Clinical trial NCT02444234
Conditions: Cystic Fibrosis
Sponsor: University of Southern California
Start date: 2015-07-01; Completion date: 2017-12-31
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The proposed study is designed to characterize the pharmacokinetics of intravenous and oral tedizolid in patients with Cystic Fibrosis.

Detailed description:
Recent epidemiological studies have demonstrated that the presence of methicillin-resistant Staphylococcus aureus (MRSA) in the airways of patients with CF is associated with more rapid lung function decline and a higher mortality. Tedizolid is a new antibiotic with potent activity against MRSA. Tedizolid is currently FDA approved for treatment of skin soft tissue infections with MRSA. The proposed study is designed to characterize the pharmacokinetics of intravenous and oral tedizolid in patients with CF.

Arms: arm 1: Tedizolid phophate 200mg tablet arm 2: Tedizolid phophate 200mg IV
Interventions: intervention 1: Tedizolid PO intervention 2: Tedizolid IV
Intervention descriptions: intervention 1: Participants will be randomized to receive tedizolid oral 200mg once daily for 3 days and crossed over to IV after a 1 week washout. intervention 2: Participants will be randomized to receive tedizolid IV 200mg once daily for 3 days and crossed over to PO after a 1 week washout.

Protocol documents:
Prot_SAP_000.pdf: 
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PROTOCOL NUMBER: 
 
 
TITLE: 
Steady-State Pharmacokinetics of Tedizolid in CF  
 
 
IND OR IDE #: 
126699 
 
 
PRINCIPAL INVESTIGATOR(S): 
Paul Beringer, Pharm.D. 
 
USC School of Pharmacy 
 
1985 Zonal Avenue, Los Angeles CA 90033 
 
TEL: 323-442-1402 
 
FAX: 626-628-3024 
 
 
CO-INVESTIGATOR(S): 
Adupa Rao, M.D. 
 
 
 
SPONSOR: 
Cubist Pharmaceuticals 
 
 
PARTICIPANTS/LOCATONS: 
University of Southern California 
 
 
AMENDMENTS/REVISIONS: 
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TABLE OF CONTENTS 
 
SCHEMA, SYNOPSIS, OR STUDY SUMMARY 
 
 
 
 
 
PAGE 
 
1.0 
BACKGROUND AND HYPOTHESES  
__1___ 
 
2.0 
OBJECTIVES AND PURPOSE 
__1___ 
 
3.0 
STUDY DESIGN  
__1___ 
 
4.0 
DRUG/DEVICE INFORMATION 
__1___ 
 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
__2___ 
 
6.0 
DESCRIPTIVE FACTORS/STRATIFICATION/RANDOMIZATION SCHEME 
__2___ 
 
7.0  
STUDY AGENT ADMINISTRATION OR INTERVENTION AND TOXICITY     
MANAGEMENT PLAN 
__2___  
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
__2___  
 
9.0 
CLINICAL AND LABORATORY EVALUATIONS 
__3___ 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS  
 
__3___ 
 
11.0 
SPECIAL INSTRUCTIONS  
 
 
 
 
 
 
__3___ 
 
12.0 
DATA COLLECTION AND MONITORING 
__3___ 
 
13.0 
STATISTICAL CONSIDERATIONS  
__4___ 
 
14.0 
REGISTRATION GUIDELINES  
__4___ 
 
15.0 
BIOHAZARD CONTAINMENT 
__4___ 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
__4___ 
 
17.0 
REFERENCES 
 
 
 
 
 
 
 
 
__4___ 
 
APPENDICES 
 
I:  Informed Consent 
 
II:  Study Calendar 


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 1.0 
BACKGROUND AND HYPOTHESES 
 
Cystic fibrosis (CF) is a genetic disorder characterized by a chronic cycle of airway infection, 
obstruction, and inflammation leading to progressive loss of lung function and eventual 
respiratory failure. Over the past decade the prevalence of infections involving Methicillin 
Resisistant Staphyoccocus Auerus (MRSA) in CF has increased dramatically.[1] Importantly, 
recent epidemiological studies have demonstrated that the presence of MRSA in the airways of 
patients with CF is associated with more rapid lung function decline [2] and a higher mortality 
[3]. Management of these patients includes prompt initiation of antibiotics at the onset of acute 
pulmonary exacerbations. A significant barrier to effective treatment is the limited number of 
safe and effective antibiotics for treatment of MRSA pulmonary infections. While vancomycin 
has been the mainstay of treatment for many years, its efficacy is limited by reduced 
susceptibility. In addition, the risk for acute kidney injury is significant in patients with CF due to 
the concomitant use of tobramycin for treatment of coinfection with Pseudomonas aeruginosa. 
While linezolid has demonstrated to be efficacious in the treatment of acute pulmonary 
exacerbations in CF, its use is significantly limited due to the high prevalence of depression (29-
46%), which is often treated with selective serotonin reupdate inhibitors/serotonin non-
epinephrine reuptake inhibitors(SSRIs/SNRIs) [4]. Tedizolid offers a significant advancement in 
the management of infections involving MRSA in CF due to its excellent activity, penetration 
into pulmonary secretions, proven safety, and reduced potential for drug interactions with 
antidepressants. 
 
The pharmacokinetics of a number of medications has shown to be altered in patients with CF. 
[5,6] In general, patients with CF demonstrate an increased volume of distribution when 
expressed in liter/kilogram (L/Kg) of body weight, and increased renal clearance. In addition, the 
oral bioavailability of lipophilic medications is reduced due to pancreatic insufficiency. To our 
knowledge no study has evaluated the pharmacokinetics of tedizolid in patients with CF. The 
proposed study is designed to characterize the pharmacokinetics of intravenous and oral tedizolid 
in patients with CF and determine the optimal dosing regimen in preparation for future efficacy 
and safety studies in CF patients experiencing acute pulmonary exacerbations. 
 
RATIONALE FOR SPUTUM TEDIZOLID CONCENTRATIONS: 
Determination of the pulmonary penetration of antibiotics is vital to predicting the optimal 
dosing regimen for treatment of lung infections. Several different sampling methods are reported 
in the literature including bronchoalveolar lavage and induced or expectorated sputum. The 
choice of sampling technique is dependent upon multiple factors such as the site of infection, 
convenience, and need for serial samples. Cystic fibrosis is characterized by chronic respiratory 
infection/inflammation that leads to airway remodeling and progressive loss of lung function. 
The site of the infection/inflammation is predominately endobronchial rather than alveolar. This 
is consistent with the location of Cystic Fibrosis Transmembrane conductance regulator (CFTR) 
within the submucosal glands and acinar serous cells of the airways. Therefore, the ideal sample 
for drug concentrations would be from the endobronchial space which is best obtained by 
induced or expectorated sputum. Fibreoptic bronchoscopy, being invasive and costly, is poorly 
suited for serial sampling of airway secretions. In addition, bronchoscopy with lavage is thought 
primarily to sample the alveolar space rather than the airways alone. Numerous publications 
including those from our group have utilized expectorated sputum to successfully characterize 
the disposition of various antibiotics within the airways and determine optimal dosing regimens 
for treatment of airway infections in CF.23-28 


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Our study hypothesis is that tedizolid will exhibit excellent oral bioavailability and sputum 
penetration in patients with cystic fibrosis. 
 
2.0 
OBJECTIVES AND PURPOSE 
 
Primary Objective: 
Determine the steady-state concentrations of tedizolid in plasma and sputum of patients 
with CF. 
 
Secondary Objective: 
Determine the target attainment for the pharmacodynamic endpoint. 
 
3.0 
STUDY DESIGN 
 
This study will be conducted using a prospective multiple dose, crossover design to characterize 
the steady-state pharmacokinetics of tedizolid intravenous/oral (IV/PO) in CF. A total of 12 adult 
patients with CF will participate in the study and will receive tedizolid 200mg IV or PO once 
daily for 3 doses followed by a minimum 2 day washout and receipt of the remaining dosage 
form.  
 
4.0 
DRUG/DEVICE INFORMATION 
 
 
4.1 
Tedizolid (Sivextro) 
Tedizolid is an oxazolidinone antibiotic with potent activity against methicillin resistant 
S. aureus (MRSA). Tedizolid is approved for the treatment of acute bacterial skin and 
skin structure infections (ABSSSI) caused by designated susceptible bacteria.  
 
The recommended dosage of tedizolid is 200 mg administered once daily orally (tablet) 
or as an intravenous infusion (IV) over 1 hour for six days. 
The most common adverse reactions (incidence of > 2%) are nausea, headache, diarrhea, 
vomiting, and dizziness. 
 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
 
 
5.1 
Inclusion Criteria:   
 
 
CF patients admitted to the hospital for pulmonary exacerbation as defined by CF 
Pulmonary Guidelines and Fuchs et al (1994) (e.g. increased cough/sputum 
production, shortness of breath, chest pain, loss of appetite/weight, and lung 
function decline) 
 
 
 
Diagnosis of CF based on positive sweat chloride or known CF mutation 
 
 
 
Age > 18 years 
 
 
 
Patients able to spontaneously expectorate sputum  
 
 
 
CF patients with or without MRSA positive sputum will be included  
 
5.2 
Exclusion Criteria 
 
 
AST/ALT > 3 x ULN 
 
 
Thrombocytopenia (Platelets < 150,000) 


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Anemia (hematocrit < 30) 
Any clinically significant abnormality noted on physical exam thought to interfere 
with the conduct of the study.  
 
 
Pregnancy 
 
 
No alcohol, nicotine, or caffeine-containing products during the study period 
 
 
Patients taking monoamine oxidase inhibitors and/or serotonergic agents.  
 
 
  
 
5.3 
Withdrawal Criteria 
 
 
Subject can be discontinued from the study for any of the following reasons: 
 
 
 
Subject’s personal reasons 
 
 
 
Allergic reaction to the medication  
 
 
 
Other significant study related adverse events 
 
6.0 
 STRATIFICATION/DESCRIPTIVE FACTORS/RANDOMIZATION SCHEME 
 
 
6.1 
Stratification factors: Not applicable. 
 
 
6.2 
Descriptive factors: Not applicable. 
 
 
6.3 
Randomization: 
 
 
Randomization sequence will be created using Excel 2007 (Microsoft, Redmond, WA, 
USA) with a 1:1 allocation using random block sizes of 2. 
Subjects will be randomized to receive one of the two treatment sequences: 
 
 
Oral Tedizolid for days 1 to 3 then Intravenous Tedizolid for days 10 to 12. 
 
 
Intravenous Tedizolid for days 1 to 3 then Oral Tedizolid for days 10 to 12.   
 
7.0 
STUDY AGENT ADMINISTRATION OR INTERVENTION AND TOXICITY 
MANAGEMENT PLAN 
 
 
7.1 
Depending on the treatment arm of the study, you will receive Tedizolid administered in 
doses of 200 mg intravenously over 1 hour or 200 mg PO once daily for 3 doses.  
 
AGENT 
DOSE 
ROUTE 
DAYS 
ReRx 
NOTES 
Tedizolid 
200 mg 
I.V. over 1 hours 
1-3 or 10-12 
Once daily 
Total of 3 doses of IV and 
Tedizolid 
200 mg 
PO 
1-3 or 10-12 
Once daily 
Total of 3 doses of PO and 


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7.2 
Criteria for removal from the study  
 
 
 
7.21 
 A patient may always be removed from study whenever he/she wishes. 
 
 
 
7.22 
A patient may be removed from the study if they experience an allergic reaction to 
the medication. 
 
 
7.3Ancillary treatments.  
 
 
Patients may continue to take their medications for treatment of CF 
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
 
 
8.1 
Side effects/Toxicities to be monitored. 
 
 
Possible side effects of Tedizolid are: 
 
 
 
The most common adverse reactions in patients treated with tedizolid were nausea 
(8%), headache (6%), diarrhea (4%), vomiting (3%), and dizziness (2%). The median 
time of onset of adverse reactions was 5 days for both Tedizolid with 12% occurring 
on the second day of treatment in both treatment groups. 
 
 
 
 
Serious adverse reactions occurred in 12/662 (1.8%) of patients treated with Tedizolid 
and in 13/662 (2.0%) of patients treated with the comparator. Tedizolid was 
discontinued due to an adverse reaction in 3/662 (0.5%) of patients and the 
comparator was discontinued due to an adverse reaction in 6/662 (0.9%) of patients 
 
The following selected adverse reactions were reported in Tediazolid treated patients 
at a rate of less than 2% in these clinical trials: 
Blood and Lymphatic System Disorders: anemia 
Cardiovascular: palpitations, tachycardia 
Eye Disorders: asthenopia, vision blurred, visual impairment, vitreous floaters 
General Disorders and Administration Site Conditions: infusion-related reactions 
Immune System Disorders: drug hypersensitivity 
Infections and Infestations: Clostridium difficile colitis, oral candidiasis, vulvovaginal 
mycotic infection 
Investigations: hepatic transaminases increased, white blood cell count decreased 
Nervous System Disorders: hypoesthesia, paresthesia, VIIth nerve paralysis 
Psychiatric Disorders: insomnia 
Skin and Subcutaneous Tissue Disorders: pruritus, urticaria, dermatitis 
Vascular Disorders: flushing, hypertension 
 
 
 
 
8.11 
Patients will be asked about the presence of nausea, vomiting, diarrhea, or 
headache. 
 
 
 
 
8.12 
CBC and CMP will be monitored at baseline 
 
 
 
8.2 
Adverse Event Reporting: 
 


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8.21 
Any significant adverse events that occurs during the course of the study will be 
documented and reported. 
 
8.22 
Reports will be submitted to:  IRB, FDA (MedWatch) 
 
 
8.3 
Data Monitoring Committee (if applicable) 
 
 
Not applicable 
 
9.0 
CLINICAL AND LABORATORY EVALUATIONS AND STUDY CALENDAR 
 
 
See Appendix A 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
 
 
The outcome status (in terms of toxicity, response, reason off study, progression, and survival) of all 
eligible patients will be reported. All eligible patients who begin treatment will be included in the 
analysis of survival and time-to-failure.  
 
 
Endpoint Definitions 
 
11.0 
SPECIAL INSTRUCTIONS: 
 
Blood samples will be obtained at the following time points after the third dose of each dosage 
form: 0 (predose), 0.5, 1, 2, 3, 4, 8, 24, and 48 hours postdose. 
 
In the case where the patient is discharged home early, we will offer subjects the option of having 
a trained healthcare professional come to the subject’s home to perform the 24 hour and 48 hour 
blood and sputum sampling.  A phleobomist not affiliated with USC will come to the subject’s 
home to collect the 24 hour and/or 48 hour blood and sputum sample.   
 
In order for the study visit to be conducted in the subject’s home, the subject’s name, addreess 
and contact telephone number will be provided to the home provider ventor.  The home provider 
vendor will provide the information to a courier, who will pick up the blood and sputum from the 
subject’s home.  If you do not want your information provided to the home provider vendor or 
courier, the subject cannot participate in the home visit. 
 
It is possible that the home provider vendor may not be available in the subject’s area or in time 
for the study visit.  In this rare event, the subject will be required to complete the study visit at 
the study doctor’s office.   
Expectorated sputum samples will be obtained from individual patients after the third dose of 
each dosage form as follows: 
  
Patients 
 
Time of sputum collection 
1-12 
 
 
Predose 
1-3 
 
 
0.5-1h 
4-6 
 
 
2h  
7-9 
 
 
3h  
10-12  
 
4h  


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1-4 
 
 
8h 
5-8 
 
 
24h 
9-12 
 
 
48h 
 
 
Blood and sputum samples will be processed and stored at -80°C until assayed for tedizolid.  
 
12.0 
DATA COLLECTION AND MONITORING 
 
Data will be collected on case report forms, which will be retained for the duration of the study. 
Data will include subject demographics, clinical characteristics, laboratory data, and results of 
pharmacokinetic analyses. Data will be coded and stored on a password protected electronic 
database.  
 
13.0 
DATA/STATISTICAL CONSIDERATIONS 
 
 
 
13.1 
Pharmacokinetic analysis 
Pharmacokinetics will be performed using standard noncompartmental methods. The 
maximum concentration and time to maximum concentration will be from the observed 
data. The area under the curve will be calculated using the trapezoidal rule. Absolute 
bioavailability will be determined by a ratio of the AUCpo/AUCiv.  
 
In addition, population pharmacokinetic analysis will be performed using the maximum 
likelihood estimation via the EM algorithm with sampling (MLEM) as implemented in 
ADAPT 5 (Biomedical Simulations Resource, University of Southern California). 
Multiple candidate models will be evaluated to identify the model that best describes the 
observed plasma and sputum concentration data. 
 
Monte Carlo simulations will be performed to determine the target attainment for the lung 
exposures (sputum AUC24h/MIC > 20) with different dosing regimens using the SIM 
module in ADAPT 5. MIC distributions used in the simulations will be based on recently 
published susceptibility data [29]. 
 
13.2  Statistical Analysis 
 
Twelve patients with CF will participate in this study. The endpoints for this study are 
descriptive in nature and the sample size is similar to other studies with these endpoints. 
Patient demographics, clinical characteristics, and pharmacokinetic parameters will be 
summarized using descriptive statistics.  
 
 
14.0 
REGISTRATION GUIDELINE 
 
 
14.1 
Subjects will be registered into the study through submission of the research order form, 
informed consent, and patient bill of rights to the Clinical Trials Office (CTO) at USC.. 
 
15.0 
BIOHAZARD COMTAINMENT 
 
 


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Not applicable   
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
 
All institutional and Federal regulations concerning the Informed Consent form will be fulfilled.  
The study will be conducted in adherence to ICH Good Clinical Practice. 
 
 
17.0 
REFERENCES 
 
1. Cystic Fibrosis Foundation. 2013. Patient registry annual data report. Cystic Fibrosis 
Foundation, Bethesda, MD. 
2. Dasenbrook, E. C., C. A. Merlo, M. Dienre-West, N. Lechtzin, and M. P. Boyle. Persistent 
methicillin-resistant Staphylococcus aureus and rate of FEV1 decline in cystic fibrosis. Am J 
Respir Crit Care Med. 2008;178:814-821. 
3) Dasenbrook, E. C., et al. Association between respiratory tract methicillin-resistant 
Staphylococcus aerureus and survival in cystic fibrosis. JAMA 2010;303:2386-2392. 
4) Quittner, A., Barker, D., Snell, C., et al. Prevalence and impact of depression in cystic fibrosis. 
Curr Opinion Pulm Med 2008;14:582-88. 
5) de Groot R, Smith AL. Antibiotic pharmacokinetics in cystic fibrosis. Differences and clinical 
significance. Clin Pharmacokinet. 1987;13:228-53. 
6) Touw DJ. Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis. Pharm World 
Sci 1998;20:149-60. 
7) Flanagan, S. D., Bien P. A., Munoz K. A., et al. Pharmacokinetics of tedizolid following oral 
administration: single and multiple dose, effect of food, and comparison of two solid forms 
of the prodrug. Pharmacotherapy 2014:34:240-250. 
8) Housman S. T., Pope J. S., Russomanno H., et al. Pumonary disposition of tedizolid following 
administration of once-daily oral 200-milligram tedizolid phosphate in healthy adult 
volunteers. Antimicrob Agents Chemother 2012;12:2627-2634. 
9) Prokocimer, P. Bien, P. Surber, H., et al. Phase 2, randomized, double-blind, dose-ranging 
study evaluating the safety, tolerability, population pharmacokinetics, and efficacy of oral 
torezolid phosphate in patients with complicated skin and skin structure infections. 
Antimicrob Agents Chemother 2011;55:583-592. 
10) Ong, V., Flanagan, S. Fang, E., et al. Absorption, distribution, metabolism, and excretion of 
the novel oxazolidinone prodrug tedizolid phosphate. Drug Metab Dispos 2014;42:1275-84. 
11) Kisgen, J., Mansour H, Unger, N.R., Childs, L. Tedizolid a new oxazolidinone antimicrobial. 
Am J Health Syst Pharm 2014;71:621-33. 
12) Lepak, A., Marchillo, K. Pichereau, S., et al. Comparative pharmacodynamics of the new 
oxazolidinone tedizolid phosphate and linezolid in a neutropenic murine Staphylococcus 
aureus pneumonia model.  
13) Beringer PM, Owens H, Nguyen A, Benitez D, Rao A, D’Argenio DZ. Pharmacokinetics of 
doxycycline in adults with cystic fibrosis. Antimicrob Agents Chemother 2012;56:70-74. 
14) Beringer PM, Kriengkauykiat J, Zhang X, Hidayat L, Liu S, Louie S, Synold T, Burckart GJ, 
Rao PA, Shapiro B, Gill M. Lack of effect of P-glycoprotein inhibition on renal clearance of 
dicloxacillin in patients with cystic fibrosis. Pharmacotherapy. 2008 Jul;28(7):883-94. 
PMID: 18576903 
15) Liu S, Beringer PM, Hidayat L, Rao AP, Louie S, Burckart GJ, Shapiro B. Probenecid, but 
not cystic fibrosis, alters the total and renal clearance of fexofenadine. J Clin Pharmacol. 
2008 Aug;48(8):957-65. PMID: 18511651 


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16) Beringer PM, Nguyen M, Hoem N, Louie S, Gill M, Gurevitch M, Wong-Beringer A. 
Population pharmacokinetic analysis to evaluate the impact of continuous enteral feedings on 
the bioavailability of linezolid in hospitalized patients. Antimicrob Agents Chemother 
2005;49:3676-3681. 
17) Beringer PM, Huynh K, Krienkauykiat J, Bi L, Hoem N, Han E, Louie S , Rao A, Shapiro 
BJ, Gill M. Bioavailability and intracellular pharmacokinetics of azithromycin in patients 
with cystic fibrosis. Antimicrob Agents Chemother 2005;49:5013-5017. 
18) Beringer PM, Han E, Louie SG, Gill MA, Shapiro BJ. Pharmacokinetics of ibuprofen in 
children with cystic fibrosis. Clin Pharmacokinet 2004;43:145-56. 
19) Aminimanizani A, Beringer PM, Tsang L, Shapiro B, Jelliffe R. Pharmacokinetics of once-
daily tobramycin administration in adult patients with cystic fibrosis. J Antimicrob 
Chemother 2002;50:553-9. 
20) Beringer PM, Aminimanizani A, Scott C, Synold T. Development of population 
pharmacokinetic models and optimal sampling times for ibuprofen in children with cystic 
fibrosis. Ther Drug Monitor 2002;24:315-21. 
21) Montgomery MJ, Beringer PM, Aminimanizani A, Louie SG, Shapiro B, Jelliffe R, Gill MA. 
Population Pharmacokinetics and use of Monte Carlo simulation to determine the optimal 
dose of ciprofloxacin in adult patients with cystic fibrosis. Antimicrob Agents Chemother 
2001;45:3468-73.  
22) Beringer PM, Vinks A, Jelliffe R, Shapiro B. Pharmacokinetics of tobramycin in adults with 
cystic fibrosis: Implications for once-daily administration. Antimicrob Agents Chemother 
2000;44:809-813.  
23) Moriarty TF, McElany JC, Elborn JS, Tunney MM. Sputum antibiotic concentrations: 
implications for treatment of cystic fibrosis lung infection. Pediatr Pulmonol 2007;42:1008-
17. 
24) Smith MJ, White LO, Bwyer H, et al. Pharmacokinetics and sputum penetration of 
ciprofloxacin in patients with cystic fibrosis. Antimicrob Agents Chemother 1986;30:614-16. 
25) Jullien V, Hubert D, Launay O, et al. Pharmacokinetics and diffusion into sputum of 
oseltamivir and oseltamivir carboxylate in adults with cystic fibrosis. Antimicrob Agents 
Chemother 2011;554183-87. 
26) Wilms EB, Touw DJ, Heijerman HGM. Pharmacokinetics and sputum penetration of 
azithromycin during once weekly dosing in cystic fibrosis patients. J Cystic Fib 2008;7:79-
84. 
27) Byl B, Baran D, Jacobs F, et al. Serum pharmacokinetics and sputum penetration of amikacin 
30 mg/kg once daily and of ceftazidime 200 mg/kg/day as a continuous infusion in cystic 
fibrosis patients. J Antimicrob Chemother 2001;48:325-327. 
28) Beringer PM, Owens H, Nguyen A, et al. Pharmacokinetics of doxycycline in adults with 
cystic fibrosis. Antimicrob Agents Chemother 2012;56:70-4. 
29) Zurenko G, Bien P, Bensci M, et al. Use of linezolid susceptibility test results as a surrogate 
for the susceptibility of gram-positive pathogens to tedizolid, a novel oxazolidinone. Ann 
Clin Microbiol Antimicrob. 2014;13:46. 
30) Fuchs H J, Borowitz D S, Christiansen D H. et al Effect of aerosolized recombinant human 
DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with 
cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994331637–642.642 
 
 
 
APPENDICES 


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Appendix I: 
Informed Consent 
 
Appendix II: Study Calendar 
 
 
 
 
 


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Screening 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6-10 
Day 7-
11 
Day 8-12  
Day 9-13 
Day 10-
14 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
Height, weight 
X 
 
 
 
 
 
 
 
 
 
 
Vital signsA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety labsB 
X 
 
 
 
 
 
 
 
 
 
 
IV drug 
administrationQ 
 
XC 
XC 
XC 
 
 
XF 
XF 
XF 
 
 
PO drug 
administration  
 
XE 
XE 
XE 
 
 
XD 
XD 
XD 
 
 
Blood 
Pharmacokinetics 
(PK) G 
 
 
 
X 
 
 
 
 
X 
 
 
Sputum 
Pharmacokinetics 
(PK):  pre doseH  
 
 
 
X 
 
 
 
 
 
 
 
Sputum PK: 
0.5 to 1 hour post 
dose 
 
 
 
XI 
 
 
 
 
XI 
 
 
SputumPK: 
2 hours post dose 
 
 
 
XJ 
 
 
 
 
XJ 
 
 
SputumPK: 
3 hours post dose 
 
 
 
XK 
 
 
 
 
XK 
 
 
SputumPK: 
4 hours post dose 
 
 
 
XL 
 
 
 
 
XL 
 
 
SputumPK: 
8 hours post dose 
 
 
 
XM 
 
 
 
 
XM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SputumPK:Q 
24 hours post dose 
 
 
 
 
XO 
 
 
 
 
XO 
 
SputumPK:Q 
48 hours post dose 
 
 
 
 
 
XP 
 
 
 
 
XP 
 
A. Vital signs to include blood pressure, heart rate, temperature, respiratory rate. 
B. Safety labs to include complete blood count with differential, complete metabolic panel 
C. For the treatment arm A:  IV Tedizolid will be done on days 1 to 3. 
D. For the treatment arm A:  PO Tedizolid will be done on days 10 to 12.  Days 10 and 11 the dose of oral Tedizolid will be done at home for the 
subject. A telephone call will be done to remind the subject to take the PO Tedizolid. 
E. For the treatment arm B:  PO Tedizolid will be done on days 1 to 3. Days 1 and 2 can be done at home.  A telephone call will be done to 
remind the subject to take the PO Tedizolid. 
F. For the treatment arm B:  IV Tedizolid will be done on days 10 to 12.   
G. All subjects will have a pre dose blood PK levels, 0.5 hour, 1, 2, 3, 4, 8, 24 and 48 hours post dose of Tedizolid (IV or PO). A 5mL EDTA 
tube will be used to collect the blood PK sample. 
H. All subjects will have a pre dose sputum sample (IV or PO). 
I. Subject number 1-3 will need to produce a sputum sample at this time period (IV or PO). 
J. Subject number 4-6 will need to produce a sputum sample at this time period (IV or PO). 
K. Subject number 7-9 will need to produce a sputum sample at this time period (IV or PO). 
L. Subject number 10-12 will need to produce a sputum sample at this time period (IV or PO). 
M. Subject number 1-4 will need to produce a sputum sample at this time period (IV or PO). 
N. Subject number 5-8will need to produce a sputum sample at this time period (IV or PO). 
O. Subject number 9-12 will need to produce a sputum sample at this time period (IV or PO). 
P. IV Tedizolid is be infused over 60 minutes.  
Q. The option of home health vendor to collect the 24 and 48 hour blood and sputum sampling.