SUBMITTED TO Prof. Gautam Singhvi Instructor-in-charge

Gunja Chaturvedi R.Vidya

2008H146101 2008H146102

Submitted for the partial fulfillment of the requirements of the course CLINICAL RESEARCH (PHA G543)


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A. Study details B. Introduction & Objectives 1. Background 2. Introduction 3. Preclinical data for the Model drug 4. Mechanism of action 5. Bioequivalence requirement 6. Pharmacology 6.1.1 6.1.2 6.1.3 6.1.4 6.1.5 6.1.6 Absorption Distribution Metabolism Excretion Adverse drug events Dosage

7. Study design 7.1.1 7.1.2 7.1.3 7.1.4 7.1.5 7.1.6 7.1.7 7.1.8 7.1.9 Summary No. of subjects planned No. of subjects enrolled No. of subjects included in primary analysis & safety datasheet Gender Mean (SD) of age Diagnosis and main criteria for eligibility Investigational product, dose and mode of administration Washout periods Page 2 of 16

7.1.10 Duration of treatment 8. Restrictions 8.1.1 8.1.2 8.1.3 Medications Diet Activity

9. Study population 9.1.1 9.1.2 9.1.3 Screening assessments (lab tests and general examinations) Inclusion criteria Exclusion criteria

10. Study endpoints 10.1.1 Primary endpoints 10.1.2 Secondary endpoints 11. Schedule of assessment 12. Study medication 12.1.1 Handling, storage & accountability procedure 12.1.2 Return or Destruction of Study Drug 13. Analytical procedures , Pharmacokinetic studies and assessment of patient compliance 13.1.1 Microbiological assessment 13.1.2 Pharmacokinetic Characteristics 13.1.3 Assessment of compliance 14. Safety: 14.1.1 Clinical safety measurement 15. Handling of safety parameters 15.1.1 Adverse drug events management 15.1.2 Reporting of Serious Adverse Events Page 3 of 16

16. Statistical considerations 17. Deviations 18. Ethical Considerations 19. Subject Compensation for Participating in the study 20. Termination of the Study 21. Study Documentation 22. Quality Assurance Audits 23. Confidentiality of Data 24. Archives 25. Publication Policy

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 Protocol title: A multicenter, Randomized, Double-Blind, Active Control, Parallel Assignment, Safety/Efficacy Study for the Model drug monotherapy versus comparator treatment (vancomycin & vancomycin + ceftazidime) Investigational product: Model drug Category: Antibacterial Indication: skin & complicated skin structure infections and Nosocomial pneumonia Brief description: This study is a multicenter, randomized, Double-Blind, Active Control, Parallel Assignment, Safety/Efficacy Study and the purpose of this study is to (1) compare the clinical cure rate of Model drug monotherapy versus a comparator (vancomycin & vancomycin + ceftazidime) in the treatment of patients with complicated skin and skin structure infections and (2) in the treatment of patients with nosocomial pneumonia. Study sponsor: ……………………….. Protocol no: 2009011OFB IND no: The study is not conducted under an IND. Study phase: Phase III Study initiation date: October 2009(the first subject enrolled) Study completion date: February 2011(last subject off the study) Clinical study manager: …………………………….. Good Clinical practice: This study is carried out in accordance with (US FDA) regulations & international conference or harmonization (ICH) Good Clinical Practice (GCP) guidelines. Essentials documents will be retained in accordance with ICH GCP.

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1. Background: Skin and skin-structure infections are common, and range from minor pyodermas to severe necrotizing infections. Complicated infections are defined as involving abnormal skin or wounds, occurring in compromised hosts, or requiring surgical intervention. Classification schemes for these infections are varied and confusing. Distinguishing characteristics include the etiological agent(s), clinical context and findings, depth of tissue involvement and rate of progression. The most common pathogens are aerobic Gram-positive cocci, but complicated infections frequently involve Gram-negative bacilli and anaerobic bacteria. Initial antibiotic therapy is usually empirical, and later modified by the results of stains and cultures of wound specimens. Broad-spectrum coverage is frequently needed for complicated infections. This study is basically a randomized, double‐blind, multicenter trial involving patients with a broad range of complicated skin and skin‐structure infections due to either gram‐positive or gram‐negative bacteria is conducted to compare Model drug monotherapy with treatment with vancomycin plus ceftazidime. 2. Introduction: Model drug is a prodrug, a prototypical cephalosporin with bactericidal activity against a broad spectrum of gram-positive bacteria, including methicillin-resistant staphylococcus species. It is also active against many gram-negative bacteria, including many Enterobacteriaceae. 3. Preclinical data for the Model drug:
Pharmacokinetic and Pharmacodynamic characteristics of the Model drug

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Mechanism of action: Model drug has a bactericidal mode of action that involves tight binding to many common essential penicillin-binding proteins (PBPs) in both gram-positive & gramnegative bacteria. It has distinctive bactericidal activity against methicillin-resistant staphylococci primarily due to its novel strong binding to the staphylococcal PBP2a, the PBP that is chiefly responsible for β-lactum resistance in methicillin-resistant staphylococci including methicillin-resistant S.aureus (MRSA).

5. Bioequivalence requirement: The requirement of the following study is to compare the efficacy of the Model drug to that of Vancomycin & vancomycin +ceftazidime combination in patients with primarily complicated skin and skin structure infections(cSSSIs) caused by gram- positive bacteria and secondly for nosocomial pneumonia. The primary objective is to assess noninferiority on the basis of the cure rates 7 to 14 days after the completion of therapy in patients. 6. Pharmacology: 6.1.1 Absorption: Model drug is administered intravenously and therefore has 100% bioavailability. Distribution: Model drug binds minimally (16%) to plasma proteins & binding is independent of the concentration. Its steady-state volume of distribution (18L) approximates extracellular fluid volume in humans. Metabolism: Conversion from the prodrug (Model drug) to the active moiety occurs rapidly and is mediated by plasma esterase.Prodrug concentrations are negligible and measurable in plasma and urine only during infusion. The active Model drug undergoes minimal metabolism to the open-ring metabolite, which is microbiologically inactive. Systemic exposure of the open-ring metabolite was considerably lower than for Model drug, accounting for approximately 45 of the parent exposure. Excretion: Model drug is eliminated primarily unchanged by renal excretion and the predominant mechanism responsible for the elimination is glomerular filtration, with some active reabsorption .In preclinical studies probenecid did not affect the pharmacokinetics of the Model drug, thereby indicating no involvement of active tubular secretion mechanisms. Elimination half life of the open-ring metabolite was slightly longer, approximately 5 hours compared with Model drug, which was approximately 3 hours. Following single dose administration, approximately 89% of the administered dose is recovered in the urine as active Model drug (83%), the open-ring metabolite (5%) and prodrug (Model drug) (<1%). Adverse drug events: Although there is no such specific adverse reactions of the model drug but since it belongs to the cephalosporin class, the precautions that are inherent to this class would still apply. This drug should be given cautiously to patients with a Page 7 of 16





hypersensitivity to penicillin, to pregnant and breast-feeding women, to patients younger than 18 years of age and to the patients with renal impairment or severe hepatic impairment. As with all antibiotics that affect normal gastrointestinal flora, Model drug may increase the risk for C. difficile infection. 6.1.6  Dosage: 500mg i.v. (equivalent to q12h over 60 min) of the Model drug or 1g Vancomycin q12h for 7 – 14 days. 500mg equivalents of the Model drug given as i.v. infusion q8hr over 120 min plus placebo q12hr over 60 min or 1g Vancomycin q12hr over 60min plus 1g ceftazidime q8hr over 120 min for 7 -14 days.


Study design: 7.1.1 Summary:In this study the patients are randomized (2:1) to receive intravenous infusions of the Model drug 500mg over 120 minutes every 8 hours and placebo over 60 minutes every 12 hours, or Vancomycin 1g over 60 minutes every 12 hours plus ceftazidime 1g over 120 minutes every 8 hours for 7 – 14 days.Vancomycin dose is adjusted based on the serum concentrations according to local practices. No. of subjects planned: 1000 No. of subjects enrolled: ………. No. of subjects included in primary analysis & safety datasheet: ………. Gender : Male =…….. & Female = ……… (No. of males and females)

7.1.2 7.1.3 7.1.4 7.1.5 7.1.6

Mean (SD) of age: The age of the enrolled subjects should be mentioned in terms of mean (standard deviation) of the age. Note: Subjects withdrawn or dropped out subsequent to dosing will not be replaced. Data will be presented on all the subjects who completed the study. If necessary, an unequal number of subjects per sequence will be used, and data will be presented on all the subjects who completed the study.


Diagnosis and main criteria for eligibility: Complicated skin and skin structure infections(cSSSI),including non-limb threatening diabetic foot infections without concomitant osteomylitis caused by Enterobacter cloacae, Escherichia coli,Klebsiella pneumonia,Proteus mirabilis, Staphylococcus aureus (including methicillin-resistant isolates) and Streptococcus pyogenes. Page 8 of 16


Investigational product, dose and mode of administration: Model drug, 500 mg and intravenous. Washout periods: 2 weeks


7.1.10 Duration of treatment: 7 – 14 days 8. Restrictions: 8.1.1 Medications - Subjects should not have received any medication (except vitamins preparations) including over the counter medications (OTC) during the 3 weeks period prior to the onset of the study. They will be instructed during screening not to take any prescription and OTC medications until the completion of the study. If drug therapy other than that specified in the protocol is required during the study or in the washout period, decisions to continue or discontinue the subject will be based on the following:  The pharmacology and pharmacokinetics of the non-study medication.  The likelihood of a drug-drug interaction, thereby affecting pharmacokinetic comparison of the study medication.  The time of administration of the non-study medication. 8.1.2 Diet – No special dietary restrictions are there as such. 8.1.3 Activity – If any special activity has to be restricted of performed will be instructed to the subjects on the spot while administering the drug. 9. Study population: 9.1.1 Screening assessments (lab tests and general examinations): URINALYSIS PHYSICAL EXAMINATION  Colour  Appearance  pH  Specific gravity  Protein  Glucose  Glomerular filtration rate  Renal Clearance MICROSCOPIC EXAMINATION  RBC  WBC  Epithelial Cells Page 9 of 16 ADDITIONAL TESTS  HIV I & II  HBsAg  HCV  VDRL

HEMATOLOGY  Haemoglobin  Total leukocyte count  Differential leukocyte count  Platelet count BIO-CHEMISTRY  Blood Urea Nitrogen  Creatinine  Total bilirubin  Alkaline phosphatase  AST  ALT  Glucose  Sodium  Potassium

      9.1.2

Chloride Calcium Magnesium Uric acid

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Crystals Casts Others

Note: The underlined tests are important test from the study point of view. All the samples during screening will be collected and analyzed at Clinical laboratory situated at BITS Clinical Pharmacology Unit. Inclusion criteria :

1. Diagnosis of an infection consistent with complicated skin and skin structure infections caused by gram-positive bacteria. 2. Age range should be in 18 – 92 years. 3. Any kind of surgical site infection within 30 days of surgery or trauma with purulent drainage or 3 or more signs of infection. 4. Abscess for less than 7 days with purulent drainage or aspirate and evidence of loculated fluid. 5. Erythema and/or induration of 20 mm or more in diameter. 6. Cellulitis for less than 7 days with advancing edema, erythema or induration and one other sign of infection. 9.1.3 Exclusion criteria :

1. Known or suspected hypersensitivity to any study medication (especially cephalosporin or vancomycin allergy) 2. If the renal clearance is less than 30ml/min or Oliguria less than 20ml/hr in response to fluid challenge. 3. Alanine aminotransferase /aspartate aminotransferase levels 3 times the upper limit of the normal. 4. Patient who is pregnant or lactating, neutropenic or HIV –infected with CD4+ count less than 0.2 X 109 /L. 5. Any known or suspected condition or concurrent treatment contraindicated by the prescribing information 6. Previous enrollment in this study 7. Treatment with any investigational drug within 30 days before enrollment. 10. Study endpoints: 10.1.1 Primary endpoints: Noninferiority of the Model drug group when compared with the Vancomycin-Ceftazidime group on clinical cure rates at the test-of-cure visit of clinically evaluable and intent-to-treat populations.

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10.1.2 Secondary endpoints: Microbiological eradication rate at 7-14 days after the end of therapy; Clinical cure rate and microbiological relapse at late follow-up visit; All deaths due to pneumonia within 30 days after randomization.

11. Schedule of assessment:The clinical evaluations (at the baseline, during treatment, and after treatment) will include a microbiological assessment of the site of infection, evaluation of the signs and symptoms of infection, and at the Test-of-cure(TOC) and Late-follow-up(LFU) visits, an evaluation of the clinical outcome. The clinical outcome at the TOC visit, 7 to 14 days following the End-of –therapy(EOT) visit, will be categorized as cure, failure, or not evaluable. Cure is defined as a resolution of all signs and symptoms of the infection or improvement to such an extent that no further antimicrobial therapy will be necessary. Failure is defined as a need for further treatment with a nonstudy antibiotic and discontinuation of the study drug due to a treatment-related Adverse Event (AE) or due to a lack of efficacy of the study drug after at least 3 days of study therapy. Patients assessed for failing therapy at the EOT visit will be considered failures at the TOC visit. Patients who will deviate from the protocol-defined treatment or evaluation procedures will be considered not evaluable. 12. Study medication: 12.1.1 Handling, storage & accountability procedure:Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug receipt log filled out and signed by the person accepting the shipment. It is important that the designated study staff counts and verifies that the shipment contains all the items noted in the shipment inventory. Any damaged or unusable study drug in a given shipment (active drug or comparator) will be documented in the study files. The investigator must notify study sponsor of any damaged or unusable study treatments that were supplied to the investigator’s site. 12.1.2 Return or Destruction of Study Drug:At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, and documented prior to return or destruction of unused study drug. Drug destroyed on site will be documented in the study files. 13. Analytical procedures , Pharmacokinetic studies and assessment of patient complaince: 13.1.1 Microbiological assessment: The microbiological assessments will include pathogen identification and susceptibility testing of all specimens, in addition to genotypic characterization of staphylococci (by testing for Panton-Valentine leukocidin [PVL] and mecA genes). Patients will be assessed for microbiological outcome at the TOC visit, and this outcome will be determined by Gram stain and culture of any discharge or infected tissues. The microbiological outcome for the patients will be categorized as eradication, presumed eradication, colonization, persistence, presumed persistence, super infection, Page 11 of 16

or not evaluable. Patients will be considered to have an eradicated microbiological outcome if no pathogen is isolated from any culture (fluid or tissue) taken at the original site of infection and to have a presumed eradicated microbiological outcome if no material suitable for culture is obtained from the primary site of infection in the absence of clinical signs or symptoms of infection. Patients will be considered not evaluable with regard to microbiological outcome if no pathogen is isolated at the time of entry into the trial, no clinical evaluation is done at the TOC visit, no data related to microbiological outcome is collected at the TOC visit, or protocol-defined procedures is not conducted. Only patients with a microbiological outcome of eradication or presumed eradication at the TOC assessment will be evaluated for relapse at the LFU assessment. 13.1.2 Pharmacokinetic Characteristics: The following pharmacokinetic parameters will be calculated for the Model drug by using suitable software like Win Nonlin . Parameters AUC0t Description
The area under the plasma concentration versus time curve, from time zero to the last measurable concentration, as calculated by the linear trapezoidal method. The area under the plasma concentration versus time curve, from time zero to infinity.



calculated as the sum of AUC0t plus the ratio of the last measurable plasma concentration to the elimination rate constant.

AUC0t/ AUC0 C max Tmax

The ratio of AUC0t/ AUC0 Maximum plasma concentration over the time span specified. Time of the maximum measured plasma concentration. If the maximum value occurs at more than 1 time point, T is defined as the first time

point with this value.


Apparent first order terminal elimination rate constant calculated from a semi-log plot of the plasma concentration versus time curve. The parameter will be calculated by linear least-square regression analysis using the maximum number of time points in the terminal lig- linear phase(e.g three or more non-zero plasma concentrations) The apparent first-order terminal elimination half life will be calculated as 0.693/ K .


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13.1.3 Assessment of compliance: Patient compliance will assessed by checking for any hypersensitivity reactions occurring after the administration of the drug. Events involving exacerbations or the worsening of preexisting illnesses will be recorded. 14. Safety: 14.1.1 Clinical safety measurement: It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site. This safety monitoring will include careful assessment and appropriate reporting of adverse events as noted above, as well as the construction and implementation of a site data and safety-monitoring plan (see section 9 Auditing, Monitoring and Inspecting). Medical monitoring will include a regular assessment of the number and type of serious adverse events. 15. Handling of safety parameters: 15.1.1 Adverse drug events management:  At each contact with the subject, the investigator must seek information on adverse events by specific questioning and, as appropriate, by examination. Information on all adverse events will be recorded immediately in the source document, and also in the appropriate adverse event module of the case report form (CRF). All clearly related signs, symptoms, and abnormal diagnostic procedures results will be recorded in the source document, though grouped under one diagnosis. All adverse events occurring during the study period must be recorded. The clinical course of each event will be followed until resolution, stabilization, or until it is determined that the study treatment or participation is not the cause. Serious adverse events continuing throughout the study period will be followed up to determine the final outcome. Any serious adverse event that occurs after the study period and is considered to be possibly related to the study treatment or study participation will also be recorded and reported immediately.

15.1.2 Reporting of Serious Adverse Events: Study Sponsor Notification by Investigator: A serious adverse event will be reported to the study sponsor by telephone within 24 hours of the event. A Serious Adverse Event (SAE) form will be completed by the investigator and faxed to the study sponsor within 24 hours. The investigator will keep a copy of this SAE form on file at the study site.

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At the time of the initial report, the following information should be provided:       Study identifier Study Center Subject number A description of the event Date of onset Current status    Whether study treatment was discontinued The reason why the event is classified as serious Investigator assessment of the association between the event and study treatment

Within the following 48 hours, the investigator will provide further information on the serious adverse event in the form of a written narrative. This will include a copy of the completed Serious Adverse Event form, and any other diagnostic information that will assist the understanding of the event. Significant new information on ongoing serious adverse events will be provided promptly to the study sponsor. 16. Statistical considerations:  This trial is designed to test the noninferiority of Model drug monotherapy compared to the effectiveness of vancomycin plus ceftazidime treatment. The primary end point is the clinical cure rate at the TOC visit. The null hypothesis is that the clinical cure rate for Model drug treated patients would be more than 10% inferior to the clinical cure rate for vancomycin plus ceftazidime -treated patients, and the alternative hypothesis will be that the clinical cure rate for Model drug -treated patients would not be more than 10% inferior to the clinical cure rate for vancomycin plus ceftazidime -treated patients. Similar hypotheses will be applied to the analysis of the microbiological outcome.  The final sample size calculation will be based on the confidence interval (CI) approach for a normal approximation of binomial probability. Clinical and microbiological outcomes will be analyzed by the use of two-sided 95% CIs for the between-treatment difference (Model drug minus vancomycin plus cetazidime) in the clinical cure rates and microbiological eradication rates at the TOC visit. The microbiological eradication rate and its CIs will be summarized by infection type and initial pathogen. 17. Deviations: All protocol deviations will be appropriately reviewed and documented in the raw data and those which will affect the integrity of the study will be reported in the final report. In addition, deviations from the original pharmacokinetic and statistical evaluation plan will be justified in the final report. 18. Ethical Considerations:  This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), applicable government regulations and Institutional research policies and procedures. Page 14 of 16

 This protocol and any amendments will be submitted to a properly constituted independent Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct. The decision of the EC/IRB concerning the conduct of the study will be made in writing to the investigator and a copy of this decision will be provided to the sponsor before commencement of this study. The investigator should provide a list of EC/IRB members and their affiliate to the sponsor.  All subjects for this study will be provided a consent form describing this study and providing sufficient information for subjects to make an informed decision about their participation in this study. The consent form will be submitted with the protocol for review and approval by the EC/IRB for the study. The formal consent of a subject, using the EC/IRB-approved consent form, must be obtained before that subject is submitted to any study procedure. This consent form must be signed by the subject or legally acceptable surrogate, and the investigatordesignated research professional obtaining the consent. Drop-out/Withdrawal of Subjects from Study: Subjects will be informed that they are free to dropout from the study at any time without stating any reason. The investigator may withdraw a subject from the study for any of the following reasons: a) The subject suffers from significant intercurrent illness or undergoes surgery during the course of the study. b) The subject experiences adverse event, when withdrawal would be in the best interest of the subjects. c) The subject fails to comply with the requirements of the protocol or if the subject is uncooperative during the study. Details of reasons for withdrawal of subjects will be recorded and reported. Every effort will be made to obtain a complete follow-up for any withdrawn subject. 19. Subject Compensation for Participating in the study: The subjects will be adequately compensated on account of their participation in the study. In case of drop-out/withdrawal of a subject before completion of the study, the guidelines issued by the Institutional Review Board of the concerned hospital will be final and binding on both BITS Research Laboratories and the study subjects. The compensation in this study will be Rs. 10,000/- per completed subject. Termination of the Study: BITS Research Laboratories reserves the right to discontinue the trial at any time. Reasons for this termination will be provided to the subjects. The Principal Investigator reserves the right to discontinue the study for safety reasons at any time.


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21. Study Documentation: All data generated during the conduct of the study will be directly entered in the raw data recording forms as governed by the SOPs of Department of Clinical Pharmacology and Development and/or Clinical Pharmacology & Pharmacokinetics, BITS Research Laboratories except the analytical data of clinical laboratory of the Clinical Pharmacology Unit, which will be transcribed into the study related forms and the raw data retained by the laboratory for records. The computer-generated chromatograms will also be treated as raw data. All raw data and transcribed data forms will be completed by the study personnel assisting in the study and will be checked wherever applicable for completeness and logistics by the Clinical Investigator or his designate Research Scientist for clinical data and the Laboratory Supervisor for the bioanalytical data. The Clinical Investigator and the Laboratory Supervisor will supervise compilation of data until ready for archiving. 22. Quality Assurance Audits: The raw data generated during the course of the study, including the clinical and analytical operations and the final reports will be liable for inspection and quality audit for conformance to this protocol and all the governing SOPs by an auditor from the Corporate Quality Assurance Department of BITS Research Laboratories. 23. Confidentiality of Data: The data identifying each study subject by name will be kept confidential and will be accessible to the study personnel, Quality Assurance Auditor during audits and if necessary, to the Institutional Review Board of the concerned hospital and various regulatory agencies. 24. Archives: A representative sample of the drug supplies used in the study will be retained at the BITS Clinical Pharmacology Unit. All data generated in connection with this study, together with the original copy of this protocol and the final report will be archived. 25. Publication Policy: Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the information provided by the sponsor for the purposes of performing the study, will be published or passed on to any third party without the consent of the study sponsor. Any investigator involved with this study is obligated to provide the sponsor with complete test results and all data derived from the study.

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