LEARNING OBJECTIVES. Do Inhaled Corticosteroids Really Affect Growth?

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1 Do Inhaled Corticosteroids Really Affect Growth? David P. Skoner, MD Director, Division of Allergy, Asthma & Immunology, Department of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania. Professor of Medicine, Temple University. Professor of Pediatrics, West Virginia University. Grant/Research Support Consultant Speaker s Bureau Stock Shareholder Greer Laboratories, Novartis, Merck, GlaxoSmithKline, Teva Merck, Sunovion, Istavision GlaxoSmithKline, Merck, Novartis, Teva, Sunovion Nothing to Disclose Employee Nothing to Disclose Other Nothing to Disclose LEARNING OBJECTIVES 1) Illustrate sources of systemic bioavailability for inhaled corticosteroids. 2) Describe the effects of inhaled corticosteroids on the growth of children with asthma. 3) Review methods to minimize and manage the risk of growth suppression. 1

2 Evolution of Asthma Management, Cincinnati Children s Hospital, 1981 Intern on 3 South, admitted 5 children with asthma by 1am Chief Resident makes rounds at 1:3am and asks two questions: 1) Can we get the theophylline levels a little higher? 2) How many did you manage to keep off steroids? The change from then until now is dramatic, since current guidelines have ICS as the foundation, and theophylline is rarely used. Trends in Preventive Asthma Medication* Use Among Children and Adolescents, (CDC). P <.1 for trend Percentage of Patients 34.9% Adherence rates are also very low, and one reason is steroid phobia! 21.2% 4% 17.8% Compared to non-hispanic white children, lower use among non-hispanic black (aor =.5) and Mexican American (aor =.6) children. * Included inhaled corticosteroids, leukotriene receptor antagonists, long-acting β- agonists, mast-cell stabilizers, and methylxanthines. Pediatrics. 212 Jan;129(1):62-9. Epub 211 Dec 5. Systemic Bioavailability of ICS Potential impact on growth 6 2

3 Potential Interaction Between Growth Axis and Nocturnal INS or ICS Administration Reduction in growth axis activity following nonphysiologic nocturnal cortisol effect Interaction of childhood growth and HPA axes. The commencement of nocturnal pulsatile growth hormone secretion normally coincides with the nadir in plasma cortisol concentrations. Consequently, the administration and absorption of airway corticosteroids at bedtime could theoretically have a disproportionate suppressing influence on growth, compared with early morning dosing. GH, growth hormone. 7 Safety of ICS in Children Growth Effect? Is it real and dose-related? How large is it? Do all ICS affect growth equally? What is the FDA s position? Does the effect change our approach to therapy? Phases of Childhood Growth Height (cm) Karlberg. Acta Paediatr Scand Suppl. 1989;356: Sex hormones Growth hormone (and thyroid hormone) Fetal growth Age (years) 3

4 Figure 1. Timeline of Growth Studies in Children with Asthma Expert Panel Report (EPR) Guidelines for the Diagnosis and Management of Asthma issued, recommending ICS as preferred therapy FDA issues draft guidance for industry on conduct of ICS growth studies in children Second study utilizing criteria in FDA guidance published (ciclesonide growth study) Numerous growth studies published (inhaled and intranasal steroids) FDA convenes meeting and recommends class labeling for all inhaled and intranasal steroids regarding possible growth suppression First study utilizing criteria in FDA guidance published (montelukast growth study) Petrisko MA, Skoner JD, Skoner DP. J Asthma 28; 45(S1): Both Sensitive Devices 11 DOSE-RESPONSE EFFECT ON GROWTH CFC Formulations 12 4

5 No Significant Difference in Mean Height After 1 Year of Treatment Open-label, randomized study of 3 children ages 5-11 yrs with asthma well-controlled on ICS (BDP or BUD); 1:3 randomization to continue CFC-BDP+S at approximately the same dose or switch to HFA-BDP at half the dose Mean change from baseline in height (cm) HFA-BDP 1-2 μg/day CFC-BDP+S 2-4 μg/day What about HFA formulations? Note lack of placebo Months Pedersen S, et al. Pediatrics. 22;19(6):e92. ONE-YEAR TRIAL OF GROWTH IN ASTHMATIC CHILDREN INCLUDING THOSE RECEIVING HIGHER-THAN-RECOMMENDED BDP DOSES* MEAN GROWTH VELOCITY FROM DAY 1 TO MONTH 12 (cm/year) * Small n values at higher doses µg/day What about HFA formulations? Pediatrics 22;19(6):e92(1-1) Most Children Remained in Same Height Centile After 1 Year of HFA- BDP Treatment Height centile month HFA-BDP 1-2 µg/day (n=156) CFC-BDP + S 2-4 µg/day (n=56) Height centile at start of treatment Note interindividual response variation Pedersen S, et al. Pediatrics. 22;19:e92. 5

6 Long-term Effects of Fluticasone Proprionate (FP) on Growth Design: Double-blind, randomized, placebocontrolled, multicenter Population: 325 prepubescent children with persistent asthma Treatment: FP powder 1 μg or 2 μg via Rotadisk or placebo for 1 year Growth Velocity: 6.1 cm/yr ±.17 Placebo 5.91 cm/yr ±.16 FP 1 μg 5.67 cm/yr ±.13 FP 2 μg Allen DB et al. J Pediatr 1998;132: Inhaled FP: Summary Percentile Control 5 mcg 1 mcg 3 3% 4% 3% 1 8% 9% 1% 25 18% 21% 31% 5 35% 44% 59% Joint PADAC/MEDAC meeting, July 3-31, Comparison of the Fluticasone ICS/INCS Formulations* Name ICS Rotadisk Dosage (mcg/puff) 5,1,25 Systemic Bioavailability 13.5% ICS pmdi 44,11,22 3% ICS Diskus 1,25,5 18% Intranasal 5 <2% * per package insert, 21 PDR Used in one-year growth study For asthma, healthy volunteers, dose delivered from actuator, primarily reflects lung delivery Plus 5mcg salmeterol/puff 18 6

7 Randomized, M-C, D-B, P-G, P-C study and 3 year olds with high asthma risk Fluticasone 44 µg/puff or placebo (2 puffs bid) Growth Velocity Nebulized Budesonide vs Conventional Asthma Therapy Mean growth velocity for 527 children treated with nebulized budesonide (BUD) or conventional asthma therapy (CAT) for 52 weeks of treatment in children aged 6 months to 8 years 1 Mild Mod/sev Mod/sev BUD Mildest patients may be the most susceptible CATto the * growth effects 6.96 of ICS *P=.2 NS NS NS Initial dose 5 µgm qd n=151 n=58 Study A Initial dose 5 µgm bid n=47 n=25 Study B Initial dose 5 µgm qd n=173 n=73 Study C n=371 n=156 Pooled Scott MB, Skoner DP. J Allergy Clin Immunol. 1999;184:S2-S29. Skoner DP et al. J Allergy Clin Immunol. 2;15: Effects of Inhaled Mometasone Furoate on Growth Velocity and Adrenal Function: A Placebo-Controlled Trial in Children 4 9 Years Old with Mild Persistent Asthma Day 14 to 7 Primary Safety Endpoint: Growth velocity (cm/year) during the 1-year treatment period Multicenter, randomized, double-blind, placebo-controlled, parallel-group study Day 1 Week 52 MF-DPI 1 mcg BID (End of treatment) (n=44) MF-DPI 1 mcg QD AM (n=48) (187 patients aged 4-9 years) MF-DPI 2 mcg QD AM (n=5) Placebo (n=45) + 3-month follow-up Skoner DP et al, J Asthma. 48: ,

8 Effects of Inhaled Mometasone Furoate on Growth Velocity and Adrenal Function: A Placebo-Controlled Trial in Children 4 9 Years Old with Mild Persistent Asthma Skoner DP et al, J Asthma. 48: , Effect of Inhaled Triamcinolone Acetonide (TAA) on the Growth of Children with Moderate Asthma (Real-World Study) 7 Mean (SE) cm Growth Difference P=.36 Normal Nonsteroidal TAA Mean 1-year growth difference (final height minus baseline height). P-value is comparison vs. normal. Skoner DP et al: J Allergy Clin Immunol. 1999:13:S INDIVIDUAL GROWTH DATA FROM REAL WORLD STUDY Skoner DP et al: J Allergy Clin Immunol. 1999:13:S

9 ICS Labeling Resulting from FDA Meeting July 1998 Prescribing information for: Beclomethasone Budesonide Fluticasone Country responsibility to make consistent with local labeling. Adapted from QVAR prescribing information, 3M, October 23; Pulmicort prescribing information, AstraZeneca, December 23; Flovent prescribing information, GlaxoSmithKline, March 24. Low-dose Step-up Medium-dose Benefit/risk Adverse effect clinical relevance 26 Drug Inhaler Rx (~mcg/day) BDP without spacer , BDP with spacer ,2 BUD MDI ,6 BUD dry powder FP Inhibition of lower leg growth using knemometry % of max BDP-DPI FP-DPI BUD-DPI BUD-pMDI Daily dose (µg) 27 9

10 21 FDA Guidelines for Evaluation of the Effects of Inhaled Corticosteroids on Growth Population Study design Analysis Pre-pubertal Mild, persistent asthma Comparable baseline demographics Primary: Regression analysis of growth velocity Total length of 95% CI.5 cm Secondary: Shift analysis in growth velocity percentile; analysis of growth velocity percentiles; growth velocity during follow-up At least 1 year treatment period Untreated control group Baseline growth velocity data (at least 16 weeks) Follow-up period (at least 8 weeks) Repeat stadiometer measurements Cortisol measurements Pulmonary function tests 28 Linear Growth Stadiometry Study in Prepubertal Asthmatic Children Design Period I Single-blind run-in Period II Double-blind treatment* Montelukast 5 mg once daily (n=12) Placebo Beclomethasone 2 µg twice daily (n=119) Placebo (n=121) 16 weeks 56 weeks *As-needed short-acting beta 2-agonist use was permitted for symptom control or pre-exercise prophylaxis; one oral corticosteroid rescue was permitted during run-in and up to four during double-blind treatment. Adapted from Becker AB et al Ann Allergy Asthma Immunol 26;96:8 87. Linear Growth Stadiometry Study in Prepubertal Asthmatic Children Aged 6 9 Years 6 9 Years Is an Appropriate Age Range for a Linear Growth Study Length/ height for typical healthy boys (cm) Age group 4 recruited for linear growth study Nutrition Growth hormone Sex steroids/growth hormone Age (year) The 2 3 years prior to puberty are likely to be the most susceptible to growth suppression by asthma drugs 5% 5% 95% Adapted from Becker AB et al Ann Allergy Asthma Immunol 26;96:8 87; Allen DB Pediatrics 22;19:373 38; Karlberg J Acta Pediatr Scand Suppl 1989;356:

11 The Effect of Montelukast and Beclomethasone on the Rate of Linear Growth in Children Change in Height (cm) form Randomization Visit (Baseline) to Week 56 (Treatment Group Mean ± Standard Error of the Mean) Change in Height (cm) Beclomethasone 4µg Montelukast 5mg Placebo Weeks on Treatment The standard errors of the treatment group means in change height are too small to be visible on the plot. Beclomethasone ex-valve dose (4 µg) is equal to 336 µg ex-activator dose. 31 Becker et al. Ann Allergy Asthma Immunol 26;96: 8-87 Linear Growth And Bone Maturation Are Unaffected By 1 Year Of Therapy With Inhaled Flunisolide Hydrofluoroalkane In Prepubescent Children With Mild Persistent Asthma: A Randomized, Double-blind, Placebo-controlled Trial Prepubescent (Tanner Stage 1) children (n=218) with mild persistent asthma ages 4 to 1 years were evaluated. After a 2 week run in, subjects were randomized (1:1) to 2 puffs flunisolide HFA twice daily (85 g/puff) or placebo for 52 weeks. Height was assessed by stadiometry. Ann Allergy Asthma Immunol. 211;17: Assessment of the Long-term Safety of Inhaled Ciclesonide on Growth in Children with Asthma (Skoner DP, et al. Pediatrics 28; Jan;121(1):e1-14.) Previous steroidal therapy Discontinued* Randomization Final double-blind treatment visit Follow-up visit Ciclesonide MDI 4 µg qd AM Ciclesonide MDI 16 µg qd AM Placebo qd AM Visit Month Screening baseline 6 months Qualifying period (Visits 3-4) Double-blind treatment 12 months Follow-up 2 months * Albuterol taken as needed for asthma control. If asthma symptoms were unresponsive to non-steroidal medications, subjects were permitted inhaled or intranasal corticosteroid treatments. No corticosteroids (oral, intranasal or inhaled) other than study medication were permitted during the double-blind treatment period. The following asthma medications were permitted as needed during the baseline and double-blind treatment periods: inhaled short-acting β-agonists, leukotriene receptor antagonists, cromones and xanthine derivatives. 33 During the qualification phase, subjects received single-blind placebo in order to practice proper dosing technique (MDI=metered-dose inhaler; qd=once-daily; AM=in the morning). 11

12 Compliance Total number of puffs recorded in daily diary Definition of compliance on a given day: study medication taken per protocol (one puff in AM) Definition of compliance between study visits: 75% overall compliance and no consecutive missed doses of >5 days Compliance method % of subjects with >85% compliance Placebo (n=221) CIC 4 µg/day (n=221) CIC 16 µg/day (n=219) Diary Canister weight Ciclesonide Growth Results: No Detectable Impact on Growth Mean Change (± SE) in Stadiometer Height (cm) From Baseline Month of Study Skoner DP, et al. Pediatrics. 28;121(1):e Placebo (n=221) CIC 4 µg/day* (n=221) CIC 16 µg/day (n=219) Start of double-blind treatment period End of double-blind treatment period Run-in Period Double-blind Treatment Period Follow-up Period FDA: Conclusions cannot be drawn from this study because compliance could not be assured 35 What Might Have Enabled Conclusions To Be Drawn From This Study? A growth effect from one of the doses An HPA axis effect from either dose (none detected) Webcam proof of adherence (not done) Detection of ciclesonide in blood (not done) An effect on FEV1 (mild asthma, normal at baseline, montelukast allowed, primary growth [not efficacy] study) 36 12

13 What More Do We Need to Know About Growth Effects of ICS? Well-designed, long-term studies and impact on final adult height Intermittent vs. continuous therapy Genetic and environmental influences at risk population Dose-response studies Comparative studies Combined intranasal and inhaled delivery Chronotherapy (optimal timing of a oncedaily ICS dose) 37 The START Study: Growth in the Budesonide Group Minus That in the Placebo Group ALL 2 mcg 4 mcg YEAR 1 YEAR 2 YEAR YRS. < 11 YRS. 11 YRS. < 11 YEARS P value <.1 <.1.3 <.1 <.1.5 Pauwels et al. Lancet. 23;361: Effects of Long-term Inhaled Budesonide on Adult Height in Children With Asthma 19 Girls Boys Measured Adult Height (cm) Target Adult Height (cm) 2 Agertoft & Pedersen. N Engl J Med. 2;343:

14 Overview of CAMP and CAMP Continuation Studies (CAMPCS) 1,41 children aged 5 to 12 years with mild to moderate asthma, 4-6 yr. treatment phase Budesonide 2 mcg twice daily (n=311) Nedocromil sodium 8 mg twice daily (n=312) Placebo (n=418) CAMPCS: additional 4.8 yr. observation phase (n=941) 1. The Childhood Asthma Program Research Group. N Engl J Med. 2;343: Tantisira KG et al. Am J Respir Crit Care Med. 28;178: Strunk RC et al. J Pediatr. 29;154: Further Analysis of CAMP Growth Velocity Varies with Developmental Stage Height velocity for boys 2 19 years of age Age at entry 97 Centiles for in CAMP boys maturing 5 14 at average time and 3 centiles at peak height 12 velocity for Early (+2SD) maturers 11 Late ( 2SD) maturers 1 9 Height 8 velocity 7 (cm/yr) 6 Maximum age 5 at completion 4 in CAMP Age (year) SD=standard deviation Adapted from Tanner JM, Davies PSW J Pediatr 1985;17(3): CAMP Study Growth Velocity with Budesonide Lower in Year 1, Similar to Placebo in Years Budesonide 2 µg twice daily (n=311) Nedocromil 8 mg twice daily (n=312) Placebo (n=418) Standing height velocity (cm/yr) Time (year) All groups had similar growth velocity by the end of the treatment period. Adapted from The Childhood Asthma Management Program Research Group N Engl J Med 2;343(15): ; Allen DB et al J Allergy Clin Immunol 23;112(3):S1 S4. 14

15 Selected Patient Characteristics at CAMPCS Completion 1 Treatment Group in CAMP Budesonide n=284 Nedocromil n=277 Placebo n=38 Age and follow-up Age at end of trial, y Age at end of posttrial, y (CAMPCS) Duration of posttrial, y (CAMPCS) % time on ICS during trial 96.8 a % time on ICS posttrial (CAMPCS) Pre-BD FEV 1 % predicted at challenge b Post-BD FEV 1 % predicted at challenge b a Statistically significant difference in the CAMP budesonide treatment group vs placebo (P<.1). b Time-dependent variables measured across all challenges. All other variables measured at baseline. 1. Adapted from Strunk RC et al. J Pediatr. 29;154: Patient Physical Growth at CAMPCS Completion 1 Physical Growth at CAMPCS Completion Budesonide n=284 Treatment Group in CAMP Nedocromil n=277 Placebo n=38 Females, n Height, cm a Females, n Bone density, g/cm Males, n Height, cm Males, n Bone density, g/cm a Statistically significant difference in the CAMP budesonide treatment group vs placebo (P=.1). 1. Adapted from Strunk RC et al. J Pediatr. 29;154: CAMP Study: 4.8 Year Follow-up Decreased mean height in the BUD group relative to the placebo group at the end of the trial (1.1 cm; P=.5) remained statistically significant (.9 cm; P=.1) Was more pronounced in girls (1.7 cm; P=.1) than in boys (.3 cm; P=.49) Strunk RC, et al. J Pediatr. 29;154:

16 DAILY VERSUS AS-NEEDED INHALED CORTICOSTEROID FOR MILD PERSISTENT ASTHMA (THE HELSINKI EARLY INTERVENTION CHILDHOOD ASTHMA STUDY) (176 children aged 5-1 years with newly detected asthma, FEV % predicted) Arch Dis Child 28;93: Budesonide 4 μg bid for 2 weeks for exacerbations PRN Use Of Beclomethasone Dipropionate (HFA) As Rescue Treatment For Children With Mild Persistent Asthma (TREXA): A Randomised, Doubleblind, Placebo-controlled Trial (Mild Asthma, 5-18 Years, Martinez FD, et al. Lancet 211; 377: 65 57) Combined: BDP-HFA 4 μg BID with BDP + albuterol as rescue; Daily: BDP-HFA 4 μg BID with placebo + albuterol as rescue; Rescue: Placebo BID with BDP + albuterol as rescue; Placebo: Placebo BID with placebo + albuterol as rescue. Rescue beclomethasone treatment was two puffs (8 μg) of BDP or placebo for each two puffs of albuterol (18 μg) needed for symptom relief. Effects of ICS on Childhood Growth Using Stadiometry (Mild disease, 1 yr, DB-PC, various ages) * LOW DOSE BDP CFC=Becker et al, Annals Allergy Asthma Immunol. 26;96:8-87 BDP HFA=Martinez et al, Lancet 211; 377: (not primary growth study) BUD=CAMP study, NEJM, 2;343: (not primary growth study) TAA=Skoner et al, J Allergy Clin Immunol. 1999:13:S61 (real-world, open, moderate, vs non-steroid) CIC=Skoner et al, Pediatrics. 28;121:e1-14 (FDA: Conclusions cannot be drawn from this study because compliance could not be assured) FP=Guilbert et al, NEJM. 26;354: (not primary growth study) MF=Skoner et al, J Asthma. 48: ,

17 Impact of Intranasal Corticosteroids on Childhood Growth Don t know much about combined intranasal and inhaled delivery in child with allergic rhinitis and Mean change in height from baseline (cm) *P<.5 **P<.1 Placebo Placebo Mometasone furoate 1 µg QD Beclomethasone 168 µg/d * 7 ** 6 asthma! 5 ** ** 4 ** 3 * * 2 1 * * Month Schenkel E, Skoner D, et al. Pediatrics. 2;15:1-7. Skoner D, et al. Pediatrics. 2;15:1-7. Month Summary of the ICS Growth Effect in Children Real, reproducible, small and dose- and device-dependent. Can be seen at low doses. Small variations in magnitude across the various ICS s and individual children. Effect on final adult height unknown. FDA: This is a Class Effect. The potential growth effects of prolonged treatment with ICS should be weighed against clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. Use safest steroid available at lowest effective dose, and address steroid phobia proactively with parent to minimize effect on adherence. Risk is manageable and does not discourage use of ICS in appropriately selected children. BALANCING SAFETY AND EFFICACY OF ICS (Skoner DP. Pediatrics 22: 19(2): ) * LTRA, LABA, THEOPHYLLINE Pick safe(est) drug Use lowest effective dose Optimize steroid-sparing strategies (environment, vaccines, concomitant disease, add-on* therapy) Consider first-line trial of ICS alternative (LTRA) in some of the mildest patients Consider add-on* to ICS (vs. double/triple ICS dose) when control is inadequate, particularly for exercise control Consider add-on* therapy when ICS dose is high Monitor: Growth in all children Other SSEs at high doses (BDP 1,6 mcg/d in adult, 8 mcg/d in child) 17

18 Do Inhaled Corticosteroids Really Affect Growth? Yes Debatable whether or not effect is significant Debatable whether or not we actually see this in practice because such a small effect size is difficult to detect and because of low adherence rates Statistically : Yes Clinically, It Depends: Yes, if: 1)No systemic bioavailability is desired; 2)Child has a growth disorder; 3)Effect is cumulative and adult height is affected; 4)Parents believe height is linked to future success; 5)Parents want child to play in NBA. No: For most children who just want to enjoy activity without asthma symptoms. Which one might have used steroids?

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