On-line supplement
Safety of formoterol in children and adolescents:
Experience from asthma clinical trials
Price JF,1 Radner F,2 Lenney W3, Lindberg B2,4
1King’s College Hospital, London, UK
2AstraZeneca R&D, Lund, Sweden
3University Hospital of North Staffordshire, Stoke on Trent, UK
4Dept of Paediatrics, University Hospital, Malmö, Sweden
Author for correspondence:
Professor John F. Price, MD FRCP FRCPCH
Consultant Respiratory Paediatrician & Professor of Paediatric Respiratory Medicine,
Variety Club Children's Hospital,
King's College Hospital,
Denmark Hill,
London
UK SE5 9RS.
Tel: +44 (0)20 3299 3215
Fax: +44 (0)20 3299 3657
E-mail:
Suggested journal: Archives of Disease in Childhood,
1
Table E1Publication status and study titles for the clinical trialsStudycode / Study title / Publication status
Trials with forrmoterol vs non-LABA comparison
D5896C00001 / A RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLED, PARALLEL-GROUP, SINGLE-DUMMY, MULTICENTER, 12 WEEK STUDY TO ASSESS THE EFFICACY AND SAFETY OF SYMBICORT PMDI 160/4.5 µG X 2 ACTUATIONS ONCE-DAILY (QD) COMPARED TO SYMBICORT PMDI 80/4.5µG X 2 ACTUATIONS QD, SYMBICORT PMDI 80/4.5µG X 2 ACTUATIONS TWICE-DAILY (BID) AND TO BUDESONIDE PMDI 160 µG X 2 ACTUATIONS QD IN ASTHMATIC SUBJECTS 12 YEARS OF AGE AND OLDER / LaForce C, Kerwin EM, Oppenheimer JJ, Miller CJ, Vervaet P, O'Dowd L, Goldman M. Safety of once-daily (qd) budesonide and formoterol administered via one pressurized metered-dose inhaler (pMDI) in adults and adolescents with asthma previously stable with twice-daily (bid) budesonide/formoterol pMDI. Journal of Allergy and Clinical Immunology 2008;121(2 Suppl 1):S153, Abs 589.
DC-037-0002 / A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF THE EFFICACY, TOLERABILITY, AND COST-EFFECTIVENESS OF FORMOTEROL TURBUHALER 6 µG AND 12 µG B.I.D. IN SIX TO ELEVEN YEAR OLD CHILDREN WITH SYMPTOMATIC ASTHMA / Zimmerman B, D’Urzo A, Bérubé D. Efficacy and safety of formoterol Turbuhaler when added to inhaled corticosteroid treatment in children with asthma. Pediatr Pulmonol 2004; 37: 122-127.
SD-037-0003 / A 3-MONTH, PLACEBO-CONTROLLED EFFICACY STUDY OF FORMOTEROL TURBUHALER 4.5 µG AND 9 µG B.I.D. (CORRESPONDING TO THE METERED DOSES 6 µG AND 12 µG, RESPECTIVELY) IN ASTHMATIC CHILDREN AGED 6 TO 17 YEARS / von Berg A, Papageorgiou Saxoni F, Wille S, Carrillo T, Kattamis C, Helms PJ. Efficacy and tolerability of formoterol Turbuhaler® in children. Int J Clin Pract 2003; 57: 852-856.
SD-037-0345 / OXIS AND PULMICORT TURBUHALER IN THE MANAGEMENT OF ASTHMA / O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom T, Svensson K, Tattersfield A. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001; 164: 1392-1397.
SD-037-0695 / A 6 MONTHS COMPARISON OF THE SAFETY AND EFFICACY PROFILES OF OXIS (FORMOTEROL) TURBUHALER AS NEEDED AND BRICANYL (TERBUTALINE) TURBUHALER AS NEEDED IN CHILDREN WITH ASTHMA ON ANTI-INFLAMMATORY TREATMENT / Villa J, Kuna P, Egner J, Brander R. Safety of formoterol reliever therapy compared with terbutaline in asthmatic children taking anti-inflammatory therapy [abstract]. Eur Respir J 2002; 20 (Suppl 38): 431.
SD-037-0699 / REAL LIFE EFFECTIVENESS OF OXIS TURBUHALER AS NEEDED IN ASTHMATIC PATIENTS DURING SIX MONTHS (RELIEF) / Pauwels RA, Sears MR, Campbell M, Villasante C, Huang S, Lindh A, Petermann W, Aubier M, Schwabe G, Bengtsson T. Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial. Eur Respir J 2003; 22: 787-794.
SD-037-0714 / A 12-MONTH COMPARISON OF FORMOTEROL TURBUHALER AND TERBUTALINE TURBUHALER BOTH USED AS NEEDED IN PATIENTS WITH ASTHMA ON ANTI-INFLAMMATORY TREATMENT / Chuchalin A, Kasl M, Bengtsson T, Nihlen U, Rosenborg J. Formoterol used as needed in patients with intermittent or mild persistent asthma. Respir Med 2005; 99: 461-470.
SD-037-0716 / A 12-MONTH COMPARISON OF FORMOTEROL TURBUHALER AND TERBUTALINE TURBUHALER BOTH USED AS NEEDED IN PATIENTS WITH ASTHMA NOT USING ANTI-INFLAMMATORY TREATMENT / Chuchalin A, Kasl M, Bengtsson T, Nihlen U, Rosenborg J. Formoterol used as needed in patients with intermittent or mild persistent asthma. Respir Med 2005; 99: 461-470.
SD-039-0353 / EFFICACY AND SAFETY OF BUDESONIDE/FORMOTEROL TURBUHALER IN A FIXED COMBINATION IN STEROID-USING ASTHMATIC CHILDREN - COMIC / Tal A, Simon G, Vermeulen JH, Petru V, Cobos N, Everard ML, de Boeck K. Budesonide/formoterol in a single inhaler versus inhaled corticosteroids alone in the treatment of asthma. Pediatr Pulmonol 2002; 34: 342-350.
SD-039-0667 / EFFICACY AND SAFETY OF SYMBICORT TURBUHALER AS SINGLE THERAPY IN PATIENTS WITH MILD TO MODERATE ASTHMA. (STEAM STUDY) / Rabe KF, Pizzichini E, Stallberg B, Romero S, Balanzat AM, Atienza T, Lier PA, Jorup C. Budesonide/formoterol in a single inhaler for maintenance and relief in mild-to-moderate asthma: a randomized, double-blind trial. Chest 2006; 129: 246-256.
SD-039-0668 / EFFICACY AND SAFETY OF SYMBICORT TBH AS SINGLE THERAPY IN PATIENTS WITH MODERATE-SEVERE ASTHMA. COMPARISON WITH CONVENTIONAL ASTHMA THERAPY, PULMICORT TBH AS MAINTENANCE TREATMENT COMPLEMENTED WITH BRICANYL TBH (STEP STUDY) / Scicchitano R, Aalbers R, Ukena D, Manjra A, Fouquert L, Centanni S, Boulet L-P, Naya IP, Hultquist C. Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma. Curr Med Res Opin 2004; 20: 1403-1418.
SD-039-0673 / EFFICACY AND SAFETY OF BUDESONIDE/FORMOTEROL (SYMBICORT) TURBUHALER AS SINGLE THERAPY IN PATIENTS WITH MILD-MODERATE ASTHMA. COMPARISON WITH SYMBICORT TURBUHALER AND PULMICORT TURBUHALER AS MAINTENANCE THERAPY, BOTH COMPLEMENTED WITH BRICANYL TBH / O’Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, Ekstrom T, Bateman ED. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005; 171: 129-136.
Bisgaard H, Le Roux P, Bjåmer D, Dymek A, Vermeulen JH, Hultquist C. Budesonide/formoterol maintenance plus reliever therapya new strategy in pediatric asthma. Chest. 2006; 130: 1733-1743.
SD-039-0681 / A RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, MULTICENTRE, PHASE III STUDY TO COMPARE THE EFFICACY AND SAFETY OF SYMBICORT PMDI160/4.5 2 ACT BID WITH THAT OF PULMICORT PMDI 200 2 ACT BID AND SYMBICORT TH 160/4.5 2 INH BID IN ADOLESCENTS AND ADULTS WITH ASTHMA / Morice AH, Osmanliev D, Arheden L, Beckman O. Therapeutic equivalence of a novel budesonide/formoterol pMDI versus budesonide/formoterol Turbuhaler® in adolescents and adults with asthma. J Allergy Clin Immunol 2005a; 115(Suppl 2): S2, Abst 8.
SD-039-0682 / A 12-WEEK, RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, MULTICENTRE, PHASE III STUDY TO COMPARE THE EFFICACY AND SAFETY OF SYMBICORT PMDI WITH THAT OF PULMICORT PMDI AND SYMBICORT TURBUHALER IN CHILDREN WITH ASTHMA / Morice AH, Peterson S, Beckman O, Kukova Z. Efficacy and safety of a new pressurised metered-dose inhaler formulation of budesonide/formoterol in children withasthma: A superiority and therapeutic equivalence study.Pulm Pharmacol Ther2008;21:152-9.
SD-039-0688 / EFFICACY AND SAFETY OF SYMBICORT COMPARED TO PULMICORT AND PULMICORT+OXIS IN STEROID USING ASTHMATIC CHILDREN / Pohunek P, Kuna P, De Boeck K. Budesonide/formoterol improves lung function compared with budesonide alone in children with asthma. Pediatr Allergy Immunol 2006; 17: 458-465.
SD-039-0689 / EFFICACY AND SAFETY OF SYMBICORT1280/36 MCG DAILY DELIVERED DOSE COMPARED TO PULMICORT 1600 MCG METERED DOSE AND PULMICORT 1600 MCG METERED DOSE PLUS OXIS 36 MCG DELIVERED DOSE VIA TURBUHALER IN STEROID USING ASTHMATIC ADOLESCENTS AND ADULTS / Jenkins C, Kolarikova R, Kuna P, Caillaud D, Sanchis J, Popp W, Pettersson E. The efficacy and safety of high-dose budesonide/formoterol (Symbicort®) compared with budesonide administered either concomitantly with formoterol or alone in patients with persistent symptomatic asthma. Respirology 2006; 11: 276-286.
SD-039-0714 / EFFICACY AND SAFETY OF BUDESONIDE/FORMOTEROL TURBUHALER (160/4.5 µG B.I.D. DELIVERED DOSE) COMPARED TO BUDESONIDE TURBUHALER (200 µG B.I.D. METERED DOSE) IN STEROID-USING ASTHMATIC ADOLESCENT PATIENTS. A DOUBLE-BLIND, DOUBLE-DUMMY, RANDOMISED, PARALLEL GROUP, PHASE III, MULTICENTRE STUDY (ATTAIN STUDY) / AstraZeneca Study SD-039-0714. AstraZeneca Clinical Trials website. Available from:
SD-039-0716 / A TWELVE-WEEK, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PLACEBO-CONTROLLED TRIAL OF SYMBICORT (80/4.5 µG) VERSUS ITS MONO-PRODUCTS (BUDESONIDE AND FORMOTEROL) IN CHILDREN (>= 6 YEARS OF AGE) AND ADULTS WITH ASTHMA - SPRUCE 80/4.5 / Murphy K, Nelson H, Parasuraman B, Boggs R, Miller C, O'Dowd L. The effect of budesonide and formoterol in one pressurized metered-dose inhaler on patient-reported outcomes in adults with mild-to-moderate persistent asthma. CurrentMedical Research and Opinion 2008;24(3):879-894
SD-039-0717 / A TWELVE-WEEK, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PLACEBO-CONTROLLED TRIAL OF SYMBICORT (160/4.5µG) VERSUS ITS MONO-PRODUCTS (BUDESONIDE AND FORMOTEROL) IN ADOLESCENTS (>= 12 YEARS OF AGE) AND ADULTS WITH ASTHMA - SPRUCE 160/4.5 / Noonan MJ, Rosenwasser LJ, Martin P, O'Brien CD, O'Dowd L. Effect of budesonide and formoterol administered via one pressurized metered-dose inhaler on lung function in adults and adolescents with moderate to severe persistent asthma.J Allergy Clin Immunol2007; 119(1 Suppl 1): S2, Abst 7.
SD-039-0718 / A TWELVE-WEEK, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY TRIAL OF SYMBICORT (40/4.5 µG) VERSUS ITS MONO-PRODUCTS (BUDESONIDE AND FORMOTEROL) IN ASTHMATIC CHILDREN AGED SIX TO ELEVEN YEARS - SEEDLING 40/4.5 / Pearlman DS, Murphy KR, Uryniak T, OBrien CD, Mezzanotte WS. Safety of budesonide/formoterol pressurized metered-dose inhaler (BUD/FM pMDI) in children withasthma previously treated with inhaled corticosteroids (ICSs).Am J Respir Crit Care Med2008;177(Abstracts issue):A710.
SD-039-0719 / A SIX-MONTH, RANDOMIZED, OPEN-LABEL SAFETY STUDY OF SYMBICORT (160/4.5µG) COMPARED TO PULMICORT TURBUHALER IN ASTHMATIC CHILDREN AGED SIX TO ELEVEN YEARS / Berger WE, Leflein JG, Geller D, Parasuraman B, Miller CJ, O’Brien CD, O’Dowd L. The safety and clinical benefit of budesonide/formoterol pressurized metered-dose inhaler versus budesonide alone inchildren.Allergy and Asthma Proceedings (in press).
SD-039-0725 / A TWELVE-WEEK, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, ACTIVE-CONTROLLED STUDY OF SYMBICORT PMDI ADMINISTERED ONCE DAILY IN CHILDREN AND ADOLESCENTS 6 TO 15 YEARS OF AGE WITH ASTHMA - SPROUT / Noonan MJ, Eid NS, Uryniak T, OBrien CD. Safety of once-daily (qd) budesonide/formoterol pressurized metered-dose inhaler (BUD/FM pMDI) in children and adolescents withasthma previously stable on twice-daily (bid) BUD/FM pMDI.Am J Respir Crit Care Med2008;177(Abstracts issue):A711.
SD-039-0726 / A TWELWE-WEEK, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PLACEBO- AND ACTIVE-CONTROLLED STUDY OF SYMBICORT PMDI ADMINISTERED ONCE DAILY IN ADULTS AND ADOLESCENTS WITH ASTHMA - STEM / Berger W, Bleecker ER, O'Dowd L, Miller CJ, Mezzanotte W. Efficacy and safety of budesonide/formoterol pressurized metered-doseinhaler: randomized controlled trial comparing once- and twice-daily dosing in patients with asthma.Allergy and Asthma Proceedings (in press).
SD-039-0728 / A 52 WEEK, RANDOMIZED, DOUBLE-BLIND, SINGLE-DUMMY, PARALLEL-GROUP, MULTICENTER STUDY COMPARING THE LONG-TERM SAFETY OF SYMBICORT PMDI 160/4.5 µG X4 INH BID TO SYMBICORT PMDI 160/4.5 µG X2 INH BID AND BUDESONIDE PMDI160 µG X4 INH BID IN ADULT AND ADOLESCENT SUBJECTS WITH ASTHMA / Peters SP, Prenner BM, Mezzanotte WS, Martin P, O'Brien CD. Long-term safety and asthma control with budesonide/formoterol versus budesonide pressurized metered-dose inhaler in asthma patients. Allergy and Asthma Proceedings 2008;29(5):499-516
Trials with forrmoterol vs LABA comparison
BU-037-0004 / EFORMOTEROL VS. SALMETEROL: REDUCTION IN SHORT-ACTING BRONCHODILATOR USAGE IN ASTHMATIC CHILDREN TREATED WITH INHALED STEROIDS: FACT / Everden P, Campbell M, Harnden C, McGoldrick H, Bodalia B, Manion V, Reynia S. Eformoterol Turbohaler® compared with salmeterol by dry powder inhaler in asthmatic children not controlled on inhaled corticosteroids. Pediatr Allergy Immunol 2004; 15: 40-47.
CF-039-0001 / COMPARAISON DE SYMBICORT® TURBUHALER® 200/6 µG À DOSES FIXES VERSUS SYMBICORT® TURBUHALER® 200/6 µG À DOSES ADAPTÉES AU CONTRÔLE DE L’ASTHME SUR 16 SEMAINES DE TRAITEMENT / Data on file
CF-039-0002 / COMPARAISON DE SYMBICORT® TURBUHALER® 200/6 µG À DOSES FIXES VERSUS SYMBICORT® TURBUHALER® 200/6 µG À DOSES ADAPTÉES AU CONTRÔLE DE L’ASTHME SUR 16 SEMAINES DE TRAITEMENT EN CONSULTATION DE MÉDECINE GÉNÉRALE / Data on file
CI-SYM-0001 / CONTROL OF ASTHMA BY SYMBICORT TURBUHALER. EFFECTIVENESS AND SAFETY OF A FLEXIBLE INDIVIDUALISED DOSING REGIMEN VERSUS A STANDARD TWICE DAILY REGIMEN / Canonica GW, Castellani P, Cazzola M, Fabbri LM, Fogliani V, Mangrella M, Moretti A, Paggiaro P, Sanguinetti CM, Vignola AM. Adjustable maintenance dosing with budesonide/formoterol in a single inhaler provides effective asthma symptom control at a lower dose than fixed maintenance dosing. Pulm Pharmacol Ther 2004; 17: 239-247
D5890C00002 / EFFICACY AND SAFETY OF SYMBICORT® TURBUHALER® 160/4.5 µG/INHALATION,TWO INHALATIONS TWICE DAILY PLUS AS-NEEDED, COMPARED WITH SERETIDE™ DISKUS™ 50/500 µG/INHALATION, ONE INHALATION TWICE DAILY PLUS TERBUTALINE TURBUHALER 0.4 MG/INHALATION AS-NEEDED - A 6-MONTH, RANDOMISED, DOUBLE-BLIND, PARALLEL-GROUP, ACTIVE-CONTROLLED, MULTI-NATIONAL PHASE IIIB STUDY IN ADULT AND ADOLESCENT PATIENTS WITH PERSISTENT ASTHMA (AHEAD STUDY) / Bousquet J, Boulet L-P, Peters MJ, Magnussen H, Quiralte J, Martinez-Aguilar NE, Carlsheimer A. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Resp Med 2007; 101: 2437-2446.
D5896C00005 / A TWO-STAGE RANDOMIZED, OPEN-LABEL, PARALLEL GROUP, PHASE III, MULTICENTER, 7-MONTH STUDY TO ASSESS THE EFFICACY AND SAFETY OF SYMBICORT PMDI ADMINISTERED EITHER AS FIXED OR AS AN ADJUSTABLE REGIMEN VERSUS A FIXED REGIMEN OF ADVAIR IN SUBJECTS 12 YEARS OF AGE AND OLDER WITH ASTHMA / Bisgaard H, Le Roux P, Bjåmer D, Dymek A, Vermeulen JH, Hultquist C. Comparison of adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler and fixed-dose fluticasone propionate/salmeterol dry powder inhaler in asthma patients.J Allergy Clin Immunol2008;121(6):1407-14
DC-039-0001 / THE EFFECTIVENESS AND SAFETY OF AN INDIVIDUALISED SYMBICORT TURBUHALER MAINTENANCE DOSING REGIMEN (SYMBICORT ASTHMA CONTROL PLAN) VERSUS SYMBICORT TURBUHALER GIVEN AS STANDARD REGULAR TWICE DAILY THERAPY – SMART / Fitzgerald JM, Sears MR, Boulet LP, Becker AB, McIvor AR, Ernst P, Smiljanic Georgijev NM, Lee JS, for the Canadian Investigators. Adjustable maintenance dosing with budesonide/formoterol reduces asthma exacerbations compared with traditional fixed dosing: a five-month multicentre Canadian study. Can Respir J 2003; 10: 427-434.
LD-039-0001 / THE EFFECTIVENESS AND SAFETY OF AN INDIVIDUALISED SYMBICORT TURBUHALER MAINTENANCE DOSING REGIMEN (SYMBICORT ASTHMA CONTROL PLAN) VERSUS SYMBICORT TURBUHALER GIVEN AS STANDARD REGULAR TWICE DAILY THERAPY / Ställberg B, Olsson P, Jörgensen LA, Lindarck N, Ekström T. Budesonide/formoterol adjustable maintenance dosing reduces asthma exacerbations versus fixed dosing. Int J Clin Pract 2003; 57: 656-666.
LD-039-0003 / AN OPEN, RANDOMIZED, PARALLEL-GROUP, MULTICENTRE, PHASE IIIB STUDY TO EVALUATE THE EFFICACY OF SYMBICORT® TURBUHALER® SINGLE INHALER THERAPY (SIT), GIVEN AS A LOW MAINTENANCE DOSE ONCE OR TWICE DAILY PLUS AS NEEDED, COMPARED TO A HIGHER MAINTENANCE DOSE OF SYMBICORT TURBUHALER GIVEN TWICE DAILY PLUS OXIS® TURBUHALER® AS NEEDED DURING 24 WEEKS IN ASTHMATIC PATIENTS / Lundborg M, Wille S, Bjermer L, Tilling B, Lundgren M, Telg G, Ekström T, Selroos O. Maintenance plus reliever budesonide/formoterol compared with a higher maintenance dose of budesonide/formoterol plus formoterol as reliever in asthma: An efficacy and cost-effectiveness study. Curr Med Res Opin 2006; 22(5): 809-821.
MA-SYM-0001 / THE EFFECTIVENESS AND SAFETY OF AN INDIVIDUALISED SYMBICORT TURBUHALER MAINTENANCE DOSING REGIMEN (SYMBICORT ASTHMA CONTROL PLAN) VERSUS SYMBICORT TURBUHALER GIVEN AS STANDARD REGULAR TWICE DAILY THERAPY. THE SYMBICORT ADJUSTABLE MAINTENANCE STUDY (SAM) / Smorzik Y, Yankova Z. Effectiveness of adjustable maintenance dosing and fixed dosing with budesonide/formoterol single inhaler in a multi-ethnic asthma population. Eur Respir J2004;24(Suppl 48):311s, Abs P1987.
PL-039-0001 / SYMBICORT® TURBUHALER® (FORMOTEROL/BUDESONIDE 4.5/160 µG) IN MILD TO MODERATE ASTHMATIC PATIENTS – COMPARISON OF THE EFFICACY OF VERSATILE DOSING REGIMEN WITH CONVENTIONAL CONSTANT DOSING REGIMEN DURING 12 WEEKS TREATMENT PERIOD / Data on file
SD-037-0739 / A 6 MONTHS, RANDOMISED, OPEN, PARALLEL GROUP, MULTICETNRE STUDY TO EXAMINE EFFICACY AND SAFETY OF AS NEEDED VERSUS MAINTENANCE USE OF OXIS 9 MCG IN SUBJECTS WELL CONTROLLED ON MAINTENANCE TREATMENT WITH INHALED GCS AND LONG ACTING B2-AGONISTS / Data on file
SD-039-0686 / SYMBICORT HIGH DOSE ONCE DAILY IN MILD TO MODERATE ASTHMATIC PATIENTS / Buhl R, Creemers JPHM, Vondra V, Martelli NA, Naya IP. Once-daily budesonide/formoterol in a single inhaler in adults with moderate persistent asthma. Respir Med 2003; 97: 323-330.
SD-039-0691 / A COMPARISON OF THE EFFECTIVENESS OF TREATMENT WITH SYMBICORT TURBUHALER (BUDESONIDE/FORMOTEROL; 160/4.5 µG) SINGLE INHALER THERAPY AND SERETIDE DISKUS (SALMETEROL/FLUTICASONE; 50/100, 50/250 OR 50/500 µG) PLUS VENTOLIN (SALBUTAMOL) AS NEEDED IN STEROID-TREATED ADULT AND ADOLESCENT ASTHMATIC SUBJECTS. A RANDOMISED, OPEN, PARALLEL-GROUP, PHASE IIIB, MULTICENTRE, 12-MONTH STUDY / Vogelmeier C, D’Urzo A, Pauwels R, Merino JM, Jaspal M, Boutet S, Naya I, Price D. Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option? Eur Respir J 2005; 26: 819-828.
SD-039-0715 / AN OPEN, PARALLEL GROUP RANDOMIZED, MULTIPLE CENTRE PHASE III STUDY TO COMPARE THE LONG TERM (52 WEEKS) SAFETY OF SYMBICORT PMDI 160/4.5 µG 2 ACTUATIONS B.I.D. WITH THAT OF SYMBICORT TBH 160/4.5 µG INH S B.I.D. IN ADULTS AND ADOLESCENTS WITH ASTHMA / Morice AH, Hochmuth L, Ekelund J, Thorén A, Puterman AS. Comparable long-term safety and efficacy of a novel budesonide/formoterol pressurized metered-dose inhaler versus budesonide/formoterol Turbuhaler® in adolescents and adults with asthma. Pulm PharmacolTher2008;21(1):32-9.
SD-039-0734 / EFFICACY OF SYMBICORT TURBUHALER 160/4.5 µG AS NEEDED VERSUS OXIS 4.5 µG AS NEEDED AND BRICANYL 0.4 MG AS NEEDED IN ADULTS AND ADOLESCENTS WITH ASTHMA RECEIVING SYMBICORT TURBUHALER 160/4.5 µG TWICE DAILY AS MAINTENANCE TREATMENT / Rabe K, Atienza T, Magyar P, Larsson P, Jorup C, Laloo U. Reduction in asthma exacerbations with budesonide in combination with formoterol for reliever therapy: a randomised, controlled, double-blind study. Lancet 2006; 368: 744-753.
SD-039-0735 / COMPARISION OF THE EFFICACY AND SAFETY OF ONE INHALATION OF SYMBICORT TURBUHALER 160/4.5 µG BID PLUS AS NEEDED WITH TWO INHALATIONS OF SERETIDE EVOHALER 25/125 µG BID PLUS TERBUTALINE TURBUHALER 0.4 MG AS-NEEDED, AND ONE INHALATION OF SYMBICORT® TURBUHALER® 320/9 µG BID PLUS TERBUTALINE TURBUHALER® 0.4 MG AS-NEEDED. A 6-MONTH, RANDOMISED, DOUBLE-BLIND, DOUBLE-DUMMY, PARALLEL-GROUP, ACTIVE-CONTROLLED, MULTICENTRE, PHASE IIIB STUDY IN ADULT AND ADOLESCENT ASTHMATIC PATIENTS / Kuna P, Peters MJ, Manjra AI, Jorup C, Naya IP, Martinez-Jimenez NE, Buhl R. Effect ofbudesonide/formoterolmaintenanceand reliever therapyon asthma exacerbations. Int J Clin Practice 2007; 61: 725-736.
1
Table E2Number of patients, exposure, number of asthma hospitalisations and number of asthma DAEsStudycode / Patients (N) / Total exposure in treatment years / Number of asthma hospitalisations / Number of asthma DAEs
Formoterol vs non-LABA trials
FORM / NON-LABA / FORM / NON-LABA / FORM / NON-LABA / FORM / NON-LABA
D5896C00001 / 73 / 24 / 16 / 6 / 0 / 0 / 0 / 0
DC-037-0002 / 200 / 101 / 44 / 20 / 1 / 1 / 7 / 6
SD-037-0003 / 164 / 84 / 37 / 18 / 4 / 0 / 7 / 6
SD-037-0345 / 93 / 125 / 80 / 107 / 2 / 1 / 1 / 0
SD-037-0695 / 277 / 275 / 126 / 125 / 6 / 7 / 6 / 7
SD-037-0699 / 1610 / 1630 / 781 / 795 / 18 / 16 / 9 / 5
SD-037-0714 / 102 / 99 / 94 / 86 / 2 / 2 / 0 / 0
SD-037-0716 / 173 / 176 / 158 / 159 / 0 / 0 / 0 / 0
SD-039-0353 / 148 / 138 / 33 / 31 / 5 / 0 / 5 / 6
SD-039-0667 / 56 / 53 / 26 / 24 / 0 / 1 / 0 / 1
SD-039-0668 / 56 / 65 / 49 / 61 / 1 / 2 / 0 / 0
SD-039-0673 / 444 / 213 / 413 / 197 / 9 / 6 / 2 / 1
SD-039-0681 / 73 / 35 / 16 / 8 / 0 / 0 / 0 / 0
SD-039-0682 / 415 / 207 / 92 / 46 / 0 / 2 / 1 / 6
SD-039-0688 / 417 / 213 / 93 / 48 / 0 / 0 / 2 / 0
SD-039-0689 / 10 / 3 / 4 / 1 / 0 / 0 / 0 / 0
SD-039-0714 / 136 / 134 / 29 / 28 / 0 / 1 / 3 / 5
SD-039-0716 / 55 / 51 / 11 / 10 / 0 / 0 / 0 / 1
SD-039-0717 / 26 / 17 / 5 / 3 / 0 / 0 / 1 / 0
SD-039-0718 / 266 / 145 / 51 / 28 / 1 / 0 / 6 / 7
SD-039-0719 / 123 / 63 / 58 / 29 / 2 / 0 / 1 / 1
SD-039-0725 / 352 / 169 / 83 / 39 / 4 / 1 / 5 / 1
SD-039-0726 / 8 / 20 / 2 / 4 / 0 / 0 / 0 / 0
SD-039-0728 / 77 / 13 / 68 / 12 / 0 / 0 / 0 / 0
Formoterol vs non-LABA trials
FORM / SALM / FORM / SALM / FORM / FORM
BU-037-0004 / 80 / 76 / 16 / 16 / 0 / 4
CF-039-0001 / 50 / - / 16 / - / 0 / 0
CF-039-0002 / 77 / - / 18 / - / 0 / 0
CI-SYM-0001 / 149 / - / 37 / - / 0 / 0
D5890C00002 / 163 / 161 / 76 / 77 / 0 / 0
D5896C00005 / 118 / 55 / 62 / 30 / 0 / 0
DC-039-0001 / 66 / - / 30 / - / 0 / 1
LD-039-0001 / 75 / - / 35 / - / 0 / 1
LD-039-0003 / 110 / - / 43 / - / 0 / 1
MA-SYM-0001 / 33 / - / 8 / - / 0 / 1
PL-039-0001 / 577 / - / 142 / - / 0 / 0
SD-037-0739 / 43 / -- / 20 / - / 0 / 0
SD-039-0686 / 11 / 4 / 6 / 2 / 0 / 0
SD-039-0691 / 37 / 39 / 35 / 33 / 0 / 0
SD-039-0715 / 89 / - / 85 / - / 2 / 1
SD-039-0734 / 354 / - / 337 / - / 4 / 1
SD-039-0735 / 410 / 211 / 186 / 96 / 0 / 0
FORM = formoterol; SALM=salmeterol
Table E3. Incidence of most common serious adverse events in the primary dataset (reported by >3 patients)Preferred term / Number (%) of patients reporting at least one SAE
FORM
N= 7796 / Non-LABA
N=4053
Asthma / 62 (0.80%) / 42 (1.04%)
Pneumonia / 11 (0.14%) / 6 (0.15%)
Appendicitis / 8 (0.10%) / 2 (0.05%)
Abdominal pain / 5 (0.06%) / 2 (0.05%)
Concussion / 4 (0.05%) / 1 (0.02%)
Upper limb fracture / 4 (0.05%) / 0
Bronchitis / 3 (0.04%) / 3 (0.07%)
Gastroenteritis / 3 (0.04%) / 3 (0.07%)
Sinusitis / 3 (0.04%) / 3 (0.07%)
Lymphadenitis / 3 (0.04%) / 1 (0.02%)
Viral infection / 2 (0.02%) / 2 (0.05%)
Upper respiratory tract infection / 1 (0.01%) / 3 (0.07%)
FORM = formoterol
Table E4Change in pulse rate in bpm from basline in two studies comparing formoterol 9 mcg daily, formoterol 18 mcg daily and placebo over 12 weeks in children 6-17 yearsDaily dose / Trial DC-037-0002 / Trial SD-037-0003
N / Mean change (bpm) from baseline to mean over on-treatment visits / N / Mean change (bpm) from baseline to end-of-treatment
Placebo / 97 / 1.6 / 84 / 0.4
9 mcg / 105 / 2.9 / 81 / 3.2
18 mcg / 87 / 2.0 / 83 / 3.0
Table E5. Incidence of most common adverse events (serious and non-serious) in trials with as well LABA as non-LABA treatment arms (MH dataset)
Preferred term / Number (%) of patients reporting at least one AE
FORM
N= 5354 / Non-LABA
N=4053
Nasopharyngitis / 563 (10.5%) / 398 (9.8%)
Upper respiratory tract infection / 352 (6.6%) / 264 (6.5%)
Asthma / 313 (5.8%) / 269 (6.6%)
Headache / 258 (4.8%) / 169 (4.2%)
Pharyngitis / 192 (3.6%) / 138 (3.4%)
Influenza / 159 (3.0%) / 112 (2.8%)
Sinusitis / 149 (2.8%) / 121 (3.0%)
Pharyngolaryngeal pain / 171 (3.2%) / 94 (2.3%)
Bronchitis / 125 (2.3%) / 117 (2.9%)
Rhinitis / 141 (2.6%) / 98 (2.4%)
FORM = formoterol
Table E6. Incidence of adverse events (serious and non-serious) related to sleep disturbances in trials with as well LABA as non-LABA treatment arms(MH dataset)Preferred term / Number (%) of patients reporting at least one AE
FORM
N= 5354 / Non-LABA
N=4053
Poor quality sleep / 0 / 1 (0.02%)
Initial insomnia / 1 (0.02%) / 0
Insomnia / 6 (0.11%) / 10 (0.25%)
Nightmare / 0 / 1 (0.02%)
Sleep disorder / 2 (0.04%) / 1 (0.02%)
FORM = formoterol