Asthma Control Asthma Management What if everything seems to fail

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1 Asthma Control Asthma Management What if everything seems to fail What is ideal asthma control? What are the advantages of controlling asthma? How well are we controlling asthma in Hong Kong? How well are our patient s doing compared with standard of care? Befe medications Anything else we can do? Are we using the right drugs? Approach to Medications titration Top-Down Bottom-up? What facts affects the efficacy of inhalers? New drug on the block? When input can a specialist provide? What me can we do when everything fails? What s me is there in the future? * Excludes reliever taken befe exercise 216 Global Initiative f Asthma, all rights reserved. Use is by express license from the owner By QaulityMetric Incpated. Copyright 22. 1

2 SYMPTOM CONTROL To achieve good symptom control Maintain nmal activity levels, including exercise REDUCE FUTURE RISK Prevent asthma exacerbations To minimize future risk of exacerbations, fixed airflow limitations and side-effects Prevent asthma mtality 216 Global Initiative f Asthma, all rights reserved. Use is by express license from the owner Among other Asian countries, asthma patients (> 12 years) from Hong Kong were surveyed by random digit telephone dialing as per GINA guideline f asthma control 6% Patient-repted frequency of symptoms in the past 4 weeks 5% 4% 3% 2% 1% % 29% 16% 22% 28% 49% 47% Every day/most 1-2 times a week 1-2 times a days month Daytime Night time Thompson PJ et al., Respirology (213) 18, Self-repted Accding to GINA Uncontrolled, 16% Controlled, 11% Others, 28% Controlled, 72% Partially controlled, 73% Only 11% of patients in Hong Kong achieved controlled asthma as determined by the GINA classification. Thompson PJ et al., Respirology (213) 18, ?Cromolyn Low dose ICS LABA / SMART [A] Medium ICS Low-dose ICS?Low-dose ICS SMART Medium ICS LABA TIO? High dose ICS LABA 6mgQD) If alternative treatment is inadequate, discontinue it and use the preferred treatment befe stepping up. 2

3 If the patient have symptoms year round Does the patient keep pets indos? What type? Does the patient dampness in any room of his home? Does he have mold visible in any part of his home? Has patient seen cockroaches rodents in his home in the past month? Is there any who smokes at home? Have there been recent renovations? If symptoms get wse at certain times of the year / Week / Day? Early spring? (Trees) Late spring? (Grasses) Late summer to autumn? (Weeds) Summer and fall? (mites) Cold months in temperate climates? (Animal dander) Does symptoms confined to wkdays? What substances are used in the patient's wksite? If symptoms get wse at certain healthrelated events? Rhinitis GERD Sulfite sensitivity (after shrimp, dried fruit, drinking beer wine)? Medication sensitivities (especially NSIADs Aspirin) Image from Wikipedia (/- Low dose ICS in patient at risk of exacerbation)? Cromolyn Low dose ICS LABA / SMART [A] Medium ICS Low-dose ICS?Low-dose ICS SMART Medium ICS LABA TIO? High dose ICS LABA 6mgQD) If alternative treatment is inadequate, discontinue it and use the preferred treatment befe stepping up.? Cromolyn Low dose ICS LABA / SMART [A] Medium ICS Low-dose ICS?Low-dose ICS SMART Medium ICS LABA TIO? High dose ICS LABA 6mgQD) If alternative treatment is inadequate, discontinue it and use the preferred treatment befe stepping up. 3

4 ?Cromolyn Low dose ICS LABA / SMART [A] Medium ICS Low-dose ICS?Low-dose ICS SMART Medium ICS LABA TIO? High dose ICS LABA 6mgQD) If alternative treatment is inadequate, discontinue it and use the preferred treatment befe stepping up.?cromolyn Low dose ICS LABA [A] Low-dose ICS Low-dose ICS SMART Medium ICS LABA TIO? High dose ICS LABA 6mgQD) If alternative treatment is inadequate, discontinue it and use the preferred treatment befe stepping up.?cromolyn Low dose ICS LABA Medium ICS LABA [A] Low-dose ICS Low-dose ICS High dose ICS LABA 6mgQD) If alternative treatment is inadequate, discontinue it and use the preferred treatment befe stepping up. NO RIGHT OR WRONG ANSWER Fact to consider Asthma brittleness vs. Healthcare Costs TOP-DOWN Maximal inhalers to achieve quick control to minimize risk of under-treatment Once control has been achieved f >/= 3 months and PFT plateau, treatment can be reduced Aims to find the patient s minimum effective treatment Patient is then maintained on such a regular controller regimen Endpoint depending on current treatment, risk facts and preferences BOTTOM-UP To start treatment as per their control, and step up to gain control; overall likely the cheapest way f a healthcare system Sustained step up (>2-3 months) Start with the control group, the follow GINA to step up every 2-3 months until the optimal controller therapy is identified Other fm of Step-up treatment - Sht-term step up (f 1-2 weeks) vs. Day-today adjustment 4

5 5% Low dose ICS LABA Medium ICS LABA [A] Low-dose ICS High dose ICS LABA 6mgQD) If alternative treatment is inadequate, discontinue it and use the preferred treatment befe stepping up. Proption of patients repting rescue and controller medication use 45% 4% 35% 3% 25% 2% 15% 1% 5% % 38% Rescue 41% Control 33% 49% 34% Inhaler Nebulizer Oral Steroids Only 33% is using an inhaler as their regular controller medication. Thompson PJ et al., Respirology (213) 18, Drug delivery Consistent dose delivery Low resistance Wks over a range of inspiraty flow rates Dose reproducibility across environment Picture Generic Trade name Fm Dosing Budesonide Fmoterol Symbict Turbuhaler 2puffs BD Budesonide Fmoterol Vannair MDI 2puffs BD Patient's preference Appropriate size Dose counter Reinfcement of delivery Favable dosing schedule Ease of Use Fewer steps required Less training requirements Lower dexterity required Fluticasone fmoterol Flutifm MDI Beclomethasone fmoterol 2puffs BD Fostair* MDI / Nexthaler 2puffs BD Fluticasone Salmeterol Seretide Accuhaler 1puff BD Fluticasone Salmeterol Seretide MDI 2puffs BD Chrystyn H, Int J Clin Pract, June 27, 61, 6,

6 Builds on design of the Diskus / Accuhaler (single blister-strip technology) Operation involves three simple steps: 1. Open a cover is opened by the patient to reveal the mouthpiece and activate the dose in one single step 2. Inhale the actuated dose is subsequently inhaled from the mouthpiece 3. Close. The dose counter indicates the remaining doses in large clear numbers. Display turn red when the device is empty. Allow f once-daily dosing Lower strength Metered (pre-dispensed) dose: FF/VI 1/25 µg Delivered dose: FF/VI 92/22 µg Higher strength Metered (pre-dispensed) dose: FF/VI 2/25 µg Delivered dose: FF/VI 184/22 µg FF (fluticasone furoate) is a different compound to FP (fluticasone propionate), with distinct pharmacological properties High affinity f GR Selectivity f GR (vs PR, AR, ER) Greater tissue retention Prolonged GR nuclear translocation Greater binding affinity and potency f GR Greater selectivity f GR than MF, BUD and Cic-AP Higher cellular accumulation and lower cellular efflux Longer nuclear duration of action than FP VI (Vilanterol) have a longer duration of action than salmetrol; bronchodilation was still apparent 22 hours after VI pretreatment High affinity f β 2 -AR Persistence of action at β 2 -AR Selectivity of β 2 -AR (vs β 1 and β 3 ) Comparable SAL Greater than fmoterol and indacaterol Comparable with indacaterol Longer than fmoterol Higher than fmoterol and indacaterol Similar to SAL Valotis A, Högger P. Resp Res. 27;8:54 62; Salter M et al. Am J Physiol Lung Cell Mol Physiol. 27;293:L66 7; Rossios C et al. Eur J Pharmacol. 211;67: Slack RJ et al. J Pharmacol Exp Ther. 213;344: Mean % nominal blister content/actuation Flow rate (L/min) FF 1 µg VI 25 µg Median (range) mass aerodynamic diameter (µm) FF 4. ( ) VI 2.3 (2. 2.6) Median mass aerodynamic diameter of both FF and VI was within the theetical range of particle size deemed to provide optimal lung deposition and clinical efficacy (2 5.8 µm) The total emitted dose of FF/VI was 84 97% f both FF and VI components, regardless of flow rate inhaler strength (data f FF/VI 2/25 µg not shown on slide). GSK data on file, DOF_214N188664; DOF_214N

7 1 1 ELLIPTA Diskus/Accuhaler How did you rate the ease of use of the inhaler? How easily are you able to tell how many doses of medication are left in the inhaler? 8 8 Turbuhaler % Easy very easy % Easy very easy At week 4, >99% of the 989 asthma patients used the inhaler crectly, with only four patients requiring one additional instruction. 15 asthma patients participated in the trials. Of these, 989 (94%) completed the questionnaire. Svedsater H et al. Prim Care Respir Med. 214;24:1419. Patients (%) % Used crectly.4% One instruction required Subjects (%) % 19.5% 68.5% At least one critical err 2.7% 38.3% 83.2% At least one err In 149 healthy volunteers without verbal instruction technique demonstration (but given inhaler handling leaflet), ELLIPTA DPI is most likely to be operated crectly. Svedsater H et al. Prim Care Respir Med. 214;24: Sharma et al. Am J Respir Crit Care Med. 214;189:A5693. Asthma clinical development programme Asthma clinical development programme Dose-ranging FF 25 1 µg vs FP 1 µg BD placebo 8-week; n=598 FFA Phase II Allergen challenge FF/VI 1/25 µg vs FF 1 µg VI 25 µg 21-day; n=27 HZA Mning versus evening dosing FF/VI 1/25 µg vs placebo 14-day; n=26 HZA Lung function FF/VI 1/25 µg vs FF 1 µg placebo 12-week; n=69 HZA Phase III Head to head versus FP/SAL FF/VI 1/25 µg vs FP/SAL 25/5 µg 24-week; n=86 HZA Safety FF/VI 1/25, 2/25 µg vs prednisolone placebo 6-week; n=185 HZA Diagnosis of asthma Aged 12 years FEV 1 reversibility 12% and 2 ml with inhaled albuterol/salbutamol Pre-bronchodilat FEV 1 4 9% predicted nmal Lung function FF/VI 1/25 µg vs FF 1 µg placebo 12-week; n=69 HZA Phase III Head to head versus FP/SAL FF/VI 1/25 µg vs FP/SAL 25/5 µg 24-week; n=86 HZA Safety FF/VI 1/25, 2/25 µg vs prednisolone placebo 6-week; n=185 HZA FF 1 4 µg vs FP 25 µg BD placebo 8-week; n=615 FFA FF 2 8 µg vs FP 5 µg BD placebo 8-week; n=622 FFA VI 3 5 µg vs placebo 4-week; n=67 B2C FF/VI 1/25 µg vs FF 1 µg placebo 28-day; n=52 HZA FF/VI 2/25 µg vs FF 2 µg FP 5 µg 24-week; n=586 HZA FF/VI 1/25, 2/25 µg vs FF 1 µg 12-week; n=139 HZA Exacerbation FF/VI 1/25 µg vs FF 1 µg week; n=219 HZA FF/VI 1/25, 2/25 µg vs FP 5 µg 52-week; n=53 HZA Previously maintained on ICS ± LABA f 12 weeks at a stable dose f 4 weeks pri to screening In the exacerbation study, patients had 1 exacerbation that required treatment with OCS and/ a hospital emergency room visit in the past year FF/VI 2/25 µg vs FF 2 µg FP 5 µg 24-week; n=586 HZA FF/VI 1/25, 2/25 µg vs FF 1 µg 12-week; n=139 HZA Exacerbation FF/VI 1/25 µg vs FF 1 µg week; n=219 HZA FF/VI 1/25, 2/25 µg vs FP 5 µg 52-week; n=53 HZA Bateman ED et al. Respir Med. 212;16:642 5; 2. Bleecker ER et al. Ann Allergy Asthma Immunol. 212;19:353 8; 3. Busse WW et al. Thax. 212;67:35 41; 4. Lötvall J et al. Eur Respir J. 212;4:57 9; 5. Oliver A et al. Allergy. 213;68: ; 6. Oliver A et al. Clin Transl Allergy. 212;2:11; 7. Kempsfd R et al. Respir Med. 213;17:1873 8; 8. Bleecker ER et al. J Allergy Clin Immunol Pract. 214;2:553 61; 9. O Byrne PM et al. Eur Respir J. 214;43:773 82; 1. Bernstein DI et al. Poster presented at ATS 214, San Diego, USA; 11. Woodcock A et al. Chest. 213;144: ; 12. Bateman ED et al. Thax. 214;69:312 9; 13. Allen A et al. Clin Respir J. 213;7:397 46; 14. Busse W et al. Thax. 213;68: Bateman ED et al. Respir Med. 212;16:642 5; 2. Bleecker ER et al. Ann Allergy Asthma Immunol. 212;19:353 8; 3. Busse WW et al. Thax. 212;67:35 41; 4. Lötvall J et al. Eur Respir J. 212;4:57 9; 5. Oliver A et al. Allergy. 213;68: ; 6. Oliver A et al. Clin Transl Allergy. 212;2:11; 7. Kempsfd R et al. Respir Med. 213;17:1873 8; 8. Bleecker ER et al. J Allergy Clin Immunol Pract. 214;2:553 61; 9. O Byrne PM et al. Eur Respir J. 214;43:773 82; 1. Bernstein DI et al. Poster presented at ATS 214, San Diego, USA; 11. Woodcock A et al. Chest. 213;144: ; 12. Bateman ED et al. Thax. 214;69:312 9; 13. Allen A et al. Clin Respir J. 213;7:397 46; 14. Busse W et al. Thax. 213;68:

8 PFT, FF/VI 1/25 PFT, FF/VI 1/25 24 h FEV 1, 95% CI (L) Time since dose (hours) Co-primary endpoint Mean change from baseline in serial ( 24 hour) wmfev 1 at week 12 FF/VI versus placebo (32 ml; P<.1) FF versus placebo (186 ml; P=.3) FF/VI versus FF (116 ml; P=.6) FF/VI 1/25 µg OD FF 1 µg OD Placebo trough FEV 1, 95% CI (L) Week of study Co-primary endpoint trough FEV 1 at week 12 FF/VI versus placebo (172 ml; P<.1) FF versus placebo (136 ml; P=.2) FF/VI versus FF (36 ml; P=.45) FF/VI 1/25 µg OD FF 1 µg OD Placebo Adapted from Bleecker ER et al. J Allergy Clin Immunol Pract. 214;2: Adapted from Bleecker ER et al. J Allergy Clin Immunol Pract. 214;2: PFT, FF/VI 2/25 PFT, FF/VI 2/25 Co-primary endpoint Co-primary endpoint 24 hour FEV 1, 95% CI (L) serial ( 24 hour) wmfev 1 at week 24 FF/VI versus FF (136 ml; P<.48) FF versus FP (26 ml; P=.3) FF/VI 2/25 µg OD FF 2 µg OD FP 5 µg BD trough FEV 1, 95% CI (L) trough FEV 1 at week 24 FF/VI versus FF (193 ml; P<.1) FF/VI versus FP (21 ml; P<.1) FF/VI 2/25 µg OD FF 2 µg OD FP 5 µg BD Time since dose (hours) Adapted from O Byrne PM et al. Eur Respir J. 214;43: Week of study Adapted from O Byrne PM et al. Eur Respir J. 214;43:

9 QOL, FF/VI 2/25 PFT, FF/VI 2/25 24-hour periods (%) % P<.1 Rescue-free 8.4% P=.1 Symptom-free Patients receiving FF/VI versus FF experienced an additional.8 rescue-free days/week.6 symptom-free days/week FF/VI 2/25 µg OD FF 2 µg OD FP 5 µg BD Adapted from O Byrne PM et al. Eur Respir J. 214;43: hour FEV 1, 95% CI (L) FF/VI FP/SAL FP/SAL Time since dose (hours) Primary endpoint serial ( 24 hour) wmfev 1 at week 24 FF/VI versus FP/SAL ( 37 ml; P=.162) FF/VI 1/25 µg OD FP/SAL 25/5 µg BD Adapted from Woodcock A et al. Chest. 213;144: QOL, FF/VI 2/25 EXACERBATION Additional endpoint Patients with.5 improvement in AQLQ12 sce at week 24 (%) % FF/VI 1/25 µg OD 38% FP/SAL 25/5 µg BD Mean change from baseline in AQLQ12 sce at week 24 FF/VI versus FP/SAL (.46 vs.37; P=NS) *Post-hoc analysis of a head-tohead study in which the primary superiity endpoint (-24 h wmfev 1 ) was not met Adapted from Woodcock A et al. Chest. 213;144: Probability of severe asthma exacerbation (%), 95% CI Probability of event at week 52 FF 15.9% FF/VI 12.8% Week 2% risk reduction (P=.36) Additional endpoint Rate of severe asthma exacerbations/patient/year FF versus FF/VI,.19 versus.14 Reduction of 25% (P=.14) FF 1 µg OD FF/VI 1/25 µg OD Bateman ED et al. Thax. 214;69:

10 SAFETY A total of 734 patients from the asthma clinical development programme and 6237 from the COPD clinical development programme were included in an integrated assessment of AEs. SAFETY Effect on HPA axis in 6 weeks with different doses of ICS Day 1 (baseline) Day 42 Very common AEs ( 1/1) Other common AEs ( 1/1 to <1/1) Headache and nasopharyngitis Bronchitis, influenza, candidiasis of mouth and throat Cough, dysphonia, opharyngeal pain Sinusitis, fractures, pyrexia Back pain, arthralgia, rhinitis, upper respiraty tract infection, pneumonia Abdominal pain and pharyngitis [With the exception of pneumonia and fractures, which were repted me commonly in patients with COPD, the safety profile was similar in patients with asthma and COPD] Time (h) FF/VI 1/25 µg OD FF/VI 2/25 µg OD Prednisolone 1 mg OD Placebo Relvar 92/22 Summary of Product Characteristics. GlaxoSmithKline; 215. Allen A et al. Clin Respir J. 213;7: SAFETY Effect on HPA axis (by Urinary ctisol)in 52 weeks with different doses of ICS 1 Week 12 1 Week 52 Establishing a Concomitant Diagnosis COPD & Bronchiolitis obliterans By PFT /- CT Bronchiectasis by HRCT Central airway obstruction PFT, CT Asthma-COPD overlap syndrome (ACOS) PFT Obstructive Sleep apnea PSG 24 hour UC excretion ratio to baseline (nmol/24 hour) Suspecting an alternate diagnosis / unexplained frequent exacerbation Allergic bronchopulmonary aspergillosis (ABPA) Blood tests, Contrast CT ANCA-Associated Vasculitis (Churg-Strauss syndrome) Blood test, NCV, bronchoscopy Unusual allergy Skin prick tests, Allergen-specific IgE Paradoxical vocal cd dysnfunciton Bronchoscopy Eosinophilic lung disease Blood test, CT Hypersensitivity pneumonitis PFT, CT, Blood tests.1 FF/VI 1/25 µg OD FF/VI 2/25 µg OD FP 5 µg BD.1 FF/VI 1/25 µg OD FF/VI 2/25 µg OD FP 5 µg BD Considering of advanced treatment Anti-IgE (Omalizumab) therapy LTOT and consideration of NIPPV Non-medical therapy Busse W et al. Thax. 213;68:

11 216 Global Initiative f Asthma, all rights reserved. Use is by express license from the owner Asthmatic.Inc. The Pharmaceutical Journal, 12 September 215, Vol 295, No 7879, online DOI: /PJ Asthma Control Asthma Management What if everything seems to fail What is ideal asthma control? What are the advantages of controlling asthma? How well are we controlling asthma in Hong Kong? How well are our patient s doing compared with standard of care? Befe medications Anything else we can do? Are we using the right drugs? Approach to Medications titration Top-Down Bottom-up? What facts affects the efficacy of inhalers? New drug on the block? When input can a specialist provide? What me can we do when everything fails? What s me is there in the future? 11