statistical Analysis Software (SAS®). 
The statistical analysis plan (SAP) incorporating the sections below, along with mock tables, 
figures, and listings shells, will be prepared, approved, and finalized by the sponsor prior to 
database lock. This plan will define populations for analysis, outline all data handling 
conventions, and specify statistical methods to be used for analysis of safety and efficacy. 
Descriptive statistics, including the numbers and percentages for categorical variables, and 
the numbers, means, standard deviation, medians, minimums, and maximums for continuous 
variables will be provided. Exploratory analyses may also be performed. Listings of 
individual subject’s data will be produced. 
All eCRFs must be completed, entered, and source-data verified; all safety and microbiology 
laboratory results must have been reported; all AEs must have been fully characterized (eg, 
relationship to test article determined) and coded; and all queries must have been resolved 
prior to database lock and unblinding. Determination of inclusion in the analysis populations, 
characterization of protocol deviations as major/minor, and final approval of the SAP will 
also be completed prior to database lock. 
12.2 Determination of Sample Size  
As the study is exploratory with respect to determination of efficacy, the sample size 
determination is provided to better ensure sufficient subjects are enrolled to provide an initial 
assessment of efficacy rather than test a specific hypothesis. A sample size of 75 subjects will 
provide approximately 80% power to detect an absolute treatment difference of 30% in 
clinical response rate at Day 84, based on clinical response rates of 15% and 45% in the 
placebo and omadacycline treatment groups respectively, using a Mantel-Haenszel test with 
2-sided alpha level of 0.05. 
12.3 Analysis Populations  
The following subject analysis sets have been defined: 
 Intent-to-treat (ITT) Analysis Set includes all randomized subjects. 
 Per-Protocol Analysis Set includes all randomized subjects who received at least 
1 dose of test article and completed the study without major protocol deviations that 
affect the assessment of efficacy. 
 Safety Analysis Set includes all subjects who received at least 1 dose of test article. 


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12.4 Demographics, Baseline Characteristics, and Subject Disposition  
Demographics (including age, gender, ethnicity, and race) and baseline characteristics will be 
summarized in the ITT Analysis Set by treatment group.  
Descriptive statistics of the duration of test article treatment will be provided by treatment 
group in the ITT and Safety Analysis Sets. The number and percentage of subjects who 
prematurely discontinued test article and the reason for discontinuation as well as the number 
and percentage of subjects prematurely discontinuing the study and the primary reason for 
discontinuation will be presented by treatment group in the ITT Analysis Set. 
12.5 Efficacy Endpoint(s)  
The study is exploratory with respect to efficacy determination. Efficacy will be evaluated 
based on endpoints defined by subject-reported NTM symptoms, subject-reported outcomes 
and quality of life measures, and microbiologic assessment. Additional endpoints to assess 
efficacy will be defined in the SAP. Nominal p-values will be provided as descriptive 
statistics. 
12.5.1 
Primary Efficacy Endpoints  
The primary determination of efficacy is based on subject assessment of symptoms. Several 
definitions of clinical response will be defined, including but not limited to those listed in 
Section 4; all definitions will be provided in the SAP.  
For each definition, the number and percentage of subjects with a clinical response and no 
clinical response will be summarized by treatment group in the ITT Analysis Set. Exact 
2-sided 95% confidence intervals (CIs) for the point estimates of the clinical response rates in 
each treatment group will be determined using the Clopper-Pearson method. The odds ratio 
(omadacycline relative to placebo) and p-value will be calculated using Cochran-Mantel-
Haenszel test, stratified by prior antibiotic use. The estimand attributes for clinical response 
will be provided in detail in the SAP. In general, clinical response will use both a treatment 
and composite policy strategy for handling intercurrent events. Subjects who receive 
alternative antibiotic therapy for treatment of the NTM infection and/or die before reaching 
Day 84 will be considered as not achieving clinical response. Subjects with missing data due 
to withdrawal of consent will also be considered as not achieving clinical response. 
Analyses will be repeated in the Per-Protocol Analysis Set as detailed in the SAP. 
12.5.2 
Secondary Efficacy Endpoints  
12.5.2.1 
Patient-Reported Outcomes and Quality of Life  
For each patient-reported outcome and quality of life endpoint, analyses will be conducted in 
the ITT Analysis Set. Available data will be used; there will be no substitutions for missing 
data. 


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The QOL-B includes domains for physical functioning, role functioning, vitality, emotional 
functioning, social functioning, treatment burden, health perceptions and respiratory 
symptoms. For each domain, scores will be standardized on a 0 to 100 scale. Descriptive 
statistics for each domain at baseline and each visit will be presented by treatment group. The 
change from baseline to each visit will be analyzed using an analysis of covariance 
(ANCOVA) and the least squares (LS) mean, standard error (SE) of the LS mean and 2-sided 
95% CI for the LS mean will be provided for each treatment group. The difference in LS 
means between treatment groups, 2-sided 95% CI and p-value will also be provided. 
For the SGRQ, the global score and score for each component (symptoms, activity, and 
impacts) will be determined. Descriptive statistics for the global score and each component 
score at each visit will be presented by treatment group. The change from baseline to each 
visit will be analyzed using an ANCOVA, and the LS mean, and 2-sided 95% CI for the LS 
mean will be provided for each treatment group. The difference in LS means between 
treatment groups, 2-sided 95% CI and p-value will also be provided. 
For the PROMIS Fatigue 7a Short Form, raw scores are converted to a standardized score. 
Descriptive statistics for the standardized score at baseline and each visit will be presented by 
treatment group. The change from baseline to each visit will be analyzed using an ANCOVA, 
and the LS mean, SE of the LS mean, and 95% CI for the LS mean will be provided for each 
treatment group. The difference in LS means between treatment groups, 95% CI and p-value 
will also be provided. 
For the PGI-S, the number and percentage of subjects with each response will be presented 
by visit and treatment group. The PGI-S will also be categorized as mild/not present vs. 
moderate/severe and the number and percentage of subjects in each category will be 
presented by visit and treatment group. Exact 2-sided 95% CIs using the Clopper-Pearson 
method for the percent improved and a p-value from Fisher’s exact test will be provided. 
For the PGI-C, the number and percentage of subjects with each response will be presented 
by visit and treatment group. The PGI-C will also be categorized as improved vs. no 
change/worse and the number and percentage of subjects in each category will be presented 
by visit and treatment group. Exact 2-sided 95% CIs using the Clopper-Pearson method for 
the percent improved and a p-value from Fisher’s exact test will be provided. 
Descriptive statistics for severity of illness from the CGI change from baseline for each visit 
will be presented by treatment group. Descriptive statistics of the global improvement and 
the efficacy index from the CGI will also be provided by treatment group for each visit. A 
p-value from the Wilcoxon rank sum test for each outcome will also be presented. 
At each visit based on the NTM Symptom Assessment Questionnaire, the number and 
percentage of subjects with a new symptom (compared with baseline) with severity worse 
than mild and no new symptoms with a severity worse than mild will be summarized by 
treatment group. Shift tables from baseline for each symptom at each visit will also be 
provided. 


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12.5.2.2 
Microbiological Response  
The number and percentage of subjects with a decrease in the mycobacterial load will be 
determined by treatment group at Day 84 in the ITT Analysis Set. Exact 2-sided 95% CIs for 
the point estimate of the percentage of subjects of subjects with a decrease in mycobacterial 
load in each treatment group will be determined using the Clopper-Pearson method. The odds 
ratio (omadacycline relative to placebo) and p-value will be calculated using 
Cochran-Mantel-Haenszel test, stratified by prior antibiotic use. 
Kaplan-Meier methods will be utilized to determine the time to growth in liquid media only 
and time to first negative sputum culture in the ITT Analysis Set. Time to growth in liquid 
medium only will be defined as the number of days from the date of test article 
administration to the date of the first assessment where growth is detected in liquid medium 
only. Time to first negative sputum culture is defined as the number of days from the date of 
test article administration to the date of the first negative sputum culture. Subjects who died, 
withdrew, or took alternative antibiotic therapy for treatment of the NTM infection prior to 
growth in liquid medium only or negative sputum will be censored at the date of the death, 
study withdrawal, or the start date of the alternative antibiotic therapy respectively. The 
median, 25th and 75th percentile for time to growth in liquid media and time to first negative 
sputum culture will be provided with 2-sided 95% CIs. A p-value will be determined using a 
log-rank test. 
12.6 Safety Endpoint(s)  
All safety data will be analyzed in the Safety Analysis Set. Adverse events will be coded 
using the Medical Dictionary of Regulatory Activities. The incidence of treatment-emergent 
adverse events will be presented by system organ class (SOC) and preferred term (PT), by 
SOC, PT and relationship to test article, and by SOC, PT and severity. Serious AEs and 
treatment-emergent adverse events that lead to discontinuation of the test article will also be 
presented by SOC and PT. Descriptive statistics for clinical laboratory, vital signs, and ECG 
parameters, including change from baseline, will be presented by timepoint collected and for 
the overall most abnormal post-baseline value (for clinical laboratory and vitals sign 
parameters). Incidences of potentially clinically significant clinical laboratory results, vital 
signs and ECG parameters as defined in the SAP, will also be summarized by timepoint 
collected and the overall most abnormal post-baseline value (for clinical laboratory and vital 
sign parameters). 
12.7 Data Monitoring Committee  
Given the exploratory nature of this Phase 2 study using a product with a well-established 
safety profile, a data monitoring committee will not be utilized for this study.  


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13 ADMINISTRATIVE CONSIDERATIONS  
13.1 Investigators and Study Administrative Structure  
The investigator will permit study-related monitoring, audits, IRB/IEC/REB review, and 
regulatory inspections by providing direct access to source data and documents. 
All information will be recorded on source documents. All required data will be recorded in 
the eCRFs. 
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the 
investigator must notify the sponsor to agree upon an acceptable solution including but not 
limited to storage for all study-related documents. Regulatory agencies will be notified with 
the appropriate documentation. 
An updated Form FDA 1572 will be filed with the sponsor for any changes in the study 
personnel reported in the current Form FDA 1572. 
13.2 Institutional Review Board or Independent Ethics Committee Approval  
The protocol and the proposed ICF must be reviewed and approved by a properly constituted 
IRB/IEC/REB before study start. A signed and dated statement that the protocol and ICF 
have been approved by the IRB/IEC/REB must be given to the sponsor before study 
initiation. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and 
all of the instructions and procedures found in this protocol and to give access to all relevant 
data and records to the sponsor, monitors, auditors, designated agents of the sponsor, 
IRBs/IECs/REBs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform the sponsor immediately 
that this request has been made. 
13.3 Ethical Conduct of the Study  
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable 
local regulations (including European Directive 2001/20/EC, US 21 Code of Federal 
Regulations, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.4 Patient Information and Consent  
The investigator will provide for the protection of the subjects by following all applicable 
regulations. These regulations are available upon request from the sponsor. The ICF must be 
reviewed by the sponsor and approved by the IRB/IEC/REB. 


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Before any procedures specified in the protocol are performed, a subject must: 
 Be informed of all pertinent aspects of the study and all elements of informed 
consent; 
 Be given time to ask questions and time to consider the decision to participate; 
 Voluntarily agree to participate in the study; 
 Sign and date an IRB/IEC/REB approved-ICF. 
 
13.5 Direct Access, Data Handling, and Record Keeping  
13.5.1 
Investigator  
The investigator will permit study-related monitoring, audits, IRB/IEC/REB review, and 
regulatory inspections by providing direct access to source data and documents. 
All information will be recorded on source documents. All required data will be recorded in 
the eCRFs. 
13.5.2 
Sponsor  
The data are entered into an electronic database via eCRFs. The sponsor medical monitor 
reviews the data for safety information. The data are reviewed for completeness and logical 
consistency. Automated validation checks identify missing data, out-of-range data, and other 
data inconsistencies. The central safety and microbiology data will be processed 
electronically. Requests for data clarification are forwarded to the study site for resolution. 
13.6 Protocol Adherence  
13.6.1 
Violations/Deviations  
Investigators will agree to apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact the sponsor or its agents to request approval of 
a prospective protocol deviation, as no authorized deviations are permitted. If the investigator 
feels a protocol deviation would improve the conduct of the study this must be considered a 
protocol amendment and it cannot be implemented unless such an amendment is agreed upon 
by the sponsor and approved by the IRB/IEC/REB. All significant protocol deviations will be 
recorded and reported in the Clinical Study Report. 
13.6.2 
Protocol Amendments  
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by the sponsor, Health Authorities where required, and the 
IRB/IEC/REB. Only amendments that are required for subject safety may be implemented 
prior to IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any subject included in this study, even if this action represents a deviation from the 


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protocol. In such cases, the sponsor should be notified of this action and the IRB/IEC/REB at 
the study site should be informed within 10 working days. 
13.7 Subject Injury  
In general, subject to specific provisions in the clinical study agreement (CSA), if a subject is 
injured as a direct result of a test article, the sponsor will pay for reasonable and necessary 
medical treatment for the injury, to the extent that such expenses are not covered by the 
subject’s medical insurance, a government program, or other responsible third party. If laws 
or regulations of the locality in which the study is taking place require additional payment of 
expenses, the sponsor shall comply with such laws or regulations. Where applicable, the 
sponsor has taken specific national insurance. 
13.8 Pre-study Documentation  
The investigator must provide the sponsor with the following documents before enrolling any 
subjects: 
 Completed and signed Form FDA 1572 or equivalent. 
 All applicable country-specific regulatory forms. 
 Current signed and dated curricula vitae and medical license (as applicable) for the 
investigator, sub-investigators, and other individuals having significant investigator 
responsibility who are listed on the Form FDA 1572 or equivalent, or the clinical 
study information form. 
 Copy of the IRB/IEC/REB approval letter for the protocol and informed consent. All 
advertising, recruitment, and other written information provided to the subject must 
be approved by the IRB/IEC/REB. Written assurance of continuing approval (at least 
annually) as well as a copy of the annual progress report submitted to the 
IRB/IEC/REB must also be provided to the sponsor. 
 Copy of the IRB/IEC/REB-approved informed consent document to be used. 
 Where applicable, a list of the IRB/IEC/REB members and their qualifications, and a 
description of the committee’s working procedure. 
 Copy of the protocol sign-off page signed by the investigator. 
 Fully executed CSA. 
 Where applicable, a financial disclosure form. 
 A written document containing the name, location, certification number, and date of 
certification of the laboratories to be used for laboratory assays and those of other 
facilities conducting tests. This document should be returned along with the statement 
of investigator form. The sponsor must be notified if the laboratory is changed or if 
any additional laboratory is to be used.  
 List of normal laboratory values and units of measure for all laboratory tests required 
by the protocol. This is required for each laboratory to be used during the study. The 
sponsor must be notified if normal values or units of measurement change. 
 


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13.9 Retention of Data  
The investigator shall retain and preserve 1 copy of all data generated in the course of the 
study, specifically including but not limited to those defined by GCP as essential, for the 
longer of: (a) 2 years after the last marketing authorization for the investigational test article 
has been approved or the sponsor has discontinued its research with respect to such 
investigational test article or (b) such longer period as required by applicable global 
regulatory requirements. At the end of such period, the investigator shall notify the sponsor 
in writing of its intent to destroy all such material. The sponsor shall have 30 days to respond 
to the investigator’s notice, and the sponsor shall have a further opportunity to retain such 
materials at the sponsor’s expense. 
13.10 Publication and Disclosure Policy  
The sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report, the results of this study will be submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
Upon completion of the study, the investigator may publish the results in recognized 
(refereed) scientific journals subject to the provisions of the CSA. Unless otherwise specified 
in the CSA, the following process shall occur: 
The institution and principal investigator (PI) shall not publish or present data from an 
individual study center until the complete multi-center study has been presented in full or for 
2 years after the termination of the multi-center study, whichever occurs first. Subsequent 
publications must refer to the multi-center findings. Thereafter, if the PI expects to 
participate in the publication of data generated from this site, the institution and PI shall 
submit reports, abstracts, manuscripts, and/or other presentation materials to the sponsor for 
review before submission for publication or presentation. The sponsor shall have 60 days to 
respond with any requested revisions, including, without limitation, the deletion of 
confidential information. The PI shall act in good faith upon requested revisions, except that 
the PI shall delete any confidential information from such proposed publication. The PI shall 
delay submission of such publication or presentation materials for up to an additional 90 days 
to have a patent application(s) filed. 


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14 REFERENCE LIST  
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Diagnosed Focal Segmental Glomerulosclerosis. Cureus. 2019;11(8):e5347. 
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mycobacterial lung disease. J Formos Med Assoc. 2020;119(Suppl 1):S42-S50. 
Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the 
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Maggioncalda EC, Story-Roller E, Mylius J, et al. A mouse model of pulmonary 
Mycobacteroides abscessus infection. Nature Scientific Reports. 2020;10:3690. 
Minhas R, Sharma S, Kundu S. Utilizing the Promise of Omadacycline in a Resistant, Non-
tubercular Mycobacterial Pulmonary Infection. Cureus. 2019;11(7):e5112. 
Morrisette T, Alosaimy S, Philley JV, et al. Preliminary, Real-World, Multicenter Experience 
with Omadacycline for Mycobacterium abscessus. OFID. 2021;8(2):ofab002. 
Paratek Pharmaceuticals, LLC. 2020. Omadacycline/PTK 0796 Investigator's Brochure, 
Edition 12.0. 
Pearson JC, Dionne B, Richterman A et al. Omadacycline for the Treatment of 
Mycobacterium abscessus Disease: A Case Series. OFID. 2020;7(10):ofaa415. 
Prevots DR, Marras TK. Epidemiology of human pulmonary infection with nontuberculous 
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Prevots DR, Shaw PA, Strickland D, et al. Nontuberculous mycobacterial lung disease 
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Spaulding AB, Lai YL, Zelazny AM, Olivier KN, Kadri SS, et al. Geographic Distribution of 
Nontuberculous Mycobacterial Species Identified among Clinical Isolates in the United 
States, 2009–2013. Ann Am Thorac Soc. 2017;14(11):1655–61. 


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Story-Roller E, Maggioncalda EC, Lamichhane G. Synergistic Efficacy of β-Lactam 
Combinations against Mycobacterium abscessus Pulmonary Infection in Mice. Antimicrob 
Agents and Chemother. 2019;63(8):e00614-19. 
Strnad L, Winthrop KL. Treatment of Mycobacterium abscessus Complex. Semin Respir Crit 
Care Med. 2018;39: 362–76. 
Strollo SE, Adjemian J, Adjemian MK, et al. The Burden of Pulmonary Nontuberculous 
Mycobacterial Disease in the United States. Ann Am Thorac Soc. 2015;12(10):1458-64. 
Winthrop KL, Marras TK, Adjemian J, et al. Incidence and Prevalence of Nontuberculous 
Mycobacterial Lung Disease in a Large U.S. Managed Care Health Plan, 2008-2015. Ann 
Am Thorac Soc. 2020;17(2):178-185. 
 


Omadacycline  
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PTK0796-NTM-20203 FINAL Version 2.0; 06-Dec-2021  
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Confidential and Proprietary 
 
Page 59 of 68 
 
Schedule of Assessments 
Study Phase 
Screening 
Double-Blind Treatment 
Follow-up 
Visit Name 
Screeninga 
Day 1 
Baselineb 
Day 14 
Tele-visitc 
Day 28 
Day 56 
Day 84/EOT 
30 Day Safety 
Follow-up Calld 
Visit Window 
N/A 
N/A 
± 2d 
± 3d 
± 3d 
+5d /- 2d 
+ 7d 
Informed consente 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Medical history/current medical 
conditions 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
X 
X 
 
BMI 
X 
 
 
 
 
 
 
Serum or urine pregnancy testf 
X 
X 
 
X 
X 
X 
 
Vital signs (BP, HR, body 
temperature, and pulse oximetry)g 
X 
X 
 
X 
X 
X 
 
Hematologyh 
X 
X 
 
X 
 
X 
 
Serum chemistry 
X 
X 
 
X 
 
X 
 
Biomarkers (serum, plasma)i 
 
X 
 
 
 
X 
 
Sputum collection for 
microbiologyj 
Xk 
X 
 
X 
X 
X 
 
CT scan of chest 
Xl 
 
 
 
 
X 
 
12-lead ECG 
X 
 
 
 
 
X 
 
NTM Symptom Assessment 
Questionnaire 
X 
X 
 
X 
X 
X 
 
St. George’s Respiratory 
Questionnaire (SGRQ) 
 
X 
 
X 
X 
X 
 


Omadacycline  
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Confidential and Proprietary 
 
Page 60 of 68 
Study Phase 
Screening 
Double-Blind Treatment 
Follow-up 
Visit Name 
Screeninga 
Day 1 
Baselineb 
Day 14 
Tele-visitc 
Day 28 
Day 56 
Day 84/EOT 
30 Day Safety 
Follow-up Calld 
Visit Window 
N/A 
N/A 
± 2d 
± 3d 
± 3d 
+5d /- 2d 
+ 7d 
Quality of Life – Bronchiectasis 
(QOL-B) 
 
X 
 
X 
X 
X 
 
PROMIS-Fatigue Short Form 7a 
 
X 
 
X 
X 
X 
 
Patient Global Impression –  
Severity (PGI-S) 
 
X 
 
X 
X 
X 
 
Patient Global Impression – 
Change (PGI-C) 
 
 
 
X 
X 
X 
 
Clinical Global Impression – 
Severity of Illness (CGI-S) 
 
X 
 
X 
X 
X 
 
Clinical Global Impression - 
Global Improvement Scale (CGI-I) 
 
 
 
X 
X 
X 
 
Dispense test article 
 
X 
 
X 
X 
 
 
Test article administrationm 
 
         X                                                                                                        X 
 
Test article accountability and 
compliance 
 
 
 
X 
X 
X 
 
Adverse eventsn 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medicationso 
X 
X 
X 
X 
X 
X 
X 
β-hCG = serum β-human chorionic gonadotropin; BMI = body mass index; BP = blood pressure; CT = computed tomography; d = day(s); ECG = 
electrocardiogram; eCRF = electronic case report form; EOT = end of treatment; HR = heart rate; ICF = informed consent form; MABc = Mycobacterium 
abscessus complex; MAC = Mycobacterium avium complex; N/A = not applicable; NTM = nontuberculous mycobacterial 
a. 
Screening period may occur for up to 8 weeks prior to randomization to allow for sputum microbiology results. Screening procedures may occur on separate 
days. Subjects may be randomized as soon as all screening procedures have been performed and results have been received to verify eligibility criteria. 
b. All Day 1/Baseline Visit procedures should be completed prior to subject dosing. 
c. 
Day 14 visit will be performed remotely via telephone to assess safety. 
d. A Safety Follow-up call will be performed 30-37 days after the subject’s last dose of test article. At the investigator’s discretion, the safety follow-up can be 
an office visit. 
e. 
Written and signed ICF must be obtained before any study-related assessment is performed. 
f. 
All female subjects will have a local urine or serum pregnancy test at Screening and at the Baseline Visit. Results will be used to confirm eligibility. In 
addition, blood will be collected for a serum β-hCG pregnancy test to be sent to the Central Laboratory at the Day 28 and Day 84/EOT visits. At Day 56 


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Confidential and Proprietary 
 
Page 61 of 68 
visit, a local urine or serum β-hCG pregnancy test may be performed. If Day 56 local pregnancy test results are positive, a serum β-hCG pregnancy test will 
be sent to the Central Laboratory for confirmation. 
g. Vital signs should be captured after at least 5 minutes (+ 5 minutes) of rest while in a non-standing position (supine or sitting). Subsequent vital sign 
measurements should be captured in the same non-standing position. 
h. Hematology includes coagulation. 
i. 
Serum and plasma for biomarkers will be collected and stored for future use for all subjects who agree to provide samples during the consenting process. 
j. 
Specimens may be obtained via spontaneous sputum expectoration or sputum induction. Approximately 5 mL of sputum should be collected per sample. To 
improve the probability of obtaining a good sputum specimen, at least 2 and preferably 3 spontaneously expectorated sputum samples will be obtained from 
subjects at each timepoint. Specimens should be collected by the subject on 2 to 3 consecutive days (when possible), just prior to, and up through the day of 
the scheduled study visit. If a subject is unable to produce sputum spontaneously and independently, sputum induction may be performed by appropriately 
qualified site staff to obtain one induced sputum specimen. 
k. To be eligible for participation, subjects must have at least 1 prior positive culture for MABc in the 6 months prior to Screening, and 1 positive culture at 
Screening (note: the prior cultures and Screening cultures must be at least 30 days apart). At least 2 and preferably 3 spontaneously expectorated sputum 
samples (approximately 5 mL each) should be collected on 2 to 3 consecutive days (when possible) during the week following the subject signing informed 
consent.  
l. 
May utilize results of chest CT scan performed within 3 months prior to Screening to determine eligibility (radiographic evidence of MABc infection). If no 
CT scan was obtained within prior 3 months, CT scan to be performed at Screening. High resolution CT scan is preferred, if available. 
m. All doses will be taken orally, once daily in a fasted state. Fasting is defined as no food, antacids or multivitamins containing multivalent cations (eg, 
aluminum, magnesium, calcium, bismuth, iron, or zinc) or drink except water for at least 4 hours before dosing. After dosing, no food for 2 hours, no dairy 
products, antacids or multivitamins containing multivalent cations (eg, aluminum, magnesium, calcium, bismuth, iron, or zinc) for 4 hours. 
n. Adverse events will be reported and recorded from signing of ICF through the Follow-up call. 
o. All antibiotics administered for the subject’s MABc or MAC infection within 2 years prior to the date of informed consent will be recorded in the eCRF. All 
significant non-pharmacological therapies related to MABc infection including patient education, airway clearance technique, inspiratory muscle training 
and exercise training administered from 30 days prior to date of informed consent, and administered throughout the duration of the study through the 30-day 
follow-up period, will be recorded in the eCRF. All pharmacological therapies (regardless of indication) that have been administered from 7 days prior to the 
date of informed consent and administered throughout the duration of the study through the 30-day follow-up period, will be recorded in the eCRF. All 
significant non-pharmacological therapies not related to MABc infection administered from 7 days prior to date of informed consent, and administered 
throughout the duration of the study through the 30-day follow-up period, will be recorded in the eCRF. 
 


Omadacycline  
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Confidential and Proprietary 
 
Page 62 of 68 
 
Equations and Conversion Factors 
1. Cockcroft-Gault equation to calculate creatinine clearance (relevant to Exclusion 
Criterion number 6): 
 
(140-age [yrs]) * weight (kg) * (Z) 
Z = 1.0, if Male 
Z = 0.85, if Female 
Cr (mg/dL) * 72 
 
 
2. Corticosteroid conversions (relevant to Exclusion Criterion number 5): 
 
Approximate 
equivalent dosea 
(mg) 
Relative 
glucocorticoid 
activity 
Relative 
mineralocorticoid 
activity 
Duration of 
action (hours) 
Glucocorticods 
Short-acting 
Hydrocortisone 
20 
1 
1 
8-12 
Cortisone 
25 
0.8 
0.8 
8-12 
Intermediate-acting 
Prednisone 
5 
4 
0.8 
12-36 
Prednisolone 
5 
4 
0.8 
12-36 
Methylprednisolone 
4 
5 
Minimal 
12-36 
Triamcinolone 
4 
5 
0 
12-36 
Long-acting 
Dexamethasone 
0.75 
30 
Minimal 
36-72 
Betamethasone 
0.6 
30 
Negligible  
36-72 
Mineralocorticoids 
Fludrocortisone 
b 
10-15 
125-150 
12-36 
a 
Equivalent dose shown is for oral or IV administration. Relative potency for intra-ocular or 
intramuscular administration may vary considerably. 
b 
Glucocorticoid doses which provide a mineralocorticoid effect that is approximately equivalent to 
0.1 mg of fludrocortisone are: prednisone or prednisolone 50 mg, or hydrocortisone 20 mg. 
Source: Liu 2013 
 
 


Omadacycline  
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PTK0796-NTM-20203 FINAL Version 2.0; 06-Dec-2021  
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Confidential and Proprietary 
 
Page 63 of 68 
 
 
Sputum Induction Guidelines 
Introduction 
Collection of adequate sputum samples (approximately 5 mL) is critical. Sputum samples 
will be collected by the subject (at home) and/or at the study site. In the event the subject is 
unable to spontaneously expectorate the required volume of sputum, induction may be 
performed at the study site by qualified site staff. This guidance document is intended to 
provide recommendations for obtaining an adequate sputum sample via sputum induction. 
Recommended Equipment 
 Standard handheld nebulizer – thoroughly cleaned and disinfected 
 Sputum specimen containers with labels 
 Sputum collection tubes (provided by the Central Laboratory) 
 Hypertonic sodium chloride solution (at minimum 3%, plus 5% and 7% if needed) 
 Other clinic supplies (eg, disinfectant/germicidal/alcohol wipes, gloves, masks, 
tissues, paper towels, etc.) 
 
CONTRAINDICATIONS TO SPUTUM INDUCTION 
 This procedure should not be performed in subjects in which severe coughing may be 
harmful, such as subjects with: 
o Recent or recurrent hemoptysis 
o Acute respiratory distress 
o Acute hypoxia (SaO2 in room air of < 90%) 
o Known pneumothorax 
o Rib fractures or chest wall musculoskeletal injury 
o Unstable cardiac conditions 
o Recent eye surgery 
 
Instructions: 
Preparation 
 Subjects should be instructed not to eat at least 1 hour prior to sputum induction. 
 Subjects should be informed of the purpose of this procedure before commencing.  
 The procedure should be discussed with the subject: 
o They will experience a salty taste in their mouth 
o They may cough 
o They will likely produce lung secretions that they will need to expectorate 
o If they have pre-existing hyperreactive airways eg, asthma, they will receive 
pre-medication with an inhaled bronchodilator 
 Sputum induction should occur in a private, contained room, following clinic 
processes to ensure sterilization and prevent contamination.  
 Site staff performing induction should wear gloves and an N95 mask for the duration 
of the procedure.  


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Confidential and Proprietary 
 
Page 64 of 68 
 All collection containers should have a sputum collection label completed with 
subject identifiers (ie: subject #, visit ID, collection date and time). 
 The induction procedure should start with using lower concentrations of saline (eg, 
3%) as per the investigator’s discretion. Approximately 3-6 mL of hypertonic saline 
should be placed in the nebulizer. 
 Subjects should be sitting up or in a semi-fowler position. 
 
Nebulization 
 Nebulization time is approximately 10 minutes in total, with breaks in nebulization at 
5-minute intervals or if the patient has respiratory distress, excessive coughing. 
 Nebulization may extend to 15 minutes if the patient is in no distress and more 
sputum needs to be collected. 
 Nebulization should stop at 15 minutes total time, even if inadequate sputum is 
collected. 
 The saline concentration may be increased to a maximum of 7% per investigator 
discretion. 
 Subjects should be instructed to breathe slowly and deeply (pausing at peak 
inspiration) through the nebulizer mouthpiece inhaling the saline mist.  
 If the subject needs to expectorate during nebulization, turn off the nebulizer and 
allow the subject to expectorate into the container. 
o If a sufficient specimen is collected, procedure can stop.  
o If an insufficient volume of sputum is collected, the subject should resume the 
nebulization treatment and complete the full 15-minute duration in three 
5-min intervals.  
 Subjects should be encouraged to blow their nose as needed during the induction to 
help prevent nasal secretions from becoming mixed with the sputum specimen. 
 Upon completion, subjects should take a few deep breaths, swallow the extra saliva in 
their mouth and attempt to forcefully cough up a sputum sample into a sputum 
container. The container should be closed immediately after the appropriate volume 
of sputum (approximately 5 mL) is collected. 
 Closely monitor the subject for tolerability issues or side effects. 
 The sputum sample should be refrigerated until it is sent to the central specialty 
microbiology laboratory. 
 Please refer to the Central Laboratory Manual for further instructions on packaging 
and shipping specimens to the lab. 


Omadacycline  
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Confidential and Proprietary 
 
Page 65 of 68 
 
NTM Symptom Questionnaires 
NTM Symptom Assessment Questionnaire – Baseline (Day 1) Visit 
PART 1: 
Instructions: Please indicate if you have experienced any of the following twelve symptoms within 
the past 7 days by using the scale below (Absent, Mild, Moderate or Severe). Please rate your 
overall impression of each symptom within the past 7 days. Please circle one response for each 
symptom. 
SYMPTOM 
Cough 
ABSENT 
MILD 
MODERATE 
SEVERE 
Coughing up blood 
ABSENT 
MILD 
MODERATE 
SEVERE 
Wheezing 
ABSENT 
MILD 
MODERATE 
SEVERE 
Chest pain 
ABSENT 
MILD 
MODERATE 
SEVERE 
Throat clearing 
ABSENT 
MILD 
MODERATE 
SEVERE 
Mucus (sputum) production 
ABSENT 
MILD 
MODERATE 
SEVERE 
Shortness of breath 
ABSENT 
MILD 
MODERATE 
SEVERE 
Fatigue 
ABSENT 
MILD 
MODERATE 
SEVERE 
Fever 
ABSENT 
MILD 
MODERATE 
SEVERE 
Night sweats 
ABSENT 
MILD 
MODERATE 
SEVERE 
Poor appetite 
ABSENT 
MILD 
MODERATE 
SEVERE 
Weight loss 
ABSENT 
MILD 
MODERATE 
SEVERE 
PART 2: 
Instructions: From the list of symptoms above, please indicate up to (3) symptoms which are most 
bothersome for you by ranking in order from most bothersome (#1) to least bothersome (#3). 
 
1. ___________________________________________ 
 
 
2. ___________________________________________ 
 
3. ___________________________________________ 


O ma dac ycli ne  
Parate k  P har mace uticals, I nc. 
P T K 0 7 9 6- N T M- 2 0 2 0 3 FI N A L Versi o n 2. 0; 0 6- Dec- 2 0 2 1  
I N D # 7 5, 9 2 8 I N D # 7 3, 4 3 1 
 
C o nfi de ntial a n d Pr o prietar y  
  
Pa ge 6 6 of 6 8 
N T M  S y m pt o m  Ass ess m e nt  Q u esti o n n air e  –  All  Ot h er  Visits 
Pl e as e i n dic at e  w hic h  visit t h e  q u esti o n n air e is  b ei n g c o m pl et e d  at: 
 Scr e e ni n g 
 D a y  2 8  Visit 
 D a y  5 6  Visit 
 D a y  8 4  Visit 
 
I nstr ucti o ns:  Pl e as e i n dic at e if  y o u  h a v e  ex p eri e nc e d  a n y  of t h e f oll o wi n g tw el v e s y m pt o ms  wit hi n 
t h e  p ast  7  d a ys  b y  usi n g t h e sc al e  b el o w ( A bs e nt,  Mil d,  M o d er ate  or  S e v er e).  Pl e as e r at e  y o ur 
o v er all  i m pr essi o n  of  e ac h s y m pt o m  wit hi n t h e  p ast  7  d a ys. Pl e as e circl e  o n e r es p o ns e f or  e ac h 
s y m pt o m. 
S Y M P T O M  
C o u g h 
A B S E N T   
MIL D   
M O D E R A T E  
S E V E R E 
C o u g hi n g  u p  bl o o d 
A B S E N T   
MIL D   
M O D E R A T E  
S E V E R E 
W h e ezi n g 
A B S E N T   
MIL D   
M O D E R A T E  
S E V E R E 
C h est  p ai n 
A B S E N T   
MIL D   
M O D E R A T E  
S E V E R E 
T hr o at cl e ari n g 
A B S E N T    
MIL D   
M O D E R A T E  
S E V E R E 
M uc us (s p ut u m) 
pr o d ucti o n 
A B S E N T   
MIL D   
M O D E R A T E  
S E V E R E 
S h ort n ess  of  br e at h 
A B S E N T   
MIL D   
M O D E R A T E  
S E V E R E 
F ati g u e 
A B S E N T   
MIL D   
M O D E R A T E  
S E V E R E 
F e v er 
A B S E N T   
MIL D   
M O D E R A T E  
S E V E R E 
Ni g ht s w e ats 
A B S E N T   
MIL D   
M O D E R A T E  
S E V E R E 
P o or  a p p etit e 
A B S E N T   
MIL D   
M O D E R A T E  
S E V E R E 
W ei g ht l oss 
A B S E N T   
MIL D   
M O D E R A T E  
S E V E R E 




Omadacycline  
Paratek Pharmaceuticals, Inc. 
PTK0796-NTM-20203 FINAL Version 2.0; 06-Dec-2021  
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary 
 
Page 68 of 68 
 
Investigator’s Signature 
Study Title: 
A Phase 2, Double-Blind, Randomized, Parallel-Group, Placebo-
Controlled, Multi-Center Study to Evaluate the Efficacy, Safety, 
and Tolerability of Oral Omadacycline in Adult Subjects with 
Nontuberculous Mycobacterial (NTM) Pulmonary Disease Caused 
by Mycobacterium abscessus complex (MABc) 
Study Number: 
PTK0796-NTM-20203 
Protocol Version 2.0 
Final Date: 
 
06-Dec-2021 
 
 
I have read the protocol described above. I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  
 
 
Signed: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 
Investigator Name:___________________________________ 
Investigator Title:____________________________________  
Investigator Affiliation:_______________________________ 
Investigator Address:_________________________________ 
Investigator Phone Number:____________________________ 
 

SAP_001.pdf: 
PTK0796-NTM-20203 Statistical Analysis Plan v5.0.
Page 1/40
CONFIDENTIAL 
Statistical Analysis Plan
Paratek Pharmaceuticals
PTK0796-NTM-20203
A Phase 2, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Multi-Center 
Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Omadacycline in Adult 
Subjects with Nontuberculous Mycobacterial (NTM) Pulmonary Disease Caused by 
Mycobacterium abscessus Complex (MABc)
Protocol Version: Protocol Version 2.0 (06 December 2021)
Sponsor:
Paratek Pharmaceuticals, Inc.
1000 First Ave 
Suite 200 
King of Prussia, PA 19406
75 Park Plaza, 3rd Floor
Boston, MA 02116
Prepared by:
Syneos Health
Version
Date
Final V1.0
07 September 2022
Final V2.0
14 August 2023
Final V3.0
13 February 2024
Final V4.0
25 June 2024
Final V5.0
18 September 2024


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PTK0796-NTM-20203
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CONFIDENTIAL 
Approval
Upon review of this document, including the table, listing, and figure shells, the undersigned 
approves the statistical analysis plan. The analysis methods and data presentation are acceptable.
Signature
Date
_
________________________________
Senior Principal Biostatistician
Syneos Health
_______________
___________________________________
Consultant Statistician 
Paratek Pharmaceuticals, Inc.
_______________
________________________________
Medical Monitor
Paratek Pharmaceuticals, Inc.
_______________
__________________________________
Global Trial Leader 
Paratek Pharmaceuticals, Inc.
_______________
Electronically signed by:
Reason: I am the author
Date: Sep 18, 2024 15:49 EDT
Electronically signed by:
Reason: I am the approver
Date: Sep 18, 2024 12:51 PDT
Electronically signed by:
Reason: I am the approver
Date: Sep 18, 2024 15:56 EDT
Electronically signed by:
Reason: I am the approver
Date: Sep 19, 2024 11:03 EDT


Paratek Pharmaceuticals, Inc. 
Statistical Analysis Plan
PTK0796-NTM-20203
18-Sep-2024
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CONFIDENTIAL 
____________________________________
Microbiologist
Paratek Pharmaceuticals, Inc.
_______________
___________________________________
 
Unblinded Statistician
Paratek Pharmaceuticals, Inc.
_______________
_______________________________
 
Unblinded Microbiologist 
Paratek Pharmaceuticals, Inc.
_______________
________________________________
VP, Clinical and Medical Operations
Paratek Pharmaceuticals, Inc.
_______________
Electronically signed by:
Reason: I am the approver
Date: Sep 18, 2024 15:58 EDT
Electronically signed by: 
Reason: I am the approver
Date: Sep 19, 2024 08:51 EDT
Electronically signed by:
Reason: I am the approver
Date: Sep 20, 2024 07:55 PDT
Electronically signed by:
Reason: I am the approver
Date: Sep 23, 2024 10:31 EDT


Paratek Pharmaceuticals, Inc. 
Statistical Analysis Plan
PTK0796-NTM-20203
18-Sep-2024
PTK0796-NTM-20203 Statistical Analysis Plan v5.0 18-Sep2024
Page 4/40
CONFIDENTIAL 
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................. 6
1.
INTRODUCTION .................................................................................................................. 8
2.
STUDY DOCUMENTS ......................................................................................................... 8
3.
STUDY OBJECTIVES........................................................................................................... 8
3.1 Primary Objectives.............................................................................................................. 8
3.2 Secondary Objectives.......................................................................................................... 8
4.
STUDY DESIGN AND PLAN .............................................................................................. 8
5.
DETERMINATION OF SAMPLE SIZE............................................................................... 9
6.
GENERAL ANALYSIS CONSIDERATIONS ..................................................................... 9
7.
NOTATION OF TREATMENT GROUPS AND VISITS................................................... 10
Table 7.1.1 Notation of Treatment Groups............................................................................... 10
Table 7.1.2 Visit Terminology.................................................................................................. 10
8.
ANALYSIS SETS ................................................................................................................ 11
9.
STUDY CONDUCT............................................................................................................. 12
9.1 Subject Disposition........................................................................................................... 12
9.2 Protocol and Good Clinical Practice (GCP) Deviations................................................... 12
9.3 Eligibility .......................................................................................................................... 12
9.4 Prior and Concomitant Medications ................................................................................. 12
10. DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........................................... 13
10.1 Demographics, Medical History and NTM Assessment................................................... 13
10.2 Microbiology..................................................................................................................... 15
10.2.1
Selection of Sample for Analysis.......................................................................... 15
10.2.2
Baseline Analyses ................................................................................................. 16
11. EFFICACY ANALYSES ..................................................................................................... 17
11.1 Efficacy Variables............................................................................................................. 17
11.2 Baseline Values................................................................................................................. 19
11.3 Adjustments for Covariates............................................................................................... 19
11.4 Handling of Dropouts or Missing Data............................................................................. 19
11.5 Interim Analysis and Data Monitoring ............................................................................. 19
11.6 Examination of Subgroups................................................................................................ 20
11.7 Multiple Comparison/Multiplicity.................................................................................... 20
11.8 Multicenter Studies........................................................................................................... 20
12. METHODS OF EFFICACY ANALYSIS............................................................................ 20
12.1 Primary Efficacy Analyses ............................................................................................... 20


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CONFIDENTIAL 
12.1.1
Primary Efficacy Endpoint ................................................................................... 20
12.1.2
Estimand Framework for the Primary Efficacy Endpoint .................................... 21
12.1.3
Other Analyses for the Primary Efficacy Endpoint .............................................. 22
12.2 Secondary Efficacy Analyses ........................................................................................... 22
12.2.1
Quality of Life – Bronchiectasis (QOL-B)........................................................... 23
12.2.2
St George’s Respiratory Questionnaire (SGRQ).................................................. 23
12.2.3
Patient-reported Outcomes Measurement Information System (PROMIS) ......... 23
12.2.4
Patient Global Impression-Change (PGI-C)......................................................... 23
12.2.5
Patient Global Impression-Severity (PGI-S) ........................................................ 23
12.2.6
Clinical Global Impression-Improvement (CGI-I)............................................... 24
12.2.7
Clinical Global Impression-Severity (CGI-S) ...................................................... 24
12.2.8
Percentage of Subjects with a new Symptom....................................................... 24
12.2.9
Percentage of Subjects with a Decrease in Quantitative Mycobacterial Sputum . 24
12.2.10
Time to Growth in Liquid Medium Only ............................................................. 25
12.2.11
Time to First Negative Sputum Culture................................................................ 25
12.3 Additional Efficacy Analyses ........................................................................................... 26
13. SAFETY ANALYSES.......................................................................................................... 27
13.1 Extent of Exposure............................................................................................................ 27
13.2 Adverse Events ................................................................................................................. 28
13.3 Clinical Laboratory Evaluation......................................................................................... 29
13.4 Vital Signs......................................................................................................................... 29
13.5 Physical Examination........................................................................................................ 30
13.6 Electrocardiogram............................................................................................................. 30
14. CHANGES TO PROTOCOL-SPECIFIED ANALYSES .................................................... 31
15. REFERENCE........................................................................................................................ 32
16. APPENDICES ...................................................................................................................... 32
APPENDIX A: PRESENTATION OF DATA AND PROGRAMMING SPECIFICATIONS... 32
General...................................................................................................................................... 32
Tables........................................................................................................................................ 32
Figures....................................................................................................................................... 33
Listings...................................................................................................................................... 33
Missing or Incomplete Dates .................................................................................................... 34
Adverse Events and Concomitant Medications........................................................................ 34
Standard Calculations ............................................................................................................... 35
APPENDIX B: SAS PROGRAMMING QUALITY CONTROL REQUIREMENTS................ 36
APPENDIX C: TABLE, FIGURE, LISTING LAYOUTS .......................................................... 37
APPENDIX D: DMID ADULT TOXICITY TABLE.................................................................. 38
APPENDIX E: DIRECTIONALITY OF WORST LABORATORY PARAMETERS............... 39


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
adverse event
ANCOVA
analysis of covariance
ATC
Anatomical Therapeutic Chemical
BMI
body mass index 
CGI-I
Clinical Global Impression - Improvement
CGI-S
Clinical Global Impression - Severity
CSR
clinical study report
ECG
electrocardiogram
eCRF
electronic case report form
EOT
end of treatment
ICE
intercurrent event
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
ITT
intent-to-treat
LS
least squares
MABc
mycobacterium abscessus complex
MAC
mycobacterium avium complex
MedDRA
Medical Dictionary for Regulatory Activities
MIC
Minimum Inhibitory Concentration
NTM
nontuberculous mycobacterial
OR
odds ratio
PCS
potentially clinically significant
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PP
per-protocol
PROMIS
Patient-reported Outcomes Measurement Information System
PT
preferred term
QC
quality control
QOL-B
Quality of Life – Bronchiectasis
QTc
corrected QT interval
QTcF
corrected QT interval according to Fridericia’s formula
SAP
statistical analysis plan
SGRQ
St Georges Respiratory Questionnaire
SOC
system organ class
TEAE
treatment-emergent adverse event


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Abbreviation
Definition
TLFs
tables, listings, and figures
WHO
World Health Organization


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1. INTRODUCTION
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Study PTK0796-NTM-20203 (A Phase 2, Double-Blind, 
Randomized, Parallel-Group, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy, 
Safety, and Tolerability of Oral Omadacycline in Adult Subjects with Nontuberculous 
Mycobacterial [NTM] Pulmonary Disease Caused by Mycobacterium abscessus Complex 
[MABc]). The purpose of this statistical analysis plan (SAP) is to provide specific guidelines 
for the statistical analyses. Any deviations from this plan will be documented in the clinical 
study report (CSR).
2. STUDY DOCUMENTS
The following study documents are used for the preparation of the SAP:
x
Protocol, version 2.0, 06-Dec-2021
x
Annotated electronic case report form (eCRF), version 2.0, 01Feb2022.
3. STUDY OBJECTIVES
3.1
Primary Objectives
Efficacy: To evaluate the efficacy of omadacycline in adult subjects with NTM pulmonary 
disease caused by MABc based upon subject assessment of symptoms.
Safety: To evaluate the safety and tolerability of omadacycline in adult subjects with NTM 
pulmonary disease caused by MABc.
3.2
Secondary Objectives
The secondary objectives of the study are:
x
To evaluate patient-reported outcomes and quality of life in adult subjects with NTM 
pulmonary disease caused by MABc
x
To evaluate the microbiological response of omadacycline in adult subjects with NTM 
pulmonary disease caused by MABc
4. STUDY DESIGN AND PLAN
This is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group, multicenter 
study in adults with NTM pulmonary disease caused by MABc.
Following a Screening period of up to 56 days (8 weeks) prior to dosing, eligible subjects will 
be randomized (1.5:1) to receive either 300 mg once daily oral omadacycline monotherapy or 
matching placebo.


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Subjects will attend monthly visits during the approximately 84 day (3-month) double-blind 
treatment period and will complete a 14-day safety tele-visit as well as a safety follow-up call
approximately 30 days after their last dose of test article (See Figure 1).
Figure 1. Study schema, protocol amendment v2.0, 06-Dec-21 
Following an estimated recruitment period of approximately 24 months, the total duration of 
subject participation in the study is approximately 5 months which includes a total duration of 
study treatment for approximately 3 months (84 days).
5. DETERMINATION OF SAMPLE SIZE
As the study is exploratory with respect to determination of efficacy, the sample size 
determination is provided to better ensure sufficient subjects are enrolled to provide an initial 
assessment of efficacy rather than test a specific hypothesis. With a randomization ratio of 
1.5:1, a sample size of 75 subjects (45 omadacycline and 30 placebo) will provide 
approximately 80% power to detect an absolute treatment difference of 30% in clinical 
response rate at Day 84, based on clinical response rates of 15% and 45% in the placebo and 
omadacycline treatment groups respectively, using a Mantel-Haenszel test with 2-sided alpha 
level of .05. 
6. GENERAL ANALYSIS CONSIDERATIONS
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) numbering convention will be used for all TLFs. Unless otherwise 
noted, all p-values will be 2-sided. No adjustments for multiplicity will be made in this study, 
and any p-values presented are not testing pre-specified inferential hypotheses.
Continuous variables will be summarized by presenting the number of observations, means, 
SDs, medians, minimums, and maximums. Other summaries (e.g., quartiles, 5%, 95% CIs) 
may be used as appropriate.


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Categorical variables will be summarized by presenting counts and percentages of subjects in 
corresponding categories. All possible categories as defined in the eCRF should be populated, 
even if they have zero counts. Percentages are based on the total number of subjects (N) for a 
given treatment and population, unless otherwise specified.
All summary tables will be presented by treatment group. Baseline summaries will also include 
a total summary column.
Individual subject data obtained from the eCRFs, external vendors, central clinical laboratory, 
central electrocardiogram (ECG) laboratory, and selected derived data will be presented by 
subject in data listings.
The analyses described in this plan are considered a priori, in that they have been defined 
before breaking the blind.
Any analyses performed after breaking the blind will be considered post hoc and exploratory. 
Post hoc analyses will be labeled as such on the output and identified in the CSR.
All analyses and tabulations will be performed using SAS£ statistical software, version 9.4 or 
higher (SAS Institute Inc). TLFs will be presented in rich text format (RTF) and/or PDF.
The process for SAS program validation and quality control (QC) for programs and outputs is
documented in the Synteract working instruction “SAS Programming Quality Control”. 
Study-specific QC requirements can be found in APPENDIX B: SAS PROGRAMMING 
QUALITY CONTROL REQUIREMENTS.
7. NOTATION OF TREATMENT GROUPS AND VISITS
Table 7.1.1 Notation of Treatment Groups
The following notation of treatment groups will be used throughout the report:
Full notation (as used in the study protocol)
Notation used throughout all tables, 
listings, and figures
300 mg oral omadacycline 
Omadacycline 300 mg
Placebo
Placebo
Table 7.1.2 Visit Terminology
Visit
Notation used throughout all tables, 
listings, and figures
Screening
Screening
Day 1 Baseline
Day 1 (in Listings)/ Baseline (in Tables 
and Figures)
Day 14 Tele-visit (± 2d)
Day 14
Day 28 (± 3d)
Day 28


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Day 56 (± 3d)
Day 56
Day 84 (+5d/-2d)
Day 84
EOT: defined as the visit occurring when subjects 
prematurely discontinue treatment (End of 
Treatment) (+5d/-2d)
EOT (shown on listings)
Day 84/EOT: defined as Day 84 for subjects who 
complete treatment or the visit occurring when 
subjects prematurely discontinue treatment (End 
of Treatment) (+5d/-2d)
Day 84/EOT (shown on tables)
30 Day Safety Follow-up Call (+7d)
Follow-up
EOT = end of treatment
For by visit summaries, the nominal visit will be summarized. If there is no nominal visit 
result, unscheduled visits that occur in the protocol defined window will be summarized 
instead. If multiple unscheduled visits occur in the window, the one closest to the nominal visit 
date will be used.  For sputum cultures, if there are multiple positive cultures on the same day 
with different MICs to omadacycline, the culture with the highest MIC to omadacycline is 
used.
Study days corresponding to measurements are calculated as:
x
Assessment date – date of first exposure to treatment + 1 (if assessment date is on or 
after the date of first exposure to treatment)
x
Assessment date – date of first exposure to treatment (if assessment date is before the 
date of first exposure to treatment)
If the date of first exposure to treatment is missing, study days will be calculated by using the 
randomization date.
8. ANALYSIS SETS
The following subject population will be used for safety analyses:
x
The safety analysis set will include all subjects who received at least 1 dose of test 
article. Treatment assignment will be based on the actual test article received the 
majority of time while on treatment. 
The following subject populations will be used for efficacy analyses:
x
The intent-to-treat (ITT) analysis set will include all randomized subjects. Treatment 
assignment will be based on the randomized treatment.
x
The per-protocol (PP) analysis set will include all randomized subjects who received at 
least 1 dose of test article and completed the study without major protocol deviations 
that affect the assessment of efficacy.  The decision whether a subject is excluded from 
the PP analysis set will be made prior to database lock and unblinding.  Treatment 
assignment will be based on randomized treatment.


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9. STUDY CONDUCT
9.1
Subject Disposition
Subject disposition information will be summarized for all subjects by treatment group and 
overall. The number and percentage of subjects who are screened, randomized, subjects in each 
analysis set for all subjects and the number and percentage of subjects who complete treatment, 
subjects who prematurely discontinued test article and the reason for discontinuation, the 
number and percentage of subjects who complete the study as well as the number and 
percentage of subjects prematurely discontinuing the study and the primary reason for 
discontinuation will be presented by treatment group in the ITT analysis set.
A listing of all subjects who prematurely discontinued from test article and the reasons for 
discontinuation and all subjects who prematurely discontinued from the trial and the reasons 
for discontinuation will be presented.
9.2
Protocol and Good Clinical Practice (GCP) Deviations
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol that may be on the part of the Investigator, site personnel, or 
the subject. GCP deviation is any breach from GCP standards due to various reasons, including 
human error, technical glitches, or unforeseen circumstances.
Major protocol and GCP deviations are a subset of protocol and GCP deviations that may 
significantly impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject's rights, safety, or well-being. 
All protocol and GCP deviations, including the deviation designation (major or minor), 
category, and indication of whether the deviation led to an exclusion of a subject from the PP
analysis set, will be presented in a data listing.
The number and percentage of subjects with any protocol and GCP deviation, with at least one 
minor, and with at least one major deviation will be summarized by treatment group in the ITT 
analysis set.  Major protocol deviations will also be summarized by deviation category and 
treatment group in the ITT analysis set.
9.3
Eligibility
A listing of subjects in the ITT analysis set not fulfilling any eligibility criteria will be 
provided.
9.4
Prior and Concomitant Medications
Prior and concomitant medication verbatim terms in the eCRFs will be mapped to the World 
Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification and 
preferred names using the WHO Drug Global dictionary B3 format, version March 2021.


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Partial dates will be imputed. For details on imputation rules, refer to Appendix A: 
Presentation of Data and Programming Specifications. Imputed dates are only used for 
classification of a medication as a prior or concomitant medication; no other calculation, such 
as durations, will be done.
Prior medications are defined as any medication with a start date before the start date of test 
article. Concomitant medications are defined as any medication that was started before the start 
date of test article and with a stop date on or after the start date of test article or are considered 
ongoing, or that are started on or after the start date of test article. Medications can be 
considered both prior and concomitant. If the medication cannot be classified as a prior or 
concomitant medication, the medication will be considered as concomitant.
Medications will be summarized for each treatment group by level 4 ATC class (where 
applicable) and preferred name. These summaries will present the number and percentage of 
subjects using each medication. Subjects may have more than 1 medication per ATC class 
(where applicable) and preferred name. At each level of subject summarization, a subject is 
counted once if he/she reported 1 or more medications at that level. Each summary will be 
ordered by descending subject count in the total column by ATC level (where applicable) and 
preferred name. The following summaries will be provided:
x
Prior antibiotics administered for MABc or MAC pulmonary disease in the ITT and 
Safety analysis sets
x
Concomitant antibiotics administered for MABc or MAC pulmonary disease from the 
last dose of test article through the date of the end of the study in the ITT and Safety 
analysis sets
x
Prior medications other than antibiotics administered for MABc or MAC pulmonary 
disease in the Safety analysis set
x
Concomitant medications other than antibiotics administered for MABc or MAC 
pulmonary disease in the Safety analysis set.
10. DEMOGRAPHICS AND BASELINE CHARACTERISTICS
10.1 Demographics, Medical History and NTM Assessment
Demographics, baseline characteristics, medical history, and baseline assessment of NTM will 
be summarized by treatment group and overall.
The NTM Symptom Assessment Questionnaire asks subjects to rank the top three most 
bothersome symptoms on the scale at the baseline visit. Each symptom will be scored with 3 
points for a top rating, 2 points for a second-place rating, and 1 point for a third place-rating. 
Each symptom will be summed within treatment group and this sum will be presented on the 
baseline characteristics table with the symptom having the highest overall sum across treatment 


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groups appearing first to the symptom with the lowest score appearing last. This will be 
referred to as the NTM Baseline Symptom Bothersome Ranking.
The following demographic and baseline characteristics will be summarized for the ITT
analysis set (except where indicated):
x
Baseline demographics and characteristics: age as a continuous variable, age 
FDWHJRUL]HG DV   DQG ! 65 years, sex, ethnicity, race, height (cm), weight (kg), body 
mass index (BMI) (kg/m2), by treatment group and overall. Baseline demographics and 
characteristics will be summarized for the ITT and safety analysis sets.
x
The number and percentage of subjects in each randomization stratum (received prior 
treatment for NTM, did not receive prior treatment for NTM) based on the prior 
antibiotic data from the CRF will be presented by treatment group and overall.  The 
table will also present the number and percentage of subjects with each severity 
category (absent, mild, moderate, severe) for the NTM symptoms at baseline from the 
NTM Symptom Questionnaire by treatment group and overall and in each 
randomization stratum.  The Most Bothersome Symptom Ranking will also be 
presented by treatment group, overall and in each randomization stratum. The 
definition of the Most Bothersome Symptom Ranking is as the following. Subjects are 
asked to list up to 3 of their most bothersome symptoms at baseline. For each subject 
the number 1 mostly highly rated symptom will be given a score of 3, the second most 
highly rated will be given a score of 2, and the third most highly rated will be given a 
score of 1. Scores for each symptom will be tallied across all subjects. The symptom 
with the highest overall score will be considered most bothersome across the entire 
population, the second highest will be considered the second most bothersome for the 
entire population, etc..
x
NTM disease history: duration of the MABc NTM pulmonary disease (defined as the 
number of days from the date of randomization to the first date of diagnosis of NTM 
pulmonary disease caused by MABc), if the subject had ever been diagnosed with 
NTM pulmonary disease caused by Mycobacterium avium complex (MAC), duration 
of NTM pulmonary disease caused by MAC (defined as the number of days from the 
date of randomization to the first date of diagnosis of NTM pulmonary disease caused 
by MAC), subjects with respiratory culture positive for MAC in the 6 months prior to 
screening, subjects having known chronic obstructive pulmonary disease (COPD), 
subjects having known bronchiectasis,  the subject’s smoking status (never smoked, 
former smoker and current smoker) and for former and current smokers, the length of 
smoking. For former smokers, length of smoking in years will be based on date started 
smoking to date stopped smoking + 1. For current smokers, length of smoking in years 
will be based on date started smoking to date of randomization + 1.  
x
Medical history: The verbatim term of the medical history condition/event will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 
24.0.


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Medical history will be summarized by treatment group and overall in the ITT and 
Safety analysis sets. The summary will show the system organ class (SOC) and 
preferred term (PT) ordered by descending subject count in the total column. Subjects 
will only be counted once for each SOC and for each PT within SOC.
10.2 Microbiology
10.2.1 Selection of Sample for Analysis
Sputum samples are collected at Screening, Baseline/Day 1, Day 28, Day 56 and Day 84/EOT.  
At least 2 and preferably 3 sputum samples are obtained at each time point. During Screening, 
samples will be collected after the subject signs the informed consent. For all subsequent visits, 
sputum samples should be collected on 2 to 3 consecutive days (when possible), just prior to, 
and up through the day of the scheduled visit. 
The sputum specimens will be processed by a Central Specialty Microbiology Lab. Acid fast 
bacilli smear testing from sputum will be performed on all specimens received. Specimens will 
be further cultured in both solid and liquid media and identification of genus and species will be 
performed, to the subspecies level for M. abscessus. 
In vitro susceptibility testing of antimicrobial drugs that may be used to treat M. abscessus 
pulmonary infection will be performed, and molecular characterization for select drug resistance 
markers will be performed.
Sputum samples noted to be of low volume will not be used for analysis unless all potential 
samples at a time point are of low volume. If all potential samples are of a low volume 
(signifying lower quality), the algorithms noted below for sample selection will be used.
For MIC susceptibility and outcome analyses of the MABc, the sample closest to but prior to 
the first dose of study drug (based on collection date and if on the same day as the first dose of 
study drug, collection date and time) which is positive for MABc is used as the baseline 
sample. If there are two samples positive for MABc with different subspecies, the one positive 
for M. abscessus subspecies abscessus is used. If multiple samples collected on the same day 
are positive for MABc, the sample positive for M. abscessus subspecies abscessus and with the 
highest MIC to omadacycline is considered the baseline sample. If the MICs are the same, the 
sample closest to the time of first dose of study drug based on time is used. The baseline 
samples for MAC and other species of mycobacterium (not abscessus) are defined in a similar 
manner and may or may not be the same sample as the one with MABc.
For post-baseline samples, a similar process is used for selecting the sample for analysis as that 
used for the baseline sample. The sample that is positive for MABc that is closest to the 
nominal/intended visit day should be selected. 


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10.2.2 Baseline Analyses 
The following will be provided for the baseline MABc specimen: 
x
Baseline positive culture for MABc and by subspecies, as well as MAC and other 
mycobacterium.
x
Distribution of the semi-quantitative score defined as follows: 
Semi-quantitative 
culture scores
Growth in 
broth   
Growth 
on agar 
plate   
CFU/mL on an agar 
plate
0
-
-
0
1
+
-
0
2
+/-
+
1 - <50
3
+/-
+
50-99
4
+/-
+
100-199
5
+/-
+
200-299
6
+/-
+

x
Distribution of MIC to amikacin, cefoxitin, ciprofloxacin, clarithromycin, 
clarithromycin-D14, clofazimine, doxycycline, imipenem, linezolid, minocycline, 
moxifloxacin, omadacycline, tigecycline, and trimethoprim/sulfamethoxazole 
x
Susceptibility profile (interpreted as resistant, susceptible and intermediate according to 
CLSI breakpoints) to each antibiotic with defined breakpoints   
x
Multidrug Resistance (MDR) defined as nonsusceptibility (MIC value interpreted as “I” 
or “R”) to at least one agent in three or more antimicrobial categories. Agents that do 
not have susceptibility interpretations i.e. those in Table 10.3.2 with ‘N/A/’ will not be 
considered in this analysis.  
x
MIC range, MIC50 and MIC90 to omadacycline 
Table 10.3.2. Antimicrobial Categories, Agents and CLSI Breakpoints 
MIC ug/mL
Antimicrobial Category 
for MDR evaluation
Antimicrobial Agent
S
I
R
Aminoglycoside
Amikacin
<16
32
!64
Cephalosporin
Cefoxitin
<16
32-64
!128
Fluoroquinolone
Ciprofloxacin
<1
2
!4
Macrolide
Clarithromycin
<2
4
!8
N/A
Clofazimine
N/A
N/A
N/A
Tetracycline
Doxycycline
<1
2-4
!8
Carbapenem
Imipenem
<4
8-16
!32
Oxazolidinone
Linezolid
<8
16
!32


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N/A
Minocycline
N/A
N/A
N/A
Fluoroquinolone
Moxifloxacin
<1
2
!4
Antifolate
Trimethoprim-sulfamethoxazole
<2/38
!4/76
N/A
Tigecycline
N/A
N/A
N/A
S=Susceptible, I=Intermediate, R=Resistant
Clinical and Laboratory Standards Institute. Performance Standards for Susceptibility Testing 
of Mycobacteria, Nocardia spp., and Other Aerobic Actinomycetes 1st ed. CLSI document 
M62. 2018. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania, 19087-1898, 
USA.
Microbiology results will be incorporated into several of the efficacy analyses, as defined in 
Section 11.1. 
The by-subject listings noted below will also be provided. On each listing, all samples will be 
presented and the baseline and post-baseline samples selected as indicated above will be 
indicated with a flag.  
x
Decreasing susceptibility (defined as a greater than 4-fold increase in MIC to a given 
antimicrobial agent from the baseline sample to the post-baseline sample) at any visit.  
The listing will show the MICs for all antimicrobials, including those that do not show 
decreasing susceptibility  
x
Drug resistance markers at all visits 
x
Smear results at all visits 
x
Colony count data including CFU count and grouped CFU count (1-49, 50- !-
 !-500 
A listing of MIC data for all samples will also be provided as will a listing of all other results 
for all samples.
11. EFFICACY ANALYSES
The primary and secondary efficacy analyses will be based on the ITT analysis set. Supportive 
efficacy analyses will be performed using the PP analysis set. 
11.1 Efficacy Variables
The primary efficacy endpoints are:  
x
Clinical response (Definition 1) is defined as improvement at the Day 84 visit in 
severity of at least 50% of symptoms on the NTM Symptom Assessment 
Questionnaire present at baseline. 


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x
Clinical response (Definition 2): is defined as improvement at the Day 84 visit in 
severity of at least 50% of symptoms on the NTM Symptom Assessment 
Questionnaire present at baseline and no deterioration in severity of any symptoms 
present at baseline.  
Supportive analyses include analysis of clinical response (Definition 1 and Definition 2) at the 
Day 28 and Day 56 visits.
The secondary efficacy endpoints are:
x
Change from baseline in Quality of Life - Bronchiectasis (QOL-B) domain scores at 
days 28, 56, 84, and Day 84/EOT
x
Change from baseline in the St George’s Respiratory Questionnaire (SGRQ) global and 
component scores at days 28, 56, 84, and Day 84/EOT
x
Change from baseline in the Patient-reported Outcomes Measurement Information 
System (PROMIS) Fatigue 7a Short Form standardized score at days 28, 56, 84, and 
Day 84/EOT
x
The Patient Global Impression – Change (PGI-C) response at days 28, 56, 84, and Day 
84/EOT
x
The Patient Global Impression – Severity (PGI-S) response at days 28, 56, 84, and Day 
84/EOT
x
The Clinical Global Impression – Improvement (CGI-I) response at days 28, 56, 84, 
and Day 84/EOT
x
The Clinical Global Impression – Severity (CGI-S) response at days 28, 56, 84, and 
Day 84/EOT
x
The percentage of subjects with a new symptom (defined as a symptom present post-
baseline but absent at baseline) on the NTM Symptom Assessment Questionnaire with 
severity worse than mild at days 28, 56, 84, and Day 84/EOT
x
The percentage of subjects with a decrease in quantitative MABc sputum culture from 
baseline to Day 84
x
Time to growth in liquid medium only
x
Time to first sputum culture negative for MABc
The additional efficacy endpoints are: 
x
Time to detection of MABc in growth media at baseline and the Day 28, 56, 84 and Day 
84/EOT visits 
x
The percentage of subjects who convert from a positive MABc sputum culture at baseline 
to a sputum culture negative for MABc at any time post-baseline and at the Day 28, 56, 
84 and Day 84/EOT visits
x
In those subjects whose first negative culture (i.e., convert from a positive MABc sputum 
culture at baseline to a negative MABc sputum culture) is on the Day 28, 56, 84 and Day 


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84/EOT visits, the number and percentage of subjects with a culture positive for M. 
avium or other non-abscessus mycobacterium species at baseline 
x
The percentage of subjects who convert from a positive MABc culture at baseline to a 
sputum culture negative for MABc post-baseline (through the Day 56 visit) and have no 
subsequent positive MABc sputum culture during the study
x
The number and percentage of subjects who convert from a positive MABc sputum 
culture at baseline to a sputum culture negative for MABc or with MABc growth only in 
liquid medium at any time post-baseline and at the Day 28, 56, 84 and Day 84/EOT visits
x
Quantitative mycobacterial load (CFU/mL) and semi-quantitative score of the MABc at 
baseline and the Day 28, 56, 84 and Day 84/EOT visits
11.2 Baseline Values
Unless otherwise noted, baseline is defined as the last non missing value recorded before the 
first dose of test article. Unscheduled visits will be used in the determination of baseline 
values, when applicable. 
For microbiologic analysis, see Section 10.3.1 for determination of the baseline sputum 
sample.
11.3 Adjustments for Covariates
The model for the primary efficacy and some secondary efficacy analyses will include 
adjustments for randomization stratification factor:
x
Prior treatment of NTM caused by MABc at baseline status (received prior antibiotic 
treatment for NTM vs did not receive prior treatment for NTM)
If the sample size is too small in one of the randomization stratification subgroups such that an 
adjusted analyses cannot be performed, unadjusted analyses will be used
11.4 Handling of Dropouts or Missing Data
Data imputation methods for the primary endpoint and other analyses for the primary endpoint 
are described in Section 11.1.
No imputations will be made for missing values for secondary endpoints. Summaries for these 
endpoints will be based on observed data only.
11.5 Interim Analysis and Data Monitoring
No interim analyses or data monitoring committee are planned for this study.


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11.6 Examination of Subgroups
Subgroup analyses by prior treatment for NTM or baseline microbiological characteristics 
(e.g., MIC values) may be conducted if subgroup sample sizes are sufficient. This will be 
predetermined prior to database lock.
11.7 Multiple Comparison/Multiplicity
As the study is exploratory with respect to efficacy, no adjustments for multiplicity will be 
made in this study.
11.8 Multicenter Studies
This is multicenter study, with approximately 20 centers in the US participating. 
Approximately 75 subjects will be randomly assigned, leading to approximately 4 subjects per 
center.
The expected low number of subjects at some centers does not allow center to be included as a 
covariate in the statistical model.
12. METHODS OF EFFICACY ANALYSIS
12.1 Primary Efficacy Analyses
The study is exploratory with respect to efficacy determination.  The study is designed to 
provide an initial assessment of efficacy rather than test a specific hypothesis.  Efficacy will be 
evaluated based on endpoints defined by subject-reported NTM symptoms, subject-reported 
outcomes and quality of life measures, and microbiologic assessment. Nominal p-values will 
be provided as descriptive statistics. 
12.1.1 Primary Efficacy Endpoint
The primary efficacy endpoint of clinical response at the Day 84 visit is defined in two ways as 
noted in Section 10.1.  For Definition 1, clinical response is defined as the improvement in 
severity of at least 50% of symptoms on the NTM Symptom Assessment Questionnaire that 
were present at baseline at the Day 84 visit and for Definition 2 clinical response is defined as 
the improvement in severity of at least 50% of symptoms on the NTM Symptom Assessment 
Questionnaire that were present at baseline at the Day 84 visit and no deterioration in severity 
of any symptoms present at baseline. The NTM Symptom Assessment Questionnaire has 12 
symptoms listed, however subjects may not be experiencing all symptoms at baseline. 
Therefore, the number of symptoms each subject has scored at least Mild severity at baseline 
will be counted and will serve as the denominator for this definition of improvement in severity 
of at least 50% of symptoms. For example, a subject with 6 symptoms scoring at least Mild 
severity at baseline would then be considered a responder in this analysis if they experienced 
improvement on at least 3 symptoms. A subject with 7 symptoms scoring at least Mild at 
baseline would require improvement on at least 4 symptoms. Symptoms which were not 


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present at baseline, or which increased in severity are not considered in Definition 1 of clinical 
response. For Definition 2, if any symptom present at baseline (i.e., not absent) worsens in 
severity at the Day 84 visit, the subject would be considered a non-responder.  Symptoms 
which were not present at baseline are not considered in Definition 2 of clinical response. 
Clinical response (both definitions) will be dependent on the presence of intercurrent events 
(ICEs) as defined in Section 11.1.2. Subjects who discontinued from the trial early or who had 
a missing Day 84 assessment for some other reasons will be considered non responders in this 
analysis.
12.1.2 Estimand Framework for the Primary Efficacy Endpoint
In general, clinical response (both definitions) will use both a treatment and composite policy 
strategy for handling intercurrent events. Subjects who receive alternative antibiotic therapy for 
treatment of the NTM infection, withdraw from study treatment early, and/or die before 
reaching Day 84 will be considered as not achieving clinical response. Subjects with missing 
data at the Day 84 assessment will also be considered as not achieving clinical response.
As detailed in the ICH E9 (R1) addendum, the following 5 attributes will define the estimand 
framework for the primary endpoint (both definitions) and sensitivity analyses around the 
primary endpoint (both definitions). The primary estimand combines responses as assessed 
with a composite variable strategy for handling ICEs.
x
Treatment condition: administration of omadacycline or placebo
x
Population: ITT analysis set
x
Endpoint: clinical response at Day 84
x
Intercurrent events: ICEs are defined below.
x
Population-level summary: between treatment group difference expressed in terms of 
an odds ratio
The following ICEs will be defined for the primary estimand and analysis:
x
ICE-1: Subjects receiving alternative antibiotic therapy for NTM (not including chronic 
macrolides). This includes subjects who prematurely discontinue test article for any 
reason, including an adverse event, and receive alternative antibiotic therapy for NTM.   
Subjects with this ICE will be considered non-responders regardless of their Day 84 
assessment for the primary analysis (Composite strategy).
x
ICE-2: Subjects receiving chronic macrolides (starting prior to first dose of study drug).  
The Day 84 value for clinical response will be used regardless of the occurrence of this 
ICE (Treatment policy)
x
ICE-3: Subjects who died prior to Day 84. Subjects with this ICE will be considered a 
non-responder for the primary analysis. (Composite strategy)
x
ICE-4: Subjects who discontinue test article for any reason and do not receive an 
alternative antibiotic for NTM.  Subjects with this ICE will be considered non-
responders (Composite strategy).


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Analyses will be conducted for both definitions of the primary endpoint.  The number and 
percentage of subjects with a clinical response and without a clinical response will be 
presented.by treatment group for the ITT analysis set.  Exact 2-sided 95% CIs for the point 
estimates of the clinical response rates in each treatment group will be determined using the 
Clopper-Pearson method. The odds ratio (OR) (Omadacycline relative to Placebo) and p-value 
will be calculated using Cochran-Mantel Haenszel (CMH) test, stratified by prior antibiotic 
use. If the sample size is too small in one of the randomization stratification subgroups such 
that an adjusted analysis cannot be performed, an unadjusted analysis (chi-squared or Fisher’s 
exact test) will be used.
12.1.3 Other Analyses for the Primary Efficacy Endpoint
The analyses described below will be performed for both definitions of the primary efficacy 
endpoint.
The primary analysis will be repeated for the PP analysis set. 
A sensitivity analysis will also be done using the treatment policy for ICE-1 in the ITT analysis 
set. The Day 84 visit value for clinical response will be used regardless of subjects receiving 
alternative antibiotic therapy for NTM (not including chronic macrolides). 
A subgroup analysis by the randomization stratification factor levels for the primary endpoint 
will also be conducted.
Clinical response Definitions 1 and 2 will also be analyzed at the Day 28 and Day 56 visits.  
12.2 Secondary Efficacy Analyses
Secondary efficacy endpoints will be presented as collected. Missing data will not be imputed 
and no adjustment for ICEs will be performed. All secondary efficacy endpoints will be 
analyzed using the ITT analysis set. All secondary efficacy endpoints will be summarized 
using descriptive statistics at each scheduled time point by treatment group as described in 
Section 6.
The Day 84 visit time point will be presented with data as collected. The Day 84/EOT visit 
timepoint will include subjects who end treatment on Day 84 as well as subjects who 
prematurely discontinue treatment.
Secondary endpoints, where appropriate, will be analyzed using an analysis of covariance 
(ANCOVA) model at each visit which will include the change from baseline as the dependent 
variable and randomized treatment group and stratification factor (prior antibiotic treatment for 
MABc NTM) as fixed factors and corresponding baseline score as a covariate. Model 
estimated least squares (LS) means, their SDs, and 95% CIs will be presented. The difference 
in LS means, SDs, 95% CIs, and a p-value testing the difference between treatment group LS 
means will be provided.


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12.2.1 Quality of Life – Bronchiectasis (QOL-B)
The first secondary efficacy endpoint is the change from baseline in the QOL-B domain scores 
at the Days 28, 56, and 84 visit, and Day 84/EOT. Descriptive statistics will be provided for 
each domain at each time point and ANCOVA estimates will be provided as described in 
Section 12.2.  A graph of the cumulative distribution of the change from baseline to Day 84 for 
the respiratory domain by treatment group will also be provided.
12.2.2 St George’s Respiratory Questionnaire (SGRQ)
The second secondary efficacy endpoint is the change from baseline in the SGRQ global and 
component scores at the Day 28, 56, and 84 visit, and Day 84/EOT. Descriptive statistics will 
be provided for the global score and each component score at each time point and ANCOVA 
estimates will be provided as described in Section 12.2.  
12.2.3 Patient-reported Outcomes Measurement Information System (PROMIS)
The third secondary efficacy endpoint is the change from baseline in the PROMIS Fatigue 7a 
Short Form standardized score at the Day 28, 56, and 84 visit, and Day 84/EOT. Descriptive 
statistics will be provided for the standardized score at each time point and ANCOVA 
estimates will be provided as described in Section 12.2.  
12.2.4 Patient Global Impression-Change (PGI-C)
The fourth secondary efficacy endpoint is the PGI-C assessed at the Day 28, 56, and 84 visit, 
and Day 84/EOT. 
Subject response will also be categorized as subjects who experienced an improvement and 
those who did not experience improvement. The number and percentage of subjects in each 
category (improvement/no improvement) will be presented by treatment group along with 
exact 2-sided 95% CIs using the Clopper-Pearson method. The difference between treatment 
groups in percentages of subjects experiencing improvement will be presented along with a 2-
sided 95% exact CI. The p-value from a Fisher’s exact test will be provided.
12.2.5 Patient Global Impression-Severity (PGI-S)
The fifth secondary efficacy endpoint is the PGI-S response at the Day 28, 56, and 84 visit, and 
Day 84/EOT. The PGI-S will be analyzed similarly to the PGI-C as described in Section 12.2.4 
except subject response will be grouped as subjects with responses of Not Present/Mild versus 
those with responses of Moderate/Severe. The difference between treatment groups in 
percentage of subjects with a response of Not Present/Mild will be presented along with a 2-
sided 95% exact CI. The p-value from a Fisher’s exact test will be provided.
An additional analysis of the PGI-S will summarize change from baseline as improved, no 
change and worsened at the Day 28, 56 and 84 visit, and Day 84/EOT.  The number and 
percentage of subjects in each change category will be provided.


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12.2.6 Clinical Global Impression-Improvement (CGI-I)
The sixth secondary efficacy endpoint is the CGI-I response at the Day 28, 56, and 84 visit, 
and Day 84/EOT. The number and percentage of subjects with each response will be presented 
by treatment group. The p-value from a Wilcoxon rank sum test will be provided. 
An additional analysis of the CGI-I will summarize change from baseline as improved, no 
change and worsened at the Day 28, 56 and 84 visit, and Day 84/EOT.  The number and 
percentage of subjects in each change category will be provided. 
12.2.7 Clinical Global Impression-Severity (CGI-S)
The seventh secondary efficacy endpoint is the CGI-S response at the Day 28, 56, and 84 visit, 
and Day 84/EOT. The CGI-S will be analyzed similarly to the CGI-I described in Section 
12.2.6. 
12.2.8 Percentage of Subjects with a new Symptom
The eighth secondary efficacy endpoint is the percentage of subjects with a new symptom 
(compared to baseline) on the NTM Symptom Assessment Questionnaire with severity worse 
than mild at the Day 28, 56, and 84 visit, and Day 84/EOT. 
For a symptom to be considered new it must be absent at baseline and graded with a severity 
worse than mild at the post-baseline assessment
The number and percentage of subjects with a new symptom worse than mild, with a new 
symptom that is not worse than mild, and no new symptom will be presented at each time 
point. 
A shift table will also be provided for the shift from baseline severity to each post-baseline 
time point severity for each symptom. 
12.2.9 Percentage of Subjects with a Decrease in Quantitative Mycobacterial Sputum
The ninth secondary efficacy endpoint is the percentage of subjects with a decrease in 
quantitative mycobacterial load from the sputum culture collected at the Day 84 visit and 
defined as a reduction in the semi-quantitative score (as defined in Table 10.3.2 ) as compared 
to baseline. The number and percentage of subjects with a reduction in the semi-quantitative 
score at the Day 84 visit will be presented for the ITT analysis set by treatment group. Exact 2-
sided 95% CIs for the point estimate of the percentage of subjects with a decrease in each 
treatment group will be determined using the Clopper-Pearson method. The odds ratio 
(omadacycline relative to placebo) and p-value will be calculated using Cochran-Mantel-
Haenszel test, stratified by prior antibiotic use. If the sample size is too small in one of the 
randomization stratification subgroups such that an adjusted analysis cannot be performed, an 
unadjusted analysis (chi-squared or Fisher’s exact test) will be used. 


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12.2.10 Time to Growth in Liquid Medium Only
Kaplan-Meier methods will be utilized to determine the time to growth in liquid medium only 
for MABc for the ITT Analysis Set by treatment group. The analysis will be limited to subjects 
with growth on agar plate at baseline in the ITT Analysis Set. Time to growth in liquid medium 
only will be defined as the number of days from the date of test article administration to the 
date of the first assessment where growth is detected in liquid medium only. If there is no 
sputum sample indicating growth in liquid medium only but there is a negative culture (defined 
in Section 12.2.11), the date of the first negative culture will be used for the determination of 
time to growth in liquid medium only.
Subjects who died, withdrew from the study, or received alternative antibiotic therapy (not 
including chronic macrolides) for treatment of the NTM infection prior to growth in liquid 
medium only for MABc (or a negative culture, if no sputum sample indicating growth in liquid 
medium only) will be censored at the date of the death, study withdrawal, or the start date of 
the alternative antibiotic therapy respectively. Subjects who have a positive sputum culture 
(defined as growth in both liquid medium and agar plate [growth on both LJ slant and biplate])
through Day 84 will be censored at the date of the Day 84 visit.
The median, 25th and 75th percentile for time to growth in liquid medium only will be 
provided with 2-sided 95% CIs for each treatment group. A p-value will be determined using a 
stratified (by prior antibiotic use) log-rank test. Kaplan-Meier curve for time to growth in 
liquid medium only will be provided in a figure.
12.2.11 Time to First Negative Sputum Culture
Kaplan-Meier methods will be utilized to determine the time to first sputum culture negative 
for MABc for the ITT Analysis Set by treatment group. Time to first negative sputum culture is 
defined as the number of days from the date of the first dose of test article administration to the 
date of the first sputum culture negative for MABc. A culture is considered negative if there is 
no growth in broth (ie, liquid medium) and no growth on agar plate (ie, no growth on either LJ 
slant or biplate) for MABc regardless of subspecies.  For example, if the baseline culture grows 
M. abcessus subspecies abcessus and the post-baseline sample grows M. abcessus subspecies 
massiliense, the culture is considered positive for MABc. Subjects who died, withdrew from 
the study, or received alternative antibiotic therapy (not including chronic macrolides) for 
treatment of the NTM infection prior to sputum culture negative for MABc will be censored at 
the date of the death, study withdrawal, or the start date of the alternative antibiotic therapy 
respectively. Subjects who have a positive sputum culture through Day 84 will be censored at 
the date of the Day 84 visit.
The median, 25th and 75th percentile for time to first negative sputum culture will be provided 
with 2-sided 95% CIs for each treatment group. The probability of a negative sputum culture at 
Days 28, 56 and 84 will also be presented along with the 2-sided 95% CIs for each treatment 
group.  A p-value will be determined using a stratified (by prior antibiotic use) log-rank test.
Kaplan-Meier curve for time to first negative sputum culture will be provided in a figure.


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12.3 Additional Efficacy Analyses
x
Time to detection of MABc (in days) in liquid growth medium at baseline and the Day 
28, 56, 84 and Day 84/EOT visits will be summarized by treatment group, including n, 
mean, SDs, median, minimum and maximum.
x
The number and percentage of subjects who convert from a positive MABc sputum 
culture at baseline to a sputum culture negative for MABc at any time post-baseline and 
at the Day 28, 56, 84 and Day 84/EOT visits and who do not convert to a negative culture 
(i.e., remain positive) will be summarized by treatment group.  
x
In those subjects whose first negative culture (i.e., convert from a positive MABc culture 
at baseline to a negative MABc culture) is on the Day 28, 56, 84 and Day 84/EOT visits, 
the number and percentage of subjects with a culture positive for M. avium or other non-
abscessus mycobacterium species at baseline and at the visit will be summarized by 
treatment group.
x
The number and percentage of subjects who convert from a positive MABc culture at 
baseline to a sputum culture negative for MABc by the Day 56 visit and have no 
subsequent positive MABc culture will be presented, as well as the number and 
percentage of subjects who convert to a negative culture by the Day 56 visit and have a 
subsequent positive culture, and those who do not convert to a negative culture by Day 56
will be summarized by treatment group.
x
The number and percentage of subjects who convert from a positive MABc sputum 
culture at baseline to a sputum culture negative for MABc or growth of MABc only in 
liquid medium at any time post-baseline and at the Day 28, 56, 84 and Day 84/EOT visits 
and who do not convert to a negative culture will be summarized by treatment group.
x
The number and percentage of subjects whose first negative culture (i.e., convert from a 
positive MABc culture at baseline to a negative MABc culture) is on the Day 28, 56, 84 
and Day 84/EOT visits will be summarized by treatment group.
x
A shift table of the semi-quantitative score from baseline to Days 28, 56, 84 and EOT 
visits will be presented by treatment group.
x
Quantitative mycobacterial load (CFU/mL) and semi-quantitative score of the MABc at 
baseline and the Day 28, 56, 84 and Day 84/EOT visits will be summarized by treatment 
group, including including n, mean, SDs, median, minimum, and maximum, geometric 
mean, 95% CI of geometric mean, and %CV for mycobacterial load and number and 
percentage of subject of each semi-quantitative score.
x
For each definition of the primary endpoint, the number and percentage of subjects with a 
clinical response and who had culture conversion (ie, converted from a positive MABc 
sputum culture at baseline to a negative sputum culture at the Day 84 visit), clinical 
response and did not have culture conversion, clinical nonresponse and had culture 


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conversion, and clinical nonresponse and did not have culture conversion, will be 
presented by treatment group.
x
The cumulative distribution of the change from baseline to the Day 84 visit in the 
respiratory domain of the QOL-B by PGI-S (categorized as improved vs. no 
change/worsened) will be provided as a graph.
x
Descriptive statistics of the change from baseline to the Day 84 visit in the respiratory 
domain of the QOL-B in subjects who converted from positive MABc sputum culture at 
baseline to a negative sputum culture at the Day 84 visit, by treatment group will be 
presented.
x
A subject will be defined as a responder if all 3 of his/her most bothersome symptoms at 
baseline are absent or mild at the Day 84 visit and a non-responder if at least one of the 
most bothersome symptoms is worse than mild.  The number and percentage of subjects 
defined as a responder and nonresponder will be presented by treatment group.
x
A sample is considered positive if there was any growth in broth or agar. A sample is 
considered negative if there was no growth in broth and agar.
13.
SAFETY ANALYSES
All safety analyses will be based on the safety analysis set.
13.1 Extent of Exposure
Test article exposure will be summarized for each treatment using the total number of doses 
taken, total dose received, and the duration of treatment. Subjects are prescribed to take 
2 tablets once per day for the duration of the study. 
Test article compliance will be calculated as follows:
x
Compliance (%): (actual number of used tablets in total) / (number of prescribed tablets 
to be taken per the actual treatment period) × 100
x
Actual number of used tablets: number of tablets dispensed – number of tablets 
returned
x
Prescribed number of tablets to be taken: duration of test article administration (days) × 
2 daily tablets
x
Duration of test article administration (days) = date of last administration – date of first 
administration + 1 
Test article compliance will be summarized by treatment group using counts and percentages 
as categorized below:


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x
!
x
<=80%
In the event that data regarding the number of tablets "returned” is missing, the compliance 
calculation will ignore this interval in the calculation of compliance. For example, if a subject 
completes through Day 56 and is dispensed a final kit, but then is lost to follow up, the 
expected duration of administration will be calculated through the last dose date recorded on 
the kit returned at the Day 56 visit and the number of tablets taken will be based on the data 
from the first 2 kits. Similarly, if data regarding the number of tablets “returned” from the 
dosing interval between Day 28 and Day 56 is missing then the duration of dosing will be 
adjusted to remove this interval and the number of tablets taken will be based on recorded data 
from dosing intervals between Baseline and Day 28, and between Day 56 and Day 84.
13.2 Adverse Events
All AE summaries will be restricted to treatment-emergent AEs (TEAEs), which are defined as 
those AEs that occurred on or after first dose of test article and those existing AEs that 
worsened on or after first dose of test article. If it cannot be determined whether the AE is 
treatment emergent due to a partial onset date, then it will be counted as such. Verbatim terms 
in the eCRFs will be mapped to SOCs and PTs using MedDRA, version 24.0.
Each AE summary will be displayed by treatment group. Summaries that are displayed by SOC 
and PTs will be ordered by descending subject count in the total column by SOC and PT.
Summaries of the following types will be presented:
x
Overall summary of AEs that contains an overview of each of the following points
x
Subject incidence of TEAEs and total number of unique TEAEs by MedDRA SOC and 
PT
x
Subject incidence of TEAEs by MedDRA PT shown in order of descending frequency 
of PT in the omadacycline group
x
Subject incidence of TEAEs by MedDRA SOC, PT, and highest severity. At each level 
of subject summarization, a subject is classified according to the highest severity if the 
subject reported 1 or more events. Adverse events with missing severity will be 
considered severe for this summary.
x
Subject incidence of TEAEs by MedDRA SOC, PT, and closest relationship to test 
article (related/not related) as classified by the principal investigator. At each level of 
subject summarization, a subject is classified according to the closest relationship if the 
subject reported 1 or more events. Adverse events with a missing relationship will be 
considered related for this summary.
x
Subject incidence of serious TEAEs and total number of unique serious TEAEs by 
MedDRA SOC and PT
x
Subject incidence of TEAEs resulting in death by MedDRA SOC and PT


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x
Subject incidence of TEAEs leading to test article discontinuation by MedDRA SOC 
and PT
x
Subject incidence of TEAEs leading to study discontinuation by MedDRA SOC and PT
x
Subject incidence of TEAEs that occurred with onset date up through Day 15 by 
MedDRA SOC and PT
x
Subject incidence of TEAEs that occurred with onset date after Day 15 by MedDRA 
SOC and PT
A summary of TEAEs experienced by treatment arm by PT will be provided.
Separate listings of serious AEs (SAEs), AEs resulting in death, AEs leading to test article 
discontinuation, and AEs leading to study discontinuation will be provided.
13.3 Clinical Laboratory Evaluation
Laboratory parameters (serum chemistry, hematology, and coagulation) will be summarized 
using descriptive statistics at baseline and at each post-baseline time point (the Day 28 and 84
visit, Day84/EOT) and for the most extreme (high and/or low) post-baseline value at any visit 
(including unscheduled results). Changes from baseline will also be summarized. 
Select laboratory parameters will be graded according to the Division of Microbiology and 
Infectious Diseases (DMID) grading criteria, version 5.0. Incidence of potentially clinically 
significant (PCS) events (at least a 2-grade increase from baseline) will be presented by time 
point and for the most extreme post-baseline value at any visit (including unscheduled results).
The number and percentage (based on the number of subjects with a normal level at baseline) 
of subjects in each treatment group with an elevated transaminase (AST or ALT) level 
! 3 × XSSHU OLPLW RI QRUPDO >8/1@ ! î8/1 DQG ! 10 × ULN), an elevated bilirubin level 
! 1.5 × 8/1 DQG ! 2 × ULN) will be presented by study visit and at any post-baseline visit.  
A listing of subjects who meet the laboratory criteria for Hy’s law at the same visit will also be 
provided.  The laboratory criteria for Hy’s law are defined as 1) $/7 RU $67! 3 × ULN, ALP 
 2.0 × 8/1 DQG WRWDO ELOLUXELQ ! 1.5 8/1 DQG  $/7 RU $67! 3 × 8/1 $/3  2.0 × ULN, 
DQG WRWDO ELOLUXELQ ! 2 × ULN.
13.4 Vital Signs
Vital signs (systolic blood pressure, diastolic blood pressure, heart rate, pulse oximetry, and 
temperature) and weight will be summarized using descriptive statistics at baseline and at each 
post-baseline time point (the Day 28, 58 and 84 visit and Day 84/EOT) as well as for the most 
extreme result (high and low). Changes from baseline will also be summarized.
Incidence of PCS events will be presented by time point and for the most extreme post-baseline 
value at any visit (including unscheduled results).


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Table 12.4
Vital Sign PCS Thresholds
Criteria for Treatment Emergent PCS Vital Signs
Vital Sign Parameter
Flag
Criterion Value
Change from Baseline
Systolic Blood Pressure 
(mmHg)
High (CH)
t 180
Increase of t 20 mmHg
Low (CL)
d 90
Decrease of t 20 mmHg
Diastolic Blood Pressure 
(mmHg)
High (CH)
t 105
Increase of t 15 mmHg
Low (CL)
d 50
Decrease of t 15 mmHg
Heart Rate (bpm)
High (CH)
t 120
Increase of t 15 bpm
Low (CL)
d 50
Decrease of t 15 bpm
Temperature (oC)
Low (CL)
<36.0
NA
High (CH)
!
NA
bpm=beats per minute; C=Celsius; DBP=diastolic blood pressure; SBP=systolic blood pressure
13.5 Physical Examination
Physical examination results will be included in data listings only.
13.6 Electrocardiogram
Overall interpretation results for ECGs will be summarized using shift tables (normal, 
abnormal not clinically significant, and abnormal clinically significant) comparing baseline to 
EOT. 
Descriptive statistics at baseline and at each post-baseline time point (the Day 84 visit, and Day 
84/EOT), as well as changes from baseline, will be summarized for each ECG parameter
(ventricular rate, RR, PR, QRS, QT, QTcF).
In addition, a categorical summary of abnormal corrected QT interval (QTc) values will be 
presented. At each time point, the number of subjects with QTc according to Fridericia’s 
formula (QTcF= QT/(RR^1/3) (seconds)) and exceeding the thresholds below will be 
presented.
Table 12.6
ECG PCS Thresholds
ECG Parameter
PCS threshold
QTc (high), unadjusted and Fridericia’s
! PVHF
! PVHF
! PVHF
QTc (increase), unadjusted and Fridericia’s
! PVHF IURP EDVHOLQH
! PVHF IURP baseline
Source is ICH E14 ECG QTcF category thresholds.


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CONFIDENTIAL 
14. CHANGES TO PROTOCOL-SPECIFIED ANALYSES
There are no changes from the protocol specified analyses.


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CONFIDENTIAL 
15. REFERENCE
A.P. Magiorakos, A. Srinivasan2 , R. B. Carey , Y. Carmeli , M. E. Falagas5, C. G. Giske , S. 
Harbarth , J. F. Hindler , G. Kahlmeter , B. Olsson-Liljequist, D. L. Paterson, L. B. Rice, J. 
Stelling, M. J. Struelens1 , A. Vatopoulos, J. T. Weber and D. L. Monnet, Multidrug-resistant, 
extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for 
interim standard definitions for acquired resistance, Clin Microbiol Infect 2012; 18:268-281 
(published online 7 May 2011).
16. APPENDICES
APPENDIX A: PRESENTATION OF DATA AND PROGRAMMING 
SPECIFICATIONS
General
x
Specialized text styles, such as bold, italics, borders, shading, and superscripted and 
subscripted text will not be used in tables, figures, and data listings (TFLs) unless they 
add significant value to the TFL.
x
Only standard keyboard characters are to be used in tables and data listings.
x
Special characters, such as nonprintable control characters and printer- or font-specific 
characters, will not be used in a TFL.
x
Hexadecimal character representations are allowed (e.g., μ, D, and ß).
x
All footnotes will be left justified and at the bottom of a page. Footnotes must be used 
sparingly and add value to the TFL.
Tables
x
Means and medians will be presented to 1 decimal place more than the raw data. 
Standard deviations will be presented to 2 decimal places more than the raw data. 
Minimums and maximums will be reported with the same number of decimal places as 
the raw data. For parameters that are a mixture of raw and calculated values (for 
example height which can be either recorded in or converted to centimeters), the 
number of decimal places will be based on the raw data.
x
Percentages will be presented to the tenths place.
x
Unless otherwise specified, for frequency counts of categorical variables, categories 
whose counts are zero will be displayed for the sake of completeness. For example, if 
none of the subjects discontinue due to “lost to follow-up,” this reason will be included 
in the table with a count of 0. Categories with zero counts will not have zero 
percentages displayed.


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x
Lower and upper CI values must be presented to 1 decimal place more than the 
raw/derived data (i.e., to the same number of decimal places as the mean).
x
Percentiles (e.g., 25% and 75%) must be presented to 1 decimal place more than the 
raw/derived data.
x
For all inferential analyses, P values will be rounded to 4 decimal places (or at the 
highest level of precision) with a leading zero (0.0001). P values less than 0.0001 will 
be presented as “<0.0001.”
x
The last footnotes will be:
-
“Source: xxx”, where xxx indicates the source table number(s), if applicable (in 
case aggregated results, such as the mean or median, are plotted), source listing(s) 
(in case individual responses are plotted), and/or source dataset(s) (e.g., ADaM).
-
“PROGRAM SOURCE: ...\\xx.sas, DATA CUTOFF DATE: DD Mmm YYYY, 
RUN DATE: DD Mmm YYYY hh:mm”.
Figures
x
Legends will be used for all figures with more than 1 variable or item displayed. 
Treatment group sizes (n=xx) will be included, as appropriate.
x
Figures will be in black and white but can be in color to add value to the clarity and 
readability of a figure. Lines must be wide enough to see the line after being copied.
x
The last footnotes will be:
-
“Source: xxx”, where xxx indicates the source listing number(s) and/or source 
dataset(s) (e.g., ADaM). 
-
“PROGRAM SOURCE: ...\\xx.sas, DATA CUTOFF DATE: DD Mmm YYYY, 
RUN DATE: DD Mmm YYYY hh:mm”.
x
Line graphs over time of change from baseline results will include a horizontal dashed 
reference line at zero.
Listings
x
If not otherwise specified, all data listings will be sorted by subject number, treatment, 
visit, and date/time, as appropriate.
x
All date values will be presented in a SAS£ statistical software, version 9.4 or higher 
(SAS Institute Inc) date format (e.g., 29AUG2001). 
x
All observed time values will be presented using a 24-hour clock format (HH:MM:SS) 
(e.g., 01:35:45 or 11:26). Seconds will only be reported if they were measured as part 
of the study.
x
The last footnote will be “PROGRAM SOURCE: ...\\xx.sas, DATA CUTOFF DATE: 
DD Mmm YYYY, RUN DATE: DD Mmm YYYY hh:mm”.


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CONFIDENTIAL 
Missing or Incomplete Dates 
Adverse Events and Concomitant Medications 
The most conservative approach will be systematically considered. If the adverse event (AE) 
onset date is missing/incomplete, it is assumed to have occurred during the study treatment 
phase (i.e., considered a treatment-emergent AE) except if the partial onset date or other data, 
such as the stop date, indicates differently. Similarly, a medication with partial start and stop 
dates could be considered as both a prior and concomitant medication. 
The following algorithms will be applied to missing and incomplete start and stop dates:
Start Dates
x
If the day portion of the start date is missing, then the start date will be estimated to be 
equal to the date of the first dose of test article, provided the start month and year are 
the same as the date of the first dose of test article and stop date is either after the date 
of the first dose of test article or completely missing. Otherwise, the missing day 
portion will be estimated as “01.” 
x
If both the day and month portions of the start date are missing, then the start date will 
be estimated to be equal to the date of the first dose of test article, provided the start 
year is the same as the date of the first dose of test article and stop date is either after 
the date of the first dose of test article or completely missing. Otherwise, the event will 
be assumed to start on the first day of the given year (e.g., ??-???-2013 is estimated as 
01-JAN-2013). 
x
If the start date is completely missing and stop date is either after the date of the first 
dose of test article or completely missing, then the start date will be estimated to be 
equal to the date of the first dose of test article. Otherwise, the start date will be 
estimated to be the first day of the same year as the stop date. All other non-AE and 
non-concomitant medication day calculations where only partial dates are available will 
be handled as follows: the first day of the month will be used in the calculations if the 
day part of a start date is missing, and January 1 will be used if both the month and day 
parts of a start date are missing.
Stop Dates
x
If only the day of resolution is unknown, the day of resolution of the event will be 
assumed to be the last day of the month (e.g., ??-JAN-2013 will be treated as 31-JAN-
2013).  
x
If both the day and month of resolution are unknown, the day of resolution of the event 
will be assumed to be the last day of the year (e.g., ??-???-2013 will be treated as 
31-DEC-2013).  


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CONFIDENTIAL 
x
If the stop date of the event is completely missing or event is continuing, the event 
resolution will be assumed to be after the first dose of test article, and the stop date will 
be imputed using the last known date on the study.
Medical History (including NTM History)
Missing day and month of the onset or end date of a medical history term (including NTM 
history) will not be imputed. However, if the month and year are present, the day will be 
imputed to 01.
Standard Calculations
Variables requiring calculation will be derived using the following formulas:
x
Days: A duration expressed in days between 1 date (date1) and another later date 
(date2) is calculated using the following formula: duration in days = date2 – date1 + 1
x
Height: Height entries made in inches are converted to centimeters using the following 
formula: height (cm) = height (in) × 2.54
x
Weight: Weight entries made in pounds are converted to kilograms using the following 
formula: weight (kg) = weight (lb)/2.2046
x
Temperature: Temperature entries in degrees Fahrenheit are converted to degrees 
centigrade using the following formula: temperature (° C) = 5/9 × [temperature (° F) –
32]
x
Body Mass Index (BMI): BMI is calculated using height and weight using and is calculated 
using the following formula: BMI (kg/m2) = weight (kg) / [[height (cm) / 100]2]
x
Change from baseline: Change from baseline will be calculated using the following 
formula: change = post-baseline value – baseline value


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CONFIDENTIAL 
APPENDIX B: SAS PROGRAMMING QUALITY CONTROL REQUIREMENTS 
Derived datasets are independently programmed by 2 programmers. The separate datasets 
produced by the 2 programmers must match 100%. Detailed specifications for the derived 
datasets are documented in the study analysis dataset specifications provided to the client at 
study conclusion.
Tables and listings are independently reprogrammed by a second programmer.
Listings are checked for consistency against corresponding tables, figures, and derived 
datasets.
The entire set of TLFs is checked for completeness and consistency prior to its delivery to the 
client by the lead biostatistician and a senior level, or above, reviewer.
Refer to TMP-SOP-0205-003 “QC Requirements” for further details.


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CONFIDENTIAL 
APPENDIX C: TABLE, FIGURE, LISTING LAYOUTS
TLF mocks are contained in a separate document.




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CONFIDENTIAL 
CHEMISTRY
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia (mEq/L)
! 135
130-135
123-129
116-122
< 116 
Hypernatremia (mEq/L)
< 146
146-150
151-157
158-165
! 165 
Hypokalemia (mEq/L)
! 3.4
3.0-3.4
2.5-2.9
2.0-2.4
< 2.0
Hyperkalemia (mEq/L)
< 5.6
5.6-6.0
6.1-6.5
6.6-7.0
! 7.0
Hypocalcemia (mg/dL) 
(corrected for albumin)
! 8.4
8.4-7.8
7.7-7.0
6.9-6.1
< 6.1
Hypercalcemia (mg/dL) 
(correct for albumin)
d 10.5
10.6-11.5
11.6-12.5
12.6-13.5
! 13.5
Hypomagnesemia (mEq/L)
! 1.4
1.4- 1.2
1.1-0.9
0.8-0.6
< 0.6
Hypophosphatemia 
(mg/dL)
t 2.5
2.0-2.4
1.5-1.9
1.0-1.4
< 1.0
Hyperbilirubinemia (total 
bilirubin)
< 1.1×ULN
1.1-1.5×ULN
! 1.5-
2.5×ULN
! 2.5-5×ULN
! 5×ULN
< 1.1×ULN
1.1-1.5×ULN 
! 1.5-
3.0×ULN
! 3.0-6×ULN
! 6×ULN 
ENZYMES
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT)
< 1.25×ULN
1.25-2.5×ULN
! 2.5-5×ULN
! 5-10×ULN
! 10×ULN
ALT (SGPT)
< 1.25×ULN
1.25-2.5×ULN
! 2.5-5×ULN
! 5-10×ULN
! 10×ULN
GGT
< 1.25×ULN
1.25-2.5×ULN
! 2.5-5×ULN
! 5-10×ULN
! 10×ULN
Alkaline 
Phosphatase
< 1.25×ULN
1.25-2.5×ULN
! 2.5-5×ULN
! 5-10×ULN
! 10×ULN
Lipase
< 1.1×ULN
1.1-1.5×ULN
! 1.5-2.0×ULN
! 2.0-5.0×ULN
! 5.0×ULN
APPENDIX E: DIRECTIONALITY OF WORST LABORATORY PARAMETERS
Laboratory 
Test
Parameter
Worst Value
Hematology
Hematocrit
Lowest value
Red blood cell count
Lowest value
Mean corpuscular hemoglobin
Lowest value
Mean corpuscular hemoglobin concentration
Lowest value
Hemoglobin
Lowest value
Mean corpuscular volume
Lowest value
White blood cell count
Lowest value
Platelets
Lowest value


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CONFIDENTIAL 
Laboratory 
Test
Parameter
Worst Value
Eosinophils 
Highest value
Neutrophils
Lowest value
Chemistry
Alkaline phosphatase (ALP)
Highest value
Alanine aminotransferase (ALT)
Highest value
Aspartate aminotransferase (AST)
Highest value
Blood urea nitrogen
Highest value
Calcium
Both highest value and lowest value
Chloride
Both highest value and lowest value
Creatinine
Highest value
Creatine phosphokinase (CK)
Highest value
Gamma-glutamyl transpeptidase (GGT)
Highest value
Lipase
Highest value
Magnesium
Both highest value and lowest value
Phosphorus
Both highest value and lowest value
Potassium
Both highest value and lowest value
Sodium
Both highest value and lowest value
Total bilirubin
Highest value
Coagulation
Prothrombin time international normalized 
ratio (INR)
Highest value