Clinical efficacy and safety of anticholinergic therapies in pediatric patients

Figures & data

Figure 1 Stepwise approach for the treatment of asthma in (A) patients aged 6 years and over and (B) children under 6 years of age, as recommended in the GINA Report.

Notes: ^*Not for children <12 years; ^**for children 6–11 years, the preferred Step 3 treatment is medium-dose ICS; ^#low-dose ICS/formoterol is the reliever medication for patients prescribed low-dose budesonide/formoterol maintenance and reliever therapy; ^{^}tiotropium by mist inhaler is an add-on treatment for patients with a history of exacerbations; it is not indicated in children <12 years. Copyright ©2018. Reproduced from Global Initiative for Asthma. GINA Report, Global strategy for asthma management and prevention.¹³
Abbreviations: FEV₁, forced expiratory volume in 1 second; GINA, Global Initiative for Asthma; HDM, house dust mite; ICS, inhaled corticosteroids; IgE, immunoglobulin E; Inc., increase; intermitt, intermittent; LABA, long-acting β₂-agonist; LTRA, leukotriene receptor antagonist; med, medium dose; OCS, oral corticosteroids; SABA, short-acting β₂-agonist; SLIT, sublingual immunotherapy; theoph, theophylline.

Table 1 Key results of Phase III studies with 2.5 and 5 µg tiotropium in children and adolescents with asthma

Study	Patients (asthma severity and age)	Baseline therapy	Treatment duration, weeks	N	Primary and key secondary endpoint	Difference from placebo
						2.5 µg tiotropium	5 µg tiotropium
RubaTinA-asthma^®^Citation37	Moderate symptomatic 12- to 17-year-olds	At least ICS	48	398	Peak FEV1,a Week 24	134 (34, 234) (P<0.01)	174 (76, 272) (P<0.001)
					Trough FEV1, Week 24	NS	117 (10, 223) (P=0.03)
PensieTinA-asthma^®^Citation41	Severe symptomatic 12- to 17-year-olds	ICS + $1 controller	12	392	Peak FEV1, Week 12	111 (2, 220) (P=0.046)	NS
					Trough FEV1, Week 12	NS	NS
CanoTinA- asthma^®^Citation38,Citation42	Moderate symptomatic 6- to 11-year-olds	At least ICS	48	401	Peak FEV1, Week 24	170 (108, 231) (P<0.001)	164 (103, 225) (P<0.001)
					Trough FEV1, Week 24	116 (46, 186) (P=0.001)	118 (48, 188) (P=0.001)
VivaTinA- asthma^®^Citation39	Severe symptomatic 6- to 11-year-olds	At least ICS + $1 controller	12	401	Peak FEV1, Week 12	35 (-28, 99) (P=0.27)	139 (75, 203) (P<0.001)
					Trough FEV1, Week 12	18 (-48, 85) (P=0.59)	87 (19, 154) (P=0.01)
NinoTinA- asthma^®^Citation40, ^Citation43	Symptomatic 1- to 5-year-olds	At least ICS	12	101	AE frequency	−17.9%	−15.4%
					PACD, weekly frequency (%) of worsening asthma symptoms at Week 12, adjusted mean (CI)	−0.658 (−2.413, −1.098) (P=0.46)	−1.063 (−2.897, 0.772) (P=0.25)
					Risk of asthma exacerbations (reported as AEs)	Reduced risk (HR 0.46; 95% CI: 0.22, 0.98) (P=0.044)	Reduced risk (HR 0.42; 95% CI: 0.19, 0.94) (P=0.035)

Note:

a FEV₁ values are mean (CI) mL.

Abbreviations: AE, adverse event; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; HR, hazard ratio; ICS, inhaled corticosteroids; NS, not significant; PACD, pediatric asthma caregiver diary.

Table 2 Pharmacokinetics of tiotropium in asthma patients across age groups

Age group	Fe0–3,ss (%)	Fe0–24,ss (%)	C0.083,ss (pg/mL)
1–5 years^Citation40,Citation43	1.08 (N=12, CV=66%)	NA	NA
6–11 years^Citation35	2.88 (N=11, CV=48%)	10.3 (N=11, CV=63%)	2.42 (N=6, CV=49%)
12–18 years^Citation34	2.42 (N=10, CV=80%)	14.3 (N=12, CV=70%)	2.19 (N=3, CV=88%)
$18 years	2.61 (N=49, CV=111%)	12.7 (N=102, CV=84%)	2.38 (N=89, CV=54%)

Note: Data from US Food and Drug Administration. Tiotropium bromide clinical pharmacology review. 2016. Available from: https://www.fda.gov/downloads/drugs/developmentapprovalprocess/developmentresources/ucm549091.pdf.54

Abbreviations: C_0.083,ss, tiotropium plasma concentration at 5 minutes post-dose at steady state; CV, coefficient of variation; Fe_0–3,ss, urine excretion fraction of unchanged tiotropium within 3 hours post-dose at steady state; Fe_0–24,ss, urine excretion fraction of unchanged tiotropium within 24 hours post-dose at steady state; NA, not applicable.

Table 3 Asthma clinical trials in adults with LAMAs other than tiotropium

Study drugs	Patients	Treatment duration	Baseline therapy	N (enrolled)	Study findings
Umeclidinium bromide 31.25 and 62.5 µg^Citation57	Symptomatic inadequately controlled	Variable 24–52 weeks	ICS/LABA	2,250	Trial ongoing
Umeclidinium bromide 15.6, 31.25, 62.5, 125 and 250 µg^Citation58	Symptomatic	14 weeks	Non-ICS controller	350	No significant dose response
Umeclidinium bromide 15.6, 31.25, 62.5, 125 and 250 µg^Citation58,Citation59	Symptomatic	14 weeks	At least ICS/LABA	421	Combination treatment significantly increased trough FEV1 compared with ICS alone
Glycopyrronium MDI 1.9, 3.6, 7.2, 14.4 and 28.8 µg^Citation60	Symptomatic	14 days	ICS or non-ICS maintenance	249	Study complete Awaiting publication
Glycopyrrolate bromide 12.5 µg^Citation61	Uncontrolled	6 weeks	ICS	98	Study complete Awaiting publication
Glycopyrronium 50 µg^Citation62	Symptomatic	96 hours	NS	13	Tiotropium provided statistically superior bronchoprotection compared with glycopyrronium
Glycopyrronium 50 µg^Citation63	Symptomatic mild-to-moderate	24–48 hours	NS	30	Study complete awaiting publication

Note: Copyright ©2017. The Korean Academy of Asthma, Allergy and Clinical Immunology. Reproduced from Aalbers R, Park HS. Positioning of long-acting muscarinic antagonists in the management of asthma. Allergy Asthma Immunol Res. 2017;9(5):386–393.²⁷

Abbreviations: FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; MDI, metered-dose inhaler; NS, not specified.

Table 4 Traditional and alternative clinical trial endpoints

Endpoint	Definition	Advantages	Disadvantages
Traditional endpoints
FEV1	Forced expiratory volume in 1 second	Robust, repeatable, standardized and simple measurement^Citation47	Does not indicate disease processes such as hyperinflation or airway plugging;^Citation69 does not correlate with severity;^Citation47,Citation68,Citation70 difficult to perform in younger children^Citation71
PEF	Peak expiratory flow	Portable PEF meters allow self-monitoring at home^Citation73	Does not correlate with severity;^Citation72 many patients do not use PEF meters correctly^Citation73
Frequency of asthma exacerbations	“Worsening of asthma requiring the use of systemic corticosteroids to prevent serious outcomes”^Citation78	Commonly used endpoint;^Citation67 prevention of exacerbations is an important aspect of asthma control^Citation75,Citation76	Definition is subjective, leading to variations between studies and investigators;^Citation74,Citation77 ethical considerations relating to use of exacerbations in placebo-controlled pediatric trials^Citation79
Questionnaires: ACQ, ACT	Asthma Control Questionnaire, Asthma Control Test	Commonly used to assess asthma control;^Citation80 allow quantification of composite scores for outcome measures^Citation80	Difficult for children to complete^Citation74,Citation80 (although an interviewer-administered ACQ has been used in some pediatric studies^Citation39,Citation42); caregiver assistance can alter outcome;^Citation74,Citation80 episodic nature of pediatric asthma confounds use of questionnaires^Citation81
cACT	Childhood ACT (recommended for baseline characterization of children aged 4–11 years^Citation67)	Completed by children and caregivers; recommended by the asthma outcomes workshop as a core baseline and observational outcome, and as a supplemental outcome for efficacy^Citation67	Episodic nature of pediatric asthma confounds use of questionnaires^Citation81
TRACK	Test for respiratory and asthma control in kids	In development^Citation82	Difficulties associated with language and capabilities of the respondent^Citation74,Citation80
Alternative endpoints
FEF25–75	Forced expiratory flow at 25%–75% of forced vital capacity	Sensitive measure of small airway obstruction;^Citation85 linked with acute wheezing, response to bronchodilators and ventilation defects;^Citation85 predictive of asthma severity^Citation85
IOS	Impulse oscillometry (mechanical measurement of the airway performed by non-invasive superimposing of pressure fluctuations on the airway during spontaneous breathing^Citation87)	Suitable for patients who cannot perform spirometry;^Citation87 complements information gained from FEV1 measurement;^Citation88 offers insights into alterations in airway mechanics in response to therapy^Citation88	Cost
Biomarkers	Naturally occurring characteristic, molecule or gene that identifies a disease or a physiological/pathological process	Objective measure of asthma control	Research is lacking in children;^Citation89 unlikely to be used as a broad measure of asthma control across ages and phenotypes

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