Administering a short-acting beta agonist (SABA) alone is strongly associated with higher risks of asthmatic exacerbations in children. Whether children with uncontrolled asthma using daily inhaled corticosteroids (ICS) or ICS in combination with a long-acting beta agonist (LABA) benefit from SABA as needed or ICS/LABA as needed is not fully clear. Recent studies examined the effects of treatment with maintenance and reliever therapy (MART) on the risk of asthmatic exacerbations in children. MART is an asthma management regimen that uses a single, combined inhaler for both daily maintenance and as-needed symptom relief, instead of requiring separate maintenance (control with inhaled corticosteroids) and reliever (bronchodilator) inhalers. MART ensures that any increase in long-acting reliever use in response to asthma symptoms is matched by an increase in ICS, ensuring that inflammation is targeted when symptoms increase. From a patient perspective, use of one inhaler may eliminate the confusion of using different devices for rescue and control. However, the current Dutch guideline “asthma in children’ does not yet discuss MART treatment whereas the Global Initiative for Asthma (GINA) report (2024) and BTS/NICE/SIGN Joint Guideline (2024) already include MART treatment as preferred track or option from treatment step 3 onwards (eg. GINA) in children of age 6 years and older.

1. Risk of Bias: very serious. Inadequate concealment of allocation during randomization process, resulting in potential for selection bias, Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, due to [reason], Imprecision: serious. One study included; Publication bias: serious. Mostly commercially funded studies;
2. Risk of Bias: very serious. Inadequate concealment of allocation during randomization process, resulting in potential for selection bias, Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, due to [reason], Imprecision: very serious. One study included, confidence interval not reported; Publication bias: serious. Mostly commercially funded studies;
3. Risk of Bias: very serious. Inadequate concealment of allocation during randomization process, resulting in potential for selection bias, Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, due to [reason], Imprecision: very serious. One study included, confidence interval not reported; Inconsistency: serious. The direction of the effect is not consistent between the three treatment arms included in the studie. Publication bias: serious. Mostly commercially funded studies;

PICO

Population: adolescents (>12 years) with persistent asthma

Intervention: MART

Comparator: Placebo or other treatment

*Data cited from the systematic review of Jorup (2018)

1. Risk of Bias: very serious. Inadequate concealment of allocation during randomization process, resulting in potential for selection bias, Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, due to [reason], Inadequate sequence generation/ generation of comparable groups, resulting in potential for selection bias; Imprecision: serious. Wide confidence intervals; Publication bias: serious. Mostly commercially funded studies;
2. Risk of Bias: serious. Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, Inadequate concealment of allocation during randomization process, resulting in potential for selection bias, Inadequate sequence generation/ generation of comparable groups, resulting in potential for selection bias; Imprecision: serious. Wide confidence intervals; Publication bias: serious. Mostly commercially funded studies;
3. Risk of Bias: serious. Inadequate concealment of allocation during randomization process, resulting in potential for selection bias, Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, Incomplete data and/or large loss to follow up; Inconsistency: serious. The confidence interval of some of the studies do not overlap with those of most included studies/ the point estimate of some of the included studies., The direction of the effect is not consistent between the included studies; Imprecision: serious. Wide confidence intervals; Publication bias: serious. Mostly commercially funded studies;
4. Risk of Bias: serious. Inadequate concealment of allocation during randomization process, resulting in potential for selection bias, Incomplete data and/or large loss to follow up; Imprecision: serious. Wide confidence intervals; Publication bias: serious. Mostly commercially funded studies;
5. Risk of Bias: serious. Inadequate concealment of allocation during randomization process, resulting in potential for selection bias, Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, Incomplete data and/or large loss to follow up; Inconsistency: serious. The direction of the effect is not consistent between the included studies; Imprecision: serious. Wide confidence intervals; Publication bias: serious. Mostly commercially funded studies;
6. Imprecision: serious. Low number of patients, Only data from one study; Publication bias: serious. Mostly commercially funded studies;
7. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, Inadequate concealment of allocation during randomization process, resulting in potential for selection bias, Incomplete data and/or large loss to follow up; Inconsistency: serious. The direction of the effect is not consistent between the included studies; Imprecision: serious. Wide confidence intervals; Publication bias: serious. Mostly commercially funded studies;
8. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, Inadequate concealment of allocation during randomization process, resulting in potential for selection bias; Imprecision: serious. Wide confidence intervals; Publication bias: serious. Mostly commercially funded studies;

Description of studies
Six randomized controlled trials in adolescents aged 12 to 17 years, which are subtracted from one post-hoc analysis (Jorup, 2018), and one randomized controlled trial in pediatrics aged 4 to 11 years (Bisgaard, 2006) reported on the relevant outcome measures and were included in the analysis of the literature.

Pediatric patients: 4-11 years
Bisgaard (2006) is included in our analysis, which performed a prospectively planned sub analysis within the main study of Byrne (2005). Data was obtained from the 12-month randomized double blind and parallel group trial at 41 centers in 12 countries. A total of 341 pediatric patients with an asthma history >= 6 months, ICS at a constant does >= 3 months plus terbutaline as needed, and at least one clinically important asthma exacerbation in the 12 months were included and allocated to fixed-fourfold higher dose BUD plus terbutaline as needed (n=106), fixed combination of BUD/FORM plus terbutaline as needed (n=117) or intervention SMART BUD/FORM maintenance and as needed medication (n=118).

Adolescents: 12-17 years
Jorup, 2018
Jorup (2018) is a post hoc study which collected data through the AstraZeneca database, from six different trials. Studies included were randomized, double blind trials comparing BUD/FORM MART versus active comparator in 12 to 18 years aged patients with persistent asthma (>6 months in duration) according to the ERS/ATS definition. For all studies, patients were enrolled if 1) history of >1 asthma exacerbations prior to study entry 2) used ICS for at least 3 months at constant dose prior to study entry 3) FEV₁ in 1 s is a certain percentage (ranging between 50 and 100%) of predicted normal 4) >12% reversibility in increase from baseline FEV₁ 15 minutes after inhalation of terbutaline.

These studies include the following trials:

1. STEP (Scicchitano, 2004)
   A randomized, double-blind, double-dummy, active controlled study with a parallel group design conducted at 211 centers in 18 countries (Argentina, Australia, Canada, Czech Republic, Finland, France, Germany, Hungary, Israel, Italy, Mexico, The Netherlands, New Zealand, Norway, Portugal, Russia, South Africa and Turkey). A total of 1890 patients aged 12 to 80 years of age were included.
2. STAY (O’Byrne, 2005)
   A randomized double blind and parallel group trial at 246 centers in 22 countries (not mentioned). A total of (number) patients aged 4 to 80 years were included. Besides the overall inclusion criteria, patients had to have used 12 or more inhalations of as-needed medication for adults and eight or more in children during the last 10 days of run-in. Analysis was done on total group of included patients, however data analysis for the group patients 11 to 17 years of age were performed by Jorup (2018) and analysis for the group patients 4 to 11 years of age were performed by Bisgaard (2006).
3. SMILE (Rabe, 2006)
   A randomized double blind and parallel group trial at 289 centers in 20 countries (mostly in Belgium, Czech Republic, Germany, Hungary, The Netherlands and South Africa). A total of 3394 patients aged 12 years or older were included.
4. STEAM (Rabe, 2006)
   A double blind, randomized, parallel group, active non-controlled study at 77 centers in 9 countries (Argentina, Brazil, China, Denmark, Indonesia, Norway, the Philippines, Spain and Sweden). A total of 697 patients aged 12 to 80 years (but also including patients 11 years of age) were included.
5. COMPASS (Kuna, 2007)
   A randomized, double-blind, double dummy-parallel group conducted at 235 centers in 16 countries (not mentioned). A total of 3172 patients aged >12 years were included.
6. AHEAD (Bousquet, 2007)
   A randomized, double blind, parallel group multinational study conducted in 184 centers in 17 countries. A total of 2309 patients aged >12 years were included, however for only 1056 in the intervention group (budesonide/formoterol) and 1040 patients in the control group, data was available due to discontinuations and loss to follow up.

A separate study search was conducted in PubMed and Cochrane to identify any non-AstraZeneca trials that met the inclusion criteria. However, there were no additional studies identified. Jorup (2018) conducted statistical analysis in subgroup per study (12-17 years). Two analyses were performed: within subgroup analysis (per study) and a meta-analysis of all individual patients’ data (all studies). For the within subgroup analysis, no further stratification analysis was performed since this the number of patients was too low. Analysis of adults aged>18 was done, but the effects could not be compared as the subset of patients was too low. Due to between-studies variations a variation test was conducted, however studies were not GRADED on method. AstraZeneca (sponsor of the studies) developed, funded and performed the analysis (plan) for this study.
Hence, we used the study results of Jorup (2018) since these results could not be abstracted from the six RCT’s. We described the six included RCT’s in Table 2 and outcome measures were GRADED.

Important study characteristics and results are summarized in table 2 per included trial. The assessment of the risk of bias is summarized in the risk of bias tables (under the tab ‘Evidence tabellen’).

Results

Asthma exacerbation frequency:

All exacerbation frequency

Bisgaard (2006) reported the number of pediatrics with all asthma excacerbations, defined as a detoriation in asthma resulting in hospitaltizaiton/emergency department (ED) treatment; treatment with steroids; increase in use of ICS or other additional treatment; morning peak expiratory flow (PEF) <70% of baseline in 2 days. Jorup (2018) did not report on all excacerbations in adolescents.
 

• Total of all exacerbations (including PEF) in 12 months – pediatrics 

Bisgaard (2006) reported that 17 out of 118 patients (14%) in the Bud/Form MART group experienced exacerbations compared to 28 out of 106 (26%) in the fixed dose Budesonide group and 44 out of 117 (38%) in the fixed-dose combination group. Between group differences was reported with a hazard ratio of Bud/Form MART group versus fixed combination dose of 0.34 (95%CI: 0.19 to 0.60) and a hazard ratio of Bud/Form MART group versus fixed dose Budesonide group of 0.49 (95%CI: 0.27 to 0.90).

Severe excacerbation frequency

Bisgaard (2006) reported the number of patients with severe exacerbations in 12 months for pediatric patients (4-11 years). Jorup (2018) reported in six studies total severe exacerbations per total patient years for adolescents. Bisgaard (2006) reported exacerbations requiring medical intervention such as hospitalization/ED treatment, treatment with oral steroids, an increase in ICS via a separate inhaler.
In the study of Jorup (2018), severe exacerbation was defined as the need for OCS (for 3 or more days) and/or hospitalization/ER care. Peak expiratory flow (PEF) was excluded from analysis.

• Total severe exacerbations in 12 months – pediatrics 

Bisgaard (2006) reported the number of patients with exacerbations requiring medical intervention. In the Bud/Form MART group 10 out of 118 patients (8%) had experienced exacerbations requiring medical interventions compared to 21 out of 106 (20%) in the fixed dose Budesonide group and 36 out of 117 (31%) in the fixed-dose combination group. Bisgraad reports a reduction in risk by MART of 75% (calculations and 95% CI not reported) versus fixed-dose combinations and 60% (calculations and 95%CI not reported) versus fixed dose budesonide 

• Total severe exacerbations per patient years in 6 months - adolescents

Three included studies reported on the number of severe exacerbations (Table 3). The study of Kuna (2007) included two control arms.

Table 3. Total severe exacerbations/total patient-years (n/n) in 6 months^*

Notes: *We reported ratios and CI from Jorup 2018. Different doses of medication are used in the studies. Estimates obtained from Poisson regression models with treatment as a factor, log time as an offset variable and adjusted for overdispersion.

The pooled rate ratio for total severe exacerbations in 6 months was 0.56 (95%CI 0.45 to 0.56) (Figure 1).

Figure 1. Forrest plot of pooled rate ratio of total severe exacerbations per patient years in 6 months
*Data from Jorup (2018) was used as input for RevMen. Confidence intervals differ slightly from the data as published in Jorup (2018).

• Total severe exacerbations per patient years in 12 months – adolescents

Three included studies reported on the number of severe exacerbations in 12 months (Table 4). The study of Rabe (2006) from the SMILE trial and O’Byrne (2005) included two control arms.

Table 4. Total severe exacerbations/total patient-years (n/n) in 12 months*

Notes:*We reported ratios and CI from Jorup 2018. Different doses of medication are used in the studies.

The pooled rate ratio for total severe exacerbations in 12 months was 0.38 (95%CI 0.20 to 0.71)  (Figure 2).

Figure 2. Forrest plot of pooled rate ratio of total severe exacerbations per patient years in 12 months
*Data from Jorup (2018) was used as input for RevMen. Confidence interval differ slightly from the data as published in Jorup (2018).

Changes in asthma symptoms
Asthma symptom score

Bisgaard (2006) reported the number of changes in asthma symptom score in 12 months for pediatric patients (4-11 years). Jorup (2018) included six studies that reported changes in asthma symptom score in 6 and 12 months for adolescents.

• Asthma symptom score in 12 months – pediatrics 

Bisgaard (2006) reported only ‘raw’ mean treatment values on asthma symptom score, and no mean differences in asthma symptom score were reported. Calculated mean changes in asthma symptom score resulted in mean differences in a score of -0.50 in the intervention group (Bud/Form MART), compared to the means difference in score of -0.56 in the fixed-Budesonide group and mean difference of score of -0.39 in the fixed dose group. Mean differences between treatments were 0.06 in the intervention group (Bud/Form Mart) versus fixed budesonide and -0.11 between Bud/Form Mart and the fixed-dose combination group.

• Asthma symptom score in 6 months - adolescents

Three included studies reported on the mean asthma symptom score (Table 5). The study of Kuna (2007) included two control arms.

Table 5. Patients with data n/mean (range) in 6 months*

Notes: *We reported ratios and CI from Jorup 2018. Different doses of medication are used in the studies. Jorup performed an ANCOVA with changes between run-in period mean and treatment period mean as the outcome variable, treatment as a factor and adjusting for the run-in period mean.

• Asthma symptom score in 12 months - adolescents

Three included studies reported on the change of asthma score in 12 months (Table 6). The study of Rabe (2006) from the SMILE trial and O’Byrne (2005) included two control arms.

Table 6. Total exacerbations/total patient-years (n/n) in 12 months*

Notes: *We reported ratios and CI from Jorup 2018. Different doses of medication are used in the studies.

Jorup performed an ANCOVA with changes between run-in period mean and treatment period mean as the outcome variable, treatment as a factor and adjusting for the run-in period mean.

Asthma control
5-item asthma control questionnaire (ACQ-5) score
Bisgaard (2006) did not report ACQ scores in pediatric patients. Jorup (2018) included three studies reported changes in ACQ score in 6 (n=2) and 12 (n=1) months for adolescents.

• ACQ-5 score in 6 months – adolescents

Two included studies reported on the ACQ score (Table 7). The study of Kuna (2007) included two control arms.

Table 7. Patients with data n/mean (range) in 6 months*

Notes: *We reported ratios and CI from Jorup 2018. Different doses of medication are used in the studies. Jorup performed an ANCOVA with changes between run-in period mean and treatment period mean as the outcome variable, treatment as a factor and adjusting for the run-in period mean.

• ACQ-5 score in 12 months - adolescents

One included studies reported on the ACQ-5 score in 12 months (Table 8). The study of Rabe (2006) from the SMILE trial included two control arms.

Table 8. Patients with data n/mean (range) in 12 months*

Notes: *We reported ratios and CI from Jorup 2018. Different doses of medication are used in the studies. Jorup performed an ANCOVA with changes between run-in period mean and treatment period mean as the outcome variable, treatment as a factor and adjusting for the run-in period mean.

Disease specific quality of life
No included studies reported outcomes on quality of life.

Corticosteroid dose reduction
No included studies reported outcomes on corticosteroid dose reduction.
 

Improvement in lung function

Forced expiratory volume in 1s (FEV₁)

Bisgaard (2006) reported the mean change in FEV₁ in 12 months for pediatric patients (4-11 years). Jorup (2018) included six studies that reported changes FEV₁ in 6 and 12 months for adolescents.

• FEV1 in 12 months – pediatrics 

Bisgaard (2006) reported only ‘raw’ mean treatment values on FEV₁ score, and no mean differences in FEV1 were reported. Calculated mean FEV₁ changes resulted in mean differences of 0.26 FEV₁L in both the intervention group (Bud/Form MART) as well as the fixed-dose Budesonide group versus 0.1 FEV₁L  in the fixed dose combination group. Mean differences between treatments were 0.16 FEV1₁L in the intervention group (Bud/Form Mart) and there were no differences between Bud/Form MART and the fixed-dose Budesonide group.

• FEV1 in 6 months – adolescents

Three included studies reported on the number of severe exacerbations (Table 9). The study of Kuna (2007) included two control arms.

Table 9. Patients with data n/mean (range) in 7 months*

Notes: *We reported mean differences and CI from Jorup 2018. Different doses of medication are used in the studies. Estimates obtained from Poisson regression models with treatment as a factor, log time as an offset variable and adjusted for overdispersion.

• FEV1 in 12 months - adolescents

Three included studies reported on the change of FEV1 in 12 months (Table 10). The study of Rabe (2006) from the SMILE trial and O’Byrne (2005) included two control arms.

Table 10. Patients with data n/mean (range) in 12 months*

Notes: *We reported mean differences and CI from Jorup 2018. Different doses of medication are used in the studies. Jorup performed an ANCOVA with changes between run-in period mean and treatment period mean as the outcome variable, treatment as a factor and adjusting for the run-in period mean.

Adverse events

All adverse events

Bisgaard (2006) did not report on all adverse events. Jorup (2018) included six studies that reported all adverse events ongoing during randomized treatment and follow up period if applicable.

• All adverse events in 12 months – pediatrics 

Bisgaard (2006) did not report on all adverse events.

• All adverse events in 6 to 12 months – adolescents 

All studies included in Jorup (2018) reported on the rate of any adverse event during randomization and follow up period. Results are not reported per follow-up period since Jorup (2018) reported Bud/FORM MART versus treatment comparison pools (see Table 11)

Table 11. All adverse events in BUD/FORM MART group versus treatment comparison pools: all adverse events*/number of patients (%).

Notes: *Patients with multiple adverse events in the same category were counted as one whereas patients with adverse events in multiple categories were counted in each of those categories.

Serious adverse events
Bisgaard (2006) did report on the rate of serious adverse events Jorup (2018) included six studies that reported all serious adverse events ongoing during randomized treatment and follow up period if applicable.

• Serious adverse events in 12 months – pediatrics 

Bisgaard (2006) reported on the rate of serious adverse events. Calculated risk ratio in the intervention group (Bud/Form MART) versus the fixed-dose combination group is 0.12 95%CI: 0.03 to 0.53) and calculated risk ratio of the same intervention group versus fixed budesonide group is 0.36 (95%CI: 0.07 to 1.81).

• Serious  adverse events in 6 to 12 months – adolescents 

All studies included in Jorup (2018) reported on the rate of serious adverse events during randomization and follow up period. Results are not reported per follow-up period since Jorup (2018) reported Bud/FORM MART versus treatment comparison pools (see Table 12)

Table 12. Serious adverse events in BUD/FORM MART group versus treatment comparison pools: serious adverse events*/number of patients (%).

Notes: *Patients with multiple adverse events in the same category were counted as one whereas patients with adverse events in multiple categories were counted in each of those categories.

A systematic review of the literature was performed to answer the following question(s):

What are the favourable and unfavourable effects of MART, compared with placebo or care as usual, in children with asthma? 

Table 1. PICO

Relevant outcome measures

The guideline panel considered improvement in severe exacerbation frequency, asthma symptoms and asthma control (ACQ-5 score) as critical outcome measures for decision making; and disease specific quality of life (AQLQ), improvement in lung function (FEV₁), cumulative dose of inhaled steroids and adverse events as important outcome measures for decision making.

A priori, the guideline panel did not define the outcome measures listed above but used the definitions used in the studies. The guideline panel would recommend future guidelines to use the recent published Core Outcome Measures sets for pediatric and adult Severe Asthma (COSMA) as a framework to further harmonize outcome measurements in the future (Khaleva, 2023)The guideline panel focusses on the most important outcomes and defined the following thresholds as a minimal clinically (patient) important difference for each outcome measure:

Search and select (Methods)

A systematic literature search was performed by a medical information specialist using the following bibliographic databases: Embase.com and Ovid/Medline. Both databases were searched from 01-01-2000 to 7-04-2025 for systematic reviews and RCTs. Systematic searches were completed using a combination of controlled vocabulary/subject headings (e.g., Emtree-terms, MeSH) wherever they were available and natural language keywords. The overall search strategy was derived from two primary search concepts: (1) asthma 2) children and (3) anti-inflammatory reliever therapy (AIR)/single maintenance and reliever therapy (SMART/MART). Duplicates were removed using EndNote software. After deduplication a total of 1115 records were imported for title/abstract screening. Initially, 40 studies were selected based on title and abstract screening based on the PICO criteria. After reading the full text, 38 studies were excluded (see the exclusion table under the tab ‘Evidence tabellen’), and 2 main studies were included. Both studies were post-hoc analysis, of which one study analysed six randomized controlled trials (RCT) and one study analyzed one RCT.
Studies that report on AIR in adolescents and/or pediatrics will be described in a separate module of this guideline.

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