Researching asthma across the ages: Insights from the National Heart, Lung, and Blood Institute’s Asthma Network
Authors: Michael D. Cabana, Susan J. Kunselman, Sharmilee M. Nyenhuis, Michael E. Wechsler
Journal: Journal of Allergy and Clinical Immunology (2013)

Clinical asthma studies across different age groups (ie, cross-age studies) can potentially offer insight into the similarities, differences, and relationships between childhood and adult asthma. The National Institutes of Health's Asthma Research Network (AsthmaNet) is unique and innovative in that it has merged pediatric and adult asthma research into a single clinical research network. This combination enhances scientific exchange between pediatric and adult asthma investigators and encourages the application of cross-age studies that involve participants from multiple age groups who are generally not studied together. The experience from AsthmaNet in the development of cross-age protocols highlights some of the issues in the evaluation of cross-age research in asthma. The aim of this review is to summarize these challenges, including the selection of parallel cross-age clinical interventions, identification of appropriate controls, measurement of meaningful clinical outcomes, and various ethical and logistic issues. Clinical asthma studies across different age groups (ie, cross-age studies) can potentially offer insight into the similarities, differences, and relationships between childhood and adult asthma. The National Institutes of Health's Asthma Research Network (AsthmaNet) is unique and innovative in that it has merged pediatric and adult asthma research into a single clinical research network. This combination enhances scientific exchange between pediatric and adult asthma investigators and encourages the application of cross-age studies that involve participants from multiple age groups who are generally not studied together. The experience from AsthmaNet in the development of cross-age protocols highlights some of the issues in the evaluation of cross-age research in asthma. The aim of this review is to summarize these challenges, including the selection of parallel cross-age clinical interventions, identification of appropriate controls, measurement of meaningful clinical outcomes, and various ethical and logistic issues. Asthma is characterized by multiple phenotypes and affects patients of all ages. Most asthma clinical trials focus on one specific age group. "Cross-age" studies, which recruit participants from multiple age groups not normally studied together, can potentially offer insight into differences in the diagnosis, treatment, and management of asthma in infants, children, adolescents, adults, and the elderly. In addition, these cross-age studies can provide additional clues regarding the natural course of asthma phenotypes. A fundamental question is whether asthma is the same in adults and children. It is not clear whether the pathophysiology and response to asthma therapy is similar across ages. In addition, patients from different age groups might respond differently to predisposing features (eg, viruses vs allergies) of asthma. Also, children have not benefited as extensively from advances in drug development compared with adults; newer therapies are often not initially studied in the pediatric age group. This gap has resulted in many commonly used pediatric drugs without US Food and Drug Administration (FDA)–approved indications for use in children.1Yoon E.Y. Davis M.M. El-Essawi H. Cabana M.D. FDA labeling status of pediatric medications.Clin Pediatr. 2006; 45: 75-77Crossref PubMed Scopus (9) Google Scholar Without pediatric data, children are at risk from inappropriate extrapolation of data from adult studies when asthma medications are used off label.2Szefler S.J. Chmiel J. Fitzpatrick A.M. Giacoia G. Green T.P. Jackson D.J. et al.Asthma across the ages: difference between adult and child asthma.J Allergy Clin Immunol. 2014; 133: 3-13Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Cross-age studies can fill potential gaps in our knowledge of asthma management for specific age groups and identify both common and unique features of the disease across different age groups. Asthma is often recognized as a syndrome with common elements but also heterogeneous phenotypes. As a result, it is important to develop more precise diagnostic, treatment, and management strategies based on phenotypic and genotypic features.3Weiss S.T. New approaches to personalized medicine for asthma: where are we?.J Allergy Clin Immunol. 2012; 129: 327-334Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar In all age groups there is a need for novel approaches to prevent exacerbations, to manage step-down care, and to escalate care when asthma is poorly controlled.4Jackson D.J. Sykes A. Mallia P. Johnston S.L. Asthma exacerbations; origin, effect and prevention.J Allergy Clin Immunol. 2011; 128: 1165-1174Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 5Busse W.W. Asthma diagnosis and treatment: filling in the information gaps.J Allergy Clin Immunol. 2011; 128: 740-750Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar There are similar needs for biomarkers that can identify different phenotypes of asthma in both adults and children. In 2008, the National Institutes of Health/National Heart, Lung, and Blood Institute (NHLBI) issued a funding opportunity announcement to establish the NHLBI's Asthma Network (AsthmaNet) as 2 other NHLBI networks, the Childhood Asthma Research and Education Network and Asthma Clinical Research Network (ACRN), were concluding in an effort to address these gaps. This new NHLBI asthma network would be unique in merging the conduct of pediatric and adult asthma research into a single network, would enhance scientific exchange between pediatric and adult asthma investigators, and would encourage cross-age studies regarding similarities, differences, and relationships between childhood and adult asthma.6National Institutes of Health. Request For Applications (RFA) number: RFA-HL-08–010 Clinical Centers for the NHLBI Asthma Network (AsthmaNet) (U10). Available at: http://grants.nih.gov/grants/guide/rfa-files/RFA-HL-08-010.html. Accessed October 12, 2013.Google Scholar AsthmaNet has developed several protocols that were initially designed as cross-age studies.7Sutherland E.R. Busse W.W. Designing clinical trials to address the needs of childhood and adult asthma: The National Heart, Lung, and Blood Institute's AsthmaNet.J Allergy Clin Immunol. 2014; 133: 34-38Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Two study protocols highlighted throughout this review are the Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma (VIDA) study and the Best African-American Response to Asthma Drugs (BARD) study. The VIDA protocol was eventually modified and initiated with only a focus on adult patients. Despite the inherent challenges in doing cross-age studies (reviewed below) and with the experience from the VIDA trial, the network developed its first cross-age protocol in the BARD study. Brief summaries of the VIDA and BARD studies are included below. The VIDA study is a randomized parallel-group trial designed to assess whether the addition of a 28-week treatment with high-dose vitamin D is superior to placebo in reducing asthma treatment failures for vitamin D–insufficient (<30 ng/mL) patients 18 years and older with persistent asthma who remain symptomatic despite low-dose inhaled corticosteroid (ICS) therapy. The vitamin D dose is a 100,000-IU load followed by 4,000 IU/d. The analysis will assess whether the addition of vitamin D reduces the likelihood of treatment failure when compared with placebo. Given the high prevalence of both vitamin D insufficiency and asthma, the VIDA study has the potential to affect daily asthma management. The BARD study is a cross-age study designed to evaluate the best step-up long-term control therapy for participants of African American descent with asthma age 5 years and older whose symptoms are inadequately controlled on low-dose ICSs. It has been noted that African American subjects experience a disproportionate burden of asthma morbidity compared with white subjects.8Mannino D.M. Homa D.M. Akinbami L.J. Moorman J.E. Gwynn C. Redd S.C. Surveillance for asthma—United States, 1980-1999.MMWR Surveill Summ. 2002; 51: 1-13Google Scholar, 9Akinbami L.J. Moorman J.E. Garbe P.L. Sondik E.J. Status of childhood asthma in the United States, 1980-2007.Pediatrics. 2009; 123: s131-s145Crossref PubMed Scopus (702) Google Scholar A possible explanation for such racial disparities in asthma is that African American subjects respond differently to asthma therapies. For example, for African American patients, there are reports suggesting a differential effect of add-on long-acting β-agonist (LABA) treatment when asthma is inadequately controlled on low doses of ICS compared with the results of studies of add-on LABA therapy with other populations.10Bailey W. Castro M. Matz J. et al.Asthma exacerbations in African Americans treated for 1 year with combination fluticasone propionate and salmeterol or fluticasone propionate alone.Curr Med Res Opin. 2008; 24: 1669-1682Crossref PubMed Scopus (37) Google Scholar, 11Brown R.W. O'Brien C.D. Martin U.J. Uryniak T. Lampl K.L. Long-term safety and asthma control measures with a budesonide/formoterol pressurized metered-dose inhaler in African American asthmatic patients: a randomized controlled trial.J Allergy Clin Immunol. 2012; 130: 362-367Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar The BARD study design is a 66-week prospective, randomized, double-blind, crossover trial for African American patients with asthma age 12 years and older and separately for African American children age 5 to 11 years with asthma. Participants enter a run-in phase receiving low-dose ICSs. If symptoms are inadequately controlled, then participants are randomized to have their ICS dose increased, have a LABA added, or both, with each participant receiving 4 different add-on treatments over the course of the follow-up period through the cross-over design. In both groups the study will examine, as a primary question, the efficacy of increasing the dose of ICS with or without the addition of a LABA. The BARD analysis will also compare the response of the pediatric and adult groups to these step-up therapies. During the development of VIDA, BARD, and other protocols, AsthmaNet encountered and addressed various challenges in study design, including the selection of study interventions, appropriate controls, and meaningful clinical outcomes, as well as ethical and logistic issues in cross-age studies (Table I), which are detailed below.Table IChallenges with studies evaluating cross-age response to asthma treatmentIssueExamplesRecruitment• Need for culturally diverse recruitment materials • Need for age-appropriate recruitment strategiesConsent/assent• Requirement of parental/guardian consent for minors• Incorporation of assent procedures for childrenIntervention selection• Difficulty in maintaining consistency of intervention therapy because of differences in dosing and drug availabilityControl selection• Limitations in the use of placebo controls for childrenOutcome measurement• Dependence on proxy reporting of outcomes for children• Dearth of cross-age instruments to measure QOL, asthma control, symptoms, and exacerbationsParticipant growth and development• Need to account for physical growth (eg, weight and height) of pediatric participantsPhysical limitations in data collection• Physical and developmental limits for testing and data collection (eg, phlebotomy, spirometry, and sputum induction)• Increased safety restrictions in testing of children (eg, methacholine bronchoprovocation)Consideration of long-term effects• Careful monitoring and follow-up for long-term developmental effects in childrenReporting of results• Determination of how data across ages will be subdivided (eg, age cutoffs, including adolescents as adults or children) Open table in a new tab Clinical trial recruitment is a challenge in all age groups, and recruitment strategies can differ across ages. Children are the most racially and ethnically diverse group in the United States.12Cooper M. Census officials, citing increasing diversity, say U.S. will be a "plurality nation.".New York Times. December 12, 2012; Google Scholar For cross-age trials involving children and diverse populations, it is necessary to include recruitment materials and methods, as well as assessment tools that are not only developmentally appropriate but also culturally and linguistically appropriate.13Flores G. Fuentes-Afflick E. Barbot O. et al.The health of Latino children: urgent priorities, unanswered questions, and a research agenda.JAMA. 2002; 288: 82-90Crossref PubMed Scopus (393) Google Scholar Specific strategies have been associated with the effective recruitment and retention of minority research participants.14Yancey A.K. Ortega A.N. Kumanyika S.K. Effective recruitment and retention of minority research participants.Annu Rev Pub Health. 2006; 27: 1-28Crossref PubMed Scopus (895) Google Scholar Ethnic and cultural background has been shown to affect perceptions of disease, understanding of disease, and even perception of pulmonary function.15Fritz G.K. McQuaid E.L. Kopel S.J. et al.Ethnic differences in perception of lung function: a factor in pediatric asthma disparities?.Am J Respir Crit Care Med. 2010; 182: 1208Crossref PubMed Scopus (52) Google Scholar Recruitment for cross-age studies should be age appropriate, as well as culturally appropriate. With the ubiquitous use of new electronic media and mobile technology, there is increasing acceptability of the use of text messaging, social networking, and e-mail by patients to use electronic media to receive asthma information.16Baptist A.P. Thompson M. Grossman K.S. Mohammed L. Sy A. Sanders G.M. Social media, text messaging, and email-preferences of asthma patients between 12 and 40 years old.J Asthma. 2011; 48: 824-830Crossref PubMed Scopus (94) Google Scholar In addition to traditional methods (eg, physician referrals, patient lists, and posted advertisements),17Sorkness C.A. Ford J.G. Lemanske R.F. Recruitment strategies in the asthma clinical research network.Control Clin Trials. 2001; 22: s222-s235Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar adolescents and young adults might be more accessible for recruitment through the Internet,18Janson C. Wist M. An Internet survey of asthma treatment.J Asthma. 2004; 41: 49-55Crossref PubMed Scopus (10) Google Scholar social networking,19O'Connor A. Jackson L. Goldsmith L. Skirton H. Can I get a retweet please? Health research recruitment and the Twittersphere.J Adv Nurs. 2013; ([Epub ahead of print])PubMed Google Scholar or text messaging. For the BARD study, AsthmaNet sites use strategies that feature a variety of electronic media strategies (eg, Internet postings, as well as the use of Facebook, Twitter, and Google advertisements). Research participants should understand the risks, benefits, alternatives, and rights associated with involvement in a clinical trial.20Title 45, Code of Federal Regulations (CFR). 46 USC, §46.116-46.117 (2009).Google Scholar For cross-age studies that include pediatric participants, the degree of participant involvement in the consent process is more complex. With few exceptions, children do not have the legal capacity to provide consent for their participation in research. Instead, informed permission from one parent or guardian is required. For those studies with greater than minimal risk, some institutional review boards might require permission from both parents. In addition, for older children, assent of the child, as well as parental permission, might be required. Assent includes a child's agreement to participate in a research study, as well as ensuring the child participant has a developmentally appropriate awareness of the study.21American Academy of Pediatrics, Committee on BioethicsInformed consent, parental permission, and assent in pediatric practice.Pediatrics. 1995; 34: 314-317Google Scholar As a result, cross-age studies require a variety of forms for consent and assent with different signature requirements. In addition to signed consent from all adult participants, the BARD protocol requires consent from a parent or legal guardian for participants between 5 and 18 years of age. Signed assent is obtained for participants 12 to 18 years of age, as well as for those participants 5 to 11 years of age, if required by an institution's institutional review board. In cross-age studies it might not be possible to maintain identical study interventions for all study participants, especially in trials focused on asthma medications. Although all medications need to be weight and age adjusted, additional modifications to study interventions might still be needed because of potential side effects, dosing issues, and drug availability issues. For example, the BARD study included crossover phases with medium- and high-dose ICSs, both with and without LABAs. The interventions in the BARD protocol were modified in the pediatric arms because of concerns related to use of high-dose ICSs unique to children.22Dahl R. Systemic side effects of inhaled corticosteroids in patients with asthma.Respir Med. 2006; 100: 1307-1317Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar Use of daily ICSs in children is associated with a risk of suppression of growth velocity and effects on final adult height.23Kelly H.W. Sternberg A.L. Lescher R. et al.Effect of inhaled glucocorticoids in childhood on adult height.N Engl J Med. 2012; 367: 904-912Crossref PubMed Scopus (315) Google Scholar In addition, the high dose ranges (500 μg of fluticasone propionate twice daily) described in the National Asthma Education and Prevention Program guidelines are based on thresholds for potential systemic effects, such as hypothalamic-pituitary-adrenal axis suppression and osteoporosis from sustained long-term use.24Szefler S.J. Eigen H. Budesonide inhalation suspension: a nebulized corticosteroid for persistent asthma.J Allergy Clin Immunol. 2002; 109: 730-742PubMed Google Scholar, 25Martin R.J. Szefler S.J. Chinchilli V.M. et al.Systemic effect comparisons of six inhaled corticosteroid preparations.Am J Respir Crit Care Med. 2002; 165: 1377-1383Crossref PubMed Scopus (233) Google Scholar As a result, for the pediatric and nonpediatric groups, the final BARD protocol was not identical in terms of ICS dosing. Both age groups use an ICS dose escalation; however, the pediatric population starts at only half the dose to be initiated in the older age group and escalates to a maximum that is half the dose of the nonpediatric population (Table II). The protocol did not start the pediatric participants at 100 μg twice daily during the run-in phase because this initial dose would result in an eventual maximum dose of 500 μg twice daily, which was considered to be unacceptable because of safety concerns. The step up in the pediatric age group is a 2-fold increase in ICS (from 1 × ICS [50 μg twice daily] to 2 × ICS [100 μg twice daily]), whereas in the older age group the first step up is a 2.5-fold increase (from 1 × ICS [100 μg twice daily] to 2.5 × ICS [250 μg twice daily]). Despite the issues in dosing, the BARD protocol is able to maintain some symmetry between the studies for pediatric and nonpediatric populations because both cohorts receive increasing doses of ICSs with and without a LABA.Table IIBARD study ICS dosing in children age 5 to 11 years and adults/adolescents age 12 years and olderChildrenAdolescents/adultsRun-in dose1 × ICS50 μg of fluticasone propionate twice daily1 × ICS100 μg of fluticasone propionate twice dailyPhase A2 × ICS100 μg of fluticasone propionate twice daily2.5 × ICS250 μg of fluticasone propionate twice dailyPhase B5 × ICS250 μg of fluticasone propionate twice daily5 × ICS500 μg of fluticasone propionate twice dailyPhase C2 × ICS + LABA100 μg of fluticasone propionate and 50 μg of salmeterol twice daily1 × ICS + LABA100 μg of fluticasone propionate and 50 μg of salmeterol twice dailyPhase D5 × ICS + LABA250 μg of fluticasone propionate and 50 μg of salmeterol twice daily2.5 × ICS + LABA250 μg of fluticasone propionate and 50 μg of salmeterol twice daily Open table in a new tab There are other modifications that had to occur in the BARD protocol to accommodate the cross-age comparison and design. For pediatric patients in the BARD protocol, the LABA is not "added on" to the lowest dose of ICS but rather to the next dose of ICS (at 100 μg twice daily vs 50 μg twice daily). This modification was pursued because of a lack of a matching placebo inhaler (and potential concerns of using 2 separate inhalers in children). Although this creates some differences in the 2 groups, the analysis can still accommodate and answer the primary and secondary research questions. A placebo control is often used as a key component in the evaluation of a new therapy in a randomized controlled trial. The need for a placebo is especially important for conditions such as asthma, in which there is the potential for a high rate of placebo response, which might lead to an overestimation of the effectiveness of an intervention.26Busse W.W. Lemanske R.F. The placebo effect in asthma: far more complex than simply "I shall please.".J Allergy Clin Immunol. 2009; 124: 445-446Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Although an alternative nonplacebo therapy potentially can be used for the control group, the effect size might be diminished. With a smaller effect size, greater numbers of subjects might be necessary, which increases a study's cost and complexity.27Hulley S.B. Cummings S.R. Browner W.S. Grady D.G. Newman T.B. Designing clinical research.4th Edition. Lippincott, Williams and Wilkins, Philadelphia2013Google Scholar The use of placebo controls in clinical trials involving children, who are a vulnerable population, leads to even greater scrutiny.28Coffey M.J. Wilfond B. Ross L.F. Ethical assessment of clinical asthma trials including children subjects.Pediatrics. 2004; 113: 87-94Crossref PubMed Scopus (27) Google Scholar The Declaration of Helsinki, which outlines international standards for the ethics of clinical trials, states that every patient in a clinical study, including those in a control group, should be assured of the care consistent with the best-proved methods when a standard of care exists.29World Medical Association. Declaration of Helsinki—ethical principles for medical research involving human subjects. Available at: http://www.wma.net/en/30publications/10policies/b3/. Accessed October 12, 2013.Google Scholar Without providing this standard of care (eg, control group patients receiving placebo when a known effective asthma treatment exists), participants would be exposed to unnecessary risk and potential harm. For example, the clinical value of daily ICS therapy for persistent asthma is well established. A clinical trial assessing the effectiveness of a new treatment for persistent asthma with a placebo control (instead of a commonly used ICS as a control) would be ethically questionable.30Miller F.G. Shorr A.F. Unnecessary use of placebo controls: the case of asthma clinical trials.Arch Intern Med. 2002; 162: 1673-1677Crossref PubMed Scopus (19) Google Scholar Professional organizations, such as the American Academy of Pediatrics, have outlined conditions under which placebos can be ethically used in pediatric clinical trials (Table III).31American Academy of Pediatrics, Committee on Drugs and Committee on Pediatric ResearchClinical report: guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations.Pediatrics. 2010; 125: 850-860Crossref PubMed Scopus (124) Google ScholarTable IIIConditions under which placebos can be ethically used in pediatric drug research∗Modified from the American Academy of Pediatrics.311. When there is no commonly accepted therapy for the condition and the agent under study is the first that can modify the course of the disease process2. When the commonly used therapy for the condition is of questionable efficacy3. When the commonly used therapy for the condition carries with it a high frequency of undesirable adverse effects and the risks might be significantly greater than the benefits4. When the placebo is used to identify the incidence and severity of adverse effects produced by adding a new treatment to an established regimen5. When the disease process is characterized by frequent and spontaneous exacerbations and remissions and the efficacy of the therapy has not been demonstrated∗ Modified from the American Academy of Pediatrics.31American Academy of Pediatrics, Committee on Drugs and Committee on Pediatric ResearchClinical report: guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations.Pediatrics. 2010; 125: 850-860Crossref PubMed Scopus (124) Google Scholar Open table in a new tab The efficacy of vitamin D therapy for the prevention of asthma exacerbations is not known. As a result, for the VIDA study, the use of a placebo would have been justifiable in reference to the potential prevention of asthma exacerbations. However, the VIDA study assesses the efficacy of vitamin D for those patients who were vitamin D insufficient (<30 ng/mL). The inclusion of pediatric participants in this study was problematic not in relation to asthma but in relation to bone and development issues. Although adults might be able to tolerate temporary periods of low vitamin D levels, the effects of vitamin D for bone growth are well established32Wagner C.L. Greer F.R. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents.Pediatrics. 2008; 122: 1142-1152Crossref PubMed Scopus (1295) Google Scholar because vitamin D is crucial for bone development, calcium homeostasis, and many metabolic processes in growing children and adolescents.33Holick M.F. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis.Am J Clin Nutr. 2004; 79: 362-371PubMed Scopus (1382) Google Scholar As a result, the use of placebo for children with documented low levels of vitamin D is not acceptable. Current guidelines recommend that children not deficient in vitamin D receive 400 IU of vitamin D per day. Although it potentially would have been possible to include pediatric participants and use 400 IU of vitamin D as a control in the VIDA study, there would have been a study design tradeoff. The difference in dose between the intervention and control doses would have been decreased by 10-fold (4000 vs 400 IU). As a result, using this dose as a control could potentially decrease the opportunity to detect an effect from the intervention or require the recruitment of a much larger sample size.27Hulley S.B. Cummings S.R. Browner W.S. Grady D.G. Newman T.B. Designing clinical research.4th Edition. Lippincott, Williams and Wilkins, Philadelphia2013Google Scholar The consistent measurement of clinical outcomes is necessary to answer the questions being addressed in a clinical trial. However, in cross-age studies it might not feasible or valid to collect such outcome measures in an identical manner. Different instruments might need to be used for different age groups. The measurement of asthma control, exacerbation, symptoms, and quality of life (QOL) are examples of this issue in cross-age studies. National Asthma Education and Prevention Program guidelines highlight asthma control as a major goal of therapy, and a patient's level of asthma control is a key factor in guidelines for how clinicians should modify their management of the disease.34National Heart, Lung, and Blood Institute. Expert panel report 3: guidelines for the diagnosis and management of asthma—full report 2007. Available at: www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed October 12, 2013.Google Scholar Ideally, in cross-age studies it would be most efficient and simplest to use an instrument that has been developed for patients of all ages (eg, Royal College of Physicians Three Questions35Thomas M. Gruffydd-Jones K. Stonham C. Ward S. Macfarlane T.V. Assessing asthma control in routine clinical practice: use of the Royal College of Physicians "3 questions.".Prim Care Respir J. 2009; 18: 83-88Crossref PubMed Scopus (239) Google Scholar and Lara Asthma Symptom Scale36Wood P.R. Smith B. O'Donnell L. et al.Quantifying asthma symptoms in adults: the Lara Asthma Symptom Scale.J Allergy Clin Immunol. 2007; 120: 1368-1372Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar); however, there is limited information on the validity, reliability, and diversity of populations tested for these instruments. The Asthma Control Questionnaire and Asthma Control Test (ACT) are commonly used instruments to assess asthma control; however, they are only applicable to older children. There are limited options for measuring asthma control in pediatrics. The Childhood Asthma Control Test (cACT) instrument can be applied to participants 4 to 11 years of age, but there are limited data about how to assess the minimal clinically important difference for cACT values, as well as the responsiveness of the cACT over time.37Cloutier M.M. Schatz M. Castro M. et al.Asthma outcomes: composite scores of asthma control.J Allergy Clin Immunol. 2012; 129: S24-S33Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar Given the limited options, the ACT and cACT were selected to measure asthma control for the BARD study. A reduction of asthma exacerbations is one of the main goals of asthma treatment as defined by practice guidelines for asthma and thus a targeted ou