INtervention Study In overweiGHT Patients With COPD
Phase: NA
Conditions: Pulmonary Disease, Chronic Obstructive, Obesity, Weight Loss, Life Style, Overweight
Sponsor: Seattle Institute for Biomedical and Clinical Research

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INtervention Study In overweiGHT patients with COPD (INSIGHT COPD) 
 
Study Protocol 
 
January 28, 2021 
 
 
 
VA Puget Sound IRB 2
Effective Date:
February 18, 2021

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1.0. 
SUMMARY OF EDITS: ...................................................................................................................................................... 4 
2.0. 
ABBREVIATIONS .............................................................................................................................................................. 5 
3.0. 
FUNDING SOURCE ........................................................................................................................................................... 6 
4.0. 
RESEARCH CONSORTIUM / STAFF .............................................................................................................................. 6 
5.0. 
ABSTRACT ......................................................................................................................................................................... 7 
6.0. 
BACKGROUND .................................................................................................................................................................. 8 
7.0. 
INNOVATION .................................................................................................................................................................... 10 
8.0. 
RATIONALE OF E-LITE AS THE BASIS OF THE INSIGHT COPD INTERVENTION .............................................. 11 
9.0. 
AIMS .................................................................................................................................................................................. 12 
10.0. 
STUDY DESIGN ............................................................................................................................................................... 12 
10.1. 
ELIGIBILITY CRITERIA ............................................................................................................................................... 13 
10.1.1. 
Inclusion..................................................................................................................................................... 13 
10.1.2. 
Exclusion ................................................................................................................................................... 13 
10.2. 
RECRUITMENT, SCREENING, AND BASELINE ASSESSMENT ...................................................................................... 13 
10.2.1. 
EHR/COPD registry-based pre-screen ............................................................................................... 14 
10.2.2. 
Initial invitation ......................................................................................................................................... 14 
10.2.3. 
Initial online, telephone, and/or clinic recruitment ......................................................................... 14 
10.2.4. 
In-person visit: screen and baseline visit ......................................................................................... 15 
10.3. 
RANDOMIZATION ....................................................................................................................................................... 17 
10.3.1. 
Participants randomized to the intervention .................................................................................... 17 
10.3.2. 
Participants randomized to the control ............................................................................................. 18 
10.3.3. 
All participants ......................................................................................................................................... 18 
10.4. 
TIME COMMITMENT ................................................................................................................................................... 18 
10.4.1. 
Control group............................................................................................................................................ 18 
10.4.2. 
Intervention group ................................................................................................................................... 18 
10.5. 
FOLLOW-UP VISIT AND DATA COLLECTION ............................................................................................................. 19 
10.5.1. 
Time Commitment: .................................................................................................................................. 19 
10.6. 
INTERVENTION ........................................................................................................................................................... 19 
10.6.1. 
Theoretical Basis ..................................................................................................................................... 20 
10.6.2. 
Evidence-based Intervention Goals .................................................................................................... 20 
10.6.3. 
Intervention Format, Structure, and Content ................................................................................... 20 
10.7. 
PAYMENTS/REMUNERATION ..................................................................................................................................... 21 
11.0. 
MEASUREMENTS ........................................................................................................................................................... 22 
11.1. 
ANTHROPOMETRIC MEASURES ................................................................................................................................. 22 
11.2. 
EXERCISE TOLERANCE ............................................................................................................................................. 22 
11.3. 
SPIROMETRY ............................................................................................................................................................. 22 
11.4. 
DYSPNEA AND FATIGUE ............................................................................................................................................ 23 
11.5. 
CARDIOVASCULAR RISK FACTORS (CVR) ............................................................................................................... 23 
11.6. 
VITAL SIGNS .............................................................................................................................................................. 23 
11.7. 
SELF-ADMINISTERED INSTRUMENTS ......................................................................................................................... 23 
11.8. 
ADDITIONAL PROCESS MEASURES .......................................................................................................................... 23 
12.0. 
SAFETY ............................................................................................................................................................................ 24 
13.0. 
RETENTION ..................................................................................................................................................................... 24 
 
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14.0. 
ANALYSIS ........................................................................................................................................................................ 26 
14.1. 
SAMPLE SIZE ............................................................................................................................................................. 26 
14.2. 
OVERVIEW OF ANALYSIS PLAN ................................................................................................................................. 26 
14.3. 
BASELINE ANALYSIS AND DESCRIPTIVE STATISTICS .............................................................................................. 26 
14.4. 
DROP OUTS AND MISSING DATA .............................................................................................................................. 26 
14.5. 
PRIMARY ANALYSIS FOR AIM 1 ................................................................................................................................ 27 
14.6. 
SENSITIVITY ANALYSES ............................................................................................................................................ 27 
14.7. 
SECONDARY ANALYSIS FOR AIM 1 .......................................................................................................................... 28 
14.8. 
INTERIM ANALYSES ................................................................................................................................................... 28 
15.0. 
DATA MANAGEMENT .................................................................................................................................................... 29 
16.0. 
TRIAL MANAGEMENT .................................................................................................................................................... 30 
17.0. 
TRAINING AND CERTIFICATION.................................................................................................................................. 31 
18.0. 
PUBLICATIONS AND ANCILLARY STUDIES ............................................................................................................. 31 
18.1. 
PUBLICATIONS .......................................................................................................................................................... 31 
18.2. 
ANCILLARY STUDIES ................................................................................................................................................. 31 
19.0. 
REFERENCES ................................................................................................................................................................. 31 
 
 
 
 
VA Puget Sound IRB 2
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1.0. 
SUMMARY OF EDITS: 
 
8/22/2016; v3.0,  
• 
Section 3.0: Replaced Eric Gunnink, biostatistician, with Peter Rise, who starts August 2016 
 
• 
Tables 6 and 8: Added as baseline and outcome data element in order to measure Framingham Risk 
Score 
 
• 
Section 9.3.1 and 9.6.3. added clarifications and details about intervention format, structure, and 
content 
 
• 
Tables 8 and 11: Eliminated spirometry from the 12-month follow-up visit to reduce unnecessary 
participant burden and reduces needed site resources 
 
• 
Sections 9.3.2 and 9.7: Updated site payment and participant remuneration information based on 
finalized capitation allowance.  Instead of paying control participant $50 as control equivalence, we will 
provide control participants with a Fitbit at their 18-month visit 
 
10/25/2017; v3.01 
• 
Section 3.0: Update Lifestyle Coach staff from UIC 
• 
9.2.4.3: Grammatical error corrected 
 
 
03/29/2018; v3.10: 
• 
Section 8.1.1. and 9.3: changed FEV1 % predicted from >40 to >30 
• 
Section 9.4: changed mMRC eligibly criteria from a score of 2 to 1 
 
07/18/2018; v4.00: 
• 
Section 3.0: Removed staff to avoid frequent protocol modification; staff information readily available 
elsewhere 
• 
Throughout: changed target number of participants from 1000 to 680; primary outcome to six-minute 
walk test distance only at 12 months, with weight moved to secondary 
• 
Section 8.7.: removed payments to site section, updated recommended payment to patients given 
elimination of 18-month visit  
• 
Section 11.0: added detail about retention efforts 
 
09/04/2018; v4.10: 
• 
Section 8.7: corrected a typo in the amount of recommended payment to participants 
• 
Section 11.: Provided more detailed retention strategies and requiring at least one phone call four-to-
eight months after randomization. 
 
10/31/2018; v5.00: 
• 
Section 8.1.1. and 9.3: changed the spirometry eligibility criteria from the ratio of Forced Expiratory 
Volume in one Second (FEV1) to Forced Vital Capacity (FVC) being less than the lower limit of normal 
(LLN) to FEV1/FVC being less than a fixed value of 0.70. 
 
01/28/2021; v5.10: 
• 
Throughout: corrected minor typos 
• 
Throughout: corrected inconsistencies in listing secondary outcomes 
• 
Throughout: Removed references to the Fitbit Zip because of model change 
• 
Section 2.0:  added abbreviations section 
• 
Section 4.0 and 16.0: updated staff 
• 
Section 10.2 and 10.5: clarified how we are determining diabetes and high blood pressure 
• 
Section 10.2.4.3: corrected description of data entry process 
• 
Section 10.3.1: updated intervention introduction procedures 
 
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• 
Section 10.5: added details on valid reasons for out-of-window visits 
• 
Section 10.6.3: removed incorrect description about automated reminders 
• 
Section 11: Table 10 updated with clarification about source of Other Measures; added details about 
some measurements; clarified procedures for measurements 
• 
Section 14: updated a priori analysis plan 
• 
Section 15: added that PLG will share de-identified data set with NHLBI’s data repository 
 
2.0. 
ABBREVIATIONS 
 
6MWT: six-minute walk test  
AE: adverse events 
ATS: American Thoracic Society 
BMI: body mass index  
BP: blood pressure  
CMS: Centers for Medicare and Medicaid Services  
COIN: Center of Innovation 
COPD: Chronic Obstructive Pulmonary Disease  
CVD: cardiovascular disease 
CVDR: cardiovascular disease risk  
CVRFs: cardiovascular risk factors  
DPP: Diabetes Prevention Program  
DSMB: Data Safety and Monitoring Board 
EHR: electronic health records  
FEV1: forced expiratory volume in one second  
FRS: Framingham Risk Score  
FVC: forced vial capacity  
GEE: Generalized Estimating Equations  
GLB: Group Lifestyle Balance  
GOLD: Global Initiative for Chronic Obstructive Lung Disease guidelines  
HIT: health information technology  
HRQoL: health-related quality-of-life  
ICMJE: International Committee of Medical Journal Editors  
ICS: inhaled corticosteroid 
INSIGHT COPD: INtervention Study In overweiGHT patients with COPD 
IRB: Institutional Review Board  
LABA: long acting beta-agonists 
LMM: linear mixed-effects model  
MAR: missing at random  
MI: multiple imputation  
MICE: multivariate imputation by chained equations  
MID: minimum important difference  
ML: maximum likelihood  
mMRC: modified Medical Research Council  
MOP: Manual of Procedures  
NEMO: Network Management Core 
NHANES: National Health and Nutrition Examination Survey  
NHLBI: National Heart, Lung, and Blood Institute  
OC: operations committee 
PCS: physical component scores  
PCT: Pragmatic Clinical Trial   
PLG: Protocol Leadership Group  
PTC: Pulmonary Trials Cooperative 
QoL: quality-of-life  
RCT: randomized control trial  
REDCap: Research Electronic Data Capture  
 
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REML: restricted maximum likelihood 
SAE: serious adverse events  
SD: standard deviation  
SF-12v2: 12-Item Short Form  
SGRQ: St. George’s Respiratory Questionnaire 
SGRQ-C: St. George’s Respiratory Questionnaire for COPD Patients  
SIBCR: Seattle Institute for Biomedical and Clinical Research  
SpO2: blood oxygen saturation level 
UC: usual care  
UIC: University of Illinois Chicago 
 
 
3.0. 
FUNDING SOURCE 
National Heart Lung Blood Institute: 1U01HL128868 
 
 
4.0. 
RESEARCH CONSORTIUM / STAFF 
Network Management Core (NEMO) for the Pulmonary Trials Cooperative (PTC), University of 
Pittsburgh:  
 
Principal Investigators: 
Steve Wisniewski, PhD; wisniew@edc.pitt.edu 
Frank Sciurba, MD; fcs@pitt.edu 
 
Co-Investigator: 
Maria Mori Brooks, PhD; biostatistician, brooks@edc.pitt.edu 
 
Seattle Institute for Biomedical and Clinical Research (SIBCR), Prime Award Recipient: 
Principal Investigator: 
David H. Au, MD, MS; dau@uw.edu 
 
 
Seattle-Denver Center of Innovation (COIN), Subcontract: 
Principal Investigator: 
David H. Au, MD, MS; dau@uw.edu 
 
Co-Investigators: 
Anna Barón, PhD; biostatistician, anna.baron@cuanschutz.edu  
 
 
University of Illinois, Chicago (UIC), Subcontract: 
Principal Investigator: 
Jun Ma, MD, PhD;  maj2015@uic.edu 
 
 
 
 
VA Puget Sound IRB 2
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INSIGHT COPD Protocol; 01/28/2021; v5.10 
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5.0. 
ABSTRACT 
Approximately 70% of patients with Chronic Obstructive Pulmonary Disease (COPD) are obese or overweight. 
Tobacco smoking that causes COPD also is associated with other poor health habits that can lead to obesity 
and cardiovascular disease.  Symptoms of COPD are often non-specific and include dyspnea and exercise 
intolerance.  COPD treatment guidelines recommend stepped escalation of inhaled medications to improve 
these symptoms, but make little mention of the effect of co-existing obesity or weight loss interventions 
because of insufficient evidence. Cardiovascular disease is a leading cause of mortality among patients with 
COPD, and obesity is associated with important risk factors for cardiovascular disease including dyslipidemia, 
hypertension, and diabetes. Comprehensive lifestyle interventions that include calorie-controlled healthy 
eating, increased physical activity, and behavioral self-management strategies consistently result in modest, 
clinically significant weight loss and associated reductions in cardiovascular risk factors.  That overweight and 
obese patients with COPD would reap similar clinical benefits from modest weight loss is an intuitive - but 
untested - concept.  Therefore, we are conducting a multicenter, patient-level randomized, pragmatic clinical 
trial to produce first-ever data on the effectiveness of an evidence-based self-directed lifestyle intervention for 
12 months targeting modest weight loss and increased physical activity among overweight and obese patients 
with COPD.  We are serving as a Protocol Leadership Group (PLG) for the National Heart, Lung, and Blood 
Institute’s (NHLBI) "Multi-Site Clinical Trials for the Pulmonary Trials Cooperative (PTC)" in order to test if 
intervention participants have better outcomes through 12 months of follow-up compared to usual care control 
patients in terms of exercise tolerance using the 6-Minute Walk Test.  Secondary outcomes include weight 
loss, dyspnea using the modified Borg scale, generic and symptom-specific quality of life using the 12-Item 
Short Form (SF-12v2) and St George’s Respiratory Questionnaire for COPD Patients (SGRQ-C), and major 
cardiovascular risk factors using Framingham risk score, central obesity by waist circumference, blood 
pressure and BMI.  We will oversee enrollment of approximately 680 patients at multiple clinical sites, chosen 
and contracted by the PTC’s Network Management Core (NEMO).  As the PLG for the INSIGHT COPD trial, 
we will cooperate with NEMO and will provide trial oversight, and data management and reporting. 
 
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6.0. 
BACKGROUND 
Obesity is common and may lead to ineffective or even harmful care among patients with COPD. COPD 
is defined by airflow limitation that is not fully reversible, affects approximately 12 million Americans, and is the 
3rd leading cause of death in the U.S.1,2  Unlike all other major causes of morbidity in the U.S., COPD is the 
only major condition that has not had significant improvement in mortality in the past 30 years.3  The leading 
cause of COPD is cigarette smoking, which is often accompanied by other unhealthy lifestyle habits that lead 
to physical limitation and weight gain.  Being overweight or obese is a leading, if not the leading, COPD 
comorbidity, affecting up to 70% of patients with COPD.  Among obese patients, attribution of dyspnea and 
other symptoms to COPD is common despite evidence that obese patients with COPD have less severe 
airflow limitation4,5 and are less responsive to guideline recommended escalation in inhaled therapies than their 
non-obese counterparts.4  Despite the known increase in the work of breathing directly attributable to obesity,6-
11 recently revised (2014) Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines12 do not 
address the problem of obesity, except by stating that “it is not advisable to aim for a BMI of less than 21 
kg/m2.”  The lack of guidance highlights the gap that can lead to the inappropriate use of inhaled medications 
to treat symptoms of airflow limitation that is potentially attributable to obesity.  Obesity directly affects both the 
physiologic measure of airflow limitation by forced volume of expired gas in 1 second percent (FEV1%) 
predicted and the report of dyspnea severity, leading to an overestimation of COPD patients’ disease severity 
and potential overtreatment.  Obese patients that receive drug treatments for their presumed COPD severity 
may be subjected to known potential harms such as pneumonia related to unnecessary inhaled corticosteroid 
(ICS) use13,14 or potential cardiovascular risk associated with short- and long-acting inhaled bronchodilators.15-
19  Exposing patients to medications that are not effective can only increase the risk, even if the overall risk is 
small.  
 
Treatment of obesity may modify other comorbid cardiovascular risk factors (CVRFs) in patients with 
COPD. COPD is an inflammatory disorder that is closely linked to cardiovascular risk;20,21 in fact, 
cardiovascular mortality is more common than COPD-specific mortality, highlighting the significance of 
modifying CVRFs, among patients with COPD.22  Inhaled bronchodilators and ICS reduce systemic markers of 
inflammation, but do not improve cardiovascular risk or mortality, among patients with COPD.23  Smoking 
cessation is the only treatment known to reduce mortality and improve lung function decline in COPD patients 
without severe resting hypoxemia,11 and it reduces cardiovascular risk, but it can also lead to significant weight 
gain.22,24,25  The weight gain linked with smoking cessation: (1) is often a concern of patients who are 
contemplating smoking cessation;24,26-29 (2) reduces the benefits of smoking cessation on lung function by 38% 
in men and 17% in women;30 and (3) lowers protection of cardiovascular risk by worsening of lipid profiles, risk 
of type 2 diabetes and hypertension.31,32  In contrast, modest weight loss (3-5% of starting weight) through 
calorie-controlled healthy eating alone or in combination with exercise effectively lowers major CVRFs, e.g., 
hypertension, dyslipidemia, diabetes, and inflammatory biomarkers including C-reactive protein.33-39 That 
obese patients with COPD would reap similar cardiovascular benefits from modest weight loss is an intuitive - 
but untested - concept.  
 
Obese patients are more likely to be misdiagnosed with COPD and receive inappropriate medications.  
In our recently published manuscript,40 we identified 5,493 patients who 
underwent pulmonary function testing and carried a clinical diagnosis of 
COPD.  Of these patients, 75% were overweight or obese.  We found 
that after excluding patients for other pulmonary conditions (e.g., 
asthma), overweight and obese patients were less likely to have 
spirometric confirmation of COPD (Table 1).   
 
We also found that obese patients without COPD were not only less likely 
to have current inhaled medications appropriately stopped (adjusted 
absolute proportion 9%, p<=0.01), but were also more likely to have new 
inhaled medications started (adjusted absolute proportion 5%, p=0.02).  
Although some of these patient may have had airflow obstruction masked 
through obesity, these results support the rationale that obese patients 
are likely being inappropriately diagnosed and treated for COPD, potentially missing the opportunity to 
appropriately reduce symptom burden and improve CVRFs through a lifestyle intervention.  
 
Table 1. Overweight and 
obesity associated with lower 
probability of having COPD on 
spirometry 
BMI 
category 
Proportion* with 
COPD (95%CI)  
18.5-<25 
0.64 (0.61-0.66) 
25-<30 
0.53 (0.50-0.55) 
30-<35 
0.43 (0.40-0.45) 
35-<40 
0.37 (0.33-0.41) 
>40 
0.30 (0.25-0.35) 
*Adjusted for age, smoking 
status, race, comorbidity 
 
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Body mass index (BMI) explains dyspnea symptoms more than severity of airflow limitation.  We 
sought to assess factors associated with the explained variability in moderate to severe dyspnea, based on 
modified Medical Research Council (mMRC) dyspnea scores, among 376 patients with COPD.  We included 
sociodemographics, health behaviors, comorbid illnesses, and measures of severity of COPD (medications, 
FEV1 % predicted).  In fully adjusted models, the total amount of explained variance was modest (10.5% total); 
however, 37.8% of the explained variance in dyspnea was attributable to BMI, comparable to the amount of the 
explained variance attributable to FEV1 (35.8%).  This finding has important implications because dyspnea 
symptoms are among the most prominent of COPD, and BMI accounts for a significant amount of the 
explained variance. 
 
Obese patients have less severe disease, more symptoms, worse health-related quality-of-life 
(HRQoL), and receive more treatment.  We examined the association of obesity and effects on symptoms, 
HRQoL measures, and medication use in patients with COPD.4  Patients were predominantly either overweight 
(n=115, 32%) or obese (n=138, 38%).  Obese and overweight subjects had better lung function (obese: mean 
FEV1 55.4% ±19.9% predicted; overweight: mean FEV1 50.0% ±20.4% predicted) than normal weight subjects 
(mean FEV1 44.2% ±19.4% predicted; p<0.05 both comparisons), but obese patients reported worse dyspnea 
(adjusted OR of MRC score ≥2= 4.91; 95% CI, 1.80 to 13.39), poorer HRQoL as measured with St. George’s 
Respiratory Questionnaire (SGRQ) [Minimum Important Difference (MID) for SGRQ total and domains = 4 
points; total score: adjusted score 5.93 (95% CI 0.97, 10.88), impact: adjusted score 5.37 (95% CI 0.11, 
10.63), and activity: adjusted score 8.16 (95% CI 1.93, 14.40)], and were more likely to be prescribed 
medications to control COPD symptoms [Long acting beta-agonists (LABA): OR 2.21 (95% CI 1.14, 4.31); ICS: 
OR 2.34 (95% CI 1.25, 4.40)] than normal weight subjects.  We also recently analyzed data from the Burden of 
COPD study that was performed in the Pacific Northwest.  As part of that study, we assessed the effect of 
obesity on SF-12 adjusting for FEV1% predicted.  Consistent with our other preliminary data, patients who 
were obese had worse HRQoL on physical component scores (Obese PCS score (95% CI): -3.1 (-1.5 to -4.6)) 
and similar mental health component scores.   
 
Obese patient with COPD have 
worse six-minute walk test (6MWT) 
distance and reported dyspnea 
despite having better lung function.  
Over a 6-month period, our 
multicenter CONCERT team recruited 
over 1,200 patients, of whom 54% had spirometrically confirmed COPD.  We found that 73% of the COPD 
cohort was overweight (35%) or obese (38%).  Consistent with our other preliminary data, and when compared 
to normal weight individuals, we found that obese patients had less severe COPD (FEV1 % predicted 56.7 vs. 
44.3 for normal weight; p<0.05) and similar 6MWT distance.  Adjusting for the severity of airflow limitation, 
obese patients had shorter 6MWT distances and worse end-exercise Borg dyspnea scores (Table 2). 
 
Obesity paradox among patients with COPD. Obesity has been associated with higher all-cause mortality in 
the general population.41 However, the obesity paradox of COPD reviewed in a recent meta-analysis suggests 
that overweight or obese patients with COPD have better survival than those patients who are at or under 
normal weight.42  A number of potential explanations have been proposed for this finding.  First, the majority of 
the studies included in the meta-analysis measured weight cross-sectionally and did not incorporate changes 
in weight over time.  Second, none of the included studies examined purposeful, modest weight loss.  
Together, these two issues raise the concern that people of lower weight were a mixture of individuals that had 
purposeful and unintended weight loss.  Among patients with severe and very severe COPD, unintended 
weight loss as well as the inability to gain weight is a poor prognostic factor43, because the resultant low weight 
is associated with increased loss of skeletal muscle mass, diaphragmatic weakness, and worse severity of 
airflow limitation.44,45  Furthermore, in one study of patients with COPD who were followed longitudinally, an 
increase in BMI was associated with a non-statistical increase in mortality (BMI category gain: 3+: RR 1.3 (0.9-
1.7)).46  Among obese patients with COPD, high quality clinical trials that encourage modest weight loss 
through proven comprehensive lifestyle interventions focused on healthy eating, increased physical activity, 
and behavioral self-management are needed to better guide treatment decisions.   
 
 
Table 2.  Obesity associated with worse 6MWT distance and 
dyspnea at end exercise.  
BMI Category 
Distance walked (ft) 
Borg dyspnea  
18.5-<25 
Referent 
Referent 
25-<30 
-40.9 (25.1, -107.0) 
0.02 (-0.39, 0.43) 
30+ 
-211.4 (-142.3,-280.5) 
0.66 (0.23, 1.07) 
 
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This Pragmatic Clinical Trial (PCT) has high scientific, clinical, and public health significance. 
Scientifically, the INtervention Study In overweiGHT patients with COPD (INSIGHT COPD) trial offers a new 
frontier in the COPD and obesity literature by investigating the effectiveness of the E-LITE self-directed lifestyle 
intervention among overweight and obese patients with spirometry-confirmed COPD.  E-LITE has proven 
effective at producing clinically significant weight loss while improving fasting glucose and lipid control.47,48  
While achieving cost efficiency through simple and pragmatic intervention delivery, we will protect internal 
validity through patient-level randomization and external validity through broad entry criteria to the population 
whom it is to be applied and important patient-centered outcomes over a 12-month follow-up period.  Clinically, 
COPD patients with comorbid obesity are a high priority population for behavioral weight loss treatment given 
the gaps in treatment guidelines and clinical practice, and the potential harm to patients, as discussed above.  
From a public health and policy perspective, both obesity and COPD are leading causes of morbidity and 
mortality in the U.S., and their coexistence is prevalent.  The proposed adoption of our previously proven 
lifestyle intervention for weight loss in primary care—one that highlighted in the 2014 USPSTF behavioral 
counseling recommendations for cardiovascular risk prevention—to treat obesity in COPD aligns with the 
Institute of Healthcare Improvement Triple Aim: population health management, patient-centered outcomes, 
and per capita cost efficiency.  This study was designed to have high significance scientifically, to clinical 
practice and the public.  
 
 
7.0. 
INNOVATION 
The INSIGHT COPD trial is the first experimental study of behavioral weight loss treatment for 
overweight and obese patients with COPD.  On a population basis, the high prevalence of overweight and 
obesity in adults with COPD suggests an important opportunity to improve the lives of many such individuals.  
While the clinical treatment of COPD should continue to emphasize implementation of proven pharmacological 
and non-pharmaceutically based strategies,12 the available evidence, as cited above, is sufficient to warrant 
the investigation of including evidence-based behavioral weight loss strategies as an adjunct therapy for COPD 
patients who are also overweight or obese.  In the INSIGHT COPD trial, the primary objective is to investigate 
whether a highly efficient, self-directed lifestyle intervention focused on calorie-controlled healthy eating, 
increased physical activity, and behavioral self-management has clinical benefits for reducing weight and 
improving COPD and comorbid disease outcomes.  As noted above, to date, the only studies that have 
examined obesity or weight loss in COPD have been observational or small studies of patients undergoing 
bariatric surgery.  None of the studies have focused on using a lifestyle intervention that is guideline 
concordant and, equally importantly, can be applied to a large number of patients in an economical, pragmatic 
fashion.  
  
The proposed intervention is the only direct adaptation of the landmark Diabetes Prevention Program 
(DPP) lifestyle intervention using a self-directed delivery approach in primary care.  We have modeled 
the INSIGHT COPD intervention after the successful E-LITE self-directed intervention,47-49 which uses a 
curriculum recognized by the National DPP program.50  The E-LITE adaptions of the DPP intervention were 
patient-centered, low cost, and pragmatic.  Delivery of healthcare requires the implementation of health plans 
developed in clinical settings (e.g., clinics) in the personal environments (e.g., homes, work places, and social 
settings). The E-LITE self-directed intervention is portable and designed to be implemented within patients’ 
non-medical environment—enabling them to make healthy choices where they work, live, and play with 
ongoing support through existing health information technology (HIT), and if desired, support from trained 
lifestyle coaches.  Although the intervention is designed to promote a sustained change toward healthier 
weight and lifestyle that have been shown to reduce the burden of diabetes and CVRFs, our preliminary results 
(below) and those of others51-56 suggest that weight loss will lead to improvement in HRQoL (particularly 
physical health) and physical functioning, outcomes of much importance in COPD.  Within the paradigm of 
outcome-driven clinical decision making, reimbursement, and quality assessment, demonstrated evidence of 
improvements in clinically relevant, patient-centered, universal health outcomes among patients with COPD 
and accompanying multimorbidity will have relevance to the wide practice and policy community. 
 
 
 
 
 
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8.0. 
RATIONALE OF E-LITE AS THE BASIS OF THE INSIGHT COPD INTERVENTION 
The overall approach is based on proven self-directed lifestyle interventions for weight loss in primary 
care.  The landmark DPP trial established the gold standard in diabetes prevention by demonstrating that an 
intensive lifestyle intervention targeting modest weight loss and increased physical activity markedly lowered 
type 2 diabetes incidence (by a mean of 58% net of control) among high risk adults across all age, sex, and 
race/ethnicity subgroups,57 the benefit persisted for at least 10 years.58  Weight loss was the dominant 
predictor of reduced diabetes risk where every kilogram of weight loss resulted in a 16% reduction in risk.59  
Despite the enormous benefit of DPP on diabetes risk, the trial 
was highly intensive and did not readily lend itself into 
implementation in clinical practice.   
 
Dr. Jun Ma and team have, through a series of primary-care–
based trials, adapted the DPP from the individual and group 
based program to one where a highly efficient self-directed DVD-
based version plus remote monitoring and coaching is 
comparable in terms of weight loss to more intensive coach-
directed versions (see below).  A pilot study by the DPP 
researchers who developed the DVD showed an intervention 
combining the Group lifestyle Balance (GLB)-DVD and 
telephonic lifestyle coaching was effective in a primary care 
practice.60  As 
the first 
randomized 
control trial 
(RCT) that has 
successfully 
translated the 
DPP lifestyle intervention into primary care in the U.S. 
 
The E-LITE study protocol49 and primary48 and additional 
publications47,61-64 detail the design, methods, and outcomes.  
Briefly it was a 15-month pragmatic RCT (n=241) which, for 
the first time, demonstrated the effectiveness of a highly 
portable and inexpensive self-directed lifestyle intervention 
(Table 3) in a primary care setting that integrated the DPP-
based 12-session GLB core curriculum60,65,66 with technology-
mediated lifestyle coaching and self-monitoring among 
overweight or obese adults with prediabetes and/or metabolic 
syndrome.  Compared with usual care (UC), both E-LITE 
interventions led to significantly greater weight loss through 15 
months, and lower levels of waist circumference, fasting 
plasma glucose, and total cholesterol,48 with good reach and 
adoption.61  Self-monitoring is the cornerstone of success in 
behavioral weight-loss interventions.67  E-LITE results showed 
a positive relationship between Heart360 self-monitoring 
frequency and weight loss over 15 months (Figure 1).62  With 
supplementary funding, results from an extended follow-up 
through 24 months showed sustained reductions in body 
weight, particularly in the self-directed intervention group (Figure 2).47   
Table 3. E-LITE intervention key components 
 
Self-Directed Intervention 
1. DPP-GLB 12-
weekly sessions* 
Take-home DVD (cost: $7 a 
set) 
2. Self-monitoring of 
progress toward 
weight & physical 
activity goals† 
Daily monitoring 
recommended; Coach did 
not routinely review records 
(cost: free Heart360 and 
$65/patient for a pedometer 
and weight scale) 
3. Personalized 
lifestyle coaching‡ 
As needed, patient-initiated 
(cost: minimal coach time—
2 messages/month/patient) 
*The DPP-based Group Lifestyle Balance (GLB) 
DVD has the 12 core curriculum sessions.60 Dr. 
Ma’s team includes a DPSC-certified GLB master 
trainer and several trained coaches.  
†Via the American Heart Association free, secure 
web portal (www.heart360.org).  
‡Via secure messaging.  Coaches could view 
Heart360 patient self-monitoring records, which 
they used to tailor their progress feedback to 
participants via secure messaging. 
 
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A post-hoc analysis of E-LITE data found that mean standard 
deviation (SD) changes in the SF-12 physical component 
scores were 1.6 (4.7) in the self-directed intervention (p = .01), 
0.7 (8.5) in the coach-led intervention (p = 0.51), and -0.4 (6.5) 
in the UC control group (p = 0.66).  Increasing physical 
component scores were significantly correlated with weight 
loss in both interventions (Figure 3).  The difference in 
physical component score change between the self-directed 
intervention and UC (p = .06; difference, 2.0; 95% CI, -0.1 to 
4.0) was 4% of baseline (baseline M [SD], 50.5 [7.5]); 3% was 
the minimally important difference used in the DPP.52  The SF-
12 mental health scores changed slightly in both E-LITE 
intervention groups and did not differ significantly from usual care.  These findings are consistent with the DPP 
and other behavioral weight-loss intervention studies.51-54 
 
An integral component to the E-LITE intervention was encouragement of graduated moderate physical activity. As 
noted above, E-LITE significantly improved SF-12 physical component scores when compared to UC control 
group.  The major drivers of the SF-12 physical component scale scores are questions about the ability to perform 
physical activities.  Although psychometrically valid, the magnitude of increases in SF-12 do not have inherent 
meaning to patients.   From a patient-centered perspective, a common complaint among patients with COPD is 
the inability to walk significant distances and preliminary evidence suggests that the E-LITE intervention may 
improve exercise tolerance.   The six-minute walk test distance is among the most commonly measured 
assessments of exercise tolerance.  The measure is valid, reliable and responsive with a well-defined 
demonstrated minimally clinically important difference68-72.  The measure has been used in multiple clinical trials of 
COPD and can be used to objectively measure dyspnea at end of test73,74.   
 
 
9.0. 
AIMS 
The overall goal of our Protocol Leadership Group (PLG) is to produce first-ever evidence on the effectiveness 
of a proven pragmatic lifestyle intervention targeted at modest, clinically meaningful weight loss and increased 
physical activity in overweight or obese patients with spirometry-confirmed COPD.  In the 12-month simple, 
pragmatic clinical trial (PCT), we efficiently focus on the intervention effects primarily on exercise tolerance; 
and secondarily on weight loss, dyspnea, generic and symptom-specific quality of life (QoL), and 
cardiovascular risk factors (CVRFs). 
 
We will implement the E-LITE self-directed lifestyle intervention in a multicenter, patient-level randomized PCT of 
approximately 680 overweight and obese patients with COPD. Our specific aims are to test whether, compared 
with usual care (UC) controls, intervention participants have better outcomes through 12 months of follow-up, 
including: 
 
1. Primary measures: Exercise tolerance measured with the 6-Minute Walk Test (6MWT) distance at 12 months 
(primary endpoint).   
 
2. Secondary measures: Greater weight loss, less dyspnea measured with the modified Borg scale, 
improvements in generic HRQoL by the SF-12v2, COPD symptom QoL by the SGRQ-C, and major CVRFs 
(central obesity by waist circumference, Framingham Risk Score, blood pressure, and BMI).  
 
10.0. STUDY DESIGN 
INSIGHT COPD is a simple, two-arm PCT in which approximately 680 overweight and obese COPD patients, 
aged 40 years and older, will be randomized to UC or UC plus the self-directed lifestyle intervention for 12 
months.  Follow-up assessment will occur at 12 months (Figure 4).  We hypothesize that intervention 
participants will have better exercise tolerance at 12 months.   
 
 
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10.1. Eligibility Criteria 
Eligible patients are age 40 years or older, overweight or obese, have COPD, and have symptoms of dyspnea.  
Inclusion criteria are broad to protect feasibility and generalizability.  Exclusion criteria are aimed at ensuring 
each participant's safety and maximizing internal validity including minimizing error associated with the primary 
outcome, and preventing possible missing data. Specific criteria are:  
 
10.1.1. Inclusion 
• 
40 years or older at time of eligibility screening;  
• 
Body mass index 25.0-44.9 kg/m2; 
• 
Smoked at least 10 pack-years of cigarettes; 
• 
Modified Medical Research Council dyspnea score of 1 or higher, i.e., “I get short of breath when hurrying 
on the level …”;  
• 
COPD, defined as an FEV1/FVC less than 0.70 and FEV1% predicted greater than 30;  
• 
Access to DVD player or internet in order to view the 12 GLB sessions; 
• 
Consent to the study protocol/procedures including: 
o time and data collection requirements of the study;  
o randomization to one of the two intervention arms;  
o adherence to the recommendations of the study intervention as assigned;  
o authorizing extraction of relevant information from their medical records. 
 
10.1.2. Exclusion 
• 
Inability to speak, read, or understand English; 
• 
Active weight loss interventions including: 
o use of prescription weight-loss medications in the past 3 months,  
o current participation in group or individual weight loss programs provided by trained personnel 
(attending peer support groups or following a self-help weight management book, "boot camp," or 
diet is not an exclusion),  
o had bariatric surgery or plans to undergo bariatric surgery during the study period;  
• 
Expected weight loss because of alternate explanations, such as from illness;  
• 
Unable to ambulate to weight scale for weight measurement; 
• 
Safety and/or adherence concerns due to severe physical or mental health issues or life expectancy <18 
months;  
• 
Pregnant, lactating, or planning to become pregnant during the study period; 
• 
Participation in other intervention studies.  
 
10.2. Recruitment, screening, and baseline assessment 
NEMO-contracted clinical sites will enroll approximately 680 overweight and obese patients with spirometry-
confirmed COPD.  Clinical sites will have coordinators identified and trained to perform the protocol.  Specific 
procedures are described in the Manual of Operations. 
 
Patients may be identified in usual approaches including clinic, other patient or provider referrals as in other 
clinical trials.  Given the volume and timeline for the recruitment processes, clinical sites may benefit from 
using an existing electronic health records (EHR) or clinical/COPD registry.   
Figure 4. Overview of trial design 
• Recruit
• Enroll
• Baseline 
measures
Randomize
12-month 
outcomes 
visit
Control
n=340
12-month self-directed 
lifestyle intervention
n=340
 
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10.2.1. EHR/COPD registry-based pre-screen  
Using a Waiver of HIPAA Authorization, the screening process for each cohort begins with identification of 
individuals who meet the following inclusion criteria using relevant data in the patients’ EHR or via a COPD 
registry as available by the site.  Other criteria may be applied according to available resources: 
• 
Age 40 years or older; 
• 
BMI 25.0-44.9 kg/m2 during the past 6 months; 
• 
Diagnosis of COPD. 
 
10.2.2. Initial invitation 
Sites send patients identified via the EHR or COPD registry an invitation to participate via EHR-integrated 
secure messaging (if user), email (if available and allowed by the Institutional Review Board [IRB]), or mail.  A 
letter and/or Information Statement, depending on site IRB requirements, will describe the research activity and 
instruct patients how to self-screen online, request additional information, or decline further participation by 
returning an opt out postcard. The invitation also explains that clinical center staff will contact them on behalf of 
the study to assess interest if they do not respond within 2 weeks.     
 
10.2.3. Initial online, telephone, and/or clinic recruitment 
Using a Waiver of Documentation of Informed Consent, or Waiver of Consent (depending on site IRB 
requirements), patients identified by any of the above methods, and who desire to be screened may complete 
a Research Electronic Data Capture (REDCap) on-line self-screen and/or telephone screen with a site 
coordinator. Those patients who choose to complete the on-line screen will answer brief questions regarding 
major exclusions (Table 4). If their answers indicate potential eligibility, or if no response has been received 
after two weeks of sending the invitation, sites contact the potential participant for a more detailed telephone 
screen. An “Eligibility Pre-review” can be conducted by the sites before contacting the participant (to screen for 
basic eligibility criteria (if site IRB approved). The telephone screen includes eligibility criteria listed in Table 4. 
The telephone screening questions may also be asked in-person if recruiting at a pulmonary clinic. If the 
potential participant is eligible based on their answers to the screening questions, the site coordinator asks 
spirometry safety questions prior to scheduling an in-person eligibility screen and baseline visit.  The safety 
questions confirm that the participant has no temporary conditions that would preclude the subject from doing 
spirometry. In the event that the participant has a condition that would preclude testing in the short term, staff 
should arrange to call the participant back at a later date to complete another telephone screen and schedule 
the visit then. 
 
Sites may send a paper copy of the baseline questionnaires (SF-12v2 and SGRQ-C) to the potential 
participant for completion prior to the person’s visit.  Questionnaires will only be collected after the Informed 
Consent Form is signed.  Table 4 summarizes the screening assessment questions and measures: 
Table 4: On-line, telephone and/or in-person screen 
Assessment/activity  
Measure 
Send invitation 
• Refusals via postcard 
On-line self-screening 
Self-report: 
• Age 
• Sex 
• Pregnancy/lactation for those indicating “female”  
• Self-report height and weight for BMI calculation 
• Smoking history (yes/no) 
• Dyspnea (yes/no) 
 
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Telephone/In-person 
screen: eligibility criteria 
Self-report: 
• Age 
• Sex 
• Pregnancy/lactation for those indicating “female”  
• Self-report height and weight for BMI calculation 
[Note: The above completed by phone only if not already 
done by patient online self-screen] 
• Smoking pack years 
• mMRC dyspnea scale score 
• Weight loss programs/surgery 
• Participation in other intervention studies 
• Expected weight loss for other reasons, e.g., illness 
• Willing/able to complete surveys in English 
• Willing to participate with intervention protocols 
• Able to ambulate for weight measurement 
• Able to return for 12-month follow-up  
• Access to DVD/internet for GLB sessions 
Telephone/In-person 
screen: spirometry 
safety check 
[Complete if patient 
screened eligible] 
• Temporary spirometry contraindications 
o Heart attack or unstable angina in last 30 days 
o Detached retina or eye surgery within past 30 days 
o Breathing problems gotten worse in the last week 
o New prescription for antibiotics or oral steroids for acute 
exacerbation) 
o Other 
 
10.2.4. In-person visit: screen and baseline visit 
All study visits will take place at clinical sites, and require a well-illuminated, quiet, setting that protects patient 
privacy.  In addition, a NEMO certified 6MWT course should be available in the immediate vicinity. 
 
10.2.4.1. Informed Consent: 
The visit begins with a site coordinator obtaining the participant’s written informed consent. The coordinator 
reviews with the participant the Informed Consent Form, detailing the responsibility of the participant to 
INSIGHT COPD, the responsibility of the investigators and staff to the participant, and participant’s personal 
risks and benefits, the concept of random assignment and what each treatment group involves, and stresses 
the importance of follow-up assessment even if he/she is not adhering to the assigned treatment.  This process 
meets the ethical obligations to maximize participants’ understanding of information required for an informed 
decision regarding participation in the INSIGHT COPD trial, and improves retention by developing rapport 
between the participant and research staff.  Each stage in the screening and enrollment process includes a 
clearly written description of information relevant to that stage and ample opportunities to answer participants’ 
questions.  Even when printed information is provided, research staff must verify that the participant 
understands what he/she has read and heard.  
 
To maximize retention and assure that participants fully understand the demands and nature of the study 
before they enroll, recruitment staff will carefully review study requirements with the participants, explain the 
concept of random assignment and what each treatment involves.  
 
10.2.4.2. HIPAA Waiver: 
Participants sign a HIPAA authorization in order that sites may review the medical record for eligibility 
confirmation, to supplement outcome measures as appropriate, and to share the research data with the PLG 
and NEMO. 
 
 
 
 
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10.2.4.3. Demographics and confirmation of eligibility: 
After the participant has signed the Informed Consent Form, a site coordinator assesses the measures 
summarized in Table 5 in order to assess the participant’s eligibility.  For items already answered via the on-
line survey or telephone/in-person screen, answers will be verified to confirm accuracy.  Those who are not 
eligible will be so informed and free to leave. 
 
The table below is a summary of activities included in the consent and eligibility confirmation process.  All data 
will be either directly entered into the INSIGHT COPD REDCap database, or recorded on a paper form for later 
entry into REDCap. For self-report surveys, the following options are available depending on participant 
preference and site infrastructure: 
• 
Completion prior to visit: sites may mail surveys to participants for completion at home and will be 
brought to the study visit. The coordinator will collect the completed surveys only after Informed 
Consent is signed and if the participant is found to be eligible to participate.  The coordinator will review 
the responses for completeness and ask for clarification as necessary.  Surveys responses will be 
entered into REDCap after the visit. 
• 
Completion at the visit: If not completed prior to the visit, participants are strongly encouraged to 
complete the surveys on paper at the study visit with data entry by the coordinator after the visit. 
Alternatively, the coordinator may ask participants the questions and enter answers directly into 
REDCap.   
 
Table 5: Consent, demographics, and eligibility confirmation 
Assessment/activity 
Measure 
Informed consent and 
HIPAA authorization 
Date of signature acquired (Informed Consent and HIPAA)  
Demographics 
Self-report: 
• Date of birth 
• Sex 
• Race 
• Ethnicity 
• Marital status 
• Educational 
• Employment status 
• Healthcare and prescription coverage 
Self-report eligibility 
criteria 
(supplement/confirm 
telephone responses) 
Self-report: 
• Date of birth 
• Pregnancy/lactation for those indicating “female”  
• Smoking pack years 
• mMRC dyspnea scale score 
• Weight loss programs/surgery 
• Participation in other intervention studies 
• Expected weight loss for other reasons, e.g., illness 
• Willing/able to complete surveys in English 
• Willing to participate with intervention protocols 
• Able to ambulate for weight measurement 
• Able to return for 12-month follow-up  
• Access to DVD/internet for GLB sessions 
Height 
Measure height 
Weight 
Measure weight 
BMI 
Calculated from height and weight 
Spirometry 
Measure pre and post bronchodilator: 
• 
FEV1/FVC 
• 
FEV1 
 
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• 
FVC 
 
 
10.2.4.4. Additional baseline measures: 
For those who are determined to be eligible to participate, the coordinator assesses the measures summarized 
in Table 6. 
 
Table 6:  Additional baseline measures 
Assessment/activity 
Measure 
Vitals 
• 
Blood oxygen saturation level (SpO2) 
• 
Resting heart rate 
Exercise tolerance 
• 
6MWT distance 
• 
Modified Borg dyspnea and leg fatigue rating pre and 
post 6MWT 
CVDR 
• 
Waist circumference 
• 
Framingham Risk Score:  
o age 
o gender  
o smoking status  
o systolic BP 
o self-report use of BP medication 
o self-report diagnosis of diabetes 
o self-report use of diabetic or hypoglycemic 
medication  
o BMI 
• 
Blood pressure 
Self-report surveys 
• 
General health status (SF-12v2) 
• 
Health inventory checklist 
• 
Medications 
• 
Health care utilization 
• 
COPD symptoms (SGRQ-C) 
 
10.2.4.5. Pre-randomization eligibility and safety screening: 
A site study investigator or appropriately qualified designee reviews the participant’s research enrollment 
record for eligibility, including adequacy of spirometry and existence of any safety concerns and health-related 
suitability prior to randomization. If deemed appropriate, the coordinator will randomize the participant via 
REDCap.  
 
10.3. Randomization  
All of the baseline assessment measures listed in Tables 5 and 6 must be completed prior to randomization.  A 
site coordinator will randomize the participant using the REDCap randomization function.  The unit of 
randomization will be the participant, performed at a ratio of 1:1.  We will stratify each site on smoking status 
(current smoker vs. non-smoker). In order to maintain blinding of the outcome assessors to the randomization 
assignment, sites may choose to: 
• 
Have one coordinator conduct the baseline assessment, conduct randomization, and orient those in 
the intervention arm to the intervention, then have a different trained coordinator conduct 12-month 
outcome assessments; or 
• 
After baseline assessment, hand-off the participant to a different coordinator who only will conduct 
randomization and orient participants to the intervention, and who will not conduct outcome 
assessments.   
 
10.3.1. Participants randomized to the intervention  
 
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Intervention introduction: A site coordinator provided the intervention materials (Table 7), set the participant up 
with MyFitnessPal and Fitbit website accounts, and link the account with the INSIGHT COPD lifestyle coach 
account. A lifestyle coach will introduce the participant to the intervention materials during the phone 
orientation with procedures including: reviewing the schedule and process for using the 12-weekly GLB DVDs 
or online videos and handouts and 10 post-core session materials; providing instruction on how to use the 
Fitbit activity tracker and weight scale for self-tracking; synchronizing the activity tracker with Fitbit.com or 
mobile application; logging weight, diet, physical activity, and session completion into MyFitnessPal or on 
Keeping Track Booklets; checking biweekly messages from the lifestyle coach on MyFitnessPal; and 
contacting the lifestyle coach via MyFitnessPal and phone, and at the participant’s discretion, by email and/or 
texting. 
 
The INSIGHT COPD trial is using MyFitnessPal instead of Heart360, which was used in E-LITE trial, for the 
following reasons: 
• 
Ease of use for participants: one login in MyFitnessPal vs. two for Heart360 because the latter requires 
a HealthVault account as well. 
• 
Availability of dietary self-tracking in MyFitnessPal, but not in Heart360. 
• 
Successful switch from Heart360 to MyFitnessPal in Dr. Ma’s R01s (HL119453 and HS022702), 
funded after the completion of E-LITE. 
 
Intervention Orientation: The lifestyle coach contacts intervention participants via phone within 1 – 2 business 
days of randomization to schedule a phone orientation session. The orientation session should take place 
within two weeks of randomization to the extent possible, although deviation from this schedule is permissible 
to accommodate participants’ scheduling needs and preferences. In the orientation session, the coach will 
review the program, benefits and options for using his/her lifestyle coaching expertise, and answer any 
questions (see section 9.6.3. “Intervention Format, Structure, and Content” for additional details).    
 
Table 7: Intervention materials 
• Group Lifestyle Balance™ DVD or online videos 
• Post Core Support Physical Activity DVD 
• GLB Binder and participant handouts pertinent to the 12-week core intervention 
activities and to the post-core activities for the remainder of the 12-month intervention 
• Weight scale 
• Fitbit activity tracker/ instructions/batteries  
• The Calorie KingTM Calorie, Fat and Carbohydrate Counter book 
• Keeping Track Booklets and postage-paid return envelopes (alternative or 
complement to tracking via MyFitnessPal and Fitbit) 
• MyFitnessPal and Fitbit Account Setup Instructions  
• Lifestyle coach contact information/options  
 
10.3.2. Participants randomized to the control  
These participants are instructed to continue their usual diet and exercise activities and weight management 
practices as desired. Control participants will be given a Fitbit activity tracker at their 12-month visit to 
approximate the weight and activity aids the intervention group received. 
 
10.3.3. All participants 
All participants receive a tote bag, water bottle, and refrigerator magnet that display the INSIGHT COPD logo. 
The PTC supplies these items to sites. 
 
10.4. Time Commitment 
10.4.1. Control group 
• 
Total time for the coordinator is approximately 3.5 hours. 
• 
Total time for the participants is approximately 2.5 hours. 
 
10.4.2. Intervention group 
 
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• 
Total time for the coordinator is approximately 4.0 hours. 
• 
Total time for the participants is approximately 3.0 hours. 
 
10.5. Follow-up Visit and Data Collection 
Participants complete a follow-up visit at 12 months post enrollment.  The target time window for completion is 
+/-2 weeks of the index post-randomization date; however, events outside the influence of the site may prevent 
this; therefore, it is acceptable to conduct the visit within +/-4 weeks.  Visits that occur outside of the 
acceptable window must be accompanied by justification.  Acceptable reasons include participant illness, or 
inability to reach the participant, participant not able to travel to the site, or suspended visits because of the 
COVID-19 pandemic. The site is expected to schedule and complete a follow-up site whenever possible even if 
it falls outside the acceptable window. The staff person conducting these assessments must be different from 
the person who conducted and oriented the participant to the randomization assignment.  The coordinator will 
assess the measures summarized in Table 8. 
 
Table 8: 12-month measures 
Assessment/activity 
Measure 
Weight 
Measure weight 
Vitals 
• 
Blood oxygen saturation level (SpO2) 
• 
Resting heart rate 
Exercise tolerance 
• 
6MWT distance 
• 
Modified Borg dyspnea and leg fatigue rating pre and 
post 6MWT 
CVDR 
• 
Waist Circumference 
• 
Framingham Risk Score: 
o age 
o gender 
o smoking status 
o systolic BP  
o self-report use of BP medication 
o self-report diagnosis of diabetes 
o self-report use of diabetic or hypoglycemic 
medication 
o BMI 
• 
Blood pressure 
Self-report surveys 
• 
General health status (SF-12v2) 
• 
Health inventory checklist 
• 
Medications 
• 
Health care utilization 
• 
COPD symptoms (SGRQ-C) 
Spirometry 
Measure pre and post bronchodilator: 
• 
FEV1/FVC 
• 
FEV1 
• 
FVC 
Intervention adherence 
• 
Self-report DVD viewing: number of sessions viewed 
self-tracked by participants via MyFitnessPal or paper 
booklets) 
 
10.5.1. Time Commitment: 
• 
Total time for the coordinator is approximately 2.25 hours for all participants; 
• 
Total time for the patients is approximately 1.25 hour for the 12-month follow-up 
 
10.6. Intervention 
 
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For patient safety and generalizability, participants in both the control and intervention arms will continue to 
receive standard medical care from their usual providers.  We chose UC only for our control group because 
pragmatic RCTs are most useful in testing interventions in real-world settings and addressing the question 
“how does the intervention compare to what we are doing now?”.  The study is also designed not interfere with 
ongoing patient care.  To control for changes in medical practice and secular trends and to protect external 
validity, no participant will be restricted from seeking weight loss treatment once enrolled.   
 
10.6.1. Theoretical Basis 
The self-directed lifestyle intervention approach is grounded in Social Cognitive Theory75 and uses time-tested 
self-regulation strategies (goal setting, self-monitoring, action planning, and problem-solving) to achieve and 
maintain realistic intervention goals: 5-10% of baseline weight and at least 150 minutes per week of moderate-
intensity physical activity.  It stresses a triadic, reciprocally deterministic relationship between the individual, 
environment, and behavior, and it recognizes that self-efficacy is enhanced through social support and gradual 
mastery of self-regulation skills.  Further, it builds on the premise that long-term changes in diet and exercise 
and sustained motivation to maintain behavior changes are most likely to occur when the strategies used to 
motivate and support behavior change are flexible, sensitive to cultural and individual differences, and broadly 
acceptable to those in the target population.  The program promotes the following goals. 
 
10.6.2. Evidence-based Intervention Goals 
Weight: The intervention is designed to achieve and maintain a weight loss of 5-10% of baseline body weight 
in a gradual stepwise fashion.  This amount of weight loss is safe, feasible and associated with clinically 
significant reductions in the risk of diabetes and CVRFs.  To help achieve and maintain the weight goal, 
participants are advised to reduce their calorie intake by 500-1000 kcal/day, as recommended in adult obesity 
guidelines.  Participants will gradually achieve the calorie goals through portion control, choices of low-energy 
nutrient-dense meals and snacks (e.g., whole fruit, vegetables, whole grains, and low-fat, unsweetened dairy 
products), reduced consumption of refined and/or added carbohydrates/sugars, healthy food preparation 
techniques, and careful selection of restaurant items.   
 
Physical Activity: The physical activity goal is to achieve and maintain a minimum of 150 minutes per week of 
moderate-intensity physical activity (such as brisk walking).  This goal is consistent with the 2008 Physical 
Activity Guidelines for Americans, and is deemed safe and attainable for most adults, including those with 
chronic conditions such as COPD.  Participants will gradually and steadily increase daily walking with a goal of 
achieving 150 minutes of brisk walking per week by the end of the 12-week DVD program.  They may also 
choose to adopt regular activities of moderate intensity other than brisk walking.  After attaining the minimum 
goal of 150 minutes per week, participants may choose to be more active; or if participants reach the 150-
minute goal but are not achieving the weight goal, they should further gradually increase to 60 minutes/day of 
moderate physical activity.  
 
10.6.3. Intervention Format, Structure, and Content 
There is a national call for the provision and coverage of multicomponent lifestyle interventions for obesity in 
primary care settings.76-78  The challenge historically with such interventions is that they are often too intensive 
to implement in the real world.  The Centers for Medicare and Medicaid Services (CMS) reimbursement policy 
promotes brief (15 minutes), lower-intensity (compared with efficacy studies), face-to-face behavioral 
counseling within a limited timeframe (i.e., 6-12 months).77  The E-LITE interventions48, upon which INSIGHT 
COPD is modeled, fit this general pragmatic framework with likely better efficiency due to use of technology.  
The INSIGHT COPD trial will contribute to the evidence base needed to inform and guide policy change, in the 
context of growing interest and evidence in technology-based interventions.   
 
INSIGHT COPD consists of a 12-month intervention that will have 2 distinct stages:  core curriculum (months 
1-3) and post core (months 4-12).  The core curriculum will be delivered using the GLB DVD or on-line viewing 
option, with supplementary remote lifestyle coaching at the participant’s discretion.  The intervention orientation 
is described in Section 9.3.1. The coach will contact intervention participants within two weeks of 
randomization for phone orientation, to review the coach role in the intervention, and describe how participants 
may request coaching if desired. Also, the coach will send biweekly standardized messages via MyFitnessPal 
as reminders and/or to reinforce the lifestyle change recommendations in the videos. 
 
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The lifestyle coach will monitor intervention adherence by downloading participants’ self-monitored data from 
MyFitnessPal and Fitbit web and mobile technologies.  For participants who do not use these tools, they will be 
instructed to mail their booklets every month. The coach will also document the number and content of 
contacts with participants in a REDCap database. 
 
The main objective of the core stage is to facilitate gradual weight loss through progressive healthful changes 
in diet quality and physical activity and behavioral skills training.  The post core stage is focused on continued 
gradual weight loss as well as maintenance through participants’ self-directed continued dietary and activity 
changes, and implementation of self-regulation skills through an iterative self-guided mastery process.79  The 
intervention components of the core curriculum stage include: 
• 
the 12-session GLB-DVD or on-line session;  
• 
goal setting and self-monitoring via the MyFitnessPal web and mobile technologies (to include: 
www.MyFitnessPal.com); 
• 
use of the Fitbit activity tracker and Fitbit.com web and mobile technologies; 
• 
use of a weight scale; 
• 
lifestyle coaching, available at patient request, by phone or by MyFitnessPal secure messaging.  Option 
for personalized lifestyle coaching will continue throughout the post core stage.  Lifestyle coaches in Dr. 
Ma’s team will be available by phone or by secure messaging that is embedded in the free 
MyFitnessPal web and mobile technologies.   
   
Self-monitoring is key to success in behavioral weight-loss interventions.67  E-LITE results supported a 
hypothesized positive relationship between the frequency of self-monitoring on Heart360 and the amount of 
weight loss.62  At the start of the intervention, sites will provide each participant in the treatment arm with a 
Fitbit activity tracker and a standard bathroom weight scale.  Participants will be strongly encouraged to self-
monitor diet, activity, weight, and session completion through MyFitnessPal and the Fitbit throughout, and 
beyond the 12-month intervention.  Participants will also connect their Fitbit device with their Fitbit.com 
account, which enables synchronized transfer of their Fitbit daily steps.  These features greatly enhance the 
intervention’s reach and adoption potential given that use of the internet and mobile technology is ubiquitous in 
the U.S.      
 
 
10.7. Payments/Remuneration 
Recommended study participant remuneration (depending on local IRB requirements) is $40 for completing the 
baseline visit and being randomized. For randomized participants, the recommended remuneration is $110 for 
completing the 12-month follow-up. Table 9 summarizes recommended participant payments.  Control patients 
will receive a Fitbit and the end of the 12-month visit. Because of the June 2018 protocol change eliminating 
the 18-month visit, sites should ask participants who have already completed the 12-month visit to return to 
complete spirometry, receive a Fitbit if they were in the control group, and receive final remuneration. 
 
Table 9: Recommended participant payments 
 
Baseline,  
randomized 
12-month 
Screen fail 
-- 
-- 
Randomized, either group 
$40 
$110 
 
 
 
 
 
 
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11.0. MEASUREMENTS 
Table 10 summarizes measurement and timing of data collection: 
 
Table 10: Timing of measurements and data collection 
 
Source 
Baseline 
12-month 
Primary outcome 
 
 
 
   Six-minute walk distance 
Measured 
x 
x 
Secondary outcomes 
 
 
 
   Weight  
Measured 
x 
x 
   Modified Borg Dyspnea scale 
Questionnaire 
x 
x 
   12-Item Short Form (SF-12v2) 
Questionnaire 
x 
x 
St. George’s Respiratory 
Questionnaire-C 
Questionnaire 
x 
x 
   CVD risk 
 
 
 
      Framingham Risk Score 
Measured/ 
Calculated 
x 
x 
      Waist circumference 
Measured 
x 
x 
      Blood pressure 
Measured 
x 
x 
      BMI 
Calculated 
x 
x  
Other measures 
 
 
 
   Height 
Measured 
x 
 
   Leg fatigue 
Questionnaire 
 
 
   Spirometry 
Measured 
x 
x 
   Health inventory checklist 
Questionnaire 
x 
x 
   Medications 
Questionnaire 
x 
x 
   Health care utilization 
Questionnaire 
x 
x 
   Demographics 
Questionnaire 
x 
 
Intervention: self-monitoring; coach 
communications 
MyFitnessPal; 
Keeping Track 
Booklets; 
REDCap 
Throughout 12-month 
intervention period 
 
11.1. Anthropometric measures   
Height, weight, and waist circumference80-82, are measured with participants wearing light indoor clothes without 
shoes, using a stadiometer, digital or balance beam scale, and tape measure, respectively.  We will use 
standardized protocols published by the PhenX Toolkit81 and the National Health and Nutrition Examination 
Survey (NHANES) Anthropometry Procedures Manual.83  BMI will be calculated.   
 
11.2. Exercise tolerance  
Exercise tolerance is assessed with the 6MWT, a widely used assessment of functional exercise capacity in 
subjects with COPD.  The test has been shown to be reliable, safe and valid for measuring functional status in 
COPD.  A coordinator will measure how far an individual can walk in six minutes breathing room air using ATS 
guidelines.84 Participants that use walking aids will use them while completing the 6MWT.  Participants that use 
supplemental oxygen are allowed to use supplemental oxygen during the 6MWT.   
 
11.3. Spirometry  
Lung function is assessed with spirometry which is considered the gold standard for assigning the diagnosis of 
COPD. We will conduct the testing according to the American Thoracic Society (ATS) recommendations85, and 
ask participants to refrain from taking inhaled medications for breathing during the six hours prior to their visit, 
unless they are having trouble with their breathing.  Spirometry is a routine clinical measure that requires the 
patient to blow forcefully into a tube for at least six seconds for three-to-eight times until three acceptable 
results show repeatability.  Coordinators will administer this test both before and after the participant inhales a 
bronchodilator, and measure forced vial capacity (FVC) and forced expiratory volume in one second (FEV1).  
 
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These measurements will allow us to determine the presence of COPD by calculating the FEV1/FVC and 
FEV1 percent predicted using each subject’s age, height, weight, and ethnicity. Participants are eligible to 
participate in INSIGHT COPD if their FEV1/FVC is less than 0.70 and FEV1% predicted >30. 
 
11.4. Dyspnea and fatigue 
Modified Medical Research Council (mMRC) dyspnea score:73 Used to assess study eligibility.  The mMRC 
asks patients to recall the degree to which every-day activities elicit dyspnea, scored on a 5-point scale with 
higher scores indicating greater dyspnea. Participants are eligible to participate in INSIGHT COPD if they 
score 1 or higher (“I get short of breath when hurrying on the level or walking up a slight hill”).  
 
Modified Borg Scale: 86-88 Used to assess dyspnea and leg fatigue level before and after the 6MWT.  This scale 
assesses symptoms at the time of exercise and does not require patient recall.  Scores on the modified scale 
range from 0 (nothing at all) to 10 (very, very severe).   
 
11.5. Cardiovascular risk factors (CVR)  
CVR is assessed by waist circumference, the Framingham Risk Score (FRS),89 blood pressure and BMI.  The 
INSIGHT COPD trial will use the FRS non-laboratory predictors to estimate participants’ 10-year risk of 
myocardial infarction and coronary mortality using age, BMI, systolic blood pressure, smoking status, presence 
of diabetes assessed by self-report diabetes diagnosis or use of diabetes medication , and self-report use of 
medication for high blood pressure. 
 
11.6. Vital signs 
Pulse: Measured in conjunction with the 6MWT according to standardized procedures.  
 
Blood pressure (BP):  Measured in conjunction with the 6MWT and used as part of the FRS. Measured using 
an automatic or manual blood pressure cuff that meets the recommendations of the American Heart 
Association.90 
 
Blood oxygen saturation (SpO2): Measured with an oximeter in conjunction with the 6MWT using standardized 
procedures.  
 
11.7. Self-administered instruments 
Demographic and health inventory:  Sites ask participants about their socio-demographic characteristics, health 
behaviors (e.g., smoking, use of personal trainer), comorbid conditions, family history of lung disease, respiratory 
symptoms, supplemental oxygen, sleep disturbance, COPD exacerbations, medications, and health care 
utilization.   
 
Generic HRQoL:91 Assessed using the 12-Item Short form Health Survey (SF-12v2),91 which is well validated 
and has physical and mental health component scores.   
 
COPD symptom QoL: Assessed using the St George’s Respiratory Questionnaire-C (SGRQ-C). The SGRQ-C, 
specifically for COPD patients, is a 40-item survey designed to measure health status for chronic airflow 
limitation. It has two parts that produce Symptom scores and Activity and Impacts scores, as well as a Total 
score.  The SGRQ-C was derived from the original version following detailed analysis of data from large 
studies in COPD. The intention was to remove the items with the weakest measurement properties in the 
original instrument, but at the same time ensure that its scores were directly comparable with the original 
SGRQ.92 
 
11.8. Additional Process Measures   
Data on the proportion and representativeness of patients willing to participate, as well as reasons for declining 
to participate, are used to assess the potential reach and the likelihood of adoption of the INSIGHT COPD 
intervention.   
 
 
 
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12.0. SAFETY 
This trial has minimal risk, as demonstrated by the excellent safety data in E-LITE.48   To ensure unbiased 
determination across treatment arms, the PLG will train clinical center staff to systematically query participants 
about possible adverse events (AEs) and serious AEs (SAEs) at each scheduled data collection time-point 
using a body system-based approach.   A clinical site clinician (MD, nurse, or other appropriately qualified 
personnel) will perform safety monitoring based on the AE query forms completed by their center staff, and 
then make a determination regarding event seriousness, expectedness, and study relatedness. Events rated 
as serious and unexpected are reviewed by a PTC medical monitor.  Sites will report events to their local IRB, 
the NEMO, Data Safety and Monitoring Board (DSMB), and/or the NHLBI according to all timelines required by 
these entities.   
 
The PLG will summarize on a semi-annual basis the number of AEs and SAEs for each unidentified treatment 
group as specified by the NEMO DSMB.  
 
AEs and SAEs will be reported to the IRB, DSMB, and Sponsor. Summaries will also be included in the 
annual progress reports to the sponsor.  At the discretion of the DSMB, the Chair may request unblinded 
results in order to determine the nature and extent of effect of the experimental intervention.  Should the DSMB 
make this request, it will be fulfilled following a procedure which will maintain blinding of the investigators and 
the staff involved in follow-up data collection and analysis.  If, at any time, the investigators believe they are 
seeing an unexpected increase in SAEs or in AEs that are a cause for concern, this will be specifically brought 
to the attention of the DSMB and their advice will be sought. 
 
Sites will also follow and comply with their own local institution’s adverse event reporting requirements. These 
reporting requirements may be more stringent than those adopted by INSIGHT COPD. Regardless of what 
INSIGHT COPD requires, each site must comply with their local IRB’s requirements. Depending on the local 
requirements, a site may report events locally that are not reported to INSIGHT COPD. 
 
Stopping rules.  Given that the follow-up period is are 12-months, and that the intervention is considered 
feasible for not only healthy adults, but also older adults and adults with chronic conditions or functional 
limitations, formal stopping rules for safety, efficacy, and futility are not proposed.  Interim monitoring of study 
outcomes for evidence of efficacy or futility is not planned.  Evidence of extremely low rates of patient accrual, 
extremely high rates of patient drop-out, and/or a marked preponderance in the rates of SAEs in the either 
study arm will trigger further consideration of both statistical and clinical evidence by the DSMB to decide 
whether the trial should continue. The DSMB will carefully weigh the risk of completing the trial as planned 
against the risk of prematurely stopping the trial for safety or futility.   
 
DSMB recommendations.  At the end of each meeting, DSMB members will make a recommendation 
regarding the continuation of the trial and the date and format of the next meeting.  In addition, there will be an 
evaluative statement regarding AE/SAEs, protocol exceptions, and other matters of data quality, integrity of the 
trial, and timeliness.  The DSMB's findings and recommendations will be documented in the meeting minutes 
and transmitted to the Investigators for their information and action.  They also will be incorporated into the 
annual Progress Reports to the sponsor.     
 
 
13.0. RETENTION 
Retention of participants is an essential component of conducting clinical trials so that the investigators can 
detect differences in outcomes between the intervention and control groups, and so that they can generalize 
study findings.  Sites will use the following strategies to maximize participant retention, including contacting 
participants at regular intervals between the baseline and 12-month visit to thank them for participating and 
remind them of their commitment to complete the 12-month visit.  At least one of the contacts must be by 
telephone four-to-eight months after randomization: 
 
 
 
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Table 1. Retention strategies by timepoint 
(apply to ALL participants, regardless of randomized group) 
Strategy 
Baseline 
Between 
visit 
12-
month 
visit 
Participant Experience 
Careful staff selection & standardized training in rapport building, interviewing 
techniques, trial-specific protocols, and problem-solving techniques as 
appropriate to study roles 
x 
x 
x 
Maintain atmosphere that allows participants to feel comfortable and valued, 
and is professional and efficient 
x 
x 
x 
Contacts by same staff member for continuity as possible while maintaining 
blinding 
x 
x 
x 
Careful eligibility screening 
x 
 
 
Consider clinical no-show rate when determining eligibility* 
x 
 
 
Careful explanation of study requirements and random assignment, including 
importance of attending follow-up visit (even if not adhering to treatment 
assignment); assurance ppt fully understands expectations 
x 
x 
 
Give clear instructions for completing questionnaires and measurements 
x 
 
x 
Keep visits running on time 
• 
modified shortened visit to obtain primary outcome data as necessary 
x 
 
x 
Snacks or meal vouchers as appropriate* 
x 
 
x 
Schedule follow-up at baseline 
x 
 
 
Flexible scheduling to accommodate participant’s needs 
x 
 
x 
Participant incentives, as appropriate, e.g.: 
• 
Free parking and/or transportation* 
• 
Sufficient remuneration 
x 
 
x 
Participant Engagement 
Promote study identity, e.g.: 
• 
refrigerator magnet 
• 
water bottle 
x 
x 
 
Maintain current contact information, including a secondary contact as 
appropriate 
x 
x 
x 
Maintain regular contact (at least every 4 months), e.g.: 
• 
at least one contact by phone four-to-eight months after randomization 
• 
holiday or birthday cards/calls  
• 
regular participation reminder letter/calls 
• 
greet at clinic visits 
 
x 
x 
Begin process of scheduling follow-up visit 2-3 months prior to 12-month date  
 
 
x 
Confirmation letter at least 1 week before appointment 
 
 
x 
Appointment confirmation call ~3 days before visit 
 
 
x 
Coordinate study visit with clinic visit to reduce trips 
x 
 
x 
Mechanism for monitoring visit cancellations and timely re-scheduling 
x 
x 
x 
Ongoing monitoring of recruitment and retention 
x 
x 
x 
Diligent efforts to re-engage inactive participants 
• 
multiple methods of contact (phone, text, email, letters) 
x 
x 
x 
 
We use systematic quality control, adherence to high quality practices, and regular reporting to clinical centers 
to maintain subject participation in this trial.  Examples of training that facilitate retention include thorough and 
fully informed roles and responsibilities of staff and participants, conveying an appreciation of participation and 
study identification, nominal remuneration for study visits and parking, and reasonable accommodations to 
participant schedules. As part of our monthly clinic site calls, we will review retention rates, making 
comparisons between sites, and re-reviewing high quality practices.  We will also work individually with sites 
that have high participant attrition. 
 
 
 
 
 
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14.0. ANALYSIS 
14.1. Sample size 
The primary endpoint is 6MWT distance at 12 months, a continuous scale outcome. An overall sample size of 
680, with 340 in each treatment group, will allow detection of a standardized mean difference (Cohen’s d) of 
0.28 between the intervention and UC groups with a power of 90%, two-sided α = 0.05, and assuming at least 
80% retention at 12 months. The decision to use a Cohen’s d of 0.28 is based on based on 30m as the MID for 
6MWT distance.93  In the CONCERT study94, the Cohen’s d effect size was approximately 0.39 for 6MWT 
distance between the 
overweight and obese 
groups. A two-sample t-
test is used to estimate 
power (Table 11).  No 
multiplicity adjustment will 
be made for secondary 
analyses, which are 
intended to complement 
the primary findings and to inform future research.  They will be interpreted within that context, considering the 
totality of evidence available.95,96   
 
14.2. Overview of analysis plan 
This is a patient-randomized trial with patients nested within site and repeated measures within patient.  This 
type of design makes it invalid to use standard approaches to assess a patient-level randomized trial because 
of the correlation between patients within site and repeated measures within patient. For the primary analysis, 
we will be evaluating the effect of the intervention at the primary endpoint (12 months through modeling of 
baseline and 12-month outcomes.  It is reasonable to expect that patients within a site are not independent of 
one another and that repeated measures within patient are not independent from one another. These effects, 
depending on the correlations within and across sites and patients, may lead to decreased variance at the 
outcome measurement level and increase the probability of a type I error. The primary research hypothesis to 
be tested is that the intervention will lead to net improvement in 6MWT distance at 12 months.  A linear mixed-
effects model (LMM) will be necessary to assess the effect of the treatment.  The statistical test will be two-
sided because it is possible that the control group is superior to the intervention in either outcome measure.  In 
other words, the statistical alternative hypothesis is two-sided, namely, the two study groups will result in 
significantly different 6MWT distances at 12 months. 
 
Statistical analysis will occur in two phases.  First, preliminary analyses will be performed to examine the 
suitability and feasibility of assumptions required to conduct more complex analysis including distributional 
assumptions (e.g., variance homogeneity, normality, etc.), collinearity and independence will be carried out.  
Second, we will conduct hypothesis testing analyses for the specific aims as described below. 
 
14.3. Baseline Analysis and Descriptive Statistics 
Equivalence of participants in the intervention and control arms will be assessed on demographic and clinical 
variables, including outcomes, health status, co-morbidity, and utilization variables. Because this is a 
randomized controlled trial, no systematic bias is anticipated. However, we will conduct sensitivity analyses 
that adjust for the covariates that are thought a priori to be related to the primary and secondary outcomes 
(e.g., age, sex). We will report summary statistics for all baseline covariates and outcomes (means, standard 
deviations, and quartiles for continuous variables; frequencies and percentages for binary variables) by 
randomized treatment group. 
 
14.4. Drop Outs and Missing Data 
We will make every effort to obtain complete data on each study participant at all data collection points. 
However, some missing data is inevitable and creates a risk for selection bias that can skew results.  We will 
document and evaluate the extent, pattern, and reasons for missing data.  Our primary analysis model will 
Table 11 Continuous Outcome: 6MWT distance 
6MW 
(m) 
Cohen’s 
d 
𝛼 
𝛽 
𝑝𝑜𝑤𝑒𝑟 
Sample size 
for each 
group 
Sample size for 
each group 
assuming 20% 
attrition rate 
24.8 
.23 
.05 
0.10 
0.90 
499 
399 
30.2 
.28 
.05 
0.10 
0.90 
336 
268 
35.6 
.33 
.05 
0.10 
0.90 
242 
193 
 
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handle missing data using restricted maximum likelihood (REML) estimation which relies on the assumption 
that the data is missing at random (MAR).  ML has been shown to yield similar results to its alternative multiple 
imputation (MI).97-99  ML is a powerful alternative to MI and valid for our data as we will collect all patient 
demographics prior to randomization.  This means that we expect to have no missing values in our explanatory 
variables, which is a necessary criterion for REML. For the MAR assumption to hold, it must be believed that 
the probability the outcome is missing depends only on the information available.  In the case of this study, this 
assumption should be acceptable as the missing outcome variables should be explained by the available 
variables.  However, should the MAR assumption appear to be violated, we will conduct sensitivity analyses 
that instead assume the data are missing not at random.  In this case, it is necessary to account for the 
missing data mechanism in the model.   
 
14.5. Primary Analysis for Aim 1 
The primary analysis will use intention-to-treat and all available data in model fitting. Our continuous primary 
outcomes and important secondary outcomes – 6MWT distance (primary), weight (secondary), and post-walk 
modified Borg dyspnea scale (secondary) – will be modeled via mixed-effects linear regression of the following 
form100-102: 
 
𝑦𝑖𝑗𝑘= 𝛽0 + 𝛽1𝑘+ 𝛽2(Intervention𝑖∗𝑘) + 𝛽3COVID𝑖𝑘+ 𝛽4BaselineSmoker𝑖+ α𝑖+ 𝛾𝑗+ 𝑒𝑖𝑗𝑘 
 
Where 𝑦𝑖𝑗𝑘 stands for the outcome measurement for patient 𝑖 of site 𝑗 at time point 𝑘 (𝑘 is equal to 0 at 
baseline and is equal to 1 at 12-month follow-up). Intervention𝑖 is an indicator variable equal to 1 for patients 
randomized to the intervention arm and is equal to 0 otherwise. COVID𝑖𝑘 is an indicator equal to 1 if 𝑦𝑖𝑗𝑘 was 
measured on or after March 19, 2020 and is equal to 0 otherwise. BaselineSmoker𝑖 is equal to 1 if patient i 
reported smoking within one month prior to baseline self-report and is equal to 0 otherwise. The α𝑖 are random 
patient-level intercepts assumed independently distributed Normal(0, 𝜎𝛼2), the 𝛾𝑗 are random site-level 
intercepts assumed independently distributed Normal(0, 𝜎𝛾2), and the 𝑒𝑖𝑗𝑘 are outcome-level errors assumed 
independently distributed Normal(0, 𝜎2). 
 
To compare the intervention arm to the control arm at significance level α = 0.05 with respect to each outcome, 
an adjusted difference in means estimate, 95% confidence interval, and p-value for testing whether the 
adjusted difference in means at 12-month follow-up is unequal to zero will be generated based on each 
primary analysis model’s 𝛽2 parameter. 
 
 
We will verify that the linear mixed effects model-based results are not sensitive to violations of model 
assumptions with permutation and bootstrap resampling tests.103,104  
 
14.6. Sensitivity Analyses  
We will summarize and visualize our outcomes based on missingness patterns across time. If this investigation 
produces evidences of missingness not at random, a multiple imputation using chained equations (MICE) 
approach will be implemented as a sensitivity analysis for each primary analysis model, with Rubin’s rules 
employed to pool inference across analyses of completed datasets.98,105-107  
 
We will also investigate whether the distribution of follow-up measurement time differs across treatment arm. If 
a difference is evidenced, each primary analysis model and MICE sensitivity analysis model, if using, will be re-
fit with a continuous covariate that counts the number of days from 12-months post-randomization date to 
actual follow-up measurement date. 
 
Additional covariates (e.g., age, sex) will be included to elucidate the primary intention-to-treat findings 
regarding treatment arm difference in our outcomes at 12-month follow-up. Further sensitivity analyses will be 
conducted using Generalized Estimating Equations (GEEs) if the distributional assumption of normality is not 
met within the LMM framework.  GEEs do not rely on this distributional assumption and will allow for an 
evaluation of the intervention in this scenario. 
 
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14.7. Secondary Analysis for Aim 1  
Dichotomized secondary outcomes for 6MWT distance, weight, and post-walk modified Borg dyspnea scale 
will be generated based on whether the respective, continuously measured primary outcome meets or exceeds 
the minimal important difference, as described below: 
• 
6MWT distance: 30m 
o Dichotomous outcome is equal to 1 if (follow-up 6MWT distance - baseline 6MWT distance) ≥ 
30m, and it is equal to 0 otherwise. 
• 
Weight: (Multiple) 
o Dichotomous outcome is equal to 1 if (follow-up weight – baseline weight)/(baseline 
weight)*100% ≥ 5%, and it is equal to 0 otherwise. 
o Dichotomous outcome is equal to 1 if (follow-up weight – baseline weight)/(baseline 
weight)*100% ≥ 3%, and it is equal to 0 otherwise.  
• 
Post-walk modified Borg dyspnea scale (i.e., shortness of breath): 1 unit 
o Dichotomous outcome is equal to 1 if (baseline shortness of breath - follow-up shortness of 
breath) ≥ 1 unit, and it is equal to 0 otherwise. 
 
Mixed-effects logistic regression models of the following form will be fit to these secondary outcomes and used 
to estimate a treatment arm standardized risk difference: 
 
𝑦𝑖𝑗= 𝛽0 + 𝛽1Intervention𝑖+ 𝛽3COVID𝑖+ 𝛽4BaselineSmoker𝑖+ 𝛾𝑗+ 𝑒𝑖𝑗 
 
Where 𝑦𝑖𝑗 stands for the dichotomized outcome for patient 𝑖 of site 𝑗. Intervention𝑖 is an indicator variable equal 
to 1 for patients randomized to the intervention arm and is equal to 0 otherwise. COVID𝑖 is an indicator equal to 
1 for patients whose follow-up outcome was measured on or after March 19, 2020 and is equal to 0 otherwise. 
BaselineSmoker𝑖 is equal to 1 if patient i reported smoking within one month prior to baseline self-report and is 
equal to 0 otherwise. The 𝛾𝑗 are random site-level intercepts assumed independently distributed Normal(0, 𝜎𝛾2), 
and the 𝑒𝑖𝑗𝑘 are outcome-level errors assumed independently distributed Normal(0, 𝜎2). 
 
Additional secondary outcomes – generic HRQoL, Framingham CVD Risk Score, waist circumference, blood 
pressure, and BMI – will be analyzed similarly as in the primary and secondary analyses of 6MWT distance, 
weight, and post-walk modified Borg dyspnea scale. 
 
14.8. Interim Analyses 
The purpose of sequential trial design is to permit assessment of early termination of a trial because of either 
major harms or benefits.  Interim analyses also are considered when the recruitment period is lengthy, or when 
there might be an opportunity to intervene during the trial experience to either remove the potential of a harmful 
intervention or to allow all participants to benefit from the intervention.    
 
The DSMB requested rationale for not proposing interim analyses for a trial as large as INSIGHT COPD.    The 
INSIGHT COPD trial seeks to test whether a behavioral intervention based on the diabetes prevention program 
(DPP) will reduce weight and improve exercise tolerance among overweight and obese patients with COPD. 
 
Conducting an interim analysis prior to the intended completion of data collection would be advisable if there 
were uncertainty regarding whether the intervention will effect an increase in adverse outcomes such as 
mortality or medical complication rates. If, during an interim analysis, there were evidence that the treatment is 
causing major harm, the application of the intervention could be immediately terminated. 
 
An interim analysis could also show evidence of an intervention effect based on data already collected. If we 
were satisfied in having shown evidence of an intervention effect at the interim analysis, we could consider 
early termination of the study to save time and resources. 
 
 
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We do not propose conducting an interim analysis in the current trial because we do not anticipate evidence of 
major harm or substantial benefit that would warrant early stopping. First, the behavioral weight loss 
intervention under study involves minimum risk and has demonstrated good safety profiles in the original 
Diabetes Prevention Program multicenter efficacy trial and in numerous subsequent studies in which the 
intervention was adapted and evaluated for diverse populations and settings. Second, we hypothesize a 
modest, clinically relevant effect of the intervention on the primary outcome as shown in our power analysis. 
This is reasonable on the basis of a large body of literature showing modest benefits of behavioral 
interventions in general for a wide range of health outcomes in different populations. The likelihood is low that 
we would have convincing evidence of an intervention effect on the primary outcome prior to the planned 
completion of the trial. Moreover, early termination would adversely affect our ability to fully assess the 
intervention’s impact on secondary outcomes, which are parsimonious and clinically important. 
 
 
15.0. DATA MANAGEMENT 
Sites enter data coded with a confidential Participant ID into the REDCap hosted by the University of 
Washington.  REDCap is a free web application tailored for research studies to build and manage online surveys 
and databases.  REDCap has sophisticated customizable capabilities important for quality and security including 
flexible form creation, granular user privileging, password management, user authentication, auto logout, logging 
and audit trails, data export and de-identification, and protective security measures.  Additional information about 
the REDCap system may be found at the following websites. 
https://redcap.vanderbilt.edu/consortium/REDCapTechnicalOverview.pdf 
https://www.iths.org/wp-content/uploads/REDCap_System_Security_Statement_29032013.pdf 
 
Data is either directly entered into REDCap by a site coordinator, or by the participant for self-report surveys (if 
the participant so chooses), or completed on paper with subsequent entry into REDCap by the site coordinator. 
The REDCap database employs automatic, real-time range, logic, and missing value checks. Research 
coordinators (blinded to treatment assignment) review participant responses on questionnaires with 
participants present, and skipped or incorrectly addressed items will be brought to the participant to verify and 
correct as appropriate.  
 
Participants may enter their diet and physical activity information into MyFitnessPal, or log information into 
paper tracking booklets identified only by the study ID.  These data are entered onto REDCap by the lifestyle 
coach. 
 
REDCap data are cleaned and verified, then downloaded into appropriate analysis software housed on the VA 
Center of Innovation for Veteran-Centered and Value-Driven Care (COIN) secure computer network servers, 
and handled in accordance with the COIN’s extensive data security policy. The study data is backed up daily 
and maintained by the COIN. One official copy of all study data and a master data dictionary are maintained 
and updated regularly by the study data manager. Data crosswalks are maintained by the clinical sites and 
kept separately from all other study data.  Paper forms are stored in locked file cabinets per local site security 
standards.   
 
The PLG takes numerous steps to maintain the integrity and security of the data system.  First and foremost 
among these are the NEMO’s provision of careful training, certification, and guidance to all staff at the PLG 
and the clinical sites. Study sites are expected to provide a secure, monitored location for their data storage.  
All involved sites are expected to use password-protected data systems. All personnel are expected to follow 
strict procedures to protect confidentiality of information and for guarding privacy of participants enrolled in the 
study. Users access REDCap via a user specific login and password provided by the University of Washington. 
The PLG restricts specific access to the REDCap INSIGHT COPD project to individuals who have 
demonstrated proficiency with the data system by correctly entering training data forms into a "certification data 
system."  This certification process is designed to highlight all important features of the data system.  The PLG 
conducts additional “back-end” quality control including review of the REDCap audit trail for all data entries and 
revisions, checks for missing data, logical inconsistencies, and other anomalous entries.      
 
 
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The PLG closely monitors: a) participant accrual and follow-up in relation to goals and timeline; b) the 
randomization process and group comparability on the balancing variables; c) key baseline characteristics of 
the sample, by group, on the primary and secondary outcome variables and proposed effect moderators and 
mediators; d) intervention adherence; and e) protocol violations.  Problems identified are addressed swiftly. 
 
All study information is accessible only by IRB approved study staff on a need-to-know basis.  Limited analytic 
datasets are shared between authorized study personnel via secure transmission and/or via a secure virtual 
private network employing industry-standard password protection and data encryption. Study information is not 
disclosed to any third party except as required by law.  A de-identified dataset will be shared with NHLBI’s data 
repository. Only aggregate data will be used to report study results.  Patient identifiers will be retained per IRB 
permissions. 
 
 
16.0. TRIAL MANAGEMENT 
Both PIs (Dr. Au and Dr. Ma) assume overall fiscal and administrative management of the PLG including 
maintaining communication among co-Investigators and key personnel at the Seattle Institute for Biomedical 
and Clinical Research, VA Puget Sound Health Care System, University of Illinois at Chicago, NEMO, and the 
study clinical centers.  Although Dr. Au serves as the contact PI for this application, communication 
requirements with NHLBI, NEMO, and IRB are shared jointly. Because Dr. Ma developed the intervention and 
has extensive experience with its implementation in prior trials, she leads efforts to finalize the protocol and 
address issues that arise to ensure the fidelity of the intervention.  Dr. Ma’s role includes oversight of 
implementation of the INSIGHT COPD intervention at the clinical sites and trouble-shooting potential issues, as 
well as hiring and overseeing the lifestyle coach(es).  She implements intervention quality assurance 
procedures to ensure that project activities are standardized across the interventionists and across the sites 
and that intervention process data are collected accurately.  She periodically reviews the protocol with clinical 
site staff to ensure fidelity and address questions that arise.  Assisted by Dr. Barón, Dr. Au has primary 
responsibility for overseeing study forms, safety monitoring, and the data management system for data 
collection, processing, storage, and analysis in a manner that ensures data quality and security.   
 
Drs. Au and Ma work together to provide trial oversight to ensure adherence of the protocol at clinical 
centers.  They share the responsibility for overseeing AE reporting to the NEMO and DSMB, ensuring data 
quality control, guiding data analysis, and writing study manuscripts.  Drs. Au and Ma work with the NEMO to 
ensure all parties involved in the execution of the INSIGHT COPD protocol comply with all applicable policies 
and regulations, including human subjects’ protection.  They will cooperate to ensure the timely and broad 
dissemination of lessons learned.  In addition, as Protocol Leadership Group PIs, Drs. Au and Ma each serve 
on the PTC operations committee (OC), along with representatives from the clinical centers and officials from 
the NHLBI. 
 
Conflict resolution.  If conflict arises, the PIs agree to meet by telephone/teleconference and attempt to 
resolve the dispute.  If the PIs are unable to resolve the conflict, the appropriate Departmental administrators 
representing the PIs shall meet by phone and attempt in good faith to settle any dispute, claim or controversy.  
If a PI moves to a new institution, attempts will be made to transfer any relevant portion of the grant to the new 
institution.  In the event that a PI cannot carry out his/her duties, a new PI will be recruited as a replacement. 
 
As noted, the two PIs along with the study team will work closely together throughout this project.  During the 
study period, Dr. Au and Dr. Ma will meet weekly by telephone/teleconference (such as Skype, Microsoft live 
meeting) to review progress, discuss and address problems and review budget status and scientific direction.  
Each will be available to one another as needed by phone/teleconferencing.  The two PIs will meet in person at 
least twice per year, usually as part of the annual meeting of the American Thoracic Society or other 
conference and at the annual OC meeting in Bethesda, MD.  Travel costs and distance between Seattle and 
Chicago are nominal, and if both agree, each PI is willing travel to the other if they are unable to meet at 
national meetings or as necessary.   
 
 
 
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17.0. TRAINING AND CERTIFICATION  
The staff of the PLG will work with NEMO to develop site training and staff certification procedures to include 
modules for conducting the protocol and REDCap data management.    
 
 
18.0. PUBLICATIONS AND ANCILLARY STUDIES 
18.1. Publications 
 
The NEMO Operations Committee coordinates, monitors, reviews, and assumes responsibility for arranging 
the preparation of all study-wide communications (press releases, interviews, presentations, and publications) 
relating to the scientific aspects of the PTC.  For the purposes publications specific to the INSIGHT COPD trial, 
Drs. Au and Ma will review all plans for publications or presentations.     
 
With respect to publications and presentations from INSIGHT COPD, the goals are to: 
• 
ensure accurate, uniform, timely, and high-quality reporting of the study activities and results; 
• 
preserve the scientific integrity of the study; 
• 
safeguard the rights and confidentiality of participants; 
• 
assure that the timing of publications and presentations serves the right of the public to know the 
results of the program without jeopardizing its conduct. 
 
Authors who participate in the writing of an INSIGHT COPD study manuscript do so in accordance with the 
International Committee of Medical Journal Editors (ICMJE) guidelines (http://www.icmje.org/icmje.pdf) and 
any additional considerations specific to non-medical journals (such as social and behavioral science journals 
that follow the standards of the American Psychological Association108).  First authors are expected to remove 
names from the final list of authors if those individuals who have not participated in the writing and/or analysis 
of the paper in accordance with the ICMJE guidelines.  All papers should also include an “Acknowledgments” 
section that lists the INSIGHT COPD investigators and key staff, unless journal policy prohibits publication of 
such a list. 
 
First authorship should be decided before data analysis for the manuscript begins.  The first author also 
determines the order of co-authorship on the manuscript.  A key criterion to co-authorship is the individual’s 
contribution to the paper.  In general, authors will appear in order of contribution to the writing and analysis of 
the paper.  When contributions to writing and analysis have been similar, priority should be given to those who 
have contributed to a greater degree to the design and implementation of the trial and to junior investigators.   
  
18.2. Ancillary Studies 
Drs. Au and Ma will evaluate proposals for studies that involve INSIGHT COPD participants and that are not a 
part of the INSIGHT COPD Protocol and Manual of Procedures (MOP).  These studies will in general, be done 
only on a subset of participants INSIGHT COPD.  Nevertheless, studies that include all INSIGHT COPD 
participants and studies that analyze INSIGHT COPD data in ways extracurricular to the INSIGHT COPD 
Protocol and MOP must be reviewed and approved by the Steering Committee.  Ancillary studies will have to 
obtain funding from outside INSIGHT COPD. 
 
Major factors in approval of ancillary studies will include: 
• 
compatibility of goals with those of INSIGHT COPD; 
• 
should not place undue burden on INSIGHT COPD participants and staff. 
  
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February 18, 2021

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VA Puget Sound IRB 2
Effective Date:
February 18, 2021