Clinical trial NCT02045875
Conditions: Asthma
Keywords: Adherence monitoring Motivational Interviewing Adherence strategies
Sponsor: Asthma Management Systems
Start date: 2014-03-04; Completion date: 2017-07-12
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
40 subjects with moderate-to-severe asthma will be randomly selected for study in which 20, will be monitored for medication use (Dulera 100/5, Dulera 200/5 and Proventil HFA) over 3 months. These intervention subjects will receive medication use feedback at each visit, while the control group will receive the standard of asthma care. Those interventional subjects with Dulera adherence\<60% will receive feedback based on an asthma adherence disease management model protocol, Asthma Adherence Pathway. Intervention clinicians will been trained in Motivational Interviewing to reduce subject ambivalence about medication use. The primary hypothesis is that subjects who receive medication monitoring and Motivational Interviewing adherence strategies will have better asthma control, as measured by the Asthma Control Questionnaire, than the control group.

Detailed description:
Primary Clinical Hypothesis: Poorly controlled subjects with moderate-to-severe asthma (measured by Asthma Control Questionnaire (ACQ) ≥ 1) despite treatment with Dulera, who are treated with the asthma adherence disease management protocol, Asthma Adherence Pathway™, will achieve greater asthma control than similar control subjects who are treated with the current standard of care.

Primary end point: There will be four measures of Asthma Control Questionnaire (ACQ) over time over 3 months. The primary endpoint is the third month measure of ACQ.

Secondary Clinical Hypothesis: The asthma adherence disease management program, Asthma Adherence Pathway™, will increase observed adherence to Dulera relative to a benchmark of 60% adherence (i.e., expected prescribed actuations).

Secondary end points: a) Average adherence to Dulera over the three month study period

Tertiary Clinical Hypothesis: Responses to Adult Asthma Adherence Questionnaire (AAAQ) will be related to Dulera Adherence

Tertiary Study Endpoints: There will be 2 measures of the AAAQ (first and last visit) and the tertiary endpoint is the last visit

Arms: arm 1: Adherence Monitoring Dulera; Identification of adherence barrier(s); Motivational Interviewing Adherence Strategies to promote adherence arm 2: Dulera standard of asthma care
Interventions: intervention 1: Dulera
Intervention descriptions: intervention 1: Dulera is a combination product containing a corticosteroid and a long-acting beta2-adrenergic agonist, FDA approved and indicated for treatment of asthma in patients 12 years of age and older.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Gentile Dulera Version Date: 20140106 
1 
 
PROTOCOL: Improving Asthma Control in the Real World: A Systematic Approach to 
ImprovingDulera Adherence - a controlled study testing the effectiveness of an adult asthma 
adherence disease management program to improve asthma control by promoting adherence to 
Dulera 
 
PROTOCOL VERSION DATE: 
January 6, 2014,Version1.0 
PRINCIPAL INVESTIGATOR: Deborah Gentlie, MD, Allegheny Singer Research Institute. 490 
East North Avenue, Suite 207, Pittsburgh, PA 15212 
 
SOURCES OF SUPPORT: Asthma Management Systems (with an award from Merck) 
 
1.0 
Objective and Specific Aims 
1) Enhance asthma control by delivering the asthma adherence disease management protoco,l 
Asthma AdherencePathway™. 
 
2) Enhance adherence to Dulera relative to a clinical benchmark by delivering asthma 
adherence disease management protocol, Asthma Adherence Pathway™. 
3) Initiate validation of Adult Asthma Adherence Questionnaire (AAAQ) 
 
Hypotheses: 
Primary   Clinical   Hypothesis:   Poorly   controlled   subjects   with   moderate-to-sveere  asthma 
(measured by Asthma Control Questionnaire (ACQ) 1) despite treatment with Dulera, who are 
treated with the asthma adherence disease management protocol, Asthma Adherence 
Pathway™, will achieve greater asthma control than similar control subjects  who  are treated  
with thecurrent standard of care. 
 
Primary end point: There will be four measures of Asthma Control Questionnaire (ACQ) over 
time over 3 months. The primary endpoint is the third month measure of ACQ. 
 
Secondary Clinical Hypothesis: The asthma adherence disease management program, Asthma 
Adherence Pathway™, will increase observed adherence to Dulera relative to a benchmark of 
60% adherence (i.e., expected prescribed actuations). 
 
Secondary end points: a) Average adherence to Dulera over the three month study period 
 
Tertiary Clinical Hypothesis: Responses to Adult Asthma Adherence Questionnaire (AAAQ) will 
be related to Dulera Adherence 
 
Tertiary Study Endpoints: There will be 2 measures of the AAAQ (first and last visit) and the 
tertiary endpoint is the last visit 
 
 
2.0 
Background and Significance 
Approximately 22 million Americans have asthma, 6 million under 18 years of a e.1 The annual 
cost of asthma care is estimated at $19.7 billion,2 with 456,000 hospitailzations and 1.5 million 


Protocol Gentile Dulera Version Date: 20140106 
2 
 
ER visits.2 African Americans are three times more likely to be hospitalized or die from asthma 
than other groups.
4 Inhaled corticosteroids effectively control symptoms and reduce morbidity, 
mortality, health care utilization and cost.5 However, 45-60% of patients do not adhere to 
preventivedrug regimens.6 7· 8• Adherence rates for inhaled corticosteroids (ICS) range from 44% 
t7o8 72%7. But only 8% to 13% of patients taking ICS continue to fill prescriptions after one year. 
• It is difficult for clinicians to determine whether treatment failure is due to an inadequate 
medication regimen or poor adherence, in part because self-reported adherence is unreliable.9 
Physicians may get a false impression of a drug's effectiveness if a patient is not truthful about 
medication taken. Non-adherent patients are at risk for excess morbidity and mortality, as well 
as excess imaging, lab tests and consultations, due to the inability to accurately determinethe 
cause of treatment failure1.0 
This study will assess adherence to the study medication, Dulera. This medication is being 
provided free of charge by Merck. Separate studies involving other asthma medications are 
warranted at a later time. The focus of this proposal is to test a treatment mode,l delivered by 
clinicians who acquire Adherence/Communicationskills, which may increase asthma control, 
improve adherence to Dulera, and enhance subjects' perception of the effectiveness of Dulera. 
The asthma adherence disease management (AADM) intervention strategy consists of three 
components: 1) objective adherence monitoring; 2) identificaiton of barriers to treatmen;t and 3) 
Motivational Interviewing adherence strategies that address specific barriers.32 In an 
uncontrolled pilot study, the Pl used medicaiton monitoring and psycho-educationaladherence 
programs in children with severe asthma to significantly reduce morbidity, ER use, 
hospitalization, and cost.11 This research led to the formulation of AADM principles to be tested 
in this controlled study.12 The research addresses two important knowledge gaps. First, NHLBI 
Expert Panel Report 3 (EPR-3) states that adherence monitoring is a key component of asthma 
management, but notes that the quality of the supporting data is weak, and encourages 
controlled trials to further evaluate the effectiveness of objective adherence monitoring.13 
Second, 56% of American Academy of Allergy Asthma & Immunology members responding to a 
survey, report that they lackcompetency managing non-adherent patients.14 
Individual components of the model have been tested inp romot ing asthma adherence and 
improving control. Milgrom et al.9 as well as Onyrimba et al.1 demonstrated the effectiveness of 
using electronic adherence monitors attached to inhaled corticosteroid MDls (ICS) to diagnose 
adherence status and improve adherence. Wilson et al demonstrated the effectiveness of 
shared-decision making, one type of patient-centered communication that has many features 
similar to Motivational Interviewing, to improve asthma control and adherence.16 Weinsteinet al 
combined  medicaiton  monitoring  with  psycho-educational   family  interventions  to  improve 
adherence and decrease morbidity and cost from asthma. The reduction in morbidity and cost 
was thought to be related to: objective feedback regarding medication use; identification of 
barriers and counseling that identified patienVfamily ambivalence about treatment; and 
enhancing motivationto follow thru with a complex treatment plan. Weinsteinemployed all three 
components of the model (ICS adherence monitors; assessment of adherence barriers; 
Motivational Interviewing adherence strategies) in reducing asthma costs by 72% in a pilot 
organized by Blue Cross Blue Shield DE.17 
The rationale for using Motivational Interviewing is the observation that educating patients about 
asthma yields little improvement in adherence or outcomes.18 Interventions that encourage 
patients to monitor symptoms or peak flow have shown significantbut small effects on asthma 
morbidity.19 Self-management approaches, including identifying barriers to adherence, self- 
monitoring medicationuse, goal setting, and problem solving, result in fewer ER visits18, short- 
term improvements in adherence,19 2•0  higher  asthma  management  self-efficacy,20 21•  improved 


Protocol Gentile Dulera Version Date: 20140106 
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• 
• 
• 
quality of life, 15 16 reduced asthma symptoms,19 22 and less beta-agonist use.19 22 Unfortunately, 
the majority of self-management studies involve more than 5.5 hours of patient contact.23 
An important limitation of both educational and self-management approaches is that they are 
predicatedontheassumption that patients aremotivated to accept treatment recommendations. 
These approaches mi ht be effecitve for those who are ready to change but less so for those 
who are not ready.24• 2 Schmaling et al.26 for example, found that asthma education resulted in 
increased knowledge but decreased motivation to use medication. There is a need for 
innovative approaches to promote motivation for medication adherence that 1) build on 
previously validated interventions, 2) are easily integrated into standard clinical care, and 3) 
target both those who are ready and those who are not ready to change. 
 
Dr. Weinstein is a Motivational Interviewing trainer, with extensive experience in helping 
clinicians acquire adherence and communication skills. He designed and is the director of the 
Adherence and Communication Course held at the American Academy of Allergy Asthma & 
Immunology annual meeting, and has provided adherence/communication training to 
Allergy/Immunology training programs in the US. The use of patient-centered Motivational 
Interviewing Adherence Strategies (MIAS, reviewed below), as well as objective feedback on 
Dulera use, is expected to improve asthma control and improve adherence2.•7  28 Dr. Weinstein 
(in his role with the Asthma Management Systems) is the recipient of the Merck grant and a 
sponsor for this study. He is not a co-investigator for the study and will not make protocol 
decisions. He will provide training to the investigators and will be provided with a de-identified 
dataset for analysis. 
 
Dr. Weinstein was part of a research team that developed a 5 question adherence questionnaire 
for adults with asthma (Adult Asthma Adherence Questionnaire-AAAQ).33 The study of 420 
subjects found that these 5 questions related to other measures of adherence and to asthma 
control can be used clinically to identify patients at risk of nonadherence and the specific 
adherence barriers involved.. Five items (Following my medication plan; forgetting; not needing 
ICS; side effects; and cost) were related to self-reported low adherence or previous ICS refill as 
well as asthma control (ACT). The AAAQ instrument will be used for the purposes of this 
research study. 
 
3.0 
Research Design and Methods 
Study design: 
This study will make use of a cluster experimental design where repeated assessments over 
time are nested within patients and patients are nested within physician. Some clinicians will be 
assigned to the treatment condition and some to the control group (which will be practicing the 
current standard of asthma care). A total of 60 subjects will be enrolled in to the study. 
Subjects being seen for regular asthma care and who are beingprescribed Dulera 100/5 based 
upon asthma severity and dosing guidelines (and regardless of participation in this research 
study) will be asked to participate in this research study. Also, these subjects with asthma are 
routinelyprescribed Proventil HFA as their rescue inhaler. For the purposes of the study, these 
medications(Dulera 100/5 and Proventli HFA) will be provided to all subjects as part of study 
participation. 
 
The subjects will be assigned to either the intervention or control group at the time they sign the 
consent form. These subjects will be placedinto their respective groups in an alternating 


Protocol Gentile Dulera Version Date: 20140106 
4 
 
process, irrespective of subject demographics, treating clinician or previous asthma treatment to 
minimize bias 
Study drug: 
Dulera is a combination product containing a corticosteroid and a long-actingbeta2-adrenergic 
agonist, FDA approved and indicated for treatment of asthma in patients 12 years of age and 
older. 
 
PROVENTIL® HFA Inhalation Aerosol is FDA approved and indicated in adults and children 4 
years of age and older for the treatment or prevention of bronchospasm with reversible 
obstructive airway disease and for the prevention of exercise-induced bronchospasm. Proventil 
will be given as a rescue medication in this study. 
 
Study drug will be kept at room-temperature in a locked cabinet located within Dr. Gentile's 
office and will be accessible only to study staff. 
During the course of the study (after the screening), bothstudy drugs will include Smartlnhaler 
adherence monitors. The Smartlnhaler is FDA approved and will provide electronic data for 
recording and monitoring actuations of prescribed MDI usage. This electronic data will be 
downloaded to a password-protected computer at the study site. 
 
Motivational interviewing: 
Prior to the patient management phase, clinicians will receive training in asthma adherence 
disease management strategies as well as in Motivational Interviewing to optimize delivery of 
the adherence interventions. They will be given a written test regarding 
adherence/communicationprinciples prior to training and at the end of the study. The curriculum 
includes articles, video examples and role-playing. Asthma Management Systems LLC has 
developed and tested a web-based Asthma Adherence Disease Program (Asthma Adherence 
Pathway-SEE MEASURES BELOW) which guides patients and clinicians through the 
adherence interventions. (28) Patients identify adherence barriers from the Asthma Adherence 
Pathway. The patients receive written and video feedback regarding the significance of their 
concerns. This feedback previews potential strategies which will be delivered by clinician. The 
clinician reviews the barriers identified by the patient. He/she is presented with links to 
Motivational Interviewing Adherence Strategies, in both written and video formats. These 
strategies serve as prompts for interventions in the study by the clinician as a clinical decision 
support system. Weinstein will review this material at the training sessions and how to use it for 
subjects. 
 
Measures (see a/so adherence flowchart below ): 
 
• 
ADHERENCE: Dulera adherence is calculated as the number of actuations measured by 
Smartlnhaler divided by the number of actuations expected between clinic visits 
o 
Definition of Dulera Adherence: Subjects with 
60% actuations during the 
interval between clinic visits 
o 
Definition of Dulera Nonadherence: Subjects with < 60% actuations during the 
interval between clinic visits (Rationale for 60% adherence cut-off is to maximize 
asthma control. 60% cut-off has been used by Ho and Bender et al (2006) as a 
suitable criterion of adherence). 
 
• 
ASTHMA CONTROL QUESTIONNAIRE (ACQ):29·  30 This brief questionnaire includes 
asthma symptoms, frequency of albuterol use and measureof pre-bronchodilator FEV-1, 


Protocol Gentile Dulera Version Date: 20140106 
5 
 
providing 7 elements for analysis. There is a 1-6 likert scale for each item. The score is 
the mean of the 7 responses. 
o 
WELL CONTROLLED: Scores 
0.75 
o 
NOT WELL CONTROLLED: Scores 
1.5 
o 
INDETERMINATE: Scores in between 0.76 and 1.49 
• 
For the INDETERMINATE group: asthma control will be determined by 
the frequencyof Proventli HFA use. 
• 
"Well controlled" will be defined as the use of the Proventil HFA 2 
inhalations 2 days per week during the interval not related to 
exercise 
• 
"Not well controlled" will be defined as the use of the ProventliHFA 2 
inhalations 3 days per week during the interval not related to 
exercise 
 
• 
ASTHMA ADHERENCE PATHWAY:™ (completedby Intervention Group):  The Asthma 
Adherence Pathway™ (AAP) is a computer-basedInterne,t clinical decision support tool 
designed to improve adherence to medication and asthma management behaviors that 
affect asthma control. The subject completes the Internet-based AAP at entry into the 
study. This permits review by both subject and provider. The system recommends 
specific actions by the subject and provider based on the system's input. The subject 
inputs attitudes and behaviors about disease management at the entry of the study. The 
subject receives asthma and adherence education in both written and video format to 
reinforce subsequent interventions by the provider. Prior to onset of the study the 
provider receives training to implement the Motivational Interviewing Adherence 
Strategies (MIAS) that address the specific concerns of the subjects. The AAP provides 
the analysis of the subject's barriers in the form of "prompts" as a clinical decision 
making tool. It gives the provider recommendations on delivering MIAS that were 
presented in the earlier training. The adherence barriers identified by the subjects 
include (11): 
o 
Ineffective management: not following the asthma medication plan; delaying 
treatment of symptoms; not removing self from an area causing symptoms; not 
following instructions to treat an asthma attack; not measuring peak flow. 
o 
Negative attitudes about treatment: do not need medication; medicine does not 
work. 
o 
Symptoms during distressing emotional states: angry; upset; frustration; 
depression; anxiety. 
o 
Lack of comprehension of care instructions: uncertain when to use which 
medication;  not  understanding  how  to  use  prescribed  medication,  especially 
inhalation technique; not understanding how to use a peak flow meter. 
o 
Quality of life disruption: sleep, recreational activities, home activities, work, 
school. 
o 
Lack of agreement by significant other with the treatment plan 
o 
Cost, side effects, forgetfulness. 
A  3-point  likert  scale  (Never,  Sometimes,  Often)  is  provided  for  patients  to  identify 
barriers. Those responses (Never or Often) depending on the wording of the question 
that denote a "significant barrier" will be reviewed by the provider. The provider uses the 
recommended Motivational Interviewing Adherence Strategies contained within the 
software and presented in the training sessions. The Adult Asthma Adherence Pathway 
has been shown to have preliminary validation for non-adherent adults.14 


Protocol Gentile Dulera Version Date: 20140106 
6 
 
• 
ADULT ASTHMA ADHERENCE QUESTIONNAIRE (AAAQ) (completed by 
lnterventional Group): The AAAQ consists of five questions related to other measures of 
adherence and to asthma control that can be used clinically, to identify patients at risk of 
nonadherence and the specific adherence barriers involved. It uses a 6 likert scale. By comparing 
objectively measured adherence to the AAAQ, it would be possible to determine the  validity of 
this brief instrument. Although only 20 subjects in the Intervention group will complete the AAAQ, 
the sponsor is conducting multiple adherence studies with the Smartlnhaler that will provide 
sufficient numbers to evaluate the validity of the AAAQ. 
 
VISIT PROCEDURES 
 
Screening visit (all subiects) - approximately 2 hours: 
• 
Subject completes consent form 
• 
Subjectgiven Dulera 100/5 and Proventli(withoutelectronic Smartlnhaler adherence 
monitors) and instructions foruse 
• Physical Examination and medical history 
• Spirometry 
• Subject completes asthma control questionnaire (ACQ) 
• Study staff collects demographic information 
• Demonstrate use of peak flow (subjects given diary to record and generate "personal 
best") 
 
If subject experiences no side effects with Dulera 100/5 they will return in two weeks for a 
baseline visit (Week 2 ± 3 days) to be alternated between either the "lnterventional"or "Contro"l 
(standard of care) group. 
 
All subjects will continue to receive Dulera throughout the course of the study and this 
medication will be provided free of charge. All subjects will be provided with the Dulera 
medication guide and an individualized asthma action plan. Subjects will be informed of the 
potential of asthma symptoms and asked to contact the investigator for further instructions if 
they develop these symptoms. 
INTERVENTIONALGROUP 
 
 
Baseline visit for Intervention group (Week 2 + 3 days) - approximately 60 minutes: 
• 
Physical examination of upper/lowerairways 
• 
Assessment of adverse events, medications, and intercurrent illnesses 
• 
Spirometry pre/post bronchodilator 
• 
Subject completes asthma control questionnaire (ACQ) 
• 
Subject completes Adult Asthma Adherence Questionnaire (AAAQ) 
• 
Subject given Dulera 100/5 and Proventil (each with Smartlnhaler device) and 
informed that it will measure MDI use and be reviewedat each visit. 
• 
Evaluation (correction if needed) of inhalation technique of MDls 
• 
Subject completes asthma adherence disease management software (Asthma 
Adherence Pathway™)to identify patient barriers (5-10 minutes) and provide asthma 
education 
• 
Clinician to initiate specific Motivational Interview  Adherence  Strategies  as 
determined by AAP. If subject has more than 2 barriers, the clinician will  review  
those at next clinic visit in 2 weeks. 


Protocol Gentile Dulera Version Date: 20140106 
7 
 
• 
Revie w Peak flow diary and Asthma Action Plan with instructions to notify provider if 
Peak Flow :s: 50 % of measured peak flow during initial  clinic visit. "Personal Best" to  
be identified at next clinic visit in 2 weeks. 
 
Follow up visits for Intervention group - 60 minutes: 
 
• 
Physical Examination 
• 
Assessment of adverse events, medications, and intercurrent illnesses 
• 
Spirometry without bronchodilator to determine ACQ 
• 
Assessment and feedback of Dulera adherence 
• 
Subject completes asthma control questionnaire(ACQ) 
• 
Assessment of inhalation technique 
• 
Review Peak Flow diary 
• 
Subject and clinical interaction based upon adherence and asthma control 
measures (see adherence flowchart below) 
 
Each time the patient is found to be nonadherent, he/she will be asked to return in 2 weeks ± 3 
days for the next assessment (up to a maximum of 6 visits). A subject who is identified as non- 
adherent 3 times during the study will be asked to return for a final visit one month later and will 
not be given adherence feedback. 
 
 STANDARD OF CARE (CONTROL) GROUP 
 
 
Baseline visit for Control group /Week 2 + 3 days} - approximatel y 60 minutes: 
• 
Physica l examination of upper/lower airways 
• 
Assessment of adverse events, medications, and intercurrent illnesses 
• 
Spirometry pre- bronchodilator to determine ACQ 
• 
Subject completes asthma control questionnaire (ACQ) 
• 
Review Peak Flow diary and develop an Asthma Action Plan 
• 
Provide Asthma Education 
 
Follow up visits for Control group (Week 6, Week 10, Week 14, all ± 3 days) - approximatel y 
60 minutes: 
• 
Physica l examination of upper/lower airways 
• 
Assessment of adverse events, medications, and intercurrent illnesses 
• 
Spirometry pre- bronchodilator to determine ACQ 
• 
Subject completes asthma control questionnaire (ACQ) 
• 
Review Peak Flow diary 
 
Dose changes: It may be a possibility that during the course of this study, the research 
physician determines it is in the subject's best interest to increase the dose of Dulera to 200/5 
based on the subject's asthma control and dosing guidelines. Any other changes in medication 
are discussed under Concomitant treatments. 
 
Early Withdrawal of Subjects: Criter ia for subjec t withdra wal or rem oval from the study include 
the following: 
• untoward reaction to the study medications 
• lost to follow up (do not report to the clinic for scheduled visit) 


Protocol Gentile Dulera Version Date: 20140106 
8 
 
• non-compliance(do not return to the clinic with medication and monitors) 
• subject consent withdrawal 
Subjects who withdraw because of Dulera or Proventli side effects will receive follow-up phone 
calls within 24 hours to evaluate need for further follow-up care. All subjects who do not 
complete the protocol will be replaced. 
Concomitant treatments: During the course of the study, the use of any other orally inhaled 
steroid formulations is prohibited, In addition, any medicaitons that are known to have a drug 
interaction with Dulera are prohibited. Any other medications are acceptable as long as dose 
remains stable over the course of the study. If it becomes necessary for the subject to begin one 
of these medications or change doses, they will be removed from the study and replaced. 


cont rol [via ACQ) 
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APPENDIX A: Dulera adherence flowchart(version 20131106) 
 
 
 
 
M easurement of 
 
 
 
 
 
 
 
 
< 60% actuations 
(Nonadherent) 
 
 
M easureme nt of 
 
)> 
:
Cz:: 
m 
:mz
:::l:J 
mn 
'rT-l 
0 
: E 
:z:: 
)> 
 
0 
Well controlled 
Indeterminate control 
Not wellcontrolled 
Well controlled 
Indeterminate control 
Not wellcontrollecl 
(ACQs:0.75) 
(0.75 <ACQ< 1.50) 
(ACQ2: 1.50) 
(ACQ,;0.75) 
(0.75 <ACQ< 1.50) 
(ACQ2:1.50) 
 
 
 
 
(0 
 
 
 
 
 
 
 
Continue initi al '4 
regimen 
;;, 60% act uati ons 
(Adherent) 
Actuati ons 
< 25 % 
Actuations 
;,; 2 5-59% 
Removed from 
the  stu d y 
1+-    -     - 
-' 
Willreceive feed- 
backand contin ue 
with Oulera 100/S 
Proventil 
HFA use 
;, 3 days/wk 
Proventil 
HFA use 
:s:2 d.i ys/w k 
Proventi l 
HFA use 
3 days/wk 
Incr ease to Dulera 
200/5 andmaintain 
th t rlnsP 
Measurement ofadherence 
[% actuatio ns or Oulera M DI) 
Proven til 
HFA use 
,; 2 days/wk 
----------- J 


Protocol Gentile Dulera Version Date: 20140106 
10 
 
4.0 
Statistical Considerations: 
 
Statistical power: The ACQ consists of 7 questions scaled from 0 (best asthma control) to 6 
(worst asthma control). Assuming a large treatment effect (i.e., a difference of .8 standard 
deviation units in the outcome) reflecting absolute change in the asthma control outcome, small- 
to-moderate levels of intraclass correlation, 40 patients nested within 8 clinicians in each 
condition, and alpha of .05, statistical power for the test of the primary hypothesis exceeds .80. 
The power analysis is based on a variance estimate of .70 and a score change of .5 in the ACQ 
being a minimal important difference.31 The study plans to enroll up to 60 subjects as subjects 
who are non-compliant will be replaced to allow for 40 total to complete the study. 
 
Planned statistical analysis: The primary analysis of the four repeated measures of the Asthma 
Control Questionnaire (ACQ) over time over 3 months will done using linear or nonlinear mixed 
modeling (Fitzmaurice, Laird, & Ware, 2011) to determine whether the intervention group 
demonstrates different average individual trajectories of change compared to the control group. 
The primary endpoint is the third month measure of the ACQ. 
Forthe AAAQ secondary analysis, wewill compare the observed versus expectedratios (mean 
or median depending on the distribution) in 1) patients with a positive (abnormal) response to 
question 1 (responses 2-6) versus those without a positive response (response 1); 
and 2) patients with a positive (abnormal) response to any question (QA: response 1-3; QB: 
response 1-4; QC: response 1-3; QD: response 1-3) versus those with no positive responses: 
QA: 4-6; QB:4-6; QC: 4-6; QD: 4-6. For the secondary analysis we will examine changes in the 
AAAQ over time (expressed as 0, 1, or 2 or more positive responses) in relationship to the 
change in observed versus expected ratios over time. The AAAQ will be completed atentry into 
the study and at the conclusion at 3 months. Suitable subjects in future studies that use 
electronic adherence monitors will also complete the AAAQ permitting an attempt to validate 
this instrument. 
No interim statistical analysis will be done prior to compleiton of all data collection. 
Missing data considerations: When dealing with missing data in a longitudinal study, restricting 
analyses to make use of only cases with complete repeatedly measured data can substantially 
bias statistical findings. Assuming data are missing at random (MAR) or missing completely at 
random (MCAR), multiple imputation and full informationmaximum likelihood estimationare two 
principled and recommended techniques for dealing with missingness. We will be using 
statistical packages (i.e., SAS, Mplus) that can accommodate missing data on the outcome 
variables and make use of all available data for each subject in planned analyses. As noted in 
the Research Design section earlier, we will include in statistical analysis all subjects who 
complete at leastthree clinical visits in either the intervention or control groups. 
 
4.1 Inclusion of Children in Research: Subjects ages 18 and under will not be includedin this 
study as this is a preliminary study and a separate, age-specific study in children is warrantedin 
the future. 
4.2 Inclusion/Exclusion Criteria: 
Inclusion Criteria 
1. Physician diagnosis of asthma of moderateseverity 
2. Subjects :2:: 18 years of age 


Protocol Gentile Dulera Version Date: 20140106 
11 
 
3. Currently receiving an inhaled corticosteroid medication and being prescribed Dulera 
100/5 as part of standard of care based upon asthma severity and dosing guidelines 
4. Asthma Control Questionnaire (ACQ) result> 1.0 at entry 
5. Demonstration of correct inhalation technique for use of meter-dosed inhalers (MDls) 
6. History of reversible airwayobstruction documented by treating physician 
Subjects will be recruited for intervention and control groups from the same geographic area 
and time of year to avoid seasonal variations of asthma symptoms and will be capable of giving 
informed consent. 
 
Exclusion Criteria 
1. Intermittentasthma (asthma exacerbations or symptoms< 3 days/week) 
2. Diagnosis of emphysema in prior year 
3. Diagnosis at any time of: chronic obstructive pulmonary disease (COPD), chronic 
bronchitis, cystic fibrosis, bronchiectasis, Churg Strauss, Wegener's, sarcoidosis, 
pulmonary hypertension or lung cancer 
4. On any medicaiton documented to have a druginteraction with Dulera 
 
4.3 Recruitment Procedures: 
Subjects will be recruited from the investigator's patient practice population and referred by 
other physicians within the health system. Regardless of where subjects are recruited, 
consenting and all study visits and associated procedures will be performed in a private area in 
Dr. Gentile's practice. 
 
Study investigators will obtain written informed consent from the subject before completing any 
study procedures.  Subjects will be given ample time to review the consent and all questions will 
be answeredto ensure the subject's understanding. 
 
4.4 Risk/BenefitRatio: 
This research study presents less than minimal risk to the subject in that the probability and 
magnitude of harm or discomfort anticipated are not greater in and of those ordinarily 
encountered in daily life or during routine physical exams or tests. 
 
Risks of Du/era 
The most common side effects of DULERA include inflammation of the nose and throat, 
inflammation of the sinuses, and headache. Less common side effects of  Dulera  include:  
serious allergic reactions, thrush (yeast infection) in the mouth and throat, a higher chance of 
infection, reduced adrenal function, increase in wheezing right after taking DULERA, lower bone 
mineral density, slowed growth in children, eye problems including glaucoma and cataracts, 
decrease in blood potassium and increase in blood sugar levels. 
 
Formoterol, one of the active ingredients in DULERA, increases the risk of asthma-related 
death. In pediatric and adolescent patients, formoterol may increase the risk of asthma-related 
hospitalization. It has not yet been determined whether the use of inhaled corticosteroids (a 
component of DULERA) or other long-term asthma-control therapy decreases or eliminates this 
risk. 
 
Risks of Proventil HFA 
Risks of Proventil HFA include fast heart rate and high blood pressure, nausea, dizziness, 
nervousness, difficulty sleeping, headache,  and a jittery or nervous feeling.   These symptoms 


Protocol Gentile Dulera Version Date: 20140106 
12 
 
usually go away within one hour. It is likely that subjects already use albuterol and are familiar 
with how they react to this medication. 
Risks of questionnaires and interview procedures 
An infrequent study risk includes fatigue and performance anxiety while completing 
questionnaires and interviews, or may cause discomfort if subject has a disagreementwith the 
physician about medication use (adherence). Throughout the process, the subject will be 
queried about fatigue and adequate time will be allottedto allow the subject to rest. Open and 
honest dialogue with physician is encouraged; however subjects will not be required to answer 
any questions that make them uncomfortable. 
 
Risks of Spirometry 
Occasionally, spirometry may cause some dizziness, shortness of breath, cough or chest 
tightness. Subjects will be treated by a study doctor if these occur. 
 
Risk of Unintentional Disclosure of your Private Health Informatio n 
Another potential risk is anunintentional disclosure of privatehealth information. However, this 
is very unlikely because the study team has procedures in place to try to prevent this from 
happening. The information collected will be stored in a locked office and on password 
protected computers. 
 
Potential benefits 
While there are no direct benefits from participationin the study, subjects may receive benefit 
from the study medication when taken, may experienceimprovement in their quality of life and 
may improve their medicaiton adherence for other treatments. 
Proteciton Against Risk 
All assessments will be completed by research staff and/or physicians trained in appropriate 
administration   of   assessment   protocols   or   procedures.   Subjects   will   be   instructed   by 
investigators to avoid medications that have interactions with Dulera/Proventil. Subjects will 
also be instructed to discontinue medication if side effects develop. 
 
Data Confidenitality and Integrity 
The data collected will be used for research purposes only, and participants will be identifiedby 
code designation. All data collected for this project will be kept strictly confidential and will be 
kept in a locked cabinet or room. All data will be catalogued using the participant's study ID 
number. All research staff members are required to respect the confidentiality of participants 
and to complete institutionally required subject protection training. 
Data and Safety Monitoring Plan 
The principal investigator and study staff will review the study annually at the time of continuing 
review to assess adequacy of procedures and to ensure subject privacy, research 
confidentiality, data quality, and study procedures. Also to be assessed are study goals and 
modifications of those goals; subject recruitment, accrual and retention, progress in data coding 
and analysis, documentaiton, identificaiton of adverse events or research subject complaints, 
and any issues or concerns at that time. Also, assessment will be made of external factors or 
relevant information that may have an impact on the safety of study participants or the ethics of 
the research study. 
 
5.0 
Costs and Payments 


Protocol Gentile Dulera Version Date: 20140106 
13 
 
5.1 Research Study Costs: Neither the participant, nor his/her insurance provider  will  be 
charged for the costs of any of the procedures performed for the purpose of this research study 
or for the Dulera and Proventil HFA study drug. The participant's health insurance will be billed  
in the standard manner for routine care costs. This includes any routine appointments  with  
his/her physician(s) or any other tesUtherapies the doctor recommends. Any deductible or co- 
payments that are part of his/her insurance coverage will apply. 
 
5.2 Research Study Payments:Participants will receive a $50 for each completed study visit, up 
to a maximum of $300 if all 6 visits are completed. Subjects will receive a Payoneer Debit 
MasterCard which can be used anywhere that debit MasterCards are accepted (including 
online). When subjects receive the card, they will be provided further information about the card 
including how to use the card, confidentiality, and privacy information. If a subjectreceives 
$600 or more from for taking part in this research study or a combination of studies in one tax 
year, they will be sent a 1099 form for tax purposes. 
 
Study results and information may lead, in the future, to new inventions or products. If the 
research investigators are able to develop new products from the use of these study results or 
informaiton, there are currently no plans to share any money or other rewards that may result 
from the development of such a new product with the subjects. 
 
6.0 
References 
1. 
Summary Health Statistics for U.S. Adults: National Health Interview Survey, 2008 
and Summary Health Statistics for U.S. Children: 
National Health Interview Survey, 2008. 
2. 
American Lung Association. Epidemiology & Statistics Unit, Research and Program 
Services. Trends in Asthma Morbidity and Mortality, November2007. 
3. 
Hall M J, DeFrances, CJ Williams SN, Golosinskiy A , SchwartzmanA. National 
Hospital Discharge Survey 2007Summary National Health Statistics Report USDepartment 
HEW, CDCP, NCHS. 
4. 
Hosp Office of Minority Health US Department of Health and Human Services; 
www.hhs.gov. 
5. 
Guidelinesfor the Diagnosis and Management of Asthma, Expert Panel Report 3 
(EPR3) 2007. NIH, NHLBI. August 2007. NIH publication no. 08-4051. 
6. 
Apter AJ,Boston RC, Georg M, et al. Modifiable barriers to adherence to inhaled 
steroids among adults with asthma: it'snot just black and white. J Allergy Clin lmmunol 
2003;111:1219-1226. 
7. 
Bender BG, Pedan A, VarastehLT. Adherence and persistencewith fluticasone 
propionate/salmeterolcombinationtherapy. J Allergy Clin lmmunol 2006; 118:899-904. 
8. 
Marceau C, Lemiere C, Berbiche D, Perreault S, Blais L. Persistence, adherence, and 
effectiveness of combinationtherapy among adult patients with asthma. J Allergy Clin lmmunol 
2006;118:574-581. 
9. 
Milgrom H, Bender B, Ackerson L, et al. Noncompliance andtreatment failure in 
children with asthma. J Allergy Clin lmmunol. 1996;98:1051-1057. 
10. 
Weinstein AG. Should patients with severepersistent asthma bemonitored for 
medicationadherence? Ann Allergy Asthma lmmunol 2005;94:251-257. 
11 
.Weinstein, AG, McKee, L, Stapleford, J, Faust, D. An Economic Evaluation of Short- 
term Inpatient Rehabilitation forSevere Asthmatic 
Children. Journal of Allergy and Clinical 
Immunology 1996; 98:264-73. 
12 
Weinstein, AG,Feldstein J, Esterly,K Final Reportofthe Medication Adherence 
Task Force Del Med Jrl 2001; 73:341-345 
13. 
Guidelinesfor the Diagnosis and Management of Asthma (EPR3) 2007. NIH, NHLBI 
August 2007. NIH publication no. 08-4051:131. 


Protocol Gentile Dulera Version Date: 20140106 
14 
 
14 
American Academy of Allergy Asthma & lmmunonology 2009. Needs Assessment for 
Continuing Medical Education for Accreditation for Graduate Medical Education. Data on file, 
2009. 
15 
Onyirimba F, Apter A, Reisine S, et al. Direct clinician-to patient discussion of inhaled 
steroid use: its effect on adherence. Ann Allergy. 2003;90:411- 415. 
16 
Wilson1, S, Strub, P, Buist SA, Knowles, S, et al Better Outcomes of Asthma Treatment 
(BOAT) Study Group Am. J. Respir. Crit. Care Med. March 15, 2010 vol. 181 no. 6 566-577. 
17. 
Blue Cross Blue Shield data onfile 
18. 
Ho J, Bender BG, Gavin LA, O'Connor SL, Wamboldt MZ, Wamboldt FS. Relations 
among asthma knowledge, treatment adherence, and outcome. J Allergy Clin lmmunol 
2003;111:498-502. 
19. 
Guevara JP, Wolf FM, Grum CM, Clark NM. Effects of educational interventions for self 
management of asthma in children and adolescents:systematic review and meta-analysis. BMJ 
2003;326:1308-9. 
20 
Walders N, Kercsmar C, Schluchter M, Redline S, Kirchner HL, Drotar D. An 
interdisciplinary intervention for undertreated pediatric asthma.Chest 2006;129:292-9. 
21. 
Smith JR, Mildenhall S, Noble MJ, Shepstone L, Koutantji M, Mugford M, et al. The 
Coping with Asthma Study: a randomised controlled trial of a home based, nurse led 
psychoeducational intervention for adults at risk of adverse asthma outcomes. Thorax 
2005;60:1003-11. 
22 
Cicutto L, Murphy S, Coutts D, O'Rourke J, Lang G, Chapman C, et al. Breaking the 
access barrier: evaluating an asthma centers' efforts to provide education to children with 
asthma in schools. Chest 2005;128: 1928-35. 
23 
Cabana MD, Le TT. Challenges in asthma patient education. J Allergy Clin lmmunol 
2005;115:1225-7. 
24 
Miller W, Rollnick S. Motivationalinterviewing: preparing people for change, 2nd ed. 
New York: Guilford Press; 2002. 
25 
Prochaska JO, DiClemente CC. Stages and processes of self-change of smoking: 
toward an integrative model of change. J Consult Clin Psycho! 1983;51:390-5. 
26 
Schmaling K, Blume A, Afari N. A randomized controlled pilot study of motivational 
interviewing to change attitudes about adherence to medications for asthma. J Clin Psych Med 
Settings 2001;8:167-72 
27 
Borrelli B, Riekert K, Weinstein A, Cardella L. Brief Motivational Interviewing as a clinical 
strategy to promote adherence to asthma therapy. J Allerg Clin lmmunol 2007;120: 1023-30 
28 
Weinstein A G The potential of asthma adherence disease management to enhance 
asthma guidelines. Annals of Allergy and Immunology 2011;106:283-291 
29 
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of 
a questionnaireto measure asthma control. Eur Respir J 1999b;14(4):902- 7. 
30 
Juniper EF, Bousquet J, Abetz L, Bateman ED, and The Goal Committee. Identifying 
'well controlled and not well-controlled asthma using the Asthma Control Questionnaire. Respir 
Med 2006; 100:616-621 
31 
G.M. Fitzmaurice, N.M. Laird, and J.H.Ware, Applied Longitudinal Analysis (2nd 
Ed.),Wiley, NewYork, 2011. 
32 
Weinstein AG Asthma adherence management for the clinician. J Allergy Clin lmmunol: 
In Practice 2013; 1:23-28 
33 
Schatz M, Zeiger RS, Yang S-J, Weinstein A, Chen W, Saris-Baglama,RN, Turner- 
Bowker, DM. Development and Preliminary Validation of the Adult Asthma Adherence 
Questionnaire J Allergy Clin lmmunol: In Practice 2013;1:280-288 


Protocol Gentile Dulera Version Date: 20140106 
1 
 
PROTOCOL: Improving Asthma Control in the Real World: A Systematic Approach to 
ImprovingDulera Adherence - a controlled study testing the effectiveness of an adult asthma 
adherence disease management program to improve asthma control by promoting adherence to 
Dulera 
 
PROTOCOL VERSION DATE: 
January 6, 2014,Version1.0 
PRINCIPAL INVESTIGATOR: Deborah Gentlie, MD, Allegheny Singer Research Institute. 490 
East North Avenue, Suite 207, Pittsburgh, PA 15212 
 
SOURCES OF SUPPORT: Asthma Management Systems (with an award from Merck) 
 
1.0 
Objective and Specific Aims 
1) Enhance asthma control by delivering the asthma adherence disease management protoco,l 
Asthma AdherencePathway™. 
 
2) Enhance adherence to Dulera relative to a clinical benchmark by delivering asthma 
adherence disease management protocol, Asthma Adherence Pathway™. 
3) Initiate validation of Adult Asthma Adherence Questionnaire (AAAQ) 
 
Hypotheses: 
Primary   Clinical   Hypothesis:   Poorly   controlled   subjects   with   moderate-to-sveere  asthma 
(measured by Asthma Control Questionnaire (ACQ) 1) despite treatment with Dulera, who are 
treated with the asthma adherence disease management protocol, Asthma Adherence 
Pathway™, will achieve greater asthma control than similar control subjects  who  are treated  
with thecurrent standard of care. 
 
Primary end point: There will be four measures of Asthma Control Questionnaire (ACQ) over 
time over 3 months. The primary endpoint is the third month measure of ACQ. 
 
Secondary Clinical Hypothesis: The asthma adherence disease management program, Asthma 
Adherence Pathway™, will increase observed adherence to Dulera relative to a benchmark of 
60% adherence (i.e., expected prescribed actuations). 
 
Secondary end points: a) Average adherence to Dulera over the three month study period 
 
Tertiary Clinical Hypothesis: Responses to Adult Asthma Adherence Questionnaire (AAAQ) will 
be related to Dulera Adherence 
 
Tertiary Study Endpoints: There will be 2 measures of the AAAQ (first and last visit) and the 
tertiary endpoint is the last visit 
 
 
2.0 
Background and Significance 
Approximately 22 million Americans have asthma, 6 million under 18 years of a e.1 The annual 
cost of asthma care is estimated at $19.7 billion,2 with 456,000 hospitailzations and 1.5 million 


Protocol Gentile Dulera Version Date: 20140106 
2 
 
ER visits.2 African Americans are three times more likely to be hospitalized or die from asthma 
than other groups.
4 Inhaled corticosteroids effectively control symptoms and reduce morbidity, 
mortality, health care utilization and cost.5 However, 45-60% of patients do not adhere to 
preventivedrug regimens.6 7· 8• Adherence rates for inhaled corticosteroids (ICS) range from 44% 
t7o8 72%7. But only 8% to 13% of patients taking ICS continue to fill prescriptions after one year. 
• It is difficult for clinicians to determine whether treatment failure is due to an inadequate 
medication regimen or poor adherence, in part because self-reported adherence is unreliable.9 
Physicians may get a false impression of a drug's effectiveness if a patient is not truthful about 
medication taken. Non-adherent patients are at risk for excess morbidity and mortality, as well 
as excess imaging, lab tests and consultations, due to the inability to accurately determinethe 
cause of treatment failure1.0 
This study will assess adherence to the study medication, Dulera. This medication is being 
provided free of charge by Merck. Separate studies involving other asthma medications are 
warranted at a later time. The focus of this proposal is to test a treatment mode,l delivered by 
clinicians who acquire Adherence/Communicationskills, which may increase asthma control, 
improve adherence to Dulera, and enhance subjects' perception of the effectiveness of Dulera. 
The asthma adherence disease management (AADM) intervention strategy consists of three 
components: 1) objective adherence monitoring; 2) identificaiton of barriers to treatmen;t and 3) 
Motivational Interviewing adherence strategies that address specific barriers.32 In an 
uncontrolled pilot study, the Pl used medicaiton monitoring and psycho-educationaladherence 
programs in children with severe asthma to significantly reduce morbidity, ER use, 
hospitalization, and cost.11 This research led to the formulation of AADM principles to be tested 
in this controlled study.12 The research addresses two important knowledge gaps. First, NHLBI 
Expert Panel Report 3 (EPR-3) states that adherence monitoring is a key component of asthma 
management, but notes that the quality of the supporting data is weak, and encourages 
controlled trials to further evaluate the effectiveness of objective adherence monitoring.13 
Second, 56% of American Academy of Allergy Asthma & Immunology members responding to a 
survey, report that they lackcompetency managing non-adherent patients.14 
Individual components of the model have been tested inp romot ing asthma adherence and 
improving control. Milgrom et al.9 as well as Onyrimba et al.1 demonstrated the effectiveness of 
using electronic adherence monitors attached to inhaled corticosteroid MDls (ICS) to diagnose 
adherence status and improve adherence. Wilson et al demonstrated the effectiveness of 
shared-decision making, one type of patient-centered communication that has many features 
similar to Motivational Interviewing, to improve asthma control and adherence.16 Weinsteinet al 
combined  medicaiton  monitoring  with  psycho-educational   family  interventions  to  improve 
adherence and decrease morbidity and cost from asthma. The reduction in morbidity and cost 
was thought to be related to: objective feedback regarding medication use; identification of 
barriers and counseling that identified patienVfamily ambivalence about treatment; and 
enhancing motivationto follow thru with a complex treatment plan. Weinsteinemployed all three 
components of the model (ICS adherence monitors; assessment of adherence barriers; 
Motivational Interviewing adherence strategies) in reducing asthma costs by 72% in a pilot 
organized by Blue Cross Blue Shield DE.17 
The rationale for using Motivational Interviewing is the observation that educating patients about 
asthma yields little improvement in adherence or outcomes.18 Interventions that encourage 
patients to monitor symptoms or peak flow have shown significantbut small effects on asthma 
morbidity.19 Self-management approaches, including identifying barriers to adherence, self- 
monitoring medicationuse, goal setting, and problem solving, result in fewer ER visits18, short- 
term improvements in adherence,19 2•0  higher  asthma  management  self-efficacy,20 21•  improved 


Protocol Gentile Dulera Version Date: 20140106 
3 
 
• 
• 
• 
quality of life, 15 16 reduced asthma symptoms,19 22 and less beta-agonist use.19 22 Unfortunately, 
the majority of self-management studies involve more than 5.5 hours of patient contact.23 
An important limitation of both educational and self-management approaches is that they are 
predicatedontheassumption that patients aremotivated to accept treatment recommendations. 
These approaches mi ht be effecitve for those who are ready to change but less so for those 
who are not ready.24• 2 Schmaling et al.26 for example, found that asthma education resulted in 
increased knowledge but decreased motivation to use medication. There is a need for 
innovative approaches to promote motivation for medication adherence that 1) build on 
previously validated interventions, 2) are easily integrated into standard clinical care, and 3) 
target both those who are ready and those who are not ready to change. 
 
Dr. Weinstein is a Motivational Interviewing trainer, with extensive experience in helping 
clinicians acquire adherence and communication skills. He designed and is the director of the 
Adherence and Communication Course held at the American Academy of Allergy Asthma & 
Immunology annual meeting, and has provided adherence/communication training to 
Allergy/Immunology training programs in the US. The use of patient-centered Motivational 
Interviewing Adherence Strategies (MIAS, reviewed below), as well as objective feedback on 
Dulera use, is expected to improve asthma control and improve adherence2.•7  28 Dr. Weinstein 
(in his role with the Asthma Management Systems) is the recipient of the Merck grant and a 
sponsor for this study. He is not a co-investigator for the study and will not make protocol 
decisions. He will provide training to the investigators and will be provided with a de-identified 
dataset for analysis. 
 
Dr. Weinstein was part of a research team that developed a 5 question adherence questionnaire 
for adults with asthma (Adult Asthma Adherence Questionnaire-AAAQ).33 The study of 420 
subjects found that these 5 questions related to other measures of adherence and to asthma 
control can be used clinically to identify patients at risk of nonadherence and the specific 
adherence barriers involved.. Five items (Following my medication plan; forgetting; not needing 
ICS; side effects; and cost) were related to self-reported low adherence or previous ICS refill as 
well as asthma control (ACT). The AAAQ instrument will be used for the purposes of this 
research study. 
 
3.0 
Research Design and Methods 
Study design: 
This study will make use of a cluster experimental design where repeated assessments over 
time are nested within patients and patients are nested within physician. Some clinicians will be 
assigned to the treatment condition and some to the control group (which will be practicing the 
current standard of asthma care). A total of 60 subjects will be enrolled in to the study. 
Subjects being seen for regular asthma care and who are beingprescribed Dulera 100/5 based 
upon asthma severity and dosing guidelines (and regardless of participation in this research 
study) will be asked to participate in this research study. Also, these subjects with asthma are 
routinelyprescribed Proventil HFA as their rescue inhaler. For the purposes of the study, these 
medications(Dulera 100/5 and Proventli HFA) will be provided to all subjects as part of study 
participation. 
 
The subjects will be assigned to either the intervention or control group at the time they sign the 
consent form. These subjects will be placedinto their respective groups in an alternating 


Protocol Gentile Dulera Version Date: 20140106 
4 
 
process, irrespective of subject demographics, treating clinician or previous asthma treatment to 
minimize bias 
Study drug: 
Dulera is a combination product containing a corticosteroid and a long-actingbeta2-adrenergic 
agonist, FDA approved and indicated for treatment of asthma in patients 12 years of age and 
older. 
 
PROVENTIL® HFA Inhalation Aerosol is FDA approved and indicated in adults and children 4 
years of age and older for the treatment or prevention of bronchospasm with reversible 
obstructive airway disease and for the prevention of exercise-induced bronchospasm. Proventil 
will be given as a rescue medication in this study. 
 
Study drug will be kept at room-temperature in a locked cabinet located within Dr. Gentile's 
office and will be accessible only to study staff. 
During the course of the study (after the screening), bothstudy drugs will include Smartlnhaler 
adherence monitors. The Smartlnhaler is FDA approved and will provide electronic data for 
recording and monitoring actuations of prescribed MDI usage. This electronic data will be 
downloaded to a password-protected computer at the study site. 
 
Motivational interviewing: 
Prior to the patient management phase, clinicians will receive training in asthma adherence 
disease management strategies as well as in Motivational Interviewing to optimize delivery of 
the adherence interventions. They will be given a written test regarding 
adherence/communicationprinciples prior to training and at the end of the study. The curriculum 
includes articles, video examples and role-playing. Asthma Management Systems LLC has 
developed and tested a web-based Asthma Adherence Disease Program (Asthma Adherence 
Pathway-SEE MEASURES BELOW) which guides patients and clinicians through the 
adherence interventions. (28) Patients identify adherence barriers from the Asthma Adherence 
Pathway. The patients receive written and video feedback regarding the significance of their 
concerns. This feedback previews potential strategies which will be delivered by clinician. The 
clinician reviews the barriers identified by the patient. He/she is presented with links to 
Motivational Interviewing Adherence Strategies, in both written and video formats. These 
strategies serve as prompts for interventions in the study by the clinician as a clinical decision 
support system. Weinstein will review this material at the training sessions and how to use it for 
subjects. 
 
Measures (see a/so adherence flowchart below ): 
 
• 
ADHERENCE: Dulera adherence is calculated as the number of actuations measured by 
Smartlnhaler divided by the number of actuations expected between clinic visits 
o 
Definition of Dulera Adherence: Subjects with 
60% actuations during the 
interval between clinic visits 
o 
Definition of Dulera Nonadherence: Subjects with < 60% actuations during the 
interval between clinic visits (Rationale for 60% adherence cut-off is to maximize 
asthma control. 60% cut-off has been used by Ho and Bender et al (2006) as a 
suitable criterion of adherence). 
 
• 
ASTHMA CONTROL QUESTIONNAIRE (ACQ):29·  30 This brief questionnaire includes 
asthma symptoms, frequency of albuterol use and measureof pre-bronchodilator FEV-1, 


Protocol Gentile Dulera Version Date: 20140106 
5 
 
providing 7 elements for analysis. There is a 1-6 likert scale for each item. The score is 
the mean of the 7 responses. 
o 
WELL CONTROLLED: Scores 
0.75 
o 
NOT WELL CONTROLLED: Scores 
1.5 
o 
INDETERMINATE: Scores in between 0.76 and 1.49 
• 
For the INDETERMINATE group: asthma control will be determined by 
the frequencyof Proventli HFA use. 
• 
"Well controlled" will be defined as the use of the Proventil HFA 2 
inhalations 2 days per week during the interval not related to 
exercise 
• 
"Not well controlled" will be defined as the use of the ProventliHFA 2 
inhalations 3 days per week during the interval not related to 
exercise 
 
• 
ASTHMA ADHERENCE PATHWAY:™ (completedby Intervention Group):  The Asthma 
Adherence Pathway™ (AAP) is a computer-basedInterne,t clinical decision support tool 
designed to improve adherence to medication and asthma management behaviors that 
affect asthma control. The subject completes the Internet-based AAP at entry into the 
study. This permits review by both subject and provider. The system recommends 
specific actions by the subject and provider based on the system's input. The subject 
inputs attitudes and behaviors about disease management at the entry of the study. The 
subject receives asthma and adherence education in both written and video format to 
reinforce subsequent interventions by the provider. Prior to onset of the study the 
provider receives training to implement the Motivational Interviewing Adherence 
Strategies (MIAS) that address the specific concerns of the subjects. The AAP provides 
the analysis of the subject's barriers in the form of "prompts" as a clinical decision 
making tool. It gives the provider recommendations on delivering MIAS that were 
presented in the earlier training. The adherence barriers identified by the subjects 
include (11): 
o 
Ineffective management: not following the asthma medication plan; delaying 
treatment of symptoms; not removing self from an area causing symptoms; not 
following instructions to treat an asthma attack; not measuring peak flow. 
o 
Negative attitudes about treatment: do not need medication; medicine does not 
work. 
o 
Symptoms during distressing emotional states: angry; upset; frustration; 
depression; anxiety. 
o 
Lack of comprehension of care instructions: uncertain when to use which 
medication;  not  understanding  how  to  use  prescribed  medication,  especially 
inhalation technique; not understanding how to use a peak flow meter. 
o 
Quality of life disruption: sleep, recreational activities, home activities, work, 
school. 
o 
Lack of agreement by significant other with the treatment plan 
o 
Cost, side effects, forgetfulness. 
A  3-point  likert  scale  (Never,  Sometimes,  Often)  is  provided  for  patients  to  identify 
barriers. Those responses (Never or Often) depending on the wording of the question 
that denote a "significant barrier" will be reviewed by the provider. The provider uses the 
recommended Motivational Interviewing Adherence Strategies contained within the 
software and presented in the training sessions. The Adult Asthma Adherence Pathway 
has been shown to have preliminary validation for non-adherent adults.14 


Protocol Gentile Dulera Version Date: 20140106 
6 
 
• 
ADULT ASTHMA ADHERENCE QUESTIONNAIRE (AAAQ) (completed by 
lnterventional Group): The AAAQ consists of five questions related to other measures of 
adherence and to asthma control that can be used clinically, to identify patients at risk of 
nonadherence and the specific adherence barriers involved. It uses a 6 likert scale. By comparing 
objectively measured adherence to the AAAQ, it would be possible to determine the  validity of 
this brief instrument. Although only 20 subjects in the Intervention group will complete the AAAQ, 
the sponsor is conducting multiple adherence studies with the Smartlnhaler that will provide 
sufficient numbers to evaluate the validity of the AAAQ. 
 
VISIT PROCEDURES 
 
Screening visit (all subiects) - approximately 2 hours: 
• 
Subject completes consent form 
• 
Subjectgiven Dulera 100/5 and Proventli(withoutelectronic Smartlnhaler adherence 
monitors) and instructions foruse 
• Physical Examination and medical history 
• Spirometry 
• Subject completes asthma control questionnaire (ACQ) 
• Study staff collects demographic information 
• Demonstrate use of peak flow (subjects given diary to record and generate "personal 
best") 
 
If subject experiences no side effects with Dulera 100/5 they will return in two weeks for a 
baseline visit (Week 2 ± 3 days) to be alternated between either the "lnterventional"or "Contro"l 
(standard of care) group. 
 
All subjects will continue to receive Dulera throughout the course of the study and this 
medication will be provided free of charge. All subjects will be provided with the Dulera 
medication guide and an individualized asthma action plan. Subjects will be informed of the 
potential of asthma symptoms and asked to contact the investigator for further instructions if 
they develop these symptoms. 
INTERVENTIONALGROUP 
 
 
Baseline visit for Intervention group (Week 2 + 3 days) - approximately 60 minutes: 
• 
Physical examination of upper/lowerairways 
• 
Assessment of adverse events, medications, and intercurrent illnesses 
• 
Spirometry pre/post bronchodilator 
• 
Subject completes asthma control questionnaire (ACQ) 
• 
Subject completes Adult Asthma Adherence Questionnaire (AAAQ) 
• 
Subject given Dulera 100/5 and Proventil (each with Smartlnhaler device) and 
informed that it will measure MDI use and be reviewedat each visit. 
• 
Evaluation (correction if needed) of inhalation technique of MDls 
• 
Subject completes asthma adherence disease management software (Asthma 
Adherence Pathway™)to identify patient barriers (5-10 minutes) and provide asthma 
education 
• 
Clinician to initiate specific Motivational Interview  Adherence  Strategies  as 
determined by AAP. If subject has more than 2 barriers, the clinician will  review  
those at next clinic visit in 2 weeks. 


Protocol Gentile Dulera Version Date: 20140106 
7 
 
• 
Revie w Peak flow diary and Asthma Action Plan with instructions to notify provider if 
Peak Flow :s: 50 % of measured peak flow during initial  clinic visit. "Personal Best" to  
be identified at next clinic visit in 2 weeks. 
 
Follow up visits for Intervention group - 60 minutes: 
 
• 
Physical Examination 
• 
Assessment of adverse events, medications, and intercurrent illnesses 
• 
Spirometry without bronchodilator to determine ACQ 
• 
Assessment and feedback of Dulera adherence 
• 
Subject completes asthma control questionnaire(ACQ) 
• 
Assessment of inhalation technique 
• 
Review Peak Flow diary 
• 
Subject and clinical interaction based upon adherence and asthma control 
measures (see adherence flowchart below) 
 
Each time the patient is found to be nonadherent, he/she will be asked to return in 2 weeks ± 3 
days for the next assessment (up to a maximum of 6 visits). A subject who is identified as non- 
adherent 3 times during the study will be asked to return for a final visit one month later and will 
not be given adherence feedback. 
 
 STANDARD OF CARE (CONTROL) GROUP 
 
 
Baseline visit for Control group /Week 2 + 3 days} - approximatel y 60 minutes: 
• 
Physica l examination of upper/lower airways 
• 
Assessment of adverse events, medications, and intercurrent illnesses 
• 
Spirometry pre- bronchodilator to determine ACQ 
• 
Subject completes asthma control questionnaire (ACQ) 
• 
Review Peak Flow diary and develop an Asthma Action Plan 
• 
Provide Asthma Education 
 
Follow up visits for Control group (Week 6, Week 10, Week 14, all ± 3 days) - approximatel y 
60 minutes: 
• 
Physica l examination of upper/lower airways 
• 
Assessment of adverse events, medications, and intercurrent illnesses 
• 
Spirometry pre- bronchodilator to determine ACQ 
• 
Subject completes asthma control questionnaire (ACQ) 
• 
Review Peak Flow diary 
 
Dose changes: It may be a possibility that during the course of this study, the research 
physician determines it is in the subject's best interest to increase the dose of Dulera to 200/5 
based on the subject's asthma control and dosing guidelines. Any other changes in medication 
are discussed under Concomitant treatments. 
 
Early Withdrawal of Subjects: Criter ia for subjec t withdra wal or rem oval from the study include 
the following: 
• untoward reaction to the study medications 
• lost to follow up (do not report to the clinic for scheduled visit) 


Protocol Gentile Dulera Version Date: 20140106 
8 
 
• non-compliance(do not return to the clinic with medication and monitors) 
• subject consent withdrawal 
Subjects who withdraw because of Dulera or Proventli side effects will receive follow-up phone 
calls within 24 hours to evaluate need for further follow-up care. All subjects who do not 
complete the protocol will be replaced. 
Concomitant treatments: During the course of the study, the use of any other orally inhaled 
steroid formulations is prohibited, In addition, any medicaitons that are known to have a drug 
interaction with Dulera are prohibited. Any other medications are acceptable as long as dose 
remains stable over the course of the study. If it becomes necessary for the subject to begin one 
of these medications or change doses, they will be removed from the study and replaced. 


cont rol [via ACQ) 
J 
  
co  nt rol
r
[via ACQ) 
o· 
n
0, 
l 
Gl 
Cl) 
 
i:o 
0 
i
C
:
:
o 
i.il 
vl 
::, 
0 
Ol 
 
Iv 
0t 
 
 
 
 
APPENDIX A: Dulera adherence flowchart(version 20131106) 
 
 
 
 
M easurement of 
 
 
 
 
 
 
 
 
< 60% actuations 
(Nonadherent) 
 
 
M easureme nt of 
 
)> 
:
Cz:: 
m 
:mz
:::l:J 
mn 
'rT-l 
0 
: E 
:z:: 
)> 
 
0 
Well controlled 
Indeterminate control 
Not wellcontrolled 
Well controlled 
Indeterminate control 
Not wellcontrollecl 
(ACQs:0.75) 
(0.75 <ACQ< 1.50) 
(ACQ2: 1.50) 
(ACQ,;0.75) 
(0.75 <ACQ< 1.50) 
(ACQ2:1.50) 
 
 
 
 
(0 
 
 
 
 
 
 
 
Continue initi al '4 
regimen 
;;, 60% act uati ons 
(Adherent) 
Actuati ons 
< 25 % 
Actuations 
;,; 2 5-59% 
Removed from 
the  stu d y 
1+-    -     - 
-' 
Willreceive feed- 
backand contin ue 
with Oulera 100/S 
Proventil 
HFA use 
;, 3 days/wk 
Proventil 
HFA use 
:s:2 d.i ys/w k 
Proventi l 
HFA use 
3 days/wk 
Incr ease to Dulera 
200/5 andmaintain 
th t rlnsP 
Measurement ofadherence 
[% actuatio ns or Oulera M DI) 
Proven til 
HFA use 
,; 2 days/wk 
----------- J 


Protocol Gentile Dulera Version Date: 20140106 
10 
 
4.0 
Statistical Considerations: 
 
Statistical power: The ACQ consists of 7 questions scaled from 0 (best asthma control) to 6 
(worst asthma control). Assuming a large treatment effect (i.e., a difference of .8 standard 
deviation units in the outcome) reflecting absolute change in the asthma control outcome, small- 
to-moderate levels of intraclass correlation, 40 patients nested within 8 clinicians in each 
condition, and alpha of .05, statistical power for the test of the primary hypothesis exceeds .80. 
The power analysis is based on a variance estimate of .70 and a score change of .5 in the ACQ 
being a minimal important difference.31 The study plans to enroll up to 60 subjects as subjects 
who are non-compliant will be replaced to allow for 40 total to complete the study. 
 
Planned statistical analysis: The primary analysis of the four repeated measures of the Asthma 
Control Questionnaire (ACQ) over time over 3 months will done using linear or nonlinear mixed 
modeling (Fitzmaurice, Laird, & Ware, 2011) to determine whether the intervention group 
demonstrates different average individual trajectories of change compared to the control group. 
The primary endpoint is the third month measure of the ACQ. 
Forthe AAAQ secondary analysis, wewill compare the observed versus expectedratios (mean 
or median depending on the distribution) in 1) patients with a positive (abnormal) response to 
question 1 (responses 2-6) versus those without a positive response (response 1); 
and 2) patients with a positive (abnormal) response to any question (QA: response 1-3; QB: 
response 1-4; QC: response 1-3; QD: response 1-3) versus those with no positive responses: 
QA: 4-6; QB:4-6; QC: 4-6; QD: 4-6. For the secondary analysis we will examine changes in the 
AAAQ over time (expressed as 0, 1, or 2 or more positive responses) in relationship to the 
change in observed versus expected ratios over time. The AAAQ will be completed atentry into 
the study and at the conclusion at 3 months. Suitable subjects in future studies that use 
electronic adherence monitors will also complete the AAAQ permitting an attempt to validate 
this instrument. 
No interim statistical analysis will be done prior to compleiton of all data collection. 
Missing data considerations: When dealing with missing data in a longitudinal study, restricting 
analyses to make use of only cases with complete repeatedly measured data can substantially 
bias statistical findings. Assuming data are missing at random (MAR) or missing completely at 
random (MCAR), multiple imputation and full informationmaximum likelihood estimationare two 
principled and recommended techniques for dealing with missingness. We will be using 
statistical packages (i.e., SAS, Mplus) that can accommodate missing data on the outcome 
variables and make use of all available data for each subject in planned analyses. As noted in 
the Research Design section earlier, we will include in statistical analysis all subjects who 
complete at leastthree clinical visits in either the intervention or control groups. 
 
4.1 Inclusion of Children in Research: Subjects ages 18 and under will not be includedin this 
study as this is a preliminary study and a separate, age-specific study in children is warrantedin 
the future. 
4.2 Inclusion/Exclusion Criteria: 
Inclusion Criteria 
1. Physician diagnosis of asthma of moderateseverity 
2. Subjects :2:: 18 years of age 


Protocol Gentile Dulera Version Date: 20140106 
11 
 
3. Currently receiving an inhaled corticosteroid medication and being prescribed Dulera 
100/5 as part of standard of care based upon asthma severity and dosing guidelines 
4. Asthma Control Questionnaire (ACQ) result> 1.0 at entry 
5. Demonstration of correct inhalation technique for use of meter-dosed inhalers (MDls) 
6. History of reversible airwayobstruction documented by treating physician 
Subjects will be recruited for intervention and control groups from the same geographic area 
and time of year to avoid seasonal variations of asthma symptoms and will be capable of giving 
informed consent. 
 
Exclusion Criteria 
1. Intermittentasthma (asthma exacerbations or symptoms< 3 days/week) 
2. Diagnosis of emphysema in prior year 
3. Diagnosis at any time of: chronic obstructive pulmonary disease (COPD), chronic 
bronchitis, cystic fibrosis, bronchiectasis, Churg Strauss, Wegener's, sarcoidosis, 
pulmonary hypertension or lung cancer 
4. On any medicaiton documented to have a druginteraction with Dulera 
 
4.3 Recruitment Procedures: 
Subjects will be recruited from the investigator's patient practice population and referred by 
other physicians within the health system. Regardless of where subjects are recruited, 
consenting and all study visits and associated procedures will be performed in a private area in 
Dr. Gentile's practice. 
 
Study investigators will obtain written informed consent from the subject before completing any 
study procedures.  Subjects will be given ample time to review the consent and all questions will 
be answeredto ensure the subject's understanding. 
 
4.4 Risk/BenefitRatio: 
This research study presents less than minimal risk to the subject in that the probability and 
magnitude of harm or discomfort anticipated are not greater in and of those ordinarily 
encountered in daily life or during routine physical exams or tests. 
 
Risks of Du/era 
The most common side effects of DULERA include inflammation of the nose and throat, 
inflammation of the sinuses, and headache. Less common side effects of  Dulera  include:  
serious allergic reactions, thrush (yeast infection) in the mouth and throat, a higher chance of 
infection, reduced adrenal function, increase in wheezing right after taking DULERA, lower bone 
mineral density, slowed growth in children, eye problems including glaucoma and cataracts, 
decrease in blood potassium and increase in blood sugar levels. 
 
Formoterol, one of the active ingredients in DULERA, increases the risk of asthma-related 
death. In pediatric and adolescent patients, formoterol may increase the risk of asthma-related 
hospitalization. It has not yet been determined whether the use of inhaled corticosteroids (a 
component of DULERA) or other long-term asthma-control therapy decreases or eliminates this 
risk. 
 
Risks of Proventil HFA 
Risks of Proventil HFA include fast heart rate and high blood pressure, nausea, dizziness, 
nervousness, difficulty sleeping, headache,  and a jittery or nervous feeling.   These symptoms 


Protocol Gentile Dulera Version Date: 20140106 
12 
 
usually go away within one hour. It is likely that subjects already use albuterol and are familiar 
with how they react to this medication. 
Risks of questionnaires and interview procedures 
An infrequent study risk includes fatigue and performance anxiety while completing 
questionnaires and interviews, or may cause discomfort if subject has a disagreementwith the 
physician about medication use (adherence). Throughout the process, the subject will be 
queried about fatigue and adequate time will be allottedto allow the subject to rest. Open and 
honest dialogue with physician is encouraged; however subjects will not be required to answer 
any questions that make them uncomfortable. 
 
Risks of Spirometry 
Occasionally, spirometry may cause some dizziness, shortness of breath, cough or chest 
tightness. Subjects will be treated by a study doctor if these occur. 
 
Risk of Unintentional Disclosure of your Private Health Informatio n 
Another potential risk is anunintentional disclosure of privatehealth information. However, this 
is very unlikely because the study team has procedures in place to try to prevent this from 
happening. The information collected will be stored in a locked office and on password 
protected computers. 
 
Potential benefits 
While there are no direct benefits from participationin the study, subjects may receive benefit 
from the study medication when taken, may experienceimprovement in their quality of life and 
may improve their medicaiton adherence for other treatments. 
Proteciton Against Risk 
All assessments will be completed by research staff and/or physicians trained in appropriate 
administration   of   assessment   protocols   or   procedures.   Subjects   will   be   instructed   by 
investigators to avoid medications that have interactions with Dulera/Proventil. Subjects will 
also be instructed to discontinue medication if side effects develop. 
 
Data Confidenitality and Integrity 
The data collected will be used for research purposes only, and participants will be identifiedby 
code designation. All data collected for this project will be kept strictly confidential and will be 
kept in a locked cabinet or room. All data will be catalogued using the participant's study ID 
number. All research staff members are required to respect the confidentiality of participants 
and to complete institutionally required subject protection training. 
Data and Safety Monitoring Plan 
The principal investigator and study staff will review the study annually at the time of continuing 
review to assess adequacy of procedures and to ensure subject privacy, research 
confidentiality, data quality, and study procedures. Also to be assessed are study goals and 
modifications of those goals; subject recruitment, accrual and retention, progress in data coding 
and analysis, documentaiton, identificaiton of adverse events or research subject complaints, 
and any issues or concerns at that time. Also, assessment will be made of external factors or 
relevant information that may have an impact on the safety of study participants or the ethics of 
the research study. 
 
5.0 
Costs and Payments 


Protocol Gentile Dulera Version Date: 20140106 
13 
 
5.1 Research Study Costs: Neither the participant, nor his/her insurance provider  will  be 
charged for the costs of any of the procedures performed for the purpose of this research study 
or for the Dulera and Proventil HFA study drug. The participant's health insurance will be billed  
in the standard manner for routine care costs. This includes any routine appointments  with  
his/her physician(s) or any other tesUtherapies the doctor recommends. Any deductible or co- 
payments that are part of his/her insurance coverage will apply. 
 
5.2 Research Study Payments:Participants will receive a $50 for each completed study visit, up 
to a maximum of $300 if all 6 visits are completed. Subjects will receive a Payoneer Debit 
MasterCard which can be used anywhere that debit MasterCards are accepted (including 
online). When subjects receive the card, they will be provided further information about the card 
including how to use the card, confidentiality, and privacy information. If a subjectreceives 
$600 or more from for taking part in this research study or a combination of studies in one tax 
year, they will be sent a 1099 form for tax purposes. 
 
Study results and information may lead, in the future, to new inventions or products. If the 
research investigators are able to develop new products from the use of these study results or 
informaiton, there are currently no plans to share any money or other rewards that may result 
from the development of such a new product with the subjects. 
 
6.0 
References 
1. 
Summary Health Statistics for U.S. Adults: National Health Interview Survey, 2008 
and Summary Health Statistics for U.S. Children: 
National Health Interview Survey, 2008. 
2. 
American Lung Association. Epidemiology & Statistics Unit, Research and Program 
Services. Trends in Asthma Morbidity and Mortality, November2007. 
3. 
Hall M J, DeFrances, CJ Williams SN, Golosinskiy A , SchwartzmanA. National 
Hospital Discharge Survey 2007Summary National Health Statistics Report USDepartment 
HEW, CDCP, NCHS. 
4. 
Hosp Office of Minority Health US Department of Health and Human Services; 
www.hhs.gov. 
5. 
Guidelinesfor the Diagnosis and Management of Asthma, Expert Panel Report 3 
(EPR3) 2007. NIH, NHLBI. August 2007. NIH publication no. 08-4051. 
6. 
Apter AJ,Boston RC, Georg M, et al. Modifiable barriers to adherence to inhaled 
steroids among adults with asthma: it'snot just black and white. J Allergy Clin lmmunol 
2003;111:1219-1226. 
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Bender BG, Pedan A, VarastehLT. Adherence and persistencewith fluticasone 
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Marceau C, Lemiere C, Berbiche D, Perreault S, Blais L. Persistence, adherence, and 
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9. 
Milgrom H, Bender B, Ackerson L, et al. Noncompliance andtreatment failure in 
children with asthma. J Allergy Clin lmmunol. 1996;98:1051-1057. 
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Weinstein AG. Should patients with severepersistent asthma bemonitored for 
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.Weinstein, AG, McKee, L, Stapleford, J, Faust, D. An Economic Evaluation of Short- 
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Weinstein, AG,Feldstein J, Esterly,K Final Reportofthe Medication Adherence 
Task Force Del Med Jrl 2001; 73:341-345 
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Guidelinesfor the Diagnosis and Management of Asthma (EPR3) 2007. NIH, NHLBI 
August 2007. NIH publication no. 08-4051:131. 


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14 
American Academy of Allergy Asthma & lmmunonology 2009. Needs Assessment for 
Continuing Medical Education for Accreditation for Graduate Medical Education. Data on file, 
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15 
Onyirimba F, Apter A, Reisine S, et al. Direct clinician-to patient discussion of inhaled 
steroid use: its effect on adherence. Ann Allergy. 2003;90:411- 415. 
16 
Wilson1, S, Strub, P, Buist SA, Knowles, S, et al Better Outcomes of Asthma Treatment 
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18. 
Ho J, Bender BG, Gavin LA, O'Connor SL, Wamboldt MZ, Wamboldt FS. Relations 
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Cicutto L, Murphy S, Coutts D, O'Rourke J, Lang G, Chapman C, et al. Breaking the 
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Cabana MD, Le TT. Challenges in asthma patient education. J Allergy Clin lmmunol 
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Miller W, Rollnick S. Motivationalinterviewing: preparing people for change, 2nd ed. 
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Prochaska JO, DiClemente CC. Stages and processes of self-change of smoking: 
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Schmaling K, Blume A, Afari N. A randomized controlled pilot study of motivational 
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27 
Borrelli B, Riekert K, Weinstein A, Cardella L. Brief Motivational Interviewing as a clinical 
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28 
Weinstein A G The potential of asthma adherence disease management to enhance 
asthma guidelines. Annals of Allergy and Immunology 2011;106:283-291 
29 
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of 
a questionnaireto measure asthma control. Eur Respir J 1999b;14(4):902- 7. 
30 
Juniper EF, Bousquet J, Abetz L, Bateman ED, and The Goal Committee. Identifying 
'well controlled and not well-controlled asthma using the Asthma Control Questionnaire. Respir 
Med 2006; 100:616-621 
31 
G.M. Fitzmaurice, N.M. Laird, and J.H.Ware, Applied Longitudinal Analysis (2nd 
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32 
Weinstein AG Asthma adherence management for the clinician. J Allergy Clin lmmunol: 
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Schatz M, Zeiger RS, Yang S-J, Weinstein A, Chen W, Saris-Baglama,RN, Turner- 
Bowker, DM. Development and Preliminary Validation of the Adult Asthma Adherence 
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