Clinical trial NCT02605122
Conditions: Community-acquired Bacterial Pneumonia
Keywords: pneumonia macrolide pediatric
Sponsor: Melinta Therapeutics, Inc.
Start date: 2016-04-01; Completion date: 2018-03-21
Enrollment: 97 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 2/3, randomized, open-label, active control, multi-center study to assess the safety and efficacy of solithromycin in children and adolescents with community-acquired bacterial pneumonia (CABP).

Detailed description:
Subjects who meet all inclusion/exclusion criteria and sign the informed consent/assent were enrolled. Subjects were randomized to receive solithromycin or a comparator antibiotic, administered IV and/or by mouth (PO) based on weight and age. Subjects were treated daily for 5 to 7 days with oral solithromycin and 5 to 7 days with IV or IV-to-oral solithromycin. Subjects were treated for 5 to 10 days with comparator antibiotics. Subjects received safety and efficacy assessments during and after treatment.

Arms: arm 1: Solithromycin will be administered orally, as capsules or as a suspension, or intravenously. Patients may receive intravenous therapy initially and switch to an oral formulation. Dosage is weight based and age based. arm 2: Comparators will be selected according to subject age and are consistent with current recommendations for treatment of CABP in children. These include intravenous ceftriaxone, ampicillin, and amoxicillin and oral amoxicillin and amoxicillin-clavulanic acid. Azithromycin or erythromycin may be added as well.
Interventions: intervention 1: Solithromycin intervention 2: Standard of Care
Intervention descriptions: intervention 1: None intervention 2: Age- and weight-based dosing as appropriate per sites standard of care.

Protocol documents:
Prot_000.pdf: 
Cempra Pharmaceuticals, Inc. 
 
Protocol CE01-203 
29 November 2017 
Confidential 
Page 1 of 107 
 
CLINICAL STUDY PROTOCOL 
Protocol Number: 
CE01-203 
Study Drug 
Solithromycin (CEM-101) 
Title: 
A Phase 2/3, Randomized, Open-Label, Multi-center 
Study to Determine the Safety and Efficacy of 
Solithromycin in Adolescents (12 to 17 years of age, 
inclusive) and Children (≥2 months to <12 years of age) 
with Suspected or Confirmed Community-Acquired 
Bacterial Pneumonia  
Study Phase: 
2/3 
Sponsor 
Cempra Pharmaceuticals, Inc. 
6320 Quadrangle Drive, Suite 360 
Chapel Hill, NC 27517 
Telephone: (919) 313-6601 
Fax: (919) 313-6620 
Version / Date: 
 
Version 4.0 / Amendment 3 29 November 2017 
Replaces: 
Version 3.0 / Amendment 2 16 December 2016 
Replaces: 
Version 2.0 / Amendment 1 19 January 2016 
Replaces: 
Version 1.0 / Original Protocol 03 September 2015 
 
 
This document is a confidential communication from Cempra Pharmaceuticals, Inc. (“Cempra”). Acceptance of 
this document constitutes an agreement by the recipient(s) that no information contained herein will be 
published or disclosed without prior written approval from Cempra, except that this document may be disclosed 
to appropriate Institutional Review Boards or Independent Ethics Committees under the condition that they are 
also required to maintain confidentiality 
 


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1 
SIGNATURE PAGE 
The signature of the investigator below constitutes his/her approval of this protocol and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol as specified in both the clinical and administrative sections, including all statements 
regarding confidentiality. This trial will be conducted in compliance with the protocol and all 
applicable regulatory requirements, in accordance with Good Clinical Practice, including 
International Conference on Harmonization Guidelines, and in general conformity with the most 
recent version of the Declaration of Helsinki. 
Principal Investigator 
Printed Name:__________________________________ 
 
 
 
 
Signature 
 
Date 
 
Representatives of the Duke Clinical Research Institute, who agree to the terms and conditions of 
this protocol include: 
Michael Cohen-Wolkowiez, MD, PhD 
Study Medical Monitor 
 
 
 
Signature 
 
Date 
Representatives of Cempra Pharmaceuticals, Inc. who agree to the terms and conditions of this 
protocol include: 
Robert Hernandez, PhD 
Director, Clinical Operations 
 
 
 
Signature 
 
Date 
 
 


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2 
SYNOPSIS 
Title of Study: A Phase 2/3, Randomized, Open-Label, Multi-center Study to Determine the Safety and 
Efficacy of Solithromycin in Adolescents (12 to 17 years of age, inclusive) and Children (≥2 months to 
<12 years of age) with Suspected or Confirmed Community-Acquired Bacterial Pneumonia  
Study No: CE01-203 
Planned Number of Investigational Sites: Approximately 90 
Clinical Phase: 2/3, to be conducted in the U.S. and approximately 7 additional countries in other regions 
of the world  
Planned Study Period: Approximately 24 months (first subject visit to last subject last visit) 
Objectives: 
Primary  
• 
Evaluate the safety and tolerability of solithromycin in adolescents and children with community-
acquired bacterial pneumonia (CABP) 
Secondary  
• 
Evaluate the efficacy of solithromycin in adolescents and children with CABP 
• 
Evaluate the population pharmacokinetics (PK) of solithromycin in adolescents and children with 
CABP 
Rationale 
There is a growing body of efficacy and safety data on solithromycin in adults, it was shown to be non-
inferior to moxifloxacin in an adult Phase 3 trial in CABP. However, the safety and efficacy of solithromycin 
have not yet been studied in pediatric subjects with CABP. There is evidence of similarities in children and 
adults in 1) CABP definitions and pathophysiology, 2) causative organisms, 3) response to intervention, 
and 4) exposure-response relationship. Therefore, extrapolation of efficacy in pediatric subjects from adult 
clinical trial efficacy data is reasonable. A safety study in pediatric subjects with CABP, however, is needed 
to compare the safety and tolerability of solithromycin to comparators. This study will gather necessary 
safety data and, as a secondary objective, assess the efficacy of solithromycin as a CABP treatment in 
pediatric subjects.  
Methodology 
This is a phase 2/3, randomized, open-label, active control, multi-center study to assess the safety and 
efficacy of solithromycin in children and adolescents with CABP. After informed consent/assent is obtained, 
subjects will be randomized to receive solithromycin or a comparator drug, administered intravenously (IV) 
or by mouth (PO) in capsules or suspension formulation. Pharmacokinetic samples will be collected to 
assess solithromycin disposition in subjects with CABP.  
Subject Participation 
The duration of participation, from the signing of the informed consent form and assent (if applicable), will 
be up to 32 days: 
• 
Up to 10 days of therapy (5 to 7 days with solithromycin, 5 to 10 days with comparator antibiotics)  
• 
Up to 32 days of adverse event (AE) and serious AE (SAE) monitoring (28 ±4 days will be reported) 
Number of Subjects Planned  
400 subjects ≥2 months to 17 years of age, inclusive, with CABP. Subjects will be randomized (3:1) into 
2 groups: solithromycin (N~300) or comparator (N~100). Randomization will be stratified by the following 
age groups: 
Age Group 1: Adolescents from 12 years to 17 years, inclusive  
Age Group 2: Children from 6 years to <12 years  
Age Group 3: Children from 24 months to <6 years  
Age Group 4: Infants from ≥2 months to <24 months  
A minimum of 40 subjects will be included in each age group. Approximately 20% of subjects will be 
enrolled in the U.S.  


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Diagnosis and Main Criteria for Inclusion 
Inclusion Criteria:  
1. Written informed consent from parents or other legally acceptable representatives and informed assent 
from subject (if age appropriate according to local requirements) 
2. ≥2 months to 17 years of age, inclusive 
3. Requiring hospitalization, emergency room, or urgent care visit   
4. Presence of CABP based on the following criteria within 72 hours prior to randomization: 
• 
History of and/or documented fever (rectal, temporal, ear, or oral temperature ≥38°C or axillary 
temperature ≥37.5°C) or hypothermia (rectal, temporal, ear, or oral temperature <35°C or axillary 
temperature <34.5°C) 
AND 
• 
Chest radiograph infiltrates consistent with bacterial pneumonia (or pneumonia caused by atypical 
bacterial agents); if a subject is outpatient and starting on oral therapy, a radiograph is not required.  
AND 
• 
Presence of at least 2 of the following signs or symptoms: 
a. Cough  
b. Difficulty breathing  
c. Production of purulent sputum 
d. Chest pain 
e. Grunting  
f. 
Hypotension  
g. Tachycardia, defined as follows:  
• 2 months to <24 months: ≥160 beats/min 
• 24 months to <10 years: ≥140 beats/min 
• ≥10 years: ≥100 beats/min   
h. Tachypnea, defined as follows: 
• 2 months to <12 months: ≥50 breaths/min 
• 12 months to <5 years: ≥40 breaths/min 
• ≥5 years: ≥20 breaths/min  
i. 
Physical exam consistent with pulmonary consolidation 
AND 
• 
Presence of at least 1 of the following:  
a. Leukocytosis (≥12,000 white blood cells [WBC]/mm3) 
b. Leukopenia (<5000 WBC/mm3)  
c. ≥10% immature neutrophils (bands) regardless of total peripheral WBC 
d. Elevated inflammatory markers (C-reactive protein or procalcitonin) 
e. Oxygen saturation <97% on room air 
f. 
Organism consistent with a typical respiratory pathogen identified from a blood culture or 
isolated from an appropriate respiratory culture/polymerase chain reaction (sputum in 
children old enough to produce an acceptable specimen; sample from the lower 
respiratory tract airways, if performed [e.g., bronchoalveolar lavage]; or pleural fluid 
culture) 
Exclusion Criteria:   
1. Confirmed or suspected respiratory tract infection attributable to sources other than community-
acquired bacterial pathogens (e.g., ventilator-associated pneumonia; hospital-acquired pneumonia). 
2. Received >48 hours of potentially effective systemic antibacterial therapy for CABP immediately prior 
to randomization (exception: clinical or microbiological treatment failure or progression of signs or 
symptoms of CABP as determined by the investigator).  
3. Confirmed or suspected bacterial meningitis. 
4. Known active pulmonary tuberculosis.  
5. Non-infectious causes of pulmonary infiltrates (e.g., cystic fibrosis, chemical pneumonitis from 
aspiration, hypersensitivity pneumonia). 


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6. Evidence or history of clinically significant medical condition that may, in the assessment of the 
investigator, impair study participation or pose a significant safety risk or diminish the subject’s ability 
to undergo all study procedures and assessments. 
7. Hepatic dysfunction evidenced by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>3 times upper limit of normal (ULN) or direct bilirubin greater than 2 times ULN (If direct bilirubin values 
are not available in a timeframe consistent with enrollment requirements, total bilirubin must be <2 times 
ULN). 
8. Treatment with the following drugs within 72 hours prior to first dose of study drug or expected to receive 
these drugs during the treatment phase: drugs that potently inhibit CYP3A4 (nefazodone, fluconazole, 
ketoconazole, conivaptan, diltiazem, verapamil, aprepitant, imatinib, protease inhibitors, clarithromycin, 
ciprofloxacin, erythromycin, itraconazole, mibefradil, posaconazole, telithromycin, and voriconazole); 
CYP3A4 inducers (rifampin, rifabutin, phenytoin, fosphenytoin, carbamazepine, phenobarbital, 
rufinamide, modafinil, armodafinil, etravirine, efavirenz, nevirapine, rilpivirine, bosentan, troglitazone, 
pioglitazone, and St. John’s wort). In addition, the following drugs may not be co-administered with 
solithromycin in this trial due to the potential for adverse drug-drug interaction: digoxin, colchicine, 
midazolam, quinidine, ergotamine, dihydroergotamine, rivaroxaban, apixaban, dabigatran, edoxaban, 
cisapride, cyclosporine, sildenafil, astemizole, and alfentanil.  
9. Breast-feeding females. 
10. Positive pregnancy test in females of childbearing potential. 
11. History of anaphylaxis to macrolide antibiotics. 
12. Previous participation in this study. 
13. Subject has received any investigational drug studied under an Investigational New Drug application in 
the U.S. or under a Clinical Trial Application in the relevant country outside of the U.S. where the subject 
is being enrolled, taken within 4 weeks before administration of the first dose of study drug.  
14. End Stage Renal Disease (dialysis requiring) OR severe renal impairment (defined as serum creatinine 
> 1.5 fold ULN for age). 
Test Product  
Dose and Mode of Administration: Solithromycin will be administered IV or PO according to the tables 
below. If dosing begins with oral therapy, the Day 1 dose will be a loading dose. No loading doses are used 
with IV solithromycin administration or if switched to oral administration. An IV-to-PO switch can occur after 
the first IV dose. Subjects starting with oral therapy will receive 5 days of solithromycin treatment and those 
starting with IV therapy (regardless of if and when they switch to oral therapy) will receive 7 days of 
solithromycin treatment. 
Capsule Dosing Regimens 
Age (years) 
Weight 
Route 
Formulation 
Day 1 
(Max dose: 800 mg)  
Days 2 to 5 
(Max dose: 400 mg)  
6 to 17 
>30 kg 
PO 
Capsules 
800 mg 
400 mg 
>20 to 30 kg 
PO 
Capsules 
600 mg 
400 mg 
≤20 kg 
PO 
Capsules 
400 mg 
200 mg 
Suspension Dosing Regimens 
Age (years) 
Route 
Formulation 
Day 1 
(Max dose: 800 mg)  
Days 2 to 5 
(Max dose: 400 mg)  
12 to 17 
PO 
Suspension 
20 mg/kg (800 mg) 
10 mg/kg (400 mg) 
6 to <12 
PO 
Suspension 
20 mg/kg 
10 mg/kg 
2 to <6 
PO 
Suspension 
20 mg/kg 
10 mg/kg 
2 mo to <2 
PO 
Suspension 
20 mg/kg 
10 mg/kg 


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Intravenous Dosing Regimens 
Age (years) 
Route 
Formulation 
Days 1 to 7 
(Maximum dose: 400 mg)  
12 to 17  
IV 
Solution 
8 mg/kg 
6 to <12 
IV 
Solution 
8 mg/kg 
2 to <6 
IV 
Solution 
8 mg/kg 
2 mo to <2 
IV 
Solution 
8 mg/kg 
Intravenous to Oral Dosing Regimens 
Age (years) 
Route 
 Oral Formulation 
Day 1 to Last IV Dosing 
Day 
(Max dose: 400 mg)  
First Oral Dosing Day 
to Day 7 
(Max dose: 400 mg)a  
12 to 17 
IV/PO 
Suspension or 
Capsules 
8 mg/kg 
10 mg/kg (400 mg) 
6 to <12 
IV/PO 
Suspension or 
Capsules 
8 mg/kg 
10 mg/kg 
2 to <6 
IV/PO 
Suspension 
8 mg/kg 
10 mg/kg 
2 mo to <2 
IV/PO 
Suspension 
8 mg/kg 
10 mg/kg 
a. The adult dose should be administered unless the subject weighs <40 kg, in which case they receive 10 mg/kg on 
the first oral dosing day through Day 7. The capsule dose is rounded upwards to the nearest 200 mg.  
Comparator Therapy  
Dose and Mode of Administration: Comparators will be selected according to subject age and are consistent 
with current recommendations for treatment of CABP in children. A dosing table is provided below. 
Children ≥2 months to <5 years of age: 
a. Ceftriaxone IV OR 
b. Ampicillin IV or amoxicillin IV OR 
c. Amoxicillin-clavulanic acid PO or IV or amoxicillin PO 
Children 5 to 17 years of age (inclusive): 
a. Ceftriaxone IV OR 
b. Ampicillin IV or amoxicillin IV OR 
c. Amoxicillin-clavulanic acid PO or IV  or amoxicillin PO 
Azithromycin IV/PO or erythromycin lactobionate IV or erythromycin PO may be added to any of the 
treatment regimens above. Azithromycin is also acceptable as a first line of treatment. 
 


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United States 
Rest of the World  
Amoxicillin 
45-90 mg/kg/day orally in 2 or 3 divided 
doses; not to exceed 3 g/day 
45-90 mg/kg/day orally in 2 or 3 divided 
doses; not to exceed 3 g/day 
50-100 mg/kg/day intravenously in equally 
divided doses every 6 hours 
Amoxicillin-
clavulanic acid 
Children <40 kg: amoxicillin component  
90 mg/kg/day orally in divided doses 
given every 12 hours [4000 mg/day max 
dose] 
 
Children ≥40 kg, 875 mg orally every 12 
hours or 500 mg orally every 8 hours 
[4000 mg/day max dose] 
Children <40 kg: 20 mg/5 mg/kg/day to 60 
mg/15 mg/kg/day given orally every 8 
hours 
 
Children ≥ 40 kg: One 500 mg/125 mg 
dose given orally every 8 hours 
Amoxicillin-
clavulanic acid 
 - 
Children >4kg but< 40kg: amoxicillin 
component 25 mg/kg intravenously every 
8 hours [1000 mg max dose] 
 
Children ≥ 40 kg: amoxicillin component 
1000 mg intravenously every 8 hours 
Ampicillin 
150-200 mg/kg/day intravenously in 
equally divided doses every 6 hours 
- 
Azithromycin 
10 mg/kg intravenously/orally on day 1 
[500 mg maximum dose] followed by 
5 mg/kg orally every 24 hours  
[250 mg maximum dose] 
10 mg/kg orally on day 1 [500 mg 
maximum dose] followed by 5 mg/kg orally 
every 24 hours [250 mg maximum dose] 
Ceftriaxone 
50-75 mg/kg/day intravenously in equally 
divided doses every 12 hours; total daily 
dose should not exceed 2 g 
50-80 mg/kg intravenously once daily 
Erythromycin 
40 mg/kg/day orally every 6 hours 
30-50 mg/kg/day orally every 6 hours 
Erythromycin 
lactobionate 
15 to 20 mg/kg/day intravenously in 
equally divided doses every 6 hours 
50 mg/kg/day intravenously/orally in 
equally divided doses every 6 hours 
Note: if doses of comparator drugs noted in the dosing table above differ from those prescribed per standard 
of care, a site can use the locally prescribed dose.  
Intravenous-to-oral switch:  
Subjects receiving an IV comparator drug in any age group may be switched to oral treatment using 
amoxicillin-clavulanic acid PO (amoxicillin component 45 mg/kg every 12 hours; subjects weighing ≥ 40 kg, 
875 mg every 12 hours or 500 mg every 8 hours) or amoxicillin alone (45 mg/kg every 12 hours, up to a 
maximum of 4 g/day). 
Duration of Treatment: 5 to 10 days. The exact duration of treatment may be determined at the investigator’s 
discretion. 
Addition of expanded gram-positive coverage to treatment and comparator groups will be allowed if empiric 
therapy for methicillin-resistant Staphylococcus aureus is desired per local standard of care.  
Criteria for Evaluation: 
Safety: 
Any study team member may perform safety assessments. An independent Data Monitoring Committee 
will assess the overall study status and safety of subjects at intervals outlined in the committee’s charter 
and will make recommendations to the sponsor on continuing or modifying the study based on these 
assessments. 
Efficacy: 
A health care provider designated as a subinvestigator blinded to treatment allocation at the site will 
document clinical response at specified time points during the study.  


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Pharmacokinetics: 
The table below provides the optimal plasma sampling collection windows for solithromycin according to 
route of administration. Every effort should be made to collect at least 2 PK samples on Day 1 and at least 
2 PK samples on days 3 through 7 during these windows (not to exceed 6 samples total); however, samples 
obtained outside of the sampling windows are acceptable. Lack of collection of samples or collection outside 
the optimal windows will not be considered protocol deviations.  
IV 
Time after dose 
Oral 
Time after dose  
Prior to dosing (within 1 hour)a 
Prior to dosing (within 1 hour)a 
End of infusion (within 10 minutes) 
0.5–1.5 hours 
2–4 hours 
2–4 hours 
8–10 hours 
8–10 hours 
16–18 hours 
16–18 hours 
20–<24 hours 
20–<24 hours 
a Not applicable to Day 1 samples. 
Statistical Methods and Data Analysis 
Efficacy population: 
All subjects who are randomized. 
Safety population: 
All subjects who receive at least 1 dose of study drug.  
PK population: 
All subjects who receive at least 1 dose of solithromycin and have at least 
1 evaluable PK sample.  
MicroITT population: 
Randomized subjects who have a microbiologically confirmed baseline pathogen.  
Safety:  
New events that occur or pre-existing conditions that worsen in frequency or intensity will be reported as 
AEs or SAEs. AEs will be reported for 16 days and SAEs for 28 days post-randomization. The investigator 
will provide date of onset and resolution, intensity, frequency, actions taken, changes in study drug dosing, 
relationship to study drug, and outcome. Laboratory determinations performed by local laboratories 
including hematology values (hemoglobin, hematocrit, WBC count with differential, and platelet count) and 
serum chemistry values (blood urea nitrogen, calcium, serum creatinine, potassium, sodium, AST, ALT, 
alkaline phosphatase, total and direct bilirubin, and albumin) obtained within 72 hours prior to the first dose 
of study drug and while the subject is on therapy will be recorded. Baseline and on-study microbiological 
cultures of blood, cerebrospinal fluid (CSF), pleural fluid, and respiratory secretions will be recorded if 
obtained within 72 hours prior to the first dose of study drug and while the subject is on therapy. If an AE or 
SAE occurs, concomitant medications will be recorded at the time of the event.  
Primary safety endpoints will be the proportion of subjects experiencing an AE and the proportion of 
subjects discontinuing study drug due to a related AE. Additional safety analyses include summaries of 
AEs, descriptive statistics of laboratory values, frequency distributions and shift tables summarizing 
abnormal laboratory values, descriptive statistics of vital signs, and frequency distributions of abnormal 
physical examinations. 
Efficacy:  
The primary efficacy endpoint is defined as clinical improvement on the last day of treatment (end of 
treatment response), and the secondary efficacy endpoints are defined as early clinical response at 
Days 2-4 and clinical success (i.e., cure) at the short-term follow-up visit (16 days [+/– 4 days] post-
randomization).  
Pharmacokinetics:  
Population PK methodologies using nonlinear mixed effects modeling in NONMEM will be used to analyze 
the concentration data. Data will be reviewed during the study to evaluate PK of solithromycin in pediatric 
CABP patients. The influence of covariates on PK parameters will be explored. Monte Carlo simulations 
will be used to evaluate optimal drug exposure. The relationship between drug exposure and safety events 
will be evaluated by calculating the proportion of subjects with AEs and SAEs at different exposure levels.


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Table 1 
Schedule of Assessments and Procedures 
Activity 
Screening/Baseline 
(Day -3 through Day -1)a 
Treatment Period 
Follow-Up 
Treatment Days up 
to Last Day of 
Treatment b 
Last Day of 
Treatment   
(+48 hours) 
Day 16 Post 
Randomization c, d 
(±4 days) 
Day 28 Post 
Randomization d 
(±4 days) 
Informed consent form 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
Eligibility criteria  
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Physical examination 
X 
Xc 
X 
X 
 
Vital signse 
X 
Xc 
X 
X 
 
Chest x-rayf 
X 
 
 
 
 
Study-required safety labsg  
Xh 
Xi 
X j 
Xi 
Xi 
Review of standard-of-care data:  
   Safety labsg, k 
   Microbiology assessmentsl 
   Radiological imagingm 
Non-pharmacological treatmentsn 
X 
X 
X 
X 
 
Pregnancy testo 
X 
Xp 
 
 
 
Concomitant medicationsq 
X 
X 
X 
 
 
Study drug or comparator 
administrationr 
 
X 
X 
 
 
Pharmacokinetic samplings 
 
X 
X 
 
 
Adverse event assessment  
X 
X 
X 
X 
 
Serious adverse event 
assessment 
X 
X 
X 
X 
X 


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Activity 
Screening/Baseline 
(Day -3 through Day -1)a 
Treatment Period 
Follow-Up 
Treatment Days up 
to Last Day of 
Treatment b 
Last Day of 
Treatment   
(+48 hours) 
Day 16 Post 
Randomization c, d 
(±4 days) 
Day 28 Post 
Randomization d 
(±4 days) 
Clinical outcomes and symptom 
assessments:  
Early Clinical Response, End of 
Treatment, and Follow-Up Post 
Treatmentt 
X 
X u 
X v 
X w 
 
a  
Screening/baseline can occur up to 72 hours prior to randomization. Standard-of-care laboratory data and radiological imaging from up to 72 hours prior to 
randomization may be used as screening procedures. Screening/baseline and first day of treatment may be the same day. 
b  
Treatment period is 5  to 7 days for solithromycin and 5 to10 days for comparators. These assessments and procedures may be done prior to Day 3 if the 
subject is discharged from the hospital before Day 3. 
c  
Record vital signs for each day available. Physical examinations should be recorded from baseline and the Day 3 to 4 visit (early clinical outcome assessment) 
and at the Last Day of Treatment visit.  
d 
Every effort should be made to bring the subject back. If the subject is unable or unwilling to return, the AEs/SAEs must be collected via telephone/other media. 
e  
Vital signs taken at the closest time post-drug administration should be noted. If vital signs following drug administration are not available, record the first value 
of the day. 
f  
Screening chest x-ray does not need to be repeated if a standard-of-care chest x-ray was performed within 72 hours of randomization. Subjects that are 
outpatient and starting on oral therapy do not need a screening x-ray.  
g     Local laboratory; includes hemoglobin*, hematocrit*, white blood cell count with differential*, platelet count*, blood urea nitrogen*, calcium,* serum creatinine, 
potassium*, sodium*, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase*, total and direct bilirubin, and albumin*. If laboratories with 
* designation are not obtained, it will not result in a protocol deviation. 
h  
A separate study sample is not required if safety labs above are obtained at baseline per standard of care. If multiple laboratory tests are obtained within 72 
hours of randomization, record test results closest to randomization. 
i 
Every effort should be made to obtain safety labs 72 (±24) hours after the first dose to include aspartate aminotransferase, alanine aminotransferase, alkaline 
phosphatase, total and direct bilirubin, and white blood cell count with differential. A separate study sample is not required if safety labs above are obtained 
within the visit window per standard of care. 
j  
Safety labs must be collected on the last day of dosing or within 48 hours after the last dose. A separate study sample is not required if safety labs above are 
obtained on the last day of dosing or within 48 hours after the last dose per standard of care. 
k  
Record the safety labs if performed per standard of care; if multiple laboratory tests are obtained on the same day, record test results closest to administration 
of study drug. 
l 
Microbiological assessments will be recorded if performed per routine medical care. These include cultures from sterile body fluids and molecular and serologic 
tests for Mycoplasma pneumoniae and Chlamydophila pneumoniae. 
m  Radiological imaging of the chest, including chest x-ray or computed tomography (CT) scan, will be recorded if performed per routine medical care. 
n  
Non-pharmacologic treatments (such as operative procedures) will be recorded if performed per routine medical care. 
o 
Female subjects of childbearing potential within 24 hours of first dose. 
p  
If the screening visit for females occurred greater than 24 hours before receiving the study drug. 
q  
Medications other than antibiotics taken within 72 hours and all antibiotics taken within 7 days prior to first dose of study drug as well as all concomitant 
medications through the follow-up visit will be recorded. 


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r 
Solithromycin should be administered approximately every 24 hours and at approximately the same time each day (± 4 hours) for 5 to 7 days.  
s  
Only in subjects receiving solithromycin; central laboratory. 
t  
Symptoms should be recorded at baseline, the Day 3 to 4 visit (early clinical response) visit, the Last Day of Treatment Visit (end-of-treatment response), and 
at the Day 16 Follow-Up visit). If the subject is discharged on Day 2 (prior to the Day 3 to 4 visit), the early clinical response assessment will be done on the day 
of discharge. 
u   Early clinical response 
v 
End of Treatment response 
w  
Day 16 post randomization response (cure) 
 
 


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3 
TABLE OF CONTENTS 
1 
SIGNATURE PAGE............................................................................................... 2 
2 
SYNOPSIS ............................................................................................................ 3 
3 
TABLE OF CONTENTS ...................................................................................... 12 
3.1 
LIST OF IN-TEXT TABLES .................................................................................................. 14 
3.2 
LIST OF IN-TEXT FIGURES ................................................................................................ 15 
3.3 
LIST OF APPENDICES ....................................................................................................... 15 
4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................ 16 
5 
INTRODUCTION ................................................................................................. 19 
5.1 
NONCLINICAL ................................................................................................................... 19 
5.1.1 
Solithromycin (CEM-101) Nonclinical Pharmacology .......................................... 19 
5.1.2 
Mechanism of Action............................................................................................. 20 
5.1.3 
In Vitro Microbiological Activity ............................................................................. 20 
5.1.4 
Nonclinical Safety Assessment ............................................................................ 21 
5.1.4.1 
Safety Pharmacology ...................................................................................... 21 
5.1.4.2 
Rat Toxicology ................................................................................................ 21 
5.1.4.3 
Monkey Toxicology ......................................................................................... 22 
5.1.4.4 
Carcinogenicity ............................................................................................... 23 
5.1.4.5 
Reproductive Toxicity ..................................................................................... 23 
5.2 
CLINICAL ......................................................................................................................... 24 
5.2.1 
Clinical Pharmacology and Biopharmaceutics ..................................................... 24 
5.2.1.1 
In Vitro ............................................................................................................. 24 
5.2.1.2 
Solithromycin Capsules .................................................................................. 25 
5.2.1.3 
Solithromycin for Injection............................................................................... 25 
5.2.1.4 
Solithromycin for Oral Suspension ................................................................. 27 
5.2.2 
Additional Clinical Pharmacology Studies ............................................................ 28 
5.2.2.1 
Drug-drug Interactions .................................................................................... 28 
5.2.2.2 
Special Populations and Special Studies ....................................................... 28 
5.2.2.2.1 
Solithromycin in Hepatic-Impaired Subjects (CE01-113) ......................... 28 
5.2.2.2.2 
Thorough QT Study (CE01-109) .............................................................. 28 
5.2.2.2.3 
Pulmonary Pharmacokinetics (CE01-114) ............................................... 29 
5.2.2.2.4 
Absorption, Metabolism, Excretion, and Mass Balance (CE01-108) ....... 29 
5.2.2.2.5 
Pediatric Subjects ..................................................................................... 29 
5.2.3 
Summary of Efficacy ............................................................................................. 30 
5.2.3.1 
Primary Efficacy Outcome: Early Clinical Response (ECR) .......................... 31 
5.2.4 
Summary of Safety ............................................................................................... 32 
5.2.4.1 
Overview of Adverse Events .......................................................................... 33 
5.3 
RATIONALE FOR THE PRESENT STUDY ............................................................................. 35 
5.4 
RATIONALE FOR THE DOSAGE REGIMEN .......................................................................... 35 
5.5 
RATIONALE FOR THE COMPARATOR ................................................................................. 37 
6 
STUDY OBJECTIVES ......................................................................................... 38 
7 
STUDY DESIGN .................................................................................................. 38 
7.1 
DURATION OF SUBJECT PARTICIPATION ........................................................................... 38 
7.2 
NUMBER OF SUBJECTS .................................................................................................... 38 
7.3 
STUDY DRUG DOSAGE AND ADMINISTRATION .................................................................. 39 
7.4 
DATA MONITORING COMMITTEE ....................................................................................... 41 


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7.5 
AGE GROUP INITIATION .................................................................................................... 42 
7.6 
STOPPING RULES ............................................................................................................ 42 
8 
SELECTION OF STUDY POPULATION ............................................................. 43 
8.1 
INCLUSION CRITERIA........................................................................................................ 43 
8.2 
EXCLUSION CRITERIA ...................................................................................................... 44 
8.3 
PRIOR AND CONCOMITANT TREATMENT ........................................................................... 45 
8.3.1 
Permitted Treatment ............................................................................................. 45 
8.3.2 
Prohibited Medications and Therapies ................................................................. 45 
9 
STUDY DRUGS ................................................................................................... 46 
9.1 
SOLITHROMYCIN (CEM-101) ........................................................................................... 46 
9.2 
COMPARATOR ................................................................................................................. 46 
9.3 
STUDY DRUG LABEL AND PACKAGING .............................................................................. 46 
9.4 
STUDY DRUG STORAGE CONDITIONS............................................................................... 46 
9.5 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................... 47 
9.6 
BLINDING ......................................................................................................................... 47 
9.7 
RECEIPT OF SUPPLIES ..................................................................................................... 47 
9.8 
STUDY DRUG ACCOUNTABILITY ....................................................................................... 47 
9.8.1 
Overall ................................................................................................................... 47 
9.8.2 
Study Drug Handling and Return.......................................................................... 47 
10 
STUDY ASSESSMENTS AND PROCEDURES .................................................. 48 
10.1 BASELINE OR SCREENING STUDY PROCEDURES (DAY -3 TO -1) ....................................... 48 
10.2 TREATMENT PERIOD PROCEDURES ................................................................................. 48 
10.2.1 
Treatment Days up to Last Day of Treatment ...................................................... 48 
10.2.2 
Last Day of Treatment (+48 Hours) ...................................................................... 49 
10.3 FOLLOW-UP PROCEDURES .............................................................................................. 50 
10.3.1 
Day 16 Post Randomization (±4 days) ................................................................. 50 
10.3.2 
Day 28 Post Randomization (±4 days) ................................................................. 50 
10.4 LABORATORY DETERMINATIONS ...................................................................................... 50 
10.4.1 
Safety Laboratory Tests ........................................................................................ 50 
10.4.1.1 
Study-Required Safety Laboratories .............................................................. 51 
10.4.1.2 
Standard-of-Care Safety Laboratories ........................................................... 51 
10.4.2 
Microbiology Assessments ................................................................................... 51 
10.4.3 
Pharmacokinetic Determinations .......................................................................... 51 
10.5 RADIOLOGICAL IMAGING AND NON-PHARMACOLOGIC TREATMENT/PROCEDURES ............. 52 
10.6 CLINICAL EFFICACY OUTCOMES ASSESSMENTS TIME POINTS .......................................... 52 
10.7 CLINICAL IMPROVEMENT DEFINITION (EARLY CLINICAL RESPONSE AND END-OF-
TREATMENT RESPONSE) ................................................................................................. 53 
10.8 CLINICAL CURE DEFINITION (DAY 16 POST RANDOMIZATION [±4 DAYS]) .......................... 53 
10.9 SIGNS AND SYMPTOMS OF CABP .................................................................................... 53 
11 
STUDY AND SUBJECT DISCONTINUATION .................................................... 54 
11.1 SCREENING FAILURES ..................................................................................................... 54 
11.2 DISCONTINUATION FROM STUDY DRUG ............................................................................ 54 
11.3 WITHDRAWAL FROM STUDY ............................................................................................. 54 
11.4 STUDY SITE DISCONTINUATION ........................................................................................ 55 
12 
SAFETY ASSESSMENTS ................................................................................... 56 
12.1 ADVERSE EVENTS ........................................................................................................... 56 
12.1.1 
Serious Adverse Events ....................................................................................... 56 
12.1.2 
Follow-up of SAEs ................................................................................................ 57 


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12.1.3 
Other Reportable Events ...................................................................................... 58 
12.1.4 
Severity of Adverse Events................................................................................... 58 
12.2 ASSESSMENT OF CAUSAL RELATIONSHIP ......................................................................... 59 
12.3 ACTION TAKEN ................................................................................................................ 59 
12.4 ADVERSE EVENT OUTCOME ............................................................................................. 59 
12.5 EXPEDITED SAFETY REPORTS TO HEALTH AUTHORITIES.................................................. 59 
13 
DATA MANAGEMENT ........................................................................................ 60 
14 
STATISICAL ASSUMPTIONS ............................................................................. 61 
14.1 STATISTICAL METHODS AND PLANNED ANALYSES ............................................................ 61 
14.1.1 
Endpoints .............................................................................................................. 61 
14.1.2 
Sample Size .......................................................................................................... 61 
14.1.3 
Safety Analysis ..................................................................................................... 61 
14.1.4 
Pharmacokinetic Analysis ..................................................................................... 62 
14.1.5 
Efficacy Analysis ................................................................................................... 62 
14.2 QUALITY ASSURANCE ...................................................................................................... 62 
15 
ADMINISTRATIVE ASPECTS ............................................................................. 63 
15.1 COMPLIANCE WITH REGULATORY REQUIREMENTS ........................................................... 63 
15.2 INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE APPROVAL ........... 63 
15.3 INFORMED CONSENT/ASSENT .......................................................................................... 63 
15.4 CONFIDENTIALITY ............................................................................................................ 63 
15.5 COMPENSATION, INSURANCE AND INDEMNITY .................................................................. 64 
15.6 PROTOCOL AMENDMENT.................................................................................................. 64 
15.7 CASE REPORT FORMS: ELECTRONIC ............................................................................... 64 
15.8 SOURCE DOCUMENT MAINTENANCE ................................................................................ 64 
15.9 STUDY MONITORING REQUIREMENTS .............................................................................. 64 
15.10 
STUDY FILE MANAGEMENT ..................................................................................... 65 
15.11 
STUDY COMPLETION ............................................................................................... 66 
15.12 
AUDITS ................................................................................................................... 66 
15.13 
RETENTION OF RECORDS ....................................................................................... 66 
15.14 
DISCLOSURE OF DATA ............................................................................................ 66 
15.15 
FINANCIAL DISCLOSURE .......................................................................................... 67 
15.16 
PUBLICATION POLICY .............................................................................................. 67 
16 
REFERENCES .................................................................................................... 69 
 
3.1 
List of In-text Tables 
Table 1 
Schedule of Assessments and Procedures ........................................................... 9 
Table 2 
Mean Pharmacokinetic Parameters for Solithromycin in Plasma on Day 1 
and Day 7 (CE01-121) .......................................................................................... 26 
Table 3 
Comparison of Adolescent and Adult PK Parameter Estimates in the 
CE01-119 Study .................................................................................................... 30 
Table 4  
Primary Efficacy Outcome: Early Clinical Response in Individual Phase 3 
Studies and Pooled Studies ................................................................................. 32 
Table 5 
Capsule Dosing Regimens ................................................................................... 39 
Table 6 
Suspension Dosing Regimens ............................................................................. 39 
Table 7 
Intravenous Dosing Regimens ............................................................................. 40 
Table 8 
Intravenous to Oral Dosing Regimens ................................................................. 40 
Table 9 
Recommended Comparator Regimens ................................................................ 41 


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Table 10 
Optimal Pharmacokinetics Sampling Windows Following Dose 
Administration ....................................................................................................... 52 
Table 11 
Probability of Observing at Least One Subject with a Serious Adverse 
Event ..................................................................................................................... 61 
Table 12 
Proportion of Subjects with Adverse Events and 95% CI .................................... 61 
3.2 
List of In-text Figures 
Figure 1 
Chemical Structure of Solithromycin .................................................................... 20 
Figure 2 
Simulated Day 5 Exposure following a Capsule Dose of 20 mg/kg on Day 
1 and 10 mg/kg on Days 2-5. ............................................................................... 36 
Figure 3 
Simulated Day 5 Exposure following a Suspension Dose of 20 mg/kg on 
Day 1 and 10 mg/kg on Days 2-5 ......................................................................... 37 
3.3 
List of Appendices 
Appendix A 
Protocol Amendments .......................................................................................... 71 
Appendix B 
BARDA-Related Terms for Sites Outside of the United States ......................... 103 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
AM 
alveolar macrophage 
AST 
aspartate aminotransferase  
AUC 
area under the concentration versus time curve 
AUC0-24 
area under the concentration versus time curve at 24 hours 
AUCtau 
area under the concentration-time curve for the dosing interval 
BARDA  
Biomedical Advanced Research and Development Authority 
bpm 
beats per minute 
CABP 
community-acquired bacterial pneumonia 
CA-MRSA 
community-acquired methicillin-resistant Staphylococcus aureus 
CBC 
complete blood count 
CE 
clinically evaluable 
CFR 
Code of Federal Regulations (U.S.) 
CI 
confidence interval 
Cmax 
maximum measured plasma concentration 
CPK 
creatine phosphokinase 
CRO 
clinical research organization 
CRU 
clinical research unit 
CSF 
cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae 
DCRI 
Duke Clinical Research Institute 
DLT 
dose-limiting toxicities  
DMC 
data monitoring committee 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
electrocardiogram 
ECR 
early clinical response 
eCRF 
electronic case report form 
ELF 
epithelial lining fluid 
EM 
electron microscopy 
FDA 
Food and Drug Administration (U.S.) 
FSH 
follicle-stimulating hormone  
GC 
gonorrhea; gonococcal infection 
GCP 
Good Clinical Practice 
GD 
gestational day 


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GI 
gastrointestinal 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HDPE 
high-density polyethylene 
HED 
human-equivalent dose 
HEENT 
head, eyes, ears, nose, throat  
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
IC50 
half-maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
INR 
international normalized ratio 
IRB 
Institutional Review Board  
ITT 
intent-to-treat 
IUD 
intra-uterine device  
IV 
intravenous 
LD 
lactation day 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LLN 
lower limit of normal  
ME 
microbiologically evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
NIH 
National Institutes of Health (U.S.) 
NOAEL 
no-observed-adverse-effect-level 
P 
parental 
PICC 
peripherally inserted central catheter 
PK 
pharmacokinetic 
PO 
by mouth 
PORT 
Pneumonia Patient Outcomes Research Team 
QD 
daily 
S. pneumoniae Streptococcus pneumoniae  
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SFU 
short-term follow-up 
TEAE 
treatment-emergent adverse event 


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TOC 
test of cure 
TQT 
Thorough QT/QTc  
ULN 
upper limit of normal  
WBC 
white blood cell 
WMA 
World Medical Association 


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5 
INTRODUCTION  
Community-acquired bacterial pneumonia (CABP) is common worldwide and associated with 
significant mortality (World Health Organization 2012). In children, the microorganisms 
responsible for CABP differ by age and include Streptococcus pneumoniae, Streptococcus 
agalactiae, Chlamydia trachomatis, Mycoplasma pneumoniae, Chlamydophila pneumoniae, 
Hemophilus influenzae, group A Streptococcus, Legionella, and Staphylococcus aureus 
(Michelow 2004, Heiskanen-Kosma 1998, Principi 2001, Ranganathan 2009). Among these 
organisms, S. pneumoniae is the most common cause of pneumonia in children older than 1 week 
of age (Gereige 2013), yet 30% of pneumococcal isolates worldwide are resistant to macrolides 
(Farrell 2008). Additionally, Mycoplasma pneumoniae, another common cause of pneumonia in 
children, has been found to have significant macrolide resistance in the pediatric population (up to 
27% in the U.S. and 80% in Asia (Wolff 2008, Liu 2009).  
Solithromycin, a 4th-generation macrolide fluoroketolide, has excellent in vitro activity against all 
of 
these 
organisms, 
including 
community-acquired 
methicillin-resistant 
S. 
aureus 
(community-acquired methicillin-resistant Staphylococcus aureus [CA-MRSA]) (Farrell 2010). 
The pharmacokinetics (PK) of oral solithromycin in adolescents has been previously characterized 
in a phase 1 study. The PK of both intravenous (IV) and oral solithromycin in adolescents and 
children has been investigated. In the completed PK studies of solithromycin in adolescents and 
children, the drug exhibits a favorable safety profile and exposure comparable to adult exposure 
following study dosing. In a global phase 3 trial comparing 5 days of oral solithromycin alone 
versus 7 days of oral moxifloxacin alone for treatment of CABP in adults, solithromycin was 
shown to be non-inferior to moxifloxacin in early clinical response and short-term follow-up 
(Oldach 2015). All of these results suggest that solithromycin could be used as monotherapy 
against pediatric CABP and other infections. However, a larger safety and efficacy study of 
solithromycin in children and adolescents has not yet been conducted.  
5.1 
Nonclinical 
5.1.1 
Solithromycin (CEM-101) Nonclinical Pharmacology 
Solithromycin is the first fluoroketolide in the macrolide class of antibiotics. It is being developed 
in IV and oral formulations for the treatment of patients with CABP. Its extended spectrum of 
activity and pharmacological properties provide potential for clinical use in other therapeutic areas 
such as gonococcal infections, malaria, and biodefense. Solithromycin is chemically described as: 
(3aS, 4R, 7S, 9R, 10R, 11R, 13R, 15R, 15aR)-1-[4-[4-(3-aminophenyl)-1H-1, 2, 3-triazol-1-
yl]butyl]-4-ethyl-7-fluorooctahydro-11-methoxy-3a, 7, 9, 11, 13, 15-hexamethyl-10-[[3, 4, 6-
trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-Oxacyclotetradecino[4, 
3-
d]oxazole-2, 6, 8, 14(1H, 7H, 9H)-tetrone. The chemical structure is shown in Figure 1. The 
molecular weight is 845 daltons. 


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Figure 1 
Chemical Structure of Solithromycin 
 
Nonclinical and clinical data on solithromycin are briefly summarized below. Please refer to the 
current Investigator’s Brochure for additional details. 
5.1.2 
Mechanism of Action 
Solithromycin inhibits bacterial protein synthesis via a unique pattern of ribosomal binding to 
domains II and V, as well as to the peptide tunnel, of the 23S component of the 50S ribosomal 
subunit. This binding pattern provides for multiple and tight ribosomal interaction sites. 
Solithromycin was also found to have a higher affinity to erm-modified (methylated) ribosomes 
than telithromycin, azithromycin, or erythromycin, which likely accounts for its improved activity 
relative to these agents against macrolide-resistant bacteria. 
5.1.3 
In Vitro Microbiological Activity 
Solithromycin has potent in vitro activity against common respiratory pathogens. It has greater 
activity against gram-positive aerobes, including S. pneumoniae and Streptococcus pyogenes, 
compared with the macrolides clarithromycin and azithromycin and the ketolide telithromycin. 
Solithromycin retains potent activity against pneumococcal strains with both ermB (ribosomal 
methylation)- and mefA (macrolide efflux)-acquired resistance genotypes. Solithromycin is highly 
active against the atypical pathogens associated with CABP, including Legionella pneumophila, 
C. pneumoniae, and M. pneumoniae. Its potency against gram-negative respiratory tract pathogens, 
including M. catarrhalis and H. influenzae is comparable to that of azithromycin. Solithromycin 
exhibits good activity against the USA-300 strain of CA-MRSA and methicillin-susceptible 
S  aureus. Solithromycin is active against S. pyogenes and other beta-hemolytic streptococcal 
species and has marked in vitro potency against enterococcal species (Enterococcus faecium, 
Enterococcus fecalis), including vancomycin-resistant strains. Solithromycin is also active in vitro 
against Bordetella pertussis.  
Solithromycin is active against the sexually transmitted disease pathogens Neisseria gonorrhoeae, 
Mycoplasma hominis, C. trachomatis, and Ureaplasma urealyticum. Solithromycin is also active 
against some enteric pathogens, including Shigella spp., Campylobacter jejuni, and Salmonella 
O
OMe
O
O
O
O
HO
NMe2
N
O
O
F
O
N
N
N
H2N


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spp; however, it is not active against E coli, Enterobacter cloacae, Klebsiella pneumoniae, and 
Serratia marcescens. The effect of solithromycin on human fecal flora is being studied in a 
healthy-volunteer trial. The in-life portion has been completed and no Clostridium difficile toxin 
gene or toxin were identified in stool samples. 
Against intracellular (intraphagocytic) S. aureus, solithromycin was more potent than 
azithromycin and clarithromycin and was able to reduce the intracellular bacterial counts to a 
greater extent than the older macrolides. Unlike azithromycin and clarithromycin, solithromycin 
is bactericidal against most pneumococci. Studies of interactions with other antibiotics have found 
solithromycin to be synergistic or additive with vancomycin, levofloxacin, gentamicin, 
ceftriaxone, and trimethoprim/ sulfamethoxazole. 
5.1.4 
Nonclinical Safety Assessment 
5.1.4.1 
Safety Pharmacology 
In an in vitro human ether-à-go-go related gene (hERG) study that assessed the tendency of 
solithromycin to inhibit the repolarizing current in the cardiac action potential, solithromycin 
inhibited the hERG channel at a half-maximal inhibitory concentration (IC50) of 25.2 µM. 
Solithromycin did not induce deleterious cardiovascular effects or QT prolongation in a 
cardiovascular safety study in dogs. Solithromycin and older macrolides could be differentiated 
from telithromycin by the activity of telithromycin and/or its metabolites against a number of 
nicotinic acetylcholine receptor subtypes in vitro. The profile of blockade of several receptor 
subtypes could help explain the unusual adverse events (AEs) of reversible blurred vision and 
rapid progression of exacerbations of myasthenia gravis that have been observed with 
telithromycin. The lack of motilin receptor activation predicts that solithromycin, unlike other 
macrolides, will not induce gastrointestinal contractions through this mechanism.  
5.1.4.2 
Rat Toxicology 
Repeat-dose oral toxicity and toxicokinetics of solithromycin in male and female Sprague-Dawley 
derived CD® rats were evaluated over a dosing period of 13 weeks in a Good Laboratory Practice 
(GLP) compliant study. Solithromycin was administered at doses of 20, 50, and 125 mg/kg/d. No 
solithromycin-related mortality or clinical signs were observed nor were there adverse effects of 
solithromycin administration on hematology, organ weights, ophthalmology, gross pathology, or 
microscopic pathology. Slightly lower body weights (8%) were observed for males at 125 mg/kg/d 
at the end of the study relative to controls. On Day 45, increased serum liver enzyme values 
(alkaline phosphatase [ALP], aspartate aminotransferase [AST], and/or alanine aminotransferase 
[ALT]) were observed in all solithromycin-treated groups; however, they were mild in severity, 
within the laboratory’s historical control range (except for ALP), generally absent or diminished 
by Day 92, without any histopathological correlate, and therefore not considered toxicologically 
significant. Kupffer cell hyperplasia was observed in males at 125 mg/kg and was not considered 
toxicologically significant. Tissue concentrations were highest in liver, lymph node, and spleen 
with mean concentrations (combined male and female) at 125 mg/kg/d on Day 91 that were 28-, 
23-, and 18-fold higher than maximum measured plasma concentration (Cmax), respectively. 
Tissues with the next highest concentrations were the salivary gland, lung, thymus, and heart. 
Concentrations in these tissues ranged from 2- to 10-fold higher than plasma Cmax. A no-observed-


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adverse-effect-level (NOAEL) of 125 mg/kg/d, the highest dose administered, was established in 
this study. 
Dosing for the 13-week study was determined from repeat-dose oral toxicity and toxicokinetics of 
solithromycin in male and female Sprague-Dawley derived CD® rats over a dosing period of 
28 days. Solithromycin was administered at doses of 40, 100, 250, and 500/250 mg/kg/d. 
Solithromycin treatment at doses of 250 mg/kg/d or higher resulted in significant toxicity, 
including changes in clinical chemistry and hematology parameters that were associated with 
microscopic changes in the liver and hematopoietic system. The NOAEL for solithromycin for the 
majority of toxicity findings in this study was 100 mg/kg/d. However, based on findings of 
histiocytosis in lymph nodes and in the lungs and vacuolar degeneration in the cecum, the overall 
NOAEL for the study was considered to be 40 mg/kg/d. 
5.1.4.3 
Monkey Toxicology 
A 13-week, GLP-compliant study evaluated doses of 20, 50, and 125 mg/kg/d in cynomolgus 
monkeys. All toxicologically significant findings were confined to the 125 mg/kg/d dose level and 
are consistent with the liver being a target organ. ALT and AST changes correlated with Kupffer 
cell hyperplasia and centrilobular hepatocyte vacuolation (phospholipidosis by EM). In addition, 
histiocytosis consistent with phospholipidosis was noted in several other tissues. These 
solithromycin-related effects appear to be reversible, as all of the clinical pathology alterations and 
many of the findings in the liver, lung, and spleen were normalized or reduced after the 12-week 
recovery period. Based on these findings, the NOAEL was determined to be 50 mg/kg/d. 
Administration of solithromycin had no effects on mortality, urinalysis, ophthalmology, or 
electrocardiograms (ECGs).  
Dose-related increases in solithromycin exposures (Cmax and area under the concentration versus 
time curve at 24 hours [AUC0-24]) were observed on Days 1, 29, and 91. Solithromycin exposures 
were higher on Days 29 and 91 than on Day 1. Most of the accumulation due to repeated dosing 
was observed by Day 29 with less additional accumulation by Day 91. 
Doses for the 13-week study were determined from a 14-day study that utilized doses of 40, 100 
or 200 mg/kg/d. Based on the findings in this study, the NOAEL was considered to be 40 mg/kg/d. 
Changes in clinical chemistry parameters included increased ALT and AST at 100 and 
200 mg/kg/d that correlated with centrilobular hepatocyte vacuolation (phospholipidosis by 
electron microscopy [EM]) at 200 mg/kg/d. Solithromycin treatment was also associated with 
histiocytosis/ phospholipidosis in other tissues, such as the gastrointestinal (GI), splenic, and 
lymphatic systems. Tissue concentrations of solithromycin were measured in lung, liver, and heart 
from these animals. Concentrations were highest in the liver and lung and reached a multiple of 
711 and 503 times, respectively, the maximum concentration in plasma at 200 mg/kg/d.  
The findings of histiocytosis and phospholipidosis are commonly observed for lipophilic 
molecules and have been reported for other macrolides, such as clarithromycin, azithromycin, and 
telithromycin (Reasor 2006).  
The mechanism by which CEM-101 induces phospholipidosis appears to be related, at least in 
part, to its ability to inhibit lysosomal phospholipase A1. As seen with azithromycin, CEM-101 


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accumulated in lysosomes and caused lysosomal phospholipidosis in relation to its capacity to 
inhibit lysosomal phospholipases. CEM-101 and azithromycin showed no association of 
phospholipidosis with apoptosis either in incubated cells (up to at least 100 µg/mL) or in 
electroporated cells, even with substantial accumulation. Therefore it was concluded that 
CEM-101, like azithromycin, inhibits lysosomal phospholipase A1 and induces lysosomal 
phospholipidosis in vitro but does not induce apoptosis.  
5.1.4.4 
Carcinogenicity 
Carcinogenicity studies have not been conducted with solithromycin. 
5.1.4.5 
Reproductive Toxicity 
Segment 1, 2, and 3 reproductive toxicity studies with oral solithromycin have been completed. 
Effects on male and female fertility and early embryonic development to implantation were 
evaluated in rats. Effects on embryo-fetal development were evaluated in rats and rabbits. Effects 
on perinatal and postnatal development were studied in rats.  
The Segment 1 study in rats evaluated the potential toxic effect of solithromycin on the estrous 
cycle, tubal transport, implantation, and development of preimplantation stages of the embryo, and 
on functional effects of male fertility. Three treatment groups of 25 male and 25 female Sprague 
Dawley rats/group were administered solithromycin at respective doses of 50, 100 or 220 mg/kg/d. 
No apparent solithromycin-related changes were noted in estrous cyclicity, sperm parameters, or 
uterine and reproductive parameters in male and female animals treated with solithromycin. 
Microscopic examination of the testes did not reveal any treatment-related changes. 
Administration of solithromycin at 50, 100 and 220 mg/kg/d by oral gavage to male and female 
rats during the premating, postmating, and gestation periods resulted in general toxicity at 100 and 
220 mg/kg/d, as evidenced by clinical findings and body weight and food consumption effects in 
these groups; there was also one solithromycin-related mortality at 220 mg/kg/d. The reproductive 
parameters in the both male and female rats were considered to be unaffected by treatment with 
solithromycin. The NOAEL for reproductive toxicity was determined to be 220 mg/kg/d, the 
highest dose tested. 
The Segment 2 study in rats evaluated the developmental toxicity, including the teratogenic 
potential, of solithromycin in pregnant rats. Three treatment groups of 25 time-mated female CD® 
rats/group were administered solithromycin at respective doses of 50, 100, or 220 mg/kg/d. 
Administration of solithromycin to pregnant rats from gestational day (GD) 6 to 17 produced 
significant maternal toxicity, particularly at 220 mg/kg/d, based on clinical signs, body weight and 
food consumption effects. A significant increase in food consumption at 220 mg/kg/d following 
cessation of dosing indicated a compensatory effect based on the significant body weight effects 
noted. The maternal necropsy, including uterine and external, visceral, and skeletal fetal 
evaluations did not reveal any adverse effects that could be attributed to treatment. The NOAEL 
for developmental toxicity was determined to be 220 mg/kg/d, the highest dose tested. In addition, 
no signs of teratogenic potential in the fetuses were identified at the doses evaluated. 


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The Segment 2 study in rabbits evaluated the developmental toxicity, including the teratogenic 
potential, of solithromycin in pregnant rabbits. Three treatment groups of 23 time-mated female 
New Zealand White rabbits/group were administered solithromycin at respective doses of 20, 110, 
or 200 mg/kg/d. Administration of solithromycin to pregnant rabbits from GD 6 to 18 resulted in 
maternal toxicity at 110 and 200 mg/kg/d, as evidenced by body weight and food consumption 
effects, including abortions at 200 mg/kg/d. Slight decreases in viable fetuses and litter size, and 
increases in postimplantation loss and resorptions, were also noted at 200 mg/kg/d. No 
solithromycin-related changes were seen in fetal body weight or identified following the fetal 
external, visceral, and skeletal examinations in the treated animals, as compared to controls. The 
NOAEL for developmental toxicity was determined to be 110 mg/kg/d. No evidence of a 
teratogenic effect was evident in any of the treatment groups at doses up to 200 mg/kg/d. 
A Segment 3 study in rats evaluated the possible adverse effects of solithromycin (50, 100 and 
200 mg/kg/d) on the pregnant/lactating female and on the development of the conceptus and the 
offspring following exposure of the female from implantation through weaning.  
No mortalities related to solithromycin were observed for the parental (P) females or the selected 
offspring (F1). Oral administration of solithromycin at 200 mg/kg/d to P females from GD 6 to 
lactation day (LD) 20 produced maternal toxicity, based on decreased body weight (9%) and food 
consumption effect, and developmental toxicity in the pups at this dose level, based on decreases 
in mean body weight during the preweaning period.  
No other toxicologically meaningful or adverse changes related to solithromycin were observed in 
the F1 pups in any dose group during the lactation, postweaning, growth, or reproductive phases.  
Solithromycin and the active side chain metabolites N-acetyl-CEM-101 and CEM-214 were 
detected in milk of the lactating dam 6 hours post-dose on LD 12. The concentrations in milk were 
significantly higher than seen in rat plasma with similar doses in previous studies.  
The NOAEL for general maternal toxicity in P females was 100 mg/kg/d, based on the body weight 
and food consumption effects at 200 mg/kg/d. The NOAEL for F1 developmental toxicity was also 
100 mg/kg/d, based on the decreases in pup weight during the preweaning period. No other drug-
related effects were observed in the F1 pups based on evaluation of behavior, physical 
development, or reproductive indices. 
5.2 
Clinical 
5.2.1 
Clinical Pharmacology and Biopharmaceutics 
5.2.1.1 
In Vitro  
Solithromycin was determined to be 78 to 84% bound to human plasma proteins, similar to other 
macrolides. Binding to human serum albumin was 43 to 50%, and binding to α-1-acid glycoprotein 
was 7 to 10%.   
Solithromycin is metabolized primarily in the liver. In vitro analysis of metabolism by reaction 
phenotyping using both a chemical inhibitor and recombinant CYP450 indicates that CYP3A4 is 
likely the major CYP450 enzyme governing the metabolism of solithromycin.  


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Studies to assess the interaction of solithromycin with the cytochrome P450 enzyme system have 
shown that solithromycin is an inhibitor (including an auto-inhibitor) and substrate of CYP3A 
isozymes and undergoes minimal metabolism by other CYP450 enzymes. Solithromycin did not 
induce CYP3A isozymes. The rate of CYP3A4 inactivation by solithromycin was comparable to 
that of clarithromycin, which was slightly slower than erythromycin.  
Solithromycin, like other macrolide antibiotics, is both a substrate and inhibitor of p-glycoprotein 
(P-gp, also known as MDR1) in vitro. Solithromycin also has the potential to inhibit the uptake 
transporter OATP1B3, but at exposures unlikely to be achieved in clinical dosing, and if so, only 
transiently. Therefore, clinically significant drug-drug interactions as a result are not expected. 
Solithromycin did not inhibit any of a panel of important efflux transporters, including breast 
cancer resistance protein and bile sort export pump, or uptake transporters, including OATP1B2, 
OAT1, OAT3, OCT1, and OCT2, to a clinically significant extent. 
5.2.1.2 
Solithromycin Capsules 
The PK of oral solithromycin has been studied in healthy adults enrolled in phase 1 PK trials and 
in drug-drug interaction studies. Single-dose solithromycin, ranging from 50 to 1600 mg, was 
administered to 35 subjects (7 cohorts of 5 subjects each; mean age 34 years, mean weight 
73.5 kg); Cmax following 400 (~5.5 mg/kg) and 800 (~11 mg/kg) mg doses were 0.78 and 
1.32 g/mL at 4.0 and 3.5 hours to peak concentration, respectively. Area under the concentration-
time curve for the dosing interval (AUCtau) in these 2 study doses was 6.94 g•h/mL and 
13.67 g•h/mL, respectively. With repeated single daily doses of 200, 400 and 600 mg over 7 days, 
AUCtau and Cmax were 1.7 to 2.2 times greater on Day 7 than on Day 1, indicating accumulation 
over the dosing period, with steady state probably achieved by approximately Day 4. Food had no 
effect on the bioavailability of solithromycin following a single dose of 400 mg.  
5.2.1.3 
Solithromycin for Injection 
Study CE01-121 evaluated a single-vial formulation that contains 400 mg solithromycin with 
3 amino acids as buffering agents. Peripheral and central (via a peripherally inserted central 
catheter [PICC]) venous administration of 400 mg daily (QD) solithromycin (or placebo) infused 
in 250 mL for 7 days was assessed. The peripheral infusion cohorts received 400 mg solithromycin 
infused over either 30 or 60 minutes; the PICC cohort received 400 mg infused over 60 minutes. 
This study also evaluated the PK of a single 800-mg IV dose infused over 40 minutes to achieve 
supratherapeutic plasma concentrations for a planned thorough QT/QTc (TQT) study, as described 
in Section 5.2.2.2. 
Twenty subjects received solithromycin 400 mg QD for 7 days via a peripheral IV line (10 subjects 
received 30-minute infusions, 10 subjects received 60-minute infusions), and 5 received 400 mg 
doses for 7 days via a PICC line. 
Infusion of multiple 400-mg doses solithromycin over 30 minutes compared to 60 minutes resulted 
in a 1.5-fold higher mean Cmax on both Days 1 (3.2 vs 2.2 µg/mL) and 7 (4.2 vs 2.9 µg/mL). 


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Central infusion of 400 mg via a PICC line resulted in a Cmax of 2.4 and 3.3 µg/mL, after 1 and 
7 days, respectively. These Cmax values were slightly (~1.1-fold) higher than after peripheral 
venous administration at the same dose and duration on both Day 1 (2.17 µg/mL) and Day 7 
(2.85 µg/mL). 
AUC0-24 values were similar after peripheral infusion of 400 mg solithromycin over either 30 or 
60 minutes. They were slightly (1.1-fold) higher when solithromycin was administered via a PICC 
line, on both Day 1 (6.5 µg•h/mL, 60 min PICC; 5.3 µg•h/mL, 60 min peripheral; and 
5.9 µg•h/mL, 30 min peripheral) and Day 7 (14.6 µg•h/mL, 60 min PICC; 12.6 µg•h/mL, 60 min 
peripheral; and 13.6 µg•h/mL, 30 min peripheral). However, given the large standard deviations 
observed in all 3 cohorts, the differences are not considered meaningful. 
Solithromycin accumulated approximately 2-fold over 7 days of 400 mg dosing in all 3 multiple 
dose cohorts (Table 2). 
Table 2 
Mean Pharmacokinetic Parameters for Solithromycin in Plasma on Day 1 
and Day 7 (CE01-121) 
Parameter 
Multiple Dose 
400 mg 
400 mg 
400 mg 
250 mL over  
60 minutes,  
Peripheral 
Administration 
250 mL over  
30 minutes,  
Peripheral 
Administration 
250 mL over  
60 minutes 
Central/PICC 
Administration 
Day 1 
N 
10 
10 
5 
Mean Cmax, µg/mL  
2.170 
3.200 
2.400 
Mean Tmax, h  
0.9 
0.475 
1 
Median t1/2, h 
ND 
ND 
ND 
Mean AUC0-24, µg•h/mL  
5.340 
5.930 
6.540 
Day 7 
N 
6 
7 
5 
Mean Cmax, µg/mL  
2.850 
4.200 
3.310 
Mean Tmax, h  
1 
0.429 
0.8 
Median t1/2, h 
8.64 
8.04 
8.23 
Mean AUC0-24, µg•h/mL  
12.600 
13.600 
14.600 
Mean CLss, L/h  
36.2 
32.0 
16.5 
Mean Vss, L  
346 
303 
275 
Mean accumulation ratio 
2.26 
2.08 
2.14 
AUC0-24, area under the concentration versus time curve at 24 hours; CLss, clearance at steady state; Cmax, maximum 
measured plasma concentration; N, number; ND, not done; PICC, peripherally inserted central catheter; t½,, half-life;  
Tmax, time of maximum drug concentration; Vss, volume of distribution at steady state  
 


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Study CE01-116 evaluated single and multiple ascending IV doses as well as an IV-to-oral step-
down regimen. Seven subjects received an IV to oral step-down regimen consisting of 7 daily 
doses of 400 mg solithromycin. With IV-to-oral dosing, the Cmax was higher during the IV infusion 
on Days 1 and 3 as compared to oral dosing on Days 4 and 7. However, the systemic exposure, as 
measured by solithromycin AUC0-24, was similar on Day 3 (IV; 13.00 µg•h/mL) and on Day 4 or 
Day 7 (oral; 11.4 and 10.9 µg•h/mL, respectively). 
Study CE01-118 evaluated multiple IV doses, a combined oral and IV single dose, as well as an 
IV-to-oral step-down regimen in 40 healthy adults, all of which received solithromycin infused in 
tri-buffer in either 4.3% mannitol in sterile water or 0.9% sodium chloride. Of 20 subjects enrolled 
in the randomized 400-mg multiple-dose cohort, 9 completed the 7-day IV dosing regimen, and 
11 switched to oral dosing before Day 7 due to infusion-related AEs. Ten subjects received a single 
1200-mg oral dose followed 5 hours later by a single 400-mg IV dose, and 10 subjects received 
the 7-day IV-to-oral step-down regimen of 400 mg IV followed by 800 mg oral on Day 4 
(3 subjects began oral dosing prior to Day 4 due to infusion-related AEs) and 400 mg orally on 
subsequent days. 
Mean Day 1 Cmax, in the IV-to-oral step-down cohort, for 5 subjects who received 400 mg over 
60 minutes, was 1.4 µg/mL and for 4 subjects who received 400 mg over 30 minutes was 
1.6 µg/mL. In this cohort, in the 7 subjects who received 400 mg IV for 3 days followed by 800 mg 
orally on Day 4 and 400 mg orally on Days 5 to 7, Day 3 mean Cmax was 2.65 µg/mL, and the 
mean AUCtau was 10.76 µg•h/mL; on Day 4 (first oral dosing day of 800 mg) the mean Cmax was 
1.7 µg/mL with a mean AUCtau of 19.97 µg•h/mL. 
5.2.1.4 
Solithromycin for Oral Suspension 
Study CE01-112 evaluated a pediatric suspension that was developed and tested for PK and safety 
in a phase 1, open-label, randomized, crossover study in healthy adult subjects. The primary 
objective of the study was to determine the relative bioavailability of solithromycin suspension 
compared to solithromycin capsules administered as a single 400-mg dose under fasting 
conditions. The suspension area under the concentration curve (AUC) was 100.5 % of the capsule 
AUC and the suspension Cmax was 95.03% that of the capsules. These highly comparable 
measurements did not demonstrate bioequivalence, given the variability of CEM-101 PK (as with 
other macrolides) and the sample size. Based on the protocol-specified lower and upper limits of 
90% confidence interval (CI) of the ratio of geometric least squares means for the 2 PK parameters 
used to evaluate bioequivalence, 400 mg solithromycin suspension was not demonstrated to be 
bioequivalent to 400 mg solithromycin capsules following oral administration under fasted 
conditions. 
The secondary objective of the study was to compare the PK, safety, and tolerability of a single 
400 mg oral dose of solithromycin suspension to that of solithromycin capsules. The PK parameter 
data showed considerable inter-subject variability, but good comparability between the capsule 
formulation and the suspension formulation when evaluated descriptively. No difference in the 
safety or tolerability was observed between the solithromycin suspension and capsule 
formulations. 


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Study CE01-124 evaluated and optimized the taste of compounded solithromycin suspension 
preparations in healthy adult subjects. The suspension had an acceptable taste and viscosity.  
5.2.2 
Additional Clinical Pharmacology Studies 
5.2.2.1 
Drug-drug Interactions 
Four drug-drug interaction studies have been conducted with solithromycin capsules. 
Solithromycin significantly decreased the clearance of midazolam, a CYP3A substrate, resulting 
in increased midazolam plasma concentrations (AUC increases of up to 9.0-fold were observed in 
a steady-state dosing interaction trial). Caution should be observed in the co-administration of 
solithromycin with CYP3A4 substrates with a narrow therapeutic window. Inhibition of CYP3A4 
by ketoconazole resulted in a 1.5-fold increase in solithromycin Cmax and a 2.6-fold increase in the 
area under the concentration-time curve from time zero to infinity of a single dose of 
solithromycin. Co-administration of solithromycin with potent CYP3A4 inhibitors should be 
avoided. When solithromycin was co-administered with rifampin, a potent CYP3A4 inducer, 
solithromycin Cmax and AUC were decreased by greater than 90%. Induction of CYP3A4 
significantly increases the first-pass metabolism of solithromycin, and its administration 
immediately following or concomitantly with CYP3A4 inducers may result in therapeutic failure 
due to accelerated metabolism. Solithromycin when co-administered with digoxin, a CYP3A4 
substrate, increased digoxin AUC0-tau and Cmax by ~38% and ~46%, respectively. Co-
administration of solithromycin and digoxin appeared to be safe and well tolerated with no safety 
concerns regarding clinical laboratories, vital signs, physical examinations, or ECG assessments. 
Monitoring of serum digoxin concentrations should be considered when solithromycin is first 
introduced to subjects and following any changes in solithromycin dose. 
5.2.2.2 
Special Populations and Special Studies 
5.2.2.2.1 
Solithromycin in Hepatic-Impaired Subjects (CE01-113) 
The safety, PK, and protein binding of solithromycin were compared in 24 subjects with mild, 
moderate, and severe hepatic impairment to 8 healthy subjects with normal hepatic function. The 
PK of plasma solithromycin in subjects with mild and moderate hepatic impairment were similar 
to those in subjects with normal liver function following a single oral 800-mg dose on the first day 
and 400 mg QD on 4 subsequent days. Total exposure to solithromycin at steady state decreased 
by approximately 41% for subjects with severe hepatic impairment compared to subjects with 
normal hepatic function. No evidence of accumulation was observed following 5 days of QD doses 
in mild, moderate, or severe cohorts. The mean plasma protein binding percentage was not 
significantly affected by mild or moderate hepatic impairment, but was slightly lower in the severe 
cohort. The results indicated that no dosage adjustment is needed when administering 
solithromycin to subjects with mild, moderate, or severe hepatic impairment.  
5.2.2.2.2 
Thorough QT Study (CE01-109) 
This randomized, placebo- and active-controlled, 3-way crossover study evaluated the ECG effects 
of a supratherapeutic exposure to solithromycin in 48 healthy adult subjects. Subjects were 
randomized to 1 of 6 different treatment sequences, each comprising 3 treatment periods in which 
subjects received IV solithromycin (800 mg infused over 40 minutes), IV saline placebo, and 


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positive control oral moxifloxacin (400 mg) with a 7-day washout between administrations. 
Continuous 12-lead ECGs were obtained for 25 hours using Holter recorders.  
The geometric mean solithromycin Cmax was 5.7 µg/mL (mean AUC0-24 23,360 ng*hr/mL). 
Change from baseline QTcF was similar after dosing with solithromycin and placebo, and the 
resulting placebo-adjusted QTcF change from baseline was small at all time points for 
solithromycin (largest change was 2.8 ms with an upper bound of the 90% CI of 4.9 ms). QTc 
prolongation after moxifloxacin dosing confirmed the study’s assay sensitivity with mean 
placebo-adjusted increase of 9.7 to 10.9 ms at the 3 pre-defined time points. In a concentration-
effect analysis, a statistically significant, negative slope of solithromycin concentration versus 
QTcF change was observed consistent with the conclusion of the primary by-time point analysis. 
Thus unlike older macrolides, ketolides, and respiratory quinolone antibiotics, solithromycin does 
not cause QT prolongation. However, solithromycin did show an effect of exposure-related 
increased heart rate in this study; immediately after the end of the infusion, the placebo-adjusted, 
mean change-from-baseline heart rate peaked at 15 beats per minute (bpm). In adult subjects with 
CABP who received a lower dose of orally administered solithromycin, there was a mean decline 
in heart rate following initiation of therapy (see Section 5.2.4).  
5.2.2.2.3 
Pulmonary Pharmacokinetics (CE01-114) 
Study CE01-114 evaluated the PK of solithromycin after 5 consecutive daily doses of 400 mg in 
lung epithelial lining fluid (ELF) and alveolar macrophages (AM). The mean solithromycin ELF 
to plasma ratio based on solithromycin AUC0-24 values ranged from 8.8 to 14.0. The corresponding 
mean ratio for solithromycin AM to plasma ranged from 132 to 345. Both analyses indicate a high 
degree of solithromycin penetration into human ELF and AM. 
5.2.2.2.4 
Absorption, Metabolism, Excretion, and Mass Balance (CE01-108) 
In CE01-108, after a single dose of 800 mg radiolabeled solithromycin (14C-CEM-101, 100 µCi) 
in solution, mean plasma concentrations and total radioactivity concentration equivalents peaked 
4 hours post-dose and remained quantifiable in most subjects for up to 48 hours (solithromycin) 
and 24 hours (total radioactivity). The t½ of solithromycin and its active side chain metabolites 
(CEM-214 [Hydroxyl destriazolyl-phenylamino CEM-101] and N-Acetyl-CEM-101 [CEM-122]) 
was approximately 7.5 hours. 
5.2.2.2.5 
Pediatric Subjects 
Solithromycin PK in adolescents following oral administration of capsules was investigated in a 
phase 1, open-label, multi-center study of 13 adolescents (12 to ≤ 17 years of age) with a suspected 
or confirmed bacterial infection (protocol CE01-119). Add-on treatment to all subjects using a 
loading dose of 12 mg/kg (maximum 800 mg) on Day 1 and 6 mg/kg (maximum 400 mg) on 
Days 2 to 5. On Day 1, the average (SD) Cmax and AUC0–24 were 0.97 μg/mL (0.73) and 
11.62 μg*h/mL (8.55), respectively. On Days 3 to 5, Cmax and AUC0–24 for solithromycin were 
0.74 μg/mL (0.61) and 9.28 μg*h/mL (6.30), respectively. PK parameters estimated in 
13 adolescents on Day 1 (median dose [range] 800 mg [400 to 800]) and Days 2 to 5 (median dose 
400 mg [200 to 400]) were comparable to observed values in healthy adults (Table 3). 


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For Streptococcus pneumoniae (S. pneumoniae) minimum inhibitory concentration (MIC) values 
of 0.015-0.03 μg/mL (>80% of isolates), and assuming protein binding of 78%, therapeutic 
exposures (1-log10 colony-forming unit reduction target) were observed in ≥90% of subjects with 
available Day 3–5 AUC0-24 (N=10). For higher S. pneumoniae MICs (up to 0.125 μg/mL), 
therapeutic exposures were observed in ≥80% of subjects with available Day 3–5 AUC0-24 
Assuming a 10-fold higher exposure in ELF, therapeutic exposures in the lung would be expected 
in ≥90% of these adolescents (up to an MIC of 0.125 μg/mL). Drug exposure was therapeutic 
against S. pneumoniae MICs (up to 0.125 μg/mL) for the vast majority of adolescents in this study. 
Table 3 
Comparison of Adolescent and Adult PK Parameter Estimates in the 
CE01-119 Study 
Day  
Parameter 
Mean (SD) 
Adolescents 
(n=13)a 
Adult Valueb 
(n=14) 
 
Solithromycin 
  1 
C
max (μg/mL) 
0.97 (0.73) 
1.53 (0.55) 
AUC
0-24 (μg*h/mL) 
11.62 (8.55) 
17.9 (7.52) 
3/4/5 
C
max (μg/mL) 
0.74 (0.61) 
1.17 (0.36) 
AUC
0-24 (μg*h/mL) 
9.28 (6.30) 
16.7 (7.16) 
t
1/2 (h) 
5.65 (1.29) 
8.02 (1.34) 
AUC0–24, area under the concentration versus time curve at 24 hours; Cmax, maximum measured plasma 
concentration; n, number; SD, standard deviation; t½, half-life 
a. 
Not all parameters have a total of 13 adolescents contributing data, and subjects were treated for 3-5 days. 
b. 
Adults received an 800-mg single dose on Day 1 and 400 mg daily on Days 2-5. Data were taken from study 
CE01-110. 
Solithromycin PK in adolescents (12 to <17 years) and children (<12 years) following oral 
(capsules, suspension) and intravenous administration was further investigated in a phase 1, open-
label, multi-center study (protocol CE01-120). Across both Phase 1 studies, 23 adolescents aged 
12 to 17 years (10 IV, 13 oral), 34 children 6 to <12 years (8 IV, 10 oral capsules and 17 oral 
suspension), 17 children 2 to <6 years (8 IV and 9 oral suspension) and 23 children <2 years 
(8 IV and 16 oral suspension) have been enrolled. Population pharmacokinetic modeling was used 
to determine the dosing regimens for oral and intravenous dosing from the data collected.  
5.2.3 
Summary of Efficacy 
Three randomized, double-blind efficacy studies in CABP with oral solithromycin have been 
completed. One open-label efficacy study in uncomplicated urogenital gonorrhea (GC) with single 
dose oral solithromycin has been completed. 
The Phase 2 oral CABP study (CE01-200) compared 5-day regimens of solithromycin (800 mg×1 
on Day 1 followed by 400 mg QD on Days 2-5) and levofloxacin (750 mg QD Days 1-5). One 


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hundred thirty-two patients were enrolled and randomized (1:1) to solithromycin or levofloxacin. 
A total of 132 patients were randomized; 65 were randomized to receive solithromycin and 
67 were randomized to receive levofloxacin.  
In the ITT population at TOC, clinical success was observed in 55 (84.6%) patients randomized to 
receive solithromycin and 58 (86.6%) patients randomized to receive levofloxacin. In the 
CE population, clinical success was observed in 46 (83.6%) patients who received solithromycin 
and 54 (93.1%) patients who received levofloxacin. Early clinical success at Day 3 (according to 
the proposed Biomarkers Consortium criteria) was observed for 47 (72.3%) and 48 (71.6%) 
patients in the solithromycin and levofloxacin groups, respectively. 
The Phase 3 CABP Studies CE01-300 and CE01-301, were randomized, double-blind, active-
controlled, multi-center, non-inferiority studies with moxifloxacin as the active comparator.  
In the oral Study CE01-300, the dosing regimen of solithromycin evaluated was 800 mg as a single 
dose on Day 1 followed by 400 mg QD on Days 2 through 5, with blinded placebo taken on Days 6 
and 7. The oral moxifloxacin dosing regimen in CE01-300 was 400 mg QD on Days 1 through 7. 
In the IV to oral Study CE01-301, all patients in both treatment groups received IV treatment on 
Day 1. Patients continued on IV treatment during the 7-day treatment course until predefined oral 
switch criteria related to clinical improvement were met and the Investigator felt it was appropriate 
to transition the patient to oral drug. Patients remained on IV treatment for the full 7 days if they 
did not meet the oral switch criteria or at the Investigator’s discretion. The dosing regimen, whether 
IV to oral or IV only was 7 days. Patients randomized to solithromycin received 400 mg IV as a 
single dose on Day 1 and on all subsequent IV dosing days. For patients who transitioned to oral 
treatment in the solithromycin group, the first oral dose of solithromycin following IV therapy was 
800 mg administered as a single dose, followed by 400 mg oral QD for the remainder of the study 
drug administration period. Moxifloxacin was administered as a 400 mg QD dose whether it was 
an IV or oral dosing day. 
Solithromycin demonstrated non-inferiority to moxifloxacin in the treatment of CABP in each 
Phase 3 study. 
5.2.3.1 
Primary Efficacy Outcome: Early Clinical Response (ECR) 
Table 4 provides a summary of the primary efficacy outcome, ECR in the ITT population, in the 
individual and pooled Phase 3 CABP studies. ECR was defined as improvement at 72 hours 
(Day 4) after the first dose of study drug in at least 2 of the following 4 cardinal symptoms of 
CABP: cough, dyspnea/shortness of breath, chest pain due to pneumonia and difficulty with 
sputum production. 
Solithromycin and moxifloxacin ECR responder rates in the ITT population were similar in each 
Phase 3 study and in the pooled studies, approximately 78 to 79% of patients. Solithromycin was 
non-inferior to moxifloxacin for the ECR outcome in each study and in the pooled studies. The 
lower limit of the 95% confidence interval (CI) around the treatment difference in responder rates 
(solithromycin minus moxifloxacin) was greater than the prespecified NI boundary of -10%. 


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Table 4  
Primary Efficacy Outcome: Early Clinical Response in Individual Phase 3 
Studies and Pooled Studies 
Early Clinical 
Response 
Study CE01-300 
Study CE01-301 
Pooled Phase 3 Studies 
Solithromycin 
Oral 
(N=425) 
n (%) 
Moxifloxacin 
Oral 
(N=431) 
n (%) 
Solithromycin 
IV to Oral 
(N=434) 
n (%) 
Moxifloxacin 
IV to Oral 
(N=429) 
n (%) 
Solithromycin 
Pooled 
(N=859) 
n (%) 
Moxifloxacin 
Pooled 
(N=860) 
n (%) 
Responder 
332 (78.1) 
336 (78.0) 
344 (79.3) 
342 (79.7) 
676 (78.7) 
678 (78.8) 
Difference  
(95% CI) 
0.16 (-5.6,5.9) 
-0.46 (-6.1,5.2) 
-0.16 (-4.0,3.7) 
Nonresponder  
93 (21.9) 
95 (22.0) 
90 (20.7) 
87 (20.3) 
183 (21.3) 
182 (21.2) 
Nonresponder 
81 (19.1) 
83 (19.3) 
76 (17.5) 
78 (18.2) 
157 (18.3) 
161 (18.7) 
Indeterminate 
12 (2.8) 
12 (2.8) 
14 (3.2) 
9 (2.1) 
26 (3.0) 
21 (2.4) 
Source Data: pooled CE01-300 and CE01-301 data 
CI=confidence interval; N=number of patients in the ITT population; n=number of patients within a specific category. 
Notes: The time window for determining early clinical response was 72h -12/+36h for CE01-300 and 72h -13/+36h for 
CE01-301). Difference=For studies CE01-300 and CE01-301, difference in responder rates (solithromycin minus 
moxifloxacin). For the pooled Phase 3 studies, the weighted (by study) difference in responder rates is presented. 
Percentages were calculated as 100 x (n/N). For studies CE01-300 and CE01-301, the CI was calculated using an 
unadjusted continuity corrected Z-test. For the pooled Phase 3 studies, the CI was stratified (for study) and calculated 
using the method of Miettinen and Nurminen with the inverse variance of the difference used as stratum weights. Per 
the ISE SAP, patients from Site 710 in Study 300 were excluded from all pooled results, unless otherwise noted. 
ECR in the clinically evaluable (CE-ECR) population in each study was consistent with the results 
observed for the primary efficacy analysis in the ITT population. In the pooled studies, the ECR 
responder rates in the CE-ECR population were 81.5% in the solithromycin group compared with 
82.0% in the moxifloxacin group. Consistent results were observed in each study. 
In subgroup analyses in the ITT population, a consistent effect was observed for ECR responder 
rates by geographic region and in demographic subpopulations, e.g., age, weight, gender and 
ethnicity.  
Subpopulation analyses were also conducted for characteristics related to baseline disease severity 
Responder rates and treatment differences were consistent in analyses of patients classified as 
PORT II (treatment difference: 1.14; 95% CI: -5.1, 7.3) or PORT III/V (treatment 
difference: -0.93; 95% CI: -5.9, 4.0). No differences in responder rates were noted based upon 
prior history of asthma/COPD or receipt a single dose of a short-acting antibiotic within 7 days 
prior to randomization. 
5.2.4 
Summary of Safety  
As of 30 April 2016, more than 2000 subjects and patients received systemic exposure to 
solithromycin. The major source of safety data are the two Phase 3 pivotal studies in patients with 
CABP (n=856).  


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5.2.4.1 
Overview of Adverse Events 
Macrolides, as a class, are well-tolerated and widely utilized. The most common AEs reported 
with the use of existing macrolides are GI, such as diarrhea, nausea and vomiting; others include 
headache and dizziness. 
Oral solithromycin has been well tolerated, the most common AEs being mild GI events in Phase 1 
and 2 trials. The most common AEs in the Phase 1 IV trials were related to infusion site tolerability; 
there were no other unique AEs relative to events reported in oral trials.  
Infrequent reports of local and systemic allergic reactions have occurred with oral and 
IV solithromycin, including anaphylaxis, urticaria, erythema and maculopapular rashes. 
The AE profile of the 5-day CABP regimen compared favorably with that of levofloxacin in the 
Phase 2 CABP trial. In the Phase 3 oral CABP study, solithromycin demonstrated a similar 
AE profile to that of moxifloxacin. In the Phase 2 GC study, the most common AEs were mild GI 
disorders, primarily diarrhea and nausea. Although both doses were acceptably tolerated, 
treatment-related GI AEs occurred less frequently with the 1000 mg dose than with 1200 mg. 
In the Phase 3 oral CABP study, 6 (1.4%) patients in the solithromycin group and 6 (1.4%) patients 
in the moxifloxacin group died during the study. None of the SAEs resulting in death was 
considered related to study drug. A total of 28 (6.6%) patients in the solithromycin group and 
27 (6.3%) patients in the moxifloxacin group reported at least 1 non-fatal SAE. No patient in either 
treatment group had an SAE that was considered related to study drug. The most common AEs 
observed in patients receiving solithromycin were headache (4.5%) and diarrhea (4.2%). 
In the Phase 3 IV to oral CABP study, 5 (1.2%) patients in the solithromycin group and 7 (1.6%) 
patients in the moxifloxacin group died during the study. None of the SAEs resulting in death was 
considered related to study drug. A total of 30 (6.9%) patients in the solithromycin group and 
23 (5.4%) patients in the moxifloxacin group reported at least 1 non-fatal SAE. Only 3 SAEs were 
considered related to study drug by the investigators (urticaria and anaphylactic reaction in 
1 patient each in solithromycin and anaphylactic reaction in 1 moxifloxacin patient). The most 
frequently reported infusion site related TEAEs were infusion site pain (10.4%), infusion site 
phlebitis (10.0%) and infusion related reaction (6.5%). Infusion site related TEAEs were mostly 
mild or moderate in intensity and infrequently led to discontinuation of study drug or withdrawal 
from the study (in 1 moxifloxacin and 10 solithromycin patients). Apart from infusion site related 
events, the most common AEs observed in patients receiving solithromycin were diarrhea (5.9%) 
and headache (4.2%) 
In the adolescent oral phase 1 study (CE01-119), 12 AEs were reported, of which 9, including 
1 SAE (limb abscess), were unrelated to solithromycin. Three subjects had AEs related to study 
drug: 2 separate episodes of mild headache and 1 episode of increased transaminases (<3×ULN).  
The most common AEs reported after multiple IV doses were general disorders and administrative 
site conditions (infusion-related pain) followed by nervous system disorders and vascular disorders 
(phlebitis), with the majority mild in severity. 


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Solithromycin, like most antibiotics and like all macrolide antibiotics, has been associated with 
hepatic aminotransferase elevations. In the pooled Phase 3 CABP trials, ALT elevations to 
>3×ULN, >5×ULN and >10×ULN were seen in 7.2%, 2.4% and 0.1% of solithromycin recipients 
compared to 3.6%, 1.0% and 0.2% of moxifloxacin recipients. Elevations of ALT to >3×ULN 
were 5.4% in the oral study and 9.1% in the IV to oral study. These elevations were typically 
asymptomatic, not associated with bilirubin elevation and readily reversible, with improvement in 
many cases seen during continued dosing. There have been no Hy’s Law cases. 
Multiple lines of evidence point to an exposure-response relationship for ALT elevation with 
solithromycin. 
In the pooled Phase 3 CABP studies, rates of bilirubin elevation to levels >ULN were comparable 
between solithromycin and moxifloxacin (4.3% vs 4.0%, respectively), and elevations >2×ULN 
were uncommon (<0.5%) in both treatment groups. Solithromycin was more frequently associated 
with alkaline phosphatase elevation to >1.5×ULN than moxifloxacin (5.2% versus 2.9%, 
respectively), consistent with the potential to induce mild degrees of cholestasis, as has been 
observed with older macrolides and other antibiotics. 
Solithromycin was generally well tolerated in subjects with cirrhosis of Child Pugh Class A, B and 
C severity in a controlled Phase 1 trial. In the Phase 3 CABP studies, the overall incidence of AEs 
was similar among subjects with and without hepatic impairment. ALT elevation to >5×ULN 
occurred with identical frequency among patients with and without hepatic impairment (2.4%), 
and AST elevation >5×ULN occurred in 1 patient with baseline hepatic impairment. 
Analysis of ALT elevation by patient characteristics including age, sex, race, history of chronic 
liver disease and concomitant exposure to statins have not revealed a population at particular risk 
for these events.  
While solithromycin can cause asymptomatic, reversible ALT elevation and mild degrees of 
cholestasis, the overall liver safety profile of clinically important events was comparable to 
moxifloxacin and may be comparable to the older macrolides. 
When solithromycin is taken for longer than 7 days, rare cases of jaundice and itching have 
occurred. These events were reversible after solithromycin treatment was stopped. 
Macrolides have been associated with QT prolongation and risk for torsades de pointes. In 
March 2013, the FDA warned the public that azithromycin may cause fatal heart rhythm 
disturbances, particularly in patients with known risk factors. A thorough QT study of 
solithromycin was negative, demonstrating that solithromycin does not have a propensity to 
prolong the QT interval in a clinically significant manner in healthy subjects.  
In the pooled Phase 3 CABP studies, cardiac AEs were observed more frequently in moxifloxacin 
recipients (4.7%) than solithromycin recipients (3.0%). Most of these events reflected the 
underlying chronic diseases of enrolled patients in the context of the severe physiologic stress of 
CABP and were not considered study drug related.  


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The thorough QT study revealed that healthy subjects with supratherapeutic exposure to 
solithromycin experience an increase in heart rate. The exact mechanism for this effect is unknown, 
although a variety of receptors and cardiac channels have been evaluated in vitro. However, in the 
Phase 3 studies, the central tendency for observed heart rate was a decline from baseline over time 
comparable to that observed with moxifloxacin, as the physiologic stressors of CABP diminished 
with response to therapy. Fewer patients receiving solithromycin than moxifloxacin experienced 
a potentially clinically significant tachycardia (>120 bpm) that was associated with an increase 
over baseline of ≥15 bpm (1.3% and 1.8%, respectively).  
In the Phase 3 studies, categorical changes from baseline in the QTcF interval of >30 msec 
occurred less frequently with solithromycin (16.7%) than with moxifloxacin (28.0%). Post-
baseline changes resulting in a QTcF >500 msec occurred in <1% of patients in both treatment 
groups. Based on these data and the results of the thorough QT study, it is clear that solithromycin 
does not present intrinsic QT prolongation risks. However, as a CYP3A4 inhibitor, solithromycin 
may pose secondary risk of QT prolongation through inhibition of metabolism of other 
QT-prolonging drugs.  
5.3 
Rationale for the Present Study 
Although there is evidence of efficacy and safety of solithromycin in adults, the safety and efficacy 
of solithromycin have not been established in children. There is evidence of similarities in children 
and adults in 1) CABP definitions and pathophysiology, 2) causative organisms, 3) response to 
intervention and 4) exposure-response relationship. Therefore, extrapolation of efficacy in 
pediatric subjects from adult clinical trial efficacy data is reasonable. A safety study in pediatric 
subjects with CABP, however, is needed to compare the safety and tolerability of solithromycin 
to comparators. The proposed study will gather necessary safety data and, as a secondary objective, 
provide an assessment of solithromycin efficacy as CABP treatment in pediatric subjects.  
5.4 
Rationale for the Dosage Regimen 
The dosing regimens to be studied are intended to provide therapeutic solithromycin exposures 
against CABP, as efficacy in pediatric subjects with CABP will be extrapolated from the results 
in the phase 3 adult CABP trials. The dosing regimens for each age group and each of the 
3 formulations (capsule, IV infusion, and suspension) were determined in phase 1 studies in 
children.  
Data from two phase 1 studies in children (N=92) were merged and used to develop a population 
PK model that informs dosing for this study for all formulations. A two compartment model with 
linear elimination characterized the solithromycin data following both oral (capsule and 
suspension) and intravenous administration. To account for the growth effects, actual body weight 
was included in the model using allometric scaling. Using the final model, Monte Carlo 
simulations were performed to identify pediatric dosing that matches adult exposure (area under 
the concentration versus time curve from 0 to 24 hours and maximal drug concentrations after 
multiple doses) observed in the phase 3 program.  
The selected dosing regimen for adolescents (12-17 years) receiving solithromycin via oral 
administration (capsules or suspension) was 800 mg on Day 1 and 400 mg on Days 2-5 if they 
weigh ≥40 kg. For subjects 12 to 17 years and <40 kg, a capsule dosing regimen of 20 mg/kg on 


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Day 1 (800 mg maximum) and 10 mg/kg on Days 2-5 (400 mg maximum) was selected based on 
simulated exposure (Figure 2). Suspension dosing for adolescents was selected based on data 
obtained from a bioequivalence study in adults between capsules and suspension and the similar 
bioavailability estimates obtained for both formulations in the population PK model.  
Figure 2 
Simulated Day 5 Exposure following a Capsule Dose of 20 mg/kg on Day 1 
and 10 mg/kg on Days 2-5.  
 
Note: Doses rounded upward to the nearest 200 mg. The dashed line represents an adult Day 4 AUC0-24 of 
12.6 mcg*h/mL.  
For the suspension dosing for children <12 years of age, a dose of 20 mg/kg on Day 1 (800 mg 
maximum) and 10 mg/kg on Days 2-5 (400 mg maximum) resulted in a comparable simulated 
Day 5 AUC0-24 across pediatric age groups (Figure 3). Although the median simulated exposure 
appears to be lower in the 0-2 years age group, the simulated exposure was within the range 
observed in adults and it’s possible that the observed values may be higher due to immature 
CYP3A4 metabolism in this age group.  
0
20
40
60
12-17yrs,<40kg
12-17yrs,≥40kg
6-12yrs,<40kg
6-12yrs,≥40kg
excludes outside values


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Figure 3 
Simulated Day 5 Exposure following a Suspension Dose of 20 mg/kg on 
Day 1 and 10 mg/kg on Days 2-5  
 
Note: The dashed line represents an adult Day 4 AUC0-24 of 12.6 mcg*h/mL. There is only one subject in the 2-6 years 
≥ 40 kg category   
Intravenous daily dosing of 8 mg/kg resulted in comparable simulated Day 5 AUC0-24 across all 
pediatric age groups: median (standard deviation) 14.4 mcg*h/mL (23.4) for 12-17 years; 
14.1 mcg*h/mL (25.4) for 6-<12 years; 11.0 mcg*h/mL (26.0) for 2-<6 years; and 9.4 mcg*h/mL 
(19.1) for 0-<2 years. The adult exposure used for matching purposes was 12.6 mcg*h/mL.  
Because of the complete efficacy extrapolation approach to determination of efficacy in the 
pediatric population, the duration of study drug regimens are the same as those in adults. Oral-only 
dosing is for 5 days intravenous-only and IV-to-oral dosing are for 7 days duration.  
5.5 
Rationale for the Comparator  
Comparators were selected following review of the Pediatric Infectious Diseases 
Society/Infectious Diseases Society of America guidelines for empiric therapy of CABP 
(Bradley 2011), recent publications on CABP therapy in children (Aurangzeb 2003; Kogan 2003; 
Bradley 2007; Awashti 2008; Ribeiro 2011; Lodha 2013), and the most recently conducted trials 
of CABP in children listed on ClinicalTrials.gov (www.clinicaltrials.gov). The group of acceptable 
0
10
20
30
40
50
6-12yrs,<40kg
6-12yrs,≥40kg
2-6yrs,<40kg
2-6yrs,≥40kg
0-2yrs,<40kg
excludes outside values


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comparator drugs was selected to include drugs commonly used per standard of care in both the 
U. S. and at international sites participating in this trial.  
6 
STUDY OBJECTIVES 
Primary  
• Evaluate the safety and tolerability of solithromycin in adolescents and children with CABP 
Secondary  
• Evaluate the efficacy of solithromycin in adolescents and children with CABP 
• Evaluate the population PK of solithromycin in adolescents and children with CABP  
7 
STUDY DESIGN 
This is a phase 2/3, randomized, open-label, active-control, multi-center study to assess the safety 
and efficacy of solithromycin in children and adolescents with CABP. Approximately 400 subjects 
(~300 in the solithromycin group and ~100 in the comparator group) will be enrolled. 
Randomization will be stratified by age group (12 through 17 yo, 6 to <12 yo, 2 to <6 yo, and 
2 months to <2 yo). At least 40 subjects will be randomized into each age group.  
Subjects who meet all inclusion/exclusion criteria and sign the informed consent/assent will be 
enrolled. Subjects will be randomized to receive solithromycin or a comparator antibiotic, 
administered IV and/or by mouth (PO) based on weight and age. Subjects will be treated daily for 
5 to 7 days with oral solithromycin and 5 to 7 days with IV or IV-to-oral solithromycin. Subjects 
will be treated for 5 to 10 days with comparator antibiotics. Subjects will have safety and efficacy 
assessments during and after treatment.  
7.1 
Duration of Subject Participation 
The duration of subject participation from signing the informed consent form (ICF) will be 
approximately 32 days (includes up to 10 days of study drug/comparator drug administration, a 
follow-up visit at 16 days [± 4 days] after randomization,  AE monitoring for 16 (±4) days, and 
SAE monitoring for 28 (±4) days  post-randomization). Adverse event monitoring 28 days after 
randomization can be conducted by telephone/other media visit. The study duration from first 
subject first visit until last subject last visit will be approximately 24 months. 
7.2 
Number of Subjects 
Approximately 400 subjects ≥2 months to 17 years of age, inclusive, will be enrolled as follows: 
• 
Age Group 1: Adolescents from 12 years to 17 years, inclusive  
• 
Age Group 2: Children from 6 years to <12 years  
• 
Age Group 3: Children from 24 months to <6 years  
• 
Age Group 4: Infants from ≥2 months to <24 months 


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A minimum of 40 subjects will be enrolled in each age group. Approximately 20% of subjects will 
be enrolled at U.S. centers.  
7.3 
Study Drug Dosage and Administration 
Solithromycin will be administered IV or PO according to Table 5 through Table 8 below. If dosing 
begins with oral therapy, the Day 1 dose will be a loading dose. No loading doses are used with 
IV solithromycin administration or if switched to oral administration. An IV-to-PO switch can 
occur after the first IV dose. Subjects starting with oral therapy will receive 5 days of solithromycin 
treatment, and those starting with IV therapy (regardless of if and when they switch to oral 
therapy), will receive 7 days of solithromycin treatment. 
For subjects receiving the capsule formulation, 200 mg solithromycin capsules will be used to 
provide the absolute dose of either 200 mg, 400 mg, or 800 mg. The capsule dose will be rounded 
upwards to the nearest 200 mg, not to exceed an 800 mg loading dose and 400 mg maintenance 
dose. Study drug should be swallowed with water approximately every 24 hours and at 
approximately the same time each day (±4 hours). Study drug can be taken without regard to food.  
Table 5 
Capsule Dosing Regimens 
Age 
(years) 
Weight 
Route 
Formulation 
Day 1 
(Max dose: 800 mg)  
Days 2 to 5 
(Max dose: 400 mg)  
6 to 17 
>30 kg 
PO 
Capsules 
800 mg 
400 mg 
>20 to 30 kg 
PO 
Capsules 
600 mg 
400 mg 
≤ 20 kg 
PO 
Capsules 
400 mg 
200 mg 
Subjects requiring an oral dosage form other than capsules will receive suspension formulation, 
provided at 275 mg/5 mL strengths, to achieve the age-appropriate mg/mL and solithromycin dose. 
Any dosing variations within 10% of the calculated suspension dose is not considered a deviation. 
Table 6 
Suspension Dosing Regimens 
Age 
(years) 
Route 
Formulation 
Day 1 
(Max dose: 800 mg)  
Days 2 to 5 
(Max dose: 400 mg)  
12 to 17 
PO 
Suspension 
20 mg/kg (800 mg) 
10 mg/kg (400 mg) 
6 to <12 
PO 
Suspension 
20 mg/kg 
10 mg/kg 
2 to <6 
PO 
Suspension 
20 mg/kg 
10 mg/kg 
2 mo to <2 
PO 
Suspension 
20 mg/kg 
10 mg/kg 
No loading doses are used with IV solithromycin administration. Intravenous solithromycin should 
be infused over approximately 60 minutes (±20 minutes) approximately every 24 hours (±4 hours). 
Changes to the infusion duration should be discussed with the study medical monitor prior to study 
drug administration. Any dosing variations within 10% of the calculated IV dose is not considered 
a deviation. 


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Table 7 
Intravenous Dosing Regimens 
Age 
(years) 
Route 
Formulation 
Days 1 to 7 
(Maximum dose: 400 mg)  
12 to 17  
IV 
Solution 
8 mg/kg 
6 to <12 
IV 
Solution 
8 mg/kg 
2 to <6 
IV 
Solution 
8 mg/kg 
2 mo to <2 
IV 
Solution 
8 mg/kg 
A subject can be converted from the IV to an oral formulation following 1 or more IV doses. The 
first oral dose will be 10 mg/kg with a maximum of 400 mg.  
Table 8 
Intravenous to Oral Dosing Regimens 
Age 
(years) 
Route 
 Oral Formulation 
Day 1 to Last IV 
Dosing Day 
(Max dose: 400 mg)  
First Oral Dosing Day 
to Day 7 
(Max dose: 400 mg)a  
12 to 17 
IV/PO 
Suspension or Capsules 
8 mg/kg 
10 mg/kg (400 mg) 
6 to <12 
IV/PO 
Suspension or Capsules 
8 mg/kg 
10 mg/kg 
2 to <6 
IV/PO 
Suspension 
8 mg/kg 
10 mg/kg 
2 mo to <2 
IV/PO 
Suspension 
8 mg/kg 
10 mg/kg 
a. 
The adult dose should be administered unless the subject weighs <40 kg, in which case they receive 10 mg/kg 
on the first oral dosing day through Day 7. The capsule dose is rounded upwards to the nearest 200 mg.  
Comparator drug: 
Comparators will be selected according to age and are consistent with current recommendations 
for treatment of CABP in children. A dosing table is provided below.  
Children ≥2 months to <5 years of age: 
a. Ceftriaxone IV OR 
b. Ampicillin IV  or amoxicillin IV  OR 
c. Amoxicillin-clavulanic acid PO or IV or amoxicillin PO 
Children 5 to 17 years of age (inclusive): 
a. Ceftriaxone IV OR 
b. Ampicillin IV  or amoxicillin IV  OR 
c. Amoxicillin-clavulanic acid PO or IV  or amoxicillin PO 
Azithromycin IV/PO or erythromycin lactobionate IV or erythromycin PO may be added to any 
of three treatment regimens above. Azithromycin is also acceptable as a first line of treatment.  


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Table 9 
Recommended Comparator Regimens 
 
United States 
Rest of the World  
Amoxicillin 
45-90 mg/kg/day orally in 2 or 3 divided 
doses; not to exceed 3 g/day 
45-90 mg/kg/day orally in 2 or 3 divided 
doses; not to exceed 3 g/day 
 
50-100 mg/kg/day intravenously in equally 
divided doses every 6 hours 
Amoxicillin-
clavulanic acid 
(oral) 
Children <40 kg: amoxicillin component  
90 mg/kg/day orally in divided doses 
given every 12 hours [4000 mg/day max 
dose] 
 
Children ≥40 kg, 875 mg orally every 12 
hours or 500 mg orally every 8 hours 
[4000 mg/day max dose] 
Children <40 kg: 20 mg/5 mg/kg/day to 60 
mg/15 mg/kg/day given orally every 8 
hours 
 
Children ≥ 40 kg: One 500 mg/125 mg 
dose given orally every 8 hours 
Amoxicillin-
clavulanic acid 
(IV) 
 - 
Children >4kg but< 40kg: amoxicillin 
component 25 mg/kg intravenously every 
8 hours [1000 mg max dose] 
 
Children ≥ 40 kg: amoxicillin component 
1000 mg intravenously every 8 hours 
Ampicillin 
150-200 mg/kg/day intravenously in 
equally divided doses every 6 hours 
- 
Azithromycin 
10 mg/kg intravenously/orally on day 1 
[500 mg maximum dose] followed by 
5 mg/kg orally every 24 hours  
[250 mg maximum dose] 
10 mg/kg orally on day 1 [500 mg 
maximum dose] followed by 5 mg/kg orally 
every 24 hours [250 mg maximum dose] 
Ceftriaxone 
50-75 mg/kg/day intravenously in equally 
divided doses every 12 hours; total daily 
dose should not exceed 2 g 
50-80 mg/kg intravenously once daily 
Erythromycin 
40 mg/kg/day orally every 6 hours 
30-50 mg/kg/day orally every 6 hours 
Erythromycin 
lactobionate 
15 to 20 mg/kg/day intravenously in 
equally divided doses every 6 hours 
50 mg/kg/day intravenously/orally in 
equally divided doses every 6 hours 
Note: if doses of comparator drugs noted in the dosing table above differ those prescribed per standard of care, a site 
can use the locally prescribed dose.  
IV-to-PO switch:  
Subjects receiving an IV comparator drug (i.e., ceftriaxone, ampicillin) in any age group may be 
switched to oral treatment using amoxicillin-clavulanic acid PO (amoxicillin component, 
45 mg/kg every 12 hours; subjects weighing ≥40 kg, 875 mg every 12 hours or 500 mg every 
8 hours) or amoxicillin alone (45 mg/kg every 12 hours, up to a maximum of 4 g/day).  
Subjects must receive 5 to 10 days of treatment with comparator. The exact duration of treatment 
may be determined at the investigator’s discretion. 
7.4 
Data Monitoring Committee 
An independent data monitoring committee (DMC) will be created and a DMC charter developed 
that defines the scope and schedule of its activities. The DMC charter will pre-specify rules 


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governing safety reporting, analyses, and study activities (i.e., stopping rules). The DMC will be 
charged with assessing the overall study status and safety of subjects at intervals outlined in their 
charter and also in response to emergent data that might require unscheduled evaluation. The DMC 
will make recommendations to the sponsor with regard to continuing or modifying the study 
conduct based on these assessments.  
7.5 
Age Group Initiation 
Enrollment will occur simultaneously for all age groups.  
7.6 
Stopping Rules 
The DMC will establish through its charter rules to govern study activities. The DMC will assess 
overall study status and subjects. In general, it is anticipated that new enrollment and dosing will 
be halted for a DMC-guided safety review if serious unexpected adverse reactions occur in 
≥2 subjects in any single age group. The DMC will make recommendations to the sponsor 
regarding resumption of the study. 


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8 
SELECTION OF STUDY POPULATION 
The following criteria for enrollment must be followed. The subject will not be enrolled unless the 
inclusion/exclusion criteria are met. The investigator or other study site personnel must document 
in the source documents that the ICF and assent form (as applicable) were signed and dated prior 
to study screening. The date the ICF was obtained will be recorded in the source documents and 
electronic case report form (eCRF). The presence of inclusion criteria and absence of exclusion 
criteria will be verified in the eCRF.  
8.1 
Inclusion Criteria 
1. Written informed consent from parent or other legally acceptable representative and 
informed assent from subject (if age appropriate according to local requirements) 
2. ≥2 months to 17 years of age, inclusive  
3. Requiring hospitalization, emergency room, or urgent care visit   
4. Presence of CABP based on the following criteria within 72 hours of randomization: 
• 
History of and/or documented fever (rectal, temporal, ear, or oral temperature ≥38°C or 
axillary temperature ≥37.5°C) or hypothermia (rectal, temporal, ear, or oral temperature 
<35°C or axillary temperature <34.5°C) 
AND 
• 
Chest radiograph infiltrates consistent with bacterial pneumonia (or pneumonia caused 
by atypical bacterial agents); if a subject is outpatient and starting on oral therapy, a 
radiograph is not required.  
AND 
• 
Presence of at least 2 of the following signs or symptoms: 
a. Cough  
b. Difficulty breathing  
c. Production of purulent sputum 
d. Chest pain 
e. Grunting  
f. Hypotension  
g. Tachycardia defined as follows:  
• 2 months to <24 months: ≥160 bpm 
• 24 months to <10 years: ≥140 bpm 
• ≥10 years: ≥100 bpm   
h. Tachypnea, defined as: 
• 2 months to <12 months: ≥50 breaths/minute  
• 12 months to <5 years: ≥40 breaths/minute 


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• ≥5 years: ≥ 20 breaths/minute 
i. Physical exam consistent with pulmonary consolidation 
AND 
• 
Presence of at least 1 of the following:  
a. Leukocytosis (≥12,000 white blood cells [WBC]/mm3) 
b. Leukopenia (<5 000 WBC/mm3)  
c. ≥ 10% immature neutrophils (bands) regardless of total peripheral WBC 
d. Elevated inflammatory markers (C-reactive protein or procalcitonin) 
e. Oxygen saturation <97% on room air 
f. Organism consistent with a typical respiratory pathogen identified from a blood culture 
or isolated from an appropriate respiratory culture/polymerase chain reaction (sputum 
in children old enough to produce an acceptable specimen; sample from the lower 
respiratory tract airways, if performed [e.g., bronchoalveolar lavage]; or pleural fluid 
culture) 
8.2 
Exclusion Criteria  
1. Confirmed or suspected respiratory-tract infection attributable to sources other than 
community-acquired bacterial pathogens (e.g., ventilator-associated pneumonia; hospital-
acquired pneumonia). 
2. Received >48 hours of potentially effective systemic antibacterial therapy for CABP 
immediately prior to randomization (exception: clinical or microbiological treatment failure or 
progression of signs or symptoms of CABP as determined by the investigator). 
3. Confirmed or suspected bacterial meningitis. 
4. Known active tuberculosis. 
5. Non-infectious causes of pulmonary infiltrates (e.g., cystic fibrosis, chemical pneumonitis 
from aspiration, hypersensitivity pneumonia). 
6. Evidence or history of clinically significant medical condition that may, in the assessment of 
the investigator, impair study participation or pose a significant safety risk or diminish the 
subject’s ability to undergo all study procedures and assessments. 
7. Hepatic dysfunction evidenced by ALT or AST >3times ULN or direct bilirubin greater than 
2 times ULN (if direct bilirubin values are not available in a time frame consistent with 
enrollment requirements, total bilirubin must be < 2times ULN). 
8. Treatment with the following drugs within 72 hours prior to first dose of study drug or expected 
to receive these drugs during the treatment phase: drugs that potently inhibit CYP3A4 
(nefazodone, fluconazole, ketoconazole,  conivaptan, diltiazem, verapamil, aprepitant, 
imatinib, protease inhibitors, clarithromycin, ciprofloxacin, erythromycin, itraconazole, 
mibefradil, posaconazole, telithromycin, and voriconazole); CYP3A4 inducers (rifampin, 
rifabutin, phenytoin, fosphenytoin, carbamazepine, phenobarbital, rufinamide, modafinil, 
armodafinil, etraverine, efavirenz, nevirapine, rilpivirine, bosentan, troglitazone, pioglitazone, 


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and St. John’s wort). In addition, the following drugs may not be co-administered with 
solithromycin in this trial due to the potential for adverse drug-drug interaction: digoxin, 
colchicine, midazolam, quinidine, ergotamine, dihydroergotamine, rivaroxaban, apixaban, 
dabigatran, edoxaban, cisapride, cyclosporine, sildenafil, astemizole, and alfentanil. 
9. Breast-feeding females. 
10. Positive pregnancy test in females of childbearing potential. 
11. History of anaphylaxis to macrolide antibiotics. 
12. Previous participation in this study. 
13. Has received any investigational drugs studied under an Investigational New Drug (IND) 
application in the U.S. or under a Clinical Trial Application in the relevant country outside of 
the U.S. where the subject is being enrolled, taken within 4 weeks before administration of the 
first dose of study drug.  
14. End Stage Renal Disease (dialysis requiring) OR severe renal impairment (defined as serum 
creatinine > 1.5 fold ULN for age).   
8.3 
Prior and Concomitant Treatment 
Reasonable efforts will be made to determine all relevant treatment (concomitant medications, 
including all prescription/non-prescription medications, herbal medications, and vitamin 
supplements; supportive therapies; and concomitant non-pharmacological treatments) received by 
the subject within 72 hours prior to randomization through the follow-up visit. All antibiotics taken 
within 7 days prior to first dose of study drug also need to be provided. The medication name, 
daily dose, and duration of the treatment/procedure (start and stop dates) will be recorded in the 
eCRF. Concomitant treatments (non-pharmacological treatments) include specific surgical or 
diagnostic procedures performed per routine medical care.  
8.3.1 
Permitted Treatment 
Medications to treat any other medical conditions or AEs the subject experiences during the study 
are permitted. Addition of expanded gram-positive coverage (clindamycin, vancomycin, linezolid, 
daptomycin) to treatment and comparator groups will be allowed if empiric therapy for MRSA is 
desired. Oral step-down therapy for subjects on comparator should be informed by antimicrobial 
susceptibility testing.  
8.3.2 
Prohibited Medications and Therapies 
For a list of prohibited medications taken prior to or during the study, see exclusion criteria 
(Section 8.2). If for any reason a subject requires any of the prohibited medications during the 
study, the investigator should discuss with the medical monitor prior to initiation of therapy. If a 
subject is unable to comply with these restrictions, the subject’s continued participation in the 
study will be re-evaluated by the investigator, in consultation with the medical monitor. 


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9 
STUDY DRUGS 
9.1 
Solithromycin (CEM-101) 
Solithromycin will be provided as hard gelatin capsules that contain 200 mg solithromycin, as a 
powder for oral suspension (POS), or as a lyophilized powder for infusion after reconstitution and 
dilution. The IV formulation of solithromycin (Solithromycin for Injection) is provided as a 
lyophilized formulation in 50 mL clear glass vials containing 400 mg of solithromycin for single 
use only. The lyophilized cake is reconstituted with sterile water for injection and then added to 
sterile 0.9% sodium chloride injection. Detailed instructions for reconstitution and dilution will be 
provided in the pharmacy manual. The inactive ingredients for all formulations will be listed in 
the pharmacy manual. Detailed instructions for the reconstitution of the powder for oral suspension 
to 275 mg/5 mL will be listed in the pharmacy manual. 
Solithromycin suspension contains aspartame and patients with phenylketonuria should be aware 
that the suspension contains 78 µg of phenylalanine (as a component of aspartame) per mL. 
9.2 
Comparator 
Comparator antibiotics may be administered “off the shelf” at the doses described above based on 
age range, local availability, and local treatment preferences. Comparator antibiotic preparation 
will be performed per local standard of care.  
9.3 
Study Drug Label and Packaging 
Cempra Pharmaceuticals or its designee will package study drug solithromycin. It will be labeled 
and supplied according to applicable regulatory requirements. 
Comparators will be procured by the site and the commercial labeling will be retained. 
9.4 
Study Drug Storage Conditions  
The investigator or an approved representative (e.g., pharmacist) will ensure that study drug 
(solithromycin) is stored in a locked secured area (with access limited to appropriate study 
personnel) only under recommended storage conditions and in accordance with applicable 
regulatory requirements.  
The oral capsules will be stored at controlled room temperature 59°F to 77°F (15°C to 25°C) and 
protected from light. Vials of lyophilized solithromycin should be stored at room temperature 
(15°C to 25°C; 59°F to 77°F) and protected from light. Daily temperature logs must be kept at the 
clinical site and all temperature excursions during storage must be reported to Cempra GCP QA 
to obtain approval for continued use. 
Once prepared, the reconstituted vials should be used within 2 hours when stored at room 
temperature; they should not be refrigerated or frozen. Room light exposure is allowed. Once the 
reconstituted solithromycin solution has been added to the saline bag, the infusion solution in the 
saline bag can be kept at room  


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temperature (15°C to 25°C; 59°F to 77°F) for up to 12 hours or stored refrigerated for up to 
24 hours before use; the bag should not be frozen at any time. Room light exposure is allowed 
during preparation, storage, and patient administration. 
Solithromycin powder for suspension and the reconstituted suspension should be stored at a 
controlled room temperature of 15°C to 25°C (59°F to 77°F) and protected from light and moisture. 
The suspension should be used within 10 days of reconstitution.  
Comparator study drug should be stored per the recommendations noted on the products drug label. 
9.5 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized separately within each age group in a 3:1 ratio of solithromycin to 
comparator antibiotics using blocked randomization. The randomization schedule will be 
generated by Duke Clinical Research Institute (DCRI) team (or designee) using the clinical 
database randomization module. Subjects randomized into the study will be assigned the treatment 
corresponding to the next available number in the respective stratum of the computer-generated 
randomization schedule. The subject will only be randomized after the inclusion and exclusion 
criteria are verified.  
9.6 
Blinding 
This study will be open-label with a blinded health care professional designated as a 
subinvestigator at each site. The blinded subinvestigator will be responsible for conducting the 
clinical outcome (efficacy) assessments.  
9.7 
Receipt of Supplies 
Upon receipt of the study drug, the pharmacist or designated study site personnel will visually 
inspect the shipment and verify the drug information, quantity, and condition of the kits received. 
The Study Drug Transmittal and Receipt Form will be completed, signed by the pharmacist or 
designated study site personnel, and forwarded to Cempra Pharmaceuticals (or its designee). The 
original signed form should be filed with the inventory/drug accountability records.  
9.8 
Study Drug Accountability  
9.8.1 
Overall 
It is the responsibility of the investigator to ensure that a current record of inventory/drug 
accountability is maintained. Inventory records must be readily available for inspection by the 
study monitor and available to regulatory agencies for inspection at any time.  
9.8.2 
Study Drug Handling and Return  
Upon the completion or termination of the study, and upon written authorization from Cempra or 
its representative, all unused and/or partially used study drug should be returned or destroyed at 
the investigational site, as specified by Cempra. It is the investigator’s responsibility to ensure that 
Cempra or its representative has provided written authorization that procedures for proper disposal 


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of the study drug have been established, and that appropriate records of the disposal are 
documented and maintained. No unused study drug may be disposed of until fully accounted for 
by the Cempra monitor (or designee). 
10 
STUDY ASSESSMENTS AND PROCEDURES  
Assessments and procedures will be performed at the time points indicated below. 
10.1 Baseline or Screening Study Procedures (Day -3 to -1) 
The following evaluations will be obtained and recorded on the eCRF (as applicable) after the ICF 
and assent (if applicable) a signed. Laboratory tests, non-pharmacologic procedures, and imaging 
studies that are considered standard of care and that were performed within 72 hours prior to the 
first dose of study drug may be used for screening procedures.  
1. Demographics (date of birth, sex, race, ethnicity) 
2. Inclusion/exclusion criteria determination as described in Sections 8.1 and 8.2.  
3. Significant past and present medical/illness history (medical history diagnoses included in 
current admission/emergency/urgent care note)  
4. Physical examination including height; weight; head, eyes, ears, nose, throat (HEENT); 
heart, lungs, abdomen, skin, and extremities. 
5. Vital signs (blood pressure, heart rate, respiratory rate, and temperature) 
6. Chest x-ray; if a subject is outpatient and starting on oral therapy, an x-ray is not required 
7. Obtain study-required safety labs as described in Section 10.4.1.1. 
8. Document standard-of-care safety labs as described in Section 10.4.1.2.  
9. Document microbiology assessments as described in Section 10.4.2.  
10. Document radiological imaging as described in Section 10.4.3.  
11. Document non-pharmacologic treatments as described in Section 10.4.3.  
12. Pregnancy test in females of childbearing potential 
13. Record all prior and concomitant medications other than antibiotics taken within 72 hours 
prior to first dose of study drug and all antibiotics taken within 7 days prior to first dose of 
study drug. 
14. Perform clinical outcomes assessment as describe in Section 10.6. 
15. Randomization 
10.2 Treatment Period Procedures 
10.2.1 
Treatment Days up to Last Day of Treatment 
1. Every effort should be made to obtain safety labs 72 hours (±24 hours) after the first dose 
to include ALT, AST, alkaline phosphatase, total and direct bilirubin, and WBC with 


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differential. A separate study sample is not required if these labs are obtained at 72 hours 
(±24 hours) after the first dose per standard of care. 
2. Document physical examination if available per standard of care on the day of clinical 
outcome assessment only.  
3. Document vital signs if available per standard of care on the day of clinical outcome 
assessment only. 
4. Document standard-of-care safety labs as described in Section 10.4.1.  
5. Document microbiology assessments as described in Section 10.4.2.  
6. Document radiological imaging as described in Section 10.4.3.  
7. Document non-pharmacologic treatments on the day of clinical outcome assessment only 
as described in Section 10.4.3.  
8. If the screening visit for females occurred more than 24 hours before receiving the study 
drug, a pregnancy test will be performed prior to first dose of study drug. 
9. Review and record concomitant medications as described in Section 8.3. 
10. Administer study drug. If the subject is an outpatient and receiving study drug orally, a 
dosing diary is included on the capsule blister pack and the label for the suspension. This 
diary should be completed for each dose taken and brought back to each visit for review 
and accountability. 
11. Obtain PK samples as described in Section 10.4.3. 
12. Review and record any AEs and SAEs as described in Section 12.1. 
13. Perform clinical outcomes assessment once on days 3–5 (ECR) if the subject is available. 
A return visit is not required to perform the outcomes assessment. 
10.2.2 
Last Day of Treatment (+48 Hours) 
1. Perform physical examination on the last day of dosing or within 48 hours after the last 
dose. 
2. Obtain vital signs on the last day of dosing or within 48 hours after the last dose. 
3. Perform safety labs as described in Section 10.4.1. Safety labs must be collected on the last 
day of dosing or within 48 hours after the last dose. A separate study sample is not required 
if safety labs above are obtained on the last day of dosing or within 48 hours after the last 
dose per standard of care. 
4. Document microbiology assessments as described in Section 10.4.2.  
5. Document radiological imaging as described in Section 10.4.3.  
6. Document non-pharmacologic treatments as described in Section 10.4.3 
7. Review and record concomitant medications as described in Section 8.3. 
8. Administer study drug and active comparator. If the subject is an outpatient and receiving 
study drug orally, a dosing diary is included on the capsule blister pack and the label for 


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the suspension. This diary should be completed for the last day of treatment and the diary 
should be returned to the study site at this visit for review and accountability. 
9. Obtain PK samples as described in Section 10.4.3. 
10. Review and record any AEs and SAEs as described in Section 12.1. 
11. Perform clinical outcomes assessment 
10.3 Follow-up Procedures 
10.3.1 
Day 16 Post Randomization (±4 days) 
1. Every effort should be made to obtain safety labs Day 16 (±4 days) after the first dose to 
include ALT, AST, alkaline phosphatase, total and direct bilirubin, and WBC with 
differential. A separate study sample is not required if these labs are obtained at Day 16 
(±4 days) after the first dose per standard of care. 
2. Perform physical examination including weight, HEENT, heart, lungs, abdomen, skin, 
and extremities. 
3. Perform vital signs (blood pressure, heart rate, respiratory rate, and temperature). 
4. Document standard-of-care safety labs as described in Section 10.4.1. 
5. Document microbiology assessments as described in Section 10.4.2.  
6. Document radiological imaging as described in Section 10.4.3.  
7. Document non-pharmacologic treatments as described in Section 10.4.3. 
8. Review and record any AEs and SAEs as described in Section 12.1. Every effort should 
be made to bring the subject back for follow up, but SAEs must be collected via 
phone/other media if the subject is unable or unwilling to return. 
9. Perform clinical outcomes assessment. 
10.3.2 
Day 28 Post Randomization (±4 days) 
1. Every effort should be made to obtain safety labs Day 28 (±4 days) after the first dose to 
include ALT, AST, alkaline phosphatase, total and direct bilirubin, and WBC with 
differential. A separate study sample is not required if these labs are obtained at Day 28 
(±4 days) after the first dose per standard of care. 
2. Review and record any SAEs as described in Section 12.1. Every effort should be made to 
bring the subject back for follow up, but SAEs must be collected via phone/other media if 
the subject is unable or unwilling to return. 
10.4 Laboratory Determinations  
10.4.1 
Safety Laboratory Tests 
Safety laboratories will include hemoglobin, hematocrit, WBC with differential, platelet count, 
blood urea nitrogen, calcium, serum creatinine, potassium, sodium, AST, ALT, ALP, total and 
direct bilirubin, and albumin. 


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10.4.1.1 
Study-Required Safety Laboratories 
All safety laboratory tests with values that become clinically significantly abnormal (as determined 
by the investigator) during the study should be repeated until the values return to baseline or normal 
values. If clinically significant abnormal laboratory values do not return to baseline or normal 
values within a reasonable period, the etiology should be identified and the medical monitor 
notified. For children <2 years of age, no more than 4 to 5 mL of whole blood for research purposes 
will be collected (including safety laboratories and PK samples), whereas for subjects aged 
≥ 2 years, no more than 10 mL of whole blood will be collected. For infants < 7 kg, no more than 
3 mL/kg will be drawn for research purposes during the study. In countries where micro laboratory 
equipment is not available, whole blood for research purposes in children < 2 years of age should 
not exceed 2.4 mL/kg. 
Laboratory samples will be analyzed by a certified laboratory at the scheduled times. Laboratories 
in the U.S. will be required to have Clinical Laboratory Improvement Amendments certifications.  
10.4.1.2 
 Standard-of-Care Safety Laboratories 
A separate study sample is not required if safety labs are obtained per standard of care. If multiple 
laboratory tests are obtained within 72 hours of first dose of study drug, record test results closest 
to administration of study drug.  
Laboratory samples will be analyzed by each clinical site’s local laboratory. 
10.4.2 
Microbiology Assessments  
Results of microbiology assessments performed in accordance with routine standard of care will 
be recorded on the study eCRF. These include all cultures from cerebrospinal fluid, pleural fluid, 
blood, urine (catheter or suprapubic tap), and sputum, as well as molecular and serologic tests for 
M. pneumoniae and C. pneumoniae.  
10.4.3 
Pharmacokinetic Determinations 
Solithromycin concentrations will be measured in plasma. Pharmacokinetics samples will be 
processed at a central lab using a validated bioanalytical assay. These data will be reviewed 
periodically during the study. Two PK samples (150 µL per sample) will be collected on Day 1. 
Additional PK samples (150 µL per sample) will be collected at varying time points on Days 3 to 
7 (maximum of 6 PK samples taken total). Every effort should be made to collect at least 2 PK 
samples on Day 1 and additional PK samples on Days 3 to 7. Table 10 below provides the optimal 
sampling collection windows for solithromycin according to route of administration. Every effort 
should be made to collect PK samples during the time windows provided; however, samples 
obtained outside of the sampling windows are acceptable. Lack of collection of samples or 
collection outside the optimal windows will not be considered protocol deviations. No more than 
6 PK samples will be collected per subject. For subjects switched from an IV to oral formulation, 
the oral sampling scheme can be used following all subsequent oral doses.  


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Table 10 
Optimal Pharmacokinetics Sampling Windows Following Dose 
Administration 
Intravenous 
Time after dose  
Oral 
Time after dose  
Prior to dosing 
(within 1 hour)a 
Prior to dosing 
(within 1 hour)a 
End of infusion  
(within 10 minutes) 
0.5–1.5 hours 
2–4 hours 
2–4 hours 
8–10 hours 
8–10 hours 
16–18 hours 
16–18 hours 
20–<24 hours 
20–<24 hours 
a. Only applicable to Days 3 to 7 PK samples. 
10.5 Radiological Imaging and Non-pharmacologic Treatment/Procedures 
Chest x-rays and CT scan of the chest will be recorded on the study eCRF. Surgeries and non-
pharmacologic procedures of interest performed in accordance with routine standard of care will 
be recorded on the study eCRF. Surgeries of interest include surgeries of the chest and chest wall, 
such as pleural tube placement and video assisted thoracoscopic surgery.  
10.6 Clinical Efficacy Outcomes Assessments Time Points 
Clinical outcomes assessments will be performed by a blinded investigator at the study site. At 
each time point, the site blinded investigator will evaluate signs and symptoms and record physical 
findings of CABP. These assessments will include cough, difficulty breathing, purulent sputum 
production, chest pain, grunting, hypotension, tachycardia, tachypnea, and evidence of pulmonary 
consolidation (further details are in the Blinded Investigator Plan). If symptoms and physical exam 
findings are available in the medical record per standard of care, these can be used for the clinical 
outcomes assessments.  
Clinical efficacy outcomes assessments will be performed at the following time points: 
• 
A baseline assessment of signs, symptoms, and physical exam findings will be completed 
at screening 
• 
Clinical improvement on the last day of treatment (+48 hours) (primary efficacy 
endpoint)  
• 
Clinical improvement on Day 3 or 4. If the subject is discharged from the hospital prior 
to Day 3, assessment may be recorded on Day 2. A return visit is not required to perform 
this assessment if the subject has been discharged prior to the assessment.  
• Clinical cure during SFU at 16 days (+/–4 days) post-randomization (secondary 
efficacy endpoint). This assessment will be conducted if information is available per 
standard of care and may be recorded from the medical record via phone/other media.  


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10.7 Clinical Improvement Definition (Early Clinical Response and End-of-
Treatment Response) 
Clinical improvement is defined as improvement of at least 1 of the presenting signs and symptoms 
of CABP with no deterioration in any presenting sign or symptom of CABP, no development of 
new sign or symptom of CABP, and no requirement for additional or alternative antimicrobial 
therapy. 
10.8 Clinical Cure Definition (Day 16 Post Randomization [±4 Days]) 
Clinical cure is defined as resolution of all presenting signs and symptoms of CABP (excluding 
cough), no development of new sign or symptoms of CABP, and no requirement for alternative 
antimicrobial therapy. 
10.9 Signs and Symptoms of CABP 
• 
Cough 
• 
Difficulty breathing  
• 
Production of purulent sputum 
• 
Chest pain 
• 
Grunting  
• 
Hypotension  
• 
Tachycardia defined as follows:  
• 2 months to <24 months: ≥160 beats/min 
• 24 months to <10 years: ≥140 beats/min 
• ≥10 years: ≥ 100 beats/min 
• 
Tachypnea, defined as follows:  
• 2 months to <12 months: ≥50 breaths/min 
• 12 months to <5 months: ≥40 breaths/min 
• ≥5 years: ≥20 breaths/min 
• Physical exam consistent with pulmonary consolidation 


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11 
STUDY AND SUBJECT DISCONTINUATION  
A clear distinction will be made between subjects who discontinue study drug dosing and those 
who withdraw or are withdrawn from the study. Only those subjects who are lost to follow-up, are 
unwilling to comply with protocol procedures, or who withdraw consent and/or refuse any further 
contact with respect to the study will be withdrawn from the study. Subjects discontinued from 
study drug dosing and/or withdrawn for the study will not be replaced, regardless of the reason.  
11.1 Screening Failures 
Subjects who sign and date the ICF and assent (if applicable) but who fail to meet the inclusion 
and exclusion criteria are defined as screen failures. A screening log, which documents the 
subject’s initials and reason(s) for screen failure, is to be maintained by the Investigator for all 
screen failures. A copy of the log should be retained in the Investigator’s study files. Screen failures 
will not be added to the eCRF. 
11.2 Discontinuation from Study Drug  
A subject may have study drug prematurely discontinued for any of the following reasons: 
• 
Safety, including AEs or development of clinically significant laboratory abnormalities. 
The subject must be followed clinically until the event is resolved or deemed stable. 
• 
Clinical failure or lack of efficacy. 
• 
Subject wishes to withdraw consent for reasons other than an adverse experience. 
• 
Subject non-compliance or unwillingness to comply with the procedures required by the 
protocol. 
• 
Investigator discretion. 
• 
Sponsor request. 
Any subject who prematurely discontinues study drug should be encouraged to complete the study 
through the last study visit. The Last Day of Treatment procedures will be performed the day 
(+48 hours) the study drug is discontinued. 
11.3 Withdrawal from Study 
A subject may be withdrawn from the study for any of the following reasons: 
• 
Subject wishes to withdraw consent for reasons other than an adverse experience 
• 
Subject wishes to withdraw consent due to an adverse experience 
• 
Subject is lost to follow-up 
• 
Subject non-compliance or unwillingness to comply with the procedures required by the 
protocol 
• 
Investigator discretion 
• 
Sponsor request 


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11.4 Study Site Discontinuation 
Reasons for discontinuation of the study at an investigational site may include, but are not limited 
to, the following: 
• 
The incidence or severity of AEs in this or other studies indicates a potential health hazard 
to subjects 
• 
Subject enrollment is unsatisfactory 
• 
Investigator request to withdraw from participation 
• 
Sponsor decision 
• 
Serious and/or persistent non-compliance by the investigator with the protocol, the 
clinical research agreement, and/or applicable regulatory guidelines in conducting the 
study 
• 
Institutional review board (IRB)/independent ethics committee (IEC) decision to 
terminate or suspend approval for the investigation or the investigator 
• 
Investigator fraud (altered data, omitted data, or manufactured data) 
• 
Recommendation from the DMC 


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12 
 SAFETY ASSESSMENTS 
Safety assessments will include attention to relevant changes in physical examinations, clinical 
condition, vital signs, and safety laboratory tests that are identified as occurring after the ICF and 
assent (if applicable) are signed regardless of relationship to study drug. Any study team member 
may conduct safety assessments. 
12.1 Adverse Events 
An AE is any untoward medical occurrence associated with the use of a study drug in humans, 
whether or not considered drug related. An AE can be a clinical event in the form of signs, 
symptoms, disease, or laboratory or physiological observations occurring in a human being 
participating in a clinical study with study drug or comparator, regardless of causal relationship. 
A “pre-existing” condition is one that is present prior to study drug administration and is reported 
as part of the subject’s medical history. A pre-existing condition should be reported as an AE only 
if the frequency, intensity, or character of the pre-existing condition worsens during the course of 
the study. 
Laboratory abnormalities are not considered AEs unless they are associated with clinical 
signs or symptoms, or require medical intervention. However, a clinically significant 
laboratory abnormality (e.g. detected on clinical chemistry or hematology) that is independent 
from the underlying medical condition and that requires medical or surgical intervention, or leads 
to study drug interruption or discontinuation, will usually be considered an AE.  
Lack of efficacy/clinical failure is captured as an efficacy measure and in general will not be 
considered an AE. 
Adverse events will be collected from the time of signing of the informed consent until 28 days 
post-randomization. In addition, the investigator (or designee) should seek to elicit any clinical or 
objective reactions by specific questioning (“How have you been feeling?”) and, as appropriate, 
by examination. Information on all AEs should be recorded on the eCRF. All clearly related signs, 
symptoms, and results of diagnostic procedures performed because of an AE should be grouped 
together and recorded as a single diagnosis. The component parts of the diagnosis may be listed 
for verification. If the AE is a laboratory abnormality that is part of a clinical condition or 
syndrome, it should be recorded as the syndrome or diagnosis rather than the individual laboratory 
abnormality. 
To avoid vague, ambiguous, or colloquial expressions, all AEs should be recorded in standard 
medical terminology on the eCRF and on the medical record rather than in the subject’s own 
words. Each AE will also be described in terms of duration (start and stop date and times), severity, 
association with the study drug, action(s) taken, and outcome. 
12.1.1 
Serious Adverse Events 
An AE or suspected adverse reaction is considered serious if, in the view of the investigator or 
sponsor, it results in any of the following outcomes:  


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• 
Death: “Death” is an outcome and is NOT the AE. In the event of death, the cause of 
death should be recorded as the AE. The only exception is “sudden death” when the cause 
is unknown. 
• 
Life-threatening AE: Places the subject at immediate risk of death at the time of the event 
as it occurred. It does not include an AE that, had it occurred in a more severe form, might 
have caused death.  
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Subject hospitalization or prolongation of hospitalization. A “planned” hospitalization for 
study procedures or preexisting conditions is NOT an SAE. 
• 
Congenital anomaly or birth defect 
Important medical events that may not result in death, be life threatening, or require hospitalization 
may be considered an SAE when, based on appropriate medical judgment, they may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias that do not result in in 
subject hospitalization, or the development of drug dependency or drug abuse.  
Serious AEs will be collected from the time of signing of informed consent until 28 (±4) days after 
randomization. All SAEs, regardless of the investigator’s assessment of causal relationship to 
study drug, must be reported by the investigator or qualified designee within 24 hours of the site’s 
knowledge of the event, and a copy of the initial SAE report must be received within 1 business 
day.  
The report must include an assessment of whether there is a reasonable possibility that the study 
drug caused the event. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the study drug and the AE. 
12.1.1.1 
Reporting of SAEs 
All SAEs must be reported to APCER Life Sciences preferably by email within 24 hours of the 
site’s knowledge of the event. APCER contact information:  
 
 
 
APCER Email: Safety.Cempra@apcerls.com 
 
 
 
Fax: 888-264-1449 
 
 
 
Phone: 888-998-7256 
12.1.2 
Follow-up of SAEs 
When additional relevant information becomes available, the investigator will record follow-up 
information according to the same process used for reporting the initial event as described above. 
The investigator will follow all SAEs until resolution, stabilization, or the event is otherwise 
explained.  


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All SAEs will be followed until resolution, stabilization, until otherwise explained, or until the last 
subject completes the final follow-up, whichever occurs first. 
12.1.3 
Other Reportable Events 
Reports of overdose (with or without an AE), inadvertent or accidental exposure, and known 
pregnancy should be forwarded in the same time frame as an SAE. 
Overdose occurs when a subject is administered or has taken a dose greater than the intended or 
scheduled dose specified by the protocol. 
All pregnancies occurring during the study must be followed for information regarding the course 
of pregnancy, delivery, and condition of the newborn. Follow-up should be provided by the 
investigator to the medical monitor in a timely manner. 
Monitoring of liver laboratory tests 
Monitoring of liver laboratory tests of special interest (AST, ALT, and direct bilirubin) will be 
conducted throughout the study. Three levels of monitoring will be performed: 
Weekly monitoring: Each week, data entered in the eCRF will be downloaded to identify any 
child enrolled in the study with a) normal AST, ALT, or direct bilirubin at baseline AND at least 
2×ULN on any of these laboratory tests at any study visit post baseline and b) any child meeting 
laboratory criteria for Hy’s Law. These data will be provided to the DCRI medical monitor and 
the sponsor for review.  
Quarterly monitoring: Each quarter, summary data of children enrolled in the study with 
a) normal AST, ALT, or direct bilirubin at baseline AND at least 3×ULN on any of these 
laboratory tests at any study visit post baseline and b) any child meeting laboratory criteria for 
Hy’s Law will be provided to the DMC chair for review. Actions by the DMC chair will be 
described in the DMC meeting minutes. 
Biannual monitoring: Twice per year, all data pertaining to liver laboratory tests will be presented 
to the DMC for review. This includes the data presented quarterly as well as listings of all 
laboratory tests at every visit.  
12.1.4  
Severity of Adverse Events 
AE severity will be graded based on the following:  
Mild: 
Transient or mild discomfort; no medical intervention/therapy required 
Moderate: 
Mild-to-moderate limitation in activity; some assistance may be needed; no or 
minimal medical intervention/therapy required 
Severe: 
Marked limitation in activity; some assistance usually required; medical 
intervention/therapy required; hospitalizations possible 


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When changes in the severity of an AE occur more frequently than once a day, the maximum 
severity for the experience that day should be noted. If the severity assessment changes over a 
number of days, then those changes should be recorded separately (with distinct onset dates).  
12.2 Assessment of Causal Relationship 
The investigator must assess the relationship of any AE to the use of study drug, based on available 
information, using the following guidelines:  
• 
Unrelated: There is not a reasonable possibility that the drug caused the event.  
• 
Related: There is a reasonable possibility that the drug caused the event; “reasonable 
possibility” means there is evidence to suggest a causal relationship between the study 
drug and the AE. 
12.3 Action Taken 
For each reported AE, the investigator must document the action taken according to the following 
criteria: 
• 
No action taken 
• 
Non-pharmacologic treatment  
• 
Pharmacologic treatment  
• 
Discontinued from study drug  
• 
Discontinued from study 
• 
New or prolonged hospitalization 
12.4 Adverse Event Outcome 
For each reported AE, the investigator must document the outcome according to the following 
criteria: 
• 
Recovered 
• 
Ongoing 
• 
Unknown 
• 
Death  
12.5 Expedited Safety Reports to Health Authorities 
Sponsor or designate will be responsible for reporting expedited and periodic safety reports to 
health authorities in accordance with the requirements of individual countries. 
For SAEs that require expedited regulatory reporting in the U.S. under 21 Code of Federal 
Regulations (CFR) 312.32(c)(1), the sponsor will notify the FDA and all participating investigators 
in a written IND safety report.  


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13 
DATA MANAGEMENT 
Study data will be entered into eCRFs at the study sites (Section 15.7). Prior to database lock, 
programmed computer edit checks will be run against the database to check for discrepancies and 
reasonableness of the data. All issues resulting from the computer-generated checks as well as 
manual data review will be resolved prior to database lock. 


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14 
STATISICAL ASSUMPTIONS  
14.1 Statistical Methods and Planned Analyses  
14.1.1 
Endpoints 
The primary endpoints for safety will be: 
a. The proportion of subjects with TEAEs 
b. The proportion of subjects with therapy not tolerated. Therapy not tolerated will be defined 
as discontinuation of drug treatment due to a related AE.  
Secondary endpoints include efficacy of solithromycin or active comparator as evidenced by 
clinical response (see Section 10.7) and population PK of solithromycin. 
14.1.2 
Sample Size 
Subjects will be randomized 3:1 (solithromycin 300: comparator 100), stratified by age, with at 
least 40 subjects randomized per age group. The sample size of 300 in the solithromycin group is 
based on the ability to observe an SAE at a frequency higher than 1% (Table 11). 
Table 11 
Probability of Observing at Least one Subject with a Serious Adverse Event 
  
Possible Serious Adverse Event Incidence with 5 Days of Dosing 
Number of 
Subjects 
0.1% 
0.25% 
0.5% 
1% 
2% 
100 
0.095 
0.22 
0.39 
0.63 
0.87 
200 
0.18 
0.39 
0.63 
0.87 
0.98 
300 
0.26 
0.53 
0.78 
0.95 
>0.99 
In addition, this sample size will provide reasonable estimates and 95% CI for safety. If 1 subject 
has an AE, then the 95% CI (exact binomial) for that AE within the subject population of 
300 subjects is 0, 1.8% (see Table 12).  
Table 12 
Proportion of Subjects with Adverse Events and 95% CI 
Number of Events 
Proportion 
95% CI 
0 
0 
0, 0.012 
1 
0.003 
0.0001, 0.018 
2 
0.007 
0.001, 0.024 
3 
0.010 
0.002, 0.029 
14.1.3 
Safety Analysis 
For the primary safety endpoints, the frequency and percentage of subjects with AEs and therapy 
not tolerated will be determined and 95% CIs calculated. Summaries will be calculated by 
treatment group for the overall safety population and stratified by age group. 


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Additional safety analyses include summaries of AEs, descriptive statistics of laboratory values, 
descriptive statistics of vital signs, and frequency distributions of abnormal physical examinations. 
Laboratory data, such as hematology and serum chemistry data, as well as safety data will be 
analyzed. Summary statistics for changes from baseline and shift tables will be presented. 
Continuous laboratory measurements will be described at each visit using descriptive statistics 
(mean, median, etc.); observed values and changes from baseline will be summarized. Laboratory 
tests reflective of liver toxicity (e.g., ALT, AST) will be further summarized in terms of the most 
extreme values and largest changes from baseline (in the appropriate direction) observed from start 
of study drug through the end of therapy. All analyses will include summaries for both treatment 
and active comparator. 
Additional details of safety analyses will be included in the Statistical Analysis Plan (SAP). 
14.1.4 
Pharmacokinetic Analysis   
A population PK analysis will be performed using non-linear mixed effects modeling in 
NONMEM. Data will be reviewed during the study to evaluate the PK of solithromycin in pediatric 
CABP patients. The influence of covariates on PK parameters will be explored. Monte Carlo 
simulations will be used to evaluate optimal drug exposure. The relationship between drug 
exposure and safety events will be evaluated by calculating the proportion of subjects with AEs 
and SAEs at different exposure levels. 
14.1.5 
Efficacy Analysis 
Efficacy will be evaluated as a binary variable representing clinical improvement on the last day 
of treatment,  as a binary variable representing early clinical improvement on treatment days 3 and 
4, and as a binary variable representing clinical cure on Day 16 (±4 days) post-randomization. The 
frequency and percentage of subjects achieving each efficacy endpoint will be determined, and a 
95% CI calculated. Summaries will be calculated by treatment group for the overall ITT population 
(and microITT population if the data is sufficient to provide meaningful analysis) and stratified by 
age group. This study is not powered for comparison of efficacy endpoints between treatment 
groups. Additional details of efficacy analyses will be included in the SAP.  
14.2 Quality Assurance 
Accurate, consistent, and reliable data and reporting will be ensured through the use of standard 
practices and procedures. 


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15 
ADMINISTRATIVE ASPECTS 
15.1 Compliance with Regulatory Requirements 
This study will be conducted in compliance with the protocol and all regulatory requirements, in 
accordance with GCP, including ICH Guidelines, and in general conformity with the most recent 
version of the Declaration of Helsinki. 
15.2 Institutional Review Board or Independent Ethics Committee Approval 
This protocol, the informed consent document, and all relevant supporting data must be submitted 
to the IRB/IEC for approval. IRB/IEC approval of the protocol, informed consent document, and 
any advertisement used to recruit study subjects must be obtained before the study may be initiated. 
The principal investigator is responsible for keeping the IRB/IEC advised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but in any case, at least 
once a year. The principal investigator is also responsible for notifying the IRB/IEC of all 
unanticipated risks involving human subjects that occur during the study. Notwithstanding the 
foregoing, studies funded by the Biomedical Advanced Research and Development Authority, 
Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, 
Department of Health and Human Services (“BARDA”), which include this study, require 
immediate notice to Cempra and the CRO of any issues that could affect the safety of the human 
subjects.  
15.3 Informed Consent/Assent 
Prior to any study-related procedures, the investigator or designee will obtain from the participant 
and/or participant’s legally authorized representative (i.e., parent/legal guardian) a signed and 
dated written study consent/authorization consistent with FDA/ICH regulations and the HIPAA 
(Health Insurance Portability and Accountability Act) Privacy Rule. Children will have the study 
explained to them as well in an understandable way, and their refusal to take part will be honored. 
Children old enough to be able to sign their name will sign an assent form. HIPAA Privacy Rule 
authorization language will be included in the informed consent/authorization form (where the 
informed consent and authorization are combined into 1 document) and must be IRB approved 
prior to study implementation. When applicable (such as in the state of California), the document 
of Bill of Rights will be attached to the ICF so that the participants can read and understand the 
same. The original signed consent/assent for each participating subject shall be filed with records 
kept by the investigator. A copy of the informed consent/assent document must be provided to the 
participant’s legally authorized representative and participant (as applicable). 
15.4 Confidentiality 
Personal study subject data collected and processed for the purposes of this study should be 
managed by the principal investigator and his/her staff with adequate precautions to ensure the 
confidentiality of those data, and in accordance with applicable national and/or local laws and 
regulations on personal data protection. 


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Monitors, auditors and other authorized agents of sponsor and the clinical research organization 
(CRO), the IRB/IEC approving this research, and the FDA, as well as any other applicable 
regulatory authorities, will be granted direct access to the study subjects’ original medical records 
for verification of clinical trial procedures and/or data, without violating the confidentiality of the 
subjects, to the extent permitted by the law and regulations. In any presentation of the results of 
this study at meetings or in publications, the subject identities will remain confidential.  
15.5 Compensation, Insurance and Indemnity 
Information regarding compensation, insurance, and indemnity is addressed in the Clinical Trial 
Research Agreement. 
15.6 Protocol Amendment 
If a protocol has been filed with regulatory agencies or submitted to an IRB/IEC and requires 
changes, a protocol amendment must be written. Any changes to the protocol will be made by the 
sponsor. All amendments will be sent to the study sites who are then responsible for submitting 
the amendment to their IRB/IECs for approval. 
15.7 Case Report Forms: Electronic 
An eCRF will be used to record all subject data specified by this protocol. The eCRF must be 
completed by designated and trained study personnel. The eCRF will be electronically signed by 
the principal investigator or a subinvestigator (listed on the Form FDA 1572). It is the 
responsibility of the principal investigator to ensure the eCRFs are completed in an accurate and 
timely manner. The processing of eCRFs will include an audit trail (to include changes made, 
reason for change, date of change and person making change). At the completion of the study, the 
sponsor will be provided with the per-subject eCRF in an individual subject profile on disk or other 
electronic medium.  
15.8 Source Document Maintenance 
Source documents are defined as the results of original observations and activities of a clinical 
investigation. Source documents may include, but are not limited to, study progress notes, e-mail 
correspondence, computer printouts, laboratory data, and drug accountability records. All source 
documents produced in this study will be maintained by the investigators and made available for 
inspection by sponsor representatives, the FDA, or other regulatory authorities. 
15.9 Study Monitoring Requirements 
Site visits will be conducted by an authorized Cempra Pharmaceuticals representative (the 
monitor) to inspect study data, subject medical records, and eCRFs in accordance with ICH 
guidelines, GCPs, and the respective U.S. or national regulations and guidelines, as applicable. 
It will be the monitor’s responsibility to inspect the eCRF at regular intervals throughout the study, 
to verify adherence to the protocol and the completeness, consistency and accuracy of the data 
being entered. The monitor should have access to laboratory test reports and other subject records 
needed to verify the entries on the eCRFs. 


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The investigator will permit representatives of the sponsor, the FDA, and/or respective health 
authorities to inspect facilities and records relevant to this study. 
15.10 Study File Management 
It is the responsibility of the principal investigators to ensure that the study file at the site is 
maintained. The study file will contain, but not be limited to: 
1. Investigator’s brochure (including updated or revised versions) 
2. Final study protocol 
3. Protocol amendments (if applicable) 
4. Fully executed Clinical Trial Agreement 
5. Investigator manual (if applicable) 
6. ICF (blank) 
7. Revised ICFs and/or all addenda (blank) 
8. Copy of signed U.S. FDA Form 1572  
9. Department of Health and Human Services number for IRB or other documentation of 
IRB/IEC compliance with FDA 
10. Curricula vitae (CV) of principal investigators and subinvestigators 
11. Financial disclosure information provided to the sponsor  
12. A list of the IRB/IEC members and their qualifications, as well as a description of the IRB 
processes 
13. If the principal investigator is a member of the IRB/IEC, documentation stating he/she did not 
vote on the study 
14. Documentation of IRB/IEC approval of protocol, consent form, any protocol amendments, and 
any consent form revisions 
15. Annual IRB/IEC updates and approvals 
16. All correspondence between the principal investigator, IRB/IEC, and sponsor (or designee) 
17. Copies of all IND Safety Reports submitted to the FDA or other regulatory agencies and 
IRB/IEC correspondence documenting their submission (if applicable) 
18. Laboratory certifications/normal laboratory value ranges 
19. Screening log 
20. Clinical research associate monitoring log 
21. Drug accountability records and invoices for receipt/return of study drug 
22. Protocol signature page 
23. Laboratory director’s CV and medical/professional license, if available 


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15.11 Study Completion 
The sponsor requires that the following data and materials be on file at the study site before a study 
can be considered completed or terminated: 
1. Laboratory findings, clinical data, and all special test results from screening through the end 
of the study follow-up period 
2. eCRFs properly completed by appropriate study personnel and electronically signed and dated 
by the principal investigator 
3. Complete drug accountability records (drug inventory log and an inventory of returned or 
destroyed clinical material) 
4. Copies of protocol amendments and IRB/IEC approval/notification, if appropriate 
5. A summary of the study prepared by the principal investigator (an IRB/IEC summary letter is 
acceptable) 
15.12 Audits 
During the course of the study, or after completion of the study, each study site may be subject to 
an audit by a sponsor quality assurance auditor (or an auditor appointed by the sponsor or its 
authorized representative) and/or an inspector from the FDA and/or other regulatory authority. 
Every attempt will be made to notify the principal investigator in writing in advance of the audit.  
15.13 Retention of Records 
The sponsor follows U.S. regulations and ICH guidelines in its retention policy. 
U.S. IND regulations (21 CFR 312.62) require that records and documents pertaining to the 
conduct of this study and the distribution of study drugs, including eCRFs, consent forms, 
laboratory test results, and medication inventory records be kept on file by the principal 
investigator for 2 years after a marketing application is approved for the drug for the indication for 
which it is being studied. If no application is filed or approved, these records must be kept for 
2 years after the investigation has been discontinued and the FDA has been notified. ICH 
guidelines indicate that documents should be retained until at least 2 years after the last approval 
of a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. If there is a country or 
institutional policy that specific records and documents be retained for a longer period than 
described above, the applicable sites must comply with those policies in addition to U.S. and ICH 
policies. No study records should be destroyed without prior authorization from the sponsor. 
15.14 Disclosure of Data 
The principal investigator agrees by his/her participation that the results of this study may be used 
for submission to national and/or international registration and supervising authorities. If required, 
these authorities will be provided with the names of principal investigators, their addresses, 


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qualifications and extent of involvement. It is understood that the investigator is required to 
provide the sponsor with all study data, complete reports, and access to all study records.  
Data generated by this study must be available for inspection by the FDA and other regulatory 
authorities, by the sponsor, and by the IRB as appropriate. At a subject’s request, medical 
information may be given to his or her personal physician or other appropriate medical personnel 
responsible for his or her welfare. Subject medical information obtained during the course of this 
study is confidential, and disclosure to third parties other than those noted above is prohibited. 
15.15 Financial Disclosure 
The FDA Financial Disclosure by Clinical Investigators (21 CFR 54) regulations require Sponsors 
to obtain certain financial information from investigators participating in covered clinical studies; 
each principal investigator and subinvestigator is required to provide the required financial 
information before participating in the study and to promptly update Cempra Pharmaceuticals with 
any relevant changes to this information throughout the course of the clinical study and for up to 
1 year after its completion. This rule applies to all investigators and subinvestigators participating 
in covered clinical studies to be submitted to the FDA in support of an application for marketing 
approval. 
15.16 Publication Policy 
The publication policy is outlined in more detail the Clinical Trial Agreement. 
Studies funded by BARDA, in whole or in part, including this study, shall acknowledge such 
funding when issuing statements, press releases, and other documents. For purposes of this section, 
"publication" is defined as an issue of printed material offered for distribution or any 
communication or oral presentation of information, including any manuscript or scientific meeting 
abstract. The principal investigator agrees to accurately and factually represent the work conducted 
under this protocol in all press releases. Any publication containing data generated under this 
protocol must be submitted for BARDA review no fewer than 30 calendar days for manuscripts 
and 15 calendar days for abstracts before submission for public presentation or publication.  
Misrepresenting protocol results or releasing information that is injurious to the integrity of 
BARDA may be construed as improper conduct. Press releases shall be considered to include the 
public release of information to any medium, excluding peer-reviewed scientific publications. 
Publications are required to include: (1) the percentage and dollar amounts of the total program or 
project costs financed by BARDA and; (2) the percentage and dollar amount of the total costs 
financed by nongovernmental sources. The principal investigator shall ensure that Cempra and 
CRO receive an advance copy of any press release related to the study no fewer than 5 working 
days prior to the issuance of the press release. Funding support shall be acknowledged in all such 
publications substantially as follows: 
"This project has been funded in whole or in part with federal funds from BARDA, Office of the 
Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health 
and Human Services, under Contract No. HHS0100201300009C." 


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For each Institution and Investigator conducting the Study or a portion thereof outside of the 
United States, Institution and Investigator acknowledge and agree that (i) the Study and all other 
activities to be performed hereunder will be supported by funding provided, and will be performed 
in support of Sponsor’s performance of its obligations, under Contract No. HHS0100201300009C 
(“Prime Award”), entitled “SOLI- Solithromycin Pediatric Development Program”, awarded by 
the United States Government through the Office of Acquisitions Management, Contracts and 
Grants (“Prime Sponsor”), and that, therefore, certain obligations are required of Sponsor’s 
subcontractors (including Institution and Investigator) and, notwithstanding anything to the 
contrary in the Clinical Trial Agreement, or any other clinical study agreement, clinical trial 
agreement, investigator agreement, or the like executed by Institution or Investigator with respect 
to the Study, (ii) the terms and conditions of the Protocol and the Clinical Trial Agreement are 
subject to the terms included as Appendix B, attached hereto and fully incorporated herein, and, 
without limitation of the foregoing, to those provisions of the Prime Award incorporated herein, 
and, in the event of any conflict between those terms included as Appendix B and the terms and 
conditions of the Protocol, the Clinical Trial Agreement, or any other clinical study agreement, 
clinical trial agreement, investigator agreement, or the like executed by Institution or Investigator 
with respect to the Study, the terms of Appendix B shall govern to the extent of such conflict. 


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16 
REFERENCES  
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Awasthi S, Agarwal G, Singh JV, et al. Effectiveness of 3-day amoxycillin vs. 5-day 
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multi-centric open labeled trial. J Trop Pediatr. 2008; 54(6):382–9. 
Bradley JS, Arguedas A, Blumer JL, et al. Comparative study of levofloxacin in the treatment of 
children with community-acquired pneumonia. Pediatr Infect Dis J. 2007; 26(10):868–78. 
Bradley JS, Byington CL, Shah SS, et al. The management of community-acquired pneumonia in 
infants and children older than 3 months of age: clinical practice guidelines by the Pediatric 
Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011; 
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Farrell DJ, Couturier C, Hryniewicz W. Distribution and antibacterial susceptibility of macrolide 
resistance genotypes in Streptococcus pneumoniae: PROTEKT Year 5 (2003-2004). Int J 
Antimicrob Agents. 2008; 31:245-9 
Farrell DJ, Castanheira M, Sader HS, Jones RN. The in vitro evaluation of solithromycin 
(CEM-101) against pathogens isolated in the United States and Europe (2009). J Infect. 2010 
61(6):476–83. 
Gereige, R, Laufer, PM. Pneumonia. Pediatrics in Review. 2013; 34 (10): 438-56 
Heiskanen-Kosma T, Korppi M, Jokinen C, et al. Etiology of childhood pneumonia: serologic 
results of a prospective, population-based study. Pediatr Infect Dis J. 1998; 17(11):986–91. 
Kogan R, Martínez MA, Rubilar L, et al. Comparative randomized trial of azithromycin versus 
erythromycin and amoxicillin for treatment of community-acquired pneumonia in children. Pediatr 
Pulmonol. 2003; 35(2):91–8. 
Liu Y, Ye X, Zhang H, et al. Antimicrobial susceptibility of Mycoplasma pneumoniae isolates and 
molecular analysis of macrolide-resistant strains from Shanghai, China. Antimicrob Agents 
Chemother. 2009; 53:2160-2. 
Lodha R, Kabra SK, Pandey RM. Antibiotics for community-acquired pneumonia in children. 
Cochrane Database Syst Rev. 2013; 6:CD004874. 
Michelow IC, Olsen K, Lozano J, et al. Epidemiology and clinical characteristics of community-
acquired pneumonia in hospitalized children. Pediatrics. 2004; 113(4):701–7. 


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Oldach D, Barrera C, Mykietiuk A, et al. The SOLITAIRE-Oral Trial – Results of a Global Phase 
3 Trial Comparing Oral Solithromycin versus Oral Moxifloxacin for Treatment of Community-
acquired Bacterial Pneumonia (CABP) in Adults. Late Break Abstract 4145; European Congress 
of Clinical Microbiology and Infectious Disease, Copenhagen, Denmark, April 2015. 
Principi N, Esposito S, Blasi F, Allegra L. Role of Mycoplasma pneumoniae and Chlamydia 
pneumoniae in children with community-acquired lower respiratory tract infections. Clin Infect 
Dis. 2001; 32(9):1281–9. 
Ranganathan, S, Sonnappa, S. Pneumoniae and Other Respiratory Infections. Pediatric Clinics of 
North America; 2009-56(1): 135-56. 
Reasor, M, Hastings K, Ulrich G. Drug-induced phospholipidosis:issues and future directions; 
Expert Opin. Drug Saf. (2006) 5(4): 567-83 
Ribeiro CF, Ferrari GF, Fioretto JR. Antibiotic treatment schemes for very severe community-
acquired pneumonia in children: a randomized clinical study. Rev Panam Salud Publica. 
2011;29(6):444-50. 
Wolff BJ, Thacker WL, Schwartz SB, et al. Detection of macrolide resistance in Mycoplasma 
pneumoniae by real-time PCR and high resolution melt analysis. Antimicrob Agents Chemother. 
2008;52:3542-9 
World Health Organization. Fact sheet N° 331. 2012 [updated August 2012; cited 2012 
31 October]; Available from: http://www.who.int/mediacentre/factsheets/fs331/en/.October]; 
Available from: http://www.who.int/mediacentre/factsheets/fs331/en/ 


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Appendix A Protocol Amendments 
Amendment #3 29 November 2017 
Rationale for Amendment 
Amendment 3 revised the oral suspension Solithromycin concentration from 320mg/5mL to 
275mg/5mL and removed the 160mg/5mL concentration.  In addition, a new exclusion criteria 
was added for an evaluation of renal failure [End Stage Renal Disease (dialysis requiring) OR 
severe renal impairment (defined as serum creatinine > 1.5 fold ULN for age).], a section was 
added to improve clarity of SAE reporting and the Cempra sign-off for the protocol was changed 
from Brian Jamieson, MD to Robert M Hernandez, PhD. 
Language has been modified in some sections to improve the clarity of the protocol requirements 
and procedures, and to correct minor typographical errors.  Typographic corrections, including 
grammatical and punctuation errors, are not shown in this rationale. 
New/revised text is in bolded italics. Deletions are identified by strikethrough. 
SIGNATURE PAGE 
Brian Jamieson, MD Robert Hernandez, PhD 
Sr. Director, Clinical Research Operations 
 
2  Synopsis 
Changes made in accordance with the revisions described below. 
Inclusion Criteria 
4…History of and/or documented fever (rectal, temporal, ear, or oral temperature ≥ 38°C or axillary 
temperature ≥ 37.5°C) or hypothermia (rectal, temporal, ear, or oral temperature < 35°C or axillary 
temperature < 34.5°C) . . . 
Exclusion Criteria 
14. End Stage Renal Disease (dialysis requiring) OR severe renal impairment (defined as 
serum creatinine > 1.5 fold ULN for age). 
Test Product 
. . . Azithromycin IV/PO or erythromycin lactobionate IV or erythromycin PO may be added to any of the 
treatment regimens above. Azithromycin is also acceptable as a first line of treatment. . .  
 
 
 


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Table 1 foot note 
g     Local laboratory; includes hemoglobin, hematocrit, white blood cell count with differential, platelet count, blood 
urea nitrogen, calcium, serum creatinine, potassium, sodium, aspartate aminotransferase, alanine 
aminotransferase, alkaline phosphatase, total and direct bilirubin, and albumin.  
      Local laboratory; includes hemoglobin*, hematocrit*, white blood cell count with differential*, platelet 
count*, blood urea nitrogen*, calcium,* serum creatinine, potassium*, sodium*, aspartate aminotransferase, 
alanine aminotransferase, alkaline phosphatase*, total and direct bilirubin, and albumin*. If laboratories 
with * designation are not obtained, it will not result in a protocol deviation. 
7.3  
Study Drug and Administration 
. . . Subjects requiring an oral dosage form other than capsules will receive suspension formulation, 
provided at 160 mg/5 mL and 320 275 mg/5 mL strengths . . .  
. . . Azithromycin IV/PO or erythromycin lactobionate IV or erythromycin PO may be added to 
any of the treatment regimens above. Azithromycin is also acceptable as a first line of treatment. 
. . 
8.1  
Inclusion Criteria 
4…History of and/or documented fever (rectal, temporal, ear, or oral temperature ≥ 38°C or 
axillary temperature ≥37.5°C) or hypothermia (rectal, temporal, ear, or oral temperature < 35°C 
or axillary temperature <34.5°C) . . . 
8.2  
Exclusion Criteria 
14. End Stage Renal Disease (dialysis requiring) OR severe renal impairment (defined as 
serum creatinine > 1.5 fold ULN for age). 
9.1  
Solithromycin (CEM-101) 
. . . Detailed instructions for the reconstitution of the powder for oral suspension to 320 
275 mg/5 mL and 160 mg/5 mL will be listed in the pharmacy manual . . . 
12.1.1  
Serious Adverse Events 
. . . All SAEs, regardless of the investigator’s assessment of causal relationship to study drug, must 
be reported by the investigator or qualified designee within 24 hours of the site’s knowledge of the 
event, and a copy of the initial SAE report must be received within 1 business day. All SAEs will 
be reported to the Medical Monitor (or designee) within 24 hours of occurring. 
12.1.1.1  
Reporting of SAEs 
All SAEs must be reported to APCER Life Sciences preferably by email within 24 hours of the 
site’s knowledge of the event. APCER contact information:  
 
 
 
APCER Email: Safety.Cempra@apcerls.com 
 
 
 
Fax: 888-264-1449 
 
 
 
Phone: 888-998-7256 


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Amendment #2 16 December 2016 
Rationale for Amendment 
Amendment 2 incorporates additional safety laboratory evaluations along with new and updated 
dosing information for all 3 formulations of solithromycin.  
Safety laboratories, including ALT, AST, ALP, total and direct bilirubin, and eosinophil count 
have been added at 72 hours (±24 hours), Day 16 (±4 days), and Day 28 (±4 days). The Day 28 
(±4 days) visit evaluates safety laboratories approximately 3 weeks after completion of dosing, 
and replaces the Day 36 (±4 days) visit. Data pertaining to liver laboratory evaluations will be 
reviewed on a regularly scheduled basis (Section 12.1.3) and presented to the DMC. 
Solithromycin suspension dosing information, including the dosage rationale, has been added for 
all age groups. The IV dose has been updated to 8 mg/kg (maximum 400 mg) for all age groups 
based on additional Phase 1 pediatric PK data. PK/PD simulations based on adult CABP patient 
data have been reassessed following an FDA recommendation to remove the loading dose on the 
first oral dosing day after IV administration; the loading dose did not appear to be required for 
efficacy but did increase the potential for ALT elevations and could be associated with dosing 
errors. Consequently, the oral loading dose after IV dosing has been replaced by the daily oral 
maintenance dose (10 mg/kg; maximum 400 mg). A loading dose will be employed only on the 
first day of oral only dosing (20 mg/kg; maximum 800 mg).  
The duration of dosing with solithromycin will be 5 days with oral only dosing, and 7 days with 
IV only or IV to oral dosing; previously the duration was 5 to 7 days for all formulations. Five-
day oral and 7-day IV and IV to oral regimens of solithromycin were demonstrated to be non-
inferior to moxifloxacin in the Phase 3 adult pneumonia studies (CE01-300 and CE01-301). 
Comparator duration of dosing will continue to be per standard of care.  
The minimum weight requirement of 60 kg for solithromycin capsule dosing in the 12 to 17 year 
old age group has been removed. This is supported by PK modeling efforts from Phase 1 studies 
as well as by safety data from more than 100 adult patients <60 kg who received solithromycin in 
completed pneumonia studies (Cempra Phase 3 studies and Toyama Phase 2 study). 
“Clinical failure or lack of efficacy” has been added as a reason for discontinuation from study 
drug, and “withdrawal of consent due to an adverse experience” has been added as a reason for 
discontinuation from study. These additional reasons will better categorize patient disposition. 
Language has been modified in some sections to improve the clarity of the protocol requirements 
and procedures, and to correct minor typographical errors. Typographic corrections, including 
grammatical and punctuation errors, are not shown. 
New/revised text is in bolded italics. Deletions are identified by strikethrough. 


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SIGNATURE PAGE 
Mike Cinoman Brian Jamieson, MD 
Sr. Director, Pediatric Clinical Research 
2. SYNOPSIS 
Changes made in accordance with the revisions described below. 
Planned Number of Investigational Sites: Approximately 90 60 
Clinical Phase: 2/3, to be conducted in the U.S. and up to approximately 7 additional countries in other 
regions of the world, including Europe  
Methodology 
“. . .capsules or suspension formulation based on age and weight.” 
Subject Participation 
. . . up to 40 32 days. 
• 
Up to 40 32 days of adverse event (AE and serious AE (SAE) monitoring (36 28 . . . 
Exclusion Criteria 
8…In addition, the following drugs may not be co-administered with solithromycin in this trial due to the 
potential for adverse drug-drug interaction: digoxin, colchicine, midazolam, quinidine, ergotamine, 
dihydroergotamine, rivaroxaban, apixaban, dabigatran, edoxaban, cisapride, cyclosporine, sildenafil, 
astemizole, and alfentanil. 
Test Product 
Dose and Mode of Administration: Solithromycin will be administered IV or PO according to the tables 
below. If dosing begins with oral therapy, the Day 1 dose will be a loading dose. No loading doses 
are used with IV solithromycin administration or if switched to oral administration. Note that oral 
dosing, either as initial exposure to solithromycin with capsules or suspension or as follow-on therapy to 
prior IV dosing, is initiated with a single (PO) loading dose. An IV-to-PO switch can occur after the first 
IV dose. No loading doses are used with IV solithromycin administration. Subjects starting with oral therapy 
will receive 5 to 7 days of solithromycin treatment and those starting with IV therapy (regardless of if and 
when they switch to oral therapy) will receive 5 to 7 days of solithromycin treatment. 
Age 
(years) 
Route 
Formulation 
Loading dose  
(Max dose: 800 mg)a 
Daily maintenance  
dose  
(Max dose: 400 mg)a 
12 to 17  
PO 
Capsulesb 
800 mg 
400 mg 
12 to 17 
PO 
Suspension 
TBD 
TBD 
12 to 17  
IV 
Solution 
 No loading dose 
6 mg/kg 
6 to <12 
PO 
Capsulesb 
TBD 
TBD 
6 to <12 
PO 
Suspension 
TBD 
TBD 
6 to <12 
IV 
Solution 
No loading dose 
7 mg/kg 
2 to <6 
PO 
Suspension 
TBD 
TBD 
2 to <6 
IV 
Solution 
No loading dose 
TBD 
2 mo to <2 
PO 
Suspension 
TBD 
TBD 
2 mo to <2 
IV 
Solution 
No loading dose 
TBD 
a. 
The maximum oral loading dose is 800 mg, and the maximum IV or oral maintenance dose is 400 mg. 
b. 
The capsule dose is rounded upwards to the nearest 200 mg.  


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c.   The adult dose should be administered unless the subject weighs <40 kg, in which case they receive 20 mg/kg  on 
Day 1and 10 mg/kg on Days 2-5. Minimum weight for using capsules is 60 kg. All smaller subjects should receive 
suspension if dosing orally. 
Capsule Dosing Regimens 
Age (years) 
Weight 
Route 
Formulation 
Day 1 
(Max dose: 800 mg)  
Days 2 to 5 
(Max dose: 400 mg)  
6 to 17 
>30 kg 
PO 
Capsules 
800 mg 
400 mg 
>20 to 30 kg 
PO 
Capsules 
600 mg 
400 mg 
≤20 kg 
PO 
Capsules 
400 mg 
200 mg 
Suspension Dosing Regimens 
Age (years) 
Route 
Formulation 
Day 1 
(Max dose: 800 mg)  
Days 2 to 5 
(Max dose: 400 mg)  
12 to 17 
PO 
Suspension 
20 mg/kg (800 mg) 
10 mg/kg (400 mg) 
6 to <12 
PO 
Suspension 
20 mg/kg 
10 mg/kg 
2 to <6 
PO 
Suspension 
20 mg/kg 
10 mg/kg 
2 mo to <2 
PO 
Suspension 
20 mg/kg 
10 mg/kg 
Intravenous Dosing Regimens 
Age (years) 
Route 
Formulation 
Days 1 to 7 
(Maximum dose: 400 mg)  
12 to 17  
IV 
Solution 
8 mg/kg 
6 to <12 
IV 
Solution 
8 mg/kg 
2 to <6 
IV 
Solution 
8 mg/kg 
2 mo to <2 
IV 
Solution 
8 mg/kg 
Intravenous to Oral Dosing Regimens 
Age (years) 
Route 
 Oral Formulation 
Day 1 to Last IV Dosing 
Day 
(Max dose: 400 mg)  
First Oral Dosing Day 
to Day 7 
(Max dose: 400 mg)a  
12 to 17 
IV/PO 
Suspension or 
Capsules 
8 mg/kg 
10 mg/kg (400 mg) 
6 to <12 
IV/PO 
Suspension or 
Capsules 
8 mg/kg 
10 mg/kg 
2 to <6 
IV/PO 
Suspension 
8 mg/kg 
10 mg/kg 
2 mo to <2 
IV/PO 
Suspension 
8 mg/kg 
10 mg/kg 
a. The adult dose should be administered unless the subject weighs <40 kg, in which case they receive 10 
mg/kg on the first oral dosing day through Day 7. The capsule dose is rounded upwards to the nearest 
200 mg.  
Comparator Therapy 
Addition of expanded gram-positive coverage to treatment and comparator groups will be allowed if 
empiric therapy for methicillin-resistant Staphylococcus aureus is desired per local standard of care. Oral 
step down therapy should be informed by antimicrobial testing. 


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Pharmacokinetics: 
The table below provides the optimal plasma sampling collection windows for solithromycin according to 
route of administration. Every effort should be made to collect at least 2 PK samples on Day 1 and at least 
2 PK samples on days 3 through 7 during these windows (not to exceed 6 samples total); however, samples 
obtained outside of the sampling windows are acceptable and will not be considered protocol deviations. 
Lack of collection of samples will also not be considered protocol deviations. 
Statistical Methods and Data Analysis 
. . . changes in study drug dosing, relationship to study drug, and outcome. Laboratory determinations 
performed by local laboratories including hematology values (hemoglobin, hematocrit, WBC count and 
differential, and platelet count, and differential) and serum chemistry values . . .  
. . . Population PK methodologies using nonlinear mixed effects modeling in NONMEM will be used to 
analyze the concentration data. Data will be reviewed during the study to evaluate PK of solithromycin 
in pediatric CABP patients. 
Added footnote ‘i’, changed the 36 day follow-up visit to a 28 day follow-up visit, and added liver 
enzymes and a white blood cell count with differential to all visits in Table 1 Schedule of 
Assessments 
5 
INTRODUCTION 
. . . The PK of both intravenous (IV) and oral solithromycin in adolescents and children is currently 
under investigation has been investigated. In both the completed and ongoing PK studies of 
solithromycin in adolescents and children . . .  
5.2.2.2.5  
Pediatric Subjects 
Solithromycin PK in adolescents (12 to <17 years) and children (<12 years) following oral 
(capsules, suspension) and intravenous administration was further investigated in a phase 1, open-
label, multi-center study (protocol CE01-120). As of July 31, 2016, 10 patients aged 12 to 17 years 
(all received IV solithromycin), 33 patients 6 to <12 years (8 IV, 9 oral capsules and 16 oral 
suspension), 15 patients 2 to <6 years (8 IV and 7 oral suspension) and 23 patients <2 years 
(8 IV and 15 oral suspension) have been enrolled. Population pharmacokinetic modeling was 
used to determine the dosing regimens for oral and intravenous dosing from the data collected. 
Intravenous data collected in this study supported the use of a 6 and 7 mg/kg intravenous daily 
dose (no loading dose required) in adolescents (12 to <17 years) and children (6 to <12 years), 
respectively. These doses resulted in a median (range) Day 3-5 Cmax and AUC0–24 of 2.3 μg/mL 
(1.2-7.7) and 12.3 μg*h/mL (8.2-19.9) in adolescents, and 2.8 μg/mL (1.0-8.1) and 10.6 μg*h/mL 
(2.7-18.4) in children, respectively. These estimates are comparable to adult median (range) values 
of 2.7 μg/mL (2.1-3.5) for Cmax and 13.7 μg*h/mL (6.1-22.3) following 400 mg of daily dosing. 
5.2.3  Summary of Efficacy 
Three randomized, double-blind efficacy studies in CABP with oral solithromycin have been 
completed. One open-label efficacy study in GC with single dose oral solithromycin has been 
completed. 
The Phase 2 oral CABP study (CE01-200) compared 5-day regimens of solithromycin 
(800 mg×1 on Day 1 followed by 400 mg QD on Days 2-5) and levofloxacin (750 mg QD Days 
1-5). One hundred thirty-two patients were enrolled and randomized (1:1) to solithromycin or 


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levofloxacin. A total of 132 patients were randomized; 65 were randomized to receive 
solithromycin and 67 were randomized to receive levofloxacin.  
In the ITT population at TOC, clinical success was observed in 55 (84.6%) patients randomized 
to receive solithromycin and 58 (86.6%) patients randomized to receive levofloxacin. In the 
CE population, clinical success was observed in 46 (83.6%) patients who received solithromycin 
and 54 (93.1%) patients who received levofloxacin. Early clinical success at Day 3 (according 
to the proposed Biomarkers Consortium criteria) was observed for 47 (72.3%) and 48 (71.6%) 
patients in the solithromycin and levofloxacin groups, respectively. 
Phase 2 studies have been conducted in CABP and uncomplicated urogenital gonorrhea. A global, 
randomized, double-blind phase 3 study in CABP subjects has been successfully completed. A 
second phase 3 study has completed enrollment; data analysis is pending. A phase 3 study in 
gonorrhea is also currently enrolling.  
Solithromycin demonstrated 100% efficacy in a phase 2 trial that evaluated single oral doses 
(1000 mg and 1200 mg) for treatment of uncomplicated gonorrhea, as evidenced by positive 
gonorrhea cultures (GCs) at baseline, with negative cultures at 1-week follow-up.  
Solithromycin demonstrated comparable efficacy and safety to oral levofloxacin in a phase 2 
CABP trial.  
The Phase 3 CABP Studies CE01-300 and CE01-301, were randomized, double-blind, active-
controlled, multi-center, non-inferiority studies with moxifloxacin as the active comparator.  
In the oral Study CE01-300, the dosing regimen of solithromycin evaluated was 800 mg as a 
single dose on Day 1 followed by 400 mg QD on Days 2 through 5, with blinded placebo taken 
on Days 6 and 7. The oral moxifloxacin dosing regimen in CE01-300 was 400 mg QD on Days 1 
through 7. 
In the IV to oral Study CE01-301, all patients in both treatment groups received IV treatment 
on Day 1. Patients continued on IV treatment during the 7-day treatment course until predefined 
oral switch criteria related to clinical improvement were met and the Investigator felt it was 
appropriate to transition the patient to oral drug. Patients remained on IV treatment for the full 
7 days if they did not meet the oral switch criteria or at the Investigator’s discretion. The dosing 
regimen, whether IV to oral or IV only was 7 days. Patients randomized to solithromycin 
received 400 mg IV as a single dose on Day 1 and on all subsequent IV dosing days. For patients 
who transitioned to oral treatment in the solithromycin group, the first oral dose of 
solithromycin following IV therapy was 800 mg administered as a single dose, followed by 
400 mg oral QD for the remainder of the study drug administration period. Moxifloxacin was 
administered as a 400 mg QD dose whether it was an IV or oral dosing day. 
Solithromycin demonstrated non-inferiority to moxifloxacin in the treatment of CABP in each 
Phase 3 study. 


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5.2.3.1  
Primary Efficacy Outcome: Early Clinical Response (ECR) 
Table 6-15 provides a summary of the primary efficacy outcome, ECR in the ITT population, in 
the individual and pooled Phase 3 CABP studies. ECR was defined as improvement at 72 hours 
(Day 4) after the first dose of study drug in at least 2 of the following 4 cardinal symptoms of 
CABP: cough, dyspnea/shortness of breath, chest pain due to pneumonia and difficulty with 
sputum production. 
Solithromycin and moxifloxacin ECR responder rates in the ITT population were similar in 
each Phase 3 study and in the pooled studies, approximately 78 to 79% of patients. 
Solithromycin was non-inferior to moxifloxacin for the ECR outcome in each study and in the 
pooled studies. The lower limit of the 95% confidence interval (CI) around the treatment 
difference in responder rates (solithromycin minus moxifloxacin) was greater than the 
prespecified NI boundary of -10%. 
Table 4 
Primary Efficacy Outcome: Early Clinical Response in Individual Phase 3 
Studies and Pooled Studies 
Early Clinical 
Response 
Study CE01-300 
Study CE01-301 
Pooled Phase 3 Studies 
Solithromycin 
Oral 
(N=425) 
n (%) 
Moxifloxacin 
Oral 
(N=431) 
n (%) 
Solithromycin 
IV to Oral 
(N=434) 
n (%) 
Moxifloxacin 
IV to Oral 
(N=429) 
n (%) 
Solithromycin 
Pooled 
(N=859) 
n (%) 
Moxifloxacin 
Pooled 
(N=860) 
n (%) 
Responder 
332 (78.1) 
336 (78.0) 
344 (79.3) 
342 (79.7) 
676 (78.7) 
678 (78.8) 
Difference  
(95% CI) 
0.16 (-5.6,5.9) 
-0.46 (-6.1,5.2) 
-0.16 (-4.0,3.7) 
Nonresponder  
93 (21.9) 
95 (22.0) 
90 (20.7) 
87 (20.3) 
183 (21.3) 
182 (21.2) 
Nonresponder 
81 (19.1) 
83 (19.3) 
76 (17.5) 
78 (18.2) 
157 (18.3) 
161 (18.7) 
Indeterminate 
12 (2.8) 
12 (2.8) 
14 (3.2) 
9 (2.1) 
26 (3.0) 
21 (2.4) 
Source Data: pooled CE01-300 and CE01-301 data 
CI=confidence interval; N=number of patients in the ITT population; n=number of patients within a specific 
category. 
Notes: The time window for determining early clinical response was 72h -12/+36h for CE01-300 and 72h -
13/+36h for CE01-301). Difference=For studies CE01-300 and CE01-301, difference in responder rates 
(solithromycin minus moxifloxacin). For the pooled Phase 3 studies, the weighted (by study) difference in 
responder rates is presented. Percentages were calculated as 100 x (n/N). For studies CE01-300 and CE01-301, 
the CI was calculated using an unadjusted continuity corrected Z-test. For the pooled Phase 3 studies, the CI 
was stratified (for study) and calculated using the method of Miettinen and Nurminen with the inverse variance 
of the difference used as stratum weights. Per the ISE SAP, patients from Site 710 in Study 300 were excluded 
from all pooled results, unless otherwise noted. 
ECR in the clinically evaluable (CE-ECR) population in each study was consistent with the 
results observed for the primary efficacy analysis in the ITT population. In the pooled studies, 
the ECR responder rates in the CE-ECR population were 81.5% in the solithromycin group 
compared with 82.0% in the moxifloxacin group. Consistent results were observed in each study. 


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In subgroup analyses in the ITT population, a consistent effect was observed for ECR responder 
rates by geographic region and in demographic subpopulations, e.g., age, weight, gender and 
ethnicity.  
Subpopulation analyses were also conducted for characteristics related to baseline disease 
severity Responder rates and treatment differences were consistent in analyses of patients 
classified as PORT II (treatment difference: 1.14; 95% CI: -5.1, 7.3) or PORT III/V (treatment 
difference: -0.93; 95% CI: -5.9, 4.0). No differences in responder rates were noted based upon 
prior history of asthma/COPD or receipt a single dose of a short-acting antibiotic within 7 days 
prior to randomization. 
A phase 3 study (Study CE01-300) of the efficacy and safety of oral solithromycin for treatment 
of moderate-to-moderately severe CABP (Pneumonia Patient Outcomes Research Team [PORT] 
II-IV classification) in comparison with oral moxifloxacin has been completed. In this double-
blind, randomized controlled trial, subjects were randomized 1:1 to receive oral solithromycin 
(single 800-mg dose on Day 1, followed by 400 mg once daily on Days 2 through Day 5 (total 
duration of dosing 5 days) or oral moxifloxacin, 400 mg once daily, Days 1 through Day 7 (total 
duration of dosing, 7 days), with evaluations at Baseline, Day 4 to assess early clinical response 
(ECR), Day 7, Days 12–17 (short-term follow-up [SFU] visit), and Day 28 (long-term follow-up). 
An ECR was defined as improvement in at least 2 of 4 cardinal symptoms (cough, chest pain, 
dyspnea, sputum production) without worsening in any. Success at SFU was determined by 
investigators. Primary objectives were demonstration of non-inferiority (10% NI margin) at ECR 
in the intent-to-treat (ITT) population (Food and Drug Administration [FDA] guidance) and at 
SFU in the ITT and clinically evaluable (CE) populations (European Medicines Agency guidance).  
Eight hundred and sixty subjects from 16 countries were randomized (ITT population); 856 
received at least 1 dose of study drug (safety population), 426 received solithromycin. Among all 
subjects, 90% met key study inclusion and exclusion criteria without confounding diagnoses and 
within pre-specified protocol windows for follow-up (CE population). The mean age of 
solithromycin subjects was 58.5 years, with 36.4% ≥ age 65, versus 56.7 years with 31.6% ≥ age 
65 for moxifloxacin.  
Solithromycin was non-inferior to moxifloxacin in the ITT in ECR (78.2 versus 77.9%) and SFU 
success (84.5 versus 86.6%) and in the CE-SFU success (88.1 versus 91.3%). Comparative ECR 
success for solithromycin was more favorable among the pre-defined subgroup of subjects ≥ age 
75 (83.9 vs 69.8%). Solithromycin demonstrated comparable safety to moxifloxacin in the 
occurrence of AEs (36.6 versus 35.6%), study drug-related AEs (10.1 versus 12.5%), SAEs 
(6.6 versus 6.3%; none attributed to study drug) and deaths (1.4 in both groups). Grade 4 ALTs 
(>8×upper limit of normal [ULN]) were observed in 5 moxifloxacin subjects and 2 solithromycin 
subjects. Two episodes of Clostridium difficile diarrhea were diagnosed, both in moxifloxacin 
recipients.  
Final efficacy results from 2 phase 3 trials: 1) IV-to-oral solithromycin (versus moxifloxacin) in 
CABP, and 2) Single-dose oral solithromycin for uncomplicated genitourinary gonococcal 
infection (versus intramuscular ceftriaxone + oral azithromycin) are pending.    


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5.2.4  Summary of Safety 
As of 30 April 2016, more than 2000 subjects and patients received systemic exposure to 
solithromycin. The major source of safety data are the two Phase 3 pivotal studies in patients 
with CABP (n=856).  
5.2.4.1 
Overview of Adverse Events 
Macrolides, as a class, are well-tolerated and widely utilized. The most common AEs reported 
with the use of existing macrolides are GI, such as diarrhea, nausea and vomiting; others 
include headache and dizziness. 
Oral solithromycin has been well tolerated, the most common AEs being mild GI events in Phase 
1 and 2 trials. The most common AEs in the Phase 1 IV trials were related to infusion site 
tolerability; there were no other unique AEs relative to events reported in oral trials.  
Infrequent reports of local and systemic allergic reactions have occurred with oral and 
IV solithromycin, including anaphylaxis, urticaria, erythema and maculopapular rashes. 
The AE profile of the 5-day CABP regimen compared favorably with that of levofloxacin in the 
Phase 2 CABP trial. In the Phase 3 oral CABP study, solithromycin demonstrated a similar AE 
profile to that of moxifloxacin. In the Phase 2 GC study, the most common AEs were mild GI 
disorders, primarily diarrhea and nausea. Although both doses were acceptably tolerated, 
treatment-related GI AEs occurred less frequently with the 1000 mg dose than with 1200 mg. 
In the Phase 3 oral CABP study, 6 (1.4%) patients in the solithromycin group and 6 (1.4%) 
patients in the moxifloxacin group died during the study. None of the SAEs resulting in death 
was considered related to study drug. A total of 28 (6.6%) patients in the solithromycin group 
and 27 (6.3%) patients in the moxifloxacin group reported at least 1 non-fatal SAE. No patient 
in either treatment group had an SAE that was considered related to study drug. The most 
common AEs observed in patients receiving solithromycin were headache (4.5%) and diarrhea 
(4.2%). 
In the Phase 3 IV to oral CABP study, 5 (1.2%) patients in the solithromycin group and 7 (1.6%) 
patients in the moxifloxacin group died during the study. None of the SAEs resulting in death 
was considered related to study drug. A total of 30 (6.9%) patients in the solithromycin group 
and 2 (5.4%) patients in the moxifloxacin group reported at least 1 non-fatal SAE. Only 3 SAEs 
were considered related to study drug by the investigators (urticaria and anaphylactic reaction 
in 1 patient each in solithromycin and anaphylactic reaction in 1 moxifloxacin patient). The 
most frequently reported infusion site related TEAEs were infusion site pain (10.4%), infusion 
site phlebitis (10.0%) and infusion related reaction (6.5%). Infusion site related TEAEs were 
mostly mild or moderate in intensity and infrequently led to discontinuation of study drug or 
withdrawal from the study (in 1 moxifloxacin and 10 solithromycin patients). Apart from 
infusion site related events, the most common AEs observed in patients receiving solithromycin 
were diarrhea (5.9%) and headache (4.2%) 
Overall, in the 13 oral Phase 1 studies, solithromycin was generally well tolerated in  healthy adults 
when administered in single doses up to 1600 mg, in multiple doses of 200, 400, and 600 mg 


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administered QD for 7 days; in multiple doses of 400 mg administered QD for 5 days; as a loading 
dose regimen of 800 mg on Day 1 followed by 400 mg QD on Days 2 to 5; and when co-
administered with digoxin (a P-gp substrate), and when co-administered with a CYP3A4 substrate 
(midazolam), inhibitor (ketoconazole), or inducer (rifampin). The most common AEs were GI 
disorders (primarily mild diarrhea and nausea) and nervous system disorders (primarily headache 
and dysgeusia). Most AEs were mild in severity.  
In initial IV phase 1 studies (CE01-104, CE01-116 and CE01-118), the most common AEs 
reported after single IV doses were general disorders and administrative site conditions (infusion-
related pain) followed by nervous system disorders (headache, dysgeusia), with the majority mild 
in severity. 
One subject who received 800 mg IV for 3 days in study CE01-116 had a marked (8×ULN) ALT 
elevation. One subject in a phase 1 IV study designed to reach the maximally tolerated dose  
(CE01-116) had a clinically significant ALT elevation to 8×ULN after receiving 3 daily doses of 
800 mg IV. Across all 3 completed IV studies, 8 other subjects had Grade 1 elevations in ALT 
(<2×ULN) and 1 had a Grade 2 elevation of ALT to 2.4×ULN (1 received multiple 200mg doses, 
and 7 received multiple 400mg doses). These 9 subjects’ ALT elevations were asymptomatic, 
transient, reversible, and not associated with bilirubin elevation. The subject with the marked ALT 
elevation had notable drug accumulation with high solithromycin plasma concentrations (5–
8 µg/mL); exposures of this magnitude have not been reached in any study with oral solithromycin 
and are not expected with 400mg IV infusions. 
Study CE01-121 evaluated a single-vial formulation of solithromycin, containing 400 mg 
solithromycin lyophilized with 3 amino acids as buffering agents. Both central and peripheral 
venous administration of multiple 400mg daily doses for 7 days were assessed, and 2 peripheral 
infusion durations, 30 and 60 minutes, were tested.  
Forty subjects were enrolled (30 solithromycin/ 10 placebo). Twenty subjects received multiple 
doses (7 daily doses) of 400 mg via a peripheral IV line, and 5 received 7 daily doses of 400 mg 
via PICC. Five subjects received a single 800mg IV dose of solithromycin given over 40 minutes 
to evaluate the safety of supratherapeutic plasma concentrations. 
Infusion-site pain was the most common AE reported. Seven subjects discontinued the study drug 
or the study due to infusion-related AEs (6 subjects due to infusion-site pain and 1 subject due to 
phlebitis). Adverse events appeared to be correlated with the duration of multiple dosing.  
Five of 25 subjects receiving multiple 400mg doses of solithromycin had 1.1 to <2×ULN 
elevations in ALT, and 2 subjects had 1.1 to <2×ULN elevations in AST. A 4.5×ULN AST 
elevation (173 U/L) was observed on Day 12 in a subject who received 6 daily doses of 400 mg 
solithromycin infused peripherally over 60 minutes. It had declined on Day 15 and returned to a 
normal level (28 U/L) on Day 36. 
One subject (PICC line cohort) had a 1.8×ULN total bilirubin elevation, mildly elevated AST 
(1.2×ULN), and elevated direct bilirubin (1.5×ULN) on Day 12. This subject had an elevated total 
bilirubin (1.2×ULN) at baseline, and at discharge (Day 9) had a normal ALT, AST, total bilirubin, 
and direct bilirubin. 


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Two of the 5 subjects who received a single 800 mg dose solithromycin over 40 minutes 
experienced an AE. The most common AE was infusion-related pain. One subject receiving 
solithromycin had a 1.1 to <1.5×ULN elevation of direct bilirubin. 
In the phase 2 CABP study (CE01-200), solithromycin was administered to 64 adult subjects as a 
loading dose of 800 mg on Day 1 followed by 400 mg QD on Days 2 to 5. The percentage of 
subjects who experienced ≥1 treatment-emergent AE (TEAE) during the study was 29.7% in the 
solithromycin group and 45.6% in the levofloxacin (comparator) group. The majority of AEs were 
GI disorders and of mild or moderate intensity. The most frequently reported GI AEs with 
solithromycin were diarrhea (7.8%) and nausea (1.6%). Two subjects randomized to solithromycin 
in this study had SAEs, neither attributed to study drug (1 elderly subject with multiple medical 
sequelae following a fall with humerus fracture and a second subject with persistent chest pain 
requiring hospitalization). There was 1 death in the study, a subject randomized to receive 
levofloxacin, who died with pulmonary embolism.  
In the phase 2 GC study, 59 adult subjects received a single dose of 1200 or 1000 mg 
solithromycin. Mild diarrhea and nausea were the most commonly reported AEs and were less 
frequent after the 1000mg dose. 
In the phase 3 oral CABP study (CE01-300), solithromycin was administered to 424 adult subjects 
(among 860 enrolled) as a loading dose of 800 mg on Day 1, followed by 400 mg QD on Days 2 
through Day 5. The percentage of subject s who experienced ≥1 TEAE during the study was 36.6% 
in the solithromycin group and 35.6% in the moxifloxacin (comparator) group. The most 
commonly reported AE was headache, occurring in 4.5% of solithromycin recipients (and in 2.5% 
of moxifloxacin recipients), of mild severity in the majority. Gastrointestinal AEs were also 
common, with diarrhea, nausea, and emesis reported by 4.2, 3.5 and 2.4% of solithromycin 
recipients, respectively. Diarrhea and nausea were more commonly reported by moxifloxacin 
recipients, while emesis was reported by 10 subjects in each arm of the trial. These GI disorders 
were of mild or moderate intensity, and were rarely treatment limiting. Serious AEs were reported 
for 6.6% of solithromycin recipients (and 6.3% of moxifloxacin recipients). None was considered 
study drug related. Among these SAEs, a wide range of medical outcomes anticipated during or 
following an episode of pneumonia were observed, including acute myocardial infarction, 
congestive heart failure, empyema, cerebrovascular accident, renal dysfunction, and respiratory 
failure. In addition, conditions which mimicked pneumonia (resulting in the subject’s enrollment) 
were also reported as SAEs, including pulmonary malignancy and tuberculosis. The mortality rate 
in both arms of the study was 1.4%, an overall figure below that which would be predicted by the 
PORT score profile of the study population.  
In the phase 3 IV-to-oral CABP study (CE01-301), solithromycin was administered in daily IV 
doses of 400 mg. When clinical stability is achieved, subjects could switch to oral solithromycin 
dosing, receiving an initial dose of 800 mg on the first oral dosing day, followed by oral dosing 
with 400 mg each day. The total duration (by IV or IV/oral dosing) of treatment was 7 days. This 
study has been completed and unblinded. However, at this time, data are currently being analyzed 
and all results would be considered preliminary.  


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Solithromycin, like most antibiotics and like all macrolide antibiotics, has been associated with 
hepatic aminotransferase elevations. In the pooled Phase 3 CABP trials, ALT elevations to 
>3×ULN, >5×ULN and >10×ULN were seen in 7.2%, 2.4% and 0.1% of solithromycin recipients 
compared to 3.6%, 1.0% and 0.2% of moxifloxacin recipients. Elevations of ALT to >3×ULN 
were 5.4% in the oral study and 9.1% in the IV to oral study. These elevations were typically 
asymptomatic, not associated with bilirubin elevation and readily reversible, with improvement 
in many cases seen during continued dosing. There have been no Hy’s Law cases. 
Multiple lines of evidence point to an exposure-response relationship for ALT elevation with 
increasing solithromycin exposure. 
In the pooled Phase 3 CABP studies, rates of bilirubin elevation to levels >ULN were 
comparable between solithromycin and moxifloxacin (4.3% vs 4.0%, respectively), and 
elevations >2×ULN were uncommon (<0.5%) in both treatment groups. Solithromycin was more 
frequently associated with alkaline phosphatase elevation to >1.5×ULN than moxifloxacin 
(5.2% versus 2.9%, respectively), consistent with the potential to induce mild degrees of 
cholestasis, as has been observed with older macrolides and other antibiotics. 
Solithromycin was generally well tolerated in subjects with cirrhosis of Child Pugh Class A, B 
and C severity in a controlled Phase 1 trial. In the Phase 3 CABP studies, the overall incidence 
of AEs was similar among subjects with and without hepatic impairment. ALT elevation to 
>5×ULN occurred with identical frequency among patients with and without hepatic 
impairment (2.4%), and AST elevation >5×ULN occurred in 1 patient with baseline hepatic 
impairment. 
Analysis of ALT elevation by patient characteristics including age, sex, race, history of chronic 
liver disease and concomitant exposure to statins have not revealed a population at particular 
risk for these events.  
While solithromycin can cause asymptomatic, reversible ALT elevation and mild degrees of 
cholestasis, the overall liver safety profile of clinically important events was comparable to 
moxifloxacin and may be comparable to the older macrolides. 
When solithromycin is taken for longer than 7 days, rare cases of jaundice and itching have 
occurred. These events were reversible after solithromycin treatment was stopped. 
Hepatic transaminase elevations have been commonly observed with macrolides, and reports of 
cholestatic hepatitis (generally reversible) and rarely, hepatic failure, have been reported after their 
use.  
The most extensive subject experience with solithromycin dosing has been obtained from the 
phase 3 oral CABP trial (CE01-300). ALT elevation (of any grade, > 1.1×ULN) occurred in 
123 subjects (29%). Grade 1 (1.1×ULN to < 2.0×ULN) and grade 2 (2.0×ULN to < 3.0×ULN) 
comprised the majority of these episodes (102/424, 24.5%). Nineteen subjects (4.6%) had grade 3 
elevation (3.0×ULN to < 8.0×ULN) of ALT), and 2 subjects (0.5%) had grade 4 ALT elevation 
(>8.0×ULN). In the 2 grade 4 ALT elevation episodes, there was evidence of cholestasis (with 
elevated ALP), without elevation of bilirubin. No subject had treatment-emergent ALT and 
bilirubin elevation consistent with Hy’s Law criteria, and there was no evidence of hepatic 


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synthetic dysfunction in any subject. Across all studies, there have been no cases of concomitant 
bilirubin and hepatic transaminase elevations meeting Hy’s Law criteria, including in the ongoing 
IV-to-oral phase 3 CABP trial (data not summarized herein, as the study remains blinded).  
Macrolides have been associated with QT prolongation and risk for torsades de pointes. In March 
2013, the U.S. FDA warned the public that azithromycin may cause fatal heart rhythm 
disturbances. Unlike the older macrolides, however, solithromycin does not prolong the QT 
interval (as summarized in Section 5.2.2.2). 
Macrolides have been associated with QT prolongation and risk for torsades de pointes. In 
March 2013, the FDA warned the public that azithromycin may cause fatal heart rhythm 
disturbances, particularly in patients with known risk factors. A thorough QT study of 
solithromycin was negative, demonstrating that solithromycin does not have a propensity to 
prolong the QT interval in a clinically significant manner in healthy subjects.  
In the pooled Phase 3 CABP studies, cardiac AEs were observed more frequently in 
moxifloxacin recipients (4.7%) than solithromycin recipients (3.0%). Most of these events 
reflected the underlying chronic diseases of enrolled patients in the context of the severe 
physiologic stress of CABP and were not considered study drug related.  
The thorough QT study revealed that healthy subjects with supratherapeutic exposure to 
solithromycin experience an increase in heart rate. The exact mechanism for this effect is 
unknown, although a variety of receptors and cardiac channels have been evaluated in vitro. 
However, in the Phase 3 studies, the central tendency for observed heart rate was a decline from 
baseline over time comparable to that observed with moxifloxacin, as the physiologic stressors 
of CABP diminished with response to therapy. Fewer patients receiving solithromycin than 
moxifloxacin experienced a potentially clinically significant tachycardia (> 120 bpm) that was 
associated with an increase over baseline of ≥ 15 bpm (1.3% and 1.8%, respectively).  
In the Phase 3 studies, categorical changes from baseline in the QTcF interval of > 30 msec 
occurred less frequently with solithromycin (16.7%) than with moxifloxacin (28.0%). Post-
baseline changes resulting in a QTcF > 500 msec occurred in < 1% of patients in both treatment 
groups. Based on these data and the results of the thorough QT study, it is clear that 
solithromycin does not present intrinsic QT prolongation risks. However, as a CYP3A4 
inhibitor, solithromycin may pose secondary risk of QT prolongation through inhibition of 
metabolism of other QT-prolonging drugs.  
A plasma concentration effect analysis of data from the TQT study showed that the increase in 
heart rate was concentration dependent. An effect on heart rate with the IV, IV/oral, and therapeutic 
regimens planned for CABP would be expected to be modest. In subjects with CABP, who may 
have an elevated baseline heart rate associated with their infection and other physiologic stressors, 
mean heart rate has declined with solithromycin therapy. In study CE01-300, among 
solithromycin-treated subjects, mean heart rate at baseline was 90.1 bpm, with decreases from 
baseline on Days 2, 4, and 7 of 9.0, 8.0, and 10.1 bpm. In contrast, among moxifloxacin-treated 
subjects, mean heart rate at baseline was 93.2 bpm, with mean decreases on these days of 13.9, 
14.1, and 14.2 bpm. Reported AEs associated with elevated heart rate (including the terms: sinus 
tachycardia, supraventricular tachycardia, tachycardia, and atrial fibrillation) occurred in < 1.0% 
of solithromycin recipients.  


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Solithromycin does not contain a pyridine moiety in its side chain, unlike telithromycin. The 
pyridine moiety has been shown to significantly inhibit nicotinic acetylcholine (nACh) receptor 
subtypes in vitro. This inhibition may be associated with certain AEs observed with telithromycin 
that are unusual for the macrolide class. All solithromycin clinical studies will continue to carefully 
monitor for these atypical AEs, and subjects with known myasthenia gravis will continue to be 
excluded from clinical studies. 
5.4  
Rationale for Dosing Regimen 
. . . The dosing regimens for each age group and each of the 3 formulations (capsule, IV infusion, 
and suspension) are being were determined in phase 1 studies in children.  
To date, data are available from phase 1 pediatric studies (CE01-119 and CE01-120) to identify 
optimal dosing following capsule and intravenous solithromycin administration in adolescents 12 
to 17 years of age and children 6 to <12 years of age. As noted in Section 5.2.2.2 and Table 2 
above, data from 13 adolescents receiving capsule administration demonstrated that >90% of 
adolescents achieved therapeutic exposures, and that PK estimates were in the range of observed 
adult values following an the recommended adult regimen (800 mg Day 1, 400 mg on Days 2-5). 
In this adolescent PK study, the majority of subjects received the recommended adult regimen, 
with variable exposure estimates and safety profile.  
Data from two phase 1 studies in children (N=92) were merged and used to develop a population 
PK model that informs dosing for this study for all formulations. A two compartment model with 
linear elimination characterized the solithromycin data following both oral (capsule and 
suspension) and intravenous administration. To account for the growth effects, actual body 
weight was included in the model using allometric scaling. Using the final model, Monte Carlo 
simulations were performed to identify pediatric dosing that matches adult exposure (area under 
the concentration versus time curve from 0 to 24 hours and maximal drug concentrations after 
multiple doses) observed in the phase 3 program.  
The selected dosing regimen for adolescents (12-17 years) receiving solithromycin via oral 
administration (capsules or suspension) was 800 mg on Day 1 and 400 mg on Days 2-5 if they 
weight ≥40 kg. For subjects 12 to 17 years and < 40 kg, a capsule dosing regimen of 20 mg/kg 
on Day 1 (800 mg maximum) and 10 mg/kg on Days 2-5 (400 mg maximum) was selected based 
on simulated exposure (Figure 2). Suspension dosing for adolescents was selected based on data 
obtained from a bioequivalence study in adults between capsules and suspension and the similar 
bioavailability estimates obtained for both formulations in the population PK model.  


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Figure 2 
Simulated Day 5 Exposure following a capsule dose of 20 mg/kg on Day 1 
and 10 mg/kg on Days 2-5 
 
Note: Doses rounded upward to the nearest 200 mg. The dashed line represents an adult Day 4 AUC0-24 of 
12.6 mcg*h/mL.  
For the suspension dosing for children <12 years of age, a dose of 20 mg/kg on Day 1 (800 mg 
maximum) and 10 mg/kg on Days 2-5 (400 mg maximum) resulted in a comparable simulated 
Day 5 AUC0-24 across pediatric age groups (Figure 3). Although the median simulated exposure 
appears to be lower in the 0-2 years age group, the simulated exposure was within the range 
observed in adults and it’s possible that the observed values may be higher due to immature 
CYP3A4 metabolism in this age group.  
0
20
40
60
12-17yrs,<40kg
12-17yrs,≥40kg
6-12yrs,<40kg
6-12yrs,≥40kg
excludes outside values


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Figure 3 
Simulated Day 5 Exposure following a suspension dose of 20 mg/kg on Day 
1 and 10 mg/kg on Days 2-5 
 
Note: The dashed line represents an adult Day 4 AUC0-24 of 12.6 mcg*h/mL. There is only one subject in the 
2-6 years ≥40 kg category   
Intravenous daily dosing of 8 mg/kg resulted in comparable simulated Day 5 AUC0-24 across all 
pediatric age groups: median (standard deviation) 14.4 mcg*h/mL (23.4) for 12-17 years; 
14.1 mcg*h/mL (25.4) for 6-<12 years; 11.0 mcg*h/mL (26.0) for 2-<6 years; and 9.4 mcg*h/mL 
(19.1) for 0-<2 years. The adult exposure used for matching purposes was 12.6 mcg*h/mL. Then 
in the follow-up study, CE01-120, an intravenous dose of 6 mg/kg daily resulted in median (range) 
Cmax and AUC0-24 estimates of 2.3 μg/mL (1.2-7.7) and 12.3 μg*h/mL (8.2-19.9), respectively, in 
six adolescents (12 to <17 years). In children (6 to <12 years), Cmax and AUC0-24 estimates were 
2.8 μg/mL (1.0-8.1) and 10.6 μg*h/mL (2.7-18.4) following 7 mg/kg daily dosing. These estimates 
are comparable to adult median (range) values of 2.7 μg/mL (2.1-3.5) for Cmax and 13.7 μg*h/mL 
(6.1-22.3) following 400 mg of daily dosing. Data for younger age groups and oral formulations 
are in development.  
Because of the complete efficacy extrapolation approach to determination of efficacy in the 
pediatric population, the duration of study dosing drug regimens are similar to those in adults. 
Oral-only dosing is for 5 to 7 days, with a loading dose on the first day. Iintravenous-only and 
IV-to-oral dosing are for 5 to 7 days duration. with a loading dose given the first day of oral 
dosing.  
0
10
20
30
40
50
6-12yrs,<40kg
6-12yrs,≥40kg
2-6yrs,<40kg
2-6yrs,≥40kg
0-2yrs,<40kg
excludes outside values


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7.3  
Study Drug Dosage and Administration 
Solithromycin will be administered IV or PO according to Tables 4 5 through 8 below. No loading 
doses are used with IV solithromycin administration or if switched to oral administration. An 
IV-to-PO switch can occur after the first IV dose. Note that oral dosing either as initial exposure 
to solithromycin with capsules or suspension, or as follow on therapy to prior IV dosing, is initiated 
with a singe (PO) loading dose. Subjects starting with oral therapy will receive 5 to 7 days of 
solithromycin treatment, and those starting with IV therapy (regardless of if and when they switch 
to oral therapy), will receive 5 to 7 days of solithromycin treatment. 
Table 4  Study Design by Age Group 
Age 
(years) 
Route 
Formulation 
Loading dose  
(Max dose: 800 mg)a 
Daily maintenance  
dose  
(Max dose: 400 mg)a 
12 to 17  
PO 
Capsulesb 
800 mg 
400 mg 
12 to 17 
PO 
Suspension 
TBD 
TBD 
12 to 17  
IV 
Solution 
 No loading dose 
6 mg/kg 
6 to <12 
PO 
Capsulesb 
TBD 
TBD 
6 to <12 
PO 
Suspension 
TBD 
TBD 
6 to <12 
IV 
Solution 
No loading dose 
7 mg/kg 
2 to <6 
PO 
Suspension 
TBD 
TBD 
2 to <6 
IV 
Solution 
No loading dose 
TBD 
2 mo to <2 
PO 
Suspension 
TBD 
TBD 
2 mo to <2 
IV 
Solution 
No loading dose 
TBD 
a. The maximum oral loading dose is 800 mg, and the maximum IV or oral maintenance dose is 400 mg. 
b. The capsule dose is rounded upwards to the nearest 200 mg.  
c.  The adult dose should be administered unless the subject weighs <40 kg, in which case they receive 20 mg/kg  on 
Day 1and 10 mg/kg on Days 2-5. Minimum weight for using capsules is 60 kg. All smaller subjects should receive 
suspension if dosing orally. 
For subjects receiving the capsule formulation, 200 mg solithromycin capsules will be used to 
provide the absolute dose of either 200 mg, 400 mg or 800 mg. The capsule dose will be rounded 
upwards to the nearest 200 mg, not to exceed an 800 mg loading dose and 400 mg maintenance 
dose. Study drug should be swallowed with water approximately every 24 hours and at 
approximately the same time each day (±4 hours). Study drug can be taken without regard to food.  
Table 5  
Capsule Dosing Regimens 
Age 
(years) 
Weight 
Route 
Formulation 
Day 1 
(Max dose: 800 mg)  
Days 2 to 5 
(Max dose: 400 mg)  
6 to 17 
>30 kg 
PO 
Capsules 
800 mg 
400 mg 
>20 to 30 kg 
PO 
Capsules 
600 mg 
400 mg 
≤20 kg 
PO 
Capsules 
400 mg 
200 mg 
Subjects requiring an oral dosage form other than capsules will receive suspension formulation, 
provided at 160 mg/5 mL and 320 mg/5 mL strengths, to achieve the age-appropriate mg/mL and 
solithromycin dose. Any dosing variations within 10% of the calculated suspension dose is not 
considered a deviation. 


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Table 6  
Suspension Dosing Regimens 
Age 
(years) 
Route 
Formulation 
Day 1 
(Max dose: 800 mg)  
Days 2 to 5 
(Max dose: 400 mg)  
12 to 17 
PO 
Suspension 
20 mg/kg (800 mg) 
10 mg/kg (400 mg) 
6 to <12 
PO 
Suspension 
20 mg/kg 
10 mg/kg 
2 to <6 
PO 
Suspension 
20 mg/kg 
10 mg/kg 
2 mo to <2 
PO 
Suspension 
20 mg/kg 
10 mg/kg 
No loading doses are used with IV solithromycin administration. Intravenous solithromycin 
should be infused over approximately 60 minutes (±20 minutes) approximately every 24 hours (±4 
hours). Changes to the infusion duration should be discussed with the study medical monitor prior 
to study drug administration. Any dosing variations within 10% of the calculated IV or 
suspension dose is not considered a deviation. 
Table 7  
Intravenous Dosing Regimens 
Age 
(years) 
Route 
Formulation 
Days 1 to 7 
(Maximum dose: 400 mg)  
12 to 17  
IV 
Solution 
8 mg/kg 
6 to <12 
IV 
Solution 
8 mg/kg 
2 to <6 
IV 
Solution 
8 mg/kg 
2 mo to <2 
IV 
Solution 
8 mg/kg 
A subject can be converted from the IV to an oral formulation following 1 or more IV doses. The 
first oral dose will be 10 mg/kg with a maximum of 400 mg. No loading doses are used with IV 
solithromycin administration. Note that oral dosing, either as initial exposure to solithromycin with 
capsules or suspension, or as follow-on therapy prior to IV dosing, is initiated with a single (oral) 
loading dose. 
Table 8  
Intravenous to Oral Dosing Regimens 
Age 
(years) 
Route 
 Oral Formulation 
Day 1 to Last IV Dosing 
Day 
(Max dose: 400 mg)  
First Oral Dosing Day 
to Day 7 
(Max dose: 400 mg)a  
12 to 17 
IV/PO 
Suspension or 
Capsules 
8 mg/kg 
10 mg/kg (400 mg) 
6 to <12 
IV/PO 
Suspension or 
Capsules 
8 mg/kg 
10 mg/kg 
2 to <6 
IV/PO 
Suspension 
8 mg/kg 
10 mg/kg 
2 mo to <2 
IV/PO 
Suspension 
8 mg/kg 
10 mg/kg 
a. 
The adult dose should be administered unless the subject weighs <40 kg, in which case they receive 
10 mg/kg on the first oral dosing day through Day 7. The capsule dose is rounded upwards to the nearest 
200 mg.  
7.5  
Age Group Initiation 
Enrollment will occur simultaneously for all age groups for which information to inform the dosing 
regimen is available.  


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8.2  
Exclusion Criteria 
8. …In addition, the following drugs may not be co-administered with solithromycin in this trial 
due to the potential for adverse drug-drug interaction: digoxin, colchicine, midazolam, 
quinidine, ergotamine, dihydroergotamine, rivaroxaban, apixaban, dabigatran, edoxaban, 
cisapride, cyclosporine, sildenafil, astemizole, and alfentanil. 
9.1  
Solithromycin (CEM-101) 
Solithromycin suspension contains aspartame and patients with phenylketonuria should be 
aware that the suspension contains 78 µg of phenylalanine (as a component of aspartame) per 
mL. 
9.4  
Study Drug Storage Conditions 
The oral capsules will…Daily temperature logs must be kept at the clinical site and all 
temperature excursions during storage must be reported to Cempra GCP QA to obtain approval 
for continued use. 
Once prepared, the reconstituted vials should be used within 2 hours when can be stored at room 
temperature for up to 24 hours; they should not be refrigerated or frozen. Room light exposure is 
allowed. Once the reconstituted solithromycin solution has been added to the saline bag, the 
infusion solution in the saline bag can be kept at room temperature (15°C to 25°C; 59°F to 77°F) 
for up to 12 hours or stored refrigerated for up to 24 hours before use the bag should not be 
refrigerated or frozen at any time. Room light exposure is allowed during preparation, storage, 
and patient administration.  
10.2.1  
Treatment Days up to Last Day of Treatment 
1. Every effort should be made to obtain safety labs 72 hours (±24 hours) after the first 
dose to include ALT, AST, alkaline phosphatase, total and direct bilirubin, and WBC 
with differential. A separate study sample is not required if these labs are obtained at 
72 hours (±24 hours) after the first dose per standard of care. 
10. Administer study drug and active comparator. 
10.2.2  
Last Day of Treatment (+48 Hours) 
3. Perform safety labs as described in Section 10.4.1.  
10.3.1  
Day 16 Post Randomization (±4 days) 
1. Every effort should be made to obtain safety labs Day 16 (±4 days) after the first dose to 
include ALT, AST, alkaline phosphatase, total and direct bilirubin, and WBC with 
differential. A separate study sample is not required if these labs are obtained at Day 16 
(±4 days) after the first dose per standard of care. 
8. Review and record any AEs and SAEs as described in Section 12.1. Every effort should 
be made to bring the subject back, but SAEs must be collected via phone/other media if 
the subject is unable or unwilling to return. 


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10.3.2  
Day 36 28 Post Randomization (±4 days) 
1. Every effort should be made to obtain safety labs Day 28 (±4 days) after the first dose 
to include ALT, AST, alkaline phosphatase, total and direct bilirubin, and WBC with 
differential. A separate study sample is not required if these labs are obtained at Day 28 
(±4 days) after the first dose per standard of care. 
2. Review and record any SAEs as described in Section 12.1. Every effort should be made 
to bring the subject back for follow up, but SAEs must be collected via phone/other media 
if the subject is unable or unwilling to return. 
Review and rcord any SAEs as described in Section 12.1. Every effort should be made to bring 
the subject back, but SAEs must be collected via phone/other media if the subject is unable or 
unwilling to return. 
10.4.1  
Safety Laboratory Tests 
Safety laboratories will include hemoglobin, hematocrit, WBC with differential, platelet count, 
blood urea nitrogen, calcium, serum creatinine, potassium, sodium, AST, ALT, ALP, total and 
direct bilirubin, and albumin. 
10.4.2  
Microbiology Assessments 
Results of microbiology assessments performed in accordance with routine standard of care will 
be recorded on the study eCRF. These include all cultures from cerebrospinal fluid, pleural fluid, 
blood, urine (catheter or suprapubic tap), and sputum sterile body fluids, as well as molecular 
and serologic tests for M. pneumoniae and C. pneumoniae.  
10.4.3  
Pharmacokinetic Determinations 
Solithromycin and metabolite concentrations will be measured in plasma. Pharmacokinetics 
samples will be processed at a central lab using a validated bioanalytical assay. These data will be 
reviewed periodically during the study. . .  
10.5  Radiological Imaging and Non-pharmacologic Treatment/Procedures 
. . . Surgeries of interest include surgeries of the chest and chest wall, such as pleural tube 
placement and video assisted thoracoscopic surgery. Surgical procedures of the head and neck area 
will also be needed.  
10.6  Clinical Efficacy Outcomes Assessments Time Points 
Clinical outcomes assessments will be performed by a blinded investigator at the study site. At 
each time point, the site blinded investigator will evaluate signs and symptoms and record physical 
findings of CABP. These assessments will include cough, difficulty breathing, purulent sputum 
production, chest pain, grunting, hypotension, tachycardia, tachypnea, and evidence of 
pulmonary consolidation (further details are in the Blinded Investigator Plan). If symptoms and 
physical exam findings are available in the medical record per standard of care, these can be used 
for the clinical outcomes assessments.  


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• 
A baseline assessment of signs, symptoms, and physical exam findings will be completed 
at screening 
10.8  Clinical Cure Definition (Day 16 Post Randomization [±4 Days]) 
Clinical cure is defined as resolution of all presenting signs and symptoms of CABP (excluding 
cough), no development of new sign or symptoms of CABP, and no requirement for additional 
alternative antimicrobial therapy. 
11.2  Discontinuation from Study Drug 
A subject may have study drug prematurely (prior to 5 to 7 oral doses days or 5 to 7 IV or IV/oral 
doses) discontinued for any of the following reasons: 
• 
Safety, including AEs or development of clinically significant laboratory abnormalities. 
The subject must be followed clinically until the event is resolved or deemed stable. 
• 
Clinical failure or lack of efficacy. 
• 
Subject wishes to withdraw consent for reasons other than an adverse experience. 
• 
Subject non-compliance or unwillingness to comply with the procedures required by the 
protocol. 
• 
Investigator discretion. 
• 
Sponsor request. 
Any subject who prematurely discontinues study drug should be encouraged to complete the study 
through the last study visit. The Last Day of Treatment procedures will be performed the day 
(+48 hours) the study drug is discontinued.    
11.3  Withdrawal from Study 
• Subject wishes to withdraw consent due to an adverse experience 
11.4  Study Site Discontinuation 
• Recommendation from the DMC 
12.1  Adverse Events 
Laboratory abnormalities are not considered AEs unless they are associated with clinical signs 
or symptoms, or require medical intervention. However, a clinically significant laboratory 
abnormality (e.g. detected on clinical chemistry or hematology) that is independent from the 
underlying medical condition and that requires medical or surgical intervention, or leads to 
study drug interruption or discontinuation, will usually be considered an AE.    
Lack of efficacy/clinical failure is captured as an efficacy measure and in general will not be 
considered an AE. 


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A laboratory abnormality that is considered clinically significant by the investigator (e.g., a change 
detected on clinical chemistry or hematology) that is independent from the underlying medical 
condition, requires medical or surgical intervention, or leads to study drug discontinuation will be 
considered an AE.  
12.1.1  
Serious Adverse Events 
• 
Death  
“Death” is an outcome and is NOT the AE. In the event of death, the cause of death 
should be recorded as the AE. The only exception is “sudden death” when the cause is 
unknown. 
• 
Subject hospitalization or prolongation of hospitalization. A “planned” hospitalization for 
study procedures or preexisting conditions is NOT an SAE. 
… 
Serious AEs will be collected from the time of signing of informed consent until 36 28 (±4) days 
after randomization.  
12.1.3  
Other Reportable Events 
Monitoring of liver laboratory tests 
Monitoring of liver laboratory tests of special interest (AST, ALT, and direct bilirubin) will be 
conducted throughout the study. Three levels of monitoring will be performed: 
Weekly monitoring: each week, data entered in the eCRF will be downloaded to identify any 
child enrolled in the study with a) normal AST, ALT, or direct bilirubin at baseline AND at least 
2×ULN on any of these laboratory tests at any study visit post baseline and b) any child meeting 
laboratory criteria for Hy’s Law. These data will be provided to the DCRI medical monitor and 
the sponsor for review.  
Quarterly monitoring: each quarter, summary data of children enrolled in the study with 
a) normal AST, ALT, or direct bilirubin at baseline AND at least 3×ULN on any of these 
laboratory tests at any study visit post baseline and b) any child meeting laboratory criteria for 
Hy’s Law will be provided to the DMC chair for review. Actions by the DMC chair will be 
described in the DMC meeting minutes. 
Biannual monitoring: twice per year, all data pertaining to liver laboratory tests will be 
presented to the DMC for review. This includes the data presented quarterly as well as listings 
of all laboratory tests at every visit.  
14.2.2  
Endpoints 
The primary endpoints for safety will be: 
a. The proportion of subjects with TEAEs 


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14.1.4  
Pharmacokinetic Analysis 
A population PK analysis will be performed using non-linear mixed effects modeling in 
NONMEM. Data will be reviewed during the study to evaluate the PK of solithromycin in 
pediatric CABP patients. 


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Amendment #1 19 January 2016 
Rationale for Amendment 
Amendment 1 adds dosing information, including the dosage rationale, for the 6-12 year old 
intravenous solithromycin age cohort, based on analysis of PK data from an ongoing Phase 1 study.    
To help ensure the integrity of randomization, follow-up visits are now based on date randomized 
instead of date of last treatment.  
A microbiological intent to treat population has been defined, to capture information on baseline 
pathogens if obtained per standard of care, and will represent an additional analysis population if 
there are sufficient numbers of subjects in this population in which to conduct a meaningful 
analysis.  
IV amoxicillin/clavulanic acid has been added as a comparator since it is a common antibiotic used 
in many countries as an appropriate treatment in pediatric patients with CABP. 
The use of diaries for outpatients who receive oral study drug has been added to help monitor 
compliance and drug accountability when drug is taken outside a healthcare setting. 
The two available suspension concentrations are described.   
Language required by the BARDA contract for sites outside the US has been added.  
Language has been modified in some sections to improve the clarity of the protocol requirements 
and procedures, and to correct minor typographical errors. Typographic corrections, including 
grammatical and punctuation errors, are not shown. 
New/revised text is in bolded italics. Deletions are identified by strikethrough. 
Protocol Synopsis 
Changes made in accordance with the revisions described below. 
Rationale:  There is a growing body of efficacy and safety data on solithromycin in adults, it and 
solithromycin was shown to be non-inferior to moxifloxacin in an adult Phase 3 trial in CABP.  
Subject Participation: 
• 
Up to 40 days of adverse event (AE) and serious AE (SAE) monitoring (treatment phase plus up 
to 30 days post completion of therapy 36 ±4 days will be reported) 


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Test Product: 
 
Age 
(years) 
Route 
Formulation 
Loading dose  
(Max dose: 800 mg)a 
Daily maintenance  
dose  
(Max dose: 400 mg)a 
12 to 17  
PO 
Capsulesb 
800 mg 
400 mg 
12 to 17 
PO 
Suspension 
TBD 
TBD 
12 to 17  
IV 
Solution 
 No loading dose 
6 mg/kg 
6 to <12 
PO 
Capsulesb 
TBD 
TBD 
6 to <12 
PO 
Suspension 
TBD 
TBD 
6 to <12 
IV 
Solution 
No loading dose 
7 mg/kg 
2 to <6 
PO 
Suspension 
TBD 
TBD 
2 to <6 
IV 
Solution 
No loading dose 
TBD 
2 mo to <2 
PO 
Suspension 
TBD 
TBD 
2 mo to <2 
IV 
Solution 
No loading dose 
TBD 
Comparator Therapy: 
Children ≥2 months to <5 years of age: 
a. Ceftriaxone IV OR 
b. Ampicillin IV (United States) or amoxicillin IV (Rest of the World)  
c. Amoxicillin-clavulanic acid (PO or IV)or amoxicillin PO 
Children 5 to 17 years of age (inclusive): 
a. Ceftriaxone IV OR 
b. Ampicillin IV (United States) or amoxicillin IV (Rest of the World) OR 
c. Amoxicillin-clavulanic acid PO or IV  or amoxicillin PO 
Azithromycin IV/PO or erythromycin lactobionate IV or erythromycin PO may be added to any of the three 
treatment regimens above.  
 
 
United States 
Rest of the World  
Amoxicillin-
clavulanic acid 
 - 
Children >4kg but< 40kg: amoxicillin 
component 25 mg/kg intravenously 
every 8 hours [1000 mg max dose] 
 
Children ≥ 40 kg: amoxicillin component 
1000 mg intravenously every 8 hours 
 


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Intravenous-to-oral switch:  
Subjects receiving an IV comparator drug (i.e. ceftriaxone, ampicillin) in any age group may be 
switched . . .  
Statistical Methods and Data Analysis 
Efficacy population: 
All subjects who are randomized. 
Safety population: 
All subjects who receive at least 1 dose of study drug.  
PK population: 
All subjects who receive at least 1 dose of solithromycin and have at least 
1 evaluable PK sample.  
MicroITT population: Randomized subjects who have a microbiologically confirmed baseline 
pathogen.  
Safety:  
New events that occur or pre-existing conditions that worsen in frequency or intensity will be reported as 
AEs or SAEs. AEs will be reported for 14 16 days and SAEs for 30 36 days following the end of therapy 
post-randomization. . .  
Efficacy:  
The primary efficacy endpoint is defined as clinical improvement on the last day of treatment (end 
of treatment response), and the secondary efficacy endpoints are defined as early clinical response 
at Days 2-4 and clinical success (i.e., cure) at the short-term follow-up visit (14 16 days [+/– 4 
days] following the end of therapy post-randomization). 
Table 1  
Schedule of Assessments and Procedures 
Column heading modified:  Day 16 10 Last Day of Treatment Post Randomization (±4 days) 
Column heading modified:  Day 36 30 Last Day of Treatment Post Randomization (±4 days) 
Footnote v modified:  Day 16 post 10 End of Treatment randomization response (cure) 
Section 5.2.3 Summary of Efficacy 
Final efficacy results are not yet available from 2 ongoing phase 3 trials: 1) IV-to-oral 
solithromycin (versus moxifloxacin) in CABP, and 2) Single-dose oral solithromycin for 
uncomplicated genitourinary gonococcal infection (versus intramuscular ceftriaxone + oral 
azithromycin) are pending.   
Section 5.2.2.2.5  Pediatric Subjects 
Added the rationale for the dosing regimen: 
 


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Solithromycin PK in adolescents (12 to <17 years) and children (<12 years) following oral 
(capsules, suspension) and intravenous administration was further investigated in a phase 1, 
open-label, multi-center study (protocol CE01-120). Intravenous data collected in this study 
supported the use of a 6 and 7 mg/kg intravenous daily dose (no loading dose required) in 
adolescents (12 to <17 years) and children (6 to <12 years), respectively. These doses resulted 
in a median (range) Day 3-5 Cmax and AUC0–24 of 2.3 μg/mL (1.2-7.7) and 12.3 μg*h/mL 
(8.2-19.9) in adolescents, and 2.8 μg/mL (1.0-8.1) and 10.6 μg*h/mL (2.7-18.4) in children, 
respectively. These estimates are comparable to adult median (range) values of 2.7 μg/mL 
(2.1-3.5) for Cmax and 13.7 μg*h/mL (6.1-22.3) following 400 mg of daily dosing. 
Section 5.2.4  Summary of Safety 
In the adolescent oral phase 1 study (CE01-119), 12 AEs were reported, of which 9, . . .  
In the ongoing phase 3 IV-to-oral CABP study (CE01-301), solithromycin was is administered in 
daily IV doses of 400 mg. When clinical stability is achieved, subjects could may switch to oral 
solithromycin dosing, receiving an initial dose of 800 mg on the first oral dosing day, followed by 
oral dosing with 400 mg each day. The total duration (by IV or IV/oral dosing) of treatment was 
is 7 days. This study has been completed and unblinded. However, at this time, data are currently 
being analyzed and all results would be considered preliminary. This trial remains blinded and 
is ongoing, therefore rates of events are not summarized herein. To date, approximately 600 
subjects have been enrolled, and an estimated 300 subjects have received solithromycin. The 
(blinded) AE and SAE profile from this study appears similar to that from study CE01-300, with 
the addition of infusion-related AEs that were not observed in that (oral dosing only) study.  
Section 5.4 Rationale for the Dosage Regimen 
To date, data are available from phase 1 pediatric studies (CE01-119 and CE01-120) to identify 
optimal dosing following capsule and intravenous solithromycin administration in adolescents 
12 to 17 years of age and children 6 to <12 years of age. . .  
Then in the follow-up study, CE01-120, an intravenous dose of 6 mg/kg daily resulted in median 
(range) Cmax and AUC0-24 estimates of 2.3 mcg/mL (1.2-7.7) and 12.3 μg*h/mL (8.2-19.9), 
respectively, in six adolescents (12 to <17 years). In children (6 to <12 years), Cmax and AUC0-24 
estimates were 2.8 μg/mL (1.0-8.1) and 10.6 μg*h/mL (2.7-18.4) following 7 mg/kg daily dosing. 
These estimates are comparable to adult median (range) estimates values of 2.7 μg/mL (2.1-3.5) 
for Cmax and 13.7 μg*h/mL (6.1-22.3) following 400 mg of daily dosing. Data for younger age 
groups and oral formulations are in development.  
Section 7.1 Duration of Subject Participation 
The duration of subject participation from signing the informed consent form (ICF) will be  
approximately 40 days (includes up to 10 days of study drug/comparator drug administration, a 
follow-up visit at 10 16 days [± 4 days] after the last day of study dose randomization,  AE 
monitoring for 10 16 (±4) days, and SAE monitoring for 30 36 (±4) days after the last dose of 
study drug post-randomization). Adverse event monitoring 30 36 days after the last dose of study 
drug randomization can be conducted by telephone/other media visit. The study duration from 
first subject first visit until last subject last visit will be approximately 24 months. 


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Section 7.3 Study Drug Dosage and Administration 
Table 4 
Study Design by Age Group: 
 
Age 
(years) 
Route 
Formulation 
Loading dose  
(Max dose: 800 mg)a 
Daily maintenance  
dose  
(Max dose: 400 mg)a 
12 to 17  
PO 
Capsulesb 
800 mg 
400 mg 
12 to 17 
PO 
Suspension 
TBD 
TBD 
12 to 17  
IV 
Solution 
 No loading dose 
6 mg/kg 
6 to <12 
PO 
Capsulesb 
TBD 
TBD 
6 to <12 
PO 
Suspension 
TBD 
TBD 
6 to <12 
IV 
Solution 
No loading dose 
7 mg/kg 
2 to <6 
PO 
Suspension 
TBD 
TBD 
2 to <6 
IV 
Solution 
No loading dose 
TBD 
2 mo to <2 
PO 
Suspension 
TBD 
TBD 
2 mo to <2 
IV 
Solution 
No loading dose 
TBD 
Subjects requiring an oral dosage form other than capsules will receive suspension formulation, 
provided at 32 160 mg/5 mL and 48 320 mg/5 mL strengths, to achieve the age-appropriate mg/mL 
and solithromycin dose.  
Children ≥2 months to <5 years of age: 
a. Ceftriaxone IV OR 
b. Ampicillin IV (United States) or amoxicillin IV (Rest of the World)  
c. Amoxicillin-clavulanic acid PO or IV or amoxicillin PO 
Children 5 to 17 years of age (inclusive): 
a. Ceftriaxone IV OR 
b. Ampicillin IV (United States) or amoxicillin IV (Rest of the World) OR 
c. Amoxicillin-clavulanic acid PO or IV  or amoxicillin PO 
 
 
United States 
Rest of the World  
Amoxicillin-
clavulanic acid 
 - 
Children >4kg but< 40kg: amoxicillin 
component 25 mg/kg intravenously 
every 8 hours [1000 mg max dose] 
 
Children ≥ 40 kg: amoxicillin component 
1000 mg intravenously every 8 hours 
 


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Section 7.5 Age Group Initiation 
Enrollment of subjects in all age groups will occur simultaneously. will occur simultaneously for 
all age groups for which information to inform the dosing regimen is available.  
Section 9.1 Solithromycin (CEM-101) 
. . . The inactive ingredients for all formulations will be listed in the pharmacy manual. Detailed 
instructions for the reconstitution of the powder for oral suspension to 320 mg/5ml and 
160 mg/5 ml will be listed in the pharmacy manual. 
Section 9.2 Comparator 
Comparator antibiotics may be administered “off the shelf” at the doses described above based on 
age range, local availability, and local treatment preferences. Comparator antibiotic preparation 
will be performed per local standard of care.  
Section 9.4 Study Drug Storage Conditions 
. . . Once prepared, the reconstituted vials can be stored at room temperature for up to 24 hours; 
they should not be refrigerated or frozen. Once the reconstituted solithromycin solution has 
been added to the saline bag, the infusion solution in the saline bag can be kept at room 
temperature (15°C to 25°C; 59°F to 77°F) for up to 12 24 hours; the bags should not be 
refrigerated nor frozen after reconstitution. . .  
Section 10.2.1 Treatment Days up to Last Day of Treatment 
9. Administer study drug and active comparator. If the subject is an outpatient and 
receiving study drug orally, a dosing diary is included on the capsule blister pack and 
the label for the suspension. This diary should be completed for each dose taken and 
brought back to each visit for review and accountability. 
Section 10.2.2 Last Day of Treatment 
9. Administer study drug and active comparator. If the subject is an outpatient and 
receiving study drug orally, a dosing diary is included on the capsule blister pack and 
the label for the suspension. This diary should be completed for each dose taken and 
brought back to each visit for review and accountability. 
Section 10.2.1 Day 10 16 Post Last Day of Treatment Randomization (±4 days) 
Section 10.2.2 Day 30 36 Post Last Day of Treatment Randomization (±4 days) 
Section 10.4.1.1 Study-Required Safety Laboratories 
. . . For infants <7 kg, no more than 3 mL/kg will be drawn for research purposes during the study.   
In countries where micro laboratory equipment is not available, whole blood for research 
purposes in children < 2 years of age should not exceed 2.4 mL/kg. 


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Section 10.7 Clinical Cure Definition (Day 10 16 Post Last Day of Treatment Randomization 
[±4 days]) 
Section 12.1 Adverse Events 
A laboratory abnormality that is considered clinically significant by the investigator (e.g., a change 
detected on clinical chemistry or hematology) that is independent from the underlying medical 
condition, requires medical or surgical intervention, or leads to study drug discontinuation will be 
considered an AE.  
Adverse events will be collected from the time of signing of the informed consent until 10 16 days 
after the last dose of study drug post-randomization . . .  
Section 12.1.1 Serious Adverse Events 
Serious AEs will be collected from the time of signing of informed consent until 30 36 (±4) days 
after the last dose of study drug randomization. 
Section 14.1.5 Efficacy Analysis 
Efficacy will be evaluated as a binary variable representing clinical improvement on the last day 
of treatment,  as a binary variable representing early clinical improvement on treatment days 3 and 
4, and as a binary variable representing clinical cure on Day 10 16 (±4 days) after the end of 
therapy post-randomization. The frequency and percentage of subjects achieving each efficacy 
endpoint will be determined, and a 95% CI calculated. Summaries will be calculated by treatment 
group for the overall ITT population (and microITT population if the data is sufficient to provide 
meaningful analysis) and stratified by age group. This study is not powered for comparison of 
efficacy endpoints between treatment groups. Additional details of efficacy analyses will be 
included in the SAP.  
Section 15.16 Publication Policy 
Added the following text along with the addition of Appendix B for clarification for sites outside 
of the United States: 
For each Institution and Investigator conducting the Study or a portion thereof outside of the 
United States, Institution and Investigator acknowledge and agree that (i) the Study and all 
other activities to be performed hereunder will be supported by funding provided, and will be 
performed in support of Sponsor’s performance of its obligations, under Contract No. 
HHS0100201300009C (“Prime Award”), entitled “SOLI- Solithromycin Pediatric Development 
Program”, awarded by the United States Government through the Office of Acquisitions 
Management, Contracts and Grants (“Prime Sponsor”), and that, therefore, certain obligations 
are required of Sponsor’s subcontractors (including Institution and Investigator) and, 
notwithstanding anything to the contrary in the Clinical Trial Agreement, or any other clinical 
study agreement, clinical trial agreement, investigator agreement, or the like executed by 
Institution or Investigator with respect to the Study, (ii) the terms and conditions of the Protocol 
and the Clinical Trial Agreement are subject to the terms included as Appendix B, attached 
hereto and fully incorporated herein, and, without limitation of the foregoing, to those 


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provisions of the Prime Award incorporated herein, and, in the event of any conflict between 
those terms included as Appendix B and the terms and conditions of the Protocol, the Clinical 
Trial Agreement, or any other clinical study agreement, clinical trial agreement, investigator 
agreement, or the like executed by Institution or Investigator with respect to the Study, the terms 
of Appendix B shall govern to the extent of such conflict. 
Added both Appendix A and Appendix B to the protocol to support the protocol amendment #1 
changes and the BARDA terms for sites outside of the United States. 


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Appendix B BARDA-Related Terms for Sites Outside of the United States 
1. Investigator and Institution acknowledge that the Study and other activities to be performed 
hereunder will be supported by funding provided, and will be performed in support of 
Sponsor’s performance of its obligations, under Contract No. HHS0100201300009C (“Prime 
Award”), entitled “SOLI- Solithromycin Pediatric Development Program”, awarded by the 
United States Government through the Office of Acquisitions Management, Contracts and 
Grants (“Prime Sponsor”), and that, therefore, certain obligations are required of Sponsor’s 
subcontractors (including Institution and Investigator). The Parties agree that the terms and 
conditions of the Protocol and the Clinical Trial Agreement are in alignment with and subject 
to the following terms, and, without limitation of the foregoing, to those provisions of the 
Prime Award incorporated herein. 
2. Compliance with U.S. Federal Acquisition Regulation (“FAR”) 52.245-1, Alternate II with 
respect to U.S. Government Property is required. Accordingly, title to property having a 
value less than US $5000 purchased with funds provided under the Clinical Trial Agreement 
vests in Investigator or Institution, as applicable, upon acquisition if approval of the U.S. 
government contracting officer concerning the Prime Award is obtained prior to acquisition. 
Upon written request of Investigator or Institution, as applicable, Sponsor will use 
commercially reasonable efforts to assist Investigator or Institution, as applicable, in 
obtaining such consent. Consistent with the Prime Award, title to equipment having a value 
above US $5000 and purchased with funds provided under the Clinical Trial Agreement shall 
vest in the U.S. Government. Investigator and Institution shall comply with the provisions of 
U.S. Department of Health and Human Services (“DHHS”) publication, "Contractor's Guide 
for Control of Government Property" with respect to any applicable property or equipment 
purchased by Investigator or Institution, as applicable, with funds provided under the Clinical 
Trial Agreement, and Investigator or Institution, as applicable, agrees to maintain records 
related to such equipment and the ownership, maintenance, care, and use thereof. 
3. In addition to all other reporting and notification requirements set forth in the Clinical Trial 
Agreement or this Appendix B, the Investigator and Institution will immediately disclose to 
Sponsor in writing formal findings of noncompliance with any law, regulation or other term 
or condition incorporated into the Clinical Trial Agreement and receipt of notices of suit or 
litigation or other formal adversary proceedings, or any formal discovery requests, related to 
the Study, the conduct thereof, or the Clinical Trial Agreement regarding any aspect of the 
Investigator or Institution. Neither Investigator nor Institution shall use funds provided under 
the Clinical Trial Agreement during a clinical hold to fund the clinical studies that are on 
hold. Neither Investigator nor Institution shall enter into any new financial obligations related 
to clinical activities for the clinical trial on clinical hold. Neither Investigator nor Institution 
shall use funds provided under the Clinical Trial Agreement to carry out any program of 
distributing sterile needles or syringes for the hypodermic injection of any illegal drug. 
4. Neither Investigator nor Institution shall (i) directly or indirectly pay or promise to pay, or 
authorize the payment of any money, or give, promise to give or authorize the giving of 
anything of value to any person or entity, whether governmental, quasi-governmental or 
private, to obtain or retain business or secure improper advantage for Chiltern or for Sponsor 
or (ii) to lobby any legislative bodies within the United States. Neither Investigator nor 
Institution shall directly or indirectly receive or solicit any money or anything of value from 
any person or entity, whether governmental, quasi-governmental or private, in order to secure 


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an improper advantage to such person or entity. Neither Investigator nor Institution will take 
any action which could render Chiltern or Sponsor liable under any other applicable laws for 
the prevention of fraud, corruption, racketeering, money laundering and/or terrorism. 
Institution and Investigator acknowledge that United States Executive Orders and Laws, 
including but not limited to E.O. 13224 and P.L. 107-56, prohibit transactions with, and the 
provision of resources and support to, individuals and organizations associated with 
terrorism. It is the legal responsibility of the Institution and Investigator to ensure compliance 
with these Executive Orders and Laws. This clause must be included in all subcontracts 
issued under the Clinical Trial Agreement. 
5. Investigator and Institution shall apply to it and Research Staff the conflicts of interest policy 
of [Sponsor] OR [Institution], and Investigator and Institution (i) certify that, if agreeing to 
apply Institution’s conflict of interest policy, that such policy complies with 45 CFR Part 94 
and (ii) agree that all such entities and individuals shall be subject to, and comply with, such 
policy, in each case, to the extent such policy relates to “financial conflicts of interest” as 
defined in 45 CFR Part 94.3 for disclosing significant financial interests that are directly 
related to Investigator’s work for Sponsor in accordance with 45 CFR Part 94. Investigator 
shall report any financial conflict of interest to Sponsor by written notice and email. Any 
financial conflicts of interest identified shall subsequently be reported by Sponsor to U.S. 
National Institutes of Health (“NIH”). Such report shall be made before expenditure of funds 
authorized in the Clinical Trial Agreement or within 45 days of any subsequently identified 
financial conflict of interest. 
6. To the extent the Prime Award and related applicable United States law, rule, and regulation 
(the ”BARDA Provisions”) require that any results, data, information, know-how, analyses, 
reports, inventions (whether or not patentable), deliverables, or intellectual property rights 
(including but not limited to patent rights) that were to be owned by Sponsor pursuant to the 
Clinical Trial Agreement are instead to be owned by Institution or Investigator (or instead 
can be owned by Institution or Investigator, in lieu of the US Government, pursuant to an 
election of title thereto by Institution or Investigator under applicable law or regulation) 
(such results, data, information, know-how, analyses, reports, inventions, deliverables, and 
intellectual property rights, “Subject IP”):  
i. Institution and Investigator agree to take such steps as may be necessary to ensure they 
own and retain title to Subject IP, instead of the US Government, subject to any rights the 
US Government may have therein under the BARDA Provisions; 
ii. Institution and Investigator hereby grant Sponsor and its affiliates a perpetual, 
irrevocable, world-wide, royalty-free, fully-paid, transferable, exclusive license, with 
rights of sublicense, under Subject IP to make, have made, use, sell, offer for sale, import, 
export, and otherwise practice Subject IP for any and all purposes; 
iii. Institution and Investigator shall, if and as requested by Cempra and at Cempra’s 
expense, (i) use reasonable efforts to obtain such waivers or permissions from the US 
Government as may be necessary to permit the assignment of all of Subcontractor’s right, 
title, and interest in Subject IP to Cempra or any designee thereof and (ii) upon receipt of 
such waivers and/or permissions, assign all of Institution’s and Investigator’s right, title, 
and interest in such Subject IP to Cempra or any designee thereof without requirement or 
obligation of any further payment or consideration; and 


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iv. clauses i., ii., and iii. above shall not apply to, or have any effect on, any allocation of 
rights between Sponsor, Institution, and Investigator with respect to any results, data, 
information, know-how, analyses, reports, inventions (whether or not patentable), 
deliverables, or intellectual property rights (including but not limited to patent rights) 
except to the extent such allocation conflicts with that required by the BARDA 
Provisions (i.e., if the BARDA Provisions do not apply to any particular intellectual 
property or do not conflict with the other applicable terms of the Clinical Trial 
Agreement or this Protocol). 
7. Notification is hereby given that Investigator, Institution, and their employees are subject to 
criminal penalties for violation of certain United States laws concerning privacy to the same 
extent as employees of the US Government. Investigator, and Institution shall assure that 
each of its employees knows the prescribed rules of conduct and that each is aware that he or 
she can be subjected to criminal penalty for violation of such laws. Institution and 
Investigator shall follow guidance concerning certain United States privacy laws. 
8. Prior to conducting the Study, Investigator and Institution certify that they have an 
appropriate and current Federal Wide Assurance of Protection for Human Subjects (or other 
applicable assurance) on file with the United States Department of Health and Human 
Services and will provide a copy of such assurance upon request. The performance of the 
Study hereunder shall be subject to, and Investigator and Institution shall comply with, such 
Federal Wide Assurance number # ________________. 
9. Neither investigator nor Institution shall use any funds supplied under the Clinical Trial 
agreement to pay any person for influencing or attempting to influence an officer or 
employee of any agency, a member of the United States Congress, an officer or employee of 
the United States Congress, or an employee of any member of the United States Congress in 
connection with any of the following: the awarding of any United States government 
contract; the making of any United States government grant; the making of any United States 
government loan; the entering into of any cooperative agreement with the United States 
government; or the modification of any United States government contract, grant, loan, or 
cooperative agreement. No funding provided under the Clinical Trial Agreement shall be 
used for publicity or propaganda purposes, for the preparation, distribution, or use of any kit, 
pamphlet, booklet, publication, radio, television, or video presentation designed to support or 
defeat legislation pending before the United States Congress, or any state or local legislature. 
No funding provided under the Clinical Trial Agreement shall be used to pay the salary or 
expenses of any contract or grant recipient, or agent acting for such recipient, related to any 
activity designed to influence legislation or appropriations pending before the United States 
Congress, or any state or local legislature. 
10. Anyone who becomes aware of the existence or apparent existence of fraud, waste and abuse 
in BARDA-funded programs is encouraged to report such matters to the United States’ 
Department of Health and Human Services’ Inspector General's Office in writing or on the 
Inspector General's Hotline. The toll free number is 1-800-HHS-TIPS (1-800-447-8477). All 
telephone calls will be handled confidentially. The e-mail address is Htips@os.dhhs.gov and 
the mailing address is: 


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Office of Inspector General 
Department of Health and Human Services 
TIPS HOTLINE 
P.O. Box 23489 
20026 
11. No information related to data obtained under this Protocol or Clinical Trial Agreement shall 
be released or publicized without the prior written consent of the Biomedical Advanced 
Research and Development Authority, Office of the Assistant Secretary for Preparedness and 
Response, Office of the Secretary, United States Department of Health and Human Services 
(“BARDA”). Institution and Investigator will acknowledge US government funding when 
issuing statements, press releases, requests for proposals, bid solicitations and other 
documents. Institution and Investigator are required to state: (1) the percentage and dollar 
amounts of the total program or project costs financed with US government funding and; (2) 
the percentage and dollar amount of the total costs financed by non-US government sources. 
Contract support shall be acknowledged in all such publications, and any publicizing or any 
release of any information related to the work performed under the Clinical Trial Agreement 
or the Clinical Trial Agreement itself, substantially as follows: 
"This project has been funded in whole or in part with United States federal funds from the 
Biomedical Advanced Research and Development Authority, Office of the Assistant 
Secretary for Preparedness and Response, Office of the Secretary, Department of Health and 
Human Services, under Contract No. HHS0100201300009C". 
12. Investigator and Institution specifically agree, to the extent applicable to the Clinical Trial 
Agreement, the Protocol, and the services performed or goods provided thereunder, that the 
applicable regulations set forth in the following tables entitled, “U.S. Federal Acquisition 
Regulations” and “U.S. Department of Health and Human Services Acquisition Regulations 
Clauses” respectively, shall flow-through and apply to it, its affiliates, and Research Staff or 
other employees, agents, representatives, or subcontractors of Institution or Investigator.  
Except as otherwise provided, as used in the cited clauses, “Government” and “Contracting 
Officer” shall refer to “Sponsor” and “authorized Sponsor representative,” respectively, and 
“Contractor” or “Offeror” shall refer to Investigator and Institution. Without limiting the 
generality of the foregoing sentence, as used in 52.246-9, "Government" and "Contracting 
Officer" shall refer to "Government" and "Contracting Officer," respectively, and 
Investigator and Institution shall have all rights and obligations of a "Contractor" under such 
provisions. Any reference in a FAR or a U.S. Department of Health and Human Services 
Acquisition Regulations ("HHSAR") clause to “Subcontractor” shall mean lower-tier 
subcontractor(s) to Investigator and/or Institution, as applicable, in instances where flow 
through to such lower-tier subcontractors is required under the FAR or HHSAR. 


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U.S. Federal Acquisition Regulations
 
U.S. Department of Health and Human Services Acquisition Regulations Clauses 
 
52.209-6 
Protecting the Government's Interests When Subcontracting With 
Contractors Debarred, Suspended, or Proposed for Debarment 
(Contracts Over $30,000) 
52.222-21 
Prohibition of Segregated Facilities 
52.222-37 
Employment Reports on Special Disabled Veterans, Veterans of the 
Vietnam Era, and Other Eligible Veterans (Contracts over $100,000) 
52.222-50 
Combating Trafficking in Persons 
52.223-18 
Encouraging Contractor Policy to Ban Text Messaging While Driving 
52.224-2 
Privacy Act 
52.225-13 
Restrictions on Certain Foreign Purchases 
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FAR 27.303(b)(2), paragraph (e) is modified to include the requirements 
in FAR 27.303(b)(2)(i) through (iv). The frequency of reporting in (i) is 
annual. 
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“Government” shall not be changed to mean “Contractor”) 
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SAP_001.pdf: 
Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 1 of 28 
 
 
 
A Phase 2/3, Randomized, Open-Label, Multi-center Study to 
Determine the Safety and Efficacy of Solithromycin in Adolescents  
(12 to 17 years of age inclusive) and  
Children (≥2 months to <12 years of age) with Suspected or 
Confirmed Community-acquired Bacterial Pneumonia 
Protocol: CE01-203 
STATISTICAL ANALYSIS PLAN 
 
 
Cempra Pharmaceuticals, Inc.  
6320 Quadrangle Drive, Suite 360 
Chapel Hill, NC 27517 
Telephone: 919-313-6601 
Fax: 919-313-6620 
 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 2 of 28 
TABLE OF CONTENTS 
1 
DOCUMENT HISTORY ......................................................................................... 3 
2 
PURPOSE OF THE ANALYSIS PLAN .................................................................. 4 
3 
STUDY OVERVIEW .............................................................................................. 5 
3.1 
STUDY DESIGN .................................................................................................................. 5 
3.2 
STUDY OBJECTIVES ........................................................................................................... 5 
3.3 
SAMPLE SIZE AND RANDOMIZATION ................................................................................... 5 
3.4 
STUDY DRUG ADMINISTRATION AND DURATION OF TREATMENT ......................................... 6 
4 
DATA SOURCES ................................................................................................ 10 
5 
STATISTICAL ISSUES ....................................................................................... 14 
5.1 
GENERAL ANALYSIS CONVENTIONS ................................................................................. 14 
5.2 
DOCUMENTATION CONVENTION ....................................................................................... 14 
5.3 
VERIFICATION OF RESULTS .............................................................................................. 14 
5.4 
HANDLING OF MISSING DATA ........................................................................................... 14 
6 
ANALYSIS POPULATIONS ................................................................................ 16 
6.1 
METHODS OF ANALYSIS ................................................................................................... 16 
7 
SUBJECT DISPOSITION .................................................................................... 17 
8 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................. 18 
9 
STUDY DRUG ADMINISTRATION ..................................................................... 19 
10 
DATA ANALYSIS ................................................................................................ 20 
10.1 SAFETY EVALUATIONS ..................................................................................................... 20 
10.2 PRIMARY SAFETY AND TOLERABILITY ENDPOINTS ............................................................ 20 
10.3 ADDITIONAL SAFETY ANALYSES ....................................................................................... 20 
10.3.1 
ADVERSE EVENTS .................................................................................................. 21 
10.3.2 
LABORATORY DATA ................................................................................................ 21 
10.3.3 
VITAL SIGNS ........................................................................................................... 22 
10.3.4 
PRIOR AND CONCOMITANT MEDICATIONS................................................................ 22 
10.3.5 
PREGNANCY TESTS ................................................................................................ 23 
10.4 SECONDARY EFFICACY/CLINICAL OUTCOMES .................................................................. 23 
10.5 STANDARD OF CARE EVALUATIONS.................................................................................. 23 
11 
INTERIM DMC DATA REVIEW ........................................................................... 25 
12 
TABLES, FIGURES, AND LISTINGS SHELLS ................................................... 26 
 
List of Tables 
Table 1 
Probability of Observing at Least 1 Subject with a Serious Adverse Event ................ 6 
Table 2 
Proportion of Subjects with Adverse Events and 95% CI ............................................ 6 
Table 3 
Solithromycin Administration Route and Formulation by Age Group .......................... 8 
Table 4 
Schedule of Assessments and Procedures ............................................................... 11 
 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 3 of 28 
1 
DOCUMENT HISTORY 
 
Version 
Date of Issue 
Summary of Changes 
1.0 
June 30, 2017 
Original finalized copy 
1.1 
May 14, 2018 
Edits to address early termination of trial 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 4 of 28 
2 
PURPOSE OF THE ANALYSIS PLAN 
The purpose of this statistical analysis plan (SAP) is to give a brief overview of the study design 
and study objectives for Cempra, Inc. study CE01-203, outline the types of analyses and 
presentations of data relevant to the study objectives, and to provide a detailed description of the 
method in which the statistical analyses will be conducted to meet protocol objectives.  
The scope of this plan applies primarily to the evaluation of the safety and efficacy objectives of 
the study as presented in the clinical protocol. The analyses of pharmacokinetic (PK) data will be 
conducted according to the PK data analysis plan contained as an appendix to this document. The 
SAP is based on the study protocol (Protocol CE01-203) and the electronic Case Report Form 
(eCRF) that were in effect at the date this SAP was finalized. An update to this SAP may be 
necessary if the protocol and/or eCRF are updated in a manner that affect the planned analyses. 
The Duke Clinical Research Institute (DCRI) on behalf of the sponsor (Cempra, Inc.) will conduct 
all statistical analyses detailed in this SAP. 
It is intended that all statistical analyses specified in the protocol will be performed. However, it 
is conceivable that due to the manner in which the study unfolds, some scheduled analyses may 
not be performed. In addition, study conditions or analysis results may suggest the need for 
additional statistical analyses of the collected study data. In either case, deviations from the 
planned statistical analysis will be fully described in the final clinical study report. Furthermore, 
any additional analyses performed beyond those specified in the protocol or this SAP will be 
descriptive in nature and will not include hypothesis testing for the purposes of inferential 
conclusions.  
 
In March 2018, the CE01-203 trial was terminated, because the sponsor discontinued development 
of Solithromycin. As a result of the early termination, the final number of enrolled participants 
was fewer than one quarter of the originally-planned sample size of 400. In consultation with the 
study investigators and the sponsor, the planned statistical analyses laid out in this SAP were 
curtailed due to the limited sample size particularly within age subgroups.  


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 5 of 28 
3 
STUDY OVERVIEW 
The overall study design and objectives are summarized in the following sections. The reader is 
referred to the study protocol and eCRFs for details of study conduct and data collection.  
3.1 
Study Design 
This is a phase 2/3, randomized, open-label, active control, multi-center study to assess the safety 
and efficacy of solithromycin in adolescents (12 to 17 years inclusive) and children (≥2 months to 
<12 years of age) with suspected or confirmed Community-acquired Bacterial Pneumonia 
(CABP). 
Subjects who meet all inclusion/exclusion criteria and sign the informed consent/assent will be 
enrolled. Subjects will be randomized to receive solithromycin or a comparator antibiotic, 
administered intravenously (IV) or by mouth (PO) in capsules or suspension formulation, with 
dosing based on a combination of weight and age. The treatment assignment will be open-label. 
Subjects will be treated for 5 days with oral solithromycin, 7 days with IV or IV-to-oral 
solithromycin, or for 5 to 10 days with comparator antibiotics (duration of comparator antibiotic 
per investigator discretion). Subjects will have daily assessments on days of treatment as detailed 
in the Protocol, and undergo a follow-up visit on last day of therapy (+48 hours). Subjects will be 
followed for the occurrence of Adverse Events (AEs) for 16 days (±4 days) after randomization, 
and Serious Adverse Event (SAE) monitoring will occur up to 28 days (±4 days) post 
randomization. PK samples will be collected to assess solithromycin disposition at specified time 
points. A blinded clinical signs and symptoms assessment will occur at Screening, and clinical 
outcomes will be assessed by a blinded health care provider at each site on the Day 3 to 4 visit 
(early clinical response), the Last Day of Treatment Visit (end-of-treatment response), and at the 
Day 16 Follow-Up visit (16 ±4 days post-randomization). If the subject is discharged on Day 2 
(prior to the Day 3 to 4 visit), the early clinical response assessment will be done on the day of 
discharge.  
3.2 
Study Objectives 
Primary: 
• 
Evaluate the safety and tolerability of solithromycin in adolescents and children with 
CABP 
Secondary: 
• 
Evaluate the efficacy of solithromycin in adolescents and children with CABP 
• 
Evaluate the population PK of solithromycin in adolescents and children with CABP  
3.3 
Sample Size and Randomization 
Approximately 400 subjects ≥2 months to 17 years of age inclusive, with CABP will be enrolled. 
Subjects will be randomized (3:1) into two groups: solithromycin (N~300) or comparator (N~100). 
Randomization will be stratified by the following age groups: 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 6 of 28 
• 
Age Group 1: Adolescents from 12 years to 17 years, inclusive  
• 
Age Group 2: Children from 6 years to <12 years  
• 
Age Group 3: Children from 24 months to <6 years  
• 
Age Group 4: Infants from ≥2 months to <24 months  
A minimum of 40 subjects will be included in each age group. Approximately 20% of subjects 
will be enrolled in the United States. Enrollment will occur simultaneously for all age groups for 
which information to inform the dosing regimen is available.  
The sample size of 300 in the solithromycin group is based on the ability to observe an SAE at a 
frequency higher than 1% (see Table 1). 
Table 1 
Probability of Observing at Least 1 Subject with a Serious Adverse Event 
  
Possible Serious Adverse Event Incidence with 5 Days of Dosing 
Number of 
subjects 
0.1% 
0.25% 
0.5% 
1% 
2% 
100 
0.095 
0.22 
0.39 
0.63 
0.87 
200 
0.18 
0.39 
0.63 
0.87 
0.98 
300 
0.26 
0.53 
0.78 
0.95 
>0.99 
In addition, this sample size will provide reasonable estimates and 95% confidence interval (CI) 
for safety. If 1 subject has an AE, then the 95% CI (exact binomial) for incidence of that AE within 
the subject population of 300 subjects is 0.01%, 1.8% (see Table 2).  
Table 2 
Proportion of Subjects with Adverse Events and 95% CI 
Number of events 
Proportion 
95% CI 
0 
0 
0, 0.012 
1 
0.003 
0.0001, 0.018 
2 
0.007 
0.001, 0.024 
3 
0.010 
0.002, 0.029 
The above estimates assume that all 300 subjects assigned to the solithromycin arm will be 
evaluable for safety and do not account for the possibility that a subject may be excluded from the 
safety analysis, for example because she/he did not receive any study drug, or withdrew consent 
prior to completing follow up evaluations for safety.  
3.4 
Study Drug Administration and Duration of Treatment 
Solithromycin will be administered IV or PO within each age group according to Table 3. Study 
drug is administered approximately every 24 hours and at approximately the same time each day 
(±4 hours). Study drug can be taken without regard to food. IV Solithromycin is infused over 
approximately 60 minutes (±20 minutes). Dosing variations within 10% of the calculated IV or 
suspension dosing are not considered protocol deviations. A subject can be converted from the IV 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 7 of 28 
to an oral formulation following 1 or more IV doses. In the event of a patient switching from IV 
to oral formulation after experiencing a study-drug related adverse event associated with the IV 
formulation (e.g., infusion pain) the action taken with study drug may be recorded as “study drug 
not changed” if full protocol-defined dosing continues with a different formulation. 
 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 8 of 28 
Table 3 
Solithromycin Administration Route and Formulation by Age Group 
Age 
Routes 
Formulations 
Solithromycin Cohort 
12 to 17 years 
PO 
Capsules 
12 to17 y, PO Capsule 
PO 
Suspension 
12 to 17 y, PO Suspension 
IV 
Solution 
12 to17 y, IV 
6 to <12 years 
PO 
Capsules 
6 to <12 y, PO Capsule 
PO 
Suspension 
6 to <12 y, PO Suspension 
IV 
Solution 
6 to <12 y, IV 
2 to <6 years 
PO 
Suspension 
2 to <6 y, PO Suspension 
IV 
Solution 
2 to <6 y, IV 
2 mo to <2 years 
PO 
Suspension 
2 mo to <2 y, PO Suspension 
IV 
Solution 
2 mo to <2 y, IV 
 
Capsule Dosing Regimens 
Age  
(years)  
Weight  
Route  
Formulation  
Day 1 (Max dose: 
800 mg)   
Days 2 to 5 (Max 
dose: 400 mg)   
6 to 17  
>30 kg  
PO  
Capsules  
800 mg  
400 mg  
>20 to 30 kg  
PO  
Capsules  
600 mg  
400 mg  
≤20 kg  
PO  
Capsules  
400 mg  
200 mg  
 
Suspension Dosing Regimens 
Age  
(years)  
Route  
Formulation  
Day 1 (Max dose: 800 
mg)   
Days 2 to 5 (Max 
dose: 400 mg)   
12 to 17  
PO  
Suspension  
20 mg/kg if weight <40 kg 
800 mg if weight ≥ 40 kg  
10 mg/kg if weight <40 kg  
400 mg if weight ≥ 40 kg  
6 to <12  
PO  
Suspension  
20 mg/kg  
10 mg/kg  
2 to <6  
PO  
Suspension  
20 mg/kg  
10 mg/kg  
2 mo to <2  
PO  
Suspension  
20 mg/kg  
10 mg/kg  
 
Intravenous Dosing Regimens 
Age  
(years)  
Route  
Formulation  
Days 1 to 7 (Max dose: 
400 mg)   
12 to 17   
IV  
Solution  
8 mg/kg  
6 to <12  
IV  
Solution  
8 mg/kg  
2 to <6  
IV  
Solution  
8 mg/kg  
2 mo to <2  
IV  
Solution  
8 mg/kg  
 
 
 
 
 
 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 9 of 28 
Switch from Intravenous to Oral Dosing Regimens 
Age  
(years)  
Route  
 Oral Formulation  
Day 1 to Last IV Dosing  
Day  
(Max dose: 400 mg)   
First Oral Dosing Day 
to Day 7  
(Max dose: 400 mg)a   
12 to 17  
IV/PO  
Suspension or 
Capsules  
8 mg/kg  
10 mg/kg  
6 to <12  
IV/PO  
Suspension or 
Capsules  
8 mg/kg  
10 mg/kg  
2 to <6  
IV/PO  
Suspension  
8 mg/kg  
10 mg/kg  
2 mo to <2  
IV/PO  
Suspension  
8 mg/kg  
10 mg/kg  
a.  The adult dose should be administered unless the subject weighs <40 kg, in which case they receive 10 mg/kg 
on the first oral dosing day through Day 7. The capsule dose is rounded upwards to the nearest 200 mg.   
Drug formulation and administration route will be decided upon by investigator discretion. 
Subjects starting with IV dosing may be switched to oral dosing at any time at the clinical 
discretion of the investigator.  Under Protocol version 3.0 subjects starting with oral therapy will 
receive 5 days of solithromycin treatment and those starting with IV therapy (regardless of if and 
when they switch to oral therapy), will receive a total of 7 days of solithromycin treatment. 
The comparator therapy drug, dose and mode of administration will be selected by the treating 
provider from those listed in the Study Protocol. The treating provider will make a selection of 
therapy according to subject weight and geographic region of enrollment, and will be consistent 
with current treatment recommendations for CABP in children as well as standard of care at the 
site. Subjects must receive 5 to 10 days of treatment with comparator. The exact duration of 
treatment may be determined at the investigator’s discretion.  
In the event that a subject is on an IV comparator medication and switches to an oral formulation 
of a different comparator drug (IV – PO switch), this will not be counted as a premature 
discontinuation of drug and will not be counted as an efficacy failure unless the site specifically 
enters that the initial drug was prematurely discontinued. In the event that a subject changes from 
a PO comparator medication to an IV formulation, or changes specific comparator drug within the 
first 5 days but remains taking the same formulation (ie changes from one IV drug to another IV 
drug, or one PO drug to another PO drug), this will be counted as a premature discontinuation of 
drug and efficacy failure.  If a patient prematurely discontinues comparator drug then all dosing of 
other medications following the initial drug will be recorded as Concomitant Medications (not as 
further Comparator Arm dosing).  


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 10 of 28 
4 
DATA SOURCES 
At each study site data will be entered on the eCRFs stored on IBM Clinical Development (run by 
Merge Healthcare, an IBM company). Normal ranges for local laboratory measures will be 
received directly from laboratories and will be integrated with the clinical database. One master 
list of randomized trial arm assignments will be uploaded to IBM Clinical Development from 
DCRI Statistics. Subject data which is downloaded from IBM Clinical Development or received 
from DCRI Data Export Services will include the randomization assignment. Solithromycin 
plasma concentrations will be received from a central laboratory and will be integrated with the 
clinical database. Prior to database lock, programmed computer edit checks will be run against the 
database to identify discrepancies and verify reasonableness of the data. Queries to resolve 
discrepancies will be generated and resolved by the sites. Periodically, DCRI Statistics will receive 
or download from DCRI Data Export Services the eCRF database as Clinical Data Interchange 
Standards Consortium Study Data Tabulation Model (CDISC SDTM version 3.1.3) datasets. 
CDISC Analysis Data Model (ADaM version 2.1) datasets will be created by DCRI Statistics for 
production of tables, figures, and listings. All planned reporting will be based off of CDISC 
datasets, but in the case of emergent safety data some reporting may occur from the raw eCRF 
data. Table 4 summarizes the variables and time points when measurements are made during the 
patient assessment period. 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 11 of 28 
Table 4 
Schedule of Assessments and Procedures 
 
Activity  
Screening/Baseline 
(Day -3 through Day -1)a  
Treatment Period  
Follow-Up  
Treatment Days up 
to Last Day of  
Treatment b  
Last Day of 
Treatment    
(+48 hours)  
Day 16 Post  
Randomization c, d 
(±4 days)  
Day 28 Post 
Randomization d  
(±4 days)  
Informed consent form  
X  
  
  
  
  
Demographic data  
X  
  
  
  
  
Eligibility criteria   
X  
  
  
  
  
Randomization  
X  
  
  
  
  
Medical history  
X  
  
  
  
  
Physical examination  
X  
Xc  
X  
X  
  
Vital signse  
X  
Xc  
X  
X  
  
Chest x-rayf  
X  
  
  
  
  
Study-required safety labsg   
Xh  
Xi  
Xj  
Xi  
Xi  
Review of standard-of-care data:   
   Safety labsg, k  
   Microbiology assessmentsl  
   Radiological imagingm  
Non-pharmacological treatmentsn  
X  
X  
X  
X  
  
Pregnancy testo  
X  
Xp  
  
  
  
Concomitant medicationsq  
X  
X  
X  
  
  
Study drug or comparator 
administrationr  
  
X  
X  
  
  
Pharmacokinetic samplings  
  
X  
X  
  
  
Adverse event assessment   
X  
X  
X  
X  
  


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 12 of 28 
Activity  
Screening/Baseline (Day 
-3 through Day -1)a 
Treatment Period  
Follow-Up  
Treatment Days up 
to Last Day of  
Treatment b  
Last Day of  
Treatment   
(+48 hours)  
Day 16 Post  
Randomization c, d 
(±4 days)  
Day 28 Post  
Randomization d 
(±4 days)  
Serious adverse event 
assessment  
X  
X  
X  
X  
X  
Clinical outcomes and symptom 
assessments:   
Early Clinical Response, End of  
Treatment, and Follow-Up Post  
Treatmentt 
X  
X u 
X v 
X w 
a 
Screening/baseline can occur up to 72 hours prior to randomization. Standard-of-care laboratory data and radiological imaging from up to 72 hours prior 
to randomization may be used as screening procedures. Screening/baseline and first day of treatment may be the same day.  
b 
Treatment period is 5  to 7 days for solithromycin and 5 to10 days for comparators. These assessments and procedures may be done prior to Day 3 if 
the subject is discharged from the hospital before Day 3.  
c 
Record vital signs for each day available. Physical examinations should be recorded from baseline and the Day 3 to 4 visit (early clinical outcome 
assessment) and at the Last Day of Treatment visit.   
d      Every effort should be made to bring the subject back. If the subject is unable or unwilling to return, the AEs/SAEs must be collected via telephone/other media. 
e       Vital signs taken at the closest time post-drug administration should be noted. If vital signs following drug administration are not available, record the first value      
       of the day.  
f 
Screening chest x-ray does not need to be repeated if a standard-of-care chest x-ray was performed within 72 hours of randomization. Subjects that are 
outpatient and starting on oral therapy do not need a screening x-ray.   
g 
Local laboratory; includes hemoglobin, hematocrit, white blood cell count with differential, platelet count, blood urea nitrogen, calcium, serum creatinine, 
potassium, sodium, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total and direct bilirubin, and albumin.   
h 
A separate study sample is not required if safety labs above are obtained at baseline per standard of care. If multiple laboratory tests are obtained within 72 
hours of randomization, record test results closest to randomization.  
i  
Every effort should be made to obtain safety labs to include aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total and direct 
bilirubin, and white blood cell count with differential. A separate study sample is not required if safety labs above are obtained within the visit window per 
standard of care.  
j 
Safety labs must be collected on the last day of dosing or within 48 hours after the last dose. A separate study sample is not required if safety labs above are 
obtained on the last day of dosing or within 48 hours after the last dose per standard of care.  
k 
Record the safety labs if performed per standard of care; if multiple laboratory tests are obtained on the same day, record test results closest to administration 
of study drug.  
l 
Microbiological assessments will be recorded if performed per routine medical care. These include cultures from sterile body fluids and molecular and 
serologic tests for Mycoplasma pneumoniae and Chlamydophila pneumoniae.  
m 
Radiological imaging of the chest, including chest x-ray or computed tomography (CT) scan, will be recorded if performed per routine medical care.  
n 
Non-pharmacologic treatments (such as operative procedures) will be recorded if performed per routine medical care.  
o 
Female subjects of childbearing potential within 24 hours of first dose. 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 13 of 28 
p 
If the screening visit for females occurred greater than 24 hours before receiving the study drug.  
q 
Medications other than antibiotics taken within 72 hours and all antibiotics taken within 7 days prior to first dose of study drug as well as all concomitant 
medications through the follow-up visit will be recorded.  
r 
Solithromycin should be administered approximately every 24 hours and at approximately the same time each day (± 4 hours) for 5 to 7 days.   
s 
Only in subjects receiving solithromycin; central laboratory.  
t 
Symptoms should be recorded at baseline, the Day 3 to 4 visit (early clinical response) visit, the Last Day of Treatment Visit (end-of-treatment response), and 
at the Day 16 Follow-Up visit). If the subject is discharged on Day 2 (prior to the Day 3 to 4 visit), the early clinical response assessment will be done on the 
day of discharge.  
u 
Early clinical response  
v 
End of Treatment response    
w 
Day 16 post randomization response (cure)  


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 14 of 28 
5 
STATISTICAL ISSUES 
5.1 
General Analysis Conventions 
Descriptive Statistics: For continuous and pseudo-continuous variables, the number of 
observations, mean, standard deviation, median, twenty-fifth percentile, seventy-fifth percentile, 
minimum and maximum will be provided. For binary yes/no, categorical, and/or ordinal variables 
a simple count and percent or tally will be provided. Other statistics may be considered if 
necessary. 
Baseline: The latest recorded measurement available prior to first dose of study drug.  
Age Group: Analysis presented “by age group” will use the categories “12 -17 years, inclusive”, 
“6 - <12 years”, “2 - <6 years”, and “2 months - <2 years.” 
Consolidated Age Group: Analysis presented “by consolidated age group” will use the categories 
“2 months - <6 years” and “6 years – 17 years.” 
Drug Route: Analysis presented “by drug route” will categorize Solithromycin patients receiving 
capsule or suspension formulations of Solithromycin as “PO” and IV solution as “IV,” based on 
the initial (Day 1) administration route of study drug. Comparator patients will not be categorized 
by drug route due to the possibility of multiple administration routes being utilized concurrently. 
5.2 
Documentation Convention 
The statistical analyses described in this SAP as well as production of tables, listings and figures 
will be performed using SAS, version 9.4 or higher (SAS Institute, Cary, NC). Additional 
statistical software may be used as needed. 
5.3 
Verification of Results 
All tables, listings, and graphs will be verified and reviewed before considered final. The 
verification process will ensure that the numbers are produced by a statistically valid method and 
that the execution of the computations is correct. Qualified statisticians or statistical programmers 
employed by the DCRI (an affiliate of the Duke University School of Medicine) who have not 
been previously involved in the production of the original programming will perform the 
verification procedures. Methods of verification will include independent programming, prior to 
issuance of the draft statistical report, of all analysis datasets/ADaM and comparison to data 
listings. Tables, listings and graphs will be reviewed for accuracy, consistency with this analysis 
plan, consistency within tables/listings/graphs, and consistency with corresponding output. Once 
verification is complete, all documentation of the verification process will be filed in a statistical 
programming documentation notebook as required by the Statistical Standard Operations 
Procedures of the DCRI.  
5.4 
Handling of Missing Data 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 15 of 28 
Efforts will be made to minimize the occurrence of missing data. However, the general approach 
will be to use only data which are complete with regard to the variable(s) and timepoint(s) being 
analyzed for descriptive summaries, or for the evaluation of safety and efficacy endpoints. In the 
case of a patient withdrawing or being lost (unrelated to documented AE or SAE), the denominator 
for rates of AE and SAE occurrence will remain as the complete Safety Population.   


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 16 of 28 
6 
ANALYSIS POPULATIONS 
Randomized population: All subjects who were enrolled and randomized in the study will be 
included in the analysis population for  evaluating efficacy. This population will be used for 
analyses of efficacy. 
Safety population: All subjects who receive at least one dose of study drug (solithromycin or active 
comparator) will be included in the analysis population for evaluating safety. This population will 
be used for analyses of safety. 
PK population: All subjects who receive at least one dose of solithromycin (regardless of 
randomization assignment) and had at least one evaluable PK sample will be included in the 
analysis population for evaluating PK. 
6.1 
Methods of Analysis 
Intention to treat (ITT): Subjects will be grouped for analysis according to their randomized 
allocation (solithromycin or active comparator) and initial solithromycin cohort (Table 3) where 
possible, regardless of whether the allocated therapy was administered, or switched (e.g., from IV-
to-oral solithromycin), and regardless of compliance, protocol deviations, withdrawal, or anything 
else that occured once randomized. For efficacy analyses the ITT grouping of subjects will be 
applied to the randomized population. For safety analyses the ITT grouping of subjects will be 
applied to the safety population.  
 
Note:  Hypothetically, a subject could be randomized to one arm and switch immediately to 
the other arm before the first dose. However, in practice, such switching did not occur. 
Therefore it is reasonable for the safety analyses (restricted to the safety population) to also 
group patients according to their randomized treatment assignment, which will be equivalent 
to grouping them according to the treatment that they initially received after being 
randomized.     


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 17 of 28 
7 
SUBJECT DISPOSITION 
This analysis will be performed on the randomized population.  The number of subjects receiving 
any amount of study drug (safety population), completing study drug administration, number who 
withdrew from the study or discontinued from study drug early, and the number who completed 
the trial will be summarized by treatment arm, by age group, and by treatment arm stratified within 
age group. The timing and reasons for early discontinuation of study drug and/or withdrawal from 
the study will be summarized. The number of subjects with major protocol deviations will be 
summarized and listed.  Additionally, a summary will be provided of subjects enrolled and 
randomized in each country. 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 18 of 28 
8 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
This analysis will be performed on the safety population.  Demographic and baseline 
characteristics including age, sex, height, weight, race, and ethnicity, are evaluated prior to 
initiation of study drug. Demographic and baseline characteristics will be summarized with 
descriptive statistics by randomized treatment arm, and consolidated age group.  


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 19 of 28 
9 
STUDY DRUG ADMINISTRATION 
Study drug administration will be summarized in the safety population, by treatment arm, and by 
treatment arm stratified within consolidated age group. Subjects randomized to solithromycin will 
also be presented by age group and formulation. Summaries will include a frequency distribution 
of number of days of drug administration, summary statistics forsolithromycin daily dosing 
amount,and frequency of active comparator antibiotics. Aggregate summaries of treatment 
discontinuation will be presented. For solithromycin, a subject will be considered to be 
prematurely discontinued if drug dosing ceases with <5 days on drug for patients starting on PO 
therapy, and <7 days on drug for patients starting on IV therapy. For active comparator a subject 
will be considered to be prematurely discontinued if drug dosing ceases with <5 days on drug, or 
if discontinuation is precipated by occurrence of an AE . For the purpose of counting days on drug, 
any date which contains at least a partial dose will be counted. In earlier versions of the protocol 
(versions 1.0-2.0), 5 to 7 days of solithromycin IV therapy was allowed. For patients enrolled 
under those protocol versions, premature discontinuation will be determined as <5 days on drug.  
For solithromycin subjects, study drug exposure information will be listed, including administered 
weight-adjusted dose (mg/kg), start and stop date, number of days of dosing, number of days 
dosing required by protocol which was in effect at the site at the time, loading dose information if 
applicable, and formulation. For active comparator subjects, details about the active comparator 
(drug name, dose, dosing frequency), the start date/stop date, and number of days of dosing will 
be listed. 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 20 of 28 
10 
DATA ANALYSIS 
10.1 Safety Evaluations 
New events that occur or pre-existing conditions that worsen through frequency or intensity will 
be reported as AEs or SAEs. The investigator will provide date of onset and resolution, intensity, 
frequency, action(s) taken, changes in study drug dosing, relationship to study drug, and outcome. 
Laboratory determinations performed by local laboratories including hematology values 
(hemoglobin, hematocrit, WBC count with differential, and platelet count) and serum chemistry 
values (blood urea nitrogen [BUN], calcium, serum creatinine, potassium, sodium, AST, ALT, 
alkaline phosphatase, total and direct bilirubin, and albumin) are required by the protocol within 
72 hours prior to the first dose, and on the last day of study drug. In addition, investigators are 
asked to make every effort to obtain safety labs (to include aspartate aminotransferase, alanine 
aminotransferase, alkaline phosphatase, total and direct bilirubin, and white blood cell count with 
differential) 72 hours (±24 hours) after the first dose, at the Day 16 and Day 28 post-randomization 
visits (implemented in Protocol version 3.0).   
10.2 Primary Safety and Tolerability Endpoints 
Primary safety endpoints will be the proportion of subjects in the safety population experiencing 
a TEAE and the proportion of subjects in the safety population discontinuing study drug due to a 
related AE. Discontinuation from related AE counts will be created by using any discontinuation 
from related AE documented in the study drug discontinuation page and the AE data for a subject. 
The first safety endpoint will be evaluated through the Day 28 visit (28 days ±4 days after 
randomization).  This will be a composite of TEAEs through Day 16 visit and TESAEs through 
Day 28 visit.  The second safety endpoint will be evaluated through the last day of study drug 
dosing.   
For the primary safety end points, the frequency and percentage of subjects with at least one 
treatment emergent adverse event, and the frequency and percentage of subjects discontinuing 
study drug due to a related AE, will be determined. Ninety-five percent Clopper-Pearson (exact) 
confidence intervals will be calculated for each incidence of occurrence by treatment arm. 
Summaries will be calculated by treatment arm for the overall safety population, by treatment arm 
stratified within age group, and within age group and formulation for the solithromycin arm. 
Patient-level information for adverse events and subjects discontinuing study drug due to a related 
AE will be listed. For this analysis subjects will be grouped according to their randomized 
treatment arm assignment (intent-to-treat analysis). 
10.3 Additional Safety Analyses 
Additional safety analyses include summaries of AEs, descriptive statistical summaries of 
abnormal laboratory values, frequency distributions and shift tables summarizing abnormal 
laboratory values, graphs of lab values and vital signs, and summaries of concomitant medications 
as well as prior medications.  Pregnancy test results and non-pharmacological treatments will be 
listed but not summarized.  These analyses will be presented in the safety population using  intent-
to-treat analysis. Summaries will be produced by treatment arm, drug route, and consolidated age 
groups (2 months - <6 years, 6 years – 17 years inclusive) with the exception of lab graphs and 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 21 of 28 
shift tables. The lab graphs and shift tables will be summarized by treatment arm, with all age 
groups combined.  Safety data will also be listed by treatment arm, age group, formulation (for 
solithromycin patients only), and subject, with relevant information such as values, normal ranges, 
and severity presented. 
10.3.1 
Adverse Events 
AEs (as defined in section 12.1 of Protocol) will be collected from the time of signing the informed 
consent and assent (if applicable) through 16 days (±4 days) after randomization. SAEs will be 
collected through 28 days (±4 days) after randomization. AEs will be tabulated by using the 
Medical Dictionary for Regulatory Activities (MedDRA v18.1) system organ class and preferred 
term. The treatment emergent adverse event (TEAE) is defined as any AE that has an onset on or 
after the first dose of either study drug, or any pre-existing AE that increases in severity after 
dosing with either study drug. Adverse events will be tabulated to show the number of subjects 
with at least one AE, number of subjects with at least one TEAE, and the number of subjects that 
experienced each individual count of AEs and TEAEs (e.g., number of subjects with 2 AEs, 
number of subjects with 3-4 AEs, etc.).  Additional summaries will be created for infusion site 
events as well as TEAEs excluding these infusion site events.  
10.3.2 
Laboratory Data 
Descriptive statistics will be generated for post-baseline abnormal laboratory data, such as 
hematology and serum chemistry values. Additionally, shift tables will be presented. The shift 
tables tabulate the number of lab values determined to be “Normal” and “Abnormal” at baseline 
and post-baseline timepoints.  The classifications on shift tables will categorize lab values as 
“Normal” when they are in an acceptable range, using a combination of clinician judgment specific 
to each lab test, and the local lab reference ranges (see below).  Laboratory values outside the 
normal range will be graded on the Labs Listing as 1x, 2x, 3x, 5x or 10x the upper limit (or .5x, 
1x the lower limit) of normal value based on appropriate increases or decreases. Lab tests reflective 
of liver toxicity (ALT, AST, and Total and Direct Bilirubin) will be further summarized in terms 
of the most extreme values and largest increases from baseline  observed from the start of study 
drug through Day 16 Post-Randomization (± 4 days). Laboratory data will also be summarized 
graphically to show the magnitude and changes in individual subject values over time relative to 
normal ranges. 
 
Laboratory Name 
Clinically Pertinent Normal Range 
Blood Urea Nitrogen [BUN] 
(0, Site Specific ULN) 
Calcium  
(Site Specific LLN, Site Specific ULN) 
Serum Creatinine 
(0, Site Specific ULN) 
Potassium 
(Site Specific LLN, Site Specific ULN) 
Sodium 
(Site Specific LLN, Site Specific ULN) 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 22 of 28 
AST 
(0, Site Specific ULN) 
ALT  
(0, Site Specific ULN) 
Alkaline Phosphatase 
(0, Site Specific ULN) 
Total Bilirubin 
(0, Site Specific ULN) 
Direct Bilirubin 
(0, Site Specific ULN) 
Albumin 
(Site Specific LLN, ∞) 
Hemoglobin 
(Site Specific LLN, ∞) 
Hematocrit 
(Site Specific LLN, ∞) 
WBC Count  
(Site Specific LLN, Site Specific ULN) 
Platelet Count 
(Site Specific LLN, Site Specific ULN) 
Neutrophils 
(Site Specific LLN, Site Specific ULN) 
Lymphocytes 
(Site Specific LLN, Site Specific ULN) 
Monocytes 
(Site Specific LLN, Site Specific ULN) 
Eosinophils 
(Site Specific LLN, Site Specific ULN) 
Basophils 
(Site Specific LLN, Site Specific ULN) 
C-reactive protein 
(0, Site Specific ULN) 
Procalcitonin 
(0, Site Specific ULN) 
 
10.3.3 
Vital Signs 
Vital sign data plots will be produced to graphically display data summaries. Each vital sign that 
is presented will include the time windows “Baseline”, “Day 1”, “Day 2-7 Combined”, and “Day 
8-10 Combined.” 
10.3.4 
Prior and Concomitant Medications 
Prior and concomitant medication use will be tabulated by generic drug name. Prior medications 
and concomitant medications generic name and anatomic therapeutic chemical classification 
(ATC) level will be coded using the September 2015 version of the World Health Organization 
Drug Dictionary (WHODD) Enhanced.  


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 23 of 28 
10.3.5 
Pregnancy Tests 
Pregnancy test results at baseline and any other reported will be listed for female participants of 
child-bearing potential. 
10.4 Secondary Efficacy/Clinical Outcomes 
Evaluation of clinical signs and symptoms of CABP, requirement for additional or alternative 
antimicrobial therapy, and efficacy will be performed by a blinded investigator or designee at the 
site. Outcomes will be assessed at the following time points: 
• 
Baseline clinical signs and symptoms assessment 
• 
Clinical improvement on Day 3 - 4. If the subject is discharged from the hospital prior 
to Day 3, assessment may be recorded on Day 2. 
• 
Clinical improvement on the last day of treatment (+48 hours)  
• 
Clinical cure during short-term follow up at 16 days (± 4 days) after randomization 
(secondary efficacy endpoint). This assessment will be conducted if information is 
available per standard of care and may be recorded from the medical record via phone 
or other media. 
Efficacy will be quantified as a binary variable at each timepoint listed above using the algorithm 
specified in Appendix 2. Clinical improvement is defined as improvement (compared to baseline) 
of at least 1 of the presenting signs and symptoms of CABP with no deterioration in any presenting 
sign or symptom of CABP (compared to baseline), no development of new sign or symptom of 
CABP, and no requirement for additional or alternative antimicrobial therapy. Clinical cure is 
defined as resolution of all presenting signs and symptoms of CABP (excluding cough), no 
development of new sign or symptoms of CABP, and no requirement for additional antimicrobial 
therapy.  Clinical improvement and cure will be determined using the specific signs and symptoms 
data recorded on the eCRF, as well as a separate question on the eCRF concerning additional 
antimicrobial therapy. These questions will be completed by the blinded investigator (or 
potentially unblinded investigator in the case of screening evaluation), who will be supplied with 
information according to the blinded investigator plan. 
Efficacy will be evaluated in the randomized population, and subjects will be evaluated in the 
treatment group to which they were randomized regardless of actual treatment received (Intention-
To-Treat analysis). The main analysis of efficacy at each time point will include subjects with 
efficacy evaluated at that time point (complete case analysis). The frequency and percentage of 
subjects achieving each efficacy end point will be determined, and a 95% Clopper-Pearson (exact) 
confidence interval calculated. Summaries will be calculated by treatment arm for the overall 
randomized population and by treatment arm stratified within consolidated age group. This study 
is not powered for comparison of efficacy end points between treatment groups.  
 
10.5 Standard of Care Evaluations 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 24 of 28 
Evaluations that are collected as part of the standard of care will be recorded. These may include 
microbiology evaluations (all cultures from sterile body fluids, as well as molecular and serologic 
tests for M. pneumoniae and C. pneumoniae), radiological imaging of the chest, including chest x-
ray or CT scan, and surgeries and non-pharmacological procedures of interest (including surgeries 
of the chest and chest wall such as pleural tube placement, video assisted thoracoscopic surgery, 
and surgical procedures of the head and neck). These evaluations will be presented in listings and 
will be summarized by treatment arm. 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 25 of 28 
11 
INTERIM DMC DATA REVIEW 
• To monitor the safety and tolerability of solithromycin in the CE01-203 trial, 4 interim data 
monitoring committee (DMC) meetings are planned to review accumulating data. Interim 
review meetings will occur at ~6 month intervals, at ~ 6, 12, 18, and 24 months after the 
initial meeting. The following data will be listed and/or summarized for the DMC. Data 
completeness to date 
• Demographic 
data, 
baseline 
characteristics 
(such 
as 
underlying 
conditions, 
suspected/identified/confirmed bacterial infection, etc.) and enrollment trends. 
• Subjects who have discontinued prematurely from the study and/or study drug: listing of 
all such subjects including date of discontinuation and reason discontinued by site  
• Study drug exposure data  
• Prior and Concomitant medication 
• Vital signs  
• Laboratory data, relative to corresponding lab normals will be listed. Additionally, a 
summary of lab abnormalities and grade will be presented in table format. 
• All serious adverse events  
• All adverse events  
• Treatment emergent adverse events 
• Aggregate summaries for safety labs and vital signs 
• PK data, if available and needed in the evaluation of safety 
• Efficacy data, if needed in the evaluation of safety 
• Additional data may be added as request by the DMC 
Summaries will be aggregated for the DMC as described in above sections of this SAP for relevant 
data elements, for example, by treatment arm and by treatment arm within consolidated age group, 
as sample size of accumulating data allows. Details of the DMC operations and responsibilities 
are laid out in the DMC Charter. 
 
 
 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 26 of 28 
12 
TABLES, FIGURES, AND LISTINGS SHELLS 
 
14.1 Patient Disposition 
Table 14.1.1 
Patient Disposition – Displaying Totals for each Age Group and each 
Treatment Arm 1 
Table 14.1.1.1 
Patient Disposition – Displaying Totals for Each Age Group * Treatment 
Arm Individually 2  
Table 14.1.2 
Enrollment by Country – By Consolidated Age Group and Treatment Arm 
Table 14.1.3 
Major Protocol Deviations – By Consolidated Age Group and Treatment 
Arm 
 
 
14.2 Demographics and Other Baseline Characteristics 
Table 14.2.1 
Demographics and Baseline Characteristics – By Consolidated Age Group 
and Treatment Arm 
 
 
14.3 Study Drug Exposure 
Table 14.3.1 
Study Drug Exposure and Treatment Discontinuation – By Consolidated 
Age Group and Treatment Arm 
Table 14.3.1.1 
Study Drug Exposure and Treatment Discontinuation – By Solithromycin 
Cohort 
 
 
14.4 Safety Data 
Table 14.4.1 
Proportion of Subjects Experiencing a Treatment Emergent Adverse Event 
or Discontinuing Study Drug Due to Related Adverse Event – By 
Treatment Arm and Age Group 
Table 14.4.1.1 
Proportion of Subjects Experiencing a Treatment Emergent Adverse Event 
or Discontinuing Study Drug Due to Related Adverse Event – By 
Treatment Arm, Age Group, and Formulation 
Table 14.4.2 
Overview of Adverse Events – By Treatment Arm, Consolidated Age 
Group, and Drug Route 
Table 14.4.2.1 
All Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term – By Treatment Arm, Consolidated Age Group, and Drug 
Route 
Table 14.4.2.1.1 
Treatment Emergent Adverse Events by System Organ Class and Preferred 
Term, Excluding Infusion Site Adverse Events – By Treatment Arm, 
Consolidated Age Group, and Drug Route 
Table 14.4.2.1.2 
Treatment Emergent Infusion Site Adverse Events by System Organ Class 
and Preferred Term – By Treatment Arm, Consolidated Age Group, and 
Drug Route 
Table 14.4.2.2 
Overview of Serious Adverse Events – By Treatment Arm, Consolidated 
Age Group, and Drug Route 
Table 14.4.2.3 
Treatment Emergent Serious Adverse Events by System Organ Class and 
Preferred Term – By Treatment Arm, Consolidated Age Group, and Drug 
Route 
 
 


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Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 27 of 28 
Table 14.4.3 
Shift from Baseline to Worst Post-Baseline Value: Hematology Tests – By 
Treatment Arm 
Table 14.4.3.1 
Abnormal Laboratory Results Summary: Hematology Tests – By 
Treatment Arm 
Figure 14.4.3.2 
Worst Post-Baseline vs Baseline Laboratory (Scaled by Normal Values): 
Hematology Tests – By Treatment Arm  
Figure 14.4.3.3 
Worst Post-Baseline vs Baseline Laboratory (Scaled by Normal Values): 
Hematology Tests – By Solithromycin Consolidated Age Group and Drug 
Formulation 
Table 14.4.3.2 
Shift from Baseline to Worst Post-Baseline Value: Chemistry Tests – By 
Treatment Arm 
Table 14.4.3.2.1 
Abnormal Laboratory Results Summary: Chemistry Tests – By Treatment 
Arm 
Figure 14.4.3.2.2 
Worst Post-Baseline vs Baseline Laboratory (Scaled by Normal Values): 
Chemistry Tests – By Treatment Arm 
Figure 14.4.3.2.3 
Worst Post-Baseline vs Baseline Laboratory (Scaled by Normal Values): 
Chemistry Tests – By Solithromycin Consolidated Age Group and Drug 
Formulation 
Table 14.4.3.2.4 
Summary of Liver Function Tests – By Treatment Arm 
Table 14.4.3.2.5 
Summary of Liver Function Tests – By Solithromycin Consolidated Age 
Group and Drug Route 
Figure 14.4.4 
Summary Plot of Vital Signs – By Treatment Arm 
Table 14.4.5 
Positive Microbiological Assessments – By Treatment Arm 
Table 14.4.6 
Prior Medications by Generic Name  – By Treatment Arm 
Table 14.4.7 
Concomitant Medications by Generic Name – By Treatment Arm 
 
 
14.5 Efficacy Data 
Table 14.5.1 
Summary of Clinical Efficacy Endpoints – By Treatment Arm and 
Consolidated Age Group 
 
 
16.2 Patient Data Listings 
 
16.2.2 Patient Disposition 
Listing 16.2.2.1 
Patient Disposition 
Listing 16.2.2.2 
Early Discontinuation from Study Drug 
Listing 16.2.2.3 
Major Protocol Deviations  
 
 
16.2.3 Demographics and Other Baseline Characteristics 
Listing 16.2.3.1 
Demographics and Baseline Characteristics  
Listing 16.2.3.2 
Medical History 
 
 
16.2.4 Study Drug Exposure 
Listing 16.2.4.1 
Study Drug Exposure – For Solithromycin Subjects 
Listing 16.2.4.2 
Study Drug Exposure – For Active Comparator Subjects 
Listing 16.2.4.3 
Patients Discontinuing Study Drug Due to a Related Adverse Event 
 
 


Cempra Pharmaceuticals, Inc. 
Statistical Analysis Plan for study CE01-203 
Solithromycin (CEM-101) 
 
CONFIDENTIAL 
Page 28 of 28 
16.2.5 Prior and Concomitant Medication 
Listing 16.2.5.1 
Prior Medications 
Listing 16.2.5.2 
Concomitant Medications  
 
 
16.2.6 Standard of Care 
Listing 16.2.6.1 
Microbiological Evaluations: Positive 
Listing 16.2.6.2 
Radiological Imaging 
Listing 16.2.6.3 
Non-Pharmacological Treatments  
 
 
16.2.7 Adverse Events 
Listing 16.2.7.1 
All Adverse Events 
Listing 16.2.7.2 
Serious Adverse Events 
Listing 16.2.7.3 
Infusion Site Adverse Events 
 
 
16.2.8 Laboratory Data 
Listing 16.2.8.1 
Laboratory Values - Hematology 
Listing 16.2.8.2 
Laboratory Values - Chemistry 
 
 
16.2.9 Vital Signs 
Listing 16.2.9.1 
Vital Signs  
 
 
16.2.10 Other Safety Data 
Listing 16.2.10.1 
Pregnancy Test  
 
 
16.2.11 Clinical Outcomes 
Listing 16.2.11.1 
Clinical Efficacy Endpoints 
 
 
1  This output will present the 4 age groups (2 Months - <2 Yrs, 2 - <6 Yrs, 6 - <12 Yrs, 12 – 17 
Yrs) as well as the two treatment arms (All Subjects Soli, All Subjects Comparator) for a total 
of 6 categories of subjects. 
2  This output will present the 8 categories: 2 Months - <2 Yrs Soli., 2 Months - <2 Yrs 
Comparator, 2 - <6 Yrs Soli., 2 - <6 Yrs Comparaor, 6 - <12 Yrs Soli., 6 - <12 Yrs Comparator, 
12 – 17 Yrs Soli., 12 – 17 Yrs Comparator.