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Supplementary appendixUnreported and overlooked: a post hoc analysis of COPD symptom-related attacks from the RISE studyGary T. Ferguson1, Tor Sk?rby2, Lars H. Nordenmark2, Rosa Lamarca3, Audrone Aksomaityte4, Dan Lythgoe4, Ileen Gilbert5, Frank Trudo51Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA;, 2BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 3BioPharmaceuticals R&D, AstraZeneca, Barcelona, Spain; 4Phastar, London, UK; 5BioPharmaceuticals Medical – US, AstraZeneca LP, Wilmington, DE, USAMethodsLower respiratory tract infection (LTRI) and pneumonia event definitionsLRTI include MedDRA (version 19.0) Preferred Term: Bronchitis, Bronchitis viral, Bronchitis bacterial, Lower respiratory tract infection, Lower respiratory tract infection viral, Lower respiratory tract infection bacterial, Infective exacerbation of chronic obstructive?airway?disease,?Pneumonia?viral.Pneumonias include: Atypical pneumonia, Enterobacter pneumonia, Lung infection, Pneumonia, Pneumonia anthrax, Pneumonia bacterial, Pneumonia Bordetella, Pneumonia chlamydial, Pneumonia Escherichia, Pneumonia haemophilus, Pneumonia Klebsiella, Pneumonia legionella, Pneumonia Moraxella, Pneumonia mycoplasmal, Pneumonia necrotising, Pneumonia pneumococcal, Pneumonia pseudomonal, Pneumonia salmonella, Pneumonia?staphylococcal, Pneumonia?streptococcal, Pneumonia?tularaemia,?PsittacosisSubject E0206010 taking formoterol 4.5 ?g x2 twice daily (BID) had a Pneumonia bacterial event and is not reported in the analysis, as they were not assigned a COPD event definition due to the lack of information on baseline rescue medication use.Electronic diary (eDiary) assessments in the RISE studyMajor/minor symptom worsening assessmentSymptoms were assessed from Visit 1 (Enrollment) onward each morning for the purposes of a symptom worsening alert. The purpose of this alert was to notify both the subject and the study center of a potential symptom worsening event that warranted contact between the subject and center for further evaluation.Each morning the subject completed 3 questions pertaining to the major symptoms of a worsening event (dyspnea, sputum volume, and sputum color; (Anthonisen et al 1987)1). A subject reporting worsening of ≥1 of these symptoms triggered assessment of the minor symptoms of a worsening event (sore throat, cold, fever without other cause, cough, and wheeze). All questions had a 24-hour recall period. Questions pertaining to the severity of symptoms vs. their usual state had 3 response options (e.g. How breathless have you been in the last 24 hours? Less breathlessness than usual, Usual level of breathlessness, More breathless than usual) whereas questions related to the presence or absence of a symptom had a dichotomous response (e.g. Have you had a sore throat in the last 24 hours? No, Yes, I had a sore throat).These questions were used for a symptom worsening alert system. An alert was triggered if ≥2 major symptoms (dyspnea, sputum volume, and sputum color/purulence) worsened for ≥2 consecutive days or if one major symptom and one or more minor symptom (sore throat, cold, fever without other cause, cough, and wheeze) worsened for ≥2 consecutive days. When either of these criteria was met, the subject was alerted via the electronic patient reported outcome (ePRO) device to contact the study site for further evaluation. Likewise, the study site was alerted to contact the subject if he or she had not yet contacted the study site for further evaluation.Rescue Medication UseThe number of inhalations of reliever medication taken during daytime and nighttime were recorded by the subject in the eDiary from Visit 1 to the end of the study.Study Medication UseStudy Medication administration was recorded in the eDiary in the morning and in the evening as “yes” or “no”.Nighttime awakeningsNighttime awakening (yes/no) were recorded in the morning upon wakening daily by the subject in the eDairy from Visit 1 to the end of the study. Subjects were instructed to record only awakenings due to respiratory symptoms (cough, worsening shortness of breath, wheezing).St. George’s Respiratory Questionnaire (SGRQ)The SGRQ is a 50-item PRO instrument developed to measure the health status of subjects with airway obstruction diseases.2 The questionnaire is divided into two parts: part 1 consists of 8 items related to the frequency of respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual’s respiratory condition. The SGRQ yields a total score and three domain scores (symptoms, activity, and impacts). The total score indicates the impact of disease on overall health status. This total score is expressed as score from 0 to 100, in which 100 represents the worst possible health status and 0 indicates the best possible health status. Likewise, the domain scores range from 0 to 100, with higher scores indicative of greater impairment. Specific details on the scoring algorithms are provided by the developer in a user manual.3 The assessment of SGRQ was only performed in countries and languages where validated translations were available. Patients who were not fluent in any of the local languages did not perform the SGRQ assessments, but they were still allowed to participate in the study. The SGRQ was completed by the subject at clinical visits.The Modified Medical Research Council (MMRC) dyspnea scaleThe MMRC dyspnea scale uses a simple grading system to assess a subject’s level of dyspnea that consists of five statements about perceived breathlessness. It is an interviewer-administered ordinal scale on which subjects provide their dyspnea according to five grades of increasing severity (scores ranges from 0 (none) to 4 (very severe)) This was recorded at Visit 2 and a score of ≥2 was required for inclusion into the study.Use of nebulizersInhaled or nebulized short-acting β2-agonist (SABA), or short-acting muscarinic antagonist (SAMA)/SABA combinations could be continued at Visit 1 but were withheld 6 hours prior to Visit 2 (Run-in). Nebulizers were then discontinued from Visit 2.Nebulized treatment with ICS, β2-agonists and ipratropium was allowed in the event of a COPD exacerbation after Visit 3 (Randomization) when given concomitantly with systemic steroids and/or antibiotics during an exacerbation; use on their own or “step-up” was not allowed. Nebulized ICS could only be given during hospitalization/ER treatment for a COPD exacerbation. Rescue use of SABA administered via nebulization, outside of managing an acute COPD exacerbation event, was discouraged unless the Investigator deemed access to nebulized SABA as essential for that subject. Occasions (number of times used) where SABA was administered via nebulization were recorded separately from pressurized metered dose inhaler (pMDI) inhalations at each clinic visit. Switching patients from SAMA/SABA combination (including nebulized form) or nebulized SAMA to SAMA pMDI was not allowed from Visit 1 and throughout the duration of the study. COPD exacerbation durationThe start of an exacerbation was defined as the start date of systemic corticosteroids and/or antibiotics or hospital admission, whichever occurred earlier, and the end date was defined as the last day of systemic corticosteroids and/or antibiotics or hospital discharge, whichever occurred later.A COPD exacerbation that occurred ≤7 days of hospital discharge, the last dose of systemic steroids (oral, intramuscular, intravenous) or antibiotics (≤10 days of the last depot injectable dose of corticosteroids), prescribed for a prior exacerbation, was counted as the same exacerbation event.ResultsSt George’s Respiratory Questionnaire (SGRQ) Symptoms dimension scoreHealth-related quality of life (HRQoL) was markedly worse for patients with ≥1 versus no COPD symptom-related attacks when the SGRQ symptoms dimension score was specifically assessed.The mean change from baseline in SGRQ symptoms dimension score was -0.55 (95% CI: -1.44, 0.35) for patients with no COPD symptom-related attacks and 9.26 (95% CI: 6.35, 12.16) for patients with ≥1 attack at the >2 inhalations/day cut-off. For the >4 inhalations/day cut-off, mean change from baseline in SGRQ symptoms dimension score was 0.14 (95% CI: -0.72, 1.01) and 10.11 (95% CI: 5.27, 14.95) for patients with no attacks and ≥1 attack, respectively. These mean changes from baseline corresponded to a mean difference change from baseline in SGRQ symptoms dimension score between no attacks and ≥1 attack of 9.81 (95% CI: 6.77, 12.84) for >2 inhalations/day above baseline and 9.97 (95% CI: 5.05, 14.88) for >4 inhalations/day above baseline.SGRQ symptoms dimension scores were also worse for patients with ≥1 versus no moderate/severe exacerbations. The mean change from baseline in SGRQ symptoms dimension score for moderate/severe exacerbations was -1.81 (95% CI: -2.76, -0.86) for patients with no exacerbations and 11.05 (95% CI: 8.94, 13.15) for patients with ≥1 exacerbation.The corresponding mean difference for moderate/severe exacerbations was 12.85 (95% CI: 10.55, 15.16) for no attacks versus ≥1 attack.Measurement of validation parametersThe median time from onset of a COPD symptom-related attack to measurement of SGRQ was 22 and 21 days for budesonide/formoterol and formoterol, respectively, at the >2 inhalations/day cut-off, and 24 and 20 days at the >4 inhalations/day cut-off. The median time from onset of a moderate/severe exacerbation to SGRQ measurement was 26 days for budesonide/formoterol and 24 days for formoterol.The median time from onset of a COPD symptom-related attack to measurement of forced expiratory volume in 1 second (FEV1) was 22 and 21 days for budesonide/formoterol and formoterol, respectively, at the >2 inhalations/day cut-off, and 24 and 20 days at the >4 inhalations/day cut-off. The median time from onset of a moderate/severe exacerbation to FEV1 measurement was 27 days for budesonide/formoterol and 25 days for formoterol (Table S1).Systemic corticosteroid useThe mean systemic corticosteroid use for moderate/severe exacerbations was 0.10 days per patient follow-up year for patients with no exacerbations, compared with 23.04 days per patient follow-up year for those with ≥1 exacerbation.References1. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987;106(2):196-204.2. Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir Med. 1991;85(Suppl B):25-31.3. Jones PW, Forde Y. St George’s Respiratory Questionnaire Manual. St George’s University of London. 2009.Table S1. Median time (days) from the onset of event until the measurement of FEV1 (first after the start of event)Event definitionBUD/FORM (n=606)FORM (n=613)Symptomatic worsening + >2 inhalations/day of rescue medication use above baseline22.421Symptomatic worsening + >4 inhalations/day of rescue medication use above baseline2420Moderate/severe exacerbation26.825BUD, budesonide; FORM, formoterol.Table S2. Lower respiratory tract infections and pneumonia events, by treatment groupEvent definitionBUD/FORM (n=605)FORM (n=613)Total LRTI & pneumonia, n (%)No. of patients in eventTotal treatment exposure (yrs)Rate (per 100 patient-years)Total LRTI & pneumonia, n (%)No. of patients in eventTotal treatment exposure (yrs)Rate (per 100 patient-years)COPD symptom-related attack (symptomatic worsening + >2 inhalations/day above baseline)0 event8 (1.52)525246.53.2514 (2.85)492221.76.31≥1 event4 (5.19)7737.210.7611 (9.57)11551.821.25COPD symptom-related attack (symptomatic worsening + >4 inhalations/day above baseline)0 event10 (1.74)576270.93.6918 (3.24)555249.57.22≥1 event2 (7.69)2612.715.777 (13.46)522429.14Moderate/severe exacerbation0 event2 (0.46)434204.90.981 (0.24)4091860.54≥1 event10 (5.85)17180.212.4725 (12.25)20490.327.68One patient taking formoterol alone had a pneumonia bacterial event and is not reported in this table as they were not assigned a COPD event definition due to the lack of baseline rescue medication use.BUD, budesonide; FORM, formoterol; LRTI, lower respiratory tract infection.List of Independent Ethics Committees (IEC)/Institutional Review Boards (IRB) consulted for the RISE study.CountryName and address of Country IEC/IRBName and address of Site IEC/IRBArgentina–Comité de ?tica en Investigación de InAER, Arenales 3146 1 B, 1425, Buenos Aires, ArgentinaComité Institucional de ?tica en Investigación VITAE, Av. San Martín 966, 9 de Julio, ArgentinaComité de ?tica de CER Investigaciones Clínicas, Vicente López 1441, B1878DVB, Quilmes, ArgentinaComite independiente de etica para ensayos en farmacologia , Av Cabildo 1536 1 B, , CABA, ArgentinaEC Comite independiente de etica Fundacion Rusculleda, Av Colon 2057, X5003DCE, Cordoba, ArgentinaBulgariaEthics Committee for Multi-centres Trials, 5 Sveta Nedelya square, 1000, Sofia, Bulgaria–Chile–Comite Etico Cientifico Servicio Salud Metropolitano Sur, Santa Rosa 3453, Piso 1, San Miguel, 8900390, Santiago, ChileCzech RepublicEticka komise pri Fakultni nemocnici Brno Bohunice, 639 00, Brno, Czech RepublicEticka komise mestske nemocnice Ostrava, Etickakomise mestske nemocnice Ostrava, Nemocnicni 20, 728 80, Ostrava 1, Czech RepublicEticka komise pri Fakultni nemocnici Brno Bohunice, Eticka komise pri Fakultni nemocniciBrno Bohunice, Jihlavska 20, 639 00, Brno, Czech RepublicEticka komise Sdruzeneho zdravotnickeho zarizeni Krnov, Eticka komise Sdruzeneho zdravotnickeho zarizeni Krnov, I.P.Pavlova 9, 794 01, Krnov, Czech RepublicGermanyEC Landesamt fur Gesundheit undSoziales (LAGeSo),Ethics Ref: 14/0248-EK10, 10707, Berlin, GermanyEC Ethikkommission des Landes Berlin, Landesamt für Gesundheit und Soziales, Fehrbelliner Platz 1,10707, Berlin, GermanyEC Ethikkommission bei der Sachsischen Landesarztekammer, Schutzenh?he 16, 01099,Dresden, GermanyLandes?rztekammer Rheinland-Pfalz EC, Deutschhausplatz 3, 55116, Mainz, GermanyEC Ethikkommission der Arztekammer Niedersachsen, Berliner Allee 20, 30175, Hannover, GermanyEC der ?rztekammer Westfalen-Lippe und der med. Fak der WWU , Gartenstra?e 210 - 214,48147, Münster, GermanyEC Ethik-Kommission (EC) der Bayerischen Landes?rztekammer , Mühlbaurstra?e 16, 81677,München, GermanyEthikKommission (EC) der Arztekammer Nordrhein , Landes?rztekammer Nordrhein,Tersteegenstr. 9, 40474, Düsseldorf, GermanyEthik-Kommission des Landes Sachsen-Anhalt, Kühnauer Stra?e 70 c/o Landesamt fürVerbraucherschutz, 6846, Dessau, GermanyMexico–Inst. Jaliscience de Investigación Clínica, Penitenciaria No. 20, Piso 1, Col. Centro, 44100,Guadalajara, MexicoEC Hospital Universitario "Dr. José Eleuterio González", Comite de Etica de Facultad de Medicina y Hosp Universi, Av. Francisco I.Madero y Gonzalitos s/n, Col. Mitras Centro , 64460, Monterrey, MexicoPolandEC Komisja Bioetyczna przy Bydgoskiej Izbie Lekarskiej, 85-681, Bydgoszcz, Poland–South Africa–EC, Pharma Ethics, Pharma Ethics, 123 Amcor Road, Lyttelton Manor 0157, Irene, 7925, Pretoria, South AfricaSpainParc de Salut Mar CEIC, 08003, Catalu?a, Barcelona, SpainParc de Salut Mar CEIC, Institut de Recerca Hospital del Mar, Parc de Recerca Biomédica deBarcelona C/ Doctor Aiguader, 88, 08003, Barcelona, SpainCEICA Comité ?tico de Investigación Clínica de Aragón, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Centro de InvestigaciónBiomédica de Aragón (CIBA), Avda. San Juan Bosco, 13, planta 1, 50009, Zaragoza, SpainEC Comite coord etica investigacion biomedica deAndalucia, Avda. Innovación s/n – Edifico Arena 1, 41020, Sevilla, SpainHospital Universitario Germans Trias i Pujol, Comité ?tico de Investigación Clínica, Ctra. delCanyet s/n, Edificio Materno-Infantil 3 planta, 08916, Badalona, SpainUSACopernicus Group IRB, OneTriangle Drive, Suite 100, 27713,Durham, United States of America– ................
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