GATE: Generalized Anxiety - A Treatment Evaluation
Phase: NA
Conditions: Generalized Anxiety Disorder
Sponsor: NYU Langone Health

Version Date: 07/20/2017 
GATE: GENERALIZED ANXIETY – A TREATMENT 
EVALUATION 
 
Study Chairman or Principal Investigator:   
Stefan G. Hofmann, Ph.D 
Professor of Psychology, Boston University 
and  
Naomi Simon, MD, MSc 
Director, Anxiety and Complicated Grief Program 
Department of Psychiatry 
NYU Langone Health 
  
 
MGH Subcontract Site Principal Investigator: 
Eric Bui, MD, Ph.D 
Assistant Director, Center for Anxiety and Traumatic Stress Disorders 
Massachusetts General Hospital 
Assistant Professor of Psychiatry, Harvard Medical School 
 
Supported by:  
The National Center for Complementary and Alternative Medicine  
1R01AT007257-01A1 & 1R01AT007258-01A1 
Study Intervention Provided by:  
No support is provided by pharmaceutical companies or device manufacturer  
 

 
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Sponsor of IND (IDE):  
There is no IND or IDE 

 
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Tool Revision History 
Version Number: 1 
Version Date: 7/2/13 
Summary of Revisions Made: N/A 
Version Number: 2 
Version Date: 8/12/13 
Summary of Revisions Made: 
Version Number: 3 
Version Date: 9/16/13 
Summary of Revisions Made:  
Version Number: 4 
Version Date: 9/30/13 
Summary of Revisions Made:  
 
Version Number 5  
Version Date 03/05/14 
 
Version Number 6 
Version Date 12/19/14 
 
Version Number 7 
Version Date 02/11/15 
Version Number 8 
Version Date 04/17/2017 
 
Version Number 9 
Version Date 07/20/2017 

 
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TABLE OF CONTENTS 
 
FULL PROTOCOL TITLE ............................................................ Error! Bookmark not defined. 
Tool Revision History ................................................................................................................. 2 
TABLE OF CONTENTS ............................................................................................................. 3 
STUDY TEAM ROSTER........................................................................................................... 6 
PARTICIPATING STUDY SITES ............................................................................................ 6 
PRÉCIS ....................................................................................................................................... 6 
1. STUDY OBJECTIVES ............................................................................................................. 6 
1.1 
Primary Objective ........................................................................................................... 8 
1.2 
Secondary Objectives...................................................................................................... 8 
2. BACKGROUND AND RATIONALE .................................................................................... 8 
2.1 
Background on Condition, Disease, or Other Primary Study Focus .............................. 8 
2.2 
Study Rationale ............................................................................................................... 9 
3. STUDY DESIGN ..................................................................................................................... 14 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS .............................................. 15 
4.1 
Inclusion Criteria .......................................................................................................... 15 
4.2 
Exclusion Criteria ......................................................................................................... 15 
4.3 
Study Enrollment Procedures ....................................................................................... 16 
5. STUDY INTERVENTIONS .................................................................................................. 18 
5.1 
Interventions, Administration, and Duration ................................................................ 18 
5.2 
Handling of Study Interventions ................................................................................... 20 
5.3 
Concomitant Interventions ............................................................................................ 21 
5.3.1 Allowed Interventions ............................................................................................... 21 
5.3.2 Required Interventions .............................................................................................. 21 
5.3.3 Prohibited Interventions ............................................................................................ 21 
5.4 
Adherence Assessment ................................................................................................. 21 
6. STUDY PROCEDURES ........................................................................................................ 22 
6.1 
Schedule of Evaluations ................................................................................................ 22 
6.2 
Description of Evaluations ............................................................................................ 24 

 
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6.2.1 Screening Evaluation ................................................................................................ 27 
6.2.2 Enrollment, Baseline, and/or Randomization ........................................................... 27 
6.2.3 Blinding..................................................................................................................... 28 
6.2.4 Followup Visits ......................................................................................................... 28 
6.2.5 Completion/Final Evaluation .................................................................................... 28 
7. SAFETY ASSESSMENTS ..................................................................................................... 29 
7.1 
Specification of Safety Parameters ............................................................................... 29 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .... 29 
7.3 
Adverse Events and Serious Adverse Events ............................................................... 30 
7.4 
Reporting Procedures .................................................................................................... 30 
7.5 
Followup for Adverse Events ....................................................................................... 31 
7.6 
Safety Monitoring ......................................................................................................... 31 
8. INTERVENTION DISCONTINUATION ........................................................................... 31 
9. STATISTICAL CONSIDERATIONS ................................................................................ 336 
9.1 
General Design Issues ................................................................................................... 37 
9.2 
Sample Size and Randomization .................................................................................. 38 
Treatment Assignment Procedures ....................................................................................... 39 
9.3  
Definition of Populations .............................................................................................. 39 
9.4 
Interim Analyses and Stopping Rules ........................................................................... 39 
9.5 
Outcomes ...................................................................................................................... 40 
9.5.1 Primary Outcome ...................................................................................................... 40 
9.6 
Data Analyses ............................................................................................................... 40 
10. DATA COLLECTION AND QUALITY ASSURANCE .................................................. 40 
10.1 
Data Collection Forms .................................................................................................. 43 
10.2 
Data Management ......................................................................................................... 43 
10.3 
Quality Assurance ......................................................................................................... 45 
10.3.1 
Training ................................................................................................................. 45 
10.3.2 
Quality Control Committee................................................................................... 46 
10.3.3 
Metrics .................................................................................................................. 46 
10.3.4 
Protocol Deviations ............................................................................................... 44 
10.3.5 
Monitoring ............................................................................................................ 44 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................... 44 
11.1 
Institutional Review Board (IRB) Review .................................................................... 44 
11.2 
Informed Consent Forms .............................................................................................. 44 

 
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11.3 
Participant Confidentiality ............................................................................................ 44 
11.4 
Study Discontinuation ................................................................................................... 45 
12. COMMITTEES..................................................................................................................... 45 
13. PUBLICATION OF RESEARCH FINDINGS .................................................................. 45 
14. REFERENCES ...................................................................................................................... 46 
15. SUPPLEMENTS/APPENDICES ........................................................................................ 48 
I. Procedures Schedule 
II. Informed Consent Form Template 

 
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STUDY TEAM ROSTER 
1) Boston University:  
Stefan G. Hofmann, Ph.D.; Department of Psychology, Boston University, 648 Beacon Street, 6th 
Fl., Boston, MA 02215, Tel: 617-353-9233; Fax: 617-353-9609, shofmann@bu.edu 
Subcontracted to BU: 
Sat Bir Khalsa, Ph.D., 3rd Floor, 900 Commonwealth Avenue, Boston, MA02215 Tel: 617 516-
6549, khalsa@hms.harvard.edu 
2) NYU Langone Health:  
Naomi Simon, M.D., M.Sc.; Department of Psychiatry, NYU Langone Health, One Park Ave, 8th 
Floor, New York, NY 10016, Tel: 646-754-4768; Fax: 617-743-4781, naomi.simon@nyumc.org 
Subcontracted to NYU: 
Massachusetts General Hospital 
T.H. Eric Bui, M.D., Ph.D. Center for Anxiety and Traumatic Stress Disorders, 
Massachusetts General Hospital, 1 Bowdoin Square, 6th Floor, Boston, MA 02114, Tel: 
617-726-7913; Fax: 617-643-0730, tebui@partners.org  
Georgetown University:  
Elizabeth Hoge, M.D.; Center for Anxiety and Traumatic Stress Disorders, Massachusetts 
General Hospital, 1 Bowdoin Square, 6th Floor, Boston, MA 02114, Tel: 714-724-0859; 
Fax: 617-643-0730, ehoge@partners.org 
3) Southern Methodist University: 
David Rosenfield, Ph.D; Department of Psychology, Southern Methodist University, 6424 
Hilltop Lane, PO Box 750442, Dallas, TX 75275, Tel: 214-768-2438, drosenfi@mail.smu.edu 
 
PARTICIPATING STUDY SITES: 
 
Boston University: 
Stefan G. Hofmann, Ph.D.; Department of Psychology, Boston University, 648 Beacon 
Street, 6th Fl., Boston, MA 02215, Tel: 617-353-9233; Fax: 617-353-9609, 
shofmann@bu.edu 
 
NYU Langone Medical Center: 
Naomi M. Simon, M.D., M.Sc.; Department of Psychiatry, NYU Langone Medical Center, 
One Park Ave, 8th Floor, New York, NY 10016, Tel. 646-754-4768; Fax: 646-754-4770, 
Naomi.Simon@nyumc.org 
 
Massachusetts General Hospital: 
Eric Bui, MD, PhD; Center for Anxiety and Traumatic Stress Disorders, Massachusetts 
General Hospital, 1 Bowdoin Square, 6th Floor, Boston, MA 02114, Tel: 617-724-1412; Fax: 

 
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617-643-0730, tebui@mgh.harvard.edu 
 
LIST OF ABBREVIATIONS 
AE 
 
 
Adverse Events 
AIC 
 
 
Akaike Information Criterion 
BAI 
 
 
Beck Anxiety Inventory 
BASC  
 
Behavior Assessment System for Children 
BDI 
 
 
Beck Depression Inventory 
BIC 
 
 
Bayesian Information Criterion 
BU 
 
 
Boston University 
CAM  
 
Complementary and Alternative Medicine 
CAMM 
 
Child Acceptance and Mindfulness Measure 
CARD  
 
Center for Anxiety and Related Disorders 
CATSD 
 
Center for Anxiety and Traumatic Stress Disorders 
CBT   
 
Cognitive Behavioral Therapy 
CGI 
 
 
Clinical Global Impression 
CGI-I  
 
Clinical Global Impression - Improvement Scale 
CGI-S  
 
Clinical Global Impression - Severity Scale 
COPD  
 
Chronic Obstructive Pulmonary Disease 
DSMB  
 
Data Safety and Monitoring Board 
DSMP  
 
Data Safety and Monitoring Plans 
DSM-V 
 
Diagnostic Statistical Manual of Mental Disorders, Fifth Edition 
DSM-IV 
 
Diagnostic Statistical Manual of Mental Disorders, Fourth Edition 
ECG  
 
Electrocardiogram 
EDC  
 
Electronic Data Capture 
FFMQ  
 
Five Facet Mindfulness Questionnaire 
FU 
 
 
Follow-Up 
GABA  
 
Gamma-amniobutyric Acid 
GAD  
 
Generalized Anxiety Disorder 
GLMM 
 
General Linear Mixed Models 
HIPAA 
 
Health Insurance Portability and Accountability Act 
HARS  
 
Hamilton Anxiety Rating Scale 
MGH  
 
Massachusetts General Hospital 

 
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ICC 
 
 
Intraclass Correlation Coefficient 
IE 
 
 
Independent Evaluators 
IRB 
 
 
Institutional Review Board 
ISI 
 
 
Insomnia Severity Index 
MCQ  
 
Meta-cognition Questionnaire 
MD 
 
 
Doctor of Medicine 
MOCA 
 
Montreal Cognitive Assessment 
MPAI  
 
Music Performance Anxiety Inventory 
MRM  
 
Mixed-effects Regression Model 
NCCAM 
 
National Center for Complementary and Alternative Medicine 
NIH 
 
 
National Institute of Health 
NYU  
 
New York University 
NYULMC 
 
NYU Langone Medical Center 
OHRP  
 
Office for Human Research Protections 
PAQ  
 
Performance Anxiety Questionnaire 
PCP 
 
 
Primary Care Physician 
PI 
 
 
Principal Investigator 
POMS  
 
Profile of Mood States 
PSQI  
 
Pittsburgh Sleep Quality Index 
PSQW  
 
Penn State Worry Questionnaire 
PSS 
 
 
Perceived Stress Scale 
QOL  
 
Quality of Life 
RCT 
 
 
Randomized Control Trial 
RN 
 
 
Registered Nurse 
RSA  
 
Respiratory Sinus Arrhythmia 
SAE 
 
 
Serious Adverse Events 
SCID  
 
Structured Diagnostic Interview 
SCL-90-R 
 
System Check List version 90 revised 
SE  
 
 
Stress Education 
SES 
 
 
Socioeconomic Status 
SIGH A 
 
Structured Interview Guide for Hamilton Anxiety Scale 
SOCID 
 
Social Identification Scale 
STAI  
 
State-Trait Anxiety Inventory 

 
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PRÉCIS 
Study Title  
Yoga for generalized anxiety disorder:  A comparison between yoga, cognitive behavioral 
therapy, and stress education training  
Objectives  
The general purpose of the study is to determine whether yoga is an effective method for 
treating GAD, and its relative efficacy compared to a standard psychosocial intervention. Our 
primary objective is to examine the short-term treatment efficacy of yoga on GAD symptoms. 
Our secondary objective is to examine the long-term treatment efficacy of yoga on GAD 
symptoms. Our tertiary objective is to examine and compare the mechanism of treatment 
changes in yoga and traditional CBT for GAD. 
Design and Outcomes   
This five-year multi-site study will examine the comparative efficacy of yoga, CBT, and 
stress education, a previously employed control condition, for patients with GAD. Across 2 
enrolling centers (BU and MGH) we will randomize 230 patients with GAD to one of three 12 
session weekly study treatments: 12-weekly yoga (n=95), CBT (n=95), or stress education (SE: 
n=40). Independent clinical assessments will occur before the 12-session intervention phase, at 
mid-treatment, after the intervention, and at 6-month follow-up. All clinician-rated outcomes will 
be assessed by trained Independent Evaluators (IEs) blind to treatment assignment. Response 
(CGI-I of 1 or 2) will serve as the primary outcome measure alongside the SIGH A as the core 
secondary continuous measure. Secondary outcome measures also include the STAI, PSS, BDI-
II and BAI, QOL, ISI, PSQI and PSWQ. The FFMQ, MCQ, pre-ejection period, and cortisol are 
examined as possible mediators of change. The Credibility/Expectancy Questionnaire will be 
administered to examine whether credibility and expectancy moderates therapy outcome. In 
addition, we will explore whether clinical characteristics (comorbid diagnoses) and demographic 
characteristics (age, sex, SES) are possible moderators. We hypothesize that Yoga and CBT will 
each be superior to SE at post-treatment FU, and Yoga and CBT will not differ based on 
equivalency analyses. We predict that treatment changes during yoga are mediated via changes 
in mindfulness and changes in vagal tone, whereas changes in CBT are mediated via changes in 
maladaptive cognitions. 
Interventions and Duration  
The interventions include 12-week yoga, CBT, or stress education sessions. Independent 
clinical assessments will occur before the 12-session intervention phase, at mid-treatment, after 
the intervention, and at 6-month follow-up. We will allow a maximum of one month for the time 
between baseline assessment of participants and randomization; should more than one month 
pass for logistical reasons, baseline psychological assessments would be repeated prior to 
randomization. Once participants complete eligibility and are randomized to a group, they will 
start treatment within 4 weeks.  
All 3 treatments will be administered in a group format to better reflect the most commonly 
available yoga format, and to maximize feasibility and cost-effectiveness (see also Integrity of 
Treatment Procedures). Providing all 3 modalities in the same sized and length group format will 

 
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also maximize integrity for the comparison of the active treatment components.  All three 
treatments will be 2 hours in duration, allowing for 15 minutes of study logistics including 
discussion of subject questions or difficulties with the home or group interventions, evaluation of 
individual subject compliance, and strategizing enhancing compliance.  The treatment itself will 
comprise a full 105 minutes training and practice in each group session. Subjects in all 3 
treatment groups will be provided with a credible rationale for the efficacy of their assigned 
treatment.  Subjects in the CBT arm will be informed of the role of CBT in the efficacy of 
changing dysfunctional thought patterns and beliefs, subjects in the yoga arm will be informed of 
the role of yoga in changing cognitive and physical emotional and stress reactivity through the 
postures, breath regulation and meditation components of yoga practice, and subjects in the 
Stress Education class will be informed about a variety of topics on stress and well-being: stress 
theory and physiology, effects of stress on body systems including cardiovascular and 
immunological, sleep efficiency, time management, nutrition, and exercise. 
Sample Size and Population  
We will randomize 230 patients with a primary diagnosis of GAD. Yoga (N = 95) will be 
compared to SE (N = 40), a commonly used control condition, and standard CBT for GAD (N = 
95). All interventions will be conducted in a group format over 12 weeks with 4-6 patients per 
group and therapists/yoga instructors. 
1. STUDY OBJECTIVES 
1.1. Primary Objective 
Our primary aim is to examine the short-term and long-term treatment efficacy of yoga 
(physical exercises/postures, meditation/mindfulness, and breathing exercises) for treating 
Generalized Anxiety Disorder (GAD) as compared to conventional CBT for GAD and to a stress 
education (SE) control condition. This study would provide the first RCT data for the 
comparative efficacy and acceptability of a standardized yoga group for the treatment of GAD 
compared to an active control, as well as gold standard CBT for GAD, and would generate a 
strong evidence base to support clinical use and future research.  
Specific Aim 1: Short-term Efficacy of Yoga: Our primary objective is to examine the short-term 
treatment efficacy of yoga on GAD symptoms. We expect that, at post-treatment, a significantly 
greater proportion of individuals randomized to receive yoga will be classified as “responders” to 
treatment (CGI-I ≤ 2) than for individuals who receive SE (Hypothesis 1.1). We further expect 
that a greater proportion of individuals receiving CBT for GAD will be classified as 
“responders” than for those receiving SE (Hypothesis 1.2). Moreover, we predict that the rate of 
“responders” in individuals receiving yoga will be comparable to those receiving CBT at post-
treatment (Hypothesis 1.3).  
Specific Aim 2: Long-term Efficacy of Yoga: Our secondary aim is to examine the long-term 
treatment efficacy of yoga on GAD symptoms. We hypothesize that yoga and CBT will be 
equally effective at the 6-month follow-up (i.e., the “responder” rate for yoga will not be inferior 
to that for CBT), and that yoga and CBT will each have higher “responder” rates than SE 
(Hypothesis 2.1-2.3).  

 
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1.2. Secondary Objectives 
Specific Aim 3: Mediation Analyses. Our tertiary aim is to examine and compare the mechanism 
of treatment changes in yoga and traditional CBT for GAD. We predict that treatment changes in 
responder rates during yoga treatment will be mediated via changes in mindfulness and changes 
in vagal tone (Hypothesis 3.1), whereas changes in CBT will be mediated via changes in 
maladaptive cognitions (Hypothesis 3.2.). Moderators of “responder rates” will also be 
examined. 
2. BACKGROUND AND RATIONALE 
2.1. Background on Condition, Disease, or Other Primary Study Focus 
 
The lifetime prevalence rate of generalized anxiety disorder (GAD) is estimated to be 
5.7% [1] and is associated with high comorbidity, suffering, and burden. Traditional cognitive 
behavior therapy (CBT) is the gold-standard intervention for treating anxiety disorders [2], 
including GAD (e.g., [3]). Individuals with GAD show lower levels of mindfulness (e.g., [4]), 
and therapy that enhances mindfulness appears to be effective for GAD (e.g., [5]). However, few 
individuals suffering from these symptoms receive adequate treatments because CBT in general, 
let alone mindfulness-based CBT is still not widely disseminated. Some yoga practices share 
many similarities to this intervention. In fact, meditation is a core component of most yoga 
practices, both historically and in practice. This notion is consistent with the NCCAM definition 
of yoga: "Yoga in its full form combines physical postures, breathing exercises, meditation, and 
a distinct philosophy." (http://nccam.nih.gov/health/yoga/introduction.htm).  
In contrast to mindfulness-based CBT, yoga has been widely adopted, more readily 
available and its popularity is increasing. Surveys suggest that 10% of the U.S. population have 
tried yoga or meditation [6], and 20 million more Americans want to [7]. Yoga has been adopted 
by the advertising industry as a symbol of health and a wholesome lifestyle. A recent survey of 
complementary and alternative medicine (CAM) use by the NIH and the Centers for Disease 
Control revealed that in 2007, 6.1% of the population had tried yoga as a therapeutic intervention 
and that yoga and its component practices of deep breathing and meditation were in the top 10 of 
the most prevalent CAM practices and among 4 that showed the greatest increase in the previous 
5 years [8].  A recent survey by Dr. Khalsa indicated that stress was one of the largest reasons 
(73%) for yoga participation [9]. The lack of evidence base for GAD is surprising, given that 
yoga practices are potentially powerful emotion regulation techniques with reductions in self-
reported anxiety reported in both healthy subjects [10-12]  and psychiatric inpatients [13]. 
Furthermore, a brain imaging study revealed that GABA neurotransmitter levels were elevated 
immediately after a single yoga class, and after 12 weeks, were associated with improvements in 
mood and anxiety in healthy subjects [14, 15]. Reductions in anxiety have also been reported 
after yoga programs applied over weeks or months in normal populations [16-18], students under 
exam stress [19], stressed caregivers [20], and otherwise healthy subjects with self-reported 
chronic distress [21, 22]. Preliminary studies by Dr. Khalsa- one of the co-investigators- have 
shown that yoga has been effective in reducing anxiety in musicians [23, 24], high school 
students, and GAD patients (see Preliminary Data). In summary, yoga is a frequently used, easily 
accessible, and a popular form of mind-body medicine that includes meditation practices. 
Previous studies suggest that yoga is an effective anxiety-reduction method. However, no 

 
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systematic investigation has been conducted to provide an evidence base, critical for clinical 
recommendations and reimbursement as well as treatment optimization for the efficacy of yoga 
for GAD.  
2.2. Study Rationale 
Yoga is an established and traditional practice that emphasizes mindful awareness. 
Mindfulness-based strategies can significantly enhance treatment of GAD. Our recent meta-
analytic review of 39 studies of mindfulness-based strategies in a variety of populations revealed 
effect sizes of 0.97 for improving anxiety symptoms in patients with a mix of anxiety disorders, 
including GAD [25]. Patients are taught to respond to stressful situations more reflectively rather 
than reflexively, thereby countering experiential avoidance strategies. Through the sustained 
regular practices of yoga that include elements of mindfulness/meditation/mind-body awareness, 
there are ultimately long-term changes that take place in perception and interpretation of both 
internal (thoughts) and external (environmental) events, leading to reduced frequency and 
intensity of stress/anxiety responses.  The physical postures and the regulation of breathing in 
yoga repetitively lead to reduced stress activation with resulting decreases in sympathetic and 
hypothalamic pituitary axis activity. Through a feedback loop, possibly through the vagal 
system, this physiological down-regulation may further enhance the effect of meditation and 
yoga to reduce perceived stress/anxiety. These strategies are also effective for targeting 
worrying, a future-oriented maladaptive cognitive process predominant in GAD (e.g., [25-27]). 
In general, exercises that encourage acceptance, mindfulness and present-moment experiences 
may be particularly promising strategies to counter worrying [5, 28, 29]. Yoga practice in its 
traditional multicomponent and contemplative-focused form should thus be particularly 
beneficial for GAD. This widely used practice is a comprehensive system of exercises for 
physical and psychological health and well-being, and incorporates multiple techniques 
including physical postures/exercises, breathing exercises, relaxation strategies, and 
meditation/concentration techniques.  Basic research on yoga and its component techniques 
demonstrate reductions in arousal, and improved mood states and health [30-39]. Clinical yoga 
research studies [40] have demonstrated improvements in anxiety in patients with a variety of 
medical conditions including cancer [41-44], migraine [45], irritable bowel syndrome [46, 47], 
depression [48, 49], and others [50].   
A review of controlled studies of yoga for anxiety problems identified 8 studies [19, 49, 51-
56], but the quality of these studies precludes definitive conclusions [57, 58]; some studies, 
including our own [59] demonstrated reductions in test anxiety [49, 59] and obsessive 
compulsive disorder [51]. Five uncontrolled (single group) published studies show 
improvements in anxiety symptoms with yoga with mixed psychopathology [60-62] or primarily 
anxiety disorders populations [63, 64], and controlled but non-randomized studies in anxiety 
disorders in India [52, 56]. To date, only 6 randomized controlled trials were published, and of 
these, 5 evaluated anxiety in mixed populations with depression or other problems [53, 54, 65-
67]. Thus, existing studies on yoga for anxiety have been of low quality with small sample sizes, 
and few with random assignment.  Most importantly, these studies have focused on a variety of 
anxiety-related conditions but with widely varied entry criteria.  Although these studies convey 
an overall impression of potential efficacy for GAD, critically, only one of these studies 
evaluated a population with DSM-IV entry criteria for GAD, and this study was primarily a 
breathing intervention [68].  The proposed study is, therefore, entirely novel in this rigorous and 
necessary approach to evaluating yoga efficacy for GAD; rigorous RCT data is needed before 

 
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Yoga can be adapted as an approved intervention by insurers and clinicians, as well as to allow 
future examination of effective yoga elements in future evidence based interventions or to target 
specific subpopulations for whom yoga may be most effective. Should yoga, which is a popular 
practice, be found effective for GAD, these results could have a significant public health impact 
as yoga could be considered by primary care doctors as a first line treatment option improving 
public health access to effective GAD interventions, including potentially reducing medication 
use, such as benzodiazepines, in primary care with its inherent risk for abuse and dependence.  
To control for attention from instructors, expectancy effects, and group support effects, 
Stress Education (SE) will be employed as an active control intervention. SE is currently used in 
NIH-funded protocols at the Benson-Henry Institute for Mind-Body Medicine at MGH (see 
Letter). Participants will be provided with detailed and extensive information about stress and 
health, but will not receive any CBT, yoga, or other mind-body training techniques. Content 
areas will include definitions of stress and the stress response, the fight or flight response, 
physiological and psychological effects of stress, stress and performance, the negative stress 
cycle, stress and health/illness, stress and immunity, stress buffers, stress hardiness, stress and 
heart disease, the role of genes and environment in health, the contribution of lifestyle behaviors 
such as caffeine and alcohol intake and cigarette smoking, and the importance of regular exercise 
and proper diet (without specific instructions for exercise or dietary changes). For the daily home 
practice subjects will listen to SE audio CDs containing information about nutrition and positive 
perspectives on lifestyle and emotions (see Research Design).  
Examining yoga as a strategy for treating GAD is highly innovative, both from a clinical and 
theoretical perspective, and would generate a strong evidence base to support clinical use as well 
as future research. This study would provide the first RCT data for the comparative efficacy and 
acceptability of a standardized yoga intervention for the treatment of GAD compared to an active 
control as well as the gold standard CBT for GAD. Yoga is widely available and popular while 
there is a paucity of trained CBT therapists and many individuals will not seek professional help. 
Should the yoga intervention be found to have efficacy for GAD, future research using 
dismantling component designs could examine the relative efficacy of the specific components 
of yoga practice (physical exercises, breath regulation, meditation, relaxation).  For example, an 
intervention primarily consisting of breath regulation in the absence of the other components 
might provide information on the contribution of this technique to efficacy of the whole 
practice.  Such information could then be used to refine the yoga intervention or allow 
development of hybrid, augmentation of other evidence based treatment approaches. Although 
this study will employ a standardized yoga intervention from a specific yoga style, it is likely 
that less standardized yoga practices, including other styles of yoga, in their traditional 
multicomponent format that are generally available to the public would also have efficacy, and 
this could also be evaluated experimentally in future studies. Initial data about the impact of 
Yoga in stress related biomarkers in GAD would further help guide future research examining 
potential biological mechanisms underlying response to Yoga in GAD. For example, future 
studies could examine the biological impact of yoga on anxiety neurocircuitry using 
neuroimaging. Finally, Yoga could be compared to first line pharmacotherapy for GAD in future 
studies. Other innovative aspects include the following: 
 (1) Clinical innovation. Although CBT is effective, few GAD patients receive adequate 
CBT, primarily because CBT is still not widely disseminated. In contrast, yoga is widely 
practiced. Although practices that encourage mindfulness may help alleviate anxiety, including 

 
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GAD (e.g., [25]). Although early data on the efficacy of yoga for GAD are promising [77], very 
little systematic research has been conducted. Results of this proposed study would have 
important clinical implications that could have immediate applicability for clinical 
recommendations about yoga.  
(2) Theoretical innovation. Worrying in GAD is a maladaptive, future-oriented, cognitive 
process (e.g., [26, 78]). Certain aspects of yoga may target worrying in GAD by enhancing 
mindfulness and present-moment awareness (e.g., [5]) as opposed to emphasizing maladaptive 
cognitive beliefs about worrying (meta-cognitions) and its consequences (e.g., [79, 80]). Directly 
comparing CBT and yoga for GAD would, therefore, answer important theoretical questions 
about the mechanism of treatment change. These results may also influence the nosology of the 
disorder, which has been a controversial issue for the DSM-V.  
CBT for GAD ([2], Journal of Clinical Psychiatry). We conducted a meta-analysis of 
randomized clinical trials that randomly assigned adults with an anxiety disorder to CBT or 
placebo. Of 1,165 studies, 27 met all inclusion criteria. Across all the anxiety disorders, random 
effect models of completer samples yielded a pooled effect size (Hedges’ g) of 0.73 (95% 
confidence interval, 0.88-1.65) for continuous anxiety severity and a pooled odds ratio of 4.06, 
demonstrating CBT for GAD was moderately effective (Hedges’ g = 0.51, 95% CI: 0.05-0.97). 
Similar results were reported by Mitte [81], with an average placebo-controlled effect size of 
0.57. The pre-post effect size for reducing anxiety was 0.82. 
Mindfulness-based interventions for GAD [25]We conducted a meta-analysis of 39 studies of 
mindfulness-based treatments for anxiety symptoms in anxiety and depression that did not 
include CBT strategies specifically targeting maladaptive cognitions, and found an effect size 
(Hedges’ g) of 0.81 (95% CI: 0.35-1.27, z=3.47, p<.01), suggesting mindfulness-based strategies 
are potentially beneficial for GAD. 
Yoga improves stress, resilience, anxiety and affect in students [82, 83]. We have shown that 
yoga yields mental health benefit in two separate semester-long randomized controlled trials. For 
students randomly assigned to 12 weeks of regular physical education or yoga classes, yoga 
resulted in significantly better outcomes on the Perceived Stress Scale (PSS; [84]) (p<0.05) and 
the Resilience Scale. Further, yoga may also have been protective against worsening on anxiety 
and test anxiety subscales of the BASC-2, the tension/anxiety subscale of the Profile of Mood 
States (POMS-SF)  and mindfulness, as measured by the Child Acceptance and Mindfulness 
Measure (CAMM: see Figure).   The slight deterioration seen in the control group has been 
previously recorded in high school settings and is consistent with the high levels of mental health 
problems in adolescents. These data suggest a protective/preventive effect of yoga on stress, 
resilience, anxiety and mindfulness. 
Yoga improves anxiety, affect and mindfulness [23, 24, 85]. In a series of studies, musicians 
in summer fellowship programs at the Tanglewood Music Center were recruited to a 6-week 
yoga program (~3 classes/week).  Our first study demonstrated significantly greater 
improvements over time in solo performance anxiety on the Performance Anxiety Questionnaire 
(PAQ) and the POMS tension/anxiety subscale (t-test p<0.05) (see figure; all figures have 
yoga=filled bar, controls= open bar) and a trend to significance on the POMS total (p=0.08, not 
shown).  
In a second study, the yoga intervention showed a significant reduction in PAQ (p=0.011) 
and the POMS tension subscale (p=0.038) (not shown). Of note, Five Facet Mindfulness 

 
16
Questionnaire (FFMQ) scores and subscales of "observing" and "awareness" were significantly 
greater in the yoga group (p<0.05). In a controlled study of yoga (n=31) compared to no 
treatment (n=25) for performance anxiety in adolescent musicians. The yoga group (filled bars in 
figure) showed a decrease from 48.9 (±17.8 SD) to 41.4 (±15.4 SD) (p<.001) on the Music 
Performance Anxiety Inventory – Adolescents (MPAI-A) with little change in the control group 
(open bars); p>0.4. In another, more recent study, Drs. Khalsa and Hofmann co-advised a 
doctoral dissertation [59] to evaluate the effectiveness of a 9-week yoga practice on reducing 
music performance anxiety in undergraduate and graduate music conservatory students, 
including both vocalists and instrumentalists. The intervention consisted of 14 60-minute yoga 
classes approximately twice a week and a brief daily home practice. Of the 24 students enrolled 
in the study, 17 attended the post-intervention assessment. Participants who completed the 
measures at both pre- and post-intervention assessments showed large decreases in music 
performance anxiety as well as in trait anxiety as measures with the STAI (d = 1.05). 
Improvements were sustained at 7- to 14-month follow-up.  
The yoga practices of the proposed study improve anxiety symptoms in GAD patients [77] 
For effect size estimates for the proposed study, we conducted a pilot trial on the efficacy of the 
planned yoga intervention in 16 participants with GAD. The majority of the sample was female 
(87.81%) and Caucasian with an average age of 50 (SD: 11.46, range: 31-70). The most common 
comorbid diagnosis was major depressive disorder (18.75%).  
Similar to earlier trials examining mindfulness-based treatments for GAD (e.g., [86]), we 
administered the Symptom Check List (SCL-90-R, [87]). In addition to paired t-tests (all 2-
tailed), we estimated the effect size using Cohen’s d: [Mpost-Mpre]/SDpre. Significant reductions 
from baseline to endpoint were observed in the anxiety subscale, t (15) = 4.88, p < .0001, d = 
.86, the depression subscale, t (15) = 4.98, p < .0001, d = .96, and the global severity subscale, t 
(15) = 4.58, p < .0001, d = .76. In this intervention, daily assigned home practice was 
recommended but not rigorously monitored; at midpoint only 10% of respondents reported no 
home practice, whereas 40% of respondents practiced with a 30-50% compliance level, 
suggesting even greater compliance can be achieved with specific emphasis and monitoring as 
will occur in the proposed trial. Overall, although no control group was included, these pilot data 
support the feasibility and potential efficacy of yoga for GAD as will be more rigorously 
examined in the proposed randomized study compared to standard CBT for GAD and a stress 
education control.  
Reason for choosing 12-weekly training: There has been no standard duration established for 
yoga treatment protocols (Sherman, 2012).  However, there is certainly ample precedent for yoga 
research trials with 12-week treatment duration.  For example, there are published yoga research 
trials with 12-week interventions for conditions including back pain (Sherman et al., 2011; 
Tilbrook et al., 2011; Herman et al., 2005), stress-related symptoms and diagnoses (Kohn et al., 
2013), cancer (Speed-Andrews et al., 2010; Bower et al., 2011, 2012; Moadel et al., 2007; 
McDonald et al., 2006), epilepsy (Rajesh et al., 2006), incarceration (Harner et al., 2010) 
hemodialysis (Yurtkuran et al. , 2007), respiratory disorders (Santana et al., 2013), dementia 
(Fan eta al., 2011), falling/balance in the elderly (Schmid et al., 2010), prediabetes (Yang et al., 
2011; Benavides et al.,2009), binge eating (McIver et al., 2009), and in healthy subjects (Streeter 
et al., 2010; Phoosuwan et al., 2009; Cohen et al., 2009).  There is currently little research 
information on the week-by-week or even month-by-month timecourse of improvements in 
outcomes in yoga trials (i.e. duration response curves) because few longitudinal studies with 

 
17
multiple assay time points have been conducted.  In two yoga research trials with back pain with 
primary outcomes measured at mid-treatment and at end-treatment at 12 weeks, there were 
progressive increases in improvements [Sherman et al. 2005, 2011].  Similarly in a study of yoga 
for COPD, 24 class-by-class measures of pain and distress throughout a 12-week yoga 
intervention showed steady and apparently linear improvements over time (Donesky-Cuenco et 
al., 2009). The co-investigator on this grant (Khalsa) has conducted a yoga intervention for 
chronic insomnia in which measures of insomnia every 2 weeks revealed that improvements 
increased incrementally over the 8 weeks of the intervention with the strongest improvements at 
the beginning of the intervention (Khalsa, 2004, 2009).  Finally, most relevant to our proposed 
trial, was a 12-week yoga intervention in incarcerated women, in which anxiety levels showed a 
similar consistent improvement from baseline through weeks 4, 8 and end-treatment at 12 weeks, 
again with the largest improvements near the beginning of the intervention but still with some 
improvements continuing near the end (Harner et al., 2010).  Moreover, given that the standard 
CBT interventions for GAD in our clinic and laboratory are 12 weeks long, it is important for the 
research design to have all 3 treatment arms of the same duration.  Otherwise, we may face the 
potential criticism that differences in outcome between the different treatment arms could be due 
to differences in treatment duration rather than to the content of the therapy itself.  Different 
treatment durations would involve differences in subject investment, time and effort, and in 
therapist interaction time; all of these are nonspecific confounding factors which would 
compromise the interpretation of the primary research goal to evaluate the difference in efficacy 
of the therapies themselves, i.e. yoga vs. CBT vs. inactive control. 
 
Reason for examining biomarkers of response with cortisol and a marker of cardiac vagal 
tone: The underlying pathological cognitive process of GAD is worrying, which is an 
anticipatory process attempting to prevent or minimize future problems and may act as a 
cognitive avoidance strategy to reduce negative emotions associated with intrusive catastrophic 
images (Borkovec et al., 1998). Worrying has been associated with reduced autonomic flexibility 
as a result of low cardiac vagal tone in numerous studies (Borkovec& Hu, 1990; Hoehn-Saric& 
McLeod, 2000; Hofmann, Moscovitch, Litz, Kim, Davis, &Pizzagalli, 2005; Hofmann, Schulz, 
Heering, Muench, &Bufka, 2010; Lyonfields, Borkovec, & Thayer, 1995; Thayer, Friedman, 
&Borkovec, 1996).  
We will measure cardiac vagal tone by recording respiratory sinus arrhythmia (RSA). 
RSA refers to the rhythmic variations in heart rate that occur at the frequency of respiration, and 
reflects parasympathetic control over the heart (e.g., Berntson, Cacioppo, & Quigley, 1993). To 
measure breathing, a flexible respiration band will be strapped around subjects’ chest. A 
software program computes RSA using the peak-valley method (Grossman, 1983). This method 
derives RSA by calculating the difference between the minimum interbeat interval during 
inspiration and the maximum interbeat interval during expiration.  
Assessment of cortisol and RSA will allow complementary assessment of biomarkers of 
response to the three interventions. These biomarkers will allow brief, inexpensive and 
standardized assessments that may suggest potential pathways for efficacy of yoga compared to 
the CBT and control conditions for GAD. 
 

 
18
 
3. STUDY DESIGN 
 
The purpose of the proposed study is to determine whether yoga is an effective method 
for treating GAD, and its relative efficacy compared to a standard psychosocial intervention. For 
this purpose, we will conduct a randomized controlled trial. Using superiority tests, yoga (N = 
95) will be compared to SE (N = 40), a commonly used control condition. Using non-inferiority 
tests, yoga will compared to standard CBT for GAD (N = 95). To improve comparisons, all 
interventions will be conducted in a group format over 12 weekly sessions with 4-6 patients per 
group and therapists/yoga instructors. We anticipate having approximately 3 yoga instructors, 3 
CBT therapists, and 3 SE instructors, along with 2 IEs per enrolling site. All interventions will be 
conducted at anxiety out-patient clinics in Boston (the Center for Anxiety and Related Disorders 
at Boston University and the Center for Anxiety and Traumatic Stress Disorders at 
Massachusetts General Hospital). The third study site, NYU Langone Medical Center in New 
York City, will not recruit participants and will conduct data analysis and interpretation as well 
as study oversight. Subjects in all 3 treatment groups will be provided with a credible rationale 
for the efficacy of their assigned treatment. At each study treatment visit, patients will complete 
various psychological measures. Some of the study visits require more in-depth assessments 
involving saliva sample collection, meeting with a study doctor, and a physical examination (see 
the section 6.1 for more information). The four independent evaluator blinded assessments occur 
pre-treatment (baseline visit), mid-treatment (Week 6), post-treatment (Week 12), and at a six-
month follow-up.  
 
 
The Clinician Global Impression-Severity Scale (CGI-S) and Improvement Scale (CGI-I) 
[93] will be used in determining remission and response criteria. Treatment response is defined 
as a CGI-I of 1 (very much improved) or 2 (much improved). Remission is defined as CGI-S of 1 
(not at all ill) or 2 (borderline ill). Treatment response will be the primary outcome measure. This 
allows for a direct comparison with other studies because CGI is the gold-standard measure 
across clinical trials. Our research team has decades of experience using the CGI, which has 
excellent psychometric properties and is treatment sensitive [94-97]. Bandelow et al. [94] 
analyzed clinical trials with more than 5,000 patients with GAD, social anxiety, and depression; 
the CGI is highly correlated with anxiety and depression scales across disorders. 
Trained study clinicians blind to randomized treatment assignment (independent 
evaluators, IEs) will administer diagnostic assessments and rating scales. All raters will be 
clinicians who will have undergone specific training to criterion in the use of the study measures 
(See Integrity of Assessment Procedures in 6.1). To assess for DSM psychiatric diagnoses, study 
approved independent evaluators (IEs) will use the standard diagnostic intake interviews at each 
site. These are the Structured Clinical Interviews for DSM-IV and DSM-5 (anticipated to be 
available in line with enrollment) at MGH and the Anxiety Disorders Interview Schedule (ADIS-
5 [92]) at BU. GAD and other diagnostic criteria are identical in the instruments, and DSM-5 is 
unchanged from DSM-IV for GAD. Each principal investigator has extensive experience with 
diagnostic interviews, and all raters will be cross certified (see section 6.1 for rater certification 
and reliability procedures and for assessment details). All clinician rated assessments will be 
administered by certified blind Independent Evaluators (IEs)  
 
Based on our current study experience, we expect that we will need to screen as 
potentially eligible twice the number of patients ultimately consenting and that 90% of patients 
consented will be ultimately enter the randomized phase of treatment after they received a study 

 
19
diagnostic assessment. We conservatively estimate that 20% of eligible participants will 
discontinue the intervention prematurely, but all participants who are randomized will be 
included in the analysis with an intent to treat analytic approach. For ethical reasons, additional 
treatment will not be withheld for non responders (defined as CGI-I > 2) or anyone for whom 
additional intervention is indicated in any intervention condition during the 6 month follow up. 
Non responders (CGI-I>2) at week 12 will be assisted in finding appropriate care from our existing 
referral resources. All participants will receive 6 month assessments, but any additional treatment 
received by non responders will be adjusted for in the analyses. 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS 
4.1 and 4.2 Inclusion and Exclusion Criteria. 
All study candidates must meet inclusion criteria and those meeting any of the exclusion criteria 
below will not be entered into the randomized trial.  
 
Table 1 below lists all inclusion and exclusion criteria.  
Table 1:  Inclusion and Exclusion Criteria and Rationale. 
Inclusion Criteria 
Rationale 
Male or female outpatients 18 years of age or older with a primary 
psychiatric diagnosis of generalized anxiety disorder 
Population under study 
CGI-severity score of 4 or higher 
Adequate pre-treatment 
severity 
Off concurrent psychotropic medication for at least 2 weeks prior to 
initiation of randomized treatment, OR stable on current medication 
for a minimum of 6 weeks and willing to maintain a stable dose  
Treatment confound  
Willingness and ability to perform the yoga intervention and to 
comply with the requirements of the study protocol. 
Human subjects concerns 
Exclusion Criteria 
Patients unable to understand study procedures and participate in the 
informed consent process.  
 
Human subjects concern 
For women of childbearing age: Pregnant (based on urine pregnancy 
test), planning to become pregnant, or lack the use of approved 
methods of birth control 
Human Subjects Safety 
Serious medical illness or instability for which hospitalization may 
be likely within the next year 
Feasibility, subject 
safety 
Significant current suicidal ideation or suicidal behaviors within the 
past 6 months   
Subject safety 
History of head trauma causing loss of consciousness, or seizure 
disorder resulting in ongoing cognitive impairment 
Treatment confound, 
subject safety 
Posttraumatic stress disorder, substance use disorder, eating 
disorder, or organic mental disorder within the past 6 months 
Treatment confound 
Lifetime history of psychotic disorder, bipolar disorder, or 
developmental disorder 
Treatment confound 
Significant personality dysfunction likely to interfere with study 
participation (assessed during the clinical interview) 
Treatment confound 
Prior experience with (more than 5 Yoga classes or CBT sessions 
within the last 3 years) and/or current practice of mind-body 
techniques (e.g., yoga, meditation, Tai-Chi, etc) or CBT 
Treatment confound 
Concomitant psychotherapy for GAD (any psychotherapy) 
Treatment confound 

 
20
Physical conditions that might cause injury from yoga (pregnancy, 
physical injuries and musculoskeletal problems)  
Human subjects 
concern and subject 
safety 
Cognitive impairment (MOCA<21) 
Human subjects 
concern and safety 
 
Equitable Selection of Subjects: 
The study population is representative of the population with a primary diagnosis of GAD that stands to 
benefit from this research. All participants will be adults capable of providing informed consent.  We are 
not excluding any participants based on race, ethnicity, or gender.  Participants are selected on the basis of 
their diagnostic status. Because the use of yoga has not been rigorously tested in pregnant women, those 
women who are pregnant or not using a reliable form of birth control are excluded from the study. 
Because the treatment approaches that will be used in this study have never been tested in individuals 
younger than 18 and might need to be adapted for younger children, children under 18 are excluded from 
this study. Children between the ages of 18 and 21 will be included. Because a full understanding of 
the group sessions (yoga, CBT, or SE) is necessary for treatment and sessions will be conducted in 
English, subjects who are not fluent in English will be excluded from participation. 
4.3. Study Enrollment Procedures 
SUBJECT RECRUITMENT 
 
 
Recruitment methods: 
Participants will be recruited from patients who present for treatment, are referred or are directly 
recruited through IRB approved advertisement at the Center for Anxiety and Related Disorders 
at Boston University (CARD) and the Center for Anxiety and Traumatic Stress Disorders 
(CATSD) at Massachusetts General Hospital (MGH). Types of recruitment strategies will 
include advertisements in the media, postings online, particular email services, and clinical 
referrals.   
 
At MGH, we will be posting information on our own program websites. At MGH, mails and 
letters will be sent out with a description of our study through the MGH All-User Broadcast and 
the RSVP for Health program. We will run advertisements in local publications, such as the 
Metro. We will use the IRB approved CATSD re-contact log (at MGH), Participants who have 
agreed to be re-contacted in the future will receive emails, letters, and/or phone calls.  
 
Similarly, we will additionally recruit participants for the BU site through postings on our web 
site, BU’s quickie-jobs, and flyers posted at public locations, such as cafes, bookstores, 
supermarkets, etc. We will further use the IRB approved CARD re-contact log, Participants who 
have agreed to be re-contacted in the future will receive emails, letters, and/or phone calls.  
 
These recruitment strategies are all aimed at reaching a diverse population.   
 
Individuals who contact our centers will be screened initially by phone for interest in the 
proposed research, as well as general diagnostic and study eligibility, and interest in research 
participation. Data for participants who undergo the phone screening process will be de-
identified and recorded in the study database phone screening log. Reasons for ineligibility and 
for non-participation of eligible subjects will be recorded.  
 

 
21
Consent and eligibility for randomization procedure: 
Interested patients who are eligible for participation will be scheduled for an evaluation meeting 
where informed consent will be obtained.  All potential participants will review the consent 
form, risks, and benefits associated with the protocol with an approved study investigator and 
will sign consent prior to completion of any study assessments in this protocol. 
The study investigator will explain the study, answer any questions, and obtain written informed 
consent. Participants will be given as much time as needed to review the consent and ask 
questions prior to participation in study procedures. The study procedures and consent form will 
be approved by the Institutional Review Board at each of the participating sites prior to study 
initiation. 
 
Potential participants will undergo formal structured clinical interviews and rating scales (see 
Assessment section 6.2 for detail) to confirm diagnosis and eligibility. Patients will then undergo 
safety assessments including medical history, medication use, and laboratory tests, including 
urine toxicology screen and pregnancy test (for women of childbearing age). In addition, our MD 
or nurse with MD oversight familiar with the yoga intervention will determine whether the 
participant is fit for yoga and CBT based on a baseline medical history and physical exam to 
determine whether study exclusion criteria are met, and any identified medical concerns will be 
reviewed with signed permission with participant’s PCP prior to study entry.  
We expect to screen and consent approximately 295 individuals such that 230 will meet 
eligibility criteria and agree to be randomized across the 2 sites. 
 
Randomization Procedure 
After eligibility criteria are determined and participants have completed a baseline 
assessment, and confirmed availability to participate, participants will be randomly assigned to 
either Yoga, CBT, or stress education (SE) using the variable-sized permuted block 
randomization procedure (stratified by site).  
Our study statisticians will set up the randomization table stratified by site and with variable-
sized permuted blocks (maximum block size will be 6 to minimize cohort effects). The variable-
sized permuted block randomization schedules will be generated by Dr. Rosenfield (the 
supervising biostatistician) prior to enrolling the first subject into the study. Randomization will 
be stratified by site, and groups of 4-6 individuals will be randomized at a time to one of the 3 
treatment conditions. Randomizations will be conducted in SAS using the procedures outlined by 
Efird (2011) [Efird, J. Blocked Randomization with Randomly Selected Block Sizes. Int. J. 
Environ. Res. Public Health., 8, 15-20.]. The randomization code will be emailed by Ms 
Keshaviah (the trial statistician) to the study coordinator only when the randomization occurs, 
i.e. once the last participant of each group has completed baseline. 
 
5. STUDY INTERVENTIONS 
5.1. Interventions, Administration, and Duration 
We propose to administer the treatment in a group format to better reflect the most 
commonly available yoga format, and to maximize feasibility and cost-effectiveness (see also 
Integrity of Treatment Procedures). Providing all 3 modalities in the same sized and length group 
format will also maximize integrity for the comparison of the active treatment components.  All 

 
22
three treatments will be 2 hours in duration, allowing for 15 minutes of study logistics including 
discussion of subject questions or difficulties with the home or group interventions, evaluation of 
individual subject compliance, and strategizing enhancing compliance.  The treatment itself will 
comprise a full 105 minutes training and practice in each group session. Subjects in all 3 
treatment groups will be provided with a credible rationale for the efficacy of their assigned 
treatment.  Subjects in the CBT arm will be informed of the role of CBT in the efficacy of 
changing dysfunctional thought patterns and beliefs, subjects in the yoga arm will be informed of 
the role of yoga in changing cognitive and physical emotional and stress reactivity through the 
postures, breath regulation and meditation components of yoga practice, and subjects in the 
stress education control will be informed of the role of stress education in understanding the 
psychophysiological basis of stress and anxiety as a basis for overcoming stress and anxiety.  
CBT: The 12 session CBT treatment will be based on the standardized protocol 
developed at one of our centers (CARD) and widely available [88]. An earlier version of this 
protocol has been empirically supported in individual and group settings [89]. This protocol is 
comprised of four primary treatment modules including cognitive restructuring, progressive 
muscle relaxation, worry exposures, and in vivo exposure exercises. See Appendix reference for 
CBT for GAD manual. The protocol describes session-by-session a 12-session CBT treatment. 
The initial sessions describe the cognitive behavioral model of worry and GAD. Each session 
consists of a different “lesson.” These lessons initially cover basic information about the nature 
of the anxiety and worry, the possible function and negative consequences of worrying, the 
maladaptive and paradoxical effects of attempting to control and suppress one’s thoughts, the 
basic cognitive errors of probability overestimation and catastrophic thinking, adaptive strategies 
to deal with worries, such as problem solving, worry exposure, which may involve exploring and 
exposing the patient to negative images and scenarios that might be behind some of the 
worrisome thoughts (e.g., a person who worries losing  his or her job might be exposed to the 
image of sitting under the bridge as an abandoned lonely homeless person). Subjects will also be 
assigned to complete approximately 20 minutes of homework daily, which will be recorded in a 
homework log.  In addition, our treatment protocol will target meta-cognitions (i.e., worrying 
about worrying). To target meta-cognitions, we will use treatment recommendations from Wells 
(2009). More specifically, the primary content of the sessions are as follows:  
 
Session 1. Discussing the basic structure of the treatment program and logistics. Discussing 
commonalities among group members. The nature of generalized anxiety disorder and worry; outlining 
of treatment procedures and basic principles underlying treatment. 
Session 2. The function of anxiety: When is it adaptive when not? Learning to recognize maladaptive 
anxiety. 
Session 3: The purpose and function of anxiety. 
Session 4: A closer look at generalized anxiety disorder. 
Session 5: Basic relaxation strategies (12-step progressive muscle relaxation). 
Session 6: Thoughts that cause anxiety I: Probability overestimation. 
Session 7: Thoughts that cause anxiety II: Catastrophic thinking (thinking the worst). 
Session 8: Thoughts that cause anxiety III: Worrying about worrying. 

 
23
Session 9: From worry exposure to worry prevention. 
Session 10: Dealing with real problems (problem solving strategies). 
Session 11: Identifying obstacles in the future.  
Session 12: Accomplishments and future plans. 
 
Yoga: The yoga intervention will apply Kundalini Yoga practices as taught by Yogi 
Bhajan.  This is a well-known, accessible style of practice in the U.S. that incorporates all of the 
traditional components of yoga including physical postures and exercises, breathing techniques, 
relaxation exercises and meditation practices.  It is a safe style of yoga that is registered with the 
Yoga Alliance that is readily and routinely adapted for therapeutic purposes. The 12-week yoga 
intervention will consist of 12 group classes and assigned daily home practice led by qualified 
and certified yoga instructors. Each group yoga session will include physical postures/exercises, 
breathing techniques, meditation and deep relaxation practice that are all easy to learn and do not 
require extensive practice or athletic ability to perform.  Subjects’ current physical health, 
flexibility and endurance will be screened at study entry. The yoga instructor will again review 
all preexisting conditions with subjects in the group at the beginning of the 12-week intervention 
and will make modifications to the practices as necessary to ensure subject safety and to prevent 
injury.  The instructor will also require subjects to report any recent changes in their health, 
injuries or conditions at the beginning of every treatment session.  Group size will be relatively 
small for yoga classes with 4-6 subjects per group, which allows for careful monitoring of 
subject safety during the class sessions. 
Audio CD’s will be provided to guide subjects through daily home practices throughout 
the 12-week intervention to achieve mastery and self-efficacy. The 20-minute session will begin 
with spinal flexibility and loosening for a physical release of tension and increased body 
awareness. Subjects will then practice a breathing meditation specifically recommended for 
coping with anxiety.  In general yoga and meditation home practice compliance is reported as 
being feasible and equivalent to that of other behavioral interventions [74, 90, 91].  Dr. Khalsa, a 
co-investigator on this study, has observed compliance in a home yoga intervention averaging 29 
minutes of a daily assigned 45-minute intervention (unpublished data).  We believe that we will 
observe adequate compliance from the proposed home intervention, and with more rigorous 
follow-up to encourage adherence, and expect better compliance than in our pilot trial (see 
preliminary data above.) 
Stress Education Group (SE): SE will also include 12 weeks of group and home practice 
sessions. SE will control for attention from instructors, expectancy effects, and group support 
effects, Stress Education (SE) will be employed as an active control intervention. SE is currently 
used in NIH-funded protocols at the Benson-Henry Institute for Mind-Body Medicine at MGH. In 
this condition, participants will be provided with detailed and extensive information about stress 
and health, but will not receive any CBT, yoga, or other mind-body training techniques. Content 
areas will include definitions of stress and the stress response, the fight or flight response, 
physiological and psychological effects of stress, stress and performance, the negative stress 
cycle, stress and health/illness, stress and immunity, stress buffers, stress hardiness, stress and 
heart disease, the role of genes and environment in health, the contribution of lifestyle behaviors 
such as caffeine and alcohol intake and cigarette smoking, and the importance of regular exercise 
and proper diet (without specific instructions for exercise or dietary changes). For the daily 20 
minute home practice subjects will listen to SE audio CDs containing information about nutrition 

 
24
and positive perspectives on lifestyle and emotions. Therefore, we believe that comparable social 
and attention controls will be placed in the SE group.   
5.2. Handling of Study Interventions (Treatment Integrity) 
Treatment Certification and Supervision Procedures 
The senior therapists who lead the CBT and yoga groups will have at least 1 year of 
practice in the treatment modality. Yoga instructors will have undergone a formal 200-hr yoga 
teacher training program, and be registered with the Yoga Alliance. CBT instructors will be 
clinical psychologists trained in CBT for GAD.  In addition, all therapists will undergo trainings 
in the specific study intervention: in CBT by Dr. Hofmann, in yoga by Dr. Khalsa and SE 
overseen by Dr. Hoge. Dr. Khalsa has extensive expertise in both yoga, as a certified yoga 
instructor with over 40 years of yoga practice and instruction, and in yoga research design, as a 
full-time yoga researcher for over 10 years and a leading yoga research consultant and 
collaborator internationally. Therapists in the stress education control treatment will have been 
trained by the Benson Henry Institute for Mind Body Medicine stress education control 
intervention currently in use in ongoing studies. The training format and level for CBT and yoga 
will be similar to the training of therapists conducted at the Beck institute (Dr. Hofmann has 
been trained as a therapist and supervisor of CBT by the Beck Institute of Cognitive Therapy). 
The training will include a 3-day workshop with ongoing supervision of cases. The training 
procedures will consist of didactic instruction and hour-for-hour supervision of one or two 
concurrent training cases. Therapists-in-training will attend supervision meetings, at which both 
specific application and general issues of the CBT and yoga treatments will be discussed. 
Therapists will continue to receive weekly supervision from Drs. Hofmann, Khalsa and Hoge, 
respectively, for the duration of the study, and variations in the protocol will be addressed during 
this weekly supervision. In the event that a therapist does not adhere to the treatment protocol or 
displays behavior of questionable competence, this study therapist may be asked to undergo 
additional training procedures before continuing as a study therapist. 
 
 
Treatment Fidelity  
Treatment integrity will be further insured through careful supervision and adherence 
monitoring of all three interventions. A random 20% of the recorded sessions of each 
intervention will be reviewed and fidelity ratings completed to provide feedback to the 
therapists/instructors using standardized adherence forms including required and prohibited 
elements for each intervention to prevent drift. All therapists will also complete a detailed and 
systematic log/report of each completed treatment session which will be reviewed in supervision 
along with Working Alliance Inventory.  
 
5.3 
Concomitant Interventions 
Subjects will be instructed not to initiate any psychotropic medications or additional 
psychological interventions during the course of the study. Subjects may receive prescription 
medications not specifically excluded by the protocol (e.g., aspirin, cold preparations, oral 
contraceptives, and vitamins). Patients have to be off concurrent psychotropic medication for at 
least 2 weeks prior to initiation of randomized treatment, or stable on current medication for a 

 
25
minimum of 6 weeks and willing to maintain a stable dose. All concomitant medication will be 
closely assessed and monitored in the study. 
 
5.3.1 Allowed Interventions 
See 5.3. 
5.3.2 Required Interventions 
None 
5.3.3 Prohibited Interventions 
1) Prior experience with Yoga and/or CBT (more than 5 Yoga classes or CBT sessions 
within the last 3 years)  
2) Current practice of mind-body techniques (e.g., yoga, meditation, Tai-Chi, etc) or CBT 
3) Also prohibited is any concomitant psychotherapy for GAD.  
4) Initiation of anxiolytic pharmacotherapy during the 12 session treatment period is not 
allowed (see 8.0 exception under Intervention Discontinuation) 
 
5.4 
Adherence Assessment 
Monthly reports will monitor subject enrollment, completion, attrition, and individual 
subject progress as well as the completion of critical assessments. Additional reports will be 
done as needed to monitor baseline characteristics, protocol adherence, and other issues of 
interest. 
Treatment integrity will be insured through careful supervision and adherence monitoring 
of all three interventions (see above Treatment Fidelity).Patient adherence will be measured by 
session attendance, and the Homework Compliance Scale. The working alliance inventory will 
also be assessed. Based on the available data, non-adherence to CBT, yoga, and SE instructions 
are unlikely to be of great concern. In fact, patients are likely to be highly motivated to practice 
strategies that may result in immediate relief of their suffering without experiencing any 
unpleasant side effects.  Nevertheless, patient adherence will be considered as a moderator in the 
final analysis. Binary adherence will be defined as for use in the per protocol analysis as 
attending at least 10 of the 12 group treatment sessions in addition to a score of at least 4 on the 
homework compliance scale (higher than moderate compliance of 3) out of a scale of 0-6. 
 

 
26
6. STUDY PROCEDURES 
6.1. Schedule of Evaluations 
Form Type 
MMeasure 
Admin Byby 
  Mo. 
-1 
(Scree
n*)o. 
-1 
(Scree
n*) 
Wk 0 
(Baseline)
Wk 0 
(Baseline) 
Wks 
   1-5  
Wk 6 
(Mid 
Tx)id- 
  Wks  
 7-11 
Wk 12-13 
(Post Tx) 
Wk 36-37 
 (6 mo. FU) 
Diagnosis & 
Screening 
Eligib 
ility/Informed 
Consent  
IE + RA pre-
screen 
X 
 
 
 
 
 
 
SCID/ADIS-5 
IE 
X 
 
 
 
 
 
 
CGI-S/CGI-I1, 
2 
IE 
X 
X 
X 
(biweekly) 
X 
X 
(biweekly) 
X 
X 
SIGH-A 
IE 
X 
X 
 
X 
 
X 
X 
Demographics 
Self 
X 
 
 
 
 
 
 
Medical 
History 
MD/RN 
X 
 
 
 
 
 
 
Screening 
Medications/T
herapy Log 
MD/RN 
X 
 
 
 
 
 
 
Physical Exam 
MD/RN 
X 
 
 
 
 
 
 
MoCA 
MD/RN 
X 
 
 
 
 
 
 
Secondary 
Outcomes 
STAI 
Self 
 
X 
 
X 
 
X 
X 
BAI 
Self 
 
X 
X 
(biweekly) 
X 
X 
(biweekly) 
X 
X 
BDI-II 
Self 
X 
X 
 
X 
 
X 
X 
PSS 
Self 
 
X 
 
X 
 
X 
X 
WHOQOL-
BREF 
Self 
 
X 
 
X 
 
X 
X 
SCL-90 
Self 
 
X 
 
X 
 
X 
X 
PSWQ 
Self 
 
X 
X 
(weekly if 
in CBT) 
X 
X 
(weekly if 
in CBT 
X 
X 
ISI 
Self 
 
X 
 
 
 
X 
 
PSQI 
Self 
 
X 
 
 
 
X 
 
SOCI 
ASQ 
Self 
Self 
 
 
X 
 
 
X 
 
X 
X 
 
X 
Mediators 
MCQ 
Self 
 
X 
 
X 
 
X 
X 
FFMQ 
Self 
 
X 
 
X 
 
X 
X 
Psycho-
physiological 
& Biological 
stress 
ECG (RSA) 
RA 
 
X 
 
X 
 
X 
X 
Salivette 
Sample 
Self 
 
X 
 
X 
 
X 
X 
Affect Grid 
RA 
 
X 
 
X 
 
X 
X 
Vital Signs 
RA 
 
X 
 
X 
 
X 
X 
Tx Details 
Credibility / 
Expectancy 
Self 
 
X 
 
X 
 
X 
X 
Homework 
compliance 
Self 
 
 
X (weekly) 
X 
X (weekly) 
X 
 
Safety & 
Integrity 
Adverse 
Events Log3 
RA 
 
X 
X (weekly) 
X 
X (weekly) 
X 
X 

 
27
Concomitant 
Medications/T
herapy Log3 
RA 
 
X 
X (weekly) 
X 
X (weekly) 
X 
X 
Suicidality 
checklist2 
IE 
X 
X 
X 
(biweekly) 
X 
X 
(biweekly) 
X 
X 
Working 
alliance 
Self 
 
 
 
X 
 
X 
 
SAFETY Form 
RA 
 
X 
X (weekly) 
X 
X (weekly) 
X 
X 
End of Study 
RA 
 
 
Completed after 6-month FU/early termination visit 
Protocol 
Deviations 
RA 
 
 
Ad hoc, as needed 
Quality 
Assurance 
Adherence/ 
Competence 
Fidelity rater 
 
 
20% of sessions (per schedule sent by study statistician) 
Inter-rater 
Reliability 
IE 
 
 
15% of sessions (per schedule sent by study statistician) 
 
*Data collected during the screening is part of routine clinical care; Wk=Week; Mo=Month; FU=Follow-up; Tx=Treatment; 
IE=Independent Evaluator; MD/RN=Physician/Nurse; 1The CGI-I will not be administered at the screening or baseline, as it 
captures post-baseline improvement; 2Administered weekly if the CGI-I≥5 at any time; 3Information gathered by the RA will be 
reviewed by the therapist/instructor prior to each weekly class. 
 
6.2 
Description of Evaluations 
Assessment Instruments and Procedures 
 
All clinician-rated outcomes will be assessed by Independent Evaluators (IEs) blind to 
treatment assignment. The IEs will be M.D., Ph.D., or experienced Masters-level diagnosticians 
with previous research experience with structured interviewing who will receive additional 
training and certification for this study under the direction of Drs. Simon and Hofmann with 
certification by Dr. Eric Bui. Any new raters will undergo training including rating at least 2 
audio or videotaped interviews then have 2 interviews taped and reviewed for agreement by an 
expert rater. In addition to the training procedures, study staff will hold weekly meetings during 
which all initial diagnostic interviews conducted that week are discussed in the presence of 
senior clinicians, and in the instance of diagnostic disagreement, the sources of these differences 
are reviewed and a consensus diagnosis is reached. The staff meeting should also reduce the 
potential for interviewer drift. A two-level system will be used to maintain the reliability of 
diagnoses and of other clinical ratings in the study, consisting of weekly supervision and ongoing 
rating of selected clinical assessments, which will all be digitally recorded. Each month, an 
independent evaluator (IE) will listen to an assessment performed by another IE associated with 
the study and independently complete the assessment instruments. These duplicate ratings will 
be used both to calculate kappa coefficients and for supervision. Differences between raters will 
be discussed during supervision to identify reasons for disagreement and improve inter-rater 
reliability. These procedures will help us ensure that IEs refine their diagnostic skills and will 
also establish common guidelines for ongoing use in diagnostic decision-making. Inter-rater 
agreement will be assessed via evaluation of digital recordings of diagnostic interviews.  
 
Interview-Based Measures 
 
Structured Diagnostic Interview (SCID): The Structured Clinical Interview for DSM-IV (SCID-
IV: will be updated to SCID5 as soon as available, anticipated prior to enrollment) will be 
administered at MGH CATSD to determine the absence of diagnostic exclusion criteria and 
assess co-occurring psychiatric disorders.  

 
28
 
The Anxiety Disorders Interview Schedule for DSM-5 (ADIS-5; [92]) will be used at BU to 
determine DSM-5 psychiatric diagnoses (please note that the ADIS-5 was developed at the 
Center for Anxiety and Related Disorders at Boston University, therefore, this interview is 
already available to us).   
 
Each principal investigator has extensive experience with diagnostic interviews, and all raters 
will be certified. Cross site certifications and quality assurance ratings will occur to assure rating 
consistency of diagnoses as administered in the SCID with the ADIS, an overlapping interview. 
 
Clinical Global Impression of Severity (CGI-S; [94-97]): This is a 1-item scale asking the 
investigator to assess the patient’s overall level of illness severity. The clinician should integrate 
all aspects of the patient’s condition when using this scale. It will be used at assessments. 
 
Clinical Global Impression of Improvement (CGI-I; [93]): This 1-item instrument allows 
evaluators to give an overall rating to subject’s level of improvement or worsening on a scale of 
1-7, with 1 correlating to very much improved and 7 correlating to very much worse. It will be 
used at assessments. 
 
 
Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A; [98])This 19-item 
structured, clinician-administered rating scale provides an overall measure of anxiety. It will be 
used at assessments.  
 
 
Self-Report Measures 
 
Demographics Form:  Patients will be asked to fill out a questionnaire regarding age, race, 
ethnicity, gender, socioeconomic status in addition to their religious beliefs and practices.   
 
State-Trait Anxiety Inventory (STAI; [100]): The STAI-A is a 40-item, multiple-choice 
questionnaire that differentiates between the temporary condition of “state anxiety” and the 
more general and long-standing quality of “trait anxiety.” As a result, it is useful in both 
clinical and research contexts. It will be used at assessments. 
 
Beck Anxiety Inventory (BAI; [101]): This 21-item self-report inventory designed to measure 
severity of anxiety symptoms in psychiatric populations has high internal consistency and test-
retest reliability. It will be used at assessments. 
 
Beck Depression Inventory (BDI-II; [102]): This 21-item self-report inventory designed to 
measure severity of depression symptoms in psychiatric populations has high internal 
consistency and test-retest reliability. It will be used at assessments. 
 
Perceived Stress Scale (PSS; [84]): This 10-item scale is the most widely used psychological 
instrument for measuring the perception of stress. It is a measure of the degree to which 
situations in one’s life are appraised as stressful. It will be used at assessments. 

 
29
 
Symptom Checklist 90 (SCL-90; [87]): This is a 90-item instrument used to assess to what 
degree certain problems and complaints bothered or distressed an individual during the past 
week. It will be used at assessments. 
 
Quality of Life Scale (WHOQOL-BREF; [103]): This instrument assesses quality of life 
enjoyment and satisfaction. It will be used at assessments.  
 
Meta-cognition Questionnaire (MCQ; [106]): This is a 65-item instrument used to assess beliefs 
people have about their thinking. It will be used at assessments. 
 
Five-Facet Mindfulness Questionnaire (FFMQ; [104,105]): This scale has recently been 
developed to measure trait-like aspects of six sub-factors: observing/noticing experience; 
acting with awareness, avoiding “auto pilot”; describing/labeling; non-judging of self-
experience; non-reacting to internal experience; kindness/compassion/friendliness. The factor 
structure of this scale has been validated. It will be used at assessments. 
 
Penn State Worry Questionnaire-Past Week (PSWQ-PW; [107]): This is a 15-item, self-report 
measure of worry (PSWQ) Items are rated on a five-point Likert scale, and are summed to form a 
total score ranging from 16 to 80. The PSWQ has excellent psychometric properties in student, 
community, and clinical samples. It will be used at assessments. 
 
Pittsburgh Sleep Quality Index (PSQI; [140]): This is a 19-item, self report measure of sleep 
quality over a one month duration. The items make up seven different component scores 
consisting of sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep 
disturbances, use of sleep medication and daytime dysfunction. This measure also generates a 
global sleep quality score. It will be used at assessments. 
 
Insomnia Severity Index (ISI; [141]): This is a 7-item, self-report measure to assess insomnia as 
defined by the DSM-IV. It will be used at assessments. 
 
Affective Style Questionnaire (ASQ; [142]): This is a 20-item, self report measure to assess 
individual differences in emotion regulation. 
 
Social Identification Scale (SOCI; [143]): A 11-item, self report measure to assess social 
identification with the treatment group in order to determine if social identification is a potential 
confounder or effect modifier for our primary and secondary outcomes. 
 
Psychophysiological/Biological Measures of Stress 
 
Endocrinological Stress Measure (Cortisol). Following the methodology by Vreeburg et 
al. [108], we will measure the salivary cortisol awakening response at each assessment point. 
Subjects will collect saliva samples using Salivettes (Sarstedt) at home on a regular working day 
representative of their regular sleep/wake schedule at 4 time points (at habitual wake time and at 
30, 45 and 60 minutes later) and will return the samples to the investigators. Cortisol analysis 
will be performed by competitive electrochemiluminescence immunoassay using standard 

 
30
procedures; the functional detection limit is 2.0 nmol/L and the intra and inter-assay variability 
coefficients in the measuring range are <10%. All 4morning salivary cortisol values will be used 
to calculate the area under the curve as a measure of the dynamic of the cortisol awakening 
response, which will be evaluated before and after the three treatments. Cortisol analyses will 
include covariates for smoking status and oral contraceptive use. 
 
We will measure cardiac vagal tone by recording respiratory sinus arrhythmia (RSA). 
RSA refers to the rhythmic variations in heart rate that occur at the frequency of respiration, and 
reflects parasympathetic control over the heart (e.g., Berntson, Cacioppo, & Quigley, 1993). To 
measure breathing, a flexible respiration band will be strapped around subjects’ chest. A 
software program computes RSA using the peak-valley method (Grossman, 1983). This method 
derives RSA by calculating the difference between the minimum interbeat interval during 
inspiration and the maximum interbeat interval during expiration. [127-134]. 
 
Treatment Moderator Measure 
 
Credibility/Expectancy Questionnaire: This questionnaire is used to examine whether credibility 
and expectancy moderates therapy outcome. 
 
Study Integrity and Safety Measures 
 
Montreal Cognitive Assessment (MoCA; [113]):This is a 10-item rapid screening instrument for 
mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, 
executive functions, memory, language, visuoconstructional skills, conceptual thinking, 
calculations, and orientation. This measure will be used to assess entry criteria. 
 
Homework Compliance Scale[110, 111]: This is a 1-item clinician-rated instrument. It assesses 
homework compliance and will be administered prior to each session. 
 
Working Alliance Inventory (Short Form; [112]): This is a 12-item self-report instrument. It 
assesses the working alliance and will be administered prior to each session. 
 
Adverse Events Monitoring Form: Adverse events will be assessed at each visit. Adverse events 
will be rated as mild (noted change in the subject’s condition that causes minor distress and does 
not affect activity), moderate (notable distress and/or mild disruption in usual activity), or severe 
(marked distress and/or major disruption in usual activity). 
 
Concomitant Medications: Concomitant medication is defined as any medication taken on or 
after the start of double-blind investigational product. Concomitant drug use will be summarized 
by the number and proportion of patients in each treatment group receiving each drug within 
each therapeutic class. Multiple drug use by a patient will be counted only once. 
 
Medical Review Form: A study nurse with MD oversight or physician will assess physical 
fitness with the medical history form and a standard physical exam, emphasizing 
musculoskeletal, neurologic, and cardiac history. Participants’ current health status, medical 

 
31
history, past surgeries, and past psychiatric medication use will be assessed. Pregnancy will be 
assessed by a urine pregnancy test at the screen for women of childbearing age. 
 
6.2.1. Screening Evaluation.  
 
Individuals who contact the Center will be screened initially by phone for interest in the 
proposed research, as well as general diagnostic and study eligibility, and interest in research 
participation. Data for participants who undergo the phone screening process will be de-
identified and recorded in the study database phone screening log. Reasons for ineligibility and 
for non-participation of eligible subjects will be recorded.  
 
Interested patients who are eligible for participation will be scheduled for an evaluation meeting 
where informed consent will be obtained.   
 
Consent: The consent process will be conducted by an experienced member of the study and 
staff. All potential participants will review the consent form, risks, and benefits associated with 
the protocol with an approved study investigator and will sign consent prior to completion of any 
study assessments in this protocol. The study investigator will explain the study, answer any 
questions, and obtain written informed consent. Participants will be given as much time as 
needed to review the consent and ask questions prior to participation in study procedures. The 
study procedures and consent form will be approved by the Institutional Review Board at each of 
the enrolling sites prior to study initiation. There will be a single informed consent form at each 
enrolling site that describes both the assessment and study procedures.  
We will allow a maximum of one month for the time between baseline assessment of 
participants and randomization. For any participant for whom completing the screening process 
is delayed, with PI approval baseline measures will be repeated prior to entry. Once participants 
complete eligibility and are randomized to a group, they will start treatment within 4 weeks. 
 
6.2.2 Enrollment, Baseline, and/or Randomization 
Enrollment 
Participants will be enrolled in the study once they sign the informed consent form.  
Enrollment will be tracked in the study enrollment log.  
Baseline Assessments 
For participants who have successfully been screened for eligibility and are enrolled into 
the study, baseline assessments are performed against which to measure the study outcome. A 
complete list of the baseline evaluations are presented in Table 6.1.  
Randomization 
Randomization will precede the intervention.  
We will allow a maximum of one month for the time between baseline assessment of 
participants and randomization; should more than one month pass for logistical reasons, baseline 
assessments would be repeated prior to randomization. Once participants complete eligibility and 
are randomized to a group, they will start treatment within 4 weeks.  

 
32
 
6.2.3 Blinding 
Independent evaluators will remain blind to treatment assignment throughout the study. 
To preserve the blind they will be instructed with a reminder script for patients not to discuss 
their treatment prior to an assessment. The randomization codes will be created by the study 
statistician prior to entry of the first patient in the trial. Randomization will be stratified only by 
site. No unblinded analyses will be performed prior to study completion, unless specifically 
requested by the DSMB, in which case study PIs will only see blinded safety comparisons of the 
study intervention groups. 
The trainers/therapists and the person handling the randomization code cannot be blinded, 
but they will not be involved in IE ratings, which will be used for outcomes in this trial. The PIs 
will supervise the treatments, and oversee all study participants including safety and adverse 
events. The PIs will not, however, know the subject’s patient codes and the PIs will not be 
involved in the independent evaluator ratings. Thus these clinical and oversight study staff will 
not have access to data and have no influence on the outcome data. Outcome ratings will be 
completed by the blinded independent evaluators. The data management and analysis will be 
completed by the study statisticians and data manager who are not involved in clinical treatment 
or safety assessment at any time.  
 
6.2.4 Follow-up Visits 
At mid-treatment visit (week 6 after enrollment), post-treatment assessment (Week 12-13) and 6-
month follow-up (Week 36-27): 
▪ Clinical improvement (CGI-I) 
▪ Self-report instruments (STAI, BDI-II, BAI, PSS, SCL-90, WHOQOL-BREF, MCQ, FFMQ, 
PSWQ, ISI, PSQI, ASQ) 
▪ Psychophysiological/biological measures of stress (RSA, cortisol) 
▪ Measures of study integrity and safety (Adverse Events, Concomitant Medications/Therapy 
log. homework compliance, working alliance) 
6.2.5 Completion/Final Evaluation 
See 6.2.4.  
6.3 
Visit Windows 
 
If a subject cannot complete a study given visit within the windows specified below, all efforts 
should be made to have the subject’s visit occur as close to the window as possible.  
 
Any visits that occur out of window should be noted by the RA in the REDCap Protocol 
Deviation (PROTDEV) Log project. 
 
Screening / Baseline  
• ≤4 weeks should elapse between a subject’s screening and baseline assessment. 

 
33
• If a subject's baseline visit cannot be scheduled within 4 weeks of their initial 
screening visit (e.g., because their cohort does not fill up due to slow accrual), then 
they will need to be re-screened. At the re-screening visit, all Screening measures 
should be repeated, and the subject's SCID/ADIS GAD diagnosis should be 
confirmed. 
 
Baseline / Treatment 
• ≤4 weeks should elapse between a subject’s baseline assessment and treatment 
initiation. 
 
IE Assessments 
• A window of +/- 7 days will be used for biweekly IE assessments  
• A window of -30/+60 days will be used for the 6-month follow-up visit 
• Week 6 and week 12 IE assessment should only occur after the week 6 and week 12 
(i.e. final) treatment sessions (CBT, yoga, or SE), respectively. 
 
Treatment Sessions 
• No visit windows will be used for weekly group treatment sessions. 
7. SAFETY ASSESSMENTS 
For reasons of patient safety, patients who do not respond to SE after the 12 week intervention 
will be given the choice to receive CBT or yoga. Specifically, non responders (CGI-I >2) will be 
assisted in finding appropriate care from our existing referral resources. Additional treatments 
will be monitored and considered in the analyses. Subjects who wish to discontinue their 
participation at any point will also receive referral assistance if they request additional treatment.  
Patients will be excluded if they report significant current suicidal ideation (as assessed with the 
BDI-II item 9 and CSS suicidality checklist) or suicidal behaviors within the past year. We will 
also exclude patients with seizures disorder resulting in ongoing cognitive impairment, patients 
with a history of head trauma causing loss of consciousness, seizures or ongoing cognitive 
impairment, patients with medical illnesses or instability for which hospitalization may be likely 
within the next year, and patients with physical conditions that might cause injury from yoga 
(e.g., physical injuries, musculoskeletal problems).  
7.1 
Specification of Safety Parameters 
A study MD or nurse with MD oversight will assess medical history and with consent will 
consult with PCPs if any medical issues that may potentially interfere with safe participation in 
yoga are identified. We have modified our study criteria to more clearly exclude all potential 
subjects with physical disabilities (evaluated with a medical history and physical exam) or 
cognitive disabilities (evaluated by the Montreal Cognitive Assessment Scale) that would clearly 
preclude safe practice of the yoga intervention or CBT.  At present there is insufficient 
information regarding the safety of yoga during pregnancy. For reasons of safety, all women of 
childbearing potential will be required to use a reliable form of birth control throughout the 
study: (e.g.: oral contraceptives, surgical sterilization (of the subject or of her male partner), IUD 
(intrauterine device), condom and spermicide or diaphragm and spermicide). Subjects with 
existing or planned pregnancy during the intervention will be excluded.  Inclusion of subjects 

 
34
with any minor preexisting conditions of potential concern will be subject to participation only 
after consented review with and approval by the subject’s primary healthcare provider.  
Each visit, adverse events will be assessed on the adverse events monitoring form and rated as 
mild, moderate, or severe (as defined in AE section below). On weeks 0, 2, 4, 8, 10 and 12 the 
CGI-S, CGI-I, BDI and a suicidality checklist will be administered to evaluate any potential 
worsening symptoms. Physical fitness will be assessed by the study nurse with MD oversight or 
MD with the medical history form and a standard physical exam, emphasizing musculoskeletal, 
neurologic and cardiac history. 
Twenty-four-hour emergency coverage with a study clinician (physician, psychologist or 
registered nurse with MD oversight) will be available. Patients will be provided with cards with 
the emergency contact number. In the event of an emergency the clinician will determine the 
necessary clinical intervention and will provide and coordinate appropriate care. 
Parameters 
All three interventions (Yoga, CBT, and SE) are safe interventions with minimal associated risk.  
We anticipate minimal risk to subjects due to their participation in this study; however, some 
risks are associated with conducting these treatments. The primary risk is the evocation of 
uncomfortable levels of anxiety or other emotions during some treatment sessions. Some patients 
may find sessions stressful and react to them with anxiety. However, it is not expected that 
anxiety will be higher than what they would experience in other life situations. Participants will 
be informed about these risks and told that they may withdraw from the study at any time and 
may refuse to complete any treatment procedures they find too uncomfortable. 
Some patients may feel uncomfortable about the treatment sessions being taped (necessary for 
supervision and treatment adherence checks). However, this will be a required procedure. The 
purpose of the taping will be explained, confidentiality will be maintained, and informed consent 
for taping will be obtained. Additionally, clients may experience some disruption of daily 
activities due to scheduling of treatment sessions. 
 
There is a possibility that a patient may become distressed when being asked about symptoms or 
personal experiences during the diagnostic evaluation or assessment sessions. The primary risks 
to the patient are discomfort associated with the assessments and the treatment procedures. 
Subjects may also experience some discomfort or anxiety from discussing personal information. 
Yet, this anxiety is not expected to be any greater than that subjects already experience, and 
subjects will be able to withdraw from the study at any time. There are risks of injury during 
yoga. The practice of the physical exercises and postures, breathing exercises, relaxation 
techniques, and meditation in the yoga treatment involve little risk, although at times subjects 
may find them challenging and difficult to complete. Overexertion on the physical exercises may 
lead to temporary muscle soreness for up to a week.  However, subjects will be instructed to 
gradually increase their effort on the physical exercises and breathing practices so as not to 
overexert themselves, and to stop if any subjects experience unexpected unpleasant 
symptoms. There may be risks and side effects that are currently unknown and/or unanticipated. 
 
Study personnel will be monitoring the patients’ clinical and physical conditions carefully and 
will withdraw patients from the study if warranted by their clinical condition. The yoga 
instructor will again review all preexisting conditions with subjects in the group at the beginning 

 
35
of the 12-week intervention and will make modifications to the practices as necessary to ensure 
subject safety and to prevent injury. The instructor will also require subjects to report any recent 
changes in their health, injuries or conditions at the beginning of every treatment session. Group 
size will be relatively small for yoga classes with 4-6 subjects per group, which allows for 
careful monitoring of subject safety during the class sessions. 
 
In addition to the risks associated with the treatments, interviews, and questionnaires, there are 
some other potential risks from the electrocardiograms, such as an allergic reaction to the 
electrode paste. However, these reactions are rare and typically very mild.  
 
Although every effort will be made to assure confidentiality, it is possible someone could 
without permission gain access to study related data during the time they are being used or stored 
for examination of results. 
 
7.3 
Adverse Events and Serious Adverse Events 
Adverse events (AEs) and serious adverse events (SAEs) are defined as follows.   
An adverse event (AE) is defined as any unfavorable and unintended diagnosis, symptom, sign 
(including an abnormal laboratory finding), syndrome or disease which either occurs during the 
study, having been absent at baseline, or if present at baseline, appears to worsen. 
A serious adverse event (SAE) is defined as any untoward medical occurrence that results in 
death, is life threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, or is a congenital 
anomaly. 
These events will be assessed at each visit using the adverse events monitoring form and 
rated as mild, moderate, or severe. These parameters are defined as follows: mild (noted change 
in the subject’s condition that causes minor distress and does not affect activity); moderate 
(notable distress and or mild disruption in usual activity); and severe (marked distress and/or 
major disruption in usual activity).  
7.4 
Reporting Procedures 
Unexpected, serious, and intervention-related SAEs will be reported to the NYU, BU and 
MGH IRBs, DSMB, and NCCAM, in accordance with requirements. Unexpected fatal or life-
threatening AEs related to the intervention will be reported to the NCCAM Program Officer 
within 7 days. Other serious and unexpected AEs related to the intervention will be reported to 
the NCCAM Program Officer within 15 days. Anticipated or unrelated SAEs will be handled in a 
less urgent manner but will be reported to the DSMB, IRB, NCCAM, and other oversight 
organizations in accordance with their requirements.   
7.5 
Follow-up for Adverse Events 
We will first administer the SAFTEY form at each visit. This form asks if any AE’s have 
occurred. If the subject answers “yes” we will then fill out the cumulative AE LOG accordingly.  
 

 
36
Adverse events will be assessed at each visit using the adverse events monitoring form 
and rated as mild, moderate, or severe. These parameters are defined as follows: mild (noted 
change in the subject’s condition that causes minor distress and does not affect activity); 
moderate (notable distress and or mild disruption in usual activity); and severe (marked distress 
and/or major disruption in usual activity).  
7.6 
Safety Monitoring 
This study will be overseen by a study DSMB and associated DSMP, as well as the IRB 
at each study site. Additional monitoring by NCCAM may occur. 
 2. 
Frequency of Data Review for this Study― The frequency of data review for this study 
differs according to the type of data and can be summarized in the following table: 
Data type 
Frequency of review 
Reviewer 
Summary figure of subject 
accrual  & summary table of 
reasons for exclusion (based on 
protocol enrollment criteria) 
PIs weekly for first three 
months of recruitment, then 
weekly accrual and 
quarterly adherence; 
DSMB yearly 
PI, DSMB 
Summary table of status of all 
randomized subjects, as of date 
of reporting  
PIs monthly, DSMB yearly 
PI, DSMB 
Summary tables of adherence to 
IE visits and treatment sessions 
PIs quarterly, DSMB yearly 
PI, DSMB 
Summary table of demographic 
characteristics of all randomized 
subjects 
PIs monthly, DSMB yearly 
PI, DSMB 
Summary tables of all (serious) 
adverse events 
PIs quarterly, DSMB yearly 
PI, DSMB 
 
 
 
Detailed descriptions of SAEs  
Per Occurrence 
PI, DSMB, IRB, NCCAM 
Full study continuing review 
Yearly 
IRB (MGH, BU, and NYU 
respectively) 
8. INTERVENTION DISCONTINUATION 
8.1 Treatment Discontinuation and Monitoring: 
 

 
37
Any participant with a CGI-I of 5 or greater at any time will undergo weekly assessment by a 
study clinician including clinical and safety assessments, CGI-S and CGI-I ratings and 
suicidality assessment (CSS suicidality checklist) Participants will be discontinued from study 
participation at their request at any time or if warranted in the clinical judgment of the study 
clinicians. Additionally, participants who score >5 on the Clinical Global Impression of 
Improvement Scale for 2 consecutive weeks (much worse) or who develop suicidality at any 
point will be discontinued from the treatment protocol and referred for clinically appropriate 
care. In these instances, the subject will be evaluated by a study clinician and a decision will be 
made regarding possible exit from the study and/or referral for treatment.  We will report all 
episodes of worsening symptoms and the outcome of the attendant monitoring procedure to our 
DSMB. 
 
In addition, if the BDI-II suicidality item (item number nine) is above 1 (scale is from 0 to 3) or 
the CSS suicide checklist is above 2, a study clinician will assess the patient weekly to determine 
suicidality and if present, assist with accessing any indicated clinical intervention. This 
assessment will occur weekly until the BDI-II item is no longer above a 1 and CSS suicidality 
item is no longer above 2. 
 
Twenty-four-hour emergency coverage with a study clinician (physician, psychologist, or 
registered nurse with MD oversight) will be available. Patients will be provided with cards with 
the emergency contact number. In the event of an emergency the clinician will determine the 
necessary clinical intervention and will provide and coordinate appropriate care. 
 
All participants will be encouraged to complete a final endpoint assessment unless clinically 
inappropriate even if they discontinue treatment, and all analyses will be intent to treat. Every 
effort will be made to keep appropriate subjects in the study for the full duration of the trial. 
Subjects dropping out of the trial will be included in data analysis as described in the Data 
Analysis Section.  
 
Non responders (CGI-I >2) will be assisted in finding appropriate care from our existing 
referral resources. Additional treatments will be monitored and considered in the analyses. 
Furthermore, subjects who wish to discontinue their participation at any point will also receive 
referral assistance if they request additional treatment.   
If at any time during the course of the study, the DSMB judges that risk to subjects 
outweighs the potential benefits, the DSMB shall have the discretion and responsibility to 
recommend that the study be terminated. 
9. STATISTICAL CONSIDERATIONS 
9.1 
General Design Issues 
The specific aims and hypotheses are as follows:  
Specific Aim 1: Short-term Efficacy of Yoga: Our primary objective is to examine the short-term 
treatment efficacy of yoga on GAD symptoms. We expect that, at post-treatment, a significantly 
greater proportion of individuals randomized to receive yoga will be classified as “responders” to 
treatment (CGI-I ≤ 2) than for individuals who receive SE (Hypothesis 1.1). We further expect 

 
38
that a greater proportion of individuals receiving CBT for GAD will be classified as 
“responders” than for those receiving SE (Hypothesis 1.2). Moreover, we predict that the rate of 
“responders” in individuals receiving yoga will be comparable to those receiving CBT at post-
treatment (Hypothesis 1.3).  
Specific Aim 2: Long-term Efficacy of Yoga (Exploratory Aim): Our secondary aim is to 
examine the long-term treatment efficacy of yoga on GAD symptoms. We hypothesize that yoga 
and CBT will be equally effective at the 6-month follow-up (i.e., the “responder” rate for yoga 
will not be inferior to that for CBT), and that yoga and CBT will each have higher “responder” 
rates than SE (Hypothesis 2.1-2.3).  
Specific Aim 3: Mediation Analyses. Our tertiary aim is to examine and compare the mechanism 
of treatment changes in yoga and traditional CBT for GAD. We predict that treatment changes in 
responder rates during yoga treatment will be mediated via changes in mindfulness and changes 
in vagal tone (Hypothesis 3.1), whereas changes in CBT will be mediated via changes in 
maladaptive cognitions (Hypothesis 3.2.). Moderators of “responder rates” will also be 
examined. 
 
These hypotheses can be tested in a five-year multi-site study to examine the comparative 
efficacy of yoga, CBT, and stress education, a previously employed control condition, for 
patients with GAD. Patients with GAD will receive 12-weekly yoga, CBT, or stress education 
sessions delivered in a group format controlling for attention, time, and group format. 
Independent evaluators will perform assessments before the 12-session intervention phase, at 
mid-treatment, after the intervention, and at 6-month follow-up. 
 
9.2 
Sample Size and Randomization 
A non-inferiority test is the most direct test of our hypothesis that Yoga will be as effective as 
CBT for both short-term and long-term outcomes. We will perform a non-inferiority test using response 
rate (response rate is defined as CGI-I ≤ 2) as the outcome on which to compare CBT and Yoga at post-
treatment and at follow-up. Since some attrition may occur, we will use last observation carried forward 
to insure an intent-to-treat analysis. The non-inferiority margin will be half the difference in response 
rates between the active comparison (CBT) and placebo. Based on earlier literature, we can expect 
response rates in our particular CBT and placebo conditions of 57.9% in CBT and 22.2% in placebo. 
Thus, our non-inferiority margin will be set at ½ the difference between 56.7 and 22.2, or 17.85%. Using 
the power analysis program PASS 12, we find that the number of subjects required to obtain .80 power 
for the non-inferiority test comparing CBT and Yoga is 95 participants in each of the 2 conditions. We 
verified this number in a 1000 simulation Monte Carlo study using these same parameters. This number 
is higher than the number proposed in the original grant. Thus, we will increase the N per cell in CBT 
and Yoga to 95 (22 additional patients per site) to have adequate power for this non-inferiority test.  
While the original study was budgeted based on a lower number of participants, with careful 
management of costs we believe we can manage this increase in participants within the full study budget 
if awarded as proposed.  
For the superiority tests (CBT vs. SE and Yoga vs. SE) on the secondary outcomes (which are 
continuous), we used the MRM power analysis program PinT 2.12. We assumed 25% missing data, and 
used data from our recent CBT trials (e.g., Stern et al., 2012) to estimate the variances and covariances 
needed for PinT. PinT indicated greater than .80 power to detect an effect size as small as d=.27, 
between a small (d=.20) and medium (d=.50) effect size.  

 
39
We predict that changes in mindfulness will mediate changes in outcome over time for 
patients in the Yoga condition, and changes in cognitions will mediate changes in CBT. Plus, 
changes in RSA and cortisol may also mediate changes in outcome across conditions. We further 
predict that treatment condition will moderate the effect of Time on the mediators (“a” paths). 
We performed a Monte Carlo study to calculate the power for our proposed bootstrap mediation 
analysis. Based on our recent trial, we assumed that the “a” paths (the effects Yoga vs. SE and of CBT 
vs. SE on the mediators) would be large, and that the relation between each mediator and the outcome 
(response to treatment) would have a medium effect size. The Monte Carlo study consisted of 400 
samples, for each of which we performed a bootstrap mediation analysis, each consisting of 1,000 
resamples for the bootstrap analysis. Results showed a power greater than .81 to detect a mediated 
pathway. 
 
Treatment Assignment Procedures 
Please see Randomization procedures section 4.3. 
Independent evaluators will remain blind to treatment assignment throughout the study. 
To preserve the blind they will be instructed with a reminder script for patients not to discuss 
their treatment prior to an assessment. The randomization codes will be created by the study 
statistician prior to entry of the first patient in the trial. Randomization will be stratified only by 
site. No unblinded analyses will be performed prior to study completion, unless specifically 
requested by the DSMB, in which case study PIs will only see blinded safety comparisons of the 
study intervention groups. 
9.3  
Definition of Populations 
Our primary analyses will use mixed-effects regression models (MRMs) with a logistic 
linking function (a GLMM analysis) since our primary outcome measure is dichotomous 
(treatment response). Analyses of secondary outcomes will be performed using MRM. MRM and 
GLMM easily accommodate nesting of repeated observations within subjects, include all who 
complete at least one assessment (including the baseline assessment), and are the preferred 
method to analyze longitudinal data (Hamer and Simpson, 2009 [135]). Our intent-to-treat 
sample includes all randomized patients who complete at least one assessment. Thus, our 
primary analyses (GLMM and MRM) are intent-to-treat analyses. We will also perform “per 
protocol” analyses. Our per protocol population will include all randomized patients who 
complete the baseline and post-treatment assessments, miss no more than 2 treatment sessions, 
who average a 4 or higher on the homework compliance scale, and who did not initiate 
prohibited treatment during the study. We will repeat our GLMM and MRM analyses using the 
per protocol sample. 
9.4 
Interim Analyses and Study Stopping Rules 
No interim analyses are planned, unless requested by the DSMB or NCCAM. DSMB reports for 
safety will be prepared yearly (see DSMP) without unblinded treatment outcomes analyses 
unless specifically requested by the DSMB. Unexpected, serious, and intervention-related SAEs 
will be reported to the NYU, BU, and MGH IRBs, DSMB, and NCCAM, in accordance with 
requirements. In addition, all study treatment discontinuations for clinical worsening will be 
reported to the DSMB. If at any time during the course of the study, the DSMB judges that risk 

 
40
to subjects outweighs the potential benefits, the DSMB shall have the discretion and 
responsibility to recommend that the study be terminated. 
9.5 
Outcomes 
As noted earlier, a non-inferiority test is the most direct test of our hypothesis that Yoga will be 
as effective as CBT for both short-term and long-term outcomes. We will perform a non-inferiority test 
using response rate (response rate is defined as CGI-I ≤ 2) as the outcome on which to compare CBT 
and Yoga at post-treatment and at follow-up. Since some attrition may occur, we will use last 
observation carried forward to insure an intent-to-treat analysis. The non-inferiority margin will be half 
the difference in response rates between the active comparison (CBT) and placebo. Based on earlier 
literature, we can expect response rates in our particular CBT and placebo conditions of 57.9% in CBT 
and 22.2% in placebo. Thus, our non-inferiority margin will be set at ½ the difference between 56.7 and 
22.2, or 17.85%. Using the power analysis program PASS 12, we find that the number of subjects 
required to obtain .80 power for the non-inferiority test comparing CBT and Yoga is 95 participants in 
each of the 2 conditions. We verified this number in a 1000 simulation Monte Carlo study using these 
same parameters. This number is higher than the number proposed in the original grant. Thus, we will 
increase the N per cell in CBT and Yoga to 95 (22 additional patients per site) to have adequate power 
for this non-inferiority test.  While the original study was budgeted based on a lower number of 
participants, with careful management of costs we believe we can manage this increase in participants 
within the full study budget if awarded as proposed.  
For the superiority tests (CBT vs. SE and Yoga vs. SE) on the secondary outcomes (which are 
continuous), we used the MRM power analysis program PinT 2.12. We assumed 25% missing data, and 
used data from our recent CBT trials (e.g., Stern et al., 2012) to estimate the variances and covariances 
needed for PinT. PinT indicated greater than .80 power to detect an effect size as small as d=.27, 
between a small (d=.20) and medium (d=.50) effect size.  
 
9.5.1 Primary Outcome 
Response (CGI-I of 1 or 2) will serve as the primary outcome measure alongside the 
SIGH-A as the core secondary continuous measure.  
 
9.5.2 Secondary Outcomes 
Secondary Outcomes: Secondary outcome measures include the STAI, PSS, BDI-II and 
BAI, WHOQOL-BREF, PSQI, ISI, ASQ, and PSWQ. The FFMQ, MCQ, RSA, and cortisol are 
examined as possible mediators of change.  
The Credibility/Expectancy Questionnaire will be administered to examine whether 
credibility and expectancy moderates therapy outcome.  
In addition, we will explore whether clinical characteristics (comorbid diagnoses) and 
demographic characteristics (age, sex, SES) are possible moderators. The data analyses are 
described for the primary measure only. 
9.6 
Data Analyses 
Primary Analyses 
 

 
41
Our primary analyses will use mixed-effects regression models (MRMs) with a logistic 
linking function (a GLMM analysis) since our primary outcome measure (response to treatment, 
defined as CGI-I≤2) is dichotomous. Analyses of secondary outcomes will be performed using 
MRM. MRM and GLMM easily accommodate nesting of repeated observations within subjects, 
include all subjects with at least one assessment, and are the preferred method to analyze 
longitudinal data (Hamer and Simpson, 2009 [135]). Since these analyses will include all 
subjects who are randomized and complete at least one assessment, it is an intent-to-treat 
analysis. Also, since subjects will undergo treatment in groups (4-6 subjects per group) our 
MRM and GLMM models will include 3 levels: repeated measurements (level 1) nested within 
subjects (level 2) who will be nested within their treatment cohort (level 3). 
Our primary model will be a GLMM in which response to treatment over time will be modeled 
as a growth curve. Our primary analyses will examine outcomes at post-treatment (Aim 1). These 
analyses will include only the 7 assessments from baseline to post-treatment, and will not include the 
follow-up (FU) assessment since it could be affected by subjects seeking other treatments during the FU 
period. Only our exploratory analyses for outcome at FU (Aim 2) will include data from the FU 
assessment. Since recent research indicates that suboptimal modeling of the growth curve can result in 
incorrect results, we will examine various linear and nonlinear models to find the optimal growth curve 
during treatment (linear, quadratic, cubic, exponential [leveling off at an asymptote], and an ANOVA 
model, in which time is coded as a categorical variable. For this ANOVA model, each assessment time 
point is modeled with a dummy coded assessment variable [coded 1 for the assessment, 0 for other 
assessments]. In this model, the means at each assessment point are freely estimated and are not 
constrained to fit any particular pattern. See our discussion of the ANOVA model in the paragraph 
below for more information).We will conduct our significance tests using the growth curve that most 
accurately models the data (comparing the various growth curve models using AIC and BIC).  
The three treatment conditions (Yoga, CBT, and SE) will be coded using 2 dummy variable 
contrasts, with SE as the “reference” treatment. The first dummy variable will contrast Yoga vs. SE, and 
the second will contrast CBT to SE. Time will be coded as weeks since baseline. To test of differences 
between treatments at post-treatment (week 12), time will be centered at week 12 (in other words, our 
Time variable in our analysis will be computed as “time minus 12”). In MRM or GLMM analyses in 
which this Time centered variable is used, the significance of the dummy variable contrasts (Yoga vs. 
SE and CBT vs. SE) provides the test of the differences between these treatment conditions at post-
treatment. A similar approach can be used to test differences between treatment conditions at follow-up. 
This growth curve model will be used to test differences between treatment conditions for 
our primary outcome (response to treatment) and for CGI-S, since these outcomes are measured 
frequently enough (7 times during treatment) to accurately model the growth curve. However, 
the other secondary outcomes are measured at most3 times during treatment (baseline, week 6, 
post-treatment), with secondary sleep measures administered only twice (baseline and post-
treatment), thus disallowing accurate assessment of their growth curve. Thus, these outcomes 
will use an MRM employing an ANOVA type design (see for example, Liu, Rovine, & 
Molenaar, 2012). In this kind of model, time is treated as a categorical variable (using2 dummy 
variables [one for each assessment except the baseline assessment] to code the 3 assessments). 
The three treatment conditions (Yoga, CBT, and SE) will be coded using the 2 dummy variable 
contrasts (Yoga vs. SE and CBT vs. SE). Interactions will be formed between each treatment 
condition contrast and each assessment dummy variable. This coding freely estimates the means 
for the outcome at each assessment, without any constraint from a specific growth curve. This 
design is similar to a 3 x 3 repeated measures ANOVA with the exception that it includes all 

 
42
patients that complete at least one assessment, the outcome can be dichotomous, the covariance 
structure of the repeated measures can take almost any form, and this approach assumes data are 
missing at random (MAR) or not missing completely at random (MCAR). The significance of 
the interaction between a treatment condition contrast (e.g., Yoga vs. SE) and an assessment 
dummy variable (e.g., for the post-treatment assessment) will test whether the change from 
baseline to that assessment is significantly different between the treatment conditions. Using this 
coding scheme, all contrasts between treatment conditions at all assessments are provided by this 
one analysis. Thus, this approach has the added benefit of having all contrasts between the 
treatment conditions at each assessment being conducted on the same sample. 
Demographics and comorbid diagnoses will be used as covariates in all analyses and 
considered as possible moderators of outcome at each assessment. An additional moderator that 
will be investigated is homework adherence.  
 
Planned Secondary Analysis of Sensitivity of Growth Curve Model for Primary Outcome 
 
To determine if the results of the analyses for Aim 1 are sensitive to the growth curve 
model, we will perform a secondary analysis, using a simple ANCOVA-type model, to verify the 
results of our primary growth curve model. Since the outcome is binary (response to treatment), 
this analysis will be performed using logistic regression, with the following predictors of 
outcome at post-treatment: baseline severity based on the CGI-S and SIGH-A, and the two 
dummy variables coding the contrast between SE and the 2 active treatments. This analysis will 
be performed twice: once as an ITT analysis with missing outcomes imputed as last observation 
carried forward, and once as a completer analysis. 
 
Per Protocol Secondary Analysis: 
 
As additional secondary analyses, we will repeat our GLMM and MRM analyses using 
the per protocol sample. We will use these analyses rather than simpler analyses (such as logistic 
regression or repeated measures ANOVA) because repeating our GLMM and MRMs will allow 
a more direct comparison to the results for the intent-to-treat sample, allows inclusion of subjects 
that miss some assessments (other than baseline and post-treatment), allows the modeling of 
complex covariances between the repeated measures, and it assumes MAR rather than MCAR. 
 
Follow Up Secondary Analyses: 
 
Analyses of outcome at FU (Aim 2) will be considered exploratory since subjects may 
seek additional treatment during follow-up. These analyses will follow the analyses of outcome 
at post-treatment, except one additional assessment (FU) will be added to these analyses. Since 
response during FU may not follow the growth curve of the treatment phase, the growth curve 
for Aim 2 will be modeled as “piecewise”, separately modeling the growth curve during 
treatment and follow-up. (Analyses of the secondary outcomes at FU will follow the mixed 
effects ANOVA model described above since these analyses include only 4 total 
assessments).We will add an additional dummy variable predictor to the analyses for Aim 2, 
coding whether or not the subject received additional treatment during FU. We will also add the 
interactions of this “additional treatment” variable with all the other predictors in the analyses to 
determine if “additional treatment” impacted response to treatment at FU. This analysis will 

 
43
allow us to assess the effect of CBT vs. SE and Yoga vs. SE separately for those who received 
additional treatment and those who did not. A further analysis will compare the rates at which 
subjects in the 3 conditions seek additional treatment during the FU period. 
 
Secondary Mediation Analysis for Primary Outcome:  
 
We are interested in mediation of our primary outcome: response at post-treatment. Thus, this 
analysis will include all assessments through and including post-treatment (but not FU). Our 
mediation analysis includes 2 independent variables (the contrast of Yoga vs. SE and the contrast 
of CBT vs. SE) and 3 mediators: mindfulness, vagal tone, and maladaptive cognitions. The “a” 
paths in the mediation analysis will be the effects of each of the 2 independent variables on each 
of the 3 mediators. These paths will be derived from three MRMs, one for each mediator as the 
dependent variable. These MRMs will be identical to the models described above with Time 
centered at post-treatment. Thus, the effect of each contrast (Yoga vs. SE and CBT vs. SE) will 
be their effect on each mediator at post-treatment. The “b” paths will be derived from the 
GLMM model (described above) for differences between treatment conditions at post-treatment, 
with the dependent variable being “response”. The 3 mediators will be included in this growth 
curve model as additional simultaneous predictors of response. The regression coefficients for 
the mediators in this analysis become the “b” paths in the mediation analysis (the paths from 
each mediator to outcome). Significance of mediated pathways will be determined using bias-
corrected bootstrap mediation analysis (e.g., Fritz and MacKinnon, 2007 [137]). We predict that 
changes in mindfulness will mediate changes in outcome over time for patients in the Yoga 
condition, and changes in cognitions will mediate changes in CBT. Plus, changes in RSA and 
cortisol may also mediate changes in outcome across conditions.  
Missing Data. Although we will make every effort to reduce missingness, it is inevitable that 
some data will be missing. We will use pattern mixture modeling (Hedeker & Gibbons, 2006; 
Enders, 2011 [138-139]) and rerun our analyses coding for various missing data patterns (no 
missing data, early dropouts, late dropouts, FU dropouts, etc.) to determine both if missingness 
impacts our findings and how the differences between treatment conditions depend on the 
missing data pattern. 
 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms 
Trained study clinicians blind to randomized treatment assignment (independent 
evaluators, IEs) will administer diagnostic assessments and rating scales (See Integrity of 
Diagnostic Assessments).   
A number of procedures are in place to assure data integrity and protocol adherence. We 
will use Research Electronic Data Capture to support direct data entry by patients and study staff. 
REDCap is a free, secure, HIPAA compliant web-based application hosted by the Partners 
HealthCare Research Computing, Enterprise Research Infrastructure & Services (ERIS) group. 
Web-based surveys rely on a study-specific data dictionary defined by members of the research 
team with planning assistance from Harvard Catalyst/The Harvard Clinical and Translational 
Science Center EDC Support Staff. These support staff will then oversee the automated export of 

 
44
study data from REDCap to a relational study database in Microsoft Access 2000, allowing for 
systematic data querying and checking.  
Data will be collected electronically using the Research Electronic Data Capture 
(REDCapTM) software, a free, secure, HIPAA compliant web-based application hosted by the 
Partners HealthCare Research Computing, Enterprise Research Infrastructure & Services (ERIS) 
group.  Self-report measures will be completed by participants on a computer, directly into 
REDCap, thus minimizing errors due to data entry.  For clinician-administered measures, trained 
independent evaluators (IEs) will enter responses directly in REDCap.  All IEs will be blind to 
randomized treatment assignment (See Integrity of Diagnostic Assessments).  
To minimize missing data for self-report forms, we will program missed question 
warnings in REDCap that will alert participants in real-time if they inadvertently skip a question.  
Participants may then go back and answer any missed questions, or, if they intentionally skipped 
questions, they may ignore the warning message and continue answer the remaining questions.  
We will also program real-time range checks in REDCap that generate error messages if a value 
outside the acceptable range is entered for a given field.  To ensure confidentiality, data will be 
identified in the database only by subject number, visit number, and date of visit. By recording 
the study data in this manner, the information can be considered ‘de-identified’ and therefore 
compliant with the Standards for Privacy of Individually Identifiable Health Information 
(“Privacy Rule”) of the Health Insurance Portability Act of 1996 (HIPAA). Any data that is 
transmitted electronically will be fully encrypted and password protected. Subjects’ names will 
not be entered into the database; each will be uniquely identified only by an ID number. Consent 
forms, any hard copy PHI, and any study measures that are completed on paper will be kept and 
filed in locked office cabinets.  
At least once a year during the course of the study, we will report on data quality and 
completeness to the DSMB. At a minimum, the report will include an overview of progress on 
patient intake and retention; a summary of patient compliance with visits, evaluations, and 
treatments as described in the protocol; any adverse events or safety concerns that arise; and a 
summary of the completeness and quality of key data elements needed to characterize patients. 
These reports will allow the DSMB to evaluate the capacity of the data capture and processing to 
support scientifically valid analyses. Any DSMB recommendations to improve subject safety, 
protocol adherence, or data quality will be included in the annual DSMB report. A copy of the 
annual DSMB report will be sent to the Partners, Boston University, and NYU Medical Center 
IRBs along with the annual renewal report. 
 
10.2 Data Management 
The study biostatisticians (see below) will oversee management of the study database. 
The principal investigators at NYU and BU, Drs. Simon and Hofmann, are ultimately 
responsible for the quality of the data collection and overall conduct of the study, and directly 
supervise the study coordinators and data management staff. Dr. Simon will oversee the 
subcontract PI, Dr. Bui, at MGH in the management and quality of data at MGH. Data 
management will include clinician and patient rated assessments (see assessments), screening 
data, fidelity data, visit adherence data, IE certification and rater reliability data and safety 
reporting. Weekly reports will monitor subject enrollment, completion, attrition, and individual 
subject progress as well as the completion of critical assessments. Additional reports will be 

 
45
done as needed to monitor baseline characteristics, protocol adherence, and other issues of 
interest.  
Research Electronic Data Capture (REDCap) will be used for direct data entry by patients 
and study staff. REDCap is a free, secure, HIPAA compliant web-based application hosted by 
Partners HealthCare Research Computing. Web-based surveys rely on a study-specific data 
dictionary defined by members of the research team with planning assistance from Harvard 
Catalyst | The Harvard Clinical and Translational Science Center EDC Support Staff. Support 
staff will oversee the automated export of study data from REDCap to a relational study database 
in Microsoft Access 2000, allowing for systematic data querying and checking. Biostatistician 
David Rosenfield, Ph.D., will oversee management of Aparna Keshaviah, M.Sc., and of the 
study database and data integrity. 
All measures that are completed on paper will be entered by the RA into REDCap, and a two 
pass verification system will be used to minimize any data entry errors. All records in REDCap 
have a form completion status that may be Incomplete (appears as a red circle in Record Status 
Dashboard), Unverified (yellow circle), or Verified. The RA initially entering data will save each 
record entered as Unverified (at which point it will appear as a yellow circle in the Record Status 
Dashboard). A second RA at each enrolling site will then go into each unverified record, 
compare each entered value against the paper source document, make any corrections, and then 
re-save the record as Verified (at which point it will appear as a green circle in the Record Status 
Dashboard). The color coding system built into REDCap readily allows for identification of 
unverified records. 
 
 Monthly reports will monitor subject enrollment, completion, attrition, and individual 
subject progress as well as completion of critical assessments. Additional reports will monitor 
baseline characteristics, protocol adherence, and other issues. Data will be identified only by 
subject number, visit number, and date of visit such that the information can be considered ‘de-
identified’ and therefore compliant with the Standards for Privacy of Individually Identifiable 
Health Information (“Privacy Rule”) of the Health Insurance Portability Act of 1996 (HIPAA). 
Any data that is transmitted electronically will be fully encrypted and password protected. 
Subjects’ names will not be entered; each will be uniquely identified only by an ID number. De-
identified data will be transmitted electronically from the MGH site to the NYULMC site in 
accordance with these guidelines for data analysis purposes. 
Consent forms and any hard copy PHI will be kept and filed in secure locked office cabinets. 
 
10.3 Quality Assurance 
10.3.1 Training 
Trained study clinicians blind to randomized treatment assignment (independent 
evaluators, IEs) will administer diagnostic assessments and rating scales. The integrity and 
reliability of the diagnostic and efficacy evaluations will be established and maintained. All 
raters will be experienced clinicians who will have undergone specific training to criterion in the 
use of the study measures. Any new raters will undergo training including rating at least 2 audio 
or videotaped interviews, then have 2 interviews taped and reviewed for agreement by an expert 
rater (IE supervisor).  The IEs will be M.D., Ph.D. or experienced Masters level diagnosticians 
with previous research experience with structured interviewing who will receive additional 

 
46
training and certification for this study under the direction of Drs. Simon and Hofmann. In 
addition to the training procedures, study staff will hold weekly meetings during which all initial 
diagnostic interviews conducted that week are discussed in the presence of senior clinicians, and 
in the instance of diagnostic disagreement, the sources of these differences are reviewed and a 
consensus diagnosis is reached. The staff meeting should also reduce the potential for 
interviewer drift. A two-level system will be used to maintain the reliability of diagnoses and of 
other clinical ratings in the study, consisting of weekly supervision and ongoing rating of 
selected clinical assessments, which will all be digitally recorded. Each month, an independent 
evaluator (IE) will listen to an assessment performed by another IE associated with the study and 
independently complete the assessment instruments (SIGH-A, CGI). In addition, each month, all 
IEs will co-rate an audiotape during a monthly conference call. These duplicate ratings will be 
used both to calculate kappa coefficients and for supervision. Differences between raters will be 
discussed during supervision to identify reasons for disagreement and improve inter-rater 
reliability. These procedures will help us ensure that IEs refine their diagnostic skills and will 
also establish common guidelines for ongoing use in diagnostic decision-making. Inter-rater 
agreement will be assessed via evaluation of digital recordings of diagnostic interviews. Kappa 
coefficients will be calculated every 12 months. If reliability falls below criteria (ICC ≥ 0.8 for 
CGIs and SIGHA, and 100% agreement on GAD diagnosis), IEs will be retrained. 
See Treatment Certification and Supervision Procedures (section 5.2) for training 
for study treatment providers 
10.3.2 Quality Control Committee  
 
The quality control committee will be the executive committee, which will meet weekly 
and will be comprised of the two PIs,  Drs. Hofmann and Simon, the MGH subcontract PI, and 
the co-investigators, Drs. Khalsa and Hoge, and the biostatistician, Dr. Rosenfield. The members 
of the committee have a long and fruitful history of collaboration. Drs. Rosenfield and Hofmann 
have collaborated on numerous empirical studies, and there is a long history of collaboration 
between Drs. Hofmann and Simon as part of a mutual NIMH grant. Furthermore, there is a 
history of research collaboration between Drs. Simon and Hoge, Drs. Simon and Bui, and Drs. 
Hofmann and Khalsa. Dr. Hofmann will chair the executive committee for this grant and bear 
primary responsibility for maintaining communication between the sites, NCCAM, and a Data 
Safety and Monitoring Board (DSMB), which will be comprised of three members overseeing 
safety issues and overall conduct of the study as detailed in the Human Subjects section of the 
grant proposal. Dr. Simon will oversee the training of independent raters, quality assurance 
procedures, data management and analysis. All key investigators as well as research staff 
working on the study will participate in weekly meetings and supervisions. The executive 
committee will review all publications and presentations derived from data garnered in this grant, 
in order to ensure its quality. Assignment of publications and other academic products of this 
project will be decided on by the executive committee, with lead roles equitably rotated among 
the three sites. In the unlikely case that disagreements arise, the issue will be resolved by 
majority decision. If this is not possible, the issue will be referred to the DSMB, which will 
review the matter and determine an equitable and binding decision. At the end of the trial, each 
site will receive a cleaned and checked data set – however, all publications and presentations 
derived from that data in the future will be vetted within the executive committee prior to 
release. 

 
47
Biostatistician David Rosenfield, Ph.D., will oversee management of the study database. 
Monthly reports will monitor subject enrollment, completion, attrition, and individual subject 
progress as well as the completion of critical assessments. Additional reports will be done as 
needed to monitor baseline characteristics, protocol adherence, and other issues of interest. In 
order to ensure confidentiality, data will be identified in the database only by subject number, 
visit number, and date of visit. By recording the study data in this manner, the information can be 
considered ‘de-identified’ and therefore compliant with the Standards for Privacy of Individually 
Identifiable Health Information (“Privacy Rule”) of the Health Insurance Portability Act of 1996 
(HIPAA). Any data that is transmitted electronically will be fully encrypted and password 
protected. Subjects’ names will not be entered into the database; each will be uniquely identified 
only by an ID number. Hardcopy data will be kept and filed in locked office cabinets. 
10.3.3 Metrics 
 
1) Rater Reliability: 
Each month, an independent evaluator (IE) will listen to an assessment performed by another IE 
associated with the study and independently complete the assessment instruments (SIGH-A, 
CGI). In addition, each month, all IE’s will co-rate an audiotape during the monthly conference 
call. Both types of co-ratings (two-by-two and group co-ratings) will be used during supervision 
to identify reasons for disagreement and improve inter-rater reliability. In addition, ratings will 
be sent to MGH site to calculate kappa coefficients. Differences between raters will be discussed 
during supervision to identify reasons for disagreement and improve inter-rater reliability. These 
procedures will help us ensure that IEs refine their diagnostic skills and will also establish 
common guidelines for ongoing use in diagnostic decision-making. Inter-rater agreement will be 
assessed via evaluation of digital recordings of diagnostic interviews. If reliability falls below 
criteria (ICC ≥ 0.8 for CGIs and SIGHA, and 100% agreement on GAD diagnosis), IEs will be 
retrained. Cross site weekly phone supervision will occur with IEs, addressing any rating 
problems.  
2) Treatment protocol non adherence: Fidelity ratings will be performed for all treatments (see 
treatment fidelity section). Twenty percent of the audiotapes will be rated for adherence and 
fidelity to ensure that prescribed and proscribed interventions coincide with the assigned groups. 
During the course of the study, if a therapist does not meet minimum standards - i.e. receives an 
adherence or competence rating below the certification standard for 2 consecutive sessions (≤5 
for adherence, ≤3 for competence) - he/she will receive more training from the supervising 
clinician (Khalsa, Hoge or Hofmann), and the next 2 sessions will be reviewed and must meet 
certification standards. In the unlikely event therapists do not meet these standards they will be 
replaced. 
 
4) Study Early Discontinuation Rates: At any review, a >20% drop-out / early termination rate 
will indicate a PI review of procedures. 
 
3) Data checks: Any data check resulting in greater than 20% of missing data will trigger PI 
level review of data procedures 
 

 
48
10.3.4 Protocol Deviations 
All minor protocol deviations will be recorded in the protocol deviation log and reported yearly 
to the DSMB and IRB at continuing review. The executive committee will review every 6 
months. Any major protocol deviations will be recorded in the protocol deviation log and 
reviewed with the study PI at weekly meetings and in monthly reports to the executive 
committee. 
10.3.5 Monitoring 
Study staff meetings will occur weekly, with PI meetings weekly. Quality control committee 
meetings will occur monthly. DSMB meetings will occur yearly as noted in the DSMP. 
See above. 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY 
11.1 Institutional Review Board (IRB) Review 
This protocol and the informed consent document has been reviewed and approved by the IRBs 
of BU, MGH, and NYU.  
11.2 Informed Consent Forms 
A signed consent form will be obtained from each participant. The consent form will describe the 
purpose of the study, the procedures to be followed, and the risks and benefits of participation. A 
copy will be given to each participant or legal guardian and this fact will be documented in the 
participant’s record. Signed consent forms will be stored in secure files.  
11.3 Participant Confidentiality 
Any data, specimens, forms, reports, video recordings, and other records that leave the site will 
be identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a locked file cabinet. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written permission of the participant, except as necessary for monitoring by IRB, the NCCAM, 
and the OHRP. 
11.4 Study Discontinuation 
The study may be discontinued at any time by the IRB, the NCCAM, the OHRP, or other 
government agencies as part of their duties to ensure that research participants are protected.  
12. COMMITTEES 
The executive committee will meet weekly and will be comprised of the two PIs, Drs. Hofmann 
and Simon, the MGH subcontract PI, Dr. Bui, and the co-investigators, Drs. Khalsa and Hoge, 
and the biostatistician, Dr. Rosenfield. The members of the committee have a long and fruitful 
history of collaboration. Drs. Rosenfield and Hofmann have collaborated on numerous empirical 
studies, and there is a long history of collaboration between Drs. Hofmann and Simon as part of 
a mutual NIMH grant. Furthermore, there is a history of research collaboration between Drs. 
Simon and Hoge, Drs. Simon and Bui, and Drs. Hofmann and Khalsa. Dr. Hofmann will chair 

 
49
the executive committee for this grant and bear primary responsibility for maintaining 
communication between the sites, NIMH, and a Data Safety and Monitoring Board (DSMB), 
which will be comprised of three members overseeing safety issues and overall conduct of the 
study as detailed in the Human Subjects section of the grant proposal. Dr. Simon will oversee the 
training of independent raters, quality assurance procedures, data management and analysis. All 
key investigators as well as research staff working on the study will participate in weekly 
meetings and supervisions, and monthly conferences.  
13. PUBLICATION OF RESEARCH FINDINGS 
The executive committee, chaired by the study PIs (Hoffmann, and Simon) will review all 
publications and presentations derived from data garnered in this grant, in order to ensure its 
quality. Assignment of authorship for publications and other academic products of this project 
will be decided on review of requests for publications with the study data request form by the 
executive committee, with lead roles equitably rotated among the three sites and final approval 
resting with the study PIs. In the unlikely case that disagreements arise that cannot be resolved 
by the study PIs, the issue will be resolved by majority decision. If this is not possible, the issue 
will be referred to the DSMB, which will review the matter and determine an equitable and 
binding decision. At the end of the trial, each site will receive a cleaned and checked data set – 
however, all publications and presentations derived from that data in the future will be vetted 
within the executive committee prior to release. Any presentation, abstract, or manuscript will be 
made available for review by all co-authors prior to submission. 
All NIH rules for public access of manuscripts will be followed. 

 
50
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15. SUPPLEMENTS/APPENDICES