Conditions: Refractory Bone or Joint Infections
Keywords: fusidic acid prosthetic joint infections bone infections osteomyelitis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
To evaluate the safety and effectiveness of oral sodium fusidate (CEM-102) as chronic antibiotic for the treatment of bone or joint infections.

Detailed description:
Prospective, open-label, non-randomized, single-arm trial to evaluate the safety and effectiveness of CEM-102 for chronic antibiotic suppressive therapy of bone or joint infections. Subjects enrolling in this study must have a refractory staphylococcal bone or joint infection that requires suppressive antibiotic therapy (e.g. having an infection that cannot be managed by complete removal of the infected bone or foreign material, a refractory infection not responding to previous treatment, or not being a candidate for long-term intravenous antibiotic therapy).

Arms:
arm 1: 1500 mg by mouth every 12 hours for 2 doses, then 600 mg by mouth every 12 hours thereafter, until end of therapy:

* 6 months of treatment; or
* 24 months of treatment (if continued on chronic suppressive therapy)

Interventions: intervention 1: sodium fusidate
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
 
 
Oral Sodium Fusidate (CEM-102) for the Treatment of Staphylococcal Bone or Joint Infections 
NCT Number: NCT02569541 
 
This supplement contains the following items: 
1. Original/Final Protocol Version 1, 07 July 2015 
2. Statistical Analysis Plan Final Version, 19 October 2017 
3. Statistical Analysis Plan Amendment 1.0, 04 December 2017 


CEM-102 Pharmaceuticals, Inc. 
Protocol CE06-302 
07 July 2015 
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Page 1 of 70 
CEM-102 Pharmaceuticals, Inc. 
Clinical Study Protocol 
Protocol Number: 
CE06-302 
Study Drug 
CEM-102 
Title: 
An Open-Label, Non-Randomized, Single-Arm Multi-
Center Study to Evaluate Oral Sodium Fusidate (CEM-
102) for the Treatment of Staphylococcal Bone or Joint 
Infections in Subjects for whom Chronic Antibiotic 
Suppressive Therapy is Indicated 
Sponsor 
CEM-102 Pharmaceuticals, Inc. 
6320 Quadrangle Drive, Suite 360 
Chapel Hill, NC 27517 
Telephone: (919) 313-6601 
Fax: (919) 313-6620 
Version / Date: 
Version 1 / Original Protocol 07 July 2015 
 
 
 
 
This document is a confidential communication from CEM-102 Pharmaceuticals, Inc. a subsidiary of Cempra, Inc. 
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 CEM-102 Pharmaceuticals, Inc., except that this 
document may be disclosed to appropriate Institutional Review Boards and Independent Ethics Committees under 
the condition that they are also required to maintain confidentiality. 


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07 July 2015 
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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 study will be conducted in compliance with the protocol and all 
applicable regulatory requirements, in accordance with Good Clinical Practices (GCPs), including 
International Conference on Harmonization (ICH) Guidelines, and in general conformity with the 
most recent version of the Declaration of Helsinki. 
Principal Investigator 
 
_____________________________________________ 
Printed Name 
 
 
 
Signature 
 
Date 
 
Representatives of CEM-102 Pharmaceuticals, Inc. who agree to the terms and conditions of this 
protocol include: 
 
Richard Pushkin, M.D.  
Executive Director, Clinical Development 
CEM-102 Pharmaceuticals, Inc. 
6320 Quadrangle Drive, Suite 360 
Chapel Hill, NC 27517 
Telephone: (919) 313-6601 
Fax: (919) 313-6620 
 
 
 
 
Signature 
 
Date 
 
 


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2 
SYNOPSIS 
Name of Sponsor Company 
CEM-102 Pharmaceuticals, Inc. 
Name of Finished Product 
CEM-102 Tablets 
Name of Active Ingredient 
Sodium Fusidate 
Title of Study: An Open-Label, Non-Randomized, Single-Arm, Multi-Center Study to Evaluate Oral 
Sodium Fusidate (CEM-102) for the Treatment of Staphylococcal Bone or Joint Infections in Subjects for 
whom Chronic Antibiotic Suppressive Therapy is Indicated 
Study No: CE06-302 
Planned Number of Subjects: 30 subjects 
Planned Number of Investigational Sites: Up to 20 (in the US) 
Planned Study Period: 3 years 
Objective: 
To evaluate the safety and effectiveness of oral sodium fusidate (CEM-102) as chronic antibiotic 
suppressive therapy in subjects with staphylococcal bone or joint infections. 
Rationale: 
Subjects with bone or joint infections (with or without prosthetic material), who are unable to undergo 
definitive surgery (i.e. removal of infected bone, sequestrations, or foreign material) because of poor 
health status, age, or comorbidities, generally undergo an initial course of intravenous (IV) antibiotics 
followed by more limited surgery, consisting of debridement and irrigation. Often, chronic suppressive 
antibiotic therapy is utilized thereafter. 
Some subjects experience an infection relapse, as manifested by bacteremia, purulent discharge, wound 
dehiscence, or pain, at some point following cessation of antibiotic therapy. Often, these subjects need 
to be hospitalized to receive another cycle of debridement, irrigation, and antibiotics (IV followed by oral 
antibiotic therapy for 3-6 months or longer). In some cases, the suppressive oral antibiotic therapy is not 
able to eliminate/reduce the pain and/or the wound drainage or to improve the ability to ambulate due to 
decreased weight bearing or lack of joint function. In addition, dosing or duration of currently available 
oral therapies may be limited by the emergence of treatment-limiting or treatment-related adverse events  
(such as renal toxicity, allergy, bone marrow suppression, paresthesias, or skin discoloration), 
comorbidities (such as renal insufficiency), or emergence of antimicrobial resistance. When any of these 
events happen, the oral antibiotic must be replaced. 
Every time the infection relapses, the subject may be hospitalized to undergo another cycle of irrigation, 
debridement and antibiotic therapy (IV followed by oral antibiotic therapy). In some cases, amputation of 
the infected limb may be considered as a last resort. 
There is clearly a need for additional effective oral antibiotics that can be safely administered and that 
will be well tolerated over extended treatment periods. Oral fusidic acid (CEM-102) has been available 
for use outside the US for over 4 decades and is considered safe and effective for the treatment and 
suppression of bone, joint, and prosthetic infections caused by staphylococcal spp. 


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Name of Sponsor Company 
CEM-102 Pharmaceuticals, Inc. 
Name of Finished Product 
CEM-102 Tablets 
Name of Active Ingredient 
Sodium Fusidate 
Methodology: 
This is a prospective, open-label, non-randomized, single-arm trial to evaluate the safety and 
effectiveness of CEM-102 for chronic antibiotic suppressive therapy of bone or joint infections. 
Subjects enrolling in this study must have a staphylococcal bone or joint infection that requires 
suppressive antibiotic therapy. Reasons a subject may be suitable for chronic oral antibiotic suppressive 
therapy include, but are not limited to, the following: 1) having an infection that cannot be managed by 
complete removal of the infected bone or foreign material, 2) having a refractory infection not responding 
to previous treatment, and 3) not being a candidate for long-term intravenous antibiotic therapy. 
Subjects must have a bone or joint infection due to an inclusionary pathogen, demonstrated from a 
positive culture from samples obtained during surgery, biopsy, or drainage procedures within 6 weeks 
prior to enrollment.  
Acceptable pathogens in this study include the following CEM-102-susceptible organisms: methicillin-
susceptible S. aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and coagulase-
negative staphylococci (CoNS) such as S. epidermidis, S. hominis, or S. haemolyticus. Specifically 
excluded from this list of pathogens is S. saprophyticus. Prior to enrollment, sensitivity of the isolate(s) 
to CEM-102 must be demonstrated. 
Co-infection with Corynebacterium spp., Propionibacterium acnes, beta–hemolytic streptococci, and 
enterococci, or other bacteria susceptible to CEM-102 is permitted.  
Co-infection with bacteria known or expected not to be susceptible to CEM-102 (e.g. Gram-negatives or 
anaerobes) is permitted, provided these bacteria can be treated with an adjunctive antibiotic to which the 
inclusionary staphylococcus is not susceptible, and there are no known drug-drug interactions with CEM-
102. 
CEM-102 must be initiated with one or more additional antibiotics (either oral or IV), referred to as 
companion antibiotics, for the first 1-2 weeks of the study. Companion antibiotic(s) will be selected per 
the Investigator’s discretion on the basis of subject-specific antibiotic tolerability and pathogen 
susceptibilities. Because concomitant administration of rifampin results in markedly reduced levels of 
CEM-102 blood levels, rifampin must not be used as a concomitant antibiotic with CEM-102.  After 1-2 
weeks of therapy, the companion antibiotic must be discontinued. To be eligible for enrollment, the 
subject must be a suitable candidate for CEM-102 monotherapy after completion of 1-2 weeks of the 
companion antibiotic, for chronic treatment of the orthopedic infection due to the inclusionary pathogen.  
This study comprises two parts: Part A (enrollment through the 6-month visit) and Part B (6-24 months 
post-enrollment). In Part A, all subjects will receive 6 months of CEM-102 treatment. The Investigator will 
evaluate each subject completing Part A for clinical response at the 6-month visit (primary endpoint). For 
Part B, a subject who completes Part A and, in the Investigator’s opinion, requires continued suppressive 
therapy may continue to receive CEM-102. Alternatively, if the Investigator considers the infection 
resolved and that no further antibiotic therapy is required, study drug will be discontinued and the subject 
followed for evidence of relapse until End of Study (EOS). 
During the first 6 months of treatment, study Part A, subjects will be monitored monthly (±1 week) for 
safety and clinical response to CEM-102. During study Part B, subjects will be monitored every 3 months 
(±2 weeks) until the End of Study Visit (24 months). 
A subject who discontinues study drug because of treatment failure will have an EOS visit at that time. 
A subject who discontinues study drug due to an adverse event (AE) will be followed until the AE is 
resolved or stabilized. A subject who discontinues study drug due to clinical cure will be followed for 
relapse until EOS. If a subject withdraws from the study at any time, for any reason, an EOS visit will be 
performed at that time. 
Duration of Subject Participation: The anticipated duration of participation for each subject will be 
24 months. If the subject requires additional long-term chronic suppressive therapy with CEM-102 
beyond study closure, the subject may be enrolled into an expanded access protocol to continue therapy. 
Number of Subjects: 30 subjects 


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07 July 2015 
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Name of Sponsor Company 
CEM-102 Pharmaceuticals, Inc. 
Name of Finished Product 
CEM-102 Tablets 
Name of Active Ingredient 
Sodium Fusidate 
Diagnosis and Criteria for Inclusion: 
Screened subjects meeting all the inclusion and exclusion criteria described below may be enrolled in 
this protocol: 
Inclusion Criteria: 
1. Male or female subject ≥ 18 years of age, and adolescents between the ages of 12 and 18 years 
who weigh greater than 60 kg. 
2. Subject must have a bone or joint infection due to an inclusionary pathogen demonstrated from a 
culture from samples obtained during surgery, biopsy, or drainage procedures within 6 weeks prior 
to enrollment.  
• 
Note: If subject does not have a confirmatory culture result, the Investigator must provide 
documentation as to why subject is suspected to have a staphylococcal infection and must 
discuss the subject with the medical monitor for approval of enrollment. 
3. Inclusionary pathogen(s) include the following staphylococcal bacteria: 
• 
S. aureus: MSSA or MRSA 
• 
CoNS, such as S. epidermidis, S. hominis, or S. haemolyticus (S. saprophyticus is not an 
inclusionary pathogen) 
Note: Co-infection with Corynebacterium spp., Propionibacterium acnes, beta-hemolytic 
streptococci, and enterococci, or other bacteria susceptible to CEM-102 is permitted. Co-infection 
with bacteria known or expected not to be susceptible to CEM-102 (e.g. Gram-negative or anaerobic 
bacteria) is permitted, provided these bacteria can be treated with an adjunctive antibiotic to which 
the inclusionary staphylococcus is not susceptible, and there are no known drug-drug interactions 
with CEM-102. 
4. Inclusionary pathogen, if identified, must be susceptible to CEM-102. 
5. If the subject has a prosthetic joint, the implant is secured and fixed. 
6. After completion of 1-2 weeks of the companion antibiotic, subject must be a suitable candidate for 
CEM-102 monotherapy for chronic treatment of the orthopedic infection due to the inclusionary 
pathogen. 
7. Subject is not a candidate, as determined by the Investigator, for suitable alternative therapy. 
Reasons include, but are not limited to, the following: 
• 
Cannot undergo definitive curative surgical treatment (removal of all infected bone, joint, or 
foreign material) due to poor health status, age, or comorbidities 
• 
Not a candidate for long-term IV antibiotic therapy 
8. The subject must be a suitable candidate for oral antibiotic therapy (i.e. able to swallow study 
medication tablets/capsules intact and have no known deficiency in gastrointestinal absorption). 
9. The subject (or subject’s legal guardian) must express commitment to comply with all study visits, 
procedures, and requirements for the duration of the study. 
10. The subject (or subject's legal guardian has voluntarily signed the Independent Ethics Committee 
(IEC) or Institutional Review Board (IRB) approved informed consent form (ICF). In cases of mental 
incapacity, the legal guardian is permitted to sign the ICF. 
11. Female subjects of childbearing potential must use an acceptable contraception method 
(abstinence or double-barrier methods) for the duration of the study-drug treatment phase of the 
study and 30 days thereafter, and must have a negative serum or urine pregnancy test at 
Screening. 
Exclusion Criteria: 
1. Medical history of hypersensitivity or allergic reaction to sodium fusidate, fusidic acid (Fucidin® or 
any systemic or topical product containing fusidic acid) or its excipients. 
2. Endovascular, infected intravascular foreign material, or infective endocarditis; or central nervous 
system infection, including meningitis 


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Name of Sponsor Company 
CEM-102 Pharmaceuticals, Inc. 
Name of Finished Product 
CEM-102 Tablets 
Name of Active Ingredient 
Sodium Fusidate 
3. Female subject who is pregnant or lactating. 
4. Known severe renal impairment, as indicated by estimated creatinine clearance (CrCl) <30 mL/min 
(by Cockcroft-Gault calculation). 
5. Immunocompromised subject or requirement for immunosuppressive therapy; Prior use of 
immunosuppressant agents (i.e. cyclosporine, TNFα antagonist) within 30 days of study 
medication administration. 
6. Malignancy requiring ongoing cytotoxic chemotherapy. 
7. Neutropenia (absolute neutrophil count <500/µL); Thrombocytopenia (platelet count <60,000/µL). 
8. Known human immunodeficiency virus (HIV) infection and currently receiving antiretroviral therapy; 
Current CD4 count 200 cells/mm3 (documented within 3 months prior to enrollment); If CD4 count 
is unknown, subject may not enroll. 
9. Evidence of significant liver disease: alanine aminotransferase (ALT) >3 × upper limit of normal 
(ULN) or direct bilirubin >ULN; known cirrhosis with decompensation (i.e. Child-Pugh Class B or C 
disease). 
10. Known hepatitis C virus (HCV) infection and currently receiving HCV-specific antiviral therapy. 
HCV infection alone, in the absence of decompensated liver disease, is not exclusionary. 
11. Seizure disorder requiring current therapy with anticonvulsant. 
12. Any underlying condition (e.g. addiction or clinically significant disease), that in the opinion of the 
Investigator, would be likely to interfere with assessment of the infection or completion of the study. 
13. The use of an investigational drug within 4 weeks prior to screening. 
14. Requires concomitant treatment with the following: 
o 
OATP1B1 and OATP1B3 substrates, in particular statins (e.g. HMG-CoA reductase 
inhibitors) 
o 
Medications metabolized by CYP2C8, such as glitazones (e.g. repaglinide) 
o 
CYP3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, 
phenobarbital, and nafcillin) 
15. Prior treatment with a CYP3A4 inducer, such as dexamethasone, phenytoin, carbamazepine, 
rifampin, phenobarbital, or nafcillin, within 7 days prior to enrollment. 
16. Subjects requiring digoxin or warfarin therapy may only be enrolled if an achievable plan for 
therapeutic monitoring of the drug (digoxin) or prothrombin time has been reviewed and approved 
by the study medical monitor. 
Dose and Mode of Administration: 
Test Product: CEM-102 
1500 mg (5×300 mg tablets) by mouth every 12 hours for 2 doses  
600 mg (2×300 mg tablets) by mouth every 12 hours thereafter 
CEM-102 must be taken within a +/- 2 hour window to the scheduled dose.  On days when PK samples 
are obtained, CEM-102 must be taken within +/- 1 hour of the scheduled dose. 
CEM-102 may be taken while fasting or with food. 
CEM-102 will be supplied by CEM-102 Pharmaceuticals (a subsidiary of Cempra, Inc.). 
Duration of Treatment: 
This study is designed to evaluate a minimum of 6 months of treatment with CEM-102. Therapy may 
extend for up to 24 months. If the subject requires chronic suppressive therapy with CEM-102 beyond 
24 months, the Investigator may choose to roll the subject into an expanded access protocol. 
Companion Antibiotic Therapy: 
CEM-102 must be initiated with one or more additional antibiotics (either oral or IV) for the first 1-2 weeks 
of the study. Companion antibiotic(s) will be selected per the Investigator’s discretion on the basis of 


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07 July 2015 
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Name of Sponsor Company 
CEM-102 Pharmaceuticals, Inc. 
Name of Finished Product 
CEM-102 Tablets 
Name of Active Ingredient 
Sodium Fusidate 
subject-specific antibiotic tolerability and pathogen susceptibilities.  Examples include, but are not limited 
to, the following: IV cefazolin, vancomycin, daptomycin, or IV/PO linezolid (rifampin must not be used as 
a concomitant antibiotic with CEM-102). The companion antibiotic will not be provided by the Sponsor, 
but will be supplied by the investigative site as standard of care. Starting an antibiotic due to signs and 
symptoms of clinical failure (e.g., worsening redness, swelling, pain, purulent discharge, sinus tract 
formation, or bacteremia) will be classified as clinical failure. 
Adjunctive Antibiotic Therapy for Co-infections: 
Treatment of co-infections due to bacteria known or expected to not be susceptible to fusidic acid is 
permitted, provided these pathogens can be treated with an adjunctive antibiotic to which the inclusionary 
pathogen is not susceptible (e.g. aztreonam and metronidazole are permitted for treatment of Gram-
negative and anaerobic co-infections).  
Concomitant Antibiotic Therapy for Unrelated Infections: 
Treatment of an unrelated infection with an antibiotic to which the inclusionary pathogen is susceptible 
is permitted only if the antibiotic is administered for ≤ 10 days on any single occasion, and ≤ 2 courses 
during any 6-month period during the study (and provided there are no known drug-drug interactions with 
CEM-102).  
Primary Endpoint: 
The primary endpoint will be the proportion of subjects in the intent to treat (ITT) analysis set who meet 
all the criteria for clinical success at the 6-Month Visit. 
Clinical success is defined to occur when subjects meet all of the following criteria: 
• 
Subject was not hospitalized due to worsening of the study-qualifying orthopedic infection at 
any point between enrollment and the 6-Month Visit 
• 
Subject did not undergo a definitive surgical procedure (such as amputation) at any point 
between enrollment and the 6-Month Visit 
• 
No additional antibiotics (after completion of companion antibiotics) are required for treatment 
of the orthopedic infection due to the inclusionary pathogen 
• 
Wound is closed, or the open area decreased in size (L x W) and, if a skin graft was done, the 
graft remains viable without evidence of infection 
• 
No purulent discharge from the surgical wound, or new or recurring sinus tract 
• 
No worsening of redness, tenderness, or swelling at the primary infection site 
• 
No bacteremia of the inclusionary pathogen at any point between enrollment and the 6-Month 
Visit 
Clinical failure defined as follows: 
• 
Failure to meet all criteria for clinical success 
• 
Death (due to the primary infection)  
• 
Discontinuation of study drug due to an AE and the requirement of additional antibiotics for 
treatment of the primary infection 
• 
Use of a concomitant antibiotic to which the inclusionary pathogen is susceptible for > 10 days 
on any occasion, or for > 2 courses during any 6-month period 
Indeterminate: 
• 
Subject withdraws consent 
• 
Subject is lost to follow-up 
Investigators will evaluate and provide documentation of each subject for a clinically meaningful 
difference in each subject’s response prior to making a determination of treatment failure for the 
primary study endpoint. 
Secondary Endpoints: 
• 
The safety and tolerability of CEM-102 for the treatment of bone and joint infections, reported 
as subject incidences of treatment emergent adverse events (TEAEs), serious adverse events 
(SAEs), deaths, and discontinuations due to AEs in the safety analysis set 


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Name of Sponsor Company 
CEM-102 Pharmaceuticals, Inc. 
Name of Finished Product 
CEM-102 Tablets 
Name of Active Ingredient 
Sodium Fusidate 
• 
The proportion of subjects in the ITT analysis set who meet all the criteria for clinical success, 
as defined above, at the 9-Month, 12-Month, 15-Month, 18-Month, 21-Month, and 24-Month 
Visits 
• 
Pharmacokinetics of CEM-102 used chronically in subjects with orthopedic infections 
Safety Evaluations: 
The 6-month history of all prior antibiotics used to treat the primary infection will be recorded in the 
electronic case report form (eCRF). All other medications taken during the period from 7 days prior to 
enrollment through the End of Study (EOS) will be recorded in the eCRF. 
AEs will be collected from the date of execution of the Informed Consent through 30 days after last dose 
of study drug or until resolution/stabilization of all AEs. Safety assessments, including laboratory 
assessments (serum chemistry and pregnancy test), physical examination, and vital signs, will be 
obtained as indicated in the Schedule of Assessments (Table 1). 
The number and percent of subjects with treatment-emergent graded laboratory abnormalities (defined 
based on the Division of Microbiology and Infectious Diseases (DMID criteria) and vital sign changes 
from Baseline will be summarized. 
The incidence of treatment-related AEs from enrollment until the end of the study (6-Month Visit or EOS 
Visit) will be tabulated by System Organ Class, preferred term, and maximum severity (mild, moderate, 
or severe/life threatening). 
Statistical Methods and Data Analysis: 
As a non-randomized, single-arm study, there will be no formal statistical analyses. This study is not 
powered for inferential statistical analyses, and no formal hypothesis testing will be conducted. Safety 
and efficacy will be descriptive. Clinical outcome will be reported as the proportion of subjects meeting 
the criteria of clinical success. 
All safety data will be summarized using the Safety analysis set. Adverse events (AEs) will be coded with 
the Medical Dictionary for Regulatory Activities (MedDRA®). The number and proportion of subjects 
having treatment-emergent AEs will be tabulated by MedDRA System Organ Class (SOC) and preferred 
term, severity, and relationship to study drug. 
Because this is a non-randomized, open-label, single-arm study, interim data may be summarized and 
reported, as needed, prior to database lock. 
Details of the analysis will be provided in a separate Statistical Analysis Plan (SAP). 
 
 
 


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Table 1 
Schedule of Assessments/Procedures 
Assessment/Procedure 
Screeninga 
Part A 
Part B 
 
Enrollment 
(Day 1 Visit)b,c 
Day 8  
(± 3 days) 
Monthly During  
First 6 Months 
(±1 week) 
Every 3 Months From 
Month 6 until End of 
Study (±2weeks) 
End of 
Study 
(EOS)d 
Informed Consent Form 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
Review 
X 
X 
 
 
 
 
Review of Clinical/ Surgical 
History 
X 
X 
X 
X 
X 
X 
Microbiological specimens for culture  
X 
X 
X e 
X e 
X e 
X e 
Enrollment 
 
X 
 
 
 
 
Vital Signsf 
X 
X 
X 
X 
X 
X 
Limited Physical Examinationg 
X 
X 
X 
X 
X 
X 
Examination of Infected Areah 
X 
X 
X 
X 
X 
X 
Safety Laboratory Assessmentsi 
X 
X 
X 
X 
X 
X 
Inflammation Laboratory 
Assessmentsj 
X 
X 
 
X 
X 
X 
CEM-102 Administration k 
 
X 
  
  
  
 
Pharmacokinetic Blood Sampling 
 
 
 
Xo 
 
 
Dispense Oral antibiotic to Subjectsl 
 
X 
X 
X 
X 
 
Perform Drug Accountability 
 
 
X 
X 
X 
X 
Record 6-Month History of Prior Antibiotic 
Used to Treat the Primary  Infection 
Leading to Enrollment 
X 
 
 
 
 
 
Record Concomitant Medications 
X 
X 
X 
X 
X 
X 
Record AEsm 
X 
X 
X 
X 
X 
X 
Investigator Assessment of Clinical 
Responsen 
 
 
 
X 
X 
X 
a. Within 6 weeks prior to enrollment, subjects must have a positive culture with an inclusionary pathogen susceptible to CEM-102, demonstrated from a culture 
from samples obtained during surgery, biopsy, or drainage procedures.  If subject does not have a confirmatory culture result, the Investigator must provide 


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documentation as to why subject is suspected to have a staphylococcal infection and must discuss the subject with the medical monitor for approval of 
enrollment. 
b. Enrollment is contingent on demonstration that subject fulfills the inclusion/exclusion criteria. 
c. 
Study Day 1 corresponds to the first day of dosing with CEM-102. 
d. Subjects who discontinue CEM-102 because of an adverse event (AE) or clinical failure should have a study visit around the time of drug discontinuation and
will continue to be followed, as needed, for appropriate observation of treatment-related AEs until AEs have resolved or stabilized. If a subject withdraws from 
the study at any time, for any reason, the EOS visit will be performed around that time. Those subjects who continue CEM-102 until the Month 24 visit will 
undergo the assessments/procedures for the EOS visit.  At study closure, at the discretion of the Investigator, subjects may be rolled over into an expanded 
access protocol to receive chronic suppressive CEM-102 therapy. 
e. If clinically indicated, microbiological samples (tissue surrounding the foreign material, synovial fluid, bone, etc.) obtained during the study should be submitted 
to the local laboratory for aerobic and anaerobic culture and susceptibility testing, including to CEM-102. All isolated bacteria are to be sub-cultured and shipped 
to the central microbiology laboratory for organism confirmation and confirmatory susceptibility testing. 
f. 
Vital sign measurements include height, weight, temperature, heart rate, respiratory rate, and blood pressure.  Results are to be recorded in the eCRF. 
g. Limited physical examination may include HEENT, cardiovascular, pulmonary, gastrointestinal, skin, lymph nodes, musculoskeletal, and extremities, among 
others. Results are to be documented in source and recorded in the eCRF. 
h. Examination of the infected area will include the following assessments: pain, erythema, mobility, joint stability, wound closure, wound drainage, and weight 
bearing [for back and lower extremity infections]. The Investigator will state whether the infected area seems to have improved, deteriorated, or remained
unchanged. Results are to be documented in the source and recorded in the eCRF. 
i. 
Safety laboratory assessments will be performed at the local laboratory and will include the following: serum chemistry (ALT, AST, alkaline phosphatase [ALP],
total and direct bilirubin, blood urea nitrogen [BUN], creatinine, albumin, total protein, sodium, total carbon dioxide, glucose, potassium, chloride, calcium, 
phosphorus, and CPK).  For female subjects of child bearing potential, a urine or serum pregnancy test will be performed at Screening and will be repeated at 
subsequent visits per Investigator’s discretion. . 
j. 
Laboratory measurements of markers of inflammation will be performed at the local laboratory and will include the following: hematology (complete blood count 
[CBC] with differential), erythrocyte sedimentation rate [ESR], and C-reactive protein [CRP]). Laboratory measurements of markers of inflammation obtained on 
the day of a surgery or debridement should be performed before the procedure when possible, because levels of these markers are known to increase after 
surgery.   
k. 
A CEM-102 loading dose strategy is utilized, in which CEM-102 is given as 1500 mg every 12 hours for 2 doses followed by 600 mg every 12 hours thereafter. 
l. 
After 6 months of therapy, the Investigator may decide to continue chronic suppressive therapy with CEM-102 or discontinue CEM-102 due to clinical cure and 
no further requirement for antibiotic therapy. Subjects who stop treatment will continue to be followed on the same schedule as those who remain on therapy to 
monitor for infection relapse until the end of the study.  Subjects who discontinue CEM-102 due to clinical failure should have an EOS visit at that time. 
m. All AEs will be collected following signing of the ICF. 
n. The Investigator will assess clinical response at Months 6, 9, 12, 15, 18, 21, 24 and at EOS. 
o. Pharmacokinetic blood sampling will be conducted at the 3-month visit as described in Section 10.6 


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Figure 1 
Schematic of Study Design 
Screening
Suppressive Therapy with Oral CEM-102
Observation for Recurrence
Oral CEM-102
24 Months
End of Study
18 Months
12 Months
6  Months 
Primary Endpoint
Enrollment
Part A
Part B
 
 
 


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3 
TABLE OF CONTENTS 
1 
SIGNATURE PAGE ................................................................................................. 2 
2 
SYNOPSIS ............................................................................................................... 3 
3 
TABLE OF CONTENTS......................................................................................... 12 
3.1 
Appendices .............................................................................................................. 14 
3.2 
Table of In-Text Tables ............................................................................................ 14 
3.3 
Table of In-Text Figures ........................................................................................... 14 
4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................. 15 
5 
INTRODUCTION .................................................................................................... 17 
5.1 
Fusidic Acid (CEM-102) ........................................................................................... 18 
5.1.1 
Mechanism of Action and Microbiological Activity .............................................. 19 
5.2 
Nonclinical ............................................................................................................... 20 
5.3 
Clinical ..................................................................................................................... 21 
5.3.1 
Clinical Pharmacology and Metabolism .............................................................. 21 
5.3.2 
Summary of Efficacy .......................................................................................... 22 
5.3.2.1 
Phase 2 ABSSSI Study ................................................................................. 22 
5.3.2.2 
Phase 2 Prosthetic Joint Infection (PJI) Study ............................................... 25 
5.3.3 
Summary of Safety ............................................................................................ 25 
5.3.3.1 
Phase 1 PK Studies ....................................................................................... 25 
5.3.3.2 
Phase 2 Studies ............................................................................................ 26 
5.3.3.3 
Ex-US Post-Marketing Safety Experience: ..................................................... 27 
5.4 
Rationale for the Use of CEM-102 in Staphylococcal Bone or Joint Infection ........... 27 
5.5 
Rationale for the Dosing Regimen ........................................................................... 28 
6 
STUDY OBJECTIVE .............................................................................................. 30 
6.1 
Primary Endpoint ..................................................................................................... 30 
6.2 
Secondary Endpoints ............................................................................................... 30 
6.3 
Pharmacokinetic Endpoints ..................................................................................... 30 
7 
OVERALL STUDY DESIGN .................................................................................. 31 
7.1 
Duration of Subject Participation .............................................................................. 32 
7.2 
Number of Subjects ................................................................................................. 32 
7.3 
Duration of Study ..................................................................................................... 32 
7.4 
Study Drug Dosage and Administration ................................................................... 32 
7.5 
Dose Modification .................................................................................................... 33 
8 
SELECTION OF STUDY POPULATION ............................................................... 34 
8.1 
Inclusion Criteria ...................................................................................................... 34 
8.2 
Exclusion Criteria ..................................................................................................... 35 
8.3 
Recording of Prior Antibiotics and Concomitant Treatment ...................................... 36 
8.4 
Permitted Medications and Treatment ..................................................................... 36 
8.5 
Companion Antibiotics to Treat the Primary Infection ............................................... 36 
8.6 
Adjunctive Antibiotic Therapy for Co-infections ........................................................ 37 
8.7 
Concomitant Antibiotic Therapy for Unrelated Infections .......................................... 37 
8.8 
Prohibited Medications ............................................................................................ 37 
9 
STUDY DRUG ....................................................................................................... 38 
9.1 
CEM-102 Tablets ..................................................................................................... 38 
9.2 
Study Drug Labeling and Packaging ........................................................................ 38 


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9.3 
Study Drug Storage Conditions................................................................................ 38 
9.4 
Receipt of Supplies .................................................................................................. 38 
9.5 
Study Drug Accountability ........................................................................................ 39 
9.5.1 
Overall ............................................................................................................... 39 
9.5.2 
Instructions for Subject....................................................................................... 39 
9.5.3 
Study Drug Handling and Return ....................................................................... 39 
10 STUDY ASSESSENTS AND PROCEDURES ....................................................... 40 
10.1 
Screening ................................................................................................................ 40 
10.2 
Treatment Period ..................................................................................................... 41 
10.2.1 
Enrollment (Study Day 1) ................................................................................... 41 
10.2.2 
Day 8 (±3 days).................................................................................................. 42 
10.2.3 
Monthly During First 6 Months (±1 Week) .......................................................... 42 
10.2.4 
Every 3 Months (+/- 2 weeks) from Month 6 until End of Study (24 Months) ...... 43 
10.3 
End of Study (EOS) ................................................................................................. 44 
10.4 
Local Laboratory Assessments ................................................................................ 44 
10.5 
Microbiology Assessments ...................................................................................... 45 
10.5.1 
Susceptibility Testing of Bacterial Pathogens (Local Laboratory) ....................... 45 
10.5.2 
Local Laboratory Storage of All Isolates ............................................................. 46 
10.5.3 
Shipping of Bacterial Strains to the Central Laboratory ...................................... 46 
10.5.4 
Central Microbiology Laboratory Procedures ..................................................... 46 
10.6 
Pharmacokinetic Assessments ................................................................................ 46 
11 STUDY DRUG DISCONTINUATION AND SUBJECT WITHDRAWAL ................. 48 
11.1 
Screening Failures ................................................................................................... 48 
11.2 
Discontinuation from Study Drug ............................................................................. 48 
11.3 
Withdrawal from Study ............................................................................................. 48 
11.4 
Study Site Discontinuation ....................................................................................... 49 
12 SAFETY ASSESSMENTS ..................................................................................... 50 
12.1 
Adverse Events ....................................................................................................... 50 
12.1.1 
Recording of Adverse Events ............................................................................. 50 
12.1.2 
Severity of Adverse Events ................................................................................ 51 
12.1.3 
Relationship Assessment ................................................................................... 51 
12.1.4 
Action Taken ...................................................................................................... 51 
12.1.5 
Outcome ............................................................................................................ 52 
12.2 
Serious Adverse Events........................................................................................... 52 
12.2.1 
Other Reportable Events .................................................................................... 53 
12.2.2 
Reporting SAEs and Other Reportable Events ................................................... 53 
13 DATA MANAGEMENT .......................................................................................... 54 
14 STATISTICAL METHODS AND DATA ANALYSIS .............................................. 55 
14.1 
Efficacy Analyses..................................................................................................... 55 
14.2 
Safety Analyses ....................................................................................................... 56 
14.3 
Pharmacokinetic Analysis ........................................................................................ 56 
15 ADMINISTRATIVE ASPECTS ............................................................................... 57 
15.1 
Compliance with Regulatory Requirements ............................................................. 57 
15.2 
Institutional Review Board or Independent Ethics Committee Approval ................... 57 
15.3 
Informed Consent .................................................................................................... 57 
15.4 
Confidentiality .......................................................................................................... 57 
15.5 
Compensation, Insurance and Indemnity ................................................................. 57 


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15.6 
Protocol Amendment ............................................................................................... 58 
15.7 
Electronic Case Report Forms (eCRF) .................................................................... 58 
15.8 
Source Document Maintenance ............................................................................... 58 
15.9 
Study Monitoring Requirements ............................................................................... 58 
15.10 
Study File Management ........................................................................................... 58 
15.11 
Study Completion .................................................................................................... 59 
15.12 
Audits ...................................................................................................................... 60 
15.13 
Retention of Records ............................................................................................... 60 
15.14 
Disclosure of Data ................................................................................................... 60 
15.15 
Financial Disclosure ................................................................................................. 61 
15.16 
Publication Policy..................................................................................................... 61 
16 REFERENCES ....................................................................................................... 62 
3.1 
Appendices 
Appendix A 
Toxicity Table ..................................................................................................... 64 
 
3.2 
Table of In-Text Tables 
Table 1 
Schedule of Assessments/Procedures ....................................................................... 9 
Table 2 
International Fusidic Acid Resistance Surveillance 2008-2011, 2014: 
Susceptibility of U.S. Isolates ................................................................................... 20 
Table 3 
Clinical Response at the TOC (Intent-to-Treat and Clinically Evaluable 
Populations)............................................................................................................. 24 
Table 4 
Clinical Response at the TOC (Microbiological Intent-to-Treat and 
Microbiologically Evaluable Populations) ................................................................. 24 
Table 5 
Disk Zone Diameter Quality Control Limits .............................................................. 45 
Table 6 
Provisional CEM-102 Disk Zone Breakpoints ........................................................... 46 
3.3 
Table of In-Text Figures 
Figure 1 
Schematic of Study Design ................................................................................ 11 
Figure 2 
Chemical Structure of Fusidic Acid .................................................................... 19 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABSSSI 
Acute bacterial skin and skin structure infection 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase  
AUC 
area under the curve 
BID 
twice a day 
BJI 
bone or joint infection 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CE 
clinically evaluable 
CEM-102 
sodium fusidate (fusidic acid) 
CF 
cystic fibrosis 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CLSI 
Clinical and Laboratory Standards Institute 
Cmax 
maximum concentration 
CoNS 
coagulase-negative staphylococci 
CPK 
creatinine phosphokinase 
CrCl 
creatinine clearance  
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae 
CYP 
cytochrome P450 
DAR 
debridement and prosthesis retention 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EF-G 
Elongation factor-G 
EOS 
End of Study 
EOT 
End of Treatment 
ESR 
erythrocyte sedimentation rate 
EUCAST 
European Committee on Antimicrobial Susceptibility Testing 
FA 
Fucidic Acid 
FDA 
US Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second  
GCP 
Good Clinical Practices 
GGT 
gamma-glutamyl transpeptidase 


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HCV 
hepatitis C virus 
HEENT 
head, eyes, ears, nose, throat 
hERG 
human ether à-go-go related gene 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IDSA 
Infectious Diseases Society of America  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
INR 
international normalized ratio 
IRB 
Institutional Review Board  
ITT 
Intent to Treat 
IV 
intravenous 
ME 
medically evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHA 
Mueller-Hinton Agar 
MIC 
Minimum Inhibitory Concentration 
mITT 
microbiological ITT 
MRCoNS 
methicillin-resistant coagulase-negative staphylococci 
MRSA 
methicillin-resistant Staphylococcus aureus 
MSSA 
methicillin-susceptible Staphylococcus aureus  
NI 
Non-inferiority 
NOAEL 
No adverse effect level 
OATP1B1/ 
OATP1B3 
hepatic drug influx transporters 
PCR 
polymerase chain reaction 
PJI 
prosthetic joint infection 
PK 
pharmacokinetic 
PO 
taken orally 
PT 
prothrombin time 
SAE 
serious AE 
SAP 
Statistical Analysis Plan 
SI 
Systeme International d’Unites 
SOC 
System, Organ, Class 
SoC 
Standard of Care 
TEAE 
treatment-emergent AE  
TID 
three times a day  
TOC 
test of cure 
UNL 
upper normal limit 
 


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5 
INTRODUCTION 
CEM-102 (sodium fusidate, fusidic acid) is the only member of a novel class of antibiotics, the 
fusidanes.  It inhibits bacterial protein synthesis by interacting with elongation factor-G (EF-G). It 
has a unique mechanism of action, and there is little cross-resistance with other antibiotics in 
clinical use. Oral tablets and topical fusidic acid have been used for over 4 decades in the United 
Kingdom and other parts of Western Europe, as well as in many other countries, to treat infections 
caused by Staphylococcus aureus. Intravenous formulations and an oral suspension have been 
developed by Leo Laboratories (Ballerup, Denmark), but their clinical use has been limited. Oral 
CEM-102 300 mg tablets are under development in the United States (US) by CEM-102 
Pharmaceuticals (a subsidiary of Cempra, Inc.) for treatment of acute bacterial skin and skin 
structure infection (ABSSSI).  
CEM-102 has potent in vitro activity against Gram-positive aerobic organisms. Antimicrobial 
activity against staphylococci recovered from US subjects with blood, bone and joint, respiratory 
tract, and skin and skin structure infections (ABSSSI) as part of international surveillance studies 
conducted between 2008 and 2014 showed that CEM-102 inhibited 99.7% of S. aureus isolates 
(and 99.8% of methicillin-resistant Staphylococcus aureus (MRSA) isolates) at a minimum 
inhibitory concentration (MIC) ≤ 1μg/mL. The majority of coagulase-negative staphylococci 
(CoNS) with or without oxacillin-resistance were similarly susceptible. Among other Gram-
positive bacteria, CEM-102 has activity against enterococci (MIC90 4 mg/L), Corynebacterium 
spp. (MICs ≤ 0.12 µg/mL), Micrococcus luteus (MICs ≤ 0.5 μg/mL), and Streptococcus pyogenes 
(MIC90 8 µg/mL). In addition, CEM-102 is active against Propionibacterium spp. (MIC90 1 
µg/mL). CEM-102 does not have significant activity against Gram-negative aerobic and anaerobic 
bacteria. 
Adkins and Gottlieb (Adkins 1999) reviewed published experience with fusidic acid in the 
treatment of bone and joint infections (BJI), citing its utility in the treatment of acute and chronic 
osteomyelitis, vertebral infection, septic arthritis, and prosthetic and other device related 
infections. The authors considered achievement of effective bone and joint fusidic acid 
concentrations a key factor in its historical efficacy in the treatment of these conditions. 
Lautenbach and colleagues measured serum and bone fusidic acid concentrations (by agar plate 
diffusion methods using a susceptible bacterial strain) in 36 patients with chronic osteomyelitis 
during the course of therapy; bone concentrations of active drug ranged from 1 to 15 µg/g, 
measured at approximately 9 hours after last oral dose (in most cases, 20 to 40 mg/kg/day, divided 
three times daily (TID) (Lautenbach 1975). Hieholzer and colleagues measured bone and soft 
tissue concentrations at 3 to 6 hours after last oral dose (500 mg TID dosing for at least 5 days) in 
a series of patients with osteomyelitis and found fusidic acid concentrations of 2 to 15 µg/g in bone 
and 4 to 17 µg/g in soft tissue (Hieholzer 1966, Hieholzer 1974). A second group of patients 
studied by the same Investigators were administered fusidic acid (500 mg TID, orally) for 5 to 13 
days prior to surgery for non-infected bone disease; bone fusidic acid concentrations were, on 
average, up to two-fold higher than those observed in patients with osteomyelitis, and mean 
concentrations ranged from 46% to 94% of those observed in serum. Chater reported fusidic acid 
concentrations in bone and serum from 7 adult patients treated with 500 mg TID oral fusidic acid 
for osteomyelitis; bone concentrations were similar to those described above, and ranged from 4% 
to 72% of serum concentrations, with consistently higher soft tissue concentrations (ranging from 
20% to >100% of serum concentrations) (Chater 1972). In summary, oral fusidic acid dosing was 


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found to achieve drug concentrations at the site of infection that were associated with effective 
treatment of osteomyelitis across a number of studies.   
Subjects with bone or joint infections (with or without prosthetic material), who are unable to 
undergo definitive surgery (i.e. removal of infected bone, sequestrations, or foreign material) 
because of poor health status, age, or comorbidities, generally undergo an initial course of 
intravenous (IV) antibiotics followed by more limited surgery, consisting of debridement and 
irrigation. Often, chronic suppressive antibiotic therapy is utilized thereafter. 
Some subjects experience an infection relapse, as manifested by bacteremia, purulent discharge, 
wound dehiscence, or pain, at some point following cessation of antibiotic therapy. Often, these 
subjects need to be hospitalized to receive another cycle of debridement, irrigation, and antibiotics 
(IV followed by oral antibiotic therapy for 3-6 months or longer). In some cases, the suppressive 
oral antibiotic therapy is not able to eliminate/reduce the pain and/or the wound drainage or to 
improve the ability to ambulate due to decreased weight bearing or lack of joint function. In 
addition, dosing or duration of currently available oral therapies may be limited by the emergence 
of treatment-limiting or treatment-related adverse events (TEAE) (such as renal toxicity, allergy, 
bone marrow suppression, paresthesias, or skin discoloration), comorbidities (such as renal 
insufficiency), or emergence of antimicrobial resistance. When any of these events happen, the 
oral antibiotic must be replaced. 
Every time the infection relapses, the subject may be hospitalized to undergo another cycle of 
irrigation, debridement, and antibiotic therapy (IV followed by oral antibiotic therapy). In some 
cases, amputation of the infected limb may be considered as a last resort. 
There is medical need for new oral agents with improved activity and good safety and tolerability 
over extended treatment periods against Gram-positive bacteria, including drug resistant 
pathogens.  The purpose of this study is to evaluate the safety and effectiveness of CEM-102 for 
chronic antibiotic suppressive therapy of bone or joint infections. 
In addition to adults, this study will also include adolescent subjects between the ages of 12 and 
18 years who weigh greater than 60 kilograms.  In a retrospective cohort study by (Olson 2014), 
the authors reviewed all patients in a children’s Infectious Disease clinic over a 2-year period who 
received ≥ 14 days of oral or intravenous antimicrobial medication.  Of 335 subjects enrolled, the 
most commonly treated principal infections were septic arthritis, acute osteomyelitis, and chronic 
osteomyelitis in 18%, 15% and 8% of subjects, respectively. Furthermore, in a study by 
Learmonth 1984, in 45 pediatric patients with osteomyelitis and septic arthritis, sodium fusidate 
and erythromycin for 3 weeks was found to be an effective first-line antibiotic regimen.  Since 
pediatric patients with orthopedic infections are not uncommon, this study will attempt to obtain 
important safety information on CEM-102 use in this adolescent population.  
5.1 
Fusidic Acid (CEM-102) 
Fusidic acid is chemically described as: sodium ent-16α-acetoxy-3β, 11β-dihydroxy-4β, 8β, 14α-
trimethyl-18-nor-5β, 10α-cholesta-(17Z)-17(20), 24-dien-21-oate. 


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Figure 2 
Chemical Structure of Fusidic Acid 
COONa
CH3
H
H
CH3
CH3
OAc
HO
1
2
3
4
5
10
7
8
9
11
12
13
14
15
16
17
20
22
23
24
25
26
27
(21)
6
H
CH3
HO
 
 
5.1.1 
Mechanism of Action and Microbiological Activity 
CEM-102, the only antibiotic of the fusidane class, is active against Gram-positive bacteria 
through inhibition of bacterial replication, and is thus considered bacteriostatic. However, as with 
many bacterial protein synthesis inhibitors, CEM-102 may be bacteriostatic or bactericidal 
depending upon the inoculum size.  
CEM-102 inhibits bacterial protein synthesis through inhibition of the Elongation Factor G (EF-
G). Elongation Factor G is an essential bacterial protein that is involved in translocation on the 
ribosome after peptide bond formation. Due to this novel mechanism of action, little cross-
resistance between fusidic acid and other antibiotics has been reported. 
CEM-102 is active against staphylococci and has potent activity against staphylococci that express 
methicillin resistance (MRSA, including USA300 strains, MIC90 0.12 g/mL for both) and 
linezolid resistance (MICs <0.25 g/mL). Coagulase negative staphylococci (CoNS) with or 
without oxacillin (methicillin) resistance are also highly susceptible to CEM-102. Among other 
Gram-positive bacteria, CEM-102 is active against Group A β-hemolytic streptococci (S. 
pyogenes) with an MIC90 of 8 g/mL. At these concentrations, CEM-102 is bactericidal for S. 
pyogenes.  
A total of 99.7% of methicillin-susceptible Staphylococcus aureus (MSSA) and 99.8% of MRSA 
isolates from US patients with blood, bone and joint, respiratory tract, and skin and skin structure 
infections, recovered during international surveillance studies conducted between 2008 and 2014, 
had an MIC90 ≤0.12 g/mL (Table 2). In addition, the MIC90 was 0.25 g/mL for CoNS with or 
without oxacillin resistance. The MICs against other Gram-positive bacteria were greater. CEM-
102 does not have significant activity against Gram-negative aerobic and anaerobic bacteria.  


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Table 2 
International Fusidic Acid Resistance Surveillance 2008-2011, 2014: 
Susceptibility of U.S. Isolates 
Organism (number tested) 
MIC50 
(g/mL) 
MIC90 
(g/mL) 
% Susceptiblea 
S. aureus (15,045) 
0.12 
0.12 
99.7 
   MSSA (7364) 
0.12 
0.12 
99.6 
   MRSA (7681) 
0.12 
0.12 
99.8 
CoNS (1798) 
0.12 
0.25 
92.6 
   MSCoNS (531) 
0.12 
0.12 
97.6 
   MRCoNS (1267) 
0.12 
0.25 
90.5 
Enterococcus spp. (3876) 
4 
4 
- 
   Vancomycin-resistant (≥8 mcg/mL) (1224) 
4 
4 
- 
Beta-hemolytic streptococci (2032) 
8 
>8 
- 
   Group A (836) 
4 
8 
- 
   Group B (906) 
8 
>8 
- 
Source: 09-CPI-04 (2008 International Surveillance for CEM-102), 09-CPI-05 (2009 International Surveillance for 
CEM-102), 09-CPI-03 (2010 International Surveillance for CEM-102), 11-CEM-01B (2011 International Surveillance 
for CEM-102), and 14-CPI-01 (2014 International Surveillance for CEM-102) 
a. Determined according to published EUCAST (2015) breakpoint criteria (MIC ≤ 1 μg/mL, susceptible). For 
enterococci and streptococcal species, EUCAST breakpoints have not been established. 
High-level resistance to fusidic acid in staphylococcal species generally occurs through mutations 
in fusA, the gene encoding EF-G (Turnidge 1999, Besier 2003). Low-level resistance is most 
commonly caused by acquisition through horizontal transfer of the genes fusB or fusC, which 
encode proteins that bind EF-G on the ribosome, enabling resumption of translation that has been 
stalled by the fucidic acid/EF-G interaction (O’Neill 2006, O’Neill 2007, Guo 2012). Emergence 
of staphylococcal resistance to fusidic acid outside of the US has probably been facilitated by the 
routine dosing practices (both as a topical therapy for minor skin infections (Rijinders 2012) and 
with oral non-loading dose strategies).  
However, even after decades of fusidic acid use outside the US, including topical use, in a 2011 
international surveillance, 93.4% of S. aureus strains circulating in Europe were susceptible to 
fusidic acid using the EUCAST breakpoint of 1 µg/mL. Only 1.5% of European S. aureus strains 
carried high-level resistance to fusidic acid (MIC ≥ 8 µg/mL).  
Furthermore, a new loading dose regimen will achieve high blood concentrations within 24 hours 
and likely will reduce the emergence of resistance. This dosing regimen consists of 1500 mg Q12h 
for two doses, followed by 600 mg Q12h thereafter. 
5.2 
Nonclinical 
CEM-102 showed weak inhibition of the hERG current (3.1% at 100 µM) in vitro. No significant 
cardiovascular effects were observed in the micropig. There were no treatment-related central 
nervous system effects in rats following repeat dosing of up to 250 mg/kg/day for 28 days. No 
treatment-related respiratory changes were observed in dogs at doses up to 250 mg/kg/day for 
4 weeks.  
CEM-102 is orally bioavailable in rodents and dogs, but achievable serum concentrations after 
oral administration are substantially lower than those expected in humans with the loading dose 


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regimens to be used in clinical studies. CEM-102 did not accumulate in plasma following 28 days 
of dosing in rats or dogs. 
No studies have examined the excretion of CEM-102; however, literature reports of studies with 
14C-labeled fusidic acid in rats and rabbits have identified the compound as primarily excreted by 
the liver into bile, with very little radioactivity in the urine.   
CEM-102 administration to rats and dogs for 4 weeks was generally well tolerated at doses up to 
250 mg/kg/day; the major target toxicity at high doses consisted of gastrointestinal effects and 
adrenal gland changes in the dog. There were no serious adverse toxicities, with a no adverse effect 
level (NOAEL) of 100 mg/kg/day for rats and 40 mg/kg/day for dogs.   
CEM-102 was not mutagenic or clastogenic in genetic toxicity assays. 
No CEM-102 related effects on fertility parameters were noted in male or female rats. The 
NOAELs for maternal toxicity and fetal development effects were 100 and 200 mg/kg in the rat 
and 115 and 175 mg/kg in the rabbit, respectively. Studies on prenatal and postnatal development 
and maternal function have not been conducted. 
5.3 
Clinical 
Cempra has conducted three Phase 1 studies with CEM-102 in healthy adult subjects, one Phase 2 
clinical study in adults with acute bacterial skin and skin structure infections (ABSSSI), and one 
phase 2 trial in prosthetic joint infection (PJI). The PJI trial was terminated because of decreased 
fusidic acid blood concentrations secondary to concomitant rifampin administration (drug-drug 
interaction). A total of 234 adult subjects have received CEM-102 in Phase 1 and Phase 2 trials.  
Two single-patient expanded access trials have been conducted, and one intermediate-size 
expanded access trial is ongoing. Study CE06-EA01 (single-patient expanded access) provided 
CEM-102 for a single patient with chronic MRSA bone and joint infection. Study CE06-EA02 
(single-patient expanded access) provided CEM-102 for chronic methicillin-resistant S. aureus 
(MRSA) pulmonary infection in a single patient with cystic fibrosis (CF), and two subjects, both 
with chronic MRSA infections of a hip prosthesis, have been treated with CEM-102 in Study 
CE06-EA03 (intermediate-size expanded access). 
5.3.1 
Clinical Pharmacology and Metabolism 
CEM-102 binds primarily to albumin in human plasma (96.3% to 96.8% bound); this binding is 
reversible.  
A food effect study showed that food had no clinically significant effect on the pharmacokinetics 
(PK) of CEM-102. Gastrointestinal side effects, primarily nausea and vomiting, appeared to be 
lessened by dosing with food.  
CEM-102 has a plasma half-life of approximately 12 hours, and slowly accumulates to steady state 
levels when administered orally as 500 mg three times daily (TID) (the recommended European 
dose schedule). In a Phase 1 study with CEM-102 given 500 mg TID, trough levels rose steadily 
from Day 1 through Day 5, attaining mean trough concentrations of 105 μg/mL prior to the final 


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dose on Day 5. However, by employing a loading dose strategy and twice daily (BID) 
administration, target therapeutic peak and trough plasma concentrations (>100 μg/mL) were 
achieved by 24 hours. With a loading dose of 1650 mg BID on Day 1 followed by 825 mg BID 
for 6.5 days, a mean trough plasma concentration of 146 μg/mL was achieved by 24 hours post-
first-dose, and a mean trough plasma concentration of 204 μg/mL was reached after 7 days of 
dosing.  
Use of a loading dose (or ‘front-loading’) strategy is anticipated to reduce the exposure of 
pathogens to sub-therapeutic drug concentrations. Pharmacokinetic studies evaluating front-
loaded dosing regimens demonstrated that it was possible to rapidly achieve and sustain trough 
fusidic acid concentrations that are well in excess of the established breakpoint for S. aureus 
(EUCAST criteria, ≤ 1.0 µg/mL). It had been previously demonstrated that fusidic acid resistance 
emergence frequencies were low at high multiples of MIC (O’Neill 2006), and this observation 
was confirmed in hollow-fiber culture models, in which loading dose PK parameter fusidic acid 
exposure substantially reduced resistance emergence (Tsuji 2011).  
CEM-102 is likely metabolized by multiple CYP450 isoforms, primarily CYP3A4, and in vitro 
does not significantly induce CYP enzymes. CEM-102 inhibits CYP2C8 activity in a dose-
dependent manner, suggesting a potential for metabolism-based interactions for drugs that are 
metabolized by CYP2C8, such as glitazones. At high concentrations, CEM-102 is a moderate 
inhibitor of other CYPs.  
CEM-102 inhibits a number of efflux and uptake transport proteins in vitro. These data suggest 
that CEM-102 has the potential to interact with a variety of drugs through transporter inhibition 
and offer a mechanistic explanation for the adverse interaction between statins and fusidic acid 
that has been previously identified, and which appears to be mediated (at least in part) by 
OATP1B1 and OATP1B3 inhibition.  
Drug-drug interaction studies have not been completed with CEM-102. Based on Fucidin® 
(sodium fusidate or fusidic acid) product labeling (Fucidin®1 2013, Fucidin®2 2013, 
Fucidin® 2014), clinical Study CE06-200, and published reports, interactions may occur with the 
following: OATP1B1 and OATP1B3 substrates (in particular, statins); CYP3A4 biotransformed 
drugs (including target specific oral anticoagulants principally metabolized by CYP3A4 such as 
rivaroxaban and apixaban), cyclosporine; human immunodeficiency virus (HIV) protease 
inhibitors; statins; estrogens; and drugs that have a similar biliary excretion pathway); CYP3A4 
inducers (such as dexamethasone, phenytoin, carbamazepine, nafcillin, rifampin, phenobarbital); 
and CYP3A4 inhibitors (such as azole antifungals; erythromycin, clarithromycin; and grapefruit 
juice). 
5.3.2 
Summary of Efficacy 
5.3.2.1 
Phase 2 ABSSSI Study 
Study CE06-300 was a Phase 2 randomized, double-blind, multi-center efficacy and safety study 
to evaluate oral CEM-102 (a loading dose of 1500 mg BID on Day 1 followed by 600 mg BID) 
compared to oral linezolid 600 mg BID administered for 10 to 14 days in the treatment of patients 
with ABSSSI. Clinical success was defined as total resolution of local and systemic signs and 


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symptoms of the infection at the test of cure (TOC) visit such that no further antibiotic therapy was 
required. The primary efficacy endpoint was clinical success at the TOC for the Intent to Treat 
(ITT) and clinically evaluable (CE) populations.  
Males and female subjects ≥18 years of age with a diagnosis of an ABSSSI (cellulitis, with or 
without focal abscess, or wound infection) suspected or confirmed to be caused by a Gram-positive 
pathogen (staphylococci or streptococci), in whom 10 to 14 days of oral antibacterial therapy was 
appropriate, were evaluated for potential enrollment. Patients were randomized using a sequence 
that was stratified by type of infection (cellulitis or wound infection), and then randomized in a 
1:1:1 ratio to 1 of 3 treatment arms within each stratum: conventional regimen (CEM-102 600 mg 
BID), loading dose regimen (CEM-102 1500 mg BID on Day 1, followed by 600 mg BID), or 
linezolid 600 mg BID, each administered orally for 10 to 14 days. 
The study was initially designed as an adaptive trial that provided for transition to a Phase 3 non-
inferiority (NI) trial (n=700) with one of the two CEM-102 regimens compared to linezolid if 
certain predictive criteria were met. Interim analyses were performed after 90, 127, and 181 
patients were enrolled and evaluated for the primary outcome of clinical response at the TOC visit 
as well as for safety and tolerability. At the 127 patient interim analysis, the CEM-102 non-loading 
dose and loading dose regimens showed comparable safety and tolerability; hence, the CEM-102 
conventional dose regimen was dropped, and the remaining patients were randomized 1:1 to CEM-
102 loading dose or linezolid. At the 181 patient interim analysis, the predictive probability of 
clinical success in the clinically evaluable population in Phase 3 was 0.89, which exceeded the 
threshold for transitioning to the Phase 3 stage of the trial; therefore, when these results were 
available, enrollment in the Phase 2 stage of the trial was terminated (total n=198). 
Four patient populations were analyzed for efficacy: ITT (all randomized patients); 
microbiological ITT (MITT; all ITT patients with ≥1 Gram-positive pathogen isolated at baseline); 
clinically evaluable (CE; ITT patients who met all enrollment criteria, received a pre-defined 
minimum course of study drug, and had a clinical response of cure or failure at the TOC [7 to 14 
days after the End of Therapy (EOT)]); and microbiologically evaluable (ME; CE patients with a 
Gram-positive pathogen isolated at baseline).   
Clinical success was defined as total resolution of local and systemic signs and symptoms of the 
ABSSSI such that no further antibiotic therapy was required. The primary efficacy endpoint was 
clinical success at the TOC for the ITT and CE populations.  A total of 198 patients were 
randomized (ITT population) and all received ≥1 dose of study medication; 43 patients received 
CEM-102 conventional dose regimen prior to discontinuation of enrollment of that treatment 
group, 78 received CEM-102 loading dose regimen, and 77 received linezolid. Comparison is 
hence made between the two treatment groups carried forward to completion of the study, the 
CEM-102 loading dose and the linezolid treatment groups.   
These two treatment groups were comparable in demographics, baseline characteristics, and 
percentages of ITT population in the MITT, CE and ME populations. Comparable percentages of 
patients in each treatment group completed study drug therapy (CEM-102 loading dose 73 of 78 
[94%]; linezolid 76 of 77 [99%]). The mean duration of study drug exposure was similar in the 
two treatment groups (CEM-102 11.3 days and linezolid 11.5 days).  


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Clinical response rates at the TOC in the ITT and the CE populations are shown in Table 3, and 
for the MITT and ME populations in Table 4. Results were similar at the EOT for all populations. 
Table 3 
Clinical Response at the TOC (Intent-to-Treat and Clinically Evaluable 
Populations) 
 
CEM-102 
Conventional 
CEM-102 
Loading Dose 
Linezolid 
ITT Population 
N=43 
N=78 
N=77 
Success 
32/43 (74.4%) 
67/78 (85.9%) 
73/77 (94.8%) 
Failure 
4/43 (9.3%) 
5/78 (6.4%) 
1/77 (1.3%) 
Indeterminate 
7/43 (16.3%) 
6/78 (7.7%) 
3/77 (3.9%) 
Difference versus linezolid 
-0.204 
-0.089 
 
95% CI versus linezolid a 
-0.36, -0.05 
-0.19, 0.02 
 
CE Population 
N=34 
N=65 
N=68 
Success 
30/34 (88.2%) 
60/65 (92.3%) 
67/68 (98.5%) 
Failure 
4/34 (11.8%) 
5/65 (7.7%) 
1/68 (1.5%) 
Difference versus linezolid 
-0.103 
-0.062 
 
95% CI versus linezolid a 
-0.24, 0.03 
-0.15, 0.02 
 
Source:  CE06-300 CSR  
a. 95% CIs were based on normal approximation of the binomial distribution with continuity correction. 
 
Table 4 
Clinical Response at the TOC (Microbiological Intent-to-Treat and 
Microbiologically Evaluable Populations) 
 
CEM-102 
Conventional 
CEM-102 
Loading Dose 
Linezolid 
MITT Population 
N=33 
N=59 
N=58 
Success 
27/33 (81.8%) 
52/59 (88.1%) 
54/58 (93.1%) 
Failure 
3/33 (9.1%) 
2/59 (3.4%) 
1/58 (1.7%) 
Indeterminate 
3/33 (9.1%) 
5/59 (8.5%) 
3/58 (5.2%) 
Difference versus linezolid 
-0.113 
-0.050 
 
95% CI versus linezolid a 
-0.28, 0.06 
-0.17, 0.07 
 
ME Population 
N=28 
N=50 
N=49 
Success 
25/28 (89.3%) 
48/50 (96.0%) 
48/49 (98.0%) 
Failure 
3/28 (10.7%) 
2/50 (4.0%) 
1/49 (2.0%) 
Difference versus linezolid 
-0.087 
-0.020 
 
95% CI versus linezolid a 
-0.24, 0.06 
-0.11, 0.07 
 
Source:  CE06-300 CSR  
a. 95% CIs were based on normal approximation of the binomial distribution with continuity correction. 
S. aureus was the most frequently isolated baseline pathogen, documented in 72% of patients; 70% 
of these were MRSA. β-hemolytic streptococci were isolated at baseline in 7% of patients. Of 
patients with a documented MRSA ABSSSI at baseline, 91.2% of patients in the CEM-102 loading 
dose treatment group and 93.2% of patients in the linezolid treatment group demonstrated clinical 
success at the TOC. 


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The CEM-102 loading dose regimen demonstrated efficacy comparable to that of linezolid in the 
ITT, CE, MITT, and ME populations. 
5.3.2.2 
Phase 2 Prosthetic Joint Infection (PJI) Study 
Study CE06-200 was designed to evaluate the safety and efficacy of CEM-102 in combination 
with oral rifampin in comparison with standard of care (SoC) IV antibiotic treatment for patients 
with prosthetic joint or spacer infection managed by two-stage prosthesis exchange or debridement 
and retention (DAR). Among the 14 randomized patients, 12 completed study drug dosing on the 
initial randomized treatment.  
Among CEM-102/RIF treated subjects, 4 of 7 (57%) were considered treatment successes. Two 
of the 3 treatment failures were not due to a microbiological failure. However, the third patient had 
unequivocal microbiological failure. MRSA isolated at the time of explant (first-stage) surgery 
was rifampin susceptible, prior to study drug therapy. Rifampin-resistant MRSA was re-isolated 
at the second-stage surgery. Although treatment failure for MRSA PJI is well described even with 
standard of care therapy, we surmise that the reduced CEM-102 exposure in this patient set the 
stage for ‘functional monotherapy’ with rifampin, with emergence of resistance as might be 
expected in this circumstance. Thus, despite the literature describing successful therapy with the 
combination of fusidic acid and rifampin, we have concluded that the interaction has clinical and 
deleterious significance.   
Among IV SoC treated subjects, 4 of 7 patients overall (57%), and 4 of 5 in whom final outcomes 
were known (80%), were treatment successes. One patient had clinical failure due to a drug related 
AE (‘vancomycin fever’) that necessitated a change in therapy (to daptomycin). 
5.3.3 
Summary of Safety 
5.3.3.1 
Phase 1 PK Studies 
Three completed Phase 1 studies showed that CEM-102 was safe and generally well tolerated in 
healthy adult subjects when administered as single oral doses up to 2200 mg, or as repeated twice 
daily doses over 5.5 days of up to 1650 mg. CEM-102 was also safe and generally well tolerated 
in healthy adult subjects when administered as loading dose regimens of up to 1650 mg Q12h on 
Day 1 followed by up to 825 mg Q12h for 6.5 days. No clinically significant changes in physical 
examinations, vital signs, electrocardiograms (ECGs), or laboratory parameters were observed in 
any subject in these studies. Transient, low-level, non-clinically significant increases in bilirubin 
were noted in Phase 1 studies. These reversible increases were dose-related and are consistent with 
the known effects of sodium fusidate. 
The threshold for gastrointestinal intolerance for multiple doses (Q12h for 5.5 consecutive days) 
was reached between 1100 and 1650 mg. AEs appeared to be related to dose and duration of 
exposure, with gastrointestinal symptoms reported more frequently after 3 to 5 days of dosing and 
at higher doses.   


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5.3.3.2 
Phase 2 Studies 
In the Phase 2 ABSSSI Study (CE06-300), the percentage of subjects who experienced ≥1 TEAE 
during the study was 46.5% in the CEM-102 conventional regimen, 61.5% in the CEM-102 
loading dose regimen, and 63.6% in the linezolid treatment group. The majority of TEAEs were 
mild or moderate in intensity. Overall, the type, incidence, and severity of TEAEs were comparable 
among the 3 treatment groups. AEs experienced by ≥5.0% of patients in the CEM-102 
conventional regimen, CEM-102 loading dose regimen, or the linezolid treatment group, 
respectively, were nausea (14.0%, 21.8%, and 26.0%), vomiting (16.3%, 12.8%, and 9.1%), 
diarrhea (0%, 12.8%, and 13.0%), headache (0%, 5.1%, and 11.7%), dizziness (7.0%, 3.8%, and 
2.6%), and dyspepsia (0%, 7.7%, and 2.6%). 
The majority of treatment-related AEs were associated with gastrointestinal disorders. Three 
subjects in the CEM-102 loading dose regimen experienced ≥1 serious AE (SAE) during the study 
(preferred terms: herpes simplex; pyelonephritis; and head injury and back pain). The SAEs were 
considered by the Investigator to be unlikely related or unrelated to study drug.  
Four subjects (1 subject in the CEM-102 conventional regimen (preferred terms: lip swelling and 
rash) and 3 subjects in the CEM-102 loading dose regimen (preferred terms: nausea and chills; 
blister and rash maculopapular; nausea, vomiting, and anorexia)) experienced ≥1 TEAE that 
resulted in premature discontinuation of study drug; of these, 1 subject in the CEM-102 loading 
dose regimen was also prematurely discontinued from the study due to TEAEs (preferred terms: 
nausea, vomiting, and anorexia).  
Clinical laboratory tests and vital sign measurements did not demonstrate clinically significant 
changes during the study. Comparison of baseline and post-treatment ECGs did not demonstrate 
clinically relevant changes following treatment with CEM-102 or linezolid. In conclusion, the 
overall safety and tolerability of the CEM-102 loading dose regimen was comparable to that of 
linezolid. 
In the Phase 2 PJI Study (CE06-200), the most frequently reported treatment-related AEs were 
gastrointestinal events (nausea, emesis, vomiting, diarrhea, loose stools) and elevated laboratory 
parameters, such as total or direct bilirubin, alanine aminotransferase (ALT), alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), and creatine kinase (CK). Elevated gamma-glutamyl 
transpeptidase (GGT) levels were also observed in Patient 111-01, and was attributed to rifampin. 
There were reports of international normalized ratio (INR) or PT elevation, skin rash, worsening 
of anemia, pruritus, worsening renal function and eye floaters. 
There were no clinically significant changes in physical examinations or vital signs in the Phase 2 
studies. Serial ECGs done in these studies demonstrated no adverse cardiac effects with 
administration of CEM-102. 


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5.3.3.3 
Ex-US Post-Marketing Safety Experience: 
The fusidic acid labeling in countries where the drug is approved notes the organ systems most 
commonly associated with AEs, and the AEs in those systems, as: 
 Gastrointestinal: flatulence, vomiting, nausea, hepatic transaminase elevation, diarrhea, 
anorexia, abdominal pain, jaundice, dyspepsia. 
 Allergic: rash, pruritus, anaphylaxis, angioneurotic edema, urticaria, edema. 
 Hematologic: leukopenia, anemia, neutropenia, thrombocytopenia, pancytopenia, 
granulocytopenia, agranulocytosis. 
 Neurologic/psychiatric: headache, blurred vision, dizziness, lethargy, psychic disturbance. 
The labeling also includes precautions regarding concomitant drug administration and use in 
patients with impaired liver function to limit potential hepatic AEs. 
Published studies and AE reports from over 4 decades of clinical use outside the US indicate that 
oral sodium fusidate is safe and generally well tolerated when administered as 500 mg 2 or 3 times 
daily for 7 to 14 days. Higher doses (3000 to 4000 mg/day) for longer periods of time have also 
been used safely to treat patients with more serious or chronic infections. The most commonly 
reported AEs (gastrointestinal disturbances) were more frequent at higher doses and were 
decreased when sodium fusidate was administered with food. The most common AEs in those 
trials were gastrointestinal, and most often, not treatment limiting.   
Hyperbilirubinemia has been reported with use of sodium fusidate; however, the 
hyperbilirubinemia was reversible and reported to result from inhibition of hepatic transporter 
function rather than hepatocellular injury. Reports of serious hepatotoxicity associated with 
sodium fusidate are rare and have primarily been reported with use of the IV formulation. 
5.4 
Rationale for the Use of CEM-102 in Staphylococcal Bone or Joint 
Infection 
The rationale for developing CEM-102 in this indication is as follows: 
 CEM-102 has a unique mechanism of action and shows little cross-resistance with any 
other known class of antibiotic. Sodium fusidate has been used for over 4 decades in many 
countries for the treatment of staphylococcal infections and has been shown to be safe and 
effective in the treatment of bone / joint infection, including prosthetic joint infection. 
 Currently, the majority of bone or joint infections occurring in the US are caused by Gram-
positive pathogens. S. aureus, including both MSSA and MRSA, is the most common 
pathogen identified. CoNS, including Staphylococcus epidermidis, are identified nearly as 
often. Other Gram-positive pathogens, including enterococci, viridans streptococci, 
propionibacteria, occasionally cause infection. In the US, the majority of these pathogens 
are susceptible to CEM-102. 
 CEM-102 displayed excellent microbiological activity against S. aureus isolates collected 
in the US from 2008 to 2014, including MRSA (MIC90 0.12 µg/mL). Of 1798 isolates of 
CoNS tested, only 133 (7.4%) were resistant to CEM-102. The MIC range of CEM-102 


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against more than 836 isolates of Group A streptococci was mostly 4 to 8 µg/mL, 
concentrations substantially lower than achievable CEM-102 plasma concentrations. 
 CEM-102 was safe and generally well tolerated when administered to healthy subjects in 
single doses of up to 2200 mg and in multiple daily doses of up to 1650 mg BID for 5.5 
days. Nausea was the most common AE, occurring most frequently after 3 to 5 days of 
dosing with 1650 mg BID. No safety concerns were identified for any single or multiple 
dosing regimens. 
 CEM-102 was safe and well tolerated in loading dose regimens of 1100/550 mg BID and 
1650/825 mg BID for a total of 7.5 days. Loading dose regimens appeared to be better 
tolerated than conventional dosing regimens for similar levels of overall plasma exposure. 
Both loading dose regimens produced trough plasma concentrations that approached 
steady-state levels at 24 hours after the first dose, suggesting that an optimal PK profile for 
treatment of target pathogens can be provided with this dosing approach. As with in vitro 
studies, fully effective antimicrobial exposures achieved earlier in treatment in a clinical 
context are expected to substantially reduce the likelihood emergence of resistance to 
CEM-102. 
5.5 
Rationale for the Dosing Regimen 
Fusidic acid has been used for several decades outside the U.S., for the treatment of Gram-positive 
pathogen skin and skin structure infections, administered in oral and intravenous formulations, 
most often dosed three times daily. In this context, the occasional emergence of fusidic acid 
resistance during therapy has been observed and the overall prevalence of staphylococci with 
fusidic acid resistance has risen gradually. The latter process has been hastened by the widespread 
use of topical fusidic acid formulations for superficial skin infections. Fusidic acid has also been 
used globally for treatment of prosthetic joint infections (PJI), most often in combination with 
rifampin, due to rifampin’s activity in biofilm associated infections.  
Cempra recognized that the use of a fusidic acid (CEM-102) loading dose (or ‘front-loading’) 
strategy would substantially reduce the exposure of pathogens to sub-therapeutic drug 
concentrations. Pharmacokinetic studies evaluating front-loaded dosing regimens demonstrated 
that it was possible to rapidly achieve and sustain trough fusidic acid concentrations that were well 
in excess of the established breakpoint for S. aureus (EUCAST criteria, ≤ 1.0 µg/mL) (Still 2011). 
It had been previously demonstrated that fusidic acid resistance emergence frequencies were low 
at high multiple of MIC (O’Neill, 2006), and this observation was confirmed in hollow-fiber 
culture models, in which loading dose PK parameter fusidic acid exposure substantially reduced 
resistance emergence (Tsuji 2011).  In a phase 2/3 ABSSSI trial that compared oral fusidic acid 
with a loading dose to oral linezolid, the success rate for S. aureus infections was 96%, comparable 
to that of linezolid (Section 5.3.2).   
Recognizing fusidic acid’s utility in the treatment of bone and joint infections, Cempra conducted 
a randomized phase 2 trial of oral fusidic acid with a loading dose in combination with rifampin 
versus standard of care intravenous antibiotics for treatment of prosthetic bone and joint infections. 
PK data was collected from enrolled subjects, and it was determined that a significant fusidic acid-
rifampin drug interaction occurs, resulting in markedly reduced fusidic acid exposure. In this 
context, emergence of rifampin-resistance (but not fusidic acid resistance) in a previously 


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susceptible MRSA strain was observed and linked as a contributing factor to a case of treatment 
failure, and the study was terminated.   
In this study, front-loaded fusidic acid (1500 mg every 12 hours for 2 doses, followed by 600 mg 
every 12 hours thereafter) will be used in combination, for the first 1-2 weeks, with a companion 
antibiotic (not rifampin). Use of the dual strategies of rapidly reducing bacterial pathogen burden 
(with companion antibiotic therapy), and assuring that steady state trough fusidic acid 
concentrations are rapidly achieved (within 24 hours) using a loading dose, is expected to set a 
high barrier to the emergence of bacterial fusidic acid resistance.  In addition, fusidic acid has been 
demonstrated to be effective against biofilm in an in vitro model with S. aureus both as a single 
agent and in combination with daptomycin, vancomycin or linezolid (Siala 2015). This observation 
is supported by the long history of successful use of fusidic acid monotherapy for the treatment of 
bone and joint infections (Adkins 1999). 


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6 
STUDY OBJECTIVE 
To evaluate the safety and effectiveness of CEM-102 as chronic antibiotic suppressive therapy in 
subjects with staphylococcal bone or joint infections. 
6.1 
Primary Endpoint 
The primary endpoint will be the proportion of subjects in the ITT analysis set who meet all the 
criteria for clinical success at the 6-Month Visit, as described in Section 14.1. 
6.2 
Secondary Endpoints 
The secondary endpoints are the proportion of subjects in the ITT analysis set who meet all criteria 
for clinical success at the 9-Month, 12-Month, 15-Month, 18-Month, 21-Month, and 24-Month 
Visits; the safety and tolerability of CEM-102 in the Safety Analysis Set, as described in 
Section 14.2, and the pharmacokinetics of CEM-102 used chronically in subjects with orthopedic 
infections. 
6.3 
Pharmacokinetic Endpoints 
 Peak measured plasma concentration (Cmax) 
 Area under the concentration versus time curve (AUC0-t, AUC0-tau) 
 Time to peak concentration (tmax) 
 Apparent terminal elimination half-life (t½) 
 Apparent first-order terminal elimination rate constant (Kel) 
 Apparent Volume of distribution (Vd/F) 
 Apparent Clearance (CL/F)  


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7 
OVERALL STUDY DESIGN  
This is a prospective, open-label, non-randomized, single-arm trial to evaluate the safety and 
effectiveness of CEM-102 for chronic antibiotic suppressive therapy of bone or joint infections. 
Subjects enrolling in this study must have a staphylococcal bone or joint infection that requires 
suppressive antibiotic therapy. Reasons a subject may be suitable for chronic oral antibiotic 
suppressive therapy include, but are not limited to, the following: 1) having an infection that cannot 
be managed by complete removal of the infected bone or foreign material, 2) having a refractory 
infection not responding to previous treatment, 3) not being a candidate for long-term intravenous 
antibiotic therapy. 
Subjects must have a bone or joint infection due to an inclusionary pathogen susceptible to CEM-
102, demonstrated from a positive culture from samples obtained during surgery, biopsy, or 
drainage procedures within 6 weeks prior to enrollment.  
Acceptable inclusionary pathogens in this study include the following CEM-102-susceptible 
organisms: methicillin-susceptible S. aureus (MSSA), methicillin-resistant Staphylococcus aureus 
(MRSA), and CoNS, such as S. epidermidis, S. hominis, or S. haemolyticus. Specifically excluded 
from this list of pathogens is S. saprophyticus. Prior to enrollment, sensitivity of the isolate(s) to 
CEM-102 must be demonstrated. 
Co-infection with Corynebacterium spp., Propionibacterium acnes, beta-hemolytic streptococci, 
enterococci, or other Gram-positive bacteria susceptible to CEM-102 is permitted.  
Co-infection with bacteria known or expected not to be susceptible to CEM-102 (e.g. Gram-
negatives or anaerobes) is permitted, provided these bacteria can be treated with an adjunctive 
antibiotic to which the inclusionary staphylococcus is not susceptible, and there are no known 
drug-drug interactions with CEM-102. 
CEM-102 must be initiated with one or more additional antibiotics (either oral or IV), referred to 
as companion antibiotics, for the first 1-2 weeks of the study. Companion antibiotic(s) will be 
selected per the Investigator’s discretion on the basis of subject-specific antibiotic tolerability and 
pathogen susceptibilities. Because concomitant administration of rifampin results in markedly 
reduced levels of CEM-102 blood levels, rifampin must not be used as a concomitant antibiotic 
with CEM-102. After 1-2 weeks of therapy, the companion antibiotic must be discontinued.  To 
be eligible for enrollment, the subject must be a suitable candidate for CEM-102 monotherapy 
after completion of 1-2 weeks of the companion antibiotic, for chronic treatment of the orthopedic 
infection due to the inclusionary pathogen.  
This study comprises two parts: Part A (enrollment through the 6-month visit) and Part B (6 to 24 
months post-enrollment). In Part A, all subjects will receive 6 months of CEM-102 treatment. The 
Investigator will evaluate each subject completing Part A for clinical response at the 6-month visit 
(primary endpoint). For Part B, a subject who completes Part A and, in the Investigator’s opinion, 
requires continued suppressive therapy, may continue to receive CEM-102. Alternatively, if the 
Investigator considers the infection resolved and that no further antibiotic therapy is required, 
study drug will be discontinued and the subject followed for evidence of relapse until the end of 
study (EOS). 


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During the first 6 months of treatment, study Part A, subjects will be monitored monthly (±1week) 
for safety and clinical response to CEM-102. During study Part B, subjects will be monitored every 
3 months (±2 weeks) until the End of Study Visit (24 months). 
A subject who discontinues study drug because of treatment failure will have an EOS visit at that 
time. A subject who discontinues study drug due to an AE will be followed until the AE is resolved 
or stabilized. A subject who discontinues study drug due to clinical success will be followed for 
relapse until EOS. 
If a subject withdraws from the study at any time, for any reason, an EOS visit will be performed 
at that time.   
7.1 
Duration of Subject Participation 
This study is designed to evaluate a minimum of 6 months of oral CEM-102 therapy but may 
extend for up to 24 months. 
This study comprises two parts: Part A (enrollment through the 6-month visit) and Part B (6 to 24 
months post-enrollment). In Part A, all subjects will receive 6 months of CEM-102 treatment. The 
Investigator will evaluate each subject completing Part A for clinical response at the 6-month visit 
(primary endpoint). For Part B, a subject who completes Part A and, in the Investigator’s opinion, 
requires continued suppressive therapy, may continue to receive CEM-102 for up to 24 months. 
Alternatively, if the Investigator considers the infection resolved and that no further antibiotic 
therapy is required, study drug will be discontinued and the subject will be followed for evidence 
of relapse until EOS.  If the subject requires chronic suppressive therapy with CEM-102 beyond 
24 months, the Investigator may choose to roll the subject into an expanded access protocol. 
7.2 
Number of Subjects 
Thirty subjects will be enrolled at up to 20 investigative sites in the United States. 
7.3 
Duration of Study 
The study duration from first subject, first visit until last subject, last visit will be determined based 
upon enrollment rates and will be will be approximately 3 years. 
7.4 
Study Drug Dosage and Administration  
Subjects will receive a loading dose of 1500 mg by mouth every 12 hours for 2 doses, followed by 
600 mg every 12 hours thereafter.   
Study drug must be taken within a +/- 2 hour window of the scheduled dose.  On days when PK 
samples are obtained, study drug must be taken within +/- 1 hour of the scheduled dose. 
After the first two loading doses are taken 12 hours apart, the dosing schedule may be adjusted 
once to allow for a more convenient dosing schedule (e.g., if a dose is to be taken between 11pm 
and 3am, then the dosage time may be rounded down to 11pm; or if the a dose is to be taken 


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between 3am and 7am, then the dosage time may be rounded up to 7am).  Subsequent dosing must 
continue on an every 12 hour dosing schedule. 
CEM-102 may be taken with or without food. 
7.5 
Dose Modification 
Dosage modifications are not required. The pharmacokinetics of CEM-102 in subjects with renal 
and hepatic insufficiency have not been studied.  Subjects with severe renal impairment (CrCl <30 
mL/min) or significant liver disease (ALT >3x ULN or direct bilirubin >ULN) are excluded at 
enrollment. 
At the discretion of the Investigator, study drug may be withheld for several days due to intolerance 
or an AE, such as a laboratory abnormality.  After appropriate follow-up, if clinically indicated, 
study drug may be restarted.  If study drug needs to be permanently discontinued due to 
intolerance/AE, and additional antibiotics are required to treat the chronic orthopedic infection due 
to the inclusionary pathogen, this will be classified as a clinical failure.   


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8 
SELECTION OF STUDY POPULATION 
The following criteria for enrollment must be followed explicitly. A 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 informed consent form (ICF) was signed and dated 
prior to study screening. The date on which 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. 
Male or female subject ≥ 18 years of age, and adolescents between the ages of 12 and 18 
years who weigh greater than 60 kg. 
2. 
Subject must have a bone or joint infection due to an inclusionary pathogen demonstrated 
from a culture from samples obtained during surgery, biopsy, or drainage procedures within 
6 weeks prior to enrollment.  
 Note: If a subject does not have a confirmatory culture result, the Investigator must provide 
documentation as to why subject is suspected to have a staphylococcal infection and must 
discuss the subject with the medical monitor for approval of enrollment. 
3. 
Inclusionary pathogen(s) include the following staphylococcal bacteria: 
 S. aureus: MSSA or MRSA 
 CoNS such as S. epidermidis, S. hominis, or S. haemolyticus (S. saprophyticus is not an 
inclusionary pathogen) 
Note: Co-infection with Corynebacterium spp., Propionibacterium acnes, beta-hemolytic 
streptococci, enterococci, or other bacteria susceptible to CEM-102 is permitted. Co-
infection with bacteria known or expected not to be susceptible to CEM-102 (e.g. Gram-
negatives or anaerobes) is permitted, provided these bacteria can be treated with an 
adjunctive antibiotic to which the staphylococcus is not susceptible, and there are no known 
drug-drug interactions with CEM-102. 
4. 
Inclusionary pathogen, if identified, must be susceptible to CEM-102.  
5. 
If the subject has a prosthetic joint, the implant is secured and fixed. 
6. 
After completion of 1-2 weeks of the companion antibiotic, the subject must be a suitable 
candidate for CEM-102 monotherapy for chronic treatment of the orthopedic infection due 
to the inclusionary pathogen.  
7. 
Subject is not a candidate, as determined by the Investigator, for suitable alternative therapy. 
Reasons include, but are not limited to, the following: 
 Cannot undergo definitive curative surgical treatment (removal of all infected bone, joint, 
or foreign material) due to poor health status, age, or comorbidities 
 Not a candidate for long-term IV antibiotic therapy 


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8. 
The subject must be a suitable candidate for oral antibiotic therapy (i.e. able to swallow study 
medication tablets/capsules intact and have no known deficiency in gastrointestinal 
absorption). 
9. 
The subject (or subject’s legal guardian) must express commitment to comply with all study 
visits, procedures, and requirements for the duration of the study. 
10. The subject, or the subject’s legal guardian, has voluntarily signed the Independent Ethics 
Committee or Institutional Review Board approved informed consent form (ICF). In cases 
of mental incapacity, the legal guardian is permitted to sign the ICF. 
11. Female subjects of childbearing potential must use an acceptable contraception method 
(abstinence or double barrier methods) for the duration of the study-drug treatment phase of 
the study and 30 days thereafter, and must have a negative serum or urine pregnancy test at 
Screening. 
8.2 
Exclusion Criteria 
Subjects may be screened on the basis of suspected or confirmed infection but will not be eligible 
for enrollment if any of the following exclusion criteria are met: 
1. 
Medical history of hypersensitivity or allergic reaction to sodium fusidate, fusidic acid 
(Fucidin® or any systemic or topical product containing fusidic acid) or its excipients. 
2. 
Endovascular, infected intravascular foreign material, or infective endocarditis; or central 
nervous system infection, including meningitis. 
3. 
Female subject who is pregnant or lactating. 
4. 
Known severe renal impairment, as indicated by estimated creatinine clearance (CrCl) <30 
mL/min (by Cockcroft-Gault calculation). 
5. 
Immunocompromised subject or requirement for immunosuppressive therapy; Prior use of 
immunosuppressant agents (i.e. cyclosporine, TNFα antagonist) within 30 days of study 
medication administration. 
6. 
Malignancy requiring ongoing cytotoxic chemotherapy. 
7. 
Neutropenia (absolute neutrophil count <500/µL); Thrombocytopenia (platelet count 
<60,000/µL). 
8. 
Known human immunodeficiency virus (HIV) infection and currently receiving 
antiretroviral therapy; Current CD4 count ≤ 200 cells/mm3 (documented within 3 month 
prior to enrollment); If CD4 count is unknown, subject may not enroll. 
9. 
Significant liver dysfunction, defined as follows: alanine aminotransferase (ALT) >3x upper 
limit of normal (ULN) or direct bilirubin >ULN; Known cirrhosis with decompensation (i.e. 
Child-Pugh Class B or C disease). 
10. Known hepatitis C virus (HCV) infection and currently receiving HCV-specific antiviral 
therapy. HCV infection alone, in the absence of decompensated liver disease, is not 
exclusionary. 
11. Seizure disorder requiring current therapy with anticonvulsant. 


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12. Any underlying condition (e.g. addiction or clinically significant disease), that in the opinion 
of the Investigator, would be likely to interfere with assessment of the infection or completion 
of the study. 
13. The use of an investigational drug within 4 weeks prior to Screening. 
14. Requires concomitant treatment with the following:: 
 OATP1B1 and OATP1B3 substrates, such as statins (HMG-CoA reductase inhibitors) 
 Metabolized by CYP2C8, such as glitazones (such as repaglinide) 
 CYP3A4 inducers (such as dexamethasone, phenytoin, carbamazepine, rifampin, 
phenobarbital, and nafcillin)  
15. Prior treatment with a CYP3A4 inducer, such as dexamethasone, phenytoin, carbamazepine, 
rifampin, phenobarbital, or nafcillin, within 7 days prior to enrollment. 
16. Subjects requiring digoxin or warfarin therapy may only be enrolled if an achievable plan 
for therapeutic monitoring of the drug (digoxin) or prothrombin time has been reviewed and 
approved by the study medical monitor. 
8.3 
Recording of Prior Antibiotics and Concomitant Treatment 
Reasonable efforts will be made to record in the electronic case report form (eCRF) the 6-month 
history of prior antibiotics used to treat the primary infection leading to enrollment.  The 
medication name, route of administration, dose, frequency, indication, and duration of the 
treatment/procedure (start and stop dates) will be recorded.  Furthermore, reasonable efforts will 
be made to determine all relevant treatment (concomitant medications, including all 
prescription/non-prescription medications, herbal medications, vitamin supplements, supportive 
therapies, and concomitant non-pharmacological treatments) received by the subject within 7 days 
before administration of study drug and will be recorded in the eCRF. The medication name, route 
of administration, dose, frequency, indication, and duration of the treatment/procedure (start and 
stop dates) will be recorded. Concomitant treatments (non-pharmacological treatments) include 
any surgical or diagnostic procedures. 
8.4 
Permitted Medications and Treatment 
Medications to treat any AE the subject experiences during the study are permitted. Routine wound 
care, including debridement of devitalized tissue, is permitted. Definitive surgical procedures to 
treat worsening of the primary infection, such as amputation or removal of infected prosthetic 
material, will be classified as clinical failure.   
8.5 
Companion Antibiotics to Treat the Primary Infection 
CEM-102 must be initiated with one or more additional antibiotics (either oral or IV) for the first 
1-2 weeks of the study. Companion antibiotic(s) will be selected per the Investigator’s discretion 
on the basis of subject-specific antibiotic tolerability and pathogen susceptibilities. Examples 
include, but are not limited to, IV cefazolin, vancomycin, daptomycin, and IV/PO linezolid. 
Rifampin must not be used as a companion antibiotic with CEM-102. After 1-2 weeks of 
companion antibiotic therapy, the companion antibiotic must be discontinued.  


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Starting an antibiotic due to signs and symptoms of clinical failure (e.g. worsening redness, 
swelling, pain, purulent discharge, sinus tract formation, or bacteremia) will be classified as 
clinical failure.  
8.6 
Adjunctive Antibiotic Therapy for Co-infections 
Treatment of co-infection(s) due to bacteria known or expected to not be susceptible to fusidic 
acid is permitted, provided these pathogens can be treated with an adjunctive antibiotic to which 
the inclusionary pathogen is not susceptible (e.g. aztreonam and metronidazole are permitted for 
treatment of Gram-negative and anaerobic co-infections).   
8.7 
Concomitant Antibiotic Therapy for Unrelated Infections 
Treatment of an unrelated infection with an antibiotic to which the inclusionary pathogen is 
susceptible is permitted only if the antibiotic is administered for ≤ 10 days on any single occasion, 
and ≤ 2 courses during any 6-month period during the study (and provided there are no known 
drug-drug interactions with CEM-102).  
Use of a concomitant antibiotic to which the inclusionary pathogen is susceptible for > 10 days on 
any occasion, or for > 2 courses during any 6-month period, will be classified as clinical failure. 
8.8 
Prohibited Medications    
Co-administration of CEM-102 with HMG-CoA reductase inhibitors (statins), as well as rifampin, 
is prohibited. Potential clinical drug-drug interactions with oral sodium fusidate are described in 
Section 7.4.1 of the CEM-102 Investigator’s Brochure and in the Fucidin® product labeling or 
published reports.  


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9 
STUDY DRUG 
This is an open-label study that requires no blinding of CEM-102. Companion antibiotic therapy 
will not be provided by the Sponsor. 
9.1 
CEM-102 Tablets 
CEM-102 300 mg tablets contain 300 mg of fusidate sodium as the active pharmaceutical 
ingredient and commonly used excipients.  
9.2 
Study Drug Labeling and Packaging 
CEM-102 300 mg tablets will be provided by CEM-102 Pharmaceuticals and will be labeled and 
supplied according to applicable regulatory requirements.   CEM-102 300 mg dual-coated tablets 
will be supplied in 120 cc PET bottles of 130 tablets in an open-label fashion. 
9.3 
Study Drug Storage Conditions 
The Investigator or an approved representative (e.g., pharmacist) will ensure that all study drugs 
are stored in a locked secured area (with limited access available to appropriate study personnel), 
only under recommended storage conditions and in accordance with applicable regulatory 
requirements. Standard of care medications will be stored in accordance with their label, as 
directed by the Investigator and/or associated care team members.  
The Investigator or approved designee (e.g. Pharmacist), will be responsible for recording daily, 
the temperature of all study drugs on the log provided or an approved existing log. Additionally, 
it is the responsibility of the Investigator to ensure that all temperature deviations and excursions 
from those noted in the protocol are reported to the Sponsor QA group who will assess the approval 
for continued use of the products. 
CEM-102 will be stored at controlled room temperature 59°F to 77°F (15°C - 25°C) and protected 
from light. Keep bottles tightly closed to protect from moisture. 
In the event of an excursion, please send an email to Anita Healey at ahealey@cempra.com 
explaining the excursion and attach temperature logs for the duration of the excursion(s).  
9.4 
Receipt of Supplies 
Upon receipt of the investigational 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 Investigational Drug Transmittal and Receipt Form will be completed and signed by 
the pharmacist.  


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9.5 
Study Drug Accountability 
9.5.1 
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.  
9.5.2 
 Instructions for Subject 
The site personnel will review the dosing instructions with the subject on the first oral dosing day 
and each subsequent study visit.  The subject will bring the bottles to each study visit through end 
of study drug treatment, when the bottle will be collected by site personnel.  The subject must 
return any study drug not taken to site personnel. 
9.5.3 
Study Drug Handling and Return  
Upon the completion or termination of the study, and upon written authorization from Sponsor or 
its representative, all unused and/or partially used study drug should be returned or destroyed at 
the investigational site, as specified by Sponsor. It is the Investigator’s responsibility to ensure that 
Sponsor or its representative has provided written authorization that procedures for proper disposal 
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 until fully accounted for by 
the Sponsor monitor (or designee). 


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10 
STUDY ASSESSENTS AND PROCEDURES 
The schedule of assessments and procedures is summarized in Table 1. Subjects will provide 
written informed consent before any study-related procedures are performed. 
10.1 
Screening  
Screening procedures may be initiated after signing of the IRB-approved ICF. The following 
information will be collected, and the following evaluations/procedures will be performed: 
1. 
Review all Inclusion/Exclusion criteria. 
2. 
Record demographics (date of birth, sex, race, and ethnicity) and significant clinical/surgical 
history.  
3. 
Obtain microbiological specimens for culture (or document a culture positive for 
inclusionary pathogen obtained within 6 weeks prior to enrollment).  
 Subjects must have a positive culture with an inclusionary pathogen susceptible to CEM-
102, demonstrated from a culture from samples obtained during surgery, biopsy, or 
drainage procedures within 6 weeks prior to enrollment.  If subject does not have a 
confirmatory culture result, the Investigator must provide documentation as to why the 
subject is suspected to have a staphylococcal infection. 
4. 
Measure vital signs (height, weight, blood pressure, heart rate, respiratory rate, and 
temperature [highest recorded temperature in the previous 24 hours]). 
5. 
Perform limited physical examination. 
6. 
Examine the infected area, including assessing pain, redness, mobility, joint stability, wound 
closure, wound drainage, and weight bearing (for back and lower extremity infections). If 
clinically relevant, measure length (L) and width (W) of the wound, using longest length in 
the head to toe orientation and widest perpendicular [90° angle] width. 
7. 
Collect blood samples for clinical safety laboratory determinations and lab measurements of 
markers of inflammation. 
8. 
For female subjects of childbearing potential, collect urine or blood for pregnancy test (either 
test is acceptable). 
9. 
Calculate the subject’s estimated CrCl using the serum creatinine value (in conventional 
units) and the Cockcroft-Gault formula below (actual body weight should be used in this 
formula):  


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Males: CrCl = (140-age in years) × weight (kg)
72 × serum creatinine (mg/dL)  
Females: CrCl = (140-age in years) × weight (kg) × 0.85
72 × serum creatinine (mg/dL)
 
If the serum creatinine value is reported in Systeme International d’Unites (SI) 
(i.e. µmol/L), convert to conventional units (mg/mL) using the following formula: 
Conventional units (mg/mL) = SI units (μmol/L)
88.4
 
10. Record 6-month history of all antibiotics administered to the subject to treatment current 
infection leading to enrollment. 
11. Record concomitant medications including all prescription/non-prescription medications, 
herbal medications, vitamin supplements, supportive therapies, and concomitant non-
pharmacological treatments received by the subject within 7 days of the Screening visit. 
12. Review of available radiographic data (imaging is not specifically requested in the protocol, 
but is expected to be performed in accordance with standard of care procedure). Results 
should be recorded in the eCRF. 
13. Review and record all AEs and SAEs 
10.2 
Treatment Period 
10.2.1 
Enrollment (Study Day 1) 
Enrollment can proceed after the subject meets all eligibility requirements.  Study Day 1 
corresponds to the first day of dosing with CEM-102. The following are performed on Study Day 
1: 
1. 
Review clinical/surgical history. 
2. 
If clinically indicated, obtain microbiological specimens for culture. 
3. 
Measure vital signs (height, weight, blood pressure, heart rate, respiratory rate, and 
temperature [highest documented temperature in the previous 24 hours]). 
4. 
Perform a limited physical examination. 
5. 
Examination the infected area and assess pain, redness, mobility, joint stability, wound 
closure, wound drainage, and weight bearing (for back and lower extremity infections). If 
clinically relevant, measure length (L) and width (W) of the wound, using longest length in 
the head to toe orientation and widest perpendicular [90° angle] width. The Investigator will 
assess whether the infected area seems to have improved, deteriorated, or remained 
unchanged from previous assessment. 
6. 
Collect blood samples for clinical safety laboratory determinations and lab measurements of 
markers of inflammation. 


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7. 
Administer a loading dose of CEM-102 (1500 mg) and instruct the subject when to take 
second loading dose 12 hours later. 
8. 
Dispense CEM-102 tablets to the subject. 
9. 
Review and record all AEs and SAEs. 
10. Record concomitant medications, including all prescription/non-prescription medications, 
herbal medications, vitamin supplements, supportive therapies, and concomitant non-
pharmacological treatments received by the subject. 
10.2.2 
Day 8 (±3 days) 
The following are performed on Study Day 8: 
1. 
Review clinical/surgical history. 
2. 
If clinically indicated, obtain microbiological specimens for culture. 
3. 
Measure vital signs (height, weight, blood pressure, heart rate, respiratory rate, and 
temperature [highest documented temperature in the previous 24 hours]). 
4. 
Perform limited physical examination. 
5. 
Examine the infected area and assess pain, redness, mobility, joint stability, wound closure, 
wound drainage, and weight bearing (for back and lower extremity infections). If clinically 
relevant, measure length (L) and width (W) of the wound, using longest length in the head 
to toe orientation and widest perpendicular [90° angle] width. The Investigator will assess 
whether the infected area seems to have improved, deteriorated, or remained unchanged. 
6. 
Collect blood samples for clinical safety laboratory determinations. 
7. 
Review and record all AEs and SAEs. 
8. 
Dispense CEM-102 tablets to the subject. 
9. 
Perform drug accountability assessment. 
10. Record concomitant medications, including all prescription/non-prescription medications, 
herbal medications, vitamin supplements, supportive therapies, and concomitant non-
pharmacological treatments received by the subject. 
10.2.3 
Monthly During First 6 Months (±1 Week) 
The following are performed monthly during the first 6 months: 
1. 
Review clinical/surgical history. 
2. 
If clinically indicated, obtain microbiological specimens for culture. 
3. 
Measure vital signs (height, weight, blood pressure, heart rate, respiratory rate, and 
temperature [highest documented temperature in the previous 24 hours]). 
4. 
Perform limited physical examination. 
5. 
Examine the infected area and assess pain, redness, mobility, joint stability, wound closure, 
wound drainage, and weight bearing (for back and lower extremity infections). If clinically 


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relevant, measure length (L) and width (W) of the wound, using longest length in the head 
to toe orientation and widest perpendicular [90° angle] width. The Investigator will assess 
whether the infected area seems to have improved, deteriorated, or remained unchanged. 
6. 
Collect blood samples for clinical safety laboratory determinations and lab measurements of 
markers of inflammation. 
7. 
Dispense CEM-102 tablets to the subject and perform a drug accountability assessment. 
8. 
Review and record all AEs and SAEs. 
9. 
Record concomitant medications including all prescription/non-prescription medications, 
herbal medications, vitamin supplements, supportive therapies, and concomitant non-
pharmacological treatments received by the subject. 
10. At 3-month visit, obtain blood for PK sampling, described in Section 10.6. If PK sampling 
cannot be done at 3-month visit, it may be completed at either the prior or subsequent 
monthly visit if needed. 
11. At 6-month visit, perform an Investigator assessment of clinical response 
10.2.4 
Every 3 Months (+/- 2 weeks) from Month 6 until End of Study (24 
Months)  
Subjects who continue on chronic suppressive antibiotic therapy with CEM-102 will be followed 
quarterly for response to therapy until EOS. If the infection is deemed to have resolved and  
antibiotic therapy is no longer required, the subject will be followed quarterly for clinical relapse 
until EOS. The following are performed every 3 months until EOS: 
1. 
Review clinical/surgical history. 
2. 
If clinically indicated, obtain microbiological specimens for culture. 
3. 
Measure vital signs (height, weight, blood pressure, heart rate, respiratory rate, and 
temperature [highest documented temperature in the previous 24 hours]). 
4. 
Perform a limited physical examination. 
5. 
Examine the infected area and assess pain, redness, mobility, joint stability, wound closure, 
wound drainage, and weight bearing (for back and lower extremity infections). If clinically 
relevant, measure length (L) and width (W) of the wound, using longest length in the head 
to toe orientation and widest perpendicular [90° angle] width. The Investigator will assess 
whether the infected area seems to have improved, deteriorated, or remained unchanged. 
6. 
Collect blood samples for clinical safety laboratory determinations and lab measurements of 
markers of inflammation.  
7. 
Dispense CEM-102 tablets to the subject and perform a drug accountability assessment (in 
subjects receiving chronic suppressive antibiotic therapy with CEM-102). 
8. 
Review and record all AEs and SAEs. 
9. 
Record concomitant medications including all prescription/non-prescription medications, 
herbal medications, vitamin supplements, supportive therapies, and concomitant non-
pharmacological treatments received by the subject.  


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10. Perform an Investigator assessment of clinical response. 
10.3 
End of Study (EOS) 
A subject who discontinues study drug because of treatment failure will have an EOS visit at that 
time. A subject who discontinues study drug due to clinical cure will be followed for relapse until 
EOS. If a subject withdraws from the study, an EOS visit will be performed at that time. 
1. Review clinical/surgical history. 
2. 
Obtain microbiological specimens for culture.  
3. 
Measure vital signs (height, weight, blood pressure, heart rate, respiratory rate and 
temperature [highest documented temperature in the previous 24 hours]). 
4. 
Perform a limited physical examination. 
5. 
Examine the infected area and assess pain, redness, mobility, joint stability, wound closure, 
wound drainage, and weight bearing (for back and lower extremity infections). If clinically 
relevant, measure length (L) and width (W) of the wound, using longest length in the head 
to toe orientation and widest perpendicular [90° angle] width. 
6. 
Collect blood samples for clinical safety laboratory determinations and lab measurements of 
markers of inflammation. 
7. 
Perform drug accountability assessment. 
8. 
Review and record all AEs and SAEs. 
9. 
Record concomitant medications including all prescription/non-prescription medications, 
herbal medications, vitamin supplements, supportive therapies, and concomitant 
non-pharmacological treatments received by the subject. 
10. Perform an Investigator assessment of clinical response. 
11. If the subject requires additional long-term chronic suppressive therapy with CEM-102 
beyond study closure, the subject may be enrolled into an expanded access protocol to 
continue therapy. 
10.4 
Local Laboratory Assessments 
The clinical safety laboratory tests outlined below will be performed locally according to the 
schedule of assessments (Table 1): 
 Serum Chemistry: creatinine, BUN (urea), aspartate aminotransferase (AST), ALT, 
alkaline phosphatase (ALP), total and direct bilirubin,  albumin, total protein, sodium, total 
carbon dioxide, glucose, potassium, chloride, calcium, phosphorus, and creatinine 
phosphokinase (CPK). 
 Markers of inflammation: complete blood count (CBC) with differential, erythrocyte 
sedimentation rate (ESR), and C-reactive protein (CRP).   
 Serum or urine pregnancy test for female subjects of childbearing potential. 


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10.5 
Microbiology Assessments 
All enrolled subjects must have a positive culture with an inclusionary pathogen, demonstrated 
from a culture from samples obtained during surgery, biopsy, or drainage procedures, within 6 
weeks prior to enrollment.  If a subject does not have a confirmatory culture result, the Investigator 
must provide documentation as to why the subject is suspected to have a staphylococcal infection 
and must discuss the subject with the medical monitor for approval of enrollment.  If clinically 
indicated, microbiological samples obtained during the study should also be submitted to the local 
laboratory for aerobic and anaerobic culture. 
Collection, transport, and processing of samples (including blood, tissue, synovial fluid, bone, etc.) 
should follow the local laboratory standard operating procedures and protocols. Each local 
laboratory will perform an initial isolate identification and susceptibility testing of Gram-positive 
pathogens. All isolated bacteria are to be sub-cultured and shipped to the Central Microbiology 
Laboratory for organism confirmation and additional susceptibility testing. 
10.5.1 
Susceptibility Testing of Bacterial Pathogens (Local Laboratory) 
Initial susceptibility testing to CEM-102 will be done by disk diffusion at the local laboratory 
following procedures detailed in the Laboratory Manual.  The Central Microbiology Laboratory 
will provide CEM-102 (10 μg) disks to be used to assess the susceptibility of Gram-positive 
species identified as pathogens. Clinical and Laboratory Standards Institute (CLSI) M02-A12 
(2015) and M100-S25 (2015) methods should be followed while performing the disk diffusion 
tests, including appropriate concurrent quality control testing (Table 5).  
Table 5 
Disk Zone Diameter Quality Control Limits 
Organism 
Media 
Fusidic Acid 
QC Rangea (mm) 
S. aureus ATCC 25923 
Mueller Hinton agar (MHA) 
24-32 
S. pneumoniae ATCC 49619 
MHA + 5% sheep blood 
9-16 
a. Quality Control Limits per the CLSI M02-A12 (2015) and CLSI M100-S25 (2015) guidelines 
The EUCAST recommended interpretive criteria for fusidic acid when testing Staphylococcus spp. 
are: (MIC [susceptible (S)/resistant (R)], ≤1/>1 µg/mL; zone diameter [S/R], ≥24/<24 mm for a 
10 µg disk). However, these breakpoints were established taking into account the plasma levels 
obtained with the European dosing regimen. Given the high plasma trough levels (>100 µg/mL) 
achieved within 24 hours using the fusidic acid loading dose regimen, and the results of a disk 
versus broth correlation analysis where applying breakpoints of <1 µg/ml (>22 mm) for S and >4 
µg/ml (<19 mm) for R provided 99.9% absolute intermethod categorical agreement (Jones 2010), 
The following provisional breakpoints for interpretation of zone diameters will be applied to 
isolates (Table 6). 


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Table 6 
Provisional CEM-102 Disk Zone Breakpoints 
Zone Diameter Breakpoints (mm) for Staphylococcal spp.a 
Susceptible (S) 
Intermediate (I) 
Resistant (R) 
≥22 
20-21 
≤19 
a. Interpretation of disk zone diameters of non-staphylococcal Gram-positive spp. should be discussed with the 
Sponsor’s Medical Monitor/Microbiologist. 
10.5.2 
Local Laboratory Storage of All Isolates 
All Baseline and any subsequent isolates will be stored frozen at ≤ -70°C (-20°C is acceptable for 
a period of no more than 35 days if a -70°C freezer is not available) in pathogen-appropriate media. 
The Central Laboratory will provide storage media in cryovials for isolate retention. Procedures 
related to freezing and storage of isolates are described in the Laboratory Manual. 
After submission of an isolate to the Central Laboratory, frozen backup isolates should be 
maintained at the local laboratory until the end of the study. 
10.5.3 
Shipping of Bacterial Strains to the Central Laboratory 
Isolates will be shipped to the Central Microbiology Laboratory for identity confirmation and 
antibiotic susceptibility testing. The Central Laboratory will provide a Laboratory Manual 
detailing handling and shipping instructions, isolate submission forms, shipping containers, and 
pre-printed air bills for sending strains to the Central Laboratory. When a shipment of isolates is 
to be initiated, the isolates should be sub-cultured from the frozen storage cryovials, grown 
overnight on routine laboratory media and inspected for purity after 24 hours incubation.  
Organism names (as reported by the local laboratory) and the accession numbers of any isolates 
sent to the Central Microbiology Laboratory will be recorded in the eCRF. If organism 
identifications from the local and Central Laboratories are discrepant, or if the Central Laboratory 
is unable to recover any isolates from the material received, the local laboratory will be requested 
to ship another sub-cultured specimen. 
10.5.4 
Central Microbiology Laboratory Procedures 
Isolates will be identified to genus and species. Additional testing to characterize isolates, 
including genetic typing and identification of virulence factors, may be performed. The Central 
Microbiology Laboratory will conduct susceptibility testing, by Kirby Bauer disk diffusion assay 
and by broth dilution or agar dilution MIC assays to CEM-102 and other antibiotics. 
10.6 
Pharmacokinetic Assessments 
Blood samples for PK analysis will be obtained from all consenting subjects at the 3-month Visit. 
PK analysis will be described in a separate Pharmacokinetics Analysis Plan. 


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PK Sampling: collected as close as possible to the following times:  
At the 3-Month Visit: Blood samples (5 in total) will be obtained at trough (30 minutes before 
study drug dosing), 1, 2, 4, and 6 hours after study drug dosing.  
If PK sampling cannot be done at 3-month visit, it may be completed at either the prior or 
subsequent monthly visit, if needed. 
An instruction manual that details the sampling, handling, and shipping procedures for PK samples 
will be provided to each participating site.   


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11 
STUDY DRUG DISCONTINUATION AND SUBJECT WITHDRAWAL 
A clear distinction will be made between subjects who discontinue study drug dosing and those 
who withdraw or are withdrawn from the study. 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 who discontinue study drug 
due to clinical failure will also 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 but who fail to meet inclusion and exclusion criteria and do 
not receive any doses of CEM-102 are defined as primary screen failures. A screening log, which 
documents the subject initials and reason for all screen failures, is to be maintained by the 
Investigator. A copy of the log should be retained in the Investigator’s study files. Screen failures 
will be entered into the eCRF. 
11.2 
Discontinuation from Study Drug  
A subject may have study drug 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. 
 Investigator discretion 
 Determination of clinical cure and no need for further antibiotic therapy to treat the primary 
infection (subject will continue to be followed for clinical relapse until EOS). 
 Pregnancy 
 Sponsor request 
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 is lost to follow-up 
 Subject non-compliance or unwillingness to comply with the procedures required by the 
protocol 
 Clinical failure 
 Investigator discretion 
 Sponsor request  
If a subject withdraws from the study at any time, for any reason, an EOS visit will be performed 
around that time.  


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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 patients 
 Subject enrollment is unsatisfactory 
 Investigator request to withdraw from participation 
 Sponsor’s 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) 


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12 
SAFETY ASSESSMENTS 
Safety assessments will include attention to relevant changes in physical examinations, vital signs, 
and safety laboratory tests that are identified as occurring after the ICF is signed. 
12.1 
Adverse Events 
An “adverse event” 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 CEM-102, 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, coagulation, 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.  
A constellation of signs and symptoms associated with an underlying etiology should be reported 
as the unifying event (for example, cough, fever, rhinorrhea, and malaise due to a cold should be 
reported as ‘viral syndrome’).     
In general, lack of efficacy/clinical failure is captured as an efficacy measure and will not be 
considered an AE.  However, clinical failure that results in hospitalization or death is 
reported as AEs/SAEs.  
12.1.1 
Recording of Adverse Events 
Adverse events will be collected following signing of the ICF through discharge from the study. 
In addition, the Investigator should seek to elicit any clinical or objective reactions by specific 
questioning (e.g. “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), severity, 
association with the study drug, action(s) taken, and outcome. 


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12.1.2 
Severity of Adverse Events 
Adverse event severity will be graded in accordance with the criteria of the Adult Toxicity Table 
(Modified) from the NIH/National Institute of Allergy and Infectious Diseases/Division of 
Microbiology and Infectious Diseases (DMID), November 2007 Adult Toxicity assessment table 
(Appendix A).   
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, hospitalization possible. 
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). 
12.1.3 
Relationship Assessment 
For each AE, the Investigator must make an assessment of the relationship of the event to the study 
drug as: 
 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 that there is evidence to suggest a causal relationship between the study 
drug and the AE) 
12.1.4 
Action Taken 
For each AE, the action(s) taken will be recorded (more than 1 may be recorded) as follows: 
 No action taken 
 Non-pharmacologic treatment 
 Pharmacologic treatment 
 Study drug discontinued 
 Withdrawn from study 
 New or prolonged hospitalization 


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12.1.5 
Outcome 
For each AE, the outcome will be recorded as either:  
 Recovered 
 Ongoing 
 Death 
 Unknown 
12.2 
Serious Adverse Events 
An SAE is any AE occurring at any dose that results in any of the following outcomes: 
 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 experience 
An AE is considered “life-threatening” if, in the view of either the Investigator or Sponsor, 
it places the subject at immediate risk of death.  It does not include an AE or suspected 
adverse reaction that, had it occurred in a more serious form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization. A “planned” 
hospitalization for study procedures or preexisting conditions is NOT an SAE. 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A congenital anomaly/birth defect. 
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent 1 of the outcomes listed 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 inpatient hospitalization, or the development of drug 
dependency or drug abuse. 


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12.2.1 
Other Reportable Events 
Reports of overdose (with or without an AE), inadvertent or accidental exposure, and pregnancy 
should be forwarded in the same time frame as an SAE. 
Overdose occurs when a patient 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.   
12.2.2 
Reporting SAEs and Other Reportable Events 
All SAEs that result in death or are life threatening, regardless of causal relationship, must be 
reported to the Medical Monitor (or designee) within 24 hours of the site’s knowledge of the event.  
A copy of the initial SAE report must be received within 1 business day. 
All other SAEs and other reportable events will be forwarded to the Medical Monitor within 1 
business day. 
The SAE report should provide as much of the required information as is available at the time.  
The following minimum information is required for reporting an SAE: subject identification, 
reporting source, causality, and an event outcome. Supplemental information may be transmitted 
using a follow-up report and should not delay the initial report. CEM-102 Pharmaceuticals or its 
designee may contact the investigational site to solicit additional information or to follow up on 
the event. 
As with all AEs (Section 12.1.3) , the report must also include an assessment of whether there is a 
reasonable possibility that the study drug caused the event (i.e. whether the event is related or 
unrelated to study drug). “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the study drug and the AE. 
If there is any doubt whether the information constitutes an SAE, the information will be treated 
as an SAE for the purposes of this protocol. 
SAEs will be followed until resolution or return to Baseline (when worsening of a pre-existing 
condition is reported). )Subjects who sign and date the informed consent form but who fail to meet 
the inclusion and exclusion criteria are defined as screen failures. A screening log, which 
documents the subject 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. 


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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 will be 
resolved. The database will be locked after all subjects have completed the EOS visit. 


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14 
STATISTICAL METHODS AND DATA ANALYSIS 
As a non-randomized, single-arm study, there will be no formal statistical analyses. This study is 
not powered for inferential statistical analyses, and no formal hypothesis testing will be conducted. 
Safety and efficacy will be descriptive. Clinical outcome will be reported as the proportion of 
subjects meeting criteria of clinical success. 
All safety data will be summarized using the Safety analysis set. Adverse events will be coded 
with the Medical Dictionary for Regulatory Activities (MedDRA®). The number and proportion 
of subjects having treatment-emergent AEs will be tabulated by MedDRA System Organ Class 
(SOC) and preferred term, severity, and relationship to study drug. 
Since this is a non-randomized, open-label, single-arm study, interim data may be summarized and 
reported, as needed, prior to database lock. 
Details of the analysis will be provided in a separate Statistical Analysis Plan (SAP).  
14.1 
Efficacy Analyses 
The primary endpoint will be the proportion of subjects in the ITT analysis set who meet all the 
criteria for clinical success at the 6-Month Visit.  
Clinical success is defined for subjects who meet all of the following criteria: 
 Subject was not hospitalized due to worsening of the study-qualifying orthopedic infection 
at any point between enrollment and the 6-Month Visit 
 Subject did not undergo a definitive surgical procedure (such as amputation) at any point 
between enrollment and the 6-Month Visit 
 No additional antibiotics (after completion of the companion antibiotics) are required for 
treatment of the orthopedic infection due to the inclusionary pathogen 
 Wound is closed, or the open area decreased in size (L x W) and, if a skin graft was done, 
the graft remains viable without evidence of infection 
 No purulent discharge from the surgical wound, or new or recurring sinus tract 
 No worsening of redness, tenderness, or swelling at the primary infection site 
 No bacteremia of the inclusionary pathogen at any point between enrollment and the 6-
Month Visit 
Clinical failure is defined as follows: 
 Not meeting all criteria for clinical success 
 Death (due to the primary infection) 
 Discontinuation of study drug due to an AE and the requirement of additional antibiotics 
for treatment of the primary infection 


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 Use of a concomitant antibiotic to which the inclusionary pathogen is susceptible for > 10 
days on any occasion, or for > 2 courses during any 6-month period 
Indeterminate: 
 Subject withdraws consent 
 Subject is lost to follow-up 
Investigators will evaluate and provide documentation of each subject for a clinically meaningful 
difference in each subject’s response prior to making a determination of treatment failure for the 
primary study endpoint. 
The secondary efficacy endpoints are as follows: 
 Proportion of subjects in the ITT analysis set who meet all criteria for clinical success, as 
defined above, at the 9-Month, 12-Month, 15-Month, 18-Month, 21-Month, and 
24-Month Visits 
 Pharmacokinetics of CEM-102 used chronically in subjects with orthopedic infections 
14.2 
Safety Analyses 
Safety and tolerability of CEM-102 for the treatment of bone and joint infections, reported as 
subject incidences of TEAEs, SAEs, deaths, and discontinuations due to AEs in the safety analysis 
set. 
14.3 
Pharmacokinetic Analysis   
Analysis of the PK data will be described in detail in the PK analysis plan.  


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15 
ADMINISTRATIVE ASPECTS 
15.1 
Compliance with Regulatory Requirements 
This protocol will be conducted in compliance with the protocol and all regulatory requirements, 
in accordance with Good Clinical Practice (GCP), including International Conference on 
Harmonization (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 (at least once per year).. The 
Principal Investigator is also responsible for notifying the IRB/IEC of all unanticipated risks 
involving human subjects that occur during the study. 
15.3 
Informed Consent 
It is the policy of CEM-102 Pharmaceuticals that written informed consent is obtained from 
subjects. The informed consent document must be signed and dated prior to any study-related 
procedures are performed at Screening/Baseline. The original signed ICF for each participating 
subject shall be filed with records kept by the Investigators(s). A copy of the informed consent 
document must be provided to the subject. Where applicable, it will be provided in a certified 
translation of the local language.   
15.4 
Confidentiality 
Personal study subject data collected and processed for the purposes of this study should be 
managed by the Investigator and his/her staff with adequate precautions to ensure the 
confidentiality of those data, in accordance with applicable national and/or local laws and 
regulations on personal data protection. 
Monitors, auditors, and other authorized agents of CEM-102 Pharmaceuticals and the clinical 
research organization (CRO), the IRB/IEC approving this research, and the US Food and Drug 
Administration (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. 


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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, which are then responsible for submitting 
the amendment to their IRB/IECs for approval. 
15.7 
Electronic Case Report Forms (eCRF) 
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 Sub-investigator (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, 
CEM-102 Pharmaceuticals 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 Investigator(s) and made available for 
inspection by CEM-102 Pharmaceuticals representatives, the FDA, or other regulatory authorities. 
15.9 
Study Monitoring Requirements 
Site visits will be conducted by an authorized CEM-102 Pharmaceuticals representative (the 
monitor) to inspect study data, subject medical records, and eCRFs in accordance with ICH 
guidelines, GCPs, and the respective US or national regulations and guidelines, as applicable. It 
will be the monitor’s responsibility to inspect the eCRF at regular intervals throughout the study 
and 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. 
The Investigator will permit representatives of CEM-102 Pharmaceuticals, the US 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 Investigator(s) to ensure that the study file at the site is maintained. 
The study file will contain, but not be limited to, the following: 
 Investigator’s Brochure (including updated or revised versions) 
 Final study protocol 
 Protocol amendments (if applicable) 


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 Fully executed Clinical Trial Agreement 
 Investigator Manual (if applicable) 
 ICF (blank) 
 Revised ICFs and/or all addenda (blank) 
 Copy of signed form(s) US FDA Form 1572  
 DHHS number for IRB or other documentation of IRB/IEC compliance with FDA 
 Curricula Vitae (CV) of Investigators and Sub-investigators 
 Financial disclosure information provided to the Sponsors 
 A list of the IRB/IEC members and their qualifications as well as a description of the IRB 
processes.  
 If the Investigator is a member of the IRB/IEC, documentation stating he/she did not vote 
on the study 
 Documentation of IRB/IEC approval of protocol, consent form, any protocol amendments, 
and any consent form revisions 
 Annual IRB/IEC updates and approvals 
 All correspondence between the Investigator, IRB/IEC, and CEM-102 Pharmaceuticals (or 
designee) 
 Copies of all Investigational New Drug (IND) Safety Reports submitted to the FDA or 
other regulatory agencies and IRB/IEC correspondence documenting their submission (if 
applicable) 
 Laboratory certifications/normal laboratory value ranges 
 Screening log 
 Clinical Research Associate (CRA) monitoring log 
 Drug accountability records and invoices for receipt/return of study drug 
 Protocol Signature Page 
 Laboratory Director’s CV and medical/professional license, if available 
15.11 
Study Completion 
CEM-102 Pharmaceuticals requires that the following data and materials be on file at the study 
site before a study can be considered completed or terminated: 
 Laboratory findings, clinical data, and all special test results from Screening through 
the end of the study follow-up period 
 eCRFs properly completed by appropriate study personnel and electronically signed 
and dated by the Investigator 


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 Complete Drug Accountability records (drug inventory log and an inventory of 
returned or destroyed clinical material) 
 Copies of protocol amendments and IRB/IEC approval/notification, if appropriate 
 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 CEM-102 Pharmaceuticals Quality Assurance Auditor (or an auditor appointed by 
CEM-102 Pharmaceuticals or its authorized representative) and/or an inspector from the FDA 
and/or other regulatory authority. Every attempt will be made to notify the Investigator in writing 
in advance of the audit. 
15.13 
Retention of Records 
CEM-102 Pharmaceuticals follows US regulations and ICH guidelines in its retention policy. 
US IND regulations (21 CFR 312.62) require that records and documents pertaining to the conduct 
of this study and the distribution of investigational 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 US and ICH policies. No study records should 
be destroyed without prior authorization from CEM-102 Pharmaceuticals. 
15.14 
Disclosure of Data 
The 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 Investigators, their addresses, qualifications, 
and extent of involvement.  It is understood that the Investigator is required to provide CEM-102 
Pharmaceuticals with all study data, complete reports, and access to all study records.  
Data generated by this study must be available for inspection by the US FDA and other regulatory 
authorities, by CEM-102 Pharmaceuticals, 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. 


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15.15 
Financial Disclosure 
The US 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 Sub-investigator is required to provide the required 
financial information before participating in the study and to promptly update CEM-102 
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 Sub-
investigators 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 the Clinical Trial Agreement. 


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16 
REFERENCES 
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Besier S, Ludwig A, Brade V, Wichelhaus TA. Molecular analysis of fusidic acid resistance in 
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CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow 
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(EUCAST) The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables 
for interpretation of MICs and zone diameters. Version 5.0, 2015.http://www.eucast.org 
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http://dx.doi.org/10.1098/rsob.120016 
Jones, R. N., M. Castanheira, P. R. Rhomberg, L. N. Wooseley, and M. A. Pfaller. 2010. 
Performance of fusidic acid (CEM-102) susceptibility testing reagents: Broth microdilution, disk 
diffusion, and Etest methods as applied to Staphylococcus aureus. J. Clin. Microb. 48:972-976. 
Lautenbach EEG, Robins RG, Koornhof HJ. Serum and tissue concentrations of sodium fusidate 
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O'Neill AJ, Chopra I.  Molecular basis of fusB-mediated resistance to fusidic acid in 
Staphylococcus aureus.  Mol Microbiol.  2006; 59(2):664-76. 
O'Neill AJ, McLaws F, Kahlmeter G, Henriksen AS, Chopra I.  Genetic basis of resistance to 
fusidic acid in staphlyococci. Antimicrob Agents Chemother. 2007; 51(5):1737-40 
Olson SC, Smith S, Weissman SJ, Kronman MP. Adverse Events in Pediatric Patients Receiving 
Long-Term Outpatient Antimicrobials. Journ of the Ped Infect Dis Soc., Vol. 4, No. 2, pp 119-25, 
2014. 
Rijinders MIA, Wolffs PFG, Hopstaken RM, den Heyer M, Bruggeman CA, Stobberingh EE.  
Spread of the epidemic European fusidic acid-resistant impetigo clone (EEFIC) in general practice 
patients in the south of The Netherlands.  J Antimicrob Chemother 2012; 67:1176-80.   
Siala W, Rodriguez-Villalobos H, Fernandes P, Tulkens PM, Van Bambeke F. Activity of fusidic 
acid (FUS) alone or in combination with daptomycin (DAP), vancomycin (VAN), or linezolid 
(LZD) in an in vitro model of Staphylococcus aureus biofilm. 25th Eur Congr Clin Microb Infect 
Dis; 2015 April 25-28; #2369. Copenhagen, Denmark.  
Still JG, Clark K, Degenhardt TP, Scott D, Fernandes P, Gutierrez MJ. Pharmacokinetics and 
safety of single, multiple, and loading doses of fusidic acid in healthy subjects. Clinical infectious 
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Tsuji BT, Okusanya OO, Bulitta JB, Forrest A, Bhavnani SM, Fernandez PB, et al. Application of 
pharmacokinetic-pharmacodynamic modeling and the justification of a novel fusidic acid dosing 
regimen: raising Lazarus from the dead. Clinical infectious diseases : an official publication of the 
Infectious Diseases Society of America. 2011;52 Suppl 7:S513-9. 
Turnidge J, Collignon P. Resistance to fusidic acid. Int J Antimicrob Agents. 1999;12 Suppl 2:S35-
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Turnidge J. Fusidic acid pharmacology, pharmacokinetics and pharmacodynamics. Int J 
Antimicrob Agents. 1999; 12 Suppl 2:S23-34. 
 


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Appendix A Toxicity Table 
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES, DIVISION OF 
MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) ADULT TOXICITY TABLE 
(MODIFIED) 
NOVEMBER 2007 - DRAFT 
ABBREVIATIONS: Abbreviations utilized in the Table: 
 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
 
Rx = Therapy  
 
 
 Req = Required 
 
Mod = Moderate 
 
 
IV = Intravenous 
 
ADL = Activities of Daily Living 
Dec = Decreased 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables, use the scale below to estimate 
grade of severity: 
GRADE 1 
Mild: Transient or mild discomfort; no medical intervention/therapy 
required 
GRADE 2 
Moderate: Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical intervention/therapy required 
GRADE 3 
Severe: Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, hospitalizations 
possible. 
GRADE 4 
Life-threatening: Extreme limitation in activity, significant 
assistance required; significant medical intervention/therapy required, 
hospitalization or hospice care probable 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered 
a grade 4 event.  
LABORATORY RANGES 
Where discrepancies in the ULN and LLN of laboratory ranges occur between those included in 
this document and those of the laboratory that performs the assays, the values provided by the 
laboratory will be used for assignment of severity grade. 
 


CEM-102 Pharmaceuticals, Inc. 
Protocol CE06-302 
07 July 2015 
Confidential 
Page 65 of 70 
HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5-10.5 gm/dL 
8.0-9.4 gm/dL 
6.5-7.9 gm/dL 
<6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000-
99,999/mm3 
50,000-
74,999/mm3 
20,000-
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000-
30,000/mm3 
>30,000 or <1,000 
mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
>80% 
90–95% 
>95% 
--------- 
Activated Partial 
Thromboplastin 
(APTT) 
1.01-1.66ULN 
1.67-2.33ULN 
2.34--3ULN 
>3ULN 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
<116 mEq/L or 
abnormal sodium 
with mental status 
changes or 
seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
>165 mEq/L or 
abnormal sodium 
with mental status 
changes or 
seizures 
Hypokalemia 
3.0-3.4 mEq/L 
2.5-2.9 mEq/L 
2.0-2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
<2.0 mEq/L or 
abnormal 
potassium with 
paresis, ileus or 
life-threatening 
arrhythmia 
Hyperkalemia 
5.6-6.0 mEq/L 
6.1-6.5 mEq/L 
6.6-7.0 mEq/L 
>7.0 mEq/L or 
abnormal 
potassium  with 
life-threatening 
arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or 
abnormal glucose 
with mental status 
changes or coma 
Hyperglycemia 
(nonfasting and no 
prior diabetes) 
116-160 mg/dL 
161-250 mg/dL 
251-500 mg/dL 
>500 mg/dL or 
abnormal glucose 
with ketoacidosis 
or seizures 
Hypocalcemia 
(corrected for albumin) 
8.4-7.8 mg/dL 
7.7-7.0 mg/dL 
6.9-6.1 mg/dL 
<6.1 mg/dL or 
abnormal calcium 
with life threatening 
arrhythmia or 
tetany 


CEM-102 Pharmaceuticals, Inc. 
Protocol CE06-302 
07 July 2015 
Confidential 
Page 66 of 70 
Hypercalcemia 
(corrected for albumin) 
10.6-11.5 mg/dL 
11.6-12.5 mg/dL 
12.6-13.5 mg/dL 
>13.5 mg/dL or 
abnormal calcium 
with life threatening 
arrhythmia 
Hypomagnesemia 
1.4-1.2 mEq/L 
1.1-0.9 mEq/L 
0.8-0.6 mEq/L 
<0.6 mEq/L or 
abnormal 
magnesium with 
life-threatening 
arrhythmia 
Hypophosphatemia 
2.0-2.4 mg/dL 
1.5-1.9 mg/dL or 
replacement Rx 
required 
1.0-1.4 mg/dL 
intensive therapy 
or hospitalization 
required 
<1.0 mg/dL or 
abnormal 
phosphate with life-
threatening 
arrhythmia 
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
test) 
1.1-<1.25xULN 
1.25-<1.5xULN 
1.5–1.75xULN 
>1.75xULN 
Hyperbilirubinemia 
(when other liver 
function tests are in 
the  normal range) 
1.1-<1.5xULN 
1.5-<2.0xULN 
2.0–3.0xULN 
>3.0xULN 
BUN 
1.25-2. 5xULN 
2.6-5xULN 
5.1-10xULN 
>10xULN 
Hyperuricemia (uric 
acid) 
7.5–10.0 mg/dL 
10.1–12.0 mg/dL 
12.1–15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1-1.5xULN  
1.6-3.0xULN 
3.1-6xULN 
>6xULN or dialysis 
required 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1-<2.0xULN 
2.0–<3. 0xULN 
3.0–8. 0xULN 
>8xULN 
ALT (SGPT) 
1.1-<2.0xULN 
2.0–<3.0xULN 
3.0–8. 0xULN 
>8xULN 
Alkaline Phosphatase 1.1-<2.0xULN 
2.0–<3.0xULN 
3.0–8. 0xULN 
>8xULN 
URINALYSIS  
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg – 
1gm loss/day 
2-3+ or 1-2 gm 
loss/day 
4+ or 2-3.5gm 
loss/day 
nephrotic 
syndrome  
or 
>3.5 gm loss/day 
Hematuria 
microscopic only 
<10 RBC/hpf 
gross, no clots 
>10 RBC/hpf 
gross, with or 
without clots, OR 
RBC casts 
obstructive or 
required 
transfusion 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent 
symptomatic Rx 
required 
unstable 
dysrhythmia; 
hospitalization and 
treatment required 


CEM-102 Pharmaceuticals, Inc. 
Protocol CE06-302 
07 July 2015 
Confidential 
Page 67 of 70 
Hypertension 
transient increase 
>20 mm/Hg; no 
treatment 
recurrent, chronic 
increase 
>20mm/Hg. 
/treatment required 
acute treatment 
required; outpatient 
treatment or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension with 
heart rate 
increased by 
<20beats/min or 
decreased by 
<10mm/Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by 
<20mm/Hg 
systolic; 
correctable with 
oral fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure  
<60 mm/Hg or end 
organ damage or 
shock; requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult mild, no 
transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood 
loss; >3 units 
transfused 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough  
transient- no 
treatment 
persistent cough; 
treatment 
responsive 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
Bronchospasm, Acute transient; no 
treatment; 
70%-80% FEV1 
of peak flow 
requires treatment; 
normalizes with 
bronchodilator; 
FEV1 50%-70% 
(of peak flow) 
no normalization 
with 
bronchodilator; 
FEV1 25%-50% 
of peak flow; or  
retractions present 
cyanosis: FEV1 
<25% 
of peak flow or 
intubation 
necessary 
Dyspnea 
dyspnea on 
exertion 
dyspnea with 
normal activity 
dyspnea at rest 
Dyspnea requiring 
oxygen therapy  
GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no significant 
intake; requires IV 
fluids 
hospitalization 
required 
Vomiting 
1 episode in 
24hours 
2-5 episodes in 
24hours 
>6 episodes in 
24hours or needing 
IV fluids 
 
 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral nutrition 
Constipation 
requiring stool 
softener or dietary 
modification 
requiring laxatives obstipation 
requiring manual 
evacuation or 
enema 
obstruction or toxic 
megacolon 


CEM-102 Pharmaceuticals, Inc. 
Protocol CE06-302 
07 July 2015 
Confidential 
Page 68 of 70 
Diarrhea 
mild or transient; 
3-4 loose 
stools/day or mild 
diarrhea last <1 
week 
moderate or 
persistent; 5-7 
loose stools/day or 
diarrhea lasting 
>1week 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2 L 
IV fluids required  
hypotensive shock 
or physiologic 
consequences 
requiring 
hospitalization  
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid foods 
unable to drink 
fluids; requires IV 
fluids 
NEUROLOGICAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
Incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety 
or depression; 
therapy required; 
change in normal 
routine 
severe mood 
changes requiring 
therapy; or suicidal 
ideation; or 
aggressive ideation 
acute psychosis 
requiring 
hospitalization; or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
subjective 
weakness, no 
objective 
symptoms/signs 
mild objective 
signs/symptoms no 
decrease in 
function 
objective 
weakness function 
limited 
Paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment required 
moderate 
discomfort; non-
narcotic analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g. 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision and/or 
hearing 
moderate 
impairment 
(moderate 
decreased 
sensation, e.g. 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint 
position or mild 
impairment that is 
not symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or wrists) or 
loss of sensation of 
at least moderate 
degree in multiple 
different body 
areas (i.e. upper 
and lower 
extremities) 
sensory loss 
involves limbs and 
trunk; paralysis or 
seizures 


CEM-102 Pharmaceuticals, Inc. 
Protocol CE06-302 
07 July 2015 
Confidential 
Page 69 of 70 
MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics and/or 
pain interfering 
with function but 
not with activities 
of daily living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain with 
inflammation, 
erythema or joint 
swelling – 
interfering with 
function, but not 
with activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling – and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
destruction 
Myalgia 
Myalgia with no 
limitation of activity 
muscle tenderness 
(at other than 
injection site) or 
with moderate 
impairment of 
activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
frank myonecrosis 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus diffuse, maculo 
papular rash, dry 
desquamation 
vesiculation or 
moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected 
Stevens-Johnson 
or necrosis 
requiring surgery 
Induration 
<15mm  
15-30 mm 
>30mm 
 
Erythema 
<15mm  
15-30 mm 
>30mm 
 
Edema 
<15mm  
15-30 mm 
>30mm 
 
Rash at Injection Site <15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus without 
rash 
localized urticaria 
generalized 
urticaria; 
angioedema 
Anaphylaxis 
Headache 
mild, no treatment 
required 
transient, 
moderate; 
treatment required 
severe; responds 
to initial narcotic 
therapy 
intractable; 
requires repeated 
narcotic therapy 


CEM-102 Pharmaceuticals, Inc. 
Protocol CE06-302 
07 July 2015 
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Page 70 of 70 
Fever: oral 
37.7-38.5C or 
100.0-101.5 F 
38.6-39.5 C or 
101.6-102.9 F 
39.6-40.5 C or 
103-105 F 
>40 C or >105 F 
Fatigue 
normal activity 
reduced <48 hours 
normal activity 
decreased 25-50% 
>48 hours 
normal activity 
decreased >50% 
can’t work 
unable to care for 
self 
 


CEM-102 Pharmaceuticals, Inc.  
CE06-302 
 
Statistical Analysis Plan                                                                                                                              Final Version 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
 
CEM-102 Pharmaceuticals, Inc. 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title: 
An Open-Label, Non-Randomized, Single-Arm Multi-Center 
Study to Evaluate Oral Sodium Fusidate (CEM-102) for the 
Treatment of Staphylococcal Bone or Joint Infections in 
Subjects for whom Chronic Antibiotic Suppressive Therapy is 
Indicated 
 
 
Phase: 
2/3 
 
 
Protocol No.: 
CE06-302  
 
 
Protocol Date 
Original Protocol: 07 July 2015 
 
 
 
 
Analysis Plan Version and 
Date 
Final Version, 19 October 2017 
 
 
Prepared By: 
Andrew Garrison, MS 
PharPoint Research, Inc. 
5003 S. Miami Blvd, Suite 100 
Durham, NC 27703 
 
 
Prepared For: 
CEM-102 Pharmaceuticals, Inc 
6320 Quadrangle Drive, Suite 360 
Chapel Hill, NC 27517 




CEM-102 Pharmaceuticals, Inc.  
CE06-302 
 
Statistical Analysis Plan                                                                                                                              Final Version                              
 
 
 
CONFIDENTIAL 
Page 3 
19 October 2017 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ..................................... 2 
1. 
INTRODUCTION .................................................................................................... 5 
1.1. 
Study Overview .............................................................................................................................. 5 
1.2. 
Schedule of Assessments/Procedures........................................................................................ 6 
1.3. 
List of abbreviations ...................................................................................................................... 8 
2. 
OBJECTIVE ............................................................................................................ 9 
3. 
ENDPOINTS ............................................................................................................ 9 
4. 
GENERAL STATISTICAL CONSIDERATIONS ..................................................... 9 
4.1. 
Sample Size and Power ................................................................................................................. 9 
4.2. 
Randomization and Masking ........................................................................................................ 9 
4.3. 
Handling of Data ........................................................................................................................... 10 
4.3.1. 
Strata and Covariates .................................................................................................................... 10 
4.3.2. 
Examination of Subject Subsets ..................................................................................................... 10 
4.3.3. 
Multiple Testing and Comparisons ................................................................................................. 10 
4.3.4. 
Missing Data and Outliers ............................................................................................................. 10 
4.3.5. 
Derived and Transformed Data ...................................................................................................... 10 
4.3.6. 
Imputation of Incomplete Dates ..................................................................................................... 10 
4.3.7. 
By-Study Visit Displays ................................................................................................................ 11 
4.3.8. 
Definitions and Terminology ......................................................................................................... 12 
4.4. 
Timing Of Analyses ...................................................................................................................... 15 
5. 
ANALYSIS POPULATIONS .................................................................................. 16 
5.1. 
Intent To Treat (ITT) Population .................................................................................................. 16 
5.2. 
Safety Population ......................................................................................................................... 16 
5.3. 
Screened Population ................................................................................................................... 16 
6. 
STATISTICAL METHODS .................................................................................... 16 
6.1. 
Subject Disposition, Demographic and Baseline Characteristics, Duration of Treatment .. 16 


CEM-102 Pharmaceuticals, Inc.  
CE06-302 
 
Statistical Analysis Plan                                                                                                                              Final Version                              
 
 
 
CONFIDENTIAL 
Page 4 
19 October 2017 
6.1.1. 
Subject Disposition and Duration of Treatment ............................................................................... 16 
6.1.2. 
Demographics and Baseline Characteristics .................................................................................... 17 
6.1.3. 
Baseline Pathogens ....................................................................................................................... 17 
6.1.4. 
Concomitant Medications.............................................................................................................. 17 
6.2. 
Efficacy ......................................................................................................................................... 17 
6.3. 
Safety............................................................................................................................................. 18 
6.3.1. 
Adverse Events ............................................................................................................................ 18 
6.3.2. 
Clinical Laboratory Assessments ................................................................................................... 19 
6.3.3. 
Other Safety Analyses .................................................................................................................. 19 
6.4. 
Pharmacokinetics Analyses ....................................................................................................... 19 
7. 
PROTOCOL DEVIATIONS ................................................................................... 19 
8. 
CHANGES IN THE PLANNED ANALYSES .......................................................... 19 
9. 
REFERENCES ....................................................................................................... 20 
10. REVISION HISTORY ............................................................................................ 20 
11. PROGRAMMING CONVENTIONS ....................................................................... 21 
12. PROPOSED TABLES, LISTINGS, AND FIGURES ................................................ 23 
13. APPENDIX I – TOXICITY GRADING................................................................... 25 
 


CEM-102 Pharmaceuticals, Inc.  
CE06-302 
 
Statistical Analysis Plan                                                                                                                              Final Version                              
 
 
 
CONFIDENTIAL 
Page 5 
19 October 2017 
1. 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the summary and 
analysis of efficacy and safety data from Protocol CE06-302.  Background information is provided for the 
overall study design and objectives.  The reader is referred to the study protocol and electronic case report 
forms (eCRFs) for details of study conduct and data collection, and to the Pharmacokinetics (PK) Report 
for the analysis of plasma concentrations of CEM-102. 
1.1. 
STUDY OVERVIEW 
Protocol CE06-302 is a phase 2/3, prospective, open-label, non-randomized, single-arm trial to evaluate 
the safety and effectiveness of CEM-102 for chronic antibiotic suppressive therapy of bone or joint 
infections. Subjects enrolling in this study must have a suspected or confirmed staphylococcal bone or 
joint infection due to an inclusionary pathogen susceptible to CEM-102 that requires suppressive 
antibiotic therapy. The infection should be demonstrated from a positive culture from samples obtained 
during surgery, biopsy, or drainage procedures within 6 weeks prior to enrollment. If the subject does not 
have a positive culture, the Investigator must provide documentation as to why the subject is suspected to 
have a staphylococcal infection and discuss with the medical monitor for approval of enrollment. 
 
This study comprises two parts: Part A (enrollment through the 6-month visit) and Part B (6 to 24 months 
post-enrollment). In Part A, all subjects will receive 6 months of CEM-102 treatment. The Investigator 
will evaluate each subject completing Part A for clinical response at the 6-month visit (primary endpoint). 
For Part B, a subject who completes Part A and, in the Investigator’s opinion, requires continued 
suppressive therapy, may continue to receive CEM-102. Alternatively, if the Investigator considers the 
infection resolved and that no further antibiotic therapy is required, study drug will be discontinued and 
the subject followed for evidence of relapse until the end of study (EOS; 24 months). 
 
During the first 6 months of treatment, study Part A, subjects will be monitored monthly (±1 week) for 
safety and clinical response to CEM-102. During study Part B, subjects will be monitored every 3 months 
(±2 weeks) until the EOS Visit (24 months). 
 
 
 


CEM-102 Pharmaceuticals, Inc.  
CE06-302 
 
Statistical Analysis Plan                                                                                                                                                                                                      Final Version                              
 
 
 
CONFIDENTIAL 
Page 6 
19 October 2017 
1.2. 
SCHEDULE OF ASSESSMENTS/PROCEDURES 
 
Assessment/Procedure 
Screeninga 
Part A 
Part B 
End of 
Study 
(EOS)d 
Enrollment 
(Day 1 Visit)b,c 
 
Day 8 
(± 3 days) 
 
Monthly During 
First 6 Months 
(±1 week) 
Every 3 Months From 
Month 6 until End of 
Study (±2weeks) 
Informed Consent Form 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
X 
 
 
 
 
Review of Clinical/ Surgical History 
X 
X 
X 
X 
X 
X 
Microbiological specimens for culture 
X 
X 
Xe 
Xe 
Xe 
Xe 
Enrollment 
X 
X 
 
 
 
 
Vital Signsf 
X 
X 
X 
X 
X 
X 
Limited Physical Examinationg 
X 
X 
X 
X 
X 
X 
Examination of Infected Areah 
X 
X 
X 
X 
X 
X 
Safety Laboratory Assessmentsi 
X 
X 
X 
X 
X 
X 
Inflammation Laboratory Assessmentsj 
X 
X 
 
X 
X 
X 
CEM-102 Administrationk 
 
X 
 
 
 
 
Pharmacokinetic Blood Sampling 
 
 
 
Xo 
 
 
Dispense Oral antibiotic to Subjectsl 
 
X 
X 
X 
X 
 
Perform Drug Accountability 
 
 
X 
X 
X 
X 
Record 6-Month History of Prior 
Antibiotic Used to Treat the Primary 
Infection Leading to Enrollment 
X 
 
 
 
 
 
Record Concomitant Medications 
X 
X 
X 
X 
X 
X 
Record AEsm 
X 
X 
X 
X 
X 
X 


CEM-102 Pharmaceuticals, Inc.  
CE06-302 
 
Statistical Analysis Plan                                                                                                                                                                                                      Final Version                              
 
 
 
CONFIDENTIAL 
Page 7 
19 October 2017 
Investigator Assessment of Clinical 
Responsen 
 
 
 
X 
X 
X 
a. Within 6 weeks prior to enrollment, subjects must have a positive culture with an inclusionary pathogen susceptible to CEM-102, demonstrated from a culture from samples obtained during surgery, 
biopsy, or drainage procedures. If subject does not have a confirmatory culture result, the Investigator must provide documentation as to why subject is suspected to have a staphylococcal infection and 
must discuss the subject with the medical monitor for approval of enrollment. 
b. Enrollment is contingent on demonstration that subject fulfills the inclusion/exclusion criteria. 
c. Study Day 1 corresponds to the first day of dosing with CEM-102. 
d. Subjects who discontinue CEM-102 because of an adverse event (AE) or clinical failure should have a study visit around the time of drug discontinuation and will continue to be followed, as needed, 
for appropriate observation of treatment-related AEs until AEs have resolved or stabilized. If a subject withdraws from the study at any time, for any reason, the EOS visit will be performed around that 
time. Those subjects who continue CEM-102 until the Month 24 visit will undergo the assessments/procedures for the EOS visit. At study closure, at the discretion of the Investigator, subjects may be 
rolled over into an expanded access protocol to receive chronic suppressive CEM-102 therapy. 
e. If clinically indicated, microbiological samples (tissue surrounding the foreign material, synovial fluid, bone, etc.) obtained during the study should be submitted to the local laboratory for aerobic and 
anaerobic culture and susceptibility testing, including to CEM-102. All isolated bacteria are to be sub-cultured and shipped to the central microbiology laboratory for organism confirmation and 
confirmatory susceptibility testing. 
f. Vital sign measurements include height, weight, temperature, heart rate, respiratory rate, and blood pressure. Results are to be recorded in the eCRF. 
g. Limited physical examination may include HEENT, cardiovascular, pulmonary, gastrointestinal, skin, lymph nodes, musculoskeletal, and extremities, among others. Results are to be documented in 
source and recorded in the eCRF. 
h. Examination of the infected area will include the following assessments: pain, erythema, mobility, joint stability, wound closure, wound drainage, and weight bearing [for back and lower extremity 
infections]. The Investigator will state whether the infected area seems to have improved, deteriorated, or remained unchanged. Results are to be documented in the source and recorded in the eCRF. 
i. Safety laboratory assessments will be performed at the local laboratory and will include the following: serum chemistry (ALT, AST, alkaline phosphatase [ALP], total and direct bilirubin, blood urea 
nitrogen [BUN], creatinine, albumin, total protein, sodium, total carbon dioxide, glucose, potassium, chloride, calcium, phosphorus, and CPK). For female subjects of child bearing potential, a urine or 
serum pregnancy test will be performed at Screening and will be repeated at subsequent visits per Investigator’s discretion . 
j. Laboratory measurements of markers of inflammation will be performed at the local laboratory and will include the following: hematology (complete blood count [CBC] with differential), erythrocyte 
sedimentation rate [ESR], and C-reactive protein [CRP]). Laboratory measurements of markers of inflammation obtained on the day of a surgery or debridement should be performed before the 
procedure when possible, because levels of these markers are known to increase after surgery. 
k. A CEM-102 loading dose strategy is utilized, in which CEM-102 is given as 1500 mg every 12 hours for 2 doses followed by 600 mg every 12 hours thereafter. 
l. After 6 months of therapy, the Investigator may decide to continue chronic suppressive therapy with CEM-102 or discontinue CEM-102 due to clinical cure and no further requirement for antibiotic 
therapy. Subjects who stop treatment will continue to be followed on the same schedule as those who remain on therapy to monitor for infection relapse until the end of the study. Subjects who 
discontinue CEM-102 due to clinical failure should have an EOS visit at that time. 
m. All AEs will be collected following signing of the ICF. 
n. The Investigator will assess clinical response at Months 6, 9, 12, 15, 18, 21, 24 and at EOS. 
o. Pharmacokinetic blood sampling will be conducted at the 3-month visit as described in Section 10.6 


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1.3. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
Alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CEM-102 
sodium fusidate (fusidic acid) 
CPK 
creatinine phosphokinase 
CRP 
C-reactive protein 
HEENT 
head, eyes, ears, nose, throat 
ICF 
informed consent form 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic 
SAE 
serious AE 
TEAE 
treatment-emergent AE 
WBC 
white blood cell 


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2. 
OBJECTIVE 
The study objective is to evaluate the safety and effectiveness of CEM-102 as chronic antibiotic 
suppressive therapy in subjects with staphylococcal bone or joint infections. 
3. 
ENDPOINTS 
Primary Endpoint 
The primary endpoint will be the proportion of subjects in the safety population who meet all the criteria 
for clinical success at the 6-Month Visit. 
Secondary Endpoints 
Efficacy  
• 
The proportion of subjects in the safety population who meet all criteria for clinical success at the 
9-Month, 12-Month, 15-Month, 18-Month, 21-Month, and 24-Month Visits 
Safety and Tolerability 
• 
The proportion of subjects in the safety population who experience a treatment-emergent adverse 
event (TEAE), a serious adverse event (SAE), an SAE that results in death, or a TEAE that 
results in discontinuation from study or study drug 
Additional Endpoints 
Efficacy 
• 
Change in composite symptom and function score at each Visit 
• 
Change in wound status at each Visit 
• 
Change in ESR as a surrogate marker of infection status over time 
Safety and Tolerability 
• 
Changes from baseline in selected chemistry and hematology laboratory assessments by visit 
• 
The proportion of subjects who experience laboratory toxicity grade shifts from baseline  
• 
The proportion of subjects who experience treatment-emergent graded laboratory abnormalities 
 
4. 
GENERAL STATISTICAL CONSIDERATIONS 
4.1. 
SAMPLE SIZE AND POWER 
As a non-randomized, single-arm study, there will be no formal statistical analyses. This study is not 
powered for inferential statistical analyses. Thirty subjects will be enrolled at up to 20 investigative sites 
in the United States. 
4.2. 
RANDOMIZATION AND MASKING 
Since this is a non-randomized open-label study, randomization and masking are not applicable. 


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4.3. 
HANDLING OF DATA 
4.3.1. Strata and Covariates 
There are no planned adjustments for covariates. 
4.3.2. Examination of Subject Subsets 
There are no planned subsets. 
4.3.3. Multiple Testing and Comparisons  
Adjustments for multiple comparisons are not applicable. 
4.3.4. Missing Data and Outliers 
Every effort will be made to obtain required data at each scheduled evaluation from all subjects.  See 
section 4.3.6 for details of imputing missing dates.  Unless otherwise specified, other missing data will not 
be imputed. 
Should an adverse event have a missing relationship to study medication, it will be classified as having the 
strongest relationship to study medication.   
4.3.5. Derived and Transformed Data  
For purposes of analysis, subjects who are deemed a clinical failure (see section 4.3.8) due to use of a 
concomitant antibiotic to which the inclusionary pathogen is susceptible for >10 days on any occasion, or 
for >2 courses during any 6-month period, will be programmatically assigned an indeterminate response. 
Signs and symptoms data from the primary infection exam will be combined to derive a composite symptom 
and function score (see section 4.3.8).  
4.3.6. Imputation of Incomplete Dates 
An incomplete date is any date for which either the day, month or year is unknown, but all three fields are 
not unknown. An incomplete date occurs when the exact date an event occurred or ended cannot be obtained 
from a subject.  For many of the analyses, a complete date is necessary in order to determine if the event 
should be included in the analysis (i.e., if the event is treatment-emergent) or to establish the duration of an 
event.  In such cases, incomplete dates will be imputed.  
For purposes of imputation of incomplete start/stop dates for adverse events and prior/concomitant 
medications, missing days will be imputed as the day component of Day 1; missing months/years will be 
imputed as the month/year of Day 1 (defined in section 4.3.8).   
All events with an incomplete end date are assumed to have ended on or before the day the form was 
completed. For scheduled visit data, missing dates will be imputed based on the nominal visit day relative 
to Day 1.  For other data, if the month/year is the same as the Day 1 month/year then the date will be set to 


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the date of Day 1.  In other cases, missing days will be imputed as the day component of Day 1; missing 
months/years will be imputed as the month/year of Day 1.  A list of incomplete and imputed dates will be 
prepared by the project statistician or statistical programmer(s) and will be submitted for review by the 
clinical project manager and sponsor. 
4.3.7. By-Study Visit Displays 
Visits will be presented according to the nominal visit (efficacy analyses) or analysis visit (safety analyses) 
as obtained from the eCRF. For vendor data, the collection date will be used to assign the visit. 
For safety analyses, all data, including scheduled and unscheduled visits, will be windowed to an analysis 
visit as follows: 
Analysis Visit  
Study Day 
Baseline 
Last non-missing value obtained prior to or on the 
day of initiation of study treatment (CEM-102) 
Day 8 
5-11 
Month 1 
23-37 
Month 2 
54-68 
Month 3 
84-98 
Month 4 
115-129 
Month 5 
145-159 
Month 6 
176-190 
Month 9 
260-288 
Month 12 
352-380 
Month 15 
443-471 
Month 18 
535-563 
Month 21 
626-654 
Month 24 
718-746 
 
For each safety outcome, analyses will utilize assessments occurring during the analysis visit windows in 
the table above. Thus, if a subject has a scheduled Month 1 visit that occurs outside of the study day 23-37 
window, the assessment will not be summarized with the Month 1 assessments but will instead be 
considered an unscheduled visit. If both a scheduled and an unscheduled visit occur within an analysis visit 
window, the value taken from the scheduled visit will be used. If multiple scheduled visits occur within an 
analysis visit window, or if multiple unscheduled visits occur and no scheduled visit occurs, then the last 
value will be used.  
For summaries of laboratory values and of treatment-emergent laboratory abnormalities, worst overall post-
baseline values will also be summarized. This will include data from all assessments.         
With the exception of worst overall post-baseline summaries, post-baseline visits that do not occur within 
any analysis visit window will be excluded from the summary presentations, but included in the listings. 


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4.3.8. Definitions and Terminology 
Baseline Value 
For purposes of analysis, the baseline value is defined as the last non-missing value obtained prior to or on 
the day of initiation of study treatment (CEM-102). Because time of initiation of treatment is not captured, 
events defined by the protocol as occurring before treatment initiation will be considered baseline-eligible. 
All pathogens recovered from cultures performed prior to first dose will be considered baseline pathogens. 
Baseline values may come from scheduled or unscheduled visits.   
Study Day  
The date vital signs were collected at the nominal Day 1 visit (a surrogate for the date of first dose of study 
drug) will be considered as study day 1, and the day before vital signs were collected at the nominal Day 1 
visit will be study day -1. 
If an event date is on or after the Day 1 date, then Study Day is calculated as:  
• 
Study Day = event date – date of Day 1+1 
If an event date is prior to the date of Day 1, then Study Day is calculated as:  
• 
Study Day = event date – date of Day 1 
Days on Study 
Days on Study is the number of days from Day 1 to the visit date of the end of study or early termination 
visit. 
Pathogens 
Pathogen determination is based on the genus and species identification from the central laboratory. If the 
local laboratory grows an acceptable pathogen but the central laboratory is not able to grow the isolate, if 
isolates are lost during transportation or storage, or there are major discrepancies between the local and 
central laboratory in the identification of species, the central laboratory will request that the local laboratory 
resend the isolate. The central laboratory identification of genus and species is used for analysis except in 
those cases where there is no central laboratory determination of genus and species. In this case, the local 
laboratory determination is used for pathogen identification. 
The following organisms recovered from baseline specimens obtained during surgery, biopsy or drainage 
procedures (e.g. tissue biopsy, bone biopsy, joint aspirate, etc.) or from blood are considered inclusionary 
pathogens: Staphylococcus aureus (including both methicillin-susceptible S. aureus [MSSA] and 
methicillin-resistant S. aureus [MRSA]), and coagulase-negative staphylococci (CoNS) such as 
Staphylococcus epidermidis, Staphylococcus hominis, or Staphylococcus haemolyticus.  Other pathogens 
include: Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Enterococcus 
faecalis, Enterococcus faecium, Corynebacterium striatum, and Propionibacterium acnes. All isolates, 
including other bacteria not listed here, will be reviewed by the Sponsor on a case-by-case basis to confirm 
BJI pathogen status. Fungal isolates (Candida albicans) will not be considered pathogens. 
S. aureus will be considered methicillin-resistant (MRSA) based on oxacillin susceptibility results (MIC 
≥4 µg/ml; resistant) from the central laboratory. If isolate test results are not available from the central 


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laboratory, MRSA/MSSA designation will be as reported in the eCRF (as part of the organism name). 
MRSA and MSSA will be considered distinct pathogens. 
Investigator Assessment of Clinical Response:  
Clinical success is defined to occur when subjects meet all of the following criteria: 
• 
Subject was not hospitalized due to worsening of the study-qualifying orthopedic infection at any 
point between enrollment and the 6-Month Visit 
• 
Subject did not undergo a definitive surgical procedure (such as amputation) at any point 
between enrollment and the 6-Month Visit 
• 
No additional antibiotics (after completion of companion antibiotics) are required for treatment 
of the orthopedic infection due to the inclusionary pathogen 
• 
Wound is closed, or the open area decreased in size (L x W) and, if a skin graft was done, the 
graft remains viable without evidence of infection 
• 
No purulent discharge from the surgical wound, or new or recurring sinus tract 
• 
No worsening of redness, tenderness, or swelling at the primary infection site 
• 
No bacteremia of the inclusionary pathogen at any point between enrollment and the 6-Month 
Visit 
Clinical failure is defined to occur when subjects meet any of the following criteria: 
• 
Failure to meet all criteria for clinical success 
• 
Death (due to the primary infection) 
• 
Discontinuation of study drug due to an AE and the requirement of additional antibiotics for 
treatment of the primary infection 
An indeterminate response is defined to occur when subjects meet any of the following criteria: 
• 
Subject withdraws consent 
• 
Subject is lost to follow-up 
For purposes of analysis, subjects who are deemed a clinical failure due to use of a concomitant antibiotic 
to which the inclusionary pathogen is susceptible for >10 days on any occasion, or for >2 courses during 
any 6-month period, will be programmatically assigned an indeterminate response. 
 
 
 
 
 
 
 


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Primary Infection Exam (Signs and Symptoms): Baseline Evaluation 
The baseline evaluation for outcome assessments is based on the Screening and Study Day 1 data 
according to the table below: 
 
Screening Visit Evaluation 
Study Day 1 Visit 
Evaluation 
Baseline Evaluation 
Present 
New 
Present 
No change 
Present 
Improved 
Present 
Worsening 
Present 
Not Assessed 
Present 
Resolved 
Absent 
Absent 
New 
Present 
No change 
Absent 
Improved 
N/A 
Worsening 
N/A 
Not Assessed 
Absent 
Resolved 
N/A 
Not Assessed 
New 
Present 
No change 
N/A 
Improved 
N/A 
Worsening 
N/A 
Not Assessed 
Not Assessed 
Resolved 
Absent 
Primary Infection Exam (Signs and Symptoms): Change from Previous Visit  
Change from previous visit for a given endpoint is defined as a qualitative comparison between the 
evaluation during the previous visit to the evaluation at the current visit. The possible responses are: 
 
New                - The sign/symptom was not present during the previous visit and is present at the           
 
                          current visit 
 
No change      - The severity of the sign/symptom has not changed from the previous visit 
 
Improved        - There is improvement from the previous visit, but the sign/symptom has not been  
 
 
             resolved 
 
Worsening      - The sign/symptom has gotten worse from the previous visit 
 
Not assessed   - The sign/symptom was not assessed during the current visit  
 
Resolved         - The sign/symptom has been resolved as of the current visit 
 
Primary Infection Exam (Signs and Symptoms): Composite Symptom and Function Score 
Data from the following signs and symptoms will be combined to derive a composite score: 
Swelling/Edema, Warmth, Redness, Pain at Rest, Pain with Movement, Decreased Mobility, and Limited 
Weight Bearing. The score will be calculated according to the following algorithm: 
 
• 
Each symptom with a baseline evaluation of “Present” will be assigned a value of 7. Each 
symptom with a baseline evaluation of “Absent” or “Not Assessed” will be assigned a value of 0. 


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• 
At each month, the individual sign and symptom scores will be calculated. These will be 
calculated by taking the baseline score and adjusting it in a cumulative manner up to the month 
being reported. The score will be adjusted according to change from previous visit result as 
follows: 
o New – increase by 7.0 
o No Change – no change 
o Improved – decrease by 0.5 
o Worsening – increase by 0.5 
o Not Assessed – no change 
o Resolved – decrease to 0 
• 
At any given timepoint, the composite score is calculated by summing the scores of each sign or 
symptom. 
Treatment-emergent Adverse Event  
Any adverse event reported on the eCRF that occurs on or after the receipt of study drug (Day 1) through 
28 days after the last dose of study drug is considered treatment-emergent.  Events with a missing start date 
or that occur on the date of dosing and have a missing start time will be considered treatment-emergent.  
Treatment-emergent Laboratory Abnormality   
A treatment-emergent laboratory abnormality is defined as an increase of at least one toxicity grade from 
the baseline assessment at any post baseline visit up to and including 28 days after the last dose date of 
study drug administration. If the relevant baseline assessment is missing, then any graded abnormality (i.e., 
at least Grade 1) is considered to be treatment-emergent. 
Laboratory abnormalities will be graded according to the Division of Microbiology and Infection Diseases 
(DMID) 1-4 scale. Values not considered Grade 1 or higher will be classified as “Normal”. Grading 
guidelines are listed in Appendix I.  
Antibiotic and Non-antibiotic Medications 
Antibiotic and non-antibiotic medications are recorded on separate forms of the eCRF. Reasons for 
antibiotic medications are recorded on the eCRF as therapy for the primary infection before enrollment, 
companion antibiotic therapy after enrollment, adjunctive antibiotic therapy for co-infections, or therapy 
for unrelated infections.   
Prior and Concomitant Medications 
A prior medication is defined as any medication taken prior to the date of first dose of study drug (Study 
Day 1). A concomitant medication (including companion and adjunctive antibiotic therapy) is defined as 
any medication that has a stop date that is on or after the date of first dose of study drug, or is ongoing. A 
medication can be considered both prior and concomitant. 
4.4. 
TIMING OF ANALYSES 
An interim analysis will be conducted once the last subject completes the 6-month visit or discontinues the 
study, and the resulting clinical database has been cleaned, quality checked, and locked. A final analysis 
will be conducted once the last subject completes or discontinues the study, and the resulting clinical 
database has been cleaned, quality checked, and locked. 


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5. 
ANALYSIS POPULATIONS 
5.1. 
INTENT TO TREAT (ITT) POPULATION 
The ITT population will include all subjects who were enrolled in the study. To be enrolled, subjects must 
provide informed consent and meet all eligibility criteria. Analysis of subject disposition, demographic and 
baseline disease characteristics, and all efficacy analyses will be conducted using the ITT population. With 
the exception of the inclusion/exclusion criteria and informed consent listing, all listings will be produced 
on the ITT population.   
5.2. 
SAFETY POPULATION 
The safety population will include all subjects who were enrolled and received at least one dose of 
CEM-102. Analysis of concomitant medications received and all safety analyses will be conducted using 
the safety population.   
5.3. 
SCREENED POPULATION 
The screened population will include all subjects who signed the informed consent form (ICF). Screen 
failures are subjects who signed the ICF and were not enrolled in the study. The inclusion/exclusion criteria 
and date of informed consent listing will be produced on the screened population. 
6. 
STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study.  Unless stated otherwise, 
the term “descriptive statistics” refers to number of subjects (n), mean, median, standard deviation (SD), 
minimum, and maximum for continuous data and frequencies and percentages for categorical data.  All 
data collected during the study will be included in data listings. Unless otherwise noted, the data will be 
sorted first by subject number, and then by date within each subject number. 
The statistical analyses will be conducted with the SAS® software package version 9.2 or higher. All 
analyses will be subject to formal verification procedures.  Specifically, results will be verified utilizing 
independent programming prior to issuance of the draft statistical report.  All documents will be verified 
by the lead statistician to ensure accuracy and consistency of analyses. 
6.1. 
SUBJECT DISPOSITION, DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS, DURATION OF TREATMENT  
6.1.1. 
Subject Disposition and Duration of Treatment 
Subject disposition will be presented, including summaries of eligibility, number of subjects who complete 
the study, number of subjects who prematurely discontinued from study, reasons for study discontinuation, 
number of subjects who discontinued study drug, reasons for study drug discontinuation, number of days 
on study, number of days on study drug, and number of subjects who completed each visit. 
Study drug dispensation and accountability will be presented in a listing. 


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6.1.2. 
Demographics and Baseline Characteristics 
Demographic data and baseline characteristics including age, sex, race, ethnicity, height, weight, BMI, 
infection type, site of infection, and risk factors for bone or joint infection will be summarized using 
descriptive statistics for the safety population.  
6.1.3. 
Baseline Pathogens 
The pathogenic organisms identified from baseline (screening or historical) cultures of the primary infection 
site or blood cultures will be summarized. MRSA and MSSA are considered distinct pathogens. The number 
and percentage of subjects with each pathogen will be presented by genus and species for the safety analysis 
population. The same pathogen identified from both the culture of a BJI specimen and/or blood culture will 
be counted only once in the summary.  
A listing will be provided that includes all culture results and will indicate the specimen collection date, 
study day, type of specimen, Gram stain results, organism name (local and central laboratory identification), 
and a flag for whether or not each isolate is considered a baseline or post-baseline pathogen. A by-subject 
listing of isolate MICs, and disk diffusion zone diameters, and susceptibilities (if applicable) will also be 
provided. Isolates are considered susceptible (S), intermediate (I), or resistant (R) to CEM-102 according 
to Table 1.  
Table 1 
Provisional Interpretative Criteria for Fusidic Acid (CEM-102) 
 
Broth Microdilution MIC (μg/mL) 
Disk Diffusion Zone Diameter (mm) 
Susceptible 
Intermediate 
Resistant 
Susceptible 
Intermediate Resistant 
Staphylococcus 
species 
≤ 1 
2 
≥ 4 
≥ 22 
20-21 
≤ 19 
β-hemolytic 
streptococcia 
≤ 1 
2-8 
≥ 16 
≥ 16 
11-15 
≤ 10 
a.  Includes: Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae 
6.1.4. 
Concomitant Medications 
Prior and concomitant medications will be coded using the World Heath Organization (WHO) Drug 
dictionary (September 2015).  Antibiotic and non-antibiotic concomitant medications will be summarized 
by frequency of classification and generic name. Antibiotic concomitant medications will be summarized 
separately for primary infections before enrollment, companion antibiotics, co-infections, and unrelated or 
other antibiotics.  Prior and concomitant medications will be presented in a data listing. 
6.2. 
EFFICACY 
The counts and percentages of subjects who have clinical success, clinical failure, and an indeterminate 
clinical response, and reasons for clinical failure and indeterminate response will be summarized at the 6-
Month, 9-Month, 12-Month, 15-Month, 18-Month, 21-Month, and 24-Month Visits. Exact, binomial 95% 
confidence intervals will be provided for the percentage of subjects who have clinical success at each visit. 


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The composite symptom and function score and change from baseline score will be summarized by visit. 
Only subjects who are on study drug at a given visit will be included in the summary for that visit. As an 
exploratory analysis to examine the relationship between the composite symptom and function score and 
the proportion of subjects who meet all the criteria for clinical success, a logistic regression model of the 
probability of clinical success with a fixed effect for composite symptom and function score will be 
performed. For this analysis, an indeterminate response will be considered a failure.  
Wound status will be characterized by three signs/symptoms from the primary infection exam: Sinus tract 
formation, open wound, and drainage. A subject will be considered to have a sign/symptom at a given visit 
if it is newly present or not resolved. The counts and percentages of subjects who have each sign/symptom 
will be presented separately. Additionally, the counts and percentages of subjects who have none of the 
three signs/symptoms and one or more of the signs/symptoms will be presented.                
Changes in primary infection site signs and symptoms and inflammation lab results will each be presented 
in a listing. 
A spaghetti plot of individual subject erythrocyte sedimentation rate values by study day will be generated 
for timepoints where the subject is either on study drug or off study drug and being followed for relapse. 
 The number of subjects with a pathogen showing decreasing susceptibility will be assessed manually by 
the Sponsor using the by-subject isolate susceptibility listing. Decreasing susceptibility of a pathogen is 
defined as a 4-fold or greater increase in CEM-102 MIC from baseline to any subsequent study time point.  
6.3. 
SAFETY 
6.3.1. 
Adverse Events 
Adverse events will be coded for preferred term and system organ classification by the Medical Dictionary 
for Regulatory Activities (MedDRA) version 18.1. 
If a subject experiences multiple events that map to a single preferred term, the greatest severity and/or 
strongest investigator assessment of relation to study medication will be assigned to the preferred term for 
the appropriate summaries.  Should an event have a missing relationship, it will be classified as having the 
strongest relationship to study medication.   
A high level summary table of the number and percentage of subjects who experience any AE, any TEAE, 
any TEAE with severe intensity, any TEAE related to study drug, any TEAE leading to study 
discontinuation, any TEAE leading to study drug discontinuation, any treatment-emergent serious adverse 
event (SAE), any treatment-emergent SAE related to study drug, any treatment-emergent SAE leading to 
study discontinuation, and any treatment-emergent SAE leading to study drug discontinuation will be 
provided. 
Summaries of treatment-emergent AEs will include any AEs starting on or after the initiation of study 
treatment through 28 days after the last dose of study drug. The occurrence of TEAEs will be summarized 
using preferred terms and system organ classifications.  Separate summaries of TEAEs overall and by 
greatest severity, TEAEs related to study drug (overall and by greatest severity), TEAEs leading to 
discontinuation of study or study drug, treatment-emergent SAEs and treatment-emergent SAEs leading to 


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death will be presented.   
All adverse event data listings will include the individual subjects showing both verbatim and preferred 
terms and system organ classification.  All adverse events that occurred prior to the initiation of the study 
treatment will be excluded from the tables.  All adverse events will be included in the listings.  
Missing onset dates will be imputed as previously outlined in Section 4.3.6 to determine treatment-emergent 
status. 
6.3.2. 
Clinical Laboratory Assessments   
Descriptive summaries of selected clinical laboratory results as well as change from baseline values will be 
presented by analysis visit and worst overall post-baseline value. Selected laboratory parameters to be 
summarized include: ALT, AST, ALP, total bilirubin, creatine kinase, creatinine, WBC count, hematocrit, 
and platelets. Frequency and percentage of subjects experiencing treatment-emergent laboratory 
abnormalities (by Grade) will be summarized by analysis visit and worst overall post-baseline value. If 
criteria in both directions are shown for a single parameter, then abnormalities in each direction will be 
summarized separately. Laboratory toxicity grade shifts from baseline will also be summarized by analysis 
visit and worst overall post-baseline value.  
All clinical laboratory test results will be provided in a listing. The listing will include the laboratory test 
value, change from baseline, and toxicity grade.  
6.3.3. 
Other Safety Analyses 
Vital sign results and all physical examination data will each be provided in a listing. 
6.4. 
PHARMACOKINETICS ANALYSES 
CEM-102 plasma concentrations will be presented in a listing. Analysis of plasma concentration data will 
be presented in a separate PK Report. 
7. 
PROTOCOL DEVIATIONS 
Protocol deviations identified by clinical monitoring will be provided in a data listing.  
8. 
CHANGES IN THE PLANNED ANALYSES 
For purposes of analysis, subjects who are deemed a clinical failure due to use of a concomitant antibiotic 
to which the inclusionary pathogen is susceptible for >10 days on any occasion, or for >2 courses during 
any 6-month period, will be programmatically assigned an indeterminate response.   
No other deviations in the conduct of the study or the planned analysis are anticipated.  Should any 
deviations from the analyses specified in the authorized statistical analysis plan arise, such deviations will 
be documented in the final clinical study report. 


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9. 
REFERENCES 
None. 
10. 
REVISION HISTORY 
Date 
Revision 
Rationale 
 
 
 
 


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11. 
PROGRAMMING CONVENTIONS 
• 
Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in landscape 
orientation.  There should be a minimum of a 1.25” boundary on the upper (bound) edge, and a 
minimum of a 1.0” boundary on the remaining three edges.  Output should be printed in Courier New 
with a point size of 8.  Titles may be printed using a larger font (e.g., Arial point size 10). 
• 
Identification of analysis population: Every summary table and figure should clearly specify the 
analysis population being summarized.  Listings will be prepared for all enrolled subjects. 
• 
Group headers: In the summary tables, the group headers will identify the dose cohort and the within-
group sample size for the indicated analysis population.  Of note, the header’s sample size does not 
necessarily equal the number of subjects actually summarized within any given summary module; 
some subjects in the analysis population may have missing values and thus may not be summarized. 
• 
Suppression of percentages corresponding to null categories: When count data are presented as 
category frequencies and corresponding percentages, the percent should be suppressed when the 
count is zero in order to draw attention to the non-zero counts. 
• 
Presentation of sample sizes: Summary modules should indicate, in one way or another, the number 
of subjects actually contributing to the summary statistics presented in any given summary module.  
As mentioned above, this may be less than the number of subjects in the analysis population. 
♦ In the quantitative modules describing continuous variables (and thus presenting sample size, 
means, and standard deviations), the sample size should be the number of non-missing 
observations 
♦ For categorical variables that are presented in frequency tables, the module should present the 
total count in addition to the count in each category.  Percentages should be calculated using this 
total as the denominator, and the percentage corresponding to the sum itself (that is, 100%) 
should be presented so as to indicate clearly to a reviewer the method of calculation. 
• 
Sorting: Listings will be sorted by subject number, dose cohort, and date, if applicable.  Listings with 
multiple observations per subject will be sorted by subject number, dose cohort, treatment and date, if 
applicable.  If a listing is sorted in a different manner, a footnote will indicate as such.  
• 
General formatting rules: Rounding for all variables will occur only as the last step, immediately prior 
to presentation in listings, tables, and figures.  No intermediate rounding will be performed on derived 
variables.  The standard rounding practice of rounding numbers ending in 0-4 down and numbers 
ending in 5-9 up will be employed.   
• 
The presentation of numerical values will adhere to the following guidelines:  
♦ Raw measurements will be reported to the number of significant digits as captured on the eCRFs.   
♦ Standard deviations will be reported to one decimal place beyond the number of decimal places 
the original parameter is presented. 


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♦ Means will be reported to the same number of significant digits as the parameter.  
♦ Calculated percentages will be reported with no decimals. 
• 
Dates will be formatted as DDMMMYYYY.  Partial dates will be presented on data listings as 
recorded on CRFs. 
♦ Time will be presented according to the 24-hour clock (HHMM). 
 


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12. 
PROPOSED TABLES, LISTINGS, AND FIGURES 
Summary Tables 
Demography and Baseline Characteristics 
14.1.1   
Subject Disposition and Treatment Duration, ITT Population 
14.1.2   
Demographics and Baseline Characteristics, ITT Population 
14.1.3   
Pathogens Identified at Baseline, ITT Population 
14.1.4  
Concomitant Medications by Generic Name and Drug Classification, Safety Population 
Efficacy 
14.2.1 
Investigator Assessment of Response and Reasons for Failure or Indeterminate   
            
Response by Visit, ITT Population 
14.2.2  
Composite Symptom and Function Score by Visit, ITT Population 
14.2.3  
Wound Status by Visit, ITT Population 
Safety 
14.3.1.1  
Overall Adverse Events, Safety Population 
14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Classification, Preferred Term, 
Overall and by Greatest Severity, Safety Population 
14.3.1.3  
Treatment-Emergent Adverse Events Related to Study Drug by System Organ 
Classification and Preferred Term, Overall and by Greatest Severity, Safety Population 
14.3.2.1  
Treatment-Emergent Adverse Events Leading to Discontinuation of Study by System 
Organ Classification and Preferred Term, Safety Population 
14.3.2.2  
Treatment-Emergent Adverse Events Leading to Discontinuation of Study Drug by 
System Organ Classification and Preferred Term, Safety Population  
14.3.2.3  
Treatment-Emergent Serious Adverse Events by System Organ Classification and 
Preferred Term, Safety Population 
14.3.2.4  
Treatment-Emergent Adverse Events Leading to Death by System Organ Classification 
and Preferred Term, Safety Population 
14.3.4.1.1  
Selected Chemistry Laboratory Values by Parameter and Visit, Safety Population 
14.3.4.1.2  
Selected Hematology Laboratory Values by Parameter and Visit, Safety Population 
14.3.4.2  
Laboratory Toxicity Grade Shifts from Baseline, Safety Population 
14.3.4.3  
Treatment-Emergent Graded Laboratory Abnormalities, Safety Population 
Figures 
14.2.1  
Individual Erythrocyte Sedimentation Rate Values by Study Month, Safety Population 
Data Listings 
16.1.6  
Study Drug Dispensation and Accountability, ITT Population 
16.2.1.1  
Subject Disposition, ITT Population 
16.2.1.2  
Inclusion/Exclusion Criteria and Date of Informed Consent, Screened Population 
16.2.2.1  
Protocol Deviations/Violations, ITT Population 
16.2.4.1 
Demographics, Baseline Characteristics, and Infection Type, ITT Population 
16.2.4.2 
Primary Infection History, ITT Population 
16.2.4.3 
Medical History and Risk Factors for BJI, ITT Population 


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16.2.5.1.1 
Prior and Concomitant Antibiotics, ITT Population 
16.2.5.1.2 
Prior and Concomitant Medications, ITT Population  
16.2.5.2 
CEM-102 Plasma Concentrations, ITT Population 
16.2.6.1 
Investigator Assessment of Response and Reasons for Failure or Indeterminate Response  
 
 
at each Visit, ITT Population 
16.2.6.2  
Primary Infection Examination (Signs and Symptoms) at each Visit, ITT Population   
16.2.6.3  
Inflammation Laboratory Test Results, ITT Population 
16.2.6.4             Microbiological Culture Results, ITT Population 
16.2.6.5             Antibiotic Susceptibility Results, ITT Population 
16.2.7.1 
Adverse Events, ITT Population  
16.2.8.1.1  
Chemistry Laboratory Tests, ITT Population 
16.2.8.1.2  
Hematology Laboratory Tests, ITT Population 
16.2.8.2 
Surgical Interventions, ITT Population 
16.2.8.3 
BJI Imaging, ITT Population 
16.2.8.4  
Vital Signs, Height, and Weight, ITT Population 
16.2.8.5 
Abnormal Physical Examination Findings, ITT Population  
 


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13. 
APPENDIX I – TOXICITY GRADING 
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES, DIVISION OF 
MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) ADULT TOXICITY TABLE 
(MODIFIED) 
NOVEMBER 2007 - DRAFT 
ABBREVIATIONS: Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal                LLN = Lower Limit of Normal 
Rx = Therapy                                            Req = Required 
Mod = Moderate                                       IV = Intravenous 
ADL = Activities of Daily Living            Dec = Decreased 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables, use the scale below to estimate 
grade of severity: 
GRADE 1 (Mild): Transient or mild discomfort; no medical intervention/therapy required 
 
GRADE 2 (Moderate): Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required 
 
GRADE 3 (Severe): Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible. 
 
GRADE 4 (Life-threatening): Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. 
 
 
 
 
 
 
 
 
 


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LABORATORY RANGES 
Where discrepancies in the ULN and LLN of laboratory ranges occur between those included in 
this document and those of the laboratory that performs the assays, the values provided by the 
laboratory will be used for assignment of severity grade. 
 
HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0 - 9.4 gm/dL 
 6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000-
99,999/mm3 
50,000-
74,999/mm3 
20,000-
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000-
30,000/mm3 
>30,000 or <1,000 
mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
 > 80% 
90 – 95% 
>95% 
--------- 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
 123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or 
abnormal sodium 
with mental status 
changes or 
seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or 
abnormal sodium 
with mental status 
changes or 
seizures 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or 
abnormal 
potassium with 
paresis, ileus or 
life-threatening 
arrhythmia 


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Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/L 
> 7.0 mEq/L or 
abnormal 
potassium  with 
life-threatening 
arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or 
abnormal glucose 
with mental status 
changes or coma 
Hyperglycemia 
(nonfasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or 
abnormal glucose 
with ketoacidosis 
or seizures 
Hypocalcemia 
(corrected for albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or 
abnormal calcium 
with life threatening 
arrhythmia or 
tetany 
Hypercalcemia 
(corrected for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or 
abnormal calcium 
with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or 
abnormal 
magnesium with 
life-threatening 
arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL or 
replacement Rx 
required 
1.0 -1.4 mg/dL 
intensive therapy 
or hospitalization 
required 
< 1.0 mg/dL or 
abnormal 
phosphate with life-
threatening 
arrhythmia 
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x ULN 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia 
(when other liver 
function tests are in 
the  normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 


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BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Creatinine 
1.1 - 1.5 x ULN  
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or 
dialysis required 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
 


CEM-102 Pharmaceuticals, Inc. 
CE06-302 
Statistical Analysis Plan     
 Amendment 1 Final Version 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
CEM-102 Pharmaceuticals, Inc. 
STATISTICAL ANALYSIS PLAN 
Study Title: 
An Open-Label, Non-Randomized, Single-Arm Multi-Center 
Study to Evaluate Oral Sodium Fusidate (CEM-102) for the 
Treatment of Staphylococcal Bone or Joint Infections in 
Subjects for whom Chronic Antibiotic Suppressive Therapy is 
Indicated 
Phase: 
2/3 
Protocol No.: 
CE06-302 
Protocol Date 
Original Protocol: 07 July 2015 
Analysis Plan Version and 
Date 
Final Version, 19 October 2017 
Amendment 1, 04 December 2017 
Prepared By: 
Andrew Garrison, MS 
PharPoint Research, Inc. 
5003 S. Miami Blvd, Suite 100 
Durham, NC 27703 
Prepared For: 
CEM-102 Pharmaceuticals, Inc. 
6320 Quadrangle Drive, Suite 360 
Chapel Hill, NC 27517 




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CE06-302 
 
Statistical Analysis Plan                                                                                                      Amendment 1 Final Version                              
 
 
 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ..................................... 2 
1. 
INTRODUCTION .................................................................................................... 5 
1.1. 
Study Overview .............................................................................................................................. 5 
1.2. 
Schedule of Assessments/Procedures........................................................................................ 6 
1.3. 
List of abbreviations ...................................................................................................................... 8 
2. 
OBJECTIVE ............................................................................................................ 9 
3. 
ENDPOINTS ............................................................................................................ 9 
4. 
GENERAL STATISTICAL CONSIDERATIONS ..................................................... 9 
4.1. 
Sample Size and Power ................................................................................................................. 9 
4.2. 
Randomization and Masking ........................................................................................................ 9 
4.3. 
Handling of Data ........................................................................................................................... 10 
4.3.1. 
Strata and Covariates .................................................................................................................... 10 
4.3.2. 
Examination of Subject Subsets ..................................................................................................... 10 
4.3.3. 
Multiple Testing and Comparisons ................................................................................................. 10 
4.3.4. 
Missing Data and Outliers ............................................................................................................. 10 
4.3.5. 
Derived and Transformed Data ...................................................................................................... 10 
4.3.6. 
Imputation of Incomplete Dates ..................................................................................................... 10 
4.3.7. 
By-Study Visit Displays ................................................................................................................ 11 
4.3.8. 
Definitions and Terminology ......................................................................................................... 12 
4.4. 
Timing Of Analyses ...................................................................................................................... 15 
5. 
ANALYSIS POPULATIONS .................................................................................. 16 
5.1. 
Intent To Treat (ITT) Population .................................................................................................. 16 
5.2. 
Safety Population ......................................................................................................................... 16 
5.3. 
Screened Population ................................................................................................................... 16 
6. 
STATISTICAL METHODS .................................................................................... 16 
6.1. 
Subject Disposition, Demographic and Baseline Characteristics, Duration of Treatment .. 16 


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6.1.1. 
Subject Disposition and Duration of Treatment ............................................................................... 16 
6.1.2. 
Demographics and Baseline Characteristics .................................................................................... 17 
6.1.3. 
Baseline Pathogens ....................................................................................................................... 17 
6.1.4. 
Concomitant Medications.............................................................................................................. 17 
6.2. 
Efficacy ......................................................................................................................................... 17 
6.3. 
Safety............................................................................................................................................. 18 
6.3.1. 
Adverse Events ............................................................................................................................ 18 
6.3.2. 
Clinical Laboratory Assessments ................................................................................................... 19 
6.3.3. 
Other Safety Analyses .................................................................................................................. 19 
6.4. 
Pharmacokinetics Analyses ....................................................................................................... 19 
7. 
PROTOCOL DEVIATIONS ................................................................................... 19 
8. 
CHANGES IN THE PLANNED ANALYSES .......................................................... 19 
9. 
REFERENCES ....................................................................................................... 20 
10. REVISION HISTORY ............................................................................................ 20 
11. PROGRAMMING CONVENTIONS ....................................................................... 21 
12. PROPOSED TABLES, LISTINGS, AND FIGURES ................................................ 23 
13. APPENDIX I – TOXICITY GRADING................................................................... 25 
 


CEM-102 Pharmaceuticals, Inc.  
CE06-302 
 
Statistical Analysis Plan                                                                                                      Amendment 1 Final Version                              
 
 
 
CONFIDENTIAL 
Page 5 
04 December 2017 
1. 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the summary and 
analysis of efficacy and safety data from Protocol CE06-302.  Background information is provided for the 
overall study design and objectives.  The reader is referred to the study protocol and electronic case report 
forms (eCRFs) for details of study conduct and data collection, and to the Pharmacokinetics (PK) Report 
for the analysis of plasma concentrations of CEM-102. 
1.1. 
STUDY OVERVIEW 
Protocol CE06-302 is a phase 2/3, prospective, open-label, non-randomized, single-arm trial to evaluate 
the safety and effectiveness of CEM-102 for chronic antibiotic suppressive therapy of bone or joint 
infections. Subjects enrolling in this study must have a suspected or confirmed staphylococcal bone or 
joint infection due to an inclusionary pathogen susceptible to CEM-102 that requires suppressive 
antibiotic therapy. The infection should be demonstrated from a positive culture from samples obtained 
during surgery, biopsy, or drainage procedures within 6 weeks prior to enrollment. If the subject does not 
have a positive culture, the Investigator must provide documentation as to why the subject is suspected to 
have a staphylococcal infection and discuss with the medical monitor for approval of enrollment. 
 
This study comprises two parts: Part A (enrollment through the 6-month visit) and Part B (6 to 24 months 
post-enrollment). In Part A, all subjects will receive 6 months of CEM-102 treatment. The Investigator 
will evaluate each subject completing Part A for clinical response at the 6-month visit (primary endpoint). 
For Part B, a subject who completes Part A and, in the Investigator’s opinion, requires continued 
suppressive therapy, may continue to receive CEM-102. Alternatively, if the Investigator considers the 
infection resolved and that no further antibiotic therapy is required, study drug will be discontinued and 
the subject followed for evidence of relapse until the end of study (EOS; 24 months). 
 
During the first 6 months of treatment, study Part A, subjects will be monitored monthly (±1 week) for 
safety and clinical response to CEM-102. During study Part B, subjects will be monitored every 3 months 
(±2 weeks) until the EOS Visit (24 months). 
 
 
 


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1.2. 
SCHEDULE OF ASSESSMENTS/PROCEDURES 
Assessment/Procedure 
Screeninga 
Part A 
Part B 
End of 
Study 
(EOS)d 
Enrollment 
(Day 1 Visit)b,c 
 
Day 8 
(± 3 days) 
 
Monthly During 
First 6 Months 
(±1 week) 
Every 3 Months From 
Month 6 until End of 
Study (±2weeks) 
Informed Consent Form 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
X 
 
 
 
 
Review of Clinical/ Surgical History 
X 
X 
X 
X 
X 
X 
Microbiological specimens for culture 
X 
X 
Xe 
Xe 
Xe 
Xe 
Enrollment 
X 
X 
 
 
 
 
Vital Signsf 
X 
X 
X 
X 
X 
X 
Limited Physical Examinationg 
X 
X 
X 
X 
X 
X 
Examination of Infected Areah 
X 
X 
X 
X 
X 
X 
Safety Laboratory Assessmentsi 
X 
X 
X 
X 
X 
X 
Inflammation Laboratory Assessmentsj 
X 
X 
 
X 
X 
X 
CEM-102 Administrationk 
 
X 
 
 
 
 
Pharmacokinetic Blood Sampling 
 
 
 
Xo 
 
 
Dispense Oral antibiotic to Subjectsl 
 
X 
X 
X 
X 
 
Perform Drug Accountability 
 
 
X 
X 
X 
X 
Record 6-Month History of Prior 
Antibiotic Used to Treat the Primary 
Infection Leading to Enrollment 
X 
 
 
 
 
 
Record Concomitant Medications 
X 
X 
X 
X 
X 
X 
Record AEsm 
X 
X 
X 
X 
X 
X 
Investigator Assessment of Clinical 
Responsen 
 
 
 
X 
X 
X 


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a. Within 6 weeks prior to enrollment, subjects must have a positive culture with an inclusionary pathogen susceptible to CEM-102, demonstrated from a culture from samples obtained during surgery, 
biopsy, or drainage procedures. If subject does not have a confirmatory culture result, the Investigator must provide documentation as to why subject is suspected to have a staphylococcal infection and 
must discuss the subject with the medical monitor for approval of enrollment. 
b. Enrollment is contingent on demonstration that subject fulfills the inclusion/exclusion criteria. 
c. Study Day 1 corresponds to the first day of dosing with CEM-102. 
d. Subjects who discontinue CEM-102 because of an adverse event (AE) or clinical failure should have a study visit around the time of drug discontinuation and will continue to be followed, as needed, 
for appropriate observation of treatment-related AEs until AEs have resolved or stabilized. If a subject withdraws from the study at any time, for any reason, the EOS visit will be performed around that 
time. Those subjects who continue CEM-102 until the Month 24 visit will undergo the assessments/procedures for the EOS visit. At study closure, at the discretion of the Investigator, subjects may be 
rolled over into an expanded access protocol to receive chronic suppressive CEM-102 therapy. 
e. If clinically indicated, microbiological samples (tissue surrounding the foreign material, synovial fluid, bone, etc.) obtained during the study should be submitted to the local laboratory for aerobic and 
anaerobic culture and susceptibility testing, including to CEM-102. All isolated bacteria are to be sub-cultured and shipped to the central microbiology laboratory for organism confirmation and 
confirmatory susceptibility testing. 
f. Vital sign measurements include height, weight, temperature, heart rate, respiratory rate, and blood pressure. Results are to be recorded in the eCRF. 
g. Limited physical examination may include HEENT, cardiovascular, pulmonary, gastrointestinal, skin, lymph nodes, musculoskeletal, and extremities, among others. Results are to be documented in 
source and recorded in the eCRF. 
h. Examination of the infected area will include the following assessments: pain, erythema, mobility, joint stability, wound closure, wound drainage, and weight bearing [for back and lower extremity 
infections]. The Investigator will state whether the infected area seems to have improved, deteriorated, or remained unchanged. Results are to be documented in the source and recorded in the eCRF. 
i. Safety laboratory assessments will be performed at the local laboratory and will include the following: serum chemistry (ALT, AST, alkaline phosphatase [ALP], total and direct bilirubin, blood urea 
nitrogen [BUN], creatinine, albumin, total protein, sodium, total carbon dioxide, glucose, potassium, chloride, calcium, phosphorus, and CPK). For female subjects of child bearing potential, a urine or 
serum pregnancy test will be performed at Screening and will be repeated at subsequent visits per Investigator’s discretion . 
j. Laboratory measurements of markers of inflammation will be performed at the local laboratory and will include the following: hematology (complete blood count [CBC] with differential), erythrocyte 
sedimentation rate [ESR], and C-reactive protein [CRP]). Laboratory measurements of markers of inflammation obtained on the day of a surgery or debridement should be performed before the 
procedure when possible, because levels of these markers are known to increase after surgery. 
k. A CEM-102 loading dose strategy is utilized, in which CEM-102 is given as 1500 mg every 12 hours for 2 doses followed by 600 mg every 12 hours thereafter. 
l. After 6 months of therapy, the Investigator may decide to continue chronic suppressive therapy with CEM-102 or discontinue CEM-102 due to clinical cure and no further requirement for antibiotic 
therapy. Subjects who stop treatment will continue to be followed on the same schedule as those who remain on therapy to monitor for infection relapse until the end of the study. Subjects who 
discontinue CEM-102 due to clinical failure should have an EOS visit at that time. 
m. All AEs will be collected following signing of the ICF. 
n. The Investigator will assess clinical response at Months 6, 9, 12, 15, 18, 21, 24 and at EOS. 
o. Pharmacokinetic blood sampling will be conducted at the 3-month visit as described in Section 10.6 


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1.3. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
Alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CEM-102 
sodium fusidate (fusidic acid) 
CPK 
creatinine phosphokinase 
CRP 
C-reactive protein 
HEENT 
head, eyes, ears, nose, throat 
ICF 
informed consent form 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic 
SAE 
serious AE 
TEAE 
treatment-emergent AE 
WBC 
white blood cell 


CEM-102 Pharmaceuticals, Inc.  
CE06-302 
 
Statistical Analysis Plan                                                                                                      Amendment 1 Final Version                              
 
 
 
CONFIDENTIAL 
Page 9 
04 December 2017 
2. 
OBJECTIVE 
The study objective is to evaluate the safety and effectiveness of CEM-102 as chronic antibiotic 
suppressive therapy in subjects with staphylococcal bone or joint infections. 
3. 
ENDPOINTS 
Primary Endpoint 
The primary endpoint will be the proportion of subjects in the safety population who meet all the criteria 
for clinical success at the 6-Month Visit. 
Secondary Endpoints 
Efficacy  
 
The proportion of subjects in the safety population who meet all criteria for clinical success at the 
9-Month, 12-Month, 15-Month, 18-Month, 21-Month, and 24-Month Visits 
Safety and Tolerability 
 
The proportion of subjects in the safety population who experience a treatment-emergent adverse 
event (TEAE), a serious adverse event (SAE), an SAE that results in death, or a TEAE that 
results in discontinuation from study or study drug 
Additional Endpoints 
Efficacy 
 
Change in composite symptom and function score at each Visit 
 
Change in wound status at each Visit 
 
Change in ESR as a surrogate marker of infection status over time 
Safety and Tolerability 
 
Changes from baseline in selected chemistry and hematology laboratory assessments by visit 
 
The proportion of subjects who experience laboratory toxicity grade shifts from baseline  
 
The proportion of subjects who experience treatment-emergent graded laboratory abnormalities 
 
4. 
GENERAL STATISTICAL CONSIDERATIONS 
4.1. 
SAMPLE SIZE AND POWER 
As a non-randomized, single-arm study, there will be no formal statistical analyses. This study is not 
powered for inferential statistical analyses. Thirty subjects will be enrolled at up to 20 investigative sites 
in the United States. 
4.2. 
RANDOMIZATION AND MASKING 
Since this is a non-randomized open-label study, randomization and masking are not applicable. 


CEM-102 Pharmaceuticals, Inc.  
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4.3. 
HANDLING OF DATA 
4.3.1. Strata and Covariates 
There are no planned adjustments for covariates. 
4.3.2. Examination of Subject Subsets 
There are no planned subsets. 
4.3.3. Multiple Testing and Comparisons  
Adjustments for multiple comparisons are not applicable. 
4.3.4. Missing Data and Outliers 
Every effort will be made to obtain required data at each scheduled evaluation from all subjects.  See section 
4.3.6 for details of imputing missing dates.  Unless otherwise specified, other missing data will not be 
imputed. 
Should an adverse event have a missing relationship to study medication, it will be classified as having the 
strongest relationship to study medication.   
4.3.5. Derived and Transformed Data  
For purposes of analysis, subjects who are deemed a clinical failure (see section 4.3.8) due to use of a 
concomitant antibiotic to which the inclusionary pathogen is susceptible for >10 days on any occasion, or 
for >2 courses during any 6-month period, will be programmatically assigned an indeterminate response. 
Signs and symptoms data from the primary infection exam will be combined to derive a composite symptom 
and function score (see section 4.3.8).  
4.3.6. Imputation of Incomplete Dates 
An incomplete date is any date for which either the day, month or year is unknown, but all three fields are 
not unknown. An incomplete date occurs when the exact date an event occurred or ended cannot be obtained 
from a subject.  For many of the analyses, a complete date is necessary in order to determine if the event 
should be included in the analysis (i.e., if the event is treatment-emergent) or to establish the duration of an 
event.  In such cases, incomplete dates will be imputed.  
For purposes of imputation of incomplete start/stop dates for adverse events and prior/concomitant 
medications, missing days will be imputed as the day component of Day 1; missing months/years will be 
imputed as the month/year of Day 1 (defined in section 4.3.8).   
All events with an incomplete end date are assumed to have ended on or before the day the form was 
completed. For scheduled visit data, missing dates will be imputed based on the nominal visit day relative 
to Day 1.  For other data, if the month/year is the same as the Day 1 month/year then the date will be set to 


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the date of Day 1.  In other cases, missing days will be imputed as the day component of Day 1; missing 
months/years will be imputed as the month/year of Day 1.  A list of incomplete and imputed dates will be 
prepared by the project statistician or statistical programmer(s) and will be submitted for review by the 
clinical project manager and sponsor. 
4.3.7. By-Study Visit Displays 
Visits will be presented according to the nominal visit (efficacy analyses) or analysis visit (safety analyses) 
as obtained from the eCRF. For vendor data, the collection date will be used to assign the visit. 
For safety analyses, all data, including scheduled and unscheduled visits, will be windowed to an analysis 
visit as follows: 
Analysis Visit  
Study Day 
Baseline 
Last non-missing value obtained prior to or on the 
day of initiation of study treatment (CEM-102) 
Day 8 
5-11 
Month 1 
23-37 
Month 2 
54-68 
Month 3 
84-98 
Month 4 
115-129 
Month 5 
145-159 
Month 6 
176-190 
Month 9 
260-288 
Month 12 
352-380 
Month 15 
443-471 
Month 18 
535-563 
Month 21 
626-654 
Month 24 
718-746 
 
For each safety outcome, analyses will utilize assessments occurring during the analysis visit windows in 
the table above. Thus, if a subject has a scheduled Month 1 visit that occurs outside of the study day 23-37 
window, the assessment will not be summarized with the Month 1 assessments but will instead be 
considered an unscheduled visit. If both a scheduled and an unscheduled visit occur within an analysis visit 
window, the value taken from the scheduled visit will be used. If multiple scheduled visits occur within an 
analysis visit window, or if multiple unscheduled visits occur and no scheduled visit occurs, then the last 
value will be used.  
For summaries of laboratory values and of treatment-emergent laboratory abnormalities, worst overall post-
baseline values will also be summarized. This will include data from all assessments.         
With the exception of worst overall post-baseline summaries, post-baseline visits that do not occur within 
any analysis visit window will be excluded from the summary presentations, but included in the listings. 


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4.3.8. Definitions and Terminology 
Baseline Value 
For purposes of analysis, the baseline value is defined as the last non-missing value obtained prior to or on 
the day of initiation of study treatment (CEM-102). Because time of initiation of treatment is not captured, 
events defined by the protocol as occurring before treatment initiation will be considered baseline-eligible. 
All pathogens recovered from cultures performed prior to first dose will be considered baseline pathogens. 
Baseline values may come from scheduled or unscheduled visits.   
Study Day  
The date vital signs were collected at the nominal Day 1 visit (a surrogate for the date of first dose of study 
drug) will be considered as study day 1, and the day before vital signs were collected at the nominal Day 1 
visit will be study day -1. 
If an event date is on or after the Day 1 date, then Study Day is calculated as:  
 
Study Day = event date – date of Day 1+1 
If an event date is prior to the date of Day 1, then Study Day is calculated as:  
 
Study Day = event date – date of Day 1 
Days on Study 
Days on Study is the number of days from Day 1 to the visit date of the end of study or early termination 
visit. 
Pathogens 
Pathogen determination is based on the genus and species identification from the central laboratory. If the 
local laboratory grows an acceptable pathogen but the central laboratory is not able to grow the isolate, if 
isolates are lost during transportation or storage, or there are major discrepancies between the local and 
central laboratory in the identification of species, the central laboratory will request that the local laboratory 
resend the isolate. The central laboratory identification of genus and species is used for analysis except in 
those cases where there is no central laboratory determination of genus and species. In this case, the local 
laboratory determination is used for pathogen identification. 
The following organisms recovered from baseline specimens obtained during surgery, biopsy or drainage 
procedures (e.g. tissue biopsy, bone biopsy, joint aspirate, etc.) or from blood are considered inclusionary 
pathogens: Staphylococcus aureus (including both methicillin-susceptible S. aureus [MSSA] and 
methicillin-resistant S. aureus [MRSA]), and coagulase-negative staphylococci (CoNS) such as 
Staphylococcus epidermidis, Staphylococcus hominis, or Staphylococcus haemolyticus.  Other pathogens 
include: Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Enterococcus 
faecalis, Enterococcus faecium, Corynebacterium striatum, and Propionibacterium acnes. All isolates, 
including other bacteria not listed here, will be reviewed by the Sponsor on a case-by-case basis to confirm 
BJI pathogen status. Fungal isolates (Candida albicans) will not be considered pathogens. 
S. aureus will be considered methicillin-resistant (MRSA) based on oxacillin susceptibility results (MIC 
≥4 µg/ml; resistant) from the central laboratory. If isolate test results are not available from the central 


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laboratory, MRSA/MSSA designation will be as reported in the eCRF (as part of the organism name). 
MRSA and MSSA will be considered distinct pathogens. 
Investigator Assessment of Clinical Response:  
Clinical success is defined to occur when subjects meet all of the following criteria: 
 
Subject was not hospitalized due to worsening of the study-qualifying orthopedic infection at any 
point between enrollment and the 6-Month Visit 
 
Subject did not undergo a definitive surgical procedure (such as amputation) at any point 
between enrollment and the 6-Month Visit 
 
No additional antibiotics (after completion of companion antibiotics) are required for treatment 
of the orthopedic infection due to the inclusionary pathogen 
 
Wound is closed, or the open area decreased in size (L x W) and, if a skin graft was done, the 
graft remains viable without evidence of infection 
 
No purulent discharge from the surgical wound, or new or recurring sinus tract 
 
No worsening of redness, tenderness, or swelling at the primary infection site 
 
No bacteremia of the inclusionary pathogen at any point between enrollment and the 6-Month 
Visit 
Clinical failure is defined to occur when subjects meet any of the following criteria: 
 
Failure to meet all criteria for clinical success 
 
Death (due to the primary infection) 
 
Discontinuation of study drug due to an AE and the requirement of additional antibiotics for 
treatment of the primary infection 
An indeterminate response is defined to occur when subjects meet any of the following criteria: 
 
Subject withdraws consent 
 
Subject is lost to follow-up 
For purposes of analysis, subjects who are deemed a clinical failure due to use of a concomitant antibiotic 
to which the inclusionary pathogen is susceptible for >10 days on any occasion, or for >2 courses during 
any 6-month period, will be programmatically assigned an indeterminate response. 
 
 
 
 
 
 
 


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Primary Infection Exam (Signs and Symptoms): Baseline Evaluation 
The baseline evaluation for outcome assessments is based on the Screening and Study Day 1 data 
according to the table below: 
 
Screening Visit Evaluation 
Study Day 1 Visit 
Evaluation 
Baseline Evaluation 
Present 
New 
Present 
No change 
Present 
Improved 
Present 
Worsening 
Present 
Not Assessed 
Present 
Resolved 
Absent 
Absent 
New 
Present 
No change 
Absent 
Improved 
N/A 
Worsening 
N/A 
Not Assessed 
Absent 
Resolved 
N/A 
Not Assessed 
New 
Present 
No change 
N/A 
Improved 
N/A 
Worsening 
N/A 
Not Assessed 
Not Assessed 
Resolved 
Absent 
Primary Infection Exam (Signs and Symptoms): Change from Previous Visit  
Change from previous visit for a given endpoint is defined as a qualitative comparison between the 
evaluation during the previous visit to the evaluation at the current visit. The possible responses are: 
 
New                - The sign/symptom was not present during the previous visit and is present at the           
 
                          current visit 
 
No change      - The severity of the sign/symptom has not changed from the previous visit 
 
Improved        - There is improvement from the previous visit, but the sign/symptom has not been  
 
 
             resolved 
 
Worsening      - The sign/symptom has gotten worse from the previous visit 
 
Not assessed   - The sign/symptom was not assessed during the current visit  
 
Resolved         - The sign/symptom has been resolved as of the current visit 
 
Primary Infection Exam (Signs and Symptoms): Composite Symptom and Function Score 
Data from the following signs and symptoms will be combined to derive a composite score: 
Swelling/Edema, Warmth, Redness, Pain at Rest, Pain with Movement, Decreased Mobility, and Limited 
Weight Bearing. The score will be calculated according to the following algorithm: 
 
 
Each symptom with a baseline evaluation of “Present” will be assigned a value of 7. Each 
symptom with a baseline evaluation of “Absent” or “Not Assessed” will be assigned a value of 0. 


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 
At each month, the individual sign and symptom scores will be calculated. These will be 
calculated by taking the baseline score and adjusting it in a cumulative manner up to the month 
being reported. The score will be adjusted according to change from previous visit result as 
follows: 
o New – increase by 7.0 
o No Change – no change 
o Improved – decrease by 0.5 
o Worsening – increase by 0.5 
o Not Assessed – no change 
o Resolved – decrease to 0 
 
At any given timepoint, the composite score is calculated by summing the scores of each sign or 
symptom. 
Treatment-emergent Adverse Event  
Any adverse event reported on the eCRF that occurs on or after the receipt of study drug (Day 1) through 
28 days after the last dose of study drug is considered treatment-emergent.  Events with a missing start date 
or that occur on the date of dosing and have a missing start time will be considered treatment-emergent.  
Treatment-emergent Laboratory Abnormality   
A treatment-emergent laboratory abnormality is defined as an increase of at least one toxicity grade from 
the baseline assessment at any post baseline visit up to and including 28 days after the last dose date of 
study drug administration. If the relevant baseline assessment is missing, then any graded abnormality (i.e., 
at least Grade 1) is considered to be treatment-emergent. 
Laboratory abnormalities will be graded according to the Division of Microbiology and Infection Diseases 
(DMID) 1-4 scale. Values not considered Grade 1 or higher will be classified as “Normal”. Grading 
guidelines are listed in Appendix I.  
Antibiotic and Non-antibiotic Medications 
Antibiotic and non-antibiotic medications are recorded on separate forms of the eCRF. Reasons for 
antibiotic medications are recorded on the eCRF as therapy for the primary infection before enrollment, 
companion antibiotic therapy after enrollment, adjunctive antibiotic therapy for co-infections, or therapy 
for unrelated infections.   
Prior and Concomitant Medications 
A prior medication is defined as any medication taken prior to the date of first dose of study drug (Study 
Day 1). A concomitant medication (including companion and adjunctive antibiotic therapy) is defined as 
any medication that has a stop date that is on or after the date of first dose of study drug, or is ongoing. A 
medication can be considered both prior and concomitant. 
4.4. 
TIMING OF ANALYSES 
An interim analysis will be conducted once the last subject completes the 6-month visit or discontinues the 
study, and the resulting clinical database has been cleaned, quality checked, and locked. A final analysis 
will be conducted once the last subject completes or discontinues the study, and the resulting clinical 
database has been cleaned, quality checked, and locked. 


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5. 
ANALYSIS POPULATIONS 
5.1. 
INTENT TO TREAT (ITT) POPULATION 
The ITT population will include all subjects who were enrolled in the study. To be enrolled, subjects must 
provide informed consent and meet all eligibility criteria. Analysis of subject disposition, demographic and 
baseline disease characteristics, and all efficacy analyses will be conducted using the ITT population. With 
the exception of the inclusion/exclusion criteria and informed consent listing, all listings will be produced 
on the ITT population.   
5.2. 
SAFETY POPULATION 
The safety population will include all subjects who were enrolled and received at least one dose of 
CEM-102. Analysis of concomitant medications received and all safety analyses will be conducted using 
the safety population.   
5.3. 
SCREENED POPULATION 
The screened population will include all subjects who signed the informed consent form (ICF). Screen 
failures are subjects who signed the ICF and were not enrolled in the study. The inclusion/exclusion criteria 
and date of informed consent listing will be produced on the screened population. 
6. 
STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study.  Unless stated otherwise, 
the term “descriptive statistics” refers to number of subjects (n), mean, median, standard deviation (SD), 
minimum, and maximum for continuous data and frequencies and percentages for categorical data.  All 
data collected during the study will be included in data listings. Unless otherwise noted, the data will be 
sorted first by subject number, and then by date within each subject number. 
The statistical analyses will be conducted with the SAS® software package version 9.2 or higher. All 
analyses will be subject to formal verification procedures.  Specifically, results will be verified utilizing 
independent programming prior to issuance of the draft statistical report.  All documents will be verified 
by the lead statistician to ensure accuracy and consistency of analyses. 
6.1. 
SUBJECT DISPOSITION, DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS, DURATION OF TREATMENT  
6.1.1. 
Subject Disposition and Duration of Treatment 
Subject disposition will be presented, including summaries of eligibility, number of subjects who complete 
the study, number of subjects who prematurely discontinued from study, reasons for study discontinuation, 
number of subjects who discontinued study drug, reasons for study drug discontinuation, number of days 
on study, number of days on study drug, and number of subjects who completed each visit. 
Study drug dispensation and accountability will be presented in a listing. 


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6.1.2. 
Demographics and Baseline Characteristics 
Demographic data and baseline characteristics including age, sex, race, ethnicity, height, weight, BMI, 
infection type, site of infection, and risk factors for bone or joint infection will be summarized using 
descriptive statistics for the safety population.  
6.1.3. 
Baseline Pathogens 
The pathogenic organisms identified from baseline (screening or historical) cultures of the primary infection 
site or blood cultures will be summarized. MRSA and MSSA are considered distinct pathogens. The number 
and percentage of subjects with each pathogen will be presented by genus and species for the safety analysis 
population. The same pathogen identified from both the culture of a BJI specimen and/or blood culture will 
be counted only once in the summary.  
A listing will be provided that includes all culture results and will indicate the specimen collection date, 
study day, type of specimen, Gram stain results, organism name (local and central laboratory identification), 
and a flag for whether or not each isolate is considered a baseline or post-baseline pathogen. A by-subject 
listing of isolate MICs, and disk diffusion zone diameters, and susceptibilities (if applicable) will also be 
provided. Isolates are considered susceptible (S), intermediate (I), or resistant (R) to CEM-102 according 
to Table 1.  
Table 1 
Provisional Interpretative Criteria for Fusidic Acid (CEM-102) 
 
Broth Microdilution MIC (μg/mL) 
Disk Diffusion Zone Diameter (mm) 
Susceptible 
Intermediate 
Resistant 
Susceptible 
Intermediate Resistant 
Staphylococcus 
species 
≤ 1 
2 
≥ 4 
≥ 22 
20-21 
≤ 19 
β-hemolytic 
streptococcia 
≤ 1 
2-8 
≥ 16 
≥ 16 
11-15 
≤ 10 
a.  Includes: Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae 
6.1.4. 
Concomitant Medications 
Prior and concomitant medications will be coded using the World Heath Organization (WHO) Drug 
dictionary (September 2015).  Antibiotic and non-antibiotic concomitant medications will be summarized 
by frequency of classification and generic name. Antibiotic concomitant medications will be summarized 
separately for primary infections before enrollment, companion antibiotics, co-infections, and unrelated or 
other antibiotics.  Prior and concomitant medications will be presented in a data listing. 
6.2. 
EFFICACY 
The counts and percentages of subjects who have clinical success, clinical failure, and an indeterminate 
clinical response, and reasons for clinical failure and indeterminate response will be summarized at the 6-
Month, 9-Month, 12-Month, 15-Month, 18-Month, 21-Month, and 24-Month Visits. Exact, binomial 95% 
confidence intervals will be provided for the percentage of subjects who have clinical success at each visit. 
Early termination results will be carried forward to all subsequent visits for subjects who did not complete 


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each visit such that the denominator will be equal to the number of subjects in the ITT population. 
The composite symptom and function score and change from baseline score will be summarized by visit. 
Only subjects who are on study drug at a given visit will be included in the summary for that visit. As an 
exploratory analysis to examine the relationship between the composite symptom and function score and 
the proportion of subjects who meet all the criteria for clinical success, a logistic regression model of the 
probability of clinical success with a fixed effect for composite symptom and function score will be 
performed. For this analysis, an indeterminate response will be considered a failure.  
Wound status will be characterized by three signs/symptoms from the primary infection exam: Sinus tract 
formation, open wound, and drainage. A subject will be considered to have a sign/symptom at a given visit 
if it is newly present or not resolved. The counts and percentages of subjects who have each sign/symptom 
will be presented separately. Additionally, the counts and percentages of subjects who have none of the 
three signs/symptoms and one or more of the signs/symptoms will be presented.                
Changes in primary infection site signs and symptoms and inflammation lab results will each be presented 
in a listing. 
A spaghetti plot of individual subject erythrocyte sedimentation rate values by study day will be generated 
for timepoints where the subject is either on study drug or off study drug and being followed for relapse. 
The number of subjects with a pathogen showing decreasing susceptibility will be assessed manually by 
the Sponsor using the by-subject isolate susceptibility listing. Decreasing susceptibility of a pathogen is 
defined as a 4-fold or greater increase in CEM-102 MIC from baseline to any subsequent study time point.  
6.3. 
SAFETY 
6.3.1. 
Adverse Events 
Adverse events will be coded for preferred term and system organ classification by the Medical Dictionary 
for Regulatory Activities (MedDRA) version 18.1. 
If a subject experiences multiple events that map to a single preferred term, the greatest severity and/or 
strongest investigator assessment of relation to study medication will be assigned to the preferred term for 
the appropriate summaries.  Should an event have a missing relationship, it will be classified as having the 
strongest relationship to study medication.   
A high level summary table of the number and percentage of subjects who experience any AE, any TEAE, 
any TEAE with severe intensity, any TEAE related to study drug, any TEAE leading to study 
discontinuation, any TEAE leading to study drug discontinuation, any treatment-emergent serious adverse 
event (SAE), any treatment-emergent SAE related to study drug, any treatment-emergent SAE leading to 
study discontinuation, and any treatment-emergent SAE leading to study drug discontinuation will be 
provided. 
Summaries of treatment-emergent AEs will include any AEs starting on or after the initiation of study 
treatment through 28 days after the last dose of study drug. The occurrence of TEAEs will be summarized 
using preferred terms and system organ classifications.  Separate summaries of TEAEs overall and by 


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greatest severity, TEAEs related to study drug (overall and by greatest severity), TEAEs leading to 
discontinuation of study or study drug, treatment-emergent SAEs and treatment-emergent SAEs leading to 
death will be presented.   
All adverse event data listings will include the individual subjects showing both verbatim and preferred 
terms and system organ classification.  All adverse events that occurred prior to the initiation of the study 
treatment will be excluded from the tables.  All adverse events will be included in the listings.  
Missing onset dates will be imputed as previously outlined in Section 4.3.6 to determine treatment-emergent 
status. 
6.3.2. 
Clinical Laboratory Assessments   
Descriptive summaries of selected clinical laboratory results as well as change from baseline values will be 
presented by analysis visit and worst overall post-baseline value. Selected laboratory parameters to be 
summarized include: ALT, AST, ALP, total bilirubin, creatine kinase, creatinine, WBC count, hematocrit, 
and platelets. Frequency and percentage of subjects experiencing treatment-emergent laboratory 
abnormalities (by Grade) will be summarized by analysis visit and worst overall post-baseline value. If 
criteria in both directions are shown for a single parameter, then abnormalities in each direction will be 
summarized separately. Laboratory toxicity grade shifts from baseline will also be summarized by analysis 
visit and worst overall post-baseline value.  
All clinical laboratory test results will be provided in a listing. The listing will include the laboratory test 
value, change from baseline, and toxicity grade.  
6.3.3. 
Other Safety Analyses 
Vital sign results and all physical examination data will each be provided in a listing. 
6.4. 
PHARMACOKINETICS ANALYSES 
CEM-102 plasma concentrations will be presented in a listing. Analysis of plasma concentration data will 
be presented in a separate PK Report. 
7. 
PROTOCOL DEVIATIONS 
Protocol deviations identified by clinical monitoring will be provided in a data listing.  
8. 
CHANGES IN THE PLANNED ANALYSES 
For purposes of analysis, subjects who are deemed a clinical failure due to use of a concomitant antibiotic 
to which the inclusionary pathogen is susceptible for >10 days on any occasion, or for >2 courses during 
any 6-month period, will be programmatically assigned an indeterminate response.   
No other deviations in the conduct of the study or the planned analysis are anticipated.  Should any 
deviations from the analyses specified in the authorized statistical analysis plan arise, such deviations will 
be documented in the final clinical study report. 


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9. 
REFERENCES 
None. 
10. 
REVISION HISTORY 
Date 
Revision 
Rationale 
04 DEC 2017 
Updated text in section 6.2 so that early 
termination results are carried forward to all 
subsequent visits for the analysis of 
Investigator Assessment of Response (Table 
14.2.1). The denominator is set to the 
number of subjects in the ITT population. 
Including early termination 
results will allow for the 
analysis of cumulative failure. 
 


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11. 
PROGRAMMING CONVENTIONS 
 
Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in landscape 
orientation.  There should be a minimum of a 1.25” boundary on the upper (bound) edge, and a 
minimum of a 1.0” boundary on the remaining three edges.  Output should be printed in Courier New 
with a point size of 8.  Titles may be printed using a larger font (e.g., Arial point size 10). 
 
Identification of analysis population: Every summary table and figure should clearly specify the 
analysis population being summarized.  Listings will be prepared for all enrolled subjects. 
 
Group headers: In the summary tables, the group headers will identify the dose cohort and the within-
group sample size for the indicated analysis population.  Of note, the header’s sample size does not 
necessarily equal the number of subjects actually summarized within any given summary module; 
some subjects in the analysis population may have missing values and thus may not be summarized. 
 
Suppression of percentages corresponding to null categories: When count data are presented as 
category frequencies and corresponding percentages, the percent should be suppressed when the 
count is zero in order to draw attention to the non-zero counts. 
 
Presentation of sample sizes: Summary modules should indicate, in one way or another, the number 
of subjects actually contributing to the summary statistics presented in any given summary module.  
As mentioned above, this may be less than the number of subjects in the analysis population. 
 In the quantitative modules describing continuous variables (and thus presenting sample size, 
means, and standard deviations), the sample size should be the number of non-missing 
observations 
 For categorical variables that are presented in frequency tables, the module should present the 
total count in addition to the count in each category.  Percentages should be calculated using this 
total as the denominator, and the percentage corresponding to the sum itself (that is, 100%) 
should be presented so as to indicate clearly to a reviewer the method of calculation. 
 
Sorting: Listings will be sorted by subject number, dose cohort, and date, if applicable.  Listings with 
multiple observations per subject will be sorted by subject number, dose cohort, treatment and date, if 
applicable.  If a listing is sorted in a different manner, a footnote will indicate as such.  
 
General formatting rules: Rounding for all variables will occur only as the last step, immediately prior 
to presentation in listings, tables, and figures.  No intermediate rounding will be performed on derived 
variables.  The standard rounding practice of rounding numbers ending in 0-4 down and numbers 
ending in 5-9 up will be employed.   
 
The presentation of numerical values will adhere to the following guidelines:  
 Raw measurements will be reported to the number of significant digits as captured on the eCRFs.   
 Standard deviations will be reported to one decimal place beyond the number of decimal places 
the original parameter is presented. 


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 Means will be reported to the same number of significant digits as the parameter.  
 Calculated percentages will be reported with no decimals. 
 
Dates will be formatted as DDMMMYYYY.  Partial dates will be presented on data listings as 
recorded on CRFs. 
 Time will be presented according to the 24-hour clock (HHMM). 
 


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12. 
PROPOSED TABLES, LISTINGS, AND FIGURES 
Summary Tables 
Demography and Baseline Characteristics 
14.1.1   
Subject Disposition and Treatment Duration, ITT Population 
14.1.2   
Demographics and Baseline Characteristics, ITT Population 
14.1.3   
Pathogens Identified at Baseline, ITT Population 
14.1.4  
Concomitant Medications by Generic Name and Drug Classification, Safety Population 
Efficacy 
14.2.1 
Investigator Assessment of Response and Reasons for Failure or Indeterminate   
            
Response by Visit, ITT Population 
14.2.2  
Composite Symptom and Function Score by Visit, ITT Population 
14.2.3  
Wound Status by Visit, ITT Population 
Safety 
14.3.1.1  
Overall Adverse Events, Safety Population 
14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Classification, Preferred Term, 
Overall and by Greatest Severity, Safety Population 
14.3.1.3  
Treatment-Emergent Adverse Events Related to Study Drug by System Organ 
Classification and Preferred Term, Overall and by Greatest Severity, Safety Population 
14.3.2.1  
Treatment-Emergent Adverse Events Leading to Discontinuation of Study by System 
Organ Classification and Preferred Term, Safety Population 
14.3.2.2  
Treatment-Emergent Adverse Events Leading to Discontinuation of Study Drug by 
System Organ Classification and Preferred Term, Safety Population  
14.3.2.3  
Treatment-Emergent Serious Adverse Events by System Organ Classification and 
Preferred Term, Safety Population 
14.3.2.4  
Treatment-Emergent Adverse Events Leading to Death by System Organ Classification 
and Preferred Term, Safety Population 
14.3.4.1.1  
Selected Chemistry Laboratory Values by Parameter and Visit, Safety Population 
14.3.4.1.2  
Selected Hematology Laboratory Values by Parameter and Visit, Safety Population 
14.3.4.2  
Laboratory Toxicity Grade Shifts from Baseline, Safety Population 
14.3.4.3  
Treatment-Emergent Graded Laboratory Abnormalities, Safety Population 
Figures 
14.2.1  
Individual Erythrocyte Sedimentation Rate Values by Study Month, Safety Population 
Data Listings 
16.1.6  
Study Drug Dispensation and Accountability, ITT Population 
16.2.1.1  
Subject Disposition, ITT Population 
16.2.1.2  
Inclusion/Exclusion Criteria and Date of Informed Consent, Screened Population 
16.2.2.1  
Protocol Deviations/Violations, ITT Population 
16.2.4.1 
Demographics, Baseline Characteristics, and Infection Type, ITT Population 
16.2.4.2 
Primary Infection History, ITT Population 
16.2.4.3 
Medical History and Risk Factors for BJI, ITT Population 


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16.2.5.1.1 
Prior and Concomitant Antibiotics, ITT Population 
16.2.5.1.2 
Prior and Concomitant Medications, ITT Population  
16.2.5.2 
CEM-102 Plasma Concentrations, ITT Population 
16.2.6.1 
Investigator Assessment of Response and Reasons for Failure or Indeterminate Response  
 
 
at each Visit, ITT Population 
16.2.6.2  
Primary Infection Examination (Signs and Symptoms) at each Visit, ITT Population   
16.2.6.3  
Inflammation Laboratory Test Results, ITT Population 
16.2.6.4             Microbiological Culture Results, ITT Population 
16.2.6.5             Antibiotic Susceptibility Results, ITT Population 
16.2.7.1 
Adverse Events, ITT Population  
16.2.8.1.1  
Chemistry Laboratory Tests, ITT Population 
16.2.8.1.2  
Hematology Laboratory Tests, ITT Population 
16.2.8.2 
Surgical Interventions, ITT Population 
16.2.8.3 
BJI Imaging, ITT Population 
16.2.8.4  
Vital Signs, Height, and Weight, ITT Population 
16.2.8.5 
Abnormal Physical Examination Findings, ITT Population  
 


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13. 
APPENDIX I – TOXICITY GRADING 
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES, DIVISION OF 
MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) ADULT TOXICITY TABLE 
(MODIFIED) 
NOVEMBER 2007 - DRAFT 
ABBREVIATIONS: Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal                LLN = Lower Limit of Normal 
Rx = Therapy                                            Req = Required 
Mod = Moderate                                       IV = Intravenous 
ADL = Activities of Daily Living            Dec = Decreased 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables, use the scale below to estimate 
grade of severity: 
GRADE 1 (Mild): Transient or mild discomfort; no medical intervention/therapy required 
 
GRADE 2 (Moderate): Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required 
 
GRADE 3 (Severe): Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible. 
 
GRADE 4 (Life-threatening): Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. 
 
 
 
 
 
 
 
 
 


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LABORATORY RANGES 
Where discrepancies in the ULN and LLN of laboratory ranges occur between those included in 
this document and those of the laboratory that performs the assays, the values provided by the 
laboratory will be used for assignment of severity grade. 
 
HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0 - 9.4 gm/dL 
 6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000-
99,999/mm3 
50,000-
74,999/mm3 
20,000-
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000-
30,000/mm3 
>30,000 or <1,000 
mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
 > 80% 
90 – 95% 
>95% 
--------- 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
 123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or 
abnormal sodium 
with mental status 
changes or 
seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or 
abnormal sodium 
with mental status 
changes or 
seizures 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or 
abnormal 
potassium with 
paresis, ileus or 
life-threatening 
arrhythmia 


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Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/L 
> 7.0 mEq/L or 
abnormal 
potassium  with 
life-threatening 
arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or 
abnormal glucose 
with mental status 
changes or coma 
Hyperglycemia 
(nonfasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or 
abnormal glucose 
with ketoacidosis 
or seizures 
Hypocalcemia 
(corrected for albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or 
abnormal calcium 
with life threatening 
arrhythmia or 
tetany 
Hypercalcemia 
(corrected for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or 
abnormal calcium 
with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or 
abnormal 
magnesium with 
life-threatening 
arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL or 
replacement Rx 
required 
1.0 -1.4 mg/dL 
intensive therapy 
or hospitalization 
required 
< 1.0 mg/dL or 
abnormal 
phosphate with life-
threatening 
arrhythmia 
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x ULN 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia 
(when other liver 
function tests are in 
the  normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 


CEM-102 Pharmaceuticals, Inc.  
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CONFIDENTIAL 
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BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Creatinine 
1.1 - 1.5 x ULN  
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or 
dialysis required 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN