GSK Clinical Study Register

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1 In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register. The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all named persons associated with the study Patient data listings will be completely removed* to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register. Aggregate data will be included; with any direct reference to individual patients excluded *Complete removal of patient data listings may mean that page numbers are no longer consecutively numbered

2 Confidential Avandia (rosiglitazone) BRL 49653C A Bioequivalence Study Comparing Tablets Manufactured with the 8 mg Anhydrate Form IV (ANF 4) to the Commercial Anhydrate Form I (ANF 1) of Rosiglitazone Maleate. 300 Final Clinical Report PharmD*, PhD* PhD*, PhD*, MD*, BS*, PhD*, MD*, MD*, MD, PhD*, MD*, PhD**, MSPH**, PhD** *Clinical Pharmacology & Discovery Medicine, N.A., **Clinical Pharmacology Statistics and Programming Signatory: Affiliation: MD Clinical Pharmacology & Discovery Medicine SB Document Number: Issue Date: 18 June

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4 TABLE OF CONTENTS Page LIST OF TABLES Abbreviations Report Synopsis Introduction Objectives Methodology Study Design Protocol Amendments Investigators Ethics Eligibility Criteria Inclusion Criteria Exclusion Criteria Treatments and Administration Study Medication Methods of Blinding Dosage and Administration Compliance with Study Medication Prior and Concomitant Medication Study Procedures Schedule of Assessments Prestudy Screening and Enrollment Treatment Phases Post-Treatment Phase Reasons for Withdrawal Reasons for Concluding Study Safety Assessments Adverse Events Vital Signs, ECGs and Safety Laboratory Tests Pharmacokinetic Assessments Collection and Preparation of Samples Assay Methods Pharmacokinetic Analysis

5 3.11 Data Quality Assurance Statistical Evaluation Target Sample Size Method of Randomization Planned Safety Analysis Planned Pharmacokinetic Analysis Study Population Study Dates Subject Disposition Protocol Violations Demographic Characteristics Presenting Conditions and Medical History Prior and Concomitant Medications Treatment Administration and Compliance Safety Results Extent of Exposure Adverse Events Deaths Serious Non-Fatal Adverse Events (SAE) Withdrawals Due to Adverse Events Vital Signs Electrocardiographic Data Laboratory Tests Pharmacokinetic Evaluation Discussion Conclusions References Data Source Tables Data Source Figures Appendices

6 LIST OF TABLES Page Table 1 Study Medication Used Table 2 Day 1 Study Procedures Table 3 Protocol-Defined Values of Potential Clinical Concern Table 4 Subject Disposition Table 5 Protocol Violations by Subject Table 6 Demographic Characteristics of Study Population Table 7 Number of Subjects Who Received Each Treatment Regimen Table 8 Number of Adverse Events Table 9 Number of Adverse Events by Regimen Table 10 Mean (SD) Pharmacokinetic Parameters for Rosiglitazone Table 11 Point Estimates and Confidence Intervals for AUC(0-Inf)(ng.h/mL), Cmax(ng/mL) and tmax(h) for Rosiglitazone

7 Abbreviations AE ALT ANOVA ANF ART AST AUC (0- ) bpm BUN C max CPEM CPU CV b dl DMPK ECG EDTA g GGT hcg hpf IUD kg L LC m meq mg ml mm MS ng PE PIMS RBC RTP SAE SD t 1/2 t max UDS UK ul WBC WHO adverse event alanine aminotransferase analysis of variance anhydrate form adverse reaction terminology aspartate aminotransferase area under the concentration-time curve to infinite time beats per minute blood urea nitrogen maximum plasma concentration clinical pharmacology and experimental medicine clinical pharmacology unit coefficient of variation between subjects deciliter drug metabolism and pharmacokinetics electrocardiogram ethylenediaminetetraacetic acid gram gamma-glutamyl transferase human chorionic gonadotropin high-power field intrauterine device kilogram liter liquid chromatography meter milliequivalent milligram milliliter millimeter mass spectrometry nanogram point estimate Phase I management system red blood cells research triangle park serious adverse event standard deviation apparent terminal half-life time to reach maximum concentration urine drug screen United Kingdom microliter white blood cells world health organization 6

8 Report Synopsis Title A Bioequivalence Study Comparing Tablets Manufactured with the 8 mg Anhydrate Form IV (ANF 4) to the Commercial Anhydrate Form I (ANF 1) of Rosiglitazone Maleate. Investigator(s) and Center(s) Publication None as of June 2004 Study Dates MD, USA 9 July 2001 to 20 August 2001 Objective(s) A clinical effort is currently underway to develop alternative formulations for rosiglitazone. The current commercial form of rosiglitazone maleate is anhydrate I (ANF1). Three alternative crystalline forms (polymorphs) have been identified since the initial filing of the manufacturing process [Anhydrate Forms II, III and IV, respectively (ANF2, ANF3, ANF4)]. Anhydrate Form IV has been shown to be the most stable form. Thus, this study was conducted to demonstrate bioequivalence between ANF1 and ANF4, so that ANF4 could be manufactured as a back-up commercial formulation of rosiglitazone maleate. The specific study objectives were: To demonstrate the bioequivalence of rosiglitazone maleate anhydrate Form IV (ANF4) relative to commercial tablets containing anhydrate Form I (ANF1) To assess the tolerability of single oral doses of tablets containing anhydrate rosiglitazone maleate Forms ANF1 and ANF4, respectively, in healthy adult subjects Study Design This was an open-label, randomized, two-period, period-balanced crossover study. Each subject received the following two treatments in a fasted state, one during each study session, in a randomized sequence (AB, BA): Regimen A: 8 mg single oral dose of the commercial tablet containing anhydrate Form I (ANF1) of rosiglitazone maleate Regimen B: 8 mg single oral dose of a tablet containing anhydrate Form IV (ANF4) of rosiglitazone maleate 7

9 Subjects were assigned to one of two treatment sequences (AB or BA) based on a randomization schedule prepared in advance of the start of the study. Following dosing, subjects remained in the Clinical Pharmacology Unit (CPU) for 24 hours. Pharmacokinetic sampling for measurement of plasma rosiglitazone was conducted at intervals over the 24-hour period following administration of study medication in each study session. There was a washout period of at least one week between treatment sessions. Female subjects returned to the CPU 10 to 14 days following the last dose of study medication for a follow-up serum pregnancy test. Study Population Healthy adult male and female (non-pregnant, non-lactating) subjects between the ages of 18 and 65, weighing at least 50 kg (and within 20% or +35% of ideal weight based on height and body frame) were eligible for the study. A sufficient number of subjects were enrolled so that a total of 24 subjects would complete the study. Treatment and Administration Rosiglitazone for oral administration was supplied as the commercially available 8 mg anhydrate Form I (ANF1) (Lot # 271A60) and as the 8 mg anhydrate Form IV (ANF4) (Batch # N01096). Study medication was administered to subjects in a fasted state with 240 ml of tepid water by study personnel. Evaluation Criteria Safety Parameters The tolerability of protocol-specified treatments was assessed during the study by monitoring the results from clinical safety laboratory tests, blood pressure, pulse rate, ECG, as well as by nursing and physician observations and spontaneous reporting of adverse events. Pharmacokinetic Parameters Blood samples (approximately 3 ml) were collected from an arm vein into EDTA tubes prior to dosing and at intervals throughout the 24 hours subsequent to dosing in each study session. Human plasma samples were assayed for rosiglitazone (BRL 49653) using LC/MS/MS analysis. Non-compartmental analysis was used to calculate the following pharmacokinetic parameters: AUC (0- ), C max, t 1/2, and t max. Descriptive statistics, by regimen, are presented for these parameters. Statistical Methods The primary pharmacokinetic endpoints of interest were AUC (0- ) and C max of rosiglitazone. The secondary pharmacokinetic endpoints were t 1/2 and t max of rosiglitazone. Additional endpoints included %Extrapolated AUC (0- ) and Total Time above the target concentration (52 ng/ml). The focus of the statistical analysis was to demonstrate bioequivalence of rosiglitazone maleate ANF4 relative to ANF1. Thus, point estimates were computed for the ratios ANF4 to ANF1 (B:A) for AUC (0- ) and C max of rosiglitazone. Accompanying 90% confidence intervals provided a range of plausible values for the true ratios. 8

10 Subject Disposition and Key Demographic Data Twenty-eight (28) healthy adult male and female subjects were enrolled in this study and randomized to treatment. Twenty-seven (27) subjects received at least one dose of study medication. Demographic data for subjects who were dosed are summarized in the following table. Group Parameter Age Height Weight (years) (m) (kg) Subjects Mean (n=27) SD Range Race: 41% White, 37% Black, 4% Oriental, 19% Other Gender: 70% Male, 30% Female subjects completed the study. Twenty-five (25) Safety Results Study medication was generally well tolerated. There were no deaths during this study. There was one serious adverse event (SAE) of atrial fibrillation which spontaneously resolved, resulted in the withdrawal of that subject, and was deemed by the investigator as unlikely to be related to study medication but rather associated with the study procedure (i.e., phlebotemy) through an episode of vasovagal syncope. There was one additional withdrawal due a suspected baseline urinary tract infection, present prior to dosing. A similar number of adverse events (AEs) were reported following Regimens A and B. Eight (8) AEs were reported for 5 subjects in Regimen A. Five (5) AEs were reported for 5 subjects in Regimen B. Four (4) AEs were deemed by the investigator as not related to study medication and nine (9) AEs were deemed by the investigator as unlikely to be related to study medication. All AEs were mild in nature, with the exception of the SAE of atrial fibrillation. The most frequently reported AEs were headache, increased micturition frequency, and dizziness. Adverse events reported during this study are summarized by regimen in the following table. Regimen A Regimen B Total Total Number of AEs Number of Subjects with AEs Number of Subjects Exposed Regimen A: single oral 8 mg dose of ANF1-commercial rosiglitazone Regimen B: single oral 8 mg dose of ANF4 There were no clinically significant changes in vital signs or safety laboratory values during this study. There was one subject with electrocardiographic findings of atrial fibrillation, deemed by the investigator as unlikely to be related to study drug. Pharmacokinetics Based on AUC (0- ) and C max, ANF4 was shown to be bioequivalent to ANF1. There were no apparent differences in t max and t 1/2 between the two anhydrate forms. The following tables show the mean (SD) for each of the pharmacokinetic parameters and corresponding statistical analysis for C max and AUC (0- ) using the bioequivalence criteria of %. 9

11 Pharmacokinetic Parameter Regimen AUC (0- ) C max t ½ t max * (ng.h/ml) (ng/ml) (h) (h) ANF (n=25) (786) (142) (0.73) ( ) ANF (n=25) (731) (143) (0.67) ( ) * Median (range) presented for t max Parameter Comparison PE 90% C.I. AUC (0- ) a B:A 1.00 ( 0.91, 1.09 ) C max a B:A 1.05 ( 0.97, 1.14 ) t max b B-A 0.00 ( -0.23, 0.22 ) Regimen Key: A: ANF1-commercial rosiglitazone, B: ANF4 a Ratio of adjusted geometric means between formulations b Estimated median difference between formulations (h) Conclusion Rosiglitazone tablets formulated using ANF4 were shown to be bioequivalent to tablets formulated using ANF1 (commercial rosiglitazone). The administration of single oral doses of ANF4 and ANF1 was generally well tolerated in healthy adult subjects. 10

12 1 Introduction The purpose of this study was to demonstrate the bioequivalence of rosiglitazone maleate anhydrate Form IV (ANF4) and anhydrate Form I (ANF1), the current commercial form. Rosiglitazone maleate (Avandia ) is a member of the thiazolidinedione class of oral diabetic agents that acts to enhance the sensitivity of the body to insulin. It has been approved by the US Food and Drug Administration for the treatment of type 2 diabetes mellitus. The current commercial form of rosiglitazone maleate is anhydrate I (ANF1). Three alternative crystalline forms (polymorphs) have been identified since the initial filing of the manufacturing process [anhydrate Forms II, III and IV, respectively (ANF2, ANF3, ANF4)]. Anhydrate Form IV has been shown to be the most stable form. With the demonstration of bioequivalence between ANF1 and ANF4 in the current study, along with supported in vitro data, ANF4 could be manufactured as a back-up commercial formulation of rosiglitazone maleate. The oral dose of rosiglitazone in each of the formulations used in this study, 8 mg, is the maximal total daily therapeutic dose that is approved worldwide for clinical use. Please refer to the Investigator Brochure (Seventh Edition, March 2001) for a review of the pre-clinical and clinical studies with Avandia.[1] 2 Objectives 1 To demonstrate the bioequivalence of rosiglitazone maleate anhydrate Form IV (ANF4) relative to commercial tablets containing anhydrate Form I (ANF1) 2 To assess the tolerability of single oral doses of tablets containing anhydrate rosiglitazone maleate forms ANF1 and ANF4, respectively, in healthy adult subjects 11

13 3 Methodology 3.1 Study Design This was an open-label, randomized, two-period, period-balanced crossover study. Each subject received the following two treatments in a fasted state, one during each study session, in a randomized sequence (AB, BA): Regimen A: 8 mg single oral dose of the commercial anhydrate Form I (ANF1) of rosiglitazone Regimen B: 8 mg single oral dose of anhydrate Form IV (ANF4) of rosiglitazone Subjects were assigned to one of two treatment sequences (AB or BA) based on a randomization schedule prepared in advance of the start of the study. Following dosing, subjects remained in the Clinical Pharmacology Unit (CPU) for 24 hours. Pharmacokinetic sampling for measurement of plasma rosiglitazone was conducted over the 24-hour period following administration of study medication in each study session. There was a washout period of at least one week between treatment sessions. Female subjects returned to the CPU 10 to 14 days following the last dose of study medication for a follow-up serum pregnancy test Protocol Amendments The protocol for this study was dated 10 May 2001 and approved by on 15 May There were no amendments to this protocol. 3.2 Investigators The study was conducted in a single center, the USA. The principal investigator of this study was MD (curriculum vitae in Appendix A). Sub-investigators at the CPU were MD, MD, MD, MSN, CRNP, MD, MD, MD, PhD., MD, PhD, MSN, CRNP, MSN, CRNP, MSN, CRNP, PA-C, RN, MSN, PhD. 12

14 Safety laboratory tests and urine drug screens were performed by the USA. Clinical data for this study are on file at GlaxoSmithKline Pharmaceuticals. 3.3 Ethics The study was conducted in accordance with Title 21 of the U.S. Code of Federal Regulations, Good Clinical Practice guidelines, and the Declaration of Helsinki (as amended in South Africa, 1996). The protocol and statement of informed consent (see Appendix A) were approved by prior to the start of the study. The nature of the study was fully explained to each subject and written informed consent was obtained from each subject prior to his or her entry into the study. Subjects were informed that they could withdraw from the study at any time. 3.4 Eligibility Criteria Inclusion Criteria 1 Healthy adult men or women who were between 18 and 65 years of age. An attempt was made to enroll equal proportions of males and females, depending on subject availability. 2 Body weight > 50 kg (110 lbs.) and within 20% or +35% of ideal weight based on height and body frame.[2] Exclusion Criteria 1 Any clinically relevant abnormality identified on the screening medical assessment, laboratory examination, or electrocardiogram (ECG) 2 Positive urine drug screen (UDS) 3 History of regular alcohol consumption exceeding 7 drinks/week for women or 14 drinks/week for men (1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor) within 6 months of screening 4 Treatment with an investigational drug within 30 days or 5 half-lives (whichever was longer) preceding the first dose of study medication 13

15 5 Pregnant or nursing women; women of childbearing potential who were unwilling or unable to use an appropriate method of contraception (as outlined in Section 3.8.3) from at least 14 days prior to study medication administration until completion of follow-up procedures 6 Use of prescription or non-prescription drugs (including vitamins and herbal supplements) within 1 week prior to dosing or during the study. Excluded from this list were: acetaminophen ( 2 g/day), hormone replacement therapy, and thyroid replacement therapy. Hormonal methods of birth control were permitted throughout the study, except postcoital methods of contraception. 7 Blood donation of greater than 500 ml within 56 days of study Day 1. 8 Hemoglobin or hematocrit below the reference range at screening. 9 History of hypersensitivity to heparin, heparin-induced thrombocytopenia, or hypersensitivity to any of the study medications or components thereof. 3.5 Treatments and Administration Study Medication Rosiglitazone was supplied by GlaxoSmithKline as described in Table 1. Table 1 Study Medication Used Study Drugs Appearance Formulation Dose Unit Batch/Lot Numbers Regimen A: rosiglitazone maleate (ANF1) red brown, film-coated pentagonal tablet commercial 8 mg rosiglitazone Lot # 271A60 Regimen B: rosiglitazone maleate (ANF4) red brown, film-coated pentagonal tablet CM-AA 8 mg rosiglitazone Batch # N01096 Source: Appendix A, Certificate of Analysis for rosiglitazone anhydrate Form IV (ANF4) only. Certificate of Analysis not available for commercial rosiglitazone. Prior to dosing in each study session, the dose for each subject was individually labeled with the protocol number, subject number, study session, and treatment description. No specific preparation of study medication was required prior to administration. Study medication was packaged in white, opaque, HDPE bottles of 30 tablets labeled with the study number, drug name and strength, quantity, and 14

16 batch number. Study medication was stored at controlled room temperature (68-77 F, C) and protected from light in a locked area Methods of Blinding Treatments were not blinded Dosage and Administration During each study session, subjects received an 8 mg single oral dose of rosiglitazone under fasting conditions as either the commercial ANF1 of rosiglitazone (Regimen A) or the ANF4 of rosiglitazone (Regimen B). All study medication was administered orally with 240 ml water by study personnel. 3.6 Compliance with Study Medication Each dose of study medication was administered under the supervision of study personnel. The oral cavity of each subject was inspected after dosing in order to ensure that study medication was taken. A record of the amount taken by the subject, together with any related information, was recorded. 3.7 Prior and Concomitant Medication A reasonable effort was made to document any medications the subject received within 7 days prior to dosing of study medication. The use of prescription or non-prescription drugs (including vitamins, and herbal and dietary supplements) was prohibited within 7 days or 5 half-lives (whichever was longer) prior to the first dose of study medication and throughout the study. By exception, acetaminophen ( 2 grams/day) and thyroid replacement therapy were permitted. Hormone replacement therapy and hormonal forms of birth control were permitted. All concomitant medication taken during the study were recorded with indication, daily dose, and start and stop dates of administration. 3.8 Study Procedures Schedule of Assessments The schedule of study procedures is contained in Section 10, Table

17 3.8.2 Prestudy Screening and Enrollment Prior to administration of study medication (within 30 days), subjects were screened to confirm that they met study entrance criteria. The screening visit included: a medical history, a medication history for the 30 days prior to screening, a physical examination, standard 12-lead ECG if not taken within the past 6 months, vital signs (blood pressure and pulse rate), contraceptive and menstruation history, and smoking history (type, e.g., pipe, cigar, chewing tobacco or cigarette, quantity and duration). Following at least a 4 hour fast, blood (up to 11 ml) and urine samples were obtained for laboratory safety tests and urinalysis (see Appendix D of the protocol, found in Appendix A of this report). Safety laboratory tests included a urine drug screen at screening, serum beta-human chorionic gonadotropin (β-hcg for females only at screening and pre-dose in all sessions) and estradiol and FSH for all post-menopausal female subjects, defined as being amenorrheic for at least 1 year. Preparation of subjects for study participation included instructions on the use of Concomitant Medications (Section 3.7) and Lifestyle Restrictions (Section 3.8.4). Subjects previously screened for another study could participate in this study provided they met the entry criteria outlined above. In such situations, written consent for this study was obtained prior to any protocol-specified procedures being performed. General screening data from the previous study was considered sufficient to satisfy the requirements of this study, and only those procedures required by this protocol, but not conducted for the other study, were performed. All screening data was obtained within 30 days prior to administration of study medication, as stipulated above Treatment Phases Subjects were required to stay in the CPU for approximately 26 hours. On the first day of each study session, subjects reported to the CPU at approximately 07:00 following an overnight fast of at least 8 hours. Subjects continued fasting for 4 hours after dosing. Prior to dosing, an intravenous cannula for collection of blood samples could have been inserted into one antecubital vein and kept patent with a dilute heparin solution ( 10 U/mL) for up to 24 hours. Appropriate study medication (Regimen A or B) was administered orally with 240 ml of tepid water at approximately 08:00. 16

18 Procedures performed are listed in Table 2: Table 2 Day 1 Study Procedures Procedures Time (Hours from Morning Dosing) Review of prior medications (Session 1) or Pre-dose concomitant medications (Session 2) Review of medical history Pre-dose (Session 1 only) Serum β-hcg* Pre-dose each session Study medication administration with 240 ml water 0 hour Meals (lunch, dinner) 4 and 10 hour after dosing Baseline signs/symptoms or Pre-dose and at 4, 10, 21 and 24 adverse events** hours after dosing Blood samples for pharmacokinetics Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, (approximately 3 ml) 8, 10, 12, 16 and 24 hours after dosing Sitting vital signs (BP, HR) Pre-dose (Session 1 only) Blood (approximately 6 ml) and urine samples Pre-dose (Session 1 only) for clinical laboratory tests (8 hour fast) * Serum β-hcg was measured pre-dose in each session for all women. Results were reported prior to dosing, and had to be negative for a subject to proceed with dosing. ** Baseline signs/symptoms were assessed pre-dose at Session 1. Adverse events were assessed by asking a non-leading question such as "How do you feel?" at all other times indicated. Pharmacokinetic Assessments Blood samples for pharmacokinetic analysis were collected into EDTA tubes. If necessary, the precise timing of pharmacokinetic sampling could have been altered. However, the maximum number of samples collected for pharmacokinetic assessment could not exceed 14 per study session. Following completion of the study procedures described above for the 24 hour time point, subjects were discharged from the CPU. There was an interval of at least seven (7) days between study sessions (i.e., administration of subsequent doses of study medication did not occur until at least seven (7) days after the previous dose of study medication). All study sessions were conducted identically as described above. Following the review of all medical and safety laboratory information at the completion of Session 2, male subjects were discharged from the study. Female subjects returned to the CPU days following the last dose of study medication for a follow-up serum pregnancy test. 17

19 Lifestyle Restrictions Diet Subjects were required to fast from all food and drink at least 4 hours prior to any laboratory safety evaluations and 8 hours prior to the start of pharmacokinetic collections. Water was allowed ad libitum during the 8 hour fast except for 1 hour before dose administration. Water could be consumed ad libitum beginning 2 hours after dosing. Soft drinks without caffeine or fruit juices could be consumed ad libitum beginning 4 hours after dosing. Lunch was provided approximately 4 hours after dosing. Dinner was provided at approximately 9 to 10 hours after dosing. An optional evening snack was permitted up until 22:00. Caffeine, Alcohol, and Tobacco Subjects abstained from ingesting caffeine- or xanthine-containing products for 24 hours prior to the start of each dosing session and until collection of the final pharmacokinetic sampling period. Subjects abstained from ingestion of alcohol for 24 hours prior to the start of each dosing session until collection of the final pharmacokinetic sampling period. For subjects who were using tobacco products at the time of screening, the type (e.g. pipe, cigar, chewing tobacco, or cigarette) quantity, and duration of use was documented. Subjects who used tobacco were instructed that tobacco use would not be permitted while they were in the CPU. Activity Subjects abstained from strenuous exercise for 24 hours prior to blood collection for clinical laboratory tests (pre-dose, Session 1). Subjects could participate in light recreational activities (e.g., watch television, read). Contraception Women of childbearing potential include the following: post-menopausal females who had been amenorrheic for less than 1 year and pre-menopausal females without a documented hysterectomy. Appropriate contraceptive methods for female subjects of childbearing potential include one of the following: abstinence or one (1) of the following methods: documented tubal ligation, documented placement of an intrauterine device (IUD), condom and diaphragm with spermicidal foam/gel/film/cream/suppository, or condom with spermicidal foam/gel/film/cream/suppository. Use of oral, injected, and implanted hormonal methods of contraception were permitted in addition to using one of the recommended methods above. Postcoital methods of contraception were not permitted during the study. 18

20 Appropriate contraception had to be used by females for at least 14 days prior to the first dose of study medication and continued until completion of follow-up procedures. Pregnancy Testing All women were tested for serum β-hcg prior to dosing with study medication in all study sessions, as well as at the follow-up visit. Results were obtained prior to dosing during each session. Subjects with a positive serum β-hcg test were to be withdrawn from the study Post-Treatment Phase Female subjects returned to the CPU 10 to 14 days following the last dose of study medication for a serum β-hcg test. Following completion of this test, the subject was discharged from the CPU. Following review of all medical and safety laboratory information, the subject was discharged from the study Reasons for Withdrawal A subject could withdraw from the study at any time at their own request, or they could have been withdrawn at any time at the discretion of the investigator for safety, behavioral, or administrative reasons. Subjects who withdrew early, for any reason, could have been replaced with another subject assigned to the same sequence of treatments Reasons for Concluding Study Subjects who participated in and completed all study sessions were considered as having completed the study. Subjects for whom clinical safety laboratory and pharmacokinetic specimens were collected at each study session were considered as being evaluable subjects. 3.9 Safety Assessments Safety and tolerability of study medication were assessed during this study by nursing and physician observation and spontaneous reporting of symptoms by subjects. These events were classified as adverse events as described in Section In addition, blood pressure, pulse rate, and clinical safety laboratory tests were performed. The results of these procedures were evaluated as described in Section

21 3.9.1 Adverse Events Adverse events (AEs) were elicited by a non-leading question such as "How do you feel?" asked of the subject by study personnel. Details of any elicited AEs and their severity, including any change in study drug administration, relationship to study drug, any corrective therapy given and outcome status were documented (see Section 5.2). Relationship of AEs to study drug was judged by the investigator to be not related, unlikely, suspected, or probable. All adverse events were coded from the verbatim term according to the World Health Organization (WHO) Adverse Reaction Terminology (ART) dictionary by body system and preferred term. A serious adverse event is defined as any AE which was fatal, life-threatening, permanently or temporarily disabling or incapacitating, which resulted in hospitalization or a prolonged hospital stay, was associated with a congenital abnormality, or any event which the investigator regarded as serious based upon appropriate medical judgment. In addition, GlaxoSmithKline policy dictates that events of cancer or overdose (either accidental or intentional) be documented and reported as for serious AEs Vital Signs, ECGs and Safety Laboratory Tests Physical examination findings obtained during the treatment phase were compared to corresponding results prior to dosing. The criteria for determination of specific values of potential clinical concern for vital sign, 12-lead ECG, and safety laboratory data were outlined in the protocol and are presented in Table 3. Any vital sign, 12-lead ECG, or clinical safety laboratory values exceeding these pre-defined thresholds were identified and tabulated (see Section 5.6, Section 5.7, and Section 5.8). Any such changes considered clinically significant were recorded as adverse events. 20

22 Table 3 Protocol-Defined Values of Potential Clinical Concern Vital Signs* Heart Rate Sitting/Supine: <35 or >120 bpm Erect: <40 or >140 bpm Blood Pressure Systolic >30 mmhg change or diastolic >20 mmhg change from baseline in same posture 12-Lead Electrocardiogram^ PR interval >300 msec QRS interval >200 msec QTc interval >500 msec Laboratory* Hematology Hemoglobin Males: <12.0 or >18.0 g/dl Females: <10.5 or >16.1 g/dl Hematocrit Males <36.0 or >54.0% Females: <31.0 or >50.6% Leukocytes >1 K/uL below or >3 K/uL above the limit of the reference range Platelets <80 or >500 K/uL Clinical Chemistry Total bilirubin 1.5 times upper limit of the reference range AST >2 times upper limit of the reference range ALT >2 times upper limit of the reference range GGT >2 times upper limit of the reference range Alk Phosphatase >1.5 times upper limit of the reference range Creatinine >1.8 mg/dl BUN >1.5 times upper limit of the reference range Glucose, fasting <60 or >126 mg/dl Uric acid >11 mg/dl Sodium >5 meq/l above or below the limits of the reference range Potassium >0.5 meq/l above or below the limits of the reference range Calcium <7.2 or >12 mg/dl Phosphate >0.8 mg/dl below or 1.0 mg/dl above the limits of the reference range Albumin >0.5 g/dl above or below the limits of the reference range Total protein >1.0 g/dl above or below the limits of the reference range Urinalysis WBC >15/hpf RBC >15/hpf Source: Protocol (Appendix E), Appendix A of the report * Clinical safety laboratory tests and vital signs were performed at screening and pre-dose in Session 1 ^12-lead ECG measurements were taken at screening only 3.10 Pharmacokinetic Assessments Collection and Preparation of Samples Blood samples (approximately 3 ml) for pharmacokinetic analysis were collected into EDTA tubes at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours after dosing. After collection, blood specimens were placed on ice. Plasma was separated using a refrigerated centrifuge and then transferred to an appropriately labeled polypropylene tube. Samples were processed as quickly as possible and were kept on ice until processed. Specimen containers were labeled with study number (BRL 49653C/300), subject number, session, and nominal time of collection. Plasma specimens were stored at approximately -20 C until transported in the frozen state to the Drug Analysis Department, DMPK, GlaxoSmithKline, UK, for further analysis. 21

23 Assay Methods Drug analysis was performed under the guidance of the Drug Analysis Department, DMPK, GlaxoSmithKline, UK. Plasma concentrations of rosiglitazone (BRL 49653) were determined using the currently approved analytical methodology. Raw data was stored in the archive, GSK Pharmacokinetic Analysis The following pharmacokinetic parameters were determined and descriptively summarized: area under the concentration-time curve to infinite time (AUC (0- ) ), maximum plasma concentration (C max ), time to reach maximum concentration (t max ), apparent terminal half-life (t 1/2 ). Pharmacokinetic analysis was conducted by Clinical Pharmacokinetics, CPEM, GlaxoSmithKline, RTP. Plasma concentration-time data were recorded in tabular and graphical form. Plasma concentration-time data for each subject in each regimen were analyzed by departmentally approved non-compartmental methods Data Quality Assurance All clinical studies performed by, or on behalf of, GlaxoSmithKline are conducted in accordance with the ethical considerations detailed in the Declaration of Helsinki and applicable national or regional Good Clinical Practice guidelines. Uniformity of study performance was controlled by a standard protocol and a validated electronic data collection and reporting system (Phase I Management System, PIMS).[3] Adherence to the protocol requirements and verification of data generation accuracy was achieved through routine monitoring while the study was ongoing. Subsequent data handling and reporting processes were subject to in-process quality control checks and this final clinical report has, in addition, been subject to an end-stage quality control review. These procedures were performed according to GlaxoSmithKline standard operating procedures. Periodic system audits for study conduct, data handling, reporting and archiving within GlaxoSmithKline indicate that the routine application of standard operating procedures and guidelines have ensured the quality and integrity of this study. No study specific audits were performed for this study. 22

24 3.12 Statistical Evaluation Target Sample Size The target sample size was 24 subjects. Sample size calculations were based on the pooled within-subject estimates of variability across all Clinical Pharmacology studies in the rosiglitazone drug development program in normal healthy subjects. For AUC (0- ) and C max of a single oral dose of rosiglitazone, these were 16.0% and 21.7%, respectively. Using the higher of the 2 average estimates of variability, it was estimated that a sample size of 24 would provide at least 90% power to demonstrate bioequivalence of the rosiglitazone maleate ANF4 (B) relative to ANF1 (A). Equivalence here would be demonstrated when the 90% confidence interval for the ratio of B:A is contained within the range (0.80, 1.25) [4] for both AUC (0- ) and C max. This range represents a symmetric 20% range on the log e -scale. This calculation is based on a two-one sided testing procedure with a type I error rate of 5% and assumes a true ratio of unity. A sensitivity analysis was conducted in the event that the variability was greater than estimated. Using the highest pooled estimate of variability (21.7% for C max ), an upper bound of the 90% confidence interval for the variability was 23.3%. Based on this larger variability, a sample size of 24 subjects should provide at least 50% power to demonstrate equivalence between Regimens A and B. This calculation was also based on a two-one sided testing procedure with a type I error rate of 5% and assumed a true ratio of unity Method of Randomization Subjects were randomized to one of two treatment sequences (AB, BA) using a randomization schedule prepared prior to the start of the study (Appendix A). The randomization schedule of intent is listed in Appendix A, Table A1. The actual treatment sequence allocation is presented in Appendix A, Table A2. There are no discrepancies between the randomization schedule of intent and the actual treatment sequence allocation Planned Safety Analysis No statistical analysis of the safety or tolerability data was planned. 23

25 Planned Pharmacokinetic Analysis The primary pharmacokinetic endpoints of interest were AUC (0- ) and C max of rosiglitazone. The secondary pharmacokinetic endpoints were t 1/2 and t max of rosiglitazone. Additional endpoints included %Extrapolated AUC (0- ) and Total Time above the target concentration (52 ng/ml, the concentration associated with 50% of maximum effect and above which the formulations were targeted to remain for the same period of time). The focus of the statistical analysis was to demonstrate bioequivalence of rosiglitazone maleate ANF4 relative to ANF1. Thus, point estimates were computed for the ratios ANF4 to ANF1 (B:A) for AUC (0- ) and C max of rosiglitazone. Accompanying 90% confidence intervals provided a range of plausible values for the true ratios. Following log e transformation, AUC (0- ) and C max were analyzed separately by analysis of variance (ANOVA) appropriate to the study design with terms for sequence, subject(sequence), period and regimen. Point estimates and 90% confidence intervals for the differences (B-A) were constructed using the residual variance from the ANOVA model. The point and interval estimates on the log e scale were then backtransformed to give point and interval estimates for the ratios B:A. Distributional assumptions underlying the analyses were assessed by visual inspection of residual plots. Normality was examined by normal probability plots, while homogeneity of variance was assessed by plotting the studentised residuals against the predicted values from the model. The parameter t max of rosiglitazone was analyzed non-parametrically using the Wilcoxon matched pairs method.[5] The point estimate and 90% confidence interval for the median difference B-A was constructed. Summary statistics (n, arithmetic mean, standard deviation, minimum, median, maximum) were calculated by regimen for AUC (0- ), C max, t max, t 1/2, %Extrapolated and Total Time above the target concentration (52 ng/ml). Geometric means and between-subject coefficients of variation for AUC (0- ) and C max were calculated for the log-transformed parameters where: Geometric mean = exp(mean on log e scale) CVb (%) = sqrt[exp(sd 2 )-1] x 100. where SD is the standard deviation on the log e scale. 24

26 Individual values for AUC (0- ), C max, t max, and t 1/2 were plotted vs. regimen. 4 Study Population 4.1 Study Dates The first study consent form was signed and study-specific procedures began on 7 July The first dose of study medication was administered on 31 July 2001, and the last study visit was on 20 August Subject Disposition Subject disposition is summarized in Table 4. Table 4 Subject Disposition Disposition Number of Subjects Total Screened 46 Total Screened But Not Used: 18 -Abnormal Labs 5 -Study Day No Show 3 -Decided Not to Participate 2 -Alternate Not Needed 2 -Positive Urine Drug Screen 2 -Abnormal Finding on Physical Exam 1 -Did Not Meet Criteria 1 -Personal Emergency 1 -Illness 1 Total Randomized/Enrolled 28 Total Withdrawn Prior to Dosing 1 Regimen A Regimen B Total Total Dosed Total Withdrawn After Dosing Serious adverse event (atrial fibrillation) -Suspected urinary tract infection Total Completed Source: Section 10, Table 10.2 and Table 10.3 and data on file, GlaxoSmithKline Pharmaceuticals Regimen A: single oral 8 mg dose of ANF1-commercial rosiglitazone Regimen B: single oral 8 mg dose of ANF4 Thus, this subject was not included in any of the summary statistics. Of the remaining 27 subjects randomized to treatment, two (2) subjects were withdrawn prior to the completion 25

27 of the study. She was asymptomatic and had no vaginal discharge. The latter was deemed to precede and to be unrelated to treatment with study medication (Section 5.8). Her urine analysis had normalized at the follow-up visit, 10 days after dosing. 4.3 Protocol Violations Subjects enrolled in the study met protocol-specified eligibility criteria and study procedures were performed according to the protocol, with the exception of the minor protocol deviations listed in the Table 5. Table 5 Protocol Violations by Subject Source: Section 10, Table 10.4 and Table 10.5 and data on file, GlaxoSmithKline Pharmaceuticals These violations did not affect the interpretation of the study results and were not considered by the investigator to have adversely affected the safety of the subjects or to be reasons for withdrawal of the subjects of the study. All other subjects enrolled in the study met protocol-specified eligibility criteria and study procedures were performed according to the protocol. 4.4 Demographic Characteristics Twenty-eight (28) healthy adult male and female subjects were enrolled in this study and randomized to treatment. Twenty-seven (27) subjects received at least one dose of study medication. Demographic data for subjects who were dosed are summarized in Table 6. 26

28 Table 6 Demographic Characteristics of Study Population Group Parameter Age Height Weight (years) (m) (kg) Subjects Mean (n=27) SD Range Source: Section 10, Table 10.3 Race: 41% White, 37% Black, 4% Oriental, 19% Other Gender: 70% Male, 30% Female 4.5 Presenting Conditions and Medical History All subjects were healthy adults. Signs and symptoms present prior to the initial dose of study medication are displayed in Section 10, Table These were not considered sufficient to affect the conduct of the study nor did they represent a potential risk to the subject during participation in the study, with one exception. When the urine analysis results were reviewed one hour post-dosing, she was withdrawn due to a suspected urinary tract infection and referred to her primary care provider for diagnosis and treatment of a suspected asymptomatic urinary tract infection, present prior to and unrelated to treatment with study medication. The subject did not follow-up with a physician, remained asymptomatic, and received no treatment. Subsequent laboratory data obtained ten days later showed full resolution of the pyuria. 4.6 Prior and Concomitant Medications The study protocol prohibited the use of prescription or non-prescription medications (other than acetaminophen at doses 2 grams/day, thyroid replacement therapy, hormone replacement therapy and hormonal methods of contraception, excluding postcoital contraceptive medications), vitamins, and herbal and dietary supplements within 7 days or 5 half-lives (whichever was longer) prior to dosing or throughout the duration of the study. Contrary to this restriction, however, two subjects received one or more doses of a prohibited medication prior to (Section 10, Table 10.4) or during the study (Section 10, Table 10.5). Nitro Glycerol is a nutritional supplement containing no 27

29 carbohydrates/sugar/fat and containing the following (per serving): Whey protein isolate (50 g), glycerol (40 g), L-glutamine (5 g), Ma Huang (200 mg), niacin (40 mg), chromate (200 ug), and a proprietary anabolic blend called SynergyMass (contains tribulus terrestris, guarana seed, BCAA s, kona nut, creatine monohydrate, orchic, L-glutamine peptide, L-lysine, L-carnitine, N-acetyl cysteine, CoQ10, RNA/DNA blend, siberian ginseng, mexican yam, smilax root, saw palmetto, plant sterols, muira puama, colostrum, magnesium carbonate, wild oats, nettle root, yerba mate, vitamin B6, vanadyl sulfate, alpha lipoic acid, royal jelly, silica, suma root, and astragalus root). These prohibited prior and concomitant medications were not deemed by the investigator to interfere with the conduct or interpretation of the study or to be reasons for withdrawal. No other prohibited medications were reportedly taken by any other subjects prior to or during the course of this study. 4.7 Treatment Administration and Compliance Subjects received either Regimen A (a single oral dose of rosiglitazone 8 mg ANF4) or Regimen B (the commercially available rosiglitazone 8 mg ANF1) at each of two study periods, which were separated by at least one (1) week. Medication administration data are presented in Section 10, Table All medication was administered under the supervision of study personnel. There was total compliance with study medication. 5 Safety Results 5.1 Extent of Exposure Table 7 Number of Subjects Who Received Each Treatment Regimen Description of Regimen Number of Subjects Regimen A: single oral 8 mg dose of ANF1-commercial 26 rosiglitazone Regimen B: single oral 8 mg dose of ANF4 26 Source: Section 10, Table

30 5.2 Adverse Events Thirteen (13) adverse events (AEs) were reported for nine (9) subjects following treatment with study medication. A similar number of AEs were reported following Regimens A and B. Eight (8) AEs were reported for 5 subjects in Regimen A. Five (5) AEs were reported for 5 subjects in Regimen B. All AEs were mild in nature, with the exception of the serious adverse event (SAE) of atrial fibrillation (see Section 5.4). Adverse events reported during this study are summarized by regimen in Table 8 and are displayed in Section 10, Table Table 8 Number of Adverse Events Regimen A Regimen B Total Total Number of AEs Number of Subjects with AEs Number of Subjects Exposed Source: Section 10, Table 10.8 Regimen A: single oral 8 mg dose of ANF1-commercial rosiglitazone Regimen B: single oral 8 mg dose of ANF4 Four (4) AEs were deemed by the investigator as not related to study medication and nine (9) AEs were deemed by the investigator as unlikely to be related to study medication. The most frequent reported AEs were headache, micturition frequency, and dizziness. None of the AEs required intervention, with the exception of the withdrawal due to atrial fibrillation. All AEs, including the atrial fibrillation, spontaneously resolved. AEs that occurred following the administration of study medications are summarized by regimen in Table 9. 29

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