Referring to Part IV of the Dossier

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1 2. SYNOPSIS Name of Company: Mundipharma Research Limited Name of Finished Product: FlutiForm Name of Active Ingredient: Fluticasone propionate / Formoterol fumarate INDIVIDUAL STUDY TABLE Referring to Part IV of the Dossier Volume: Page: (For National Authority Use Only) Title of the Study: A Phase1 open-label, single dose, parallel group study to determine the systemic exposure of FlutiForm pmdi 125/5 µg (250/10 µg total dose) in adult and adolescent subjects with mild to moderate asthma. Investigator: Dr. Ischen Müller, Parexel International (South Africa) (Pty) Limited, George, South Africa. Publication (Reference): None Study Dates: 01 June 2009 to 07 August 2009 Study Status: Completed Phase of Development: Phase 1 Objective: The objective of this study was to determine the systemic exposure of FlutiForm pmdi 125/5 µg (250/10 µg total dose) in adult and adolescent subjects with mild to moderate asthma, based on the pharmacokinetic data. Methodology: Open-label, single dose, parallel group. The study had a screening visit, a 1-week wash-out period, a 2-day treatment period, and a post-study visit 4-7 days after study drug dosing. During the screening period, subjects continued to take their pre-study asthma medication. During the wash-out and study period, salbutamol was taken as rescue medication, if required, up to 4 times/day. Number of Subjects: Planned: 68 subjects. Received study treatment: 65 subjects. Completed: 65 subjects (31 adolescents [14 subjects aged and 17 subjects aged 15-17] and 34 adults). Indication and Criteria for Inclusion: Male or female subjects aged 12 to 17 years inclusive in the adolescent group and 18 to 55 years inclusive in the adult group, with known history of mild to moderate reversible asthma for 6 months prior to screening. Test Treatment, Dose, and Mode of Administration: Study Medication Dosage Form Unit Strength Dosing Frequency Mode of Administration FlutiForm pmdi (Fluticasone/ Formoterol) 2 puffs 125/5 µg Once The spacer device used was the AeroChamber Plus Inhaled with Spacer FlutiForm was manufactured by Sanofi-Aventis, UK. Batch number AA80010/PN3422. The test treatment was used with a spacer device. The spacer device to be used in the study was the AeroChamber Plus. pmdi = pressurised Metered Dose Inhaler. Reference Treatment, Dose, and Mode of Administration: Not applicable. Duration of Treatment: Subjects attended a screening visit 14 days prior to starting a 1-week wash-out period. Total duration of the screening and wash-out period was 21 days. On successful completion of the wash-out period, subjects attended a check-in visit (Day -1) and had two overnight stays in the study unit. Subjects received a single dose of study drug on the morning of Day 1 and were discharged from the study unit on the evening of Day 2, following blood and urine sampling for PK assessments up to 36 hours post-dose. Subjects attended a post-study visit 4-7 days after study drug dosing. Total duration of the study was up to 28 days. CSR Page 1 of 6

2 Treatment Schedule: Subjects continued on their current asthma medication between the screening visit (Visit 1) and the start of the wash-out period (Visit 2). During the wash-out period, all subjects stopped taking their current asthma therapy. Salbutamol 100 µg (2 puffs on up to 4 occasions per day) was used as rescue medication. Subjects recorded rescue medication use in a diary, which they returned to the study unit at Visit 3 (Day -1). Subjects who met all eligibility criteria were enrolled to receive study drug the following morning (Day 1) and were given training in the use of the study drug and spacer device. On the morning of Day 1, subjects administered a single dose of study drug (FlutiForm 125/5 µg, 2 puffs). A spacer device (AeroChamber Plus) was used. The spacer device and pmdi device were primed by the Investigator prior to dosing. After dosing, subjects rinsed their mouth with water and spat the water out. Subjects were allowed to take rescue medication, if required, during the 2-day treatment period. On discharge from the study unit (Day 2, or earlier if the subject discontinued from the study during the treatment period), subjects resumed their pre-study prescription asthma medication. Criteria for Evaluation: Analysis Populations: Enrolled population: All subjects that provided written informed consent to participate in the study. Safety population: All subjects who received study treatment. Full analysis population for PK: All subjects who received study treatment and had at least one PK parameter. Fluticasone primary analysis population for PK parameters: All subjects in the full analysis population for PK parameters, excluding those subjects with a quantifiable fluticasone propionate pre-dose concentration >5% of Cmax. Per protocol population: All subjects in the full analysis population for pharmacokinetics without any major protocol violations. Drug Concentration Measurements: Blood samples (9 ml each) for analysis of fluticasone propionate and formoterol fumarate were taken at the following timepoints: Day 1: pre-dose and at 0.05 (3 min), 0.1 (6 min), (10 min), 0.25 (15 min), (20 min), 0.5 (30 min), 0.75 (45 min), 1, 1.5, 2, 4, 6, 9, 12, 16, 24, and 36 hours post-dose (18 samples). Approximately 162 ml of blood (18 samples of 9 ml) were taken from each subject for PK measurements. Serial urine collection for analysis of formoterol fumarate was taken at the following timepoints: Day 1: pre-dose and at 0-1, 1-2, 2-4, 4-8, 8-12, 12-24, and hours post-dose. Bioanalytical Methods: Plasma samples were analysed by validated bioanalytical assays for fluticasone propionate and formoterol fumarate. Urine samples were analysed by a validated bioanalytical assay for formoterol fumarate. Efficacy Analyses: Not applicable Interim Analyses: None planned CSR Page 2 of 6

3 Pharmacokinetic Parameters: a) Plasma: The following PK parameters were calculated for fluticasone propionate and formoterol fumarate in plasma: AUCt, AUCINF, Cmax, tmax, LambdaZ, and t1/2z. Areas under the plasma concentration-time curve calculated from the time of dosing to the last measurable concentration (AUCt) were determined using the log-linear trapezoidal method. Where possible, the terminal phase rate constants (LambdaZ) were estimated using those points determined to be in the terminal log-linear phase. Half-lives (t1/2z) were determined from the ratio of ln 2 to LambdaZ. The areas under the plasma concentration-time curve between the last measured point and infinity were calculated from the ratio of the final observed plasma concentration (Clast) to LambdaZ. This was added to the AUCt to yield the area under the plasma concentration-time curve between the time of administration and infinity (AUCINF). The maximum observed plasma concentration (Cmax) and times to Cmax (tmax) were obtained directly from the reported plasma concentration-time data. All PK calculations were performed with the current version of WinNonlin Enterprise Edition (Version 4.1 or later). b) Urine: The following PK parameters were calculated for formoterol fumarate in urine: Rt1-t2, Rmax, Ae0h-t2, Ae0h-12h, Ae0h-36h, Fe0h-t2, Fe0h-12h, Fe0h-36h, t1/2z (urine). The urinary excretion rate of formoterol fumarate was determined over the listed collection intervals. The maximal urinary excretion rate of formoterol fumarate was determined. The cumulative amount and corresponding fraction of dose excreted over the defined collection periods were determined. An attempt was made to determine the urine half-life of formoterol fumarate. Safety Assessments: All safety data were summarised for subjects in the safety population. Safety was assessed by documentation of spontaneously reported adverse events, clinical laboratory results, vital signs, physical examinations, ECGs, lung function tests, asthma symptom scores, sleep disturbance scores, and rescue medication use. Statistical Methods: CSR Page 3 of 6

4 Pharmacokinetic Plasma Analyses Plasma concentration data were summarised descriptively by time point and group (adult and adolescent) for subjects in the full analysis population for pharmacokinetics. Summary statistics for the PK plasma parameters were calculated on the log transformed data (except for LambdaZ, t1/2z, and tmax), and back transformed for presentation in the summary tables. PK plasma parameters were summarised by group as continuous data for subjects in the full analysis population and subjects in the fluticasone primary analysis population for PK parameters (fluticasone propionate only). In addition, the data in the adolescent group were summarised descriptively by age group (12-14 and years). Log transformed data for AUCt, AUCINF (if available), and Cmax were analysed using Analysis of Variance (ANOVA), with a fixed term for group for subjects in the full analysis population and subjects in the fluticasone primary analysis population for PK parameters (fluticasone propionate only). The statistical model was used to calculate the difference between the groups (adolescent minus adult), and the 90% and 95% confidence intervals. The values were back transformed and multiplied by 100. The full analysis population for PK parameters was the primary analysis population for formoterol fumarate. The fluticasone primary analysis population for PK parameters was the primary analysis population for fluticasone propionate. It was to be concluded that systemic exposure was no greater in adolescents than adults if the upper limit of the 90% confidence interval lay completely below 125% for the AUCt, AUCINF, and Cmax parameters. A Wilcoxon rank sum test was used to analyse tmax. Median treatment difference, and 90% and 95% confidence intervals were calculated using the Hodges-Lehmann method. Due to the discovery of quantifiable pre-dose plasma fluticasone propionate concentrations for a significant number of subjects in this study, the PK analysis for fluticasone propionate was performed both including and excluding subjects with quantifiable pre-dose concentrations for fluticasone propionate, in accordance with the EMEA Draft Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98, Rev 1). In accordance with this guideline, the analysis with these subjects excluded was considered primary, with subjects excluded from this analysis if the pre-dose concentration of fluticasone propionate exceeded 5% of the Cmax value for that subject. Pharmacokinetic Urine Analyses PK urine concentration data were only available for formoterol fumarate. PK urine concentration data were summarised by time point and group (adult and adolescent) as continuous data for subjects in the full analysis population for pharmacokinetics. Summary statistics for the PK urine parameters were calculated on the log transformed data, and back transformed for presentation in the summary tables. PK urine parameters were summarised by group as continuous data. In addition, the data in the adolescent group were summarised descriptively by age group (12-14 and 15-17). Safety Analyses All safety data were summarised for subjects in the safety population. Adverse Events were coded using the Medical Dictionary for Regulatory Activities (MedDRA ) coding system to give a System Organ Class (SOC) and preferred term for each event. The number and percentage of subjects reporting any adverse event was summarised by SOC and preferred term for each group. Adverse events were also summarised by severity, relationship to study drug and action taken. Vital sign, laboratory and ECG data were summarised descriptively by time point and group. Change from baseline was also summarised descriptively. In addition, abnormal values were identified as those outside (above or below) a specified range. Rescue medication use was also summarised descriptively by group. Asthma symptom scores and sleep disturbance scores were listed. CSR Page 4 of 6

5 Sample Size Rationale: This study was designed to have a power of 90% to demonstrate that the systemic exposure of FlutiForm pmdi 125/5 µg (250/10 µg total dose) in adolescent subjects was no greater than 1.25 times that in adult subjects. Assuming a coefficient of variation of 0.4 and a true ratio of 0.9 (90%) between test (adolescent) and reference (adult), and a one-sided alpha of 0.025, this could be achieved with 30 completing subjects per group. An expected ratio of 90% between adolescent and adult subjects was selected, based on the expectation that systemic exposure was less in adolescents than in adults. A total of 86 subjects were enrolled to receive study drug with the aim that 30 subjects per group completed the study and provided pharmacokinetic data. It was to be concluded that systemic exposure was no greater in adolescents than adults if the upper limit of the 90% confidence interval lay completely below 125% for the AUCt, AUCINF and Cmax parameters. Results: Efficacy: Not applicable. Pharmacokinetics: Fluticasone Propionate plasma: As previously described, fluticasone propionate plasma levels were analysed using two different analysis populations excluding and including subjects with pre-dose fluticasone propionate concentrations. The results of the primary analysis (fluticasone primary analysis population for PK parameters) were consistent with the results of the secondary analysis (full analysis population for PK parameters). In both analyses, the systemic availability of fluticasone propionate was higher in adolescents compared with adults, based on comparisons of both AUCt (primary; mean ratio 174% (90% CI )) and AUCINF (primary; mean ratio 181% (90% CI )). The maximum observed plasma concentration for fluticasone propionate was more similar between adults and adolescents, however the upper bound of the 90% confidence interval did not meet the primary end point (primary; mean ratio 117% (90% CI ). The fluticasone propionate half-life was found to be similar between adults (primary; hours) and adolescents (primary; hours). Tmax was found to be similar between adults and adolescents for both the primary and secondary fluticasone propionate analyses. Since both the primary and secondary fluticasone propionate analyses resulted in the same conclusions according to the primary end point, the occurrence of quantifiable fluticasone propionate pre-dose concentrations did not influence the outcome of the study. Formoterol Fumarate plasma: The systemic availability of formoterol fumarate was higher in adolescents compared with adults, based on comparisons of both AUCt (mean ratio 116% (90% CI )) and AUCINF (mean ratio 110% (90%CI )), but there was less of a difference than what was observed for fluticasone propionate. The maximum observed plasma concentration for formoterol fumarate was higher in adolescents compared with adults (mean ratio 131% (90% CI )). Formoterol fumarate half-life was similar between adults (7.11 hours) and adolescents (8.16 hours). Formoterol fumarate tmax was also found to be similar between adults and adolescents. Formoterol Fumarate urine: The fraction of nominal dose of formoterol fumarate excreted in urine over the entire urine collection period (Fe0h-36h) was similar for both adults (2.74%) and adolescents (2.90%). A similar formoterol fumarate urinary half-life was observed between adults (9.40 hours) and adolescents (8.12 hours), which were also comparable to the formoterol fumarate half-lives for for each age group that were observed in plasma. CSR Page 5 of 6

6 Safety: There were no deaths or other serious adverse events. Post-treatment AEs were reported by 8 subjects (12.3%), including 5 adults (14.7%) and 3 adolescents (9.7%). The most frequent AEs were headaches (7.7% overall) as reported by 2 adult (5.9%) and 3 adolescent (9.7%) subjects. There was also one subject reporting (1.5% overall) dizziness, and one subject each reporting nausea, vomiting, and nasopharyngitis (1.5% overall) in the adult treatment arm of the study. All incidents of AEs were either mild or moderate in severity. All incidents of headache, nausea, vomiting, and nasopharyngitis were deemed by the Investigator as unlikely to be related, and the incidence of dizziness as not related to study treatment. No subject discontinued in the treatment period due to AEs. There were no clinically significant findings in the laboratory tests, vital signs, or ECG results for either the adult or adolescent treatment group. Conclusions: The systemic exposure of fluticasone propionate was increased in adolescents compared with adults. The systemic exposure of formoterol fumarate was also increased in adolescents compared with adults, but to a lesser degree than fluticasone propionate Increased systemic exposure is likely to be due to a similar lung deposition between adults and adolescents along with a lower body weight (and volume of distribution) in the adolescent age group therefore this is likely to be class effect for all fluticasone and formoterol containing products Neither fluticasone propionate or formoterol fumarate met the primary end points for adolescent systemic exposure compared with adults in terms of AUCt, AUCINF, or Cmax Since both the primary and secondary fluticasone propionate analyses resulted in the same conclusions according to the primary end points, the occurrence of quantifiable fluticasone propionate pre-dose concentrations did not influence the outcome of the study A similar fraction of formoterol fumarate nominal dose excreted in urine was observed in adults and adolescents FlutiForm was safe and well tolerated. Post-treatment adverse events were reported by 8 subjects (12.3%). The most frequently reported AEs were headaches from both treatment groups, as well as dizziness, nausea, vomiting, and nasopharyngitis in the adult treatment arm of the study. All of the adverse events reported were either mild or moderate in severity, and deemed either unlikely to be or not related to study treatment by the Investigator. No subject discontinued in the treatment period due to AEs. There were no clinically significant findings in the laboratory tests, vital signs, or ECG results in either the adult or adolescent treatment group. Date of the Report: CSR Page 6 of 6