Clinical Study Synopsis

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1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare AG. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare AG. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.

2 Clinical Trial Results Synopsis Study Design Description Study Sponsor: Bayer Healthcare AG Study Number: NCT EudraCT number: Test Product Study Phase: I Official Study Title: Therapeutic Area: Anti-infectives Non-blinded, single dose, single centre trial to assess the pulmonary deposition as well as pharmacokinetics, safety and tolerability of 99m Tc- labeled ciprofloxacin when delivered as a single dose from a dry powder inhaler to healthy subjects with and without block and patients suffering from bronchiectasis and COPD Name of Test Product: Ciprofloxacin (Ciprofloxacin DPI, Bay q 3939) Name of Active Ingredient: Ciprofloxacin (BAY q 3939) Dose and Mode of Administration: Single dose contains 32.5 mg ciprofloxacin corresponding to 50 mg ciprofloxacin PulmoSphere inhalation powder, oral inhalation Reference Therapy/Placebo Reference Therapy: None Dose and Mode of Administration: Not applicable Duration of Treatment: Single dose inhalation for patients suffering from bronchiectasis and chronic obstructive pulmonary disease (COPD) Single dose inhalations (with and without block) on two different treatment days for healthy subjects. Studied period: Date of first subjects first visit: 16 APR 2012 Date of last subjects last visit: 25 JUL 2012 Premature Study Suspension / Termination: Substantial Study Protocol Amendments: No Amendment 1 (forming integrated protocol Version 2.0, dated 20 July 2011) specified the following substantial changes: Additional exclusion criterion Subjects with acute episode or history of anxiety disorder and / or depression were not to be included in the study. Additional information on the T-326 dry powder inhaler A statement was added that the T-326 dry powder inhaler was affixed with a CE-marking and was used in accordance with its intended purpose. Amendment 2 (forming integrated protocol Version 3.0, dated 25 August 2011) specified the following substantial change: Withdrawal of patients suffering from cystic fibrosis The subject group of patients suffering from cystic fibrosis was Page 1 of 11

3 not to be enrolled in this study. The sponsor decided to focus on patients suffering from bronchiectasis and COPD only. Study Centre(s): One center in Germany Methodology: This was a single-center, partially randomized (randomization with respect to treatments with and without in the healthy subject group), non-blinded design study. Parallel design for comparison of cohorts: Healthy subjects Patients with bronchiectasis Patients with COPD 2-way randomized crossover in healthy subjects: 32.5 mg ciprofloxacin 32.5 mg ciprofloxacin after a block Indication/ Main Inclusion Criteria: Four (4) to 14 days after inclusion in the study, study participants inhaled a single dose of 99m Tc-labeled ciprofloxacin (32.5 mg). Immediately thereafter, gamma camera images were taken to assess pulmonary deposition. Samples of plasma and urine were obtained up to 24 hours after Ciprofloxacin dry powder for inhalation (DPI) administration for pharmacokinetic measurements. For assessment of lung contours a Krypton ventilation scan was performed once during the study. Additionally, the cohort of healthy subjects inhaled a second dose of 99m Tc-labeled ciprofloxacin at 7 to 12 days after the first treatment visit to assess pulmonary deposition and pharmacokinetics. They were given a block (carbo medicinalis g at times 15 min predose, 2 and 4 hours post dose) to prevent the absorption of the ciprofloxacin fraction from the intestinal tract that was swallowed during the inhalation maneuver which is the prerequisite to allow estimation of the lung deposition based on pharmacokinetic evaluations derived from plasma concentrations. The block was given either at the first treatment visit or at the second treatment visit in randomized order. Seven (7) to 14 days after the last treatment visit all subjects underwent follow-up procedures. Indication: COPD, bronchiectasis Inclusion criteria for all subjects: Understanding of the study and written informed consent prior to any study-related procedures Additional inclusion criteria for healthy subjects: Age: 18 to 65 years (inclusive) at screening visit Males Non- or ex-smokers who smoked < 5 pack-years and stopped smoking >1 year prior to screening visit Good physical and mental status determined on the basis of the medical history and a general clinical examination Results of laboratory tests within the normal ranges; minor deviations are acceptable provided that they are not judged Page 2 of 11

4 Study Objectives: clinically significant by the investigator Additional inclusion criteria for patients with COPD: Age: 40 to 70 years (inclusive) at screening visit Males and females All patients must have a diagnosis of COPD of Stage II or III according to the Global Initiative for Chroni c Obstructive Lung Disease (GOLD) Classification (post-bronchodilator forced expiratory volume in 1 second [FEV1]: 80% > FEV1 30% of predicted values and a post-bronchodilator FEV1/FVC [forced vital capacity] 70%) Minimum smoking history of 10 pack-years Additional inclusion criteria for patients with bronchiectasis: Primary: Age: 18 to 75 years (inclusive) at screening visit Males and females Diagnosis of bronchiectasis Pulmonary deposition and pharmacokinetics of 99m Tc-ciprofloxacin when delivered as a single dose from a dry powder inhaler to healthy subjects with and without block and patients suffering from bronchiectasis and COPD Secondary: Safety and tolerability of a single dose from a dry powder inhaler Evaluation Criteria: Efficacy Not applicable. Safety: Adverse events, lung function (FEV1, FVC), vital signs including body weight, Electrocardiogram (ECG) findings, and laboratory findings Pharmacokinetics: Pulmonary deposition Primary parameter: DL,N-Intrapulmonary deposition Secondary parameters: C/P (central to peripheral ratio in pulmonary deposition), DE,N (extrathoracic deposition relative to nominal dose), DX,N (exhaled radiolabeled drug fraction relative to nominal dose), DR,N (deposited radiolabeled drug fraction on the dry powder inhaler relative to nominal dose) Pharmacokinetic evaluation Primary parameters: AUC (area under the concentration versus time curve from zero to infinity after single dose), AUC(0-24) ( area under the concentration versus time curve from zero to 24 hours after single dose), Cmax (maximum drug concentration after single dose administration), tmax (time to reach maximum drug concentration after single dose) Secondary parameters: AUCnorm (area under the curve divided by dose per kilogram body weight), Page 3 of 11

5 Statistical Methods: Number of Subjects: AUC(0-24)norm (area under the curve from zero to 24 hours after single dose divided by dose per kilogram body weight), Cmax,norm (maximum drug concentration after single dose administration divided by dose per kilogram body weight), AUC(0-tlast) (area under the concentration versus time curve from time 0 to the last data point after single dose), t1/2 (half-life associated with the terminal slope), MRT (mean residence time), Vz/f (apparent volume of distribution during terminal phase after single dose), Efficacy: CL/f (total body clearance of drug calculated after single dose), Aeur (amount of drug excreted via urine), CLR (renal body clearance of drug) Not applicable Safety: Safety parameters were summarized by using frequency tables for qualitative data and descriptive statistics for quantitative data (hematology, blood chemistry, vital signs, ECG, spirometry). Pharmacokinetics: All data were listed and trial summary tables were provided. The pharmacokinetic parameters AUC, AUC(0-24), Cmax and Aeur were analyzed assuming log-normally distributed data. To compare bioavailability in patients and healthy subjects the logarithms of AUC, AUC(0-24) and Cmax were analyzed using analysis of variance (ANOVA) including cohort effects. Based on these analyses, point estimates (LS-Means) and exploratory 90% confidence intervals (CI) for the ratios bronchiectasis patients / healthy subjects and COPD patients / healthy subjects were calculated by retransformation of the logarithmic data using the intra-individual standard deviation of the ANOVA. Data of healthy subjects from the period with block were excluded for this analysis. To assess bioavailability with and without block in healthy subjects the logarithms of AUC, AUC(0-24), Cmax and Aeur were analyzed using analysis of variance (ANOVA) including treatment (with block, without block) and subject effects. Based on these analyses, point estimates (LS-Means) and exploratory 90% confidence intervals for the ratio with block / without block were calculated by re-transformation of the logarithmic data using the intraindividual standard deviation of the ANOVA. Data of bronchiectasis patients and COPD patients were excluded for this analysis Six patients suffering from bronchiectasis, 6 patients suffering from COPD and 12 healthy subjects were to be enrolled in the study to yield at least 4 subjects in each of the two patient groups and 8 healthy subjects who completed the study according to protocol. Planned: Healthy subjects (n=12) Patients with bronchiectasis Patients with COPD Analyzed: Page 4 of 11

6 Healthy subjects (n=12) Patients with bronchiectasis Patients with COPD Results Summary Subject Disposition and Baseline Study Results 31 subjects were recruited and screened. Seven of them were screening failures, one of them presenting a SAE. 24 subjects (12 healthy subject, 6 patients with COPD and 6 patients with bronchiectasis) were treated with the radiolabelled study medication. None of them discontinued the study prematurely. All 24 subjects completed the study according to study protocol. Subjects complied with inclusion criteria with regard to age (healthy subjects: 18 to 65 years / COPD patients: 40 to 70 years / bronchiectasis patients: 18 to 75 years) and body mass index (healthy subjects and COPD patients: up to 32 kg/m²). All healthy subjects and patients with bronchiectasis were non-smokers. Among the 6 patients with COPD, 4 were past or current smokers. 5 of 24 subjects were abstinent from alcohol, while 19 subjects reported light alcohol consumption as a lifestyle habit. Table 1 summarizes baseline demographic characteristics of the study populations. Table 1: Demographics (all subjects valid for safety, n=24) Healthy: A-B *) Healthy: B-A *) Bronchiectasis COPD Total (n=24) Age (years) Arithmetic mean Range Race White n Sex Female n Male n Weight (kg) Arithmetic mean SD Height (cm) Arithmetic mean SD BMI (kg/m 2 ) Arithmetic mean SD *) A = 32.5 mg Ciprofloxacin DPI B = 32.5 mg Ciprofloxacin DPI with block Results Summary Efficacy Not applicable Results Summary Safety Page 5 of 11

7 Adverse events 12 of 24 subjects reported at least one adverse event during the study (not including one COPD patient with a serious adverse event before study drug administration). In 8 subjects at least one adverse event was treatment emergent, i.e. started after inhalation of Ciprofloxacin DPI powder. Table 2 summarizes the incidences of treatment emergent adverse events and Table 3 summarizes treatment emergent study drug related adverse events. Table2: Incidence of subjects with treatment emergent adverse events (all subjects valid for safety, n=24) MedDRA primary SOC Preferred Term Healthy w/o (n=12) Healthy with (n=12) COPD Bronchiectasis Number of subjects with any adverse event 4 (33%) 3 (25%) 0 (0%) 2 (33%) GASTROINTESTINAL DISORDERS Nausea 1 (8%) INFECTIONS AND INFESTATIONS Lower respiratory tract infection 1 (17%) Nasopharyngitis 1 (8%) INJURY, POISONING AND PROCEDURAL COMPLICATIONS Periorbital haematoma 1 (17%) MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 1 (8%) NERVOUS SYSTEM DISORDERS Dizziness 1 (8%) 1 (8%) Dysgeusia 1 (8%) Headache 2 (17%) 1 (8%) 1 (17%) SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash 1 (8%) With respect to cohorts / administration of block, adverse events occurred in 4 of 12 healthy subjects without block (33%), in 3 of 12 healthy subjects with block (25%) and in 2 of 6 patients with bronchiectasis (33%). Patients with COPD reported no treatment emergent adverse events. Overall no higher incidence of adverse events or more severe intensity of adverse events was seen in the patients with lung diseases after inhalation of a dry powder formulation. The most frequent adverse event was headache in 4 subjects. Drug related adverse events were headache with nausea (1 healthy subject) and dysgeusia (1 healthy subject). Table 3: Incidence of subjects with study drug related treatment emergent adverse events - (all subjects valid for safety, n=24) MedDRA primary SOC Preferred Term Healthy w/o (n=12) Healthy with (n=12) COPD Bronchi-ectasis Number of subjects with any AE 2 (17%) 0 (0%) 0 (0%) 0 (0%) GASTROINTESTINAL DISORDERS Page 6 of 11

8 Nausea 1 (8%) NERVOUS SYSTEM DISORDERS Dysgeusia 1 (8%) Headache 1 (8%) Screening failures After screening and before administration of ciprofloxacin, one patient with COPD suffered a serious adverse event. After training of the inhalation maneuver with placebo capsules, he presented in reduced general condition suffering from severe dyspnea. The patient was hospitalized and recovered completely within one day. The event was serious and not related to the inhalation of study drugs. Considering all aspects and symptoms, an allergic reaction to the T-326 DPI placebo capsules used for training purposes could not fully be excluded due to the temporal relation between the inhalation and the beginning of dyspnea and due to the positive response to Fenistil and Solu-Decortin. The patient did not further participate in the study. Additional safety parameters Lung function Lung function parameters FEV1, FVC and FEV1/FVC were not clinically relevant affected by the inhalation of Ciprofloxacin DPI powder in healthy subjects and patients with COPD or bronchiectasis. Predose FEV1 mean values were 104% (of normal) in healthy subjects, 54% in COPD patients and 49% in bronchiectasis patients. Assessments 2 hours and 1 day after dosing provided no evidence for a decrease of FEV1 on average. Individual decreases of FEV1 did not exceed 4% in patients and 6% in healthy subjects. Prior to dosing, healthy subjects had a mean FVC of %, COPD patients of 79% and bronchiectasis patients of 55%. On average, no relevant changes to predose were observed 2 hours and 1 day thereafter. Individual decreases of FVC did not exceed 7% in bronchiectasis patients and healthy subjects. In COPD patients, maximum decrease was 10% after 2 hours and 16% after 1 day in 2 different patients. Changes were within the methodological range for the procedure. Drug relation of decreased FVC 24 h after inhalation of ciprofloxacin is highly unlikely. Prior to dosing FEV1/FVC (Tiffeneau) ratio was 78% in healthy subjects, 50.3% in COPD patients and 62.5% in bronchiectasis patients with variability in the range of up to 8% in patients. Vital signs At baseline (0d00h), mean pulse rate was higher in patients with COPD (78 beats per minute [BPM]) and patients with bronchiectasis (76 BPM) than in healthy subjects (66-67 BPM). Mean systolic and diastolic blood pressure were higher in COPD patients (132 and 87 mmhg) than in healthy subjects ( and mmhg) and in patients with bronchiectasis (113 and 73 mmhg). Blood pressure and heart rate were not clinically relevant affected by inhalation of Ciprofloxacin DPI. Up to 2 hours after administration, study participants were asked to remain seated as much as possible and avoid strenuous activities, which explains the decrease of mean pulse rate at that time (healthy subjects: 9 to 10 BPM, COPD patients: 8 BPM, bronchiectasis patient: 3 BPM). With one exception - pulse rate of 44 BPM, which is not uncommon in healthy sportive subjects - values of pulse rate, systolic and diastolic blood pressure 2 hours after administration remained within the safety margins requested in the exclusion criteria: pulse rate BPM; systolic blood pressure: mmhg; diastolic blood pressure: mmhg). All healthy subjects and patients had a normal sinus rhythm at screening and at the final examination. All ECGs were normal or without clinically significant abnormalities. At the final examination, one patient with COPD had QTc prolongations >30-60ms according to Bazett s correction formula. No prolongations of QTc according to Fridericia s correction Page 7 of 11

9 were observed. QTc prolongations (Bazett or Fridericia) 60 ms vs. baseline were not observed. Individual QTc values > 450 ms (for men) or 470 ms (for women) were not observed. Due to the low systemic exposure of ciprofloxacin any effect on ECG parameters as well as on the sytemic vital signs parameters is considered unlikely. Laboratory parameters No clinically relevant changes of laboratory parameters were reported as treatment emergent adverse events. One bronchiectasis patient had a mildly elevated bilirubin at baseline (1.24 times ULN [upper limit of normal] at Day 0d00h) and showed a transient elevation of elevated bilirubin of 2.0 times ULN on Day 1. Results Summary Pharmacokinetics Lung deposition assessed by scintigraphy Lung deposition patterns showed similar distribution of the drug in the lung in healthy subjects and patients with COPD and bronchiectasis at low inter-individual variability: The intrapulmonary deposition amounted to little more than 50% of the nominal dose of 32.5 mg ciprofloxacin (52/53% in healthy subjects with/without block, 51% in patients with COPD and 53% in patients with bronchiectasis). Deposition in the central parts was more pronounced than in the peripheral parts of the lung in healthy subjects (central/peripheral [C/P] ratio ~1.80), bronchiectasis patients (C/P ratio 1.95) and COPD patients (C/P ratio 2.32). COPD patients tended towards higher C/P ratios than healthy subjects and bronchiectasis patients. The fraction deposited in the extrathoracic (i.e. oropharyngeal) space was similar for healthy subjects and patients (45/43% in healthy subject with/without block, 43% in patients with COPD and 39% in patients with bronchiectasis). For patients with COPD or bronchiectasis on average, approximately 5 to 7% of the dose remained in the inhaler compared to approximately 3% in healthy subjects. In all groups, the amount of exhaled ciprofloxacin was low with less than 1% on average. Though mean FEV1 at baseline was 104% for healthy subjects, 54% for COPD patients and 49% for bronchiectasis patients, intrapulmonary deposition of ciprofloxacin was similar with about 50% of the dose in the 3 cohorts suggesting absence of a correlation between the lung function parameters FEV1(%) and FVC(%) at baseline (0d00h) and the pulmonary deposition pattern. Lung deposition of radiolabeled ciprofloxacin is summarized in Table 4 (to allow for a direct comparison of statistics based on identical subjects a subanalysis of the data for the group healthy with including and excluding one subject who was invalid for PK in the group without was performed.) Table 4: Lung deposition - scintigraphic data [mean/sd (range)] (all subjects valid for safety, n=24) Deposition Extrathoracic fraction (DE,N) % of nominal dose Healthy w/o (n=11) 43.04/7.31 ( ) Healthy with (n=11) 45.04/7.60 ( ) Healthy with (n=12) 44.63/7.38 ( ) COPD 42.77/7.09 ( ) Bronchiectasis 39.38/11.51 ( ) Intrapulmonary fraction (DL,N) % of nominal dose 53.14/7.78 ( ) 51.24/7.39 ( ) 51.51/7.11 ( ) 50.87/9.71 ( ) 52.52/10.55 ( ) Central to peripheral pulmonary deposition (C/P) 1.825/0.647 ( ) 1.765/0.663 ( ) 1.765/0.632 ( ) 2.322/ ( ) 1.950/0.934 ( ) Remained in device (DR,N) % of nominal dose 3.38/1.01 ( ) 3.33/1.25 ( ) 3.47/1.28 ( ) 5.43/2.97 ( ) 7.13/3.55 ( ) Page 8 of 11

10 Exhaled fraction (DX,N) % of nominal dose 0.45/0.32 ( ) 0.43/0.20 ( ) 0.43/0.19 ( ) 0.92/1.10 ( ) 0.95/0.54 ( ) The scintigraphic results were not affected by the block procedure in healthy subjects. At low intra-individual variability the ratios for the extrathoracic and intrapulmonary fraction and for the central to peripheral ratio were close to unity (Table 5). Lung deposition of radiolabeled ciprofloxacin is summarized in Table 5 for healthy subjects with and without block. Table 5:Intra-subject variability of pulmonary deposition parameters - ratios with / without block [mean/%cv* (range)] (all healthy subjects valid for this evaluation, n=11) Parameter n Arithmetic mean %CV (range) Extrathoracic fraction (DE,N) ( ) Intrapulmonary fraction (DL,N) ( ) Central to peripheral pulmonary deposition (C/P) ( ) Remained in device (DR,N) ( ) Exhaled fraction (DX,N) ( ) *%cv: coefficient of variation Lung deposition assessed by the block method In addition to scintigraphic assessment of intrapulmonary deposition, the block method was used to estimate the amount of drug absorbed via lung tissue based on pharmacokinetic considerations, which is a recommended measure of estimating intrapulmonary deposition. Activated prevents absorption of drug which was inevitably swallowed down during an oral inhalation maneuver. Results are summarized in Table 6. Table 6: Comparison of methods to calculate pulmonary deposition: block vs. scintigraphic method (all healthy subjects valid for this evaluation, n=12) Parameter n Arithmetic mean Scintigraphic data Deposition: Intrapulmonary fraction (DL,N) (%) SD Charcoal block method Clearance estimates* Deposition: Intrapulmonary fraction (DL, CB) (%) Clearance calculated from scintigraphic data (L/h) CL calculated according to literature a (L/h) Clearance ratio a Shah, A et al. Journal of antimicrobial chemotherapy (1996) 38, pp *CL estimate used to double check quality of deposition parameter estimate Calculation of intrapulmonary deposition with the block method provided a lower result with 30% of the nominal dose deposited in the intrapulmonary space compared to 52% measured by scintigraphy. Ciprofloxacin clearance after inhalation of Ciprofloxacin DPI powder (according to CL/f = Dose/AUC) using the lung dose calculated from scintigraphic data was almost twice as high (73.3 L/h) as compared to the clearance for the study population derived from Shah et al, 1996 (38.6 L/h). This difference can be explained by method specific factors: a) The additional reduction of systemic exposure of ciprofloxacin after dry powder inhalation caused by blocking reabsorption of drug which is actively secreted from the systemic Page 9 of 11

11 circulation into the Gastrointestinal-tract. b) Physiological processes such as mucociliary clearance occurring after the end of the inhalation maneuver; i.e.drug is brought up from the lung, subsequently swallowed down and blocked by the ingested. Pharmacokinetics of ciprofloxacin in healthy subjects and patients with COPD and bronchiectasis Similar concentration vs time profiles were observed for healthy subjects (without block) and patients with COPD following inhalation of 32.5 mg ciprofloxacin. Results were also similar to those in previously conducted studies with Ciprofloxacin DPI powder. Patients with bronchiectasis showed about 50 to 60% higher AUC and 36% higher Cmax compared to healthy subjects without block, while dose and body weight normalized AUC was similar. For a summary of the key pharmacokinetic parameters comparing the cohorts refer to Table 7 (for the healthy group with a subanalysis with and without one subject who was invalid for PK in the group without was performed. However, the respective subject was valid for the overall PK.). Results of the ANOVA comparing patients with COPD or bronchiectasis to healthy subjects without block are displayed in Table 8. Table 7: Pharmacokinetic parameters of ciprofloxacin in plasma following a single dose of Ciprofloxacin DPI 32.5 mg (total amount of powder: 50 mg) (geometric mean/%cv(range), all subjects valid for PK, n=24) Parameter Unit Healthy w/o (n=11) AUC mg*h/l /31.2 ( ) AUCnorm kg*h/l 1.620/31.4 ( ) Cmax mg/l /26.1 ( ) Healthy with (n=11) a /39.7 ( ) /39.40 ( ) /39.7 ( ) Healthy with (n=12) a /38.2 ( ) /37.7 ( ) /38.0 ( ) /37.6 COPD /31.5 ( ) 1.771/39.3 ( ) /13.0 ( ) Bronchiectasi s /36.7 ( ) 1.979/41.2 ( ) /32.2 ( ) Cmax, norm kg/l /30.8 ( ) /39.4 ( ) ( ) /23.4 ( ) /46.7 ( ) tmax b h ( ) ( ) ( ) ( ) ( ) t1/2 h 5.695/ / / / /14.7 ( ) ( ) ( ) ( ) ( ) %Aeur c % 37.83/ / / / /16.07 ( ) ( ) ( ) ( ) ( ) CLR L/h 20.64/ / / / /63.8 ( ) ( ) ( ) ( ) ( ) a For the healthy group with a subanalysis with and without one subject who was invalid for PK in the group without was performed b median(range) c arithmetic Mean/SD (Range) Table 8: Point estimators (LS-means) and two-sided 90% confidence intervals of selected pharmacokinetic parameters for the cohort ratios (all subjects valid for PK, n=23) Ratio Parameter Unit n %CV Estimated ratio (%) 90% confidence interval (%) COPD/ healthy AUC g*h/l [84.21; ] without AUC(0-24) g*h/l [84.37; ] Cmax g/l [96.21; ] Bronchiectasis / healthy without AUC g*h/l [119.38; ] AUC(0-24) g*h/l [116.62; ] Cmax g/l [109.64; ] Page 10 of 11

12 Effect of the block on ciprofloxacin pharmacokinetics in healthy subjects The effect of the block given to healthy subjects was assessed in a 2-way crossover design. Subjects received oral 15 minutes prior to ciprofloxacin inhalation (20 g) and 2 and 4 hours post inhalation (10 g each). In the presence of, the AUC and AUC(0-24) in plasma decreased to 38.1 and 37.5% of the corresponding value for healthy subjects, which corresponds to a more than 60% reduction. Cmax was reduced by 58%. The estimated ratios (LS-Means) and two-sided 90% confidence intervals for the block effect ratios of AUC, AUC(0-24), Cmax and Aeur of ciprofloxacin, resulting from an ANOVA model are summarized in Table 9. Table 9: Point estimators (LS-means) and two-sided 90% confidence intervals of selected ciprofloxacin pharmacokinetic parameters for the block effect ratios (all healthy subjects valid for PK, n=12) Ratio Parameter Unit n %CV Healthy with / healthy without Estimated ratio (%) 90% confidence interval (%) AUC g*h/l [29.86; 48.48] AUC(0-24) g*h/l [29.64; 47.55] Cmax g/l [33.20; 52.07] Aeur g [27.93; 46.44] Conclusion(s) Inhalation of Ciprofloxacin DPI 32.5 mg (total amount of powder: 50 mg) via the T-326 device was safe and well tolerated in healthy subjects and patients with COPD or bronchiectasis, without any serious adverse event or relevant clinical effects Lung function parameters FEV1, FVC and FEV1/FVC were not clinically relevantly affected by inhalation of Ciprofloxacin DPI 32.5 mg (total amount of powder: 50 mg) High and reproducible targeting of ciprofloxacin into the lung of patients and healthy subjects was achieved that allows drug targeting to the lung at lower systemic drug exposure Lung deposition patterns of COPD and bronchiectasis patients were similar to those of healthy subjects (% of normal dose): a) Range of means for the extrathoracic fraction (DE,N): 39.4 to 45.0% b) Range of means for the intrapulmonary fraction (DL,N): 50.9 to 53.1% c) Range of means for the remainders in device (DR,N): 3.3 to 7.1% d) Range of means for the exhaled fraction (DX,N): 0.4 to 1.0% e) Range of means for the central to peripheral ratio (CP): 1.8 to 2.3 Lung deposition estimates obtained from the block method was lower compared to the results of the scintigraphic investigation (estimated intrapulmonary fraction: 29.7% of normal dose). Taking into respect their individual scientific concepts, consistency was shown between the deposition data generated by different methods (scintigraphy vs. block). The systemic drug exposure in patients observed in this study is in alignment with typical findings for inhalation drugs. Publication(s): None Date Created or Date Last Updated: 23 Jul 2013 Date of Clinical Study Report: 11 Jul 2013 Page 11 of 11

13 Appendix to Clinical Study Synopsis Investigational Site List Marketing Authorization Holder in Germany Name Postal Address Bayer Vital GmbH D Leverkusen Germany Sponsor in Germany (if applicable) Legal Entity Name Bayer Pharma AG Postal Address D Leverkusen Germany List of Investigational Sites No Investigator Name Facility Name Street ZIP Code City Country 1 Hr. D Kappeler Inamed GmbH Robert-Koch-Allee Gauting Germany Page 1 of 1