The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: SMS20011 Title: A Five-Week, Randomized, Double-Blind, Double-Dummy, Two-Period, Four-ment Crossover, -Controlled, Balanced, Incomplete Block Design, Multi-Center Study of Salmeterol Inhalation Aerosol 25mcg BID, 25mcg TID, 50mcg BID and Administered via a Holding Chamber with Facemask in Subjects with Asthma Aged 6 to 23 Months Rationale: The dose of inhaled drugs delivered to the lung from a metered-dose inhaler (MDI) depends on various factors including airway anatomy and disease state, along with the subjects inhalation pattern. In small children less than 4 years of age, the dose of salmeterol inhalation aerosol required to achieve optimum therapy has not been defined. The aim of this study is to evaluate the safety of three doses of salmeterol versus placebo delivered by MDI with attached holding chamber and facemask. Phase: II Study Period: 01 August 2001 27 September 2002 Study Design: Study SMS20011 was a 5-week, randomized, double-blind, double-dummy, 2-period, 4-treatment crossover, placebo-controlled, balanced incomplete block design, multi-center study of salmeterol chlorofluorocarbons (CFC) inhalation aerosol, 25 micrograms (mcg) twice daily (BID), 25mcg 3 times daily (TID), and 50mcg BID (dosage ex-valve) administered via a valved holding chamber (AeroChamber Plus) with attached facemask in subjects with asthma aged 6 to 23 months. Centres: This study was conducted at 12 sites in the United States (US). Indication: Pediatric Asthma ment: Salmeterol CFC inhalation aerosol (25mcg strength) and placebo inhalation aerosol were administered via a valved holding chamber (AeroChamber Plus) with attached facemask. Subjects were randomly assigned to 1 of 4 study treatment groups at Visit 2 in accordance with the randomization schedule. The study treatment groups were as follows: salmeterol CFC inhalation aerosol 25mcg BID; salmeterol CFC inhalation aerosol 25mcg TID; salmeterol CFC inhalation aerosol 50mcg BID; or placebo inhalation aerosol TID. ments were administered for a duration of 7 (+ 4) days. Following a 5-day (±2 days) washout period, each subject was crossed over in a blinded fashion to 1 of the remaining 3 treatments at Visit 4. Each treatment period was followed by a 5-day (±2-days) washout period. Objectives: The primary objective of this study was to evaluate the safety of salmeterol CFC inhalation aerosol, 25mcg BID, 25mcg TID, and 50mcg BID administered via a valved-holding chamber with attached facemask versus placebo over a 1 week treatment period in subjects with mild to moderate asthma aged 6 to 23 months. Primary Outcome: The primary endpoint of the study was to evaluate the effect of study drug following 7 (+4) days of therapy on 24-hour heart rate (HR), obtained via Holter monitoring, including mean, peak, trough, and diurnal variation in HR. Secondary Outcome/Efficacy Variable(s): Other safety measures included electrocardiogram (ECG) results, adverse event (AE) assessment, clinical laboratory tests, physical examinations, vital signs, tremor assessment, and symptoms of adrenergic stimulation, which were addressed by the Functional Status II(R) Questionnaire [FSII(R)]. Efficacy endpoints included individual daytime and night-time asthma symptom scores as assessed by the parent/guardian and albuterol use. Health status was evaluated using the FSII(R) questionnaire. Statistical Methods: The planned sample size of 36 completed subjects (3 replicates of a balanced incomplete block design) ensured that each treatment was represented within 18 of the 36 subjects as requested and agreed upon by the FDA. Subject recruitment was planned for approximately 10 study sites in the United States. Since 1 block contained 3 subjects, the planned number of subjects per site was 3 to 6. In an effort to ensure treatment balance within the 2 age ranges (ie, 6 to 11 months and 12 to 23 months) the randomization was stratified at a ratio of 1:2 into these 2 groups. The Intent-to- Population (ITT), defined as all randomized subjects who received at least 1 dose of study drug, was used for all statistical analyses. The ITT Population was the primary population for all summaries and analyses of demographics/background, safety, efficacy, and health outcome data. No statistical inference was performed for this study. Study Population: Males and females, 6 to 23 months of age. All subjects must have experienced exacerbation of wheeze and cough within the preceding 6 months. In addition, subjects must have fulfilled the following criteria prior to Visit 1: required therapy with a maintenance asthma medication (other than systemic corticosteroids) and/or required therapy with a short-acting beta-agonist for relief of respiratory symptoms at least twice per week over the preceding 3 weeks. Parents/guardians of subjects had the ability to read, comprehend and record diary information collected throughout the study. After meeting all inclusion criteria for the screening period, a subject was eligible for inclusion 1
into the treatment phase of the study at Visit 2 if all of the following randomization criteria applied. 1) The subject s parents/guardians demonstrated the ability to comply with use of the diary card defined as completion of all questions on at least 80% of the days during the screening period. 2) The subject's parent/guardian was able to adequately utilize the metered dose inhaler with the provided holding chamber with facemask as assessed by the investigator. 3) The subject had not experienced a severe exacerbation during the screening period requiring an emergency room visit and/or systemic corticosteroid use. 4) Parent/guardian was capable of supervising the Holter monitor. Number of Subjects: Total Planned, N 36 Screened (Total Subjects), N: 52 Randomized (ITT), N 45 Completed, 35 (78) Total Number Subjects Withdrawn, 10 (22) Withdrawn due to AEs, 1 (2) Withdrawn due to Lack of Efficacy, 1 (2) Withdrawn for Other Reasons, 8 (18) Demographics: Total N (ITT) 45 Females:Males, n:n 11:34 Mean Age, months (SD) 14.6 (5.57) Caucasian, 23 (51) Primary Safety Results (ITT): Mean 24-Hour Cardiac Rates Determined by Holter Monitoring (ITT Population) a During ment a Chg from ment N Mean Min; Max n Mean Min; Max n Mean Min; Max 20 122 73, 185 18 121 75, 188 18-1.0 1.9, 2.2 21 127 76, 193 18 127 73, 193 18-0.5-2.9, -0.6 21 125 78, 189 20 125 79, 190 20-1.4 1.3, 0.6 20 125 76, 192 19 127 76, 188 19 2.2 0.5, -2.1 a. Values for cardiac rates at and during treatment were rounded to the nearest whole number Summary of Ventricular Ectopic (VEs) Events Determined by Holter Monitoring (ITT Population - Study SMS20011) During ment with Single with Single ment N VEs Mean Range n VEs Mean Range 20 3 (15) 0.2 0-1 18 5 (28) 0.8 0-9 21 3 (14) 0.1 0-1 19 2 (11) 0.1 0-1 21 6 (29) 0.3 0-1 20 2 (10) 0.2 0-2 20 2 (10) 0.1 0-1 19 3 (16) 0.6 0-7 Summary of Supraventricular Ectopic (SVE) Events Determined by Holter Monitoring (ITT Population) During ment ment N Mean Median Range n Mean Median Range 20 0.7 0 0-4 18 0.9 0 0-5 21 1.0 0 0-8 19 1.0 1 0-4 21 0.5 0 0-2 20 1.6 0 0-24 20 1.0 1 0-8 19 0.6 0 0-3 Summary of Cardiac Rate, VEs, and SVEs for Subjects with 18 or More Hours of Holter Monitoring Data at Each Visit (ITT Population) Cardiac Rate (Mean) a VEs (Mean) SVEs (Mean) 2
ment n Chg Chg Chg 15 123 121-2.0 0.1 0.9 0.8 0.7 1.0 0.3 17 128 127-0.6 0.2 0.1-0.1 1.0 0.9-0.1 12 129 125-4.6 0.3 0.2-0.2 0.6 0.5-0.1 16 126 127 1.1 0.1 0.5 0.4 1.1 0.6-0.4 a. Mean values for cardiac rates at and during treatment are rounded to the nearest whole number Summary of Mean QT and QTc Intervals, QRS Duration, and PR Interval Recorded by ECG (ITT Population) Salm 25mcg BID Salm 25mcg TID Salm 50mcg BID n Mean n Mean n Mean n Mean QT Interval (msec) a 20 266 21 258 21 264 20 263 End of ment a 18 263 18 264 20 268 16 268 Change from 18-0.5 18 5.7 20 5.4 16-0.5 QTc Interval b (msec) a 20 336 21 334 21 338 20 338 End of ment a 18 331 18 338 20 342 16 348 Change from 18-3.7 18 4.2 20 5.4 16 5.2 QRS Duration (msec) a 20 66 21 67 21 69 20 66 End of ment a 18 68 18 69 20 71 16 68 Change from 18 1.1 18 3.1 20 2.1 16-0.3 PR Interval (msec) a 20 121 21 112 21 120 20 114 End of ment a 18 120 18 117 20 122 16 115 Change from 18-1.1 18 6.7 20 2.1 16 1.3 a. Mean values for and End of ment are rounded to the nearest whole number b. Corrected using Fridericia s formula Summary of Mean Heart Rate via ECG (Beats/min) (ITT Population) Heart Rate a n Mean n Mean n Mean n Mean 20 129 21 132 21 130 20 133 End of ment 18 126 18 128 20 129 16 137 Change from 18-4.4 18-4.2 20-1.8 16 8.3 Standard error 18 4.22 18 4.76 20 3.26 16 6.49 Min, max 18-37, 18 18-40, 25 20-25, 30 16-46, 52 a. Mean values at and end of treatment are rounded to the nearest whole number Efficacy Results: Summary of Mean Daytime and Nighttime Asthma Symptom Scores (ITT Population) Daytime (n) 20 21 21 19 Mean 0.72 1.05 0.77 0.94 During treatment (n) 20 20 20 19 Mean 0.55 0.83 0.64 0.82 Mean change from -0.17-0.20-0.16-0.12 3
Night-time (n) 20 21 21 19 Mean 0.61 0.89 0.73 0.76 During treatment (n) 20 19 20 19 Mean 0.53 0.81 0.57 0.73 Mean change from -0.08-0.16-0.18-0.03 Asthma symptom score scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe Summary of Daily Albuterol Use (Number of Puffs) (ITT Population) (n) 19 21 20 19 Mean 1.70 2.62 2.11 2.70 During ment (n) 19 21 20 19 Mean 1.28 1.31 1.40 1.29 Change from (n) 19 21 19 19 Mean -0.42-1.31-0.90-1.40 Health Outcomes Results: Comparison of Mean Total FSII (R) Scores: Overall Group and Same-Parent Subset (ITT Population) N Mean N Mean N Mean N Mean a All Subjects 20 88 21 88 21 89 19 88 Same parent/guardian 16 89 16 88 19 89 19 88 ment (Actual Value) a All Subjects 18 97 19 90 21 92 19 86 Same parent/guardian 16 97 16 90 19 91 19 86 Change from All Subjects 18 8.1 19 1.6 21 3.2 19-2.0 Same parent/guardian 16 8.4 16 2.1 19 2.1 19-2.0 Mean values for and ment are rounded to the nearest whole number Summary of Mean FSII(R) Scores Possibly Related to Adrenergic Stimulation at and Endpoint (ITT Population) Item n=20 n=18 Sleep Well 1.7 1.9 1.7 1.8 1.6 1.7 1.5 1.6 Content/Cheerful 1.8 2.0 1.8 1.8 1.9 1.8 1.9 1.8 Act Moody 1.6 1.8 1.5 1.5 1.5 1.8 1.3 1.5 Unusually Irritable 1.6 2.0 1.6 1.6 1.5 1.8 1.6 1.5 Sleep Thru Night 1.7 1.9 1.7 1.8 1.7 1.8 1.8 1.5 Unusually Difficult 1.6 2.0 1.7 1.7 1.9 1.8 1.7 1.7 React by Crying 1.7 1.8 1.7 1.6 1.7 1.9 1.8 1.6 =Visit 2/Day 1, prior to treatment administration; = end of treatment period Adverse Events: Adverse events were collected from the time of entry into the study (Visit 1) through Visit 6 (Week 5) or at premature discontinuation. Adverse events that onset during Washout Period 1 were assigned to the treatment received during ment Period 1, and events that onset during Washout Period 2 were assigned to the treatment received during ment Period 2. Non-fatal serious adverse events () occurring after randomization were summarized over all treatments and by treatment. Most Frequent Adverse Events On Therapy 4
Subjects with any Event 5 (25) 15 (71) 8 (38) 6 (30) Upper respiratory tract 3 (15) 3 (14) 1 (5) 0 infection Ear, nose, and throat 1 (5) 4 (19) 0 1 (5) infections Fever 0 2 (10) 1 (5) 2 (10) Diarrhea 0 2 (10) 2 (10) 0 Serious Adverse Events [n considered by the investigator to be related to study medication] Subjects With Non-Fatal Subjects With Non-Fatal 0 0 0 1 (5) [0] Chest sounds 0 1 (5) [0] 0 0 Cough 0 1 (5) [0] 0 0 Subjects With Fatal Subjects with fatal 0 0 0 0 Conclusions: The results of this study demonstrate that salmeterol CFC inhalation aerosol at doses of 25mcg BID, 25mcg TID and 50mcg BID, delivered via the Aerochamber Plus with attached facemask have a cardiovascular safety profile similar to that of placebo, and support the use of 50mcg BID as the highest safe dose. Adverse events were reported in 5(25%) of the placebo group, 15 (71%) of the SALM 25mcg BID group, 8 (38%) of the SALM 25mcg TID group and 6 (30%) of the SAL 50mcg BID group. The most frequently reported adverse events were upper respiratory tract infection, and ear, nose and throat infection in the placebo and SALM 25mcg BID group; diarrhea in the SALM 25mcg TID group, and fever in the SALM 50mcg BID group. Serious adverse events were reported in 1 subject in the SALM 25mg BID group. No fatal were reported. Publications: No Publication Date Updated: 06-Oct-2005 5