Conditions: Knee Osteoarthritis
Keywords: Knee Osteoarthritis NSAID Cognitive Behavioral Therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 490
Healthy volunteers: no

Brief summary:
Knee osteoarthritis (OA) is now recognized as a major health problem. It is the number one cause of lower extremity disability and has significant deleterious effects on quality of life. While there are numerous therapies available for knee OA, most have limited efficacy. Of particular concern, is the widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs) for this disorder. Veterans, as a group, are at high risk for both gastrointestinal and cardiovascular NSAID-induced complications. In this study the investigators propose to examine whether replacing NSAIDs with cognitive behavioral therapy delivered by telephone is an effective strategy for Veterans with knee OA. Telephone-administered therapy is particularly appealing since Veterans with knee OA are more likely to have limited mobility. If successful, this program may result in significant cost-savings for both Veterans (decreased co-pays and transportation costs) and the VA (decreased hospitalizations due to NSAID induced toxicity).

Detailed description:
Knee osteoarthritis (OA) is a major cause of disability among Veterans and is the primary indication of knee replacement in the VA. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed medications for knee OA. Though short-term studies have demonstrated that NSAIDs are more effective than placebo and acetaminophen, there are no long-term data supporting their use. This is of concern, because long-term use of NSAIDs is associated with significant morbidity and mortality. Guidelines have been published to improve safe use of NSAIDs; however, adherence to these evidence-based recommendations is low in the VA. There is therefore an important need to determine if the long-term use of NSAIDs offers any incremental benefit over safer alternatives. This is especially true for Veterans, a population at high risk for NSAID-induced toxicity.

Cognitive behavioral therapy (CBT) is an effective and safe treatment alternative for OA. This modality is becoming increasingly available in the VA for treatment of chronic pain as well as other chronic disorders such as depression, post-traumatic stress disorder and insomnia. CBT can be successfully administered over the telephone and thus stands to benefit Veterans living in more remote areas with limited access to hospital or community-based outpatient clinics.

In this study, the investigators propose to conduct a 2-phase randomized withdrawal trial (RWT). The trial will focus on recruiting Veterans with knee OA who have been using NSAIDs for at least 3 months.

In the first phase of the study, 544 Veterans with knee OA will be randomized to continue NSAIDs or to placebo for 4 weeks. This double-blind phase will enable us to infer whether placebo is non-inferior to continued NSAID use. In the second phase, subjects in the NSAIDs group will continue NSAIDs and those on placebo will stop taking the placebo and participate in a 10-week CBT program. The second, single-blind, phase will allow us to infer whether CBT is non-inferior to NSAIDs. All study data will be collected over the telephone thus enabling Veterans who have difficulty arranging transportation to the VA to participate.

The investigators will test for between-group differences in knee pain measured using the well-validated Western Ontario and McMaster Universities Osteoarthritis Index (primary outcome) at 4 and 14 weeks. The investigators will also test for between group differences in lower extremity disability, subjects' global impression of change and use of co-therapies (secondary outcomes). As recommended for non-inferiority trials, the investigators will perform both an intent to treat and per protocol analysis. Lastly, the investigators will estimate the potential cost-effectiveness of the CBT protocol compared with continued NSAID use.

Though it would be ideal for subjects randomized to the active study drug to continue their current NSAID, having the VA pharmacy formulate multiple different active drugs and maintaining the blind is not possible. Therefore, the investigators will include a 2-week run-in period where study subjects will replace their NSAID with meloxicam. Meloxicam was chosen as the study drug because it is the most commonly prescribed at the investigators' center and has a favorable safety profile compared to other NSAIDS.

If successful, the trial will improve the quality of care delivered to Veterans with chronic knee pain due to OA. The proposed strategy is particularly appealing because it replaces the widespread use of NSAIDs with a safer alternative, enables delivery of care to Veterans with limited access, and is likely to be cost saving.

Arms:
arm 1: Eligible subjects will be randomized to Meloxicam 15 mg po per day (QD) vs placebo arm 2: Eligible subjects will be randomized to Meloxicam 15 mg po QD vs placebo

Interventions: intervention 1: Meloxicam 15 mg po QD intervention 2: Cognitive Behavioral Therapy
Intervention descriptions: intervention 1: Eligible subjects will be take Meloxicam 15 mg po QD intervention 2: Subjects originally assigned to placebo will receive cognitive behavioral therapy for 10 weeks

Protocol document:
Prot_SAP_000.pdf: 
NCT01799213 
 
Discontinuing NSAIDs in Veterans With Knee 
Osteoarthritis 
 
June 28, 2013 


1 
 
ABBREVIATIONS 
 
 
 
 
 
 
Version 4 6/28/13 
A. RESEARCH PLAN 
A.1 Overview: Knee osteoarthritis (OA) is a major cause of 
disability among Veterans 1. Nonsteroidal anti-inflammatory drugs 
(NSAIDs) are the most commonly prescribed medications for this 
disorder 2 with over 50% of people with OA reporting regular use 3. 
While short-term studies have demonstrated that NSAIDs are more 
effective than placebo and acetaminophen, there are no long-term 
data supporting the use of these medications 2,4. Maximum benefits 
are reported within 1 month and the single published long-term 
study showed no significant difference in knee pain at 1 year 
between NSAIDs and placebo 5. Moreover, the decrease in pain 
conferred by NSAIDs does not meet patient-defined thresholds 
indicating clinically significant improvement (Figure 1) 6. Given these 
data and the substantial morbidity associated with long-term NSAID 
use, discontinuation trials to determine whether there is a clinically 
significant incremental benefit of NSAIDs over and above placebo 
are warranted.  
The objectives of this proposal are to determine whether 1) placebo 
is as effective as continued NSAIDs, and 2) cognitive behavioral 
therapy (CBT) is a viable alternative to continued NSAID use. While 
acetaminophen is also a viable alternative, the vast majority of patients with knee OA have failed this 
medication before initiating NSAIDs. The same argument applies to topical agents. CBT is safe and 
appropriate for patients with varying levels of pain. We chose CBT over a self-management program given the 
ability of CBT to address comorbidities that are commonly associated with OA and frequent among Veterans 
(e.g. depression and insomnia 7,8) and the Pain Research Informatics Medical Comorbidity and Education 
(PRIME) Center’s extensive experience and expertise in delivering CBT. 
To address our objectives, we propose a 2-phase randomized withdrawal trial (RWT) (see Figure 2, section D): 
Phase 1: Veterans with knee OA will be randomized to continue NSAIDs or to placebo for 4 weeks. This 
double-blind phase will enable us to infer whether placebo is non-inferior to continued NSAID use.  
Phase 2: At week 4, subjects in the NSAIDs group will continue NSAIDs. Those on placebo will stop taking the 
placebo and participate in a 10-week CBT program. The second phase will allow us to infer whether CBT is 
non-inferior to NSAIDs. This adjunctive, non-pharmacologic treatment was chosen because it 1) has already 
been found to be effective in OA 9-11, 2) can be safely administered to all potential subjects, and 3) can be 
tailored to benefit patients based on their individual needs. Placebo will not be continued during Phase 2 since 
it may potentiate the effects of CBT. 
The proposal is designed to focus on Veterans who have adapted to their current heath state and is not 
suitable for subjects with levels of pain warranting escalation of analgesics (Please see Exclusion criteria in 
D.2). We acknowledge that patients and physicians may be reluctant to stop a medication which they perceive 
as being effective. In order to maximize enrollment, we will recruit subjects for whom a trial of NSAID 
AEs: Adverse Events 
ITT: Intent-to-Treat 
PRIME: Pain Research Informatics 
AUC: Area Under the Curve 
LME: Linear Mixed Effects  
Medical Comorbidity and Education 
ASA: Aspirin 
MCID: Minimally Clinically 
QALY: Quality Adjusted Life Year 
CBT: Cognitive Behavioral Therapy 
Difference 
RCT: Randomized Controlled Trial 
COX-2: Cyclooxygenase-2  
NSAIDs: Nonsteroidal Anti- 
RDW: Regional Data Warehouse 
EMR: Electronic Medical Record 
Inflammatory Drugs 
RWT: Randomized Withdrawal Trial 
EBP: Evidence-Base Psychotherapy 
OA: Osteoarthritis 
Rx: Prescription 
HUI3: Health Utility Index Mark 3 
OTC: Over-the-Counter 
WOMAC: Western Ontario and McMaster  
ICER: Incremental Cost 
PP: Per Protocol 
Universities Osteoarthritis Index 
Effectiveness Ratio 
PPI: Proton Pump Inhibitor 
VACHS: VA Connecticut Healthcare System 
Figure 1. Effect of NSAIDs over Placebo 


2 
 
discontinuation is most important: 1) subjects who continue to have symptoms despite regular uses of NSAIDs 
and 2) subjects at increased risk for NSAID-related toxicity (detailed in D.2).  
To the best of our knowledge this will be the first trial to examine the effects of withdrawing NSAIDs. The study 
design is innovative in that it will definitively answer whether physicians should attempt to withdraw NSAIDs in 
patients who are comparable to those meeting the eligibility criteria described in this proposal. If positive, the 
data generated from the study may empower both physicians and patients to try safer treatment alternatives 
for knee OA. This project will address the VA’s commitment to improve care for Veterans with chronic pain as 
well as those with limited access to VA onsite services. The trial will be supported by the VA Connecticut 
Healthcare System (VACHS) PRIME Center. The proposed team of investigators includes experienced health 
services researchers, with expertise in OA, pain, CBT, and cost-effectiveness studies (see section C).  
B. BACKGROUND 
B.1 Impact of Knee OA: Knee OA is the most common cause of knee pain and lower extremity disability in 
older adults 12. Veterans have an even higher prevalence of OA compared to non-Veterans 1 and over half 
report being limited in their daily activities because of joint symptoms 13. Persons with knee OA have 
significantly lower quality of life scores in all domains compared to age-matched controls 14. This disease 
affects approximately 27 million Americans and the current annual healthcare cost estimates for knee OA 
range between 68 and 95 billion dollars. Annual costs due to absenteeism are approximately 10.3 billion US 
dollars 15. The impact and costs related to knee OA are expected to rise exponentially as the number of older 
adults in the population increases. The impact of OA in Veterans is not limited to older adults. Rates are 26% 
higher in service members age 20 to 24 than in the general population and troops over the age of 40 are more 
than twice as likely to develop OA as civilians 16. Injuries are likely to play a role in the pathogenesis of OA in 
younger Veterans returning from Iraq and Afghanistan. Research studies focused on developing safe 
approaches to managing pain in this younger population are particularly important given the chronicity of the 
disease. 
B.2 Management of Knee OA: OA is characterized by progressive joint degeneration. At present, there is no 
cure for the disease nor has any intervention been shown to alter its progression. Medical treatment of OA 
(which includes both pharmacologic and non-pharmacologic options) is aimed at management of symptoms 
(pain, swelling and stiffness) and maintenance or improvement of lower extremity function. In general, the 
effect sizes related to these options are modest 2. In contrast, total knee arthroplasty is a highly effective 
treatment option for patients with knee OA 17. Yet, not all patients want, or are eligible for surgery. 
B.3 Efficacy and Toxicity of NSAIDs: Short-term trials have demonstrated that NSAIDs are more effective at 
decreasing knee pain in OA compared to both placebo and acetaminophen 18. However, the effect sizes are 
small and there are no data to support the use of NSAIDs beyond 3 months 19. A meta-analysis focusing on the 
efficacy of NSAIDs for knee OA found that subjects improved by 15.6% (as measured by changes in pain 
severity using a visual analogue scale) after 2 to 13 weeks. The corresponding effect size, in a random effects 
model, was 0.3 (0.2-0.4) 4. Maximum NSAID related benefits occur within 1 month and there is no proven 
difference in knee OA pain at 1 year between NSAIDs and placebo 5.  
Despite the limited data supporting their use, NSAIDs are the most commonly prescribed medications for OA. 
More than 100 million prescriptions are written for NSAIDs in the US each year. This dramatic figure does not 
account for the number of OTC NSAIDs used. The widespread use of NSAIDs for OA warrants careful scrutiny 
because of the known significant toxicity associated with this class of medications. NSAIDs increase the risk of 
gastrointestinal ulcer disease and hemorrhage, acute renal failure, serious cardiovascular events (including 
stroke and myocardial infarction) and worsening of preexisting heart failure 20,21. Complications related to long-
term NSAID use result in approximately 103,000 hospitalizations and 16,500 deaths annually. The number 
needed to harm in Veterans for an NSAID-related death is 105 for a gastrointestinal hemorrhage, 11 for a 
myocardial infarction, and 20 for a stroke 22. That is, only 20 NSAID-users would have to suffer a NSAID-
related stroke to result in 1 additional death within 30 days. Forty-three percent of Veterans are considered to 
be at high risk of NSAID-related complications, and yet adherence to evidence-based guidelines for safer 
prescription of NSAIDs is low (27%) in the VA 23.  


3 
 
B.4 CBT and Pain: CBT is the most commonly cited psychological alternative to more traditional medical and 
rehabilitation approaches to chronic pain management, and has demonstrated efficacy for reducing pain and 
improving function in persons with a broad spectrum of conditions 24. CBT is informed by a theory of chronic 
pain that hypothesizes that patients' idiosyncratic beliefs, attitudes and coping resources play a central role in 
determining their experiences of pain 25. The overarching goal of CBT is to assist the patient in the 
development of an adaptive problem-solving, self-directed approach to pain management based on a 
conceptualization of pain as controllable and a personal attitude of self-efficacy and self-control. CBT is a 
structured and goal-oriented therapeutic approach that can be delivered in either small group or individual 
sessions. During therapy, a range of cognitive pain coping skills (e.g., challenging unhealthy thoughts, 
development of positive coping self-statements) and behavioral strategies (e.g., activity pacing, mental 
relaxation and other stress reduction) are taught. Progress toward overall treatment goals and pain coping skill 
practice are encouraged through the development of intersession homework assignments. Naylor et al 26 
recently published the results of a trial designed to examine the effects of CBT on NSAID and opioid usage. In 
this trial, after 11 weeks of group CBT, 51 subjects with chronic musculoskeletal pain were randomized to a 
therapeutic interactive voice response program and 25 subjects were randomized to receive usual care. 
Between-groups analysis demonstrated significant reductions in opioid use at 8 months among subjects 
randomized to the experimental arm. NSAID use was lower after 4, but not after 8 months of follow-up. 
B.5 CBT and Knee OA: Experimental studies have demonstrated that CBT is an effective treatment for 
patients with OA. Keefe et al 9 conducted a 3-arm, 10-week RCT in which patients with knee OA were 
randomized to CBT, arthritis education, or usual care. The CBT program included weekly group sessions 
which trained participants to recognize and reduce irrational cognitions and to adopt attention diversion and 
activity modification. The education intervention included weekly sessions in which participants were provided 
with detailed information about knee OA. The trial demonstrated that patients receiving pain coping skills 
training had significantly lower levels of pain and psychological disability post treatment than patients receiving 
arthritis education or standard care after adjusting for age, gender, obesity and pretreatment scores. 
Participants in the pain coping skills training group who reported increases in the perceived effectiveness of 
their coping strategies were more likely to have lower levels of physical disability post-treatment. After 6 
months, participants randomized to CBT continued to have lower levels of psychological and physical disability 
than those who had received education and usual care.  
Calfas et al 27 conducted a trial to compare CBT and education in OA. CBT was delivered in 10 weekly group 
sessions and education included 10 weekly didactic lectures given by health professionals. After one year, 
subjects in both groups demonstrated significant improvements in depressive symptoms, quality of well-being 
and pain; however, there were no between-group differences. In a recent trial examining the closely associated 
variables of sleep disturbance and pain, CBT improved sleep and decreased pain in subjects with OA, 
whereas subjects randomized to an attention control reported no improvements in either condition 7. In 
addition, a meta-analysis found that CBT has significant beneficial effects on pain, anxiety, depression and 
coping skills in patients with arthritis 28. This review concluded that there was strong evidence to support an 
incremental benefit of CBT over and above standard medical care. 
There are also some indirect data to suggest that the proposed strategy may be cost effective for the VA. 
Cronan et al 29 found that OA patients receiving interventions emphasizing self-management incurred 
significantly fewer costs than those randomized to routine care after 3 years of follow-up. Similarly, Mazzuca et 
al 30 found that a self-care program reduced cost in knee OA by decreasing the number of primary care visits in 
the year following completion of the intervention. The proposed trial may result in decreased utilization of 
services related to treatment for OA; however, we expect that cost savings will result primarily from decreased 
NSAID-related hospitalization rates. 
B.6 Appeal of Telephone-Based Strategies: Telephone-based interventions have the potential to greatly 
expand delivery of care at an affordable cost to Veterans with limited access to outpatient clinics (due to 
geographic, financial, or health-related barriers). This is especially true for older adults with OA living in regions 
with poor public transportation. Telephone-based behavioral interventions can frequently be delivered at lower 
cost than face-to-face interventions, and are less impeded by the time and space constraints inherent to many 
subspecialty clinics within the VA.  


4 
 
B.6.a Telephone-Based Programs for OA: Previous controlled studies have demonstrated that telephone-
based programs can improve functional status in patients with OA. Rene et al 31 found that a telephone-
administered educational intervention improved patients’ functional status. In a separate study, Maisiuk et al 32 
demonstrated that treatment counseling provided over the telephone every 2 weeks for 5 weeks and then 
monthly for 6 months resulted in greater improvement in arthritis-related health status and fewer medical visits 
compared to usual care. The recently published Self-Management of Osteoarthritis in Veterans Study 
demonstrated that a telephone-based self-management intervention significantly reduced pain in a non-
treatment seeking sample of Veterans with OA 33. The treatment was delivered monthly, over 12 months using 
short telephone contacts averaging 9 minutes per call supplemented with audio and written materials. Given 
the success of this treatment, we have retained many of its elements in the proposed study. Specifically, the 
treatment in the proposed study emphasizes the use of pain management skills such as relaxation, reframing 
of pain-related cognitions, sleep hygiene, regular exercise, goal setting and skill practice to encourage skill use 
and mastery. We have, however, opted for more frequent and longer (~30-45 minute) sessions in order to 
effectively deliver a comprehensive CBT program.  
B.6.b Telephone-Administered CBT: Several experimental studies have demonstrated that CBT can be 
successfully administered over the telephone. Lovell et al 34 found that telephone-administered CBT was just 
as effective as face-to-face CBT in treating subjects with obsessive compulsive disorder. Taylor et al 35 also 
demonstrated the efficacy of telephone-administered CBT in subjects with this disorder. Mohr et al 36 found that 
telephone-administered CBT was more effective than telephone-delivered supportive emotion-focused therapy 
in treating depression amongst patients with multiple sclerosis. DuHamel et al 37 demonstrated that telephone-
administered CBT was effective at treating posttraumatic stress disorder in cancer survivors.  
B.7 Randomized Withdrawal Trials: While the traditional RCT is the most commonly used design to assess 
treatment efficacy, the large number of Veterans with knee OA already using NSAIDs, the expected number of 
drop-outs in a long-term pain study, the safety concerns related to initiating long-term use of NSAIDs in an 
experimental setting, and the expected increased use of co-therapies with time, warrant consideration of an 
alternative approach. Amery and Dony first proposed the RWT design as a method to examine the long-term 
efficacy of non-curative treatment options in 1975 38. In contrast to the classic RCT, the RWT randomizes 
subjects currently using the intervention to continued use or to placebo. This approach is particularly useful for 
examining the efficacy of symptomatic (i.e. non-curative) treatments when prolonged use of placebo and 
expected number of drop-outs is likely to threaten the internal validity of the trial. The RWT is also a practical 
method of obtaining evidence to support or refute the continued use of medications which are already widely 
prescribed despite the lack of definitive evidence justifying their use. 
A systematic review of RWTs evaluating analgesics 39 and a second paper utilizing computer simulation 
models 40 concluded that the RWT is an efficient design requiring sample sizes of 20% to 50% of those in 
classic RCTs. The required sample sizes are smaller because of the greater homogeneity in the study 
population. Carryover and withdrawal syndromes, important limitations of this approach, are not relevant for 
the proposed study, as NSAIDs have relatively short half-lives and unlike opioids do not cause withdrawal 
symptoms (apart from recurrent pain) upon discontinuation.  
A Medline search on October 27, 2011 of the following Medline terms (text words: discontinuation trial or 
withdrawal trial and MESH terms: analgesics or pain or arthritis or NSAIDs) revealed 7 published RWTs 41-47. 
Six used an enriched enrollment randomized design, in which patients who respond to the study drug during 
the initial phase were subsequently randomly assigned to continue the study drug or to placebo. All were 
designed as superiority trials and demonstrated significant differences between the active drug and the 
placebo. The eighth study is the most relevant to the RWT described in this application. In this study, Cibere et 
al 42 randomized 137 subjects currently using glucosamine (a widely available neutraceutical used for arthritis) 
to continued use of glucosamine versus placebo. The authors chose to use a RWT design because of the 
prevalent use of glucosamine and the assumed, albeit unproven, long-term effectiveness of the compound. 
After 6 months, the active neutraceutical was not found to be more effective than placebo. However, because 
the study was designed as a superiority trial, it cannot conclude that there is no difference between placebo 
and glucosamine. For this reason the proposed trial is designed as a non-inferiority trial. 
B.8 Non-Inferiority Trials: Because the clinical question of interest is to determine whether placebo + CBT is 
no worse than continued NSAID use, a superiority trial is not well-suited to this proposal. A superiority trial 


5 
 
would not allow us to determine whether Veterans who discontinue NSAIDs do not experience more pain 
compared to those who continue NSAIDs ─ even if well powered and negative 48. While superiority trials, which 
fail to reject the null hypothesis, are frequently interpreted as negative (i.e., no difference between the 2 
groups), they should be interpreted as indeterminate (uncertain) 48. A non-inferiority trial is appropriate in this 
context because the new strategy under investigation is safer than the current widespread long-term use of 
NSAIDs for knee OA 49. We acknowledge, however, that there are important issues to be considered in 
designing a non-inferiority trial, including:  
1. Assay sensitivity: We will take several precautions to reduce the factors that can limit assay sensitivity (i.e., 
the ability of a trial to demonstrate a real difference between the 2 arms if one truly exists). We will include 
a run-in period to ensure that subjects respond to and are able to tolerate the study drug. We will include 
measures to enhance CBT treatment fidelity (see D.16). We will measure the primary outcome and 
adherence weekly, employ a well-validated primary outcome measure, and use both an intent-to-treat (ITT) 
and a “completers” or per protocol analysis (PP) as justified below. These design features are 
recommended to minimize biases towards the null 49. 
2. Choice of the non-inferiority margin: The margin of non-inferiority will be pre-stated and informed by both 
clinical judgment and the expected differences between study arms 49. 
3. Analyses: Because the ITT approach analyzes all subjects according to their initial group assignment, 
including those who do not complete the protocol, it tends to bias toward making the results look similar 
across groups. Consequently, we will perform both ITT and PP analyses. Experts recommend that 
objectives in non-inferiority trials be met by both approaches 49.  
B.9 Study Drug: Though it would be ideal for subjects randomized to the active study drug to continue their 
current NSAID, having the VA pharmacy formulate multiple different active drugs and maintaining the blind 
would be unwieldy and cost prohibitive. Given that studies have failed to demonstrate any significant 
differences amongst NSAIDs in treating subjects with OA 18 the use of a single active drug in this protocol is 
justified. However, we acknowledge, that individual patients may respond differently to specific NSAIDs. To 
ensure that lack of a response or intolerance to meloxicam does not bias our results towards the null, we will 
include a 2-week run-in period where study subjects will replace their NSAID with the study drug (see D. 6). 
The duration of the run-in period was chosen based on data demonstrating that patients with OA respond to 
meloxicam by 2 weeks 50. 
The decision to use meloxicam as the study drug was based on local practices and safety concerns 50,51. At the 
VACHS, the most commonly prescribed NSAID is meloxicam 15mg orally once daily. Of the 8,514 orders for 
NSAIDs written between October 2009 and October 2010, 1,975 were for meloxicam 15mg (only 6 were for 
meloxicam 7.5mg) and most of the remaining prescriptions were for varying doses of naproxen and ibuprofen. 
Reliable data on the most commonly used OTC NSAIDs are not available. RCT data demonstrate that the 
efficacy of meloxicam is comparable to other NSAIDs in subjects with knee OA 52. A trial conducted by Yocum 
et al 50 found that meloxicam was as effective, but better tolerated than diclofenac, in subjects whose previous 
NSAID was withdrawn. The latter study provides particular support for the use of this agent in our trial. In terms 
of safety, meloxicam inhibits Cox-2 more than Cox-1 and has been shown to have improved gastrointestinal 
tolerability compared to other NSAIDs. In a systematic review of clinical trials, serious gastrointestinal events 
(defined as perforation, ulceration or bleeding) was 0.2% in subjects receiving meloxicam, 1.2% in subjects 
receiving piroxicam, 0.6% in subjects receiving diclofenac, and 2.1% in subjects receiving naproxen 52. 
B.10 Importance of this Project to Veterans: Knee OA is now recognized as a major health problem. It is the 
number one cause of lower extremity disability and has significant deleterious effects on quality of life 1. While 
there are numerous therapies available for knee OA, most have limited efficacy 2. Of particular concern is the 
widespread use of NSAIDs and their associated increased rates of morbidity and mortality. Veterans, as a 
group, are at particularly high risk for both gastrointestinal and cardiovascular NSAID-induced complications. 
The proposed study is especially appealing because: 1) it may decrease drug-related morbidity and mortality; 
2) we now recognize that access to VA health services is a significant barrier for at least one third of the 3 
million Veterans living in rural areas; 3) Veterans with knee OA are often among those likely to have difficulty 
with transportation because they are older and suffer from pain and subsequent limited mobility; 4) telephone-


6 
 
administered programs have been shown to benefit patients with knee OA; 5) if successful, implementation of 
this strategy will be greatly facilitated by the vast telehealth expertise already in place within the VA; and 6) this 
program may result in significant cost savings for both Veterans (decreased co-pays and transportation costs) 
and the VA (decreased hospitalizations due to NSAID-induced toxicity). This work will also provide the VA with 
data enabling prioritized, value-based health care, where treatment strategies offering greater clinical benefit at 
equal or reduced cost could be supported or expanded, while lower value strategies could be restricted or have 
increased cost-sharing, resulting in amplification of health benefits without increased health expenditures 53. 
C. INVESTIGATORS’ QUALIFICATIONS 
PRIME Center investigators have an established reputation for the development of models for psychological 
interventions for chronic pain, for the development of measures of pain outcomes and process, for the conduct 
of high quality RCTs of psychological interventions, and for the evaluation of published research in this area. 
Recently completed is a Clinical Science R&D Merit project of the efficacy of tailored CBT for chronic back pain 
that supports the efficacy of a pain coping skill training approach for Veterans with chronic musculoskeletal 
pain. Expanded, proactive methods for recruitment similar to those proposed in the current trial have recently 
been approved by our local IRB. 
Liana Fraenkel, MD, MPH is Associate Professor of Medicine at Yale University, Chief of Rheumatology at the 
VACHS, Co-Director of the VA Connecticut Bone and Joint Clinic, and a research scientist at the VACHS 
Clinical Epidemiologic Research Center (CERC, John Concato PI), and a Core Investigator of the VACHS 
PRIME Center (Robert Kerns PI). She has secured career development and project support over the past 12 
years from the VA Health Services and Research Department. Dr. Fraenkel has received funding as PI for 3 
Merit Review projects. She has previously conducted clinical studies in OA, including a pilot RCT of a decision 
support tool for knee OA treatment within the VA, and is currently supervising a rheumatology research fellow 
conducting an RCT to determine if ultrasound-guided intraarticular corticosteroid injections are more effective 
than sham ultrasound injection. 
Alicia Heapy, PhD is a doctoral level psychologist (8/8ths at VACHS) who has served as a co-investigator on 
a number of funded projects investigating the efficacy of psychological intervention for the management of 
chronic pain. She is the Associate Director and a Core investigator of the PRIME Center and an Associate 
Research Scientist at the Yale University School of Medicine. She has extensive expertise in CBT and 
particular experience in adapting manualized psychological treatments to address chronic pain complaints in 
patients with co-morbid chronic conditions. Dr. Heapy has also used telephone and interactive voice response 
technology to increase the availability of empirically-validated psychological treatments for Veterans with 
chronic pain who are geographically, medically, or financially limited in their ability to travel to the VA for 
treatment. She is currently the PI for an HSR&D funded IIR RCT of a CBT intervention for Veterans with 
chronic low back pain. 
Cynthia Brandt, MD is Director of the Informatics Core for the VACHS PRIME Center (8/8ths at VACHS). She 
is a staff physician at VACHS, Associate Professor at Yale University School of Medicine, Director of the Yale 
Center for Medical Informatics and Director of the Medical Informatics Core of the PRIME Center. Dr. Brandt 
has been extensively involved with clinical research database development and research, with a particular 
research focus on metadata management. She is PI for several VA grants, including West Haven's 
postdoctoral training program in Medical Informatics and the HSR&D funded Women Veteran’s Cohort Study, 
and site PI at West Haven for the Consortium for Informatics Health Research grant. She performs research on 
issues such as the management of clinical vocabularies used in clinical research databases and the creation 
and use of study-specific and disease-specific databases that store focused and carefully defined sets of data. 
As a result, Dr. Brandt has extensive experience working with electronic medical record (EMR) systems 
including the VA EMR data.  
Joseph Goulet, PhD, MS is Director of the Biostatistics and Methodology Core for the PRIME Center and 
Associate Research Scientist in the Department of Psychiatry at the Yale University School of Medicine (8/8ths 
at VACHS). He is highly experienced in collaborating with biomedical researchers in the design, analysis and 
interpretation of VA data. His research interests are in the development and application of statistical methods 
for the analysis of observational data; clustering algorithms; and longitudinal analysis. He has published on 


7 
 
genetic epidemiology, psychiatry, HIV, and pain management in terminal care and is the lead statistician on 
other PRIME Center behavioral RCTs. 
Robert Kerns, PhD is VHA National Program Director for Pain Management, Director of the VACHS PRIME 
Center, and Professor of Psychiatry, Neurology and Psychology at Yale University (8/8ths at VACHS). He is 
widely recognized as a leading expert in the field of pain and pain management within the broader context of 
clinical health psychology and behavioral medicine. In his role as National Program Director for Pain 
Management, he has broad responsibilities for policy development, implementation, and oversight for the VHA 
National Pain Management Strategy. Of particular relevance to the proposed project, he has published on the 
processes of engaging persons with arthritis in self-management approaches to pain and disability.  
Francis Keefe, PhD is Professor in the Department of Psychiatry and Behavioral Sciences and a member of 
the Cancer Prevention, Detection, and Control Program of the Duke Comprehensive Cancer Center. Dr. Keefe 
directs an active clinical research program concerned with the behavioral assessment and treatment of 
patients having acute and persistent pain and played a key role in the development of clinical pain services 
and pain research programs at Duke Medical Center. For 20 years, he directed the Pain Management Program 
and was a leader in the development of Duke Medical Center's multidisciplinary pain programs (both out-
patient and in-patient). Dr. Keefe has developed and refined a number of treatment protocols for persistent 
pain conditions (e.g. cancer, arthritis) including spouse- and partner-assisted pain coping skills training 
interventions. He served as the Clinical Psychology Field Editor for the journal PAIN from 1999 to 2010. 
Lisa Gale Suter, MD is an attending rheumatologist at the VACHS and VA Connecticut Bone and Joint Clinic, 
and a research scientist at the VACHS CERC and PRIME Center. She is also an Assistant Professor in the 
Department of Internal Medicine at the Yale University School of Medicine. She has secured continuous 
independent funding from both NIH and the Arthritis Foundation to develop and perform cost-effectiveness 
research in rheumatology since 2006. She has published several articles on cost-effectiveness in 
musculosketelal medicine using a variety of decision analytic methods. Her work on the cost-effectiveness of 
adding magnetic resonance imaging to early RA management has been recently published in Archives of 
Internal Medicine 54. Dr. Suter is also a collaborator on the Osteoarthritis Policy Model, a NIH-funded state-
transition simulation model of the natural history and management of knee OA (Elena Losina PI, Brigham and 
Women’s Hospital, Boston, MA). Dr. Suter's novel work identifying optimal candidates for arthroscopic partial 
meniscectomy was selected as one of the 2009 Top 10 Arthritis Advances by the Arthritis Foundation. 
Doug Leslie, PhD is Professor in the Departments of Public Health Sciences and Psychiatry at the Penn State 
College of Medicine. He is an economist whose research focuses on the field of health economics and health 
services research. His areas of study have included the effects of managed care on service use and costs, 
factors affecting access to and the quality of health care, adherence to treatment guidelines, and the 
pharmacoeconomics of prescription medications. Dr. Leslie has extensive experience using VA administrative 
databases to track patterns of health care service use and costs. He has over 60 peer-reviewed publications 
and is the PI of 2 Federally-funded grants to use large administrative claims databases to examine patterns of 
service use and costs over time and across states. Dr. Leslie has established working relationships with 
PRIME Center investigators and has been working with Drs. Brandt and Goulet on the Women Veterans 
Cohort Study (HSR&D funded IIR) since November 2007.    
Sam Poon, MD is a Staff Rheumatologist at the Roger Williams Medical Center and the VA Providence 
Medical Center. He will meet with subjects to describe the study and will obtain written consent at this 
neighboring site. 
Robert Swift, MD, Ph.D. is the Associate Chief of Staff for Research at the VA Providence Medical Center.  He 
is a psychiatrist and pharmacologist with more than 20 years of experience conducting controlled clinical trials.  
He has been a site PI or overall PI for clinical trials with naltrexone, antidepressants and second generation 
antipsychotics in outpatient clinical research settings.  He has also been a site PI for the NIAAA COMBINE 
Alcoholism Treatment Trial and other NIH and industry sponsored multi-site clinical trials.  Moreover, he has 
had experience with multi-site VA studies managed by the VA Central IRB. 
 


8 
 
D. METHODS 
Overview: Participants will participate in a 2-week run-in period where all subjects will replace their current 
NSAID with the study drug (meloxicam 15mg per day). Those who remain eligible at the end of the run-in 
period, will participate in a 4-week, double-blind, placebo-controlled, non-inferiority RWT. After 4 weeks, 
subjects in the meloxicam arm will continue on the study drug. Subjects in the placebo arm will stop the 
placebo and participate in a 10-week CBT program (Figure 2).  
 
 
 
 
 
 
 
 
   0  
 
 
 
 
 
 
 
 
 
 
 
14-weeks  
 
 
 
Aim 1: To determine whether placebo is non-inferior to continued NSAID use: 680 subjects will be 
enrolled into a 2-week run-in period where they will stop their current NSAID and start taking the study drug 
(meloxicam 15mg per day). Those who remain eligible after the run-in period will be randomized to continued 
meloxicam use versus placebo for 4 weeks. 
Aim 2: To determine whether CBT is non-inferior to continued NSAID use: After 4 weeks, subjects in the 
meloxicam arm will continue on the study drug. Those in the placebo arm will stop the placebo and participate 
in a 10-week CBT program. 
D.1 Subjects: Participants will be drawn from Veterans with knee OA currently enrolled in the VACHS and the 
Providence VA Medical Center. Both centers serve Veterans with similar demographics; approximately 85% 
Veterans are White, 14% are Black, 0.3% are Pacific Islanders, 0.2% are Native American, and 0.1% are 
Asian. Twelve percent describe themselves as being Hispanic. As of 2012, West Haven had 1987 women 
enrolled: 38% between the ages of 18 and 44, 37% between the ages of 45-64, and 25% over the age of 65. 
The corresponding numbers of women at the Providence VA are: Total = 1098: 31% between the ages of 18 
and 44, 39% between the ages of 45-64, and 29% over the age of 65. We will oversample women during the 
recruitment phase by ensuring that up to 50% of the opt-out letters sent are to women. The same approach will 
be used to improve representation of minorities. 
D.2 Eligibility 
Subjects will include those for whom a discontinuation trial of NSAIDs is most appropriate: 1) Veterans with 
knee pain despite NSAID use and/or 2) Veterans at relatively higher risk of NSAID toxicity 55-59 as ascertained 
by meeting 1 or more of the following 4 criteria: 
• 
Answer affirmatively to the question: “Do you have some knee pain on most days over the past 3 months?” 
• 
Have 1 or more risk factors for NSAID-induced nephrotoxicity (age greater than 60 years, atherosclerotic 
cardiovascular disease, current diuretic use, chronic renal insufficiency, congestive heart failure (New York 
Heart Association class I–II. Note, Class III and IV are excluded). 
• 
Have 1 or more risk factors for NSAID-induced gastrointestinal toxicity (history of peptic ulcer disease, age 
> 65 years, concurrent use of daily ASA or corticosteroids), and are currently on a gastro-protective agent. 
• 
Have 1 or more risk factors for NSAID-induced cardiovascular toxicity (prevalent cardiovascular disease, 
hypertension, hypercholesterolemia, diabetes, smoking, family history of early heart disease or age greater 
than 55 years for women). 
In addition, subjects must: 
Phase 1 
4-week RWT 
Phase 2 
10-week trial 
2-week 
Run In  
Placebo  
Meloxicam  
Stop Placebo + Start CBT  
Continue Meloxicam 
Randomize 
Figure 2. Study Design 


9 
 
• 
Be age 20 years or older. While the usual cut off for knee OA is approximately 40 years, we chose to lower 
 
the age cutoff as younger Veterans have a higher than expected risk of OA (see B.1). 
• 
Have radiographic evidence of knee OA reported in the VistA electronic system. 
• 
Be using an NSAID (other than daily ASA) for knee pain on most days of the month for at least the past 3 
months. 
• 
Be able to understand and speak English and have a telephone. 
• 
Be willing to engage in a CBT program, to discontinue (or replace) their NSAID, and to restrict co-therapies 
to acetaminophen for 14 weeks. 
Exclusion criteria are: 
• 
Subjects desiring escalation of analgesics for their current level of knee pain as determined by 
endorsement of the following statement: “Is your knee pain bad enough that you want to talk to your doctor 
about taking stronger pain medications?” 
• 
Current use of opioids and/or Celebrex. 
• 
Current use of an NSAID (not including ASA) for a painful condition in addition to knee OA.  
• 
Contraindications to chronic NSAID use: current use of warfarin or antiplatelet agent other than ASA, 
allergy to any NSAID, active upper gastrointestinal ulceration in the previous 30 days, upper 
gastrointestinal bleeding in the past year, history of gastroduodenal perforation or obstruction, 
cardiovascular event within the past 6 months (myocardial infarction, cerebrovascular event, coronary-
artery bypass graft, invasive coronary revascularisation, or new-onset angina), severe congestive heart 
failure (New York Heart Association class III–IV), evidence of serious anemia, hepatic, renal (including 
nephrotic syndrome), or blood coagulation disorders, and pregnancy. 
***Though we are proposing a RWT – and thus will not be initiating NSAID therapy – it would not be 
appropriate to continue NSAIDs (even when prescribed) in high-risk patients. We acknowledge that these 
exclusion criteria limit generalizability, but we feel they are justified to ensure subjects’ safety.*** 
• 
Previous hyaluronic acid knee injections (within 6 months) or corticosteroid knee injections (within 3 
months). 
• 
Scheduled knee hyaluronic acid or corticosteroid injections, arthroscopy, or knee surgery. 
• 
Co-morbid conditions that include the following: known other causes of arthritis (infectious arthritis, 
rheumatoid arthritis, connective tissue disease, gout, pseudogout, or psoriatic arthritis), peripheral 
neuropathy or cardiopulmonary disease that limits walking more than knee pain, bone metastases or 
Paget’s disease involving the lower extremities, and history of drug or alcohol abuse within the past 2 
years, bilateral knee replacements or knee pain in the replaced knee only. 
• 
Current involvement in litigation or receiving workmen’s compensation. 
• 
Hearing, cognitive impairment or mental illness, as determined by chart review that would preclude 
participation in a CBT program.  
• 
For Women of Childbearing Age:  Must not currently be pregnant, agree to avoid getting pregnant during 
the course of the study and should inform the study team if pregnancy occurs at any time during study 
participation.  
• 
D.3 Screening Procedures: We will request the appropriate HIPAA and informed consent waivers to 
perform the searches described below. We have obtained waivers for similar screening and recruitment 
approaches in previous and ongoing studies. 
D.3.a RDW/CDW Search: We will identify potential Veterans for inclusion from available EMR data in 
RDW/CDW. The VA RDW includes patient clinical data including demographics, encounters, vital signs, health 
factors and radiology reports. We will extend previously applied methods of information retrieval, concept 
indexing, and mapping to identify potentially eligible subjects for the study. All Veterans 20 years or older from 
VA CT and the Providence VA Medical Center with a radiology report performed during 01/01/2007-12/31/2011 
that contains text indicative of knee OA will be identified using simple text searches. We have used a similar 
approach previously for the Lung Cancer Tracking System developed at the VACHS. This approach uses 


10 
 
radiology reports to identify patients with lung nodules using natural language processing techniques for case 
management purposes. We will then identify Veterans in this group to exclude those who are taking 
medications such as Cox-2 inhibitors (other than meloxicam), warfarin, or antiplatelet drugs other than NSAIDs 
and ASA within the past 6 months. We will use ICD9 codes and encounter data to further exclude patients with 
a hospitalization for active upper gastrointestinal ulceration in the previous 30 days, upper gastrointestinal 
bleeding in the past year, gastroduodenal perforation or obstruction at any time, or a cardiovascular event 
within the past 6 months (myocardial infarction, cerebrovascular event, coronary-artery bypass graft, invasive 
coronary revascularisation, new-onset angina or congestive heart failure). 
D.3.b Chart Review: For Veterans who remain potentially eligible, we will perform a focused EMR review to 
check for evidence of serious anemia, hepatic, renal, or blood coagulation disorders; previous hyaluronic acid 
knee injections (within 6 months) or corticosteroid knee injections (within 3 months); co-morbid conditions that 
include the following: known other causes of arthritis (infectious arthritis, rheumatoid arthritis, connective tissue 
disease, gout, pseudogout, or psoriatic arthritis), peripheral neuropathy or cardiopulmonary disease that limits 
walking more than knee pain, bone metastases or Paget’s disease involving the lower extremities; history of 
drug or alcohol abuse within the past 2 years; bilateral knee replacements or knee pain limited to a single 
replaced knee; current involvement in litigation or receiving workmen’s compensation; and mental illness, 
hearing or cognitive impairment that would preclude participation in a CBT program. 
D.3.c Recruitment: We will use several methods of recruitment to maximize enrollment.  
• 
Mailings: Veterans meeting initial eligibility criteria will be sampled in blocks of 25-50 and mailed a letter 
informing them of the purpose of the study. The letter will notify the potential subjects that they will be 
telephoned by the project coordinator and will offer them the opportunity to refuse this contact by calling an 
answering machine and leaving a message. The project coordinator will telephone all patients who do not 
“opt out.” To minimize any intrusion on Veterans’ privacy, the project coordinator will be trained by the PI 
on how and when to contact potential subjects. Specifically, we will only telephone people during the day or 
early evening (7:00-8:00). We will not contact people during dinner (5:30 to 7:00). If someone other than 
the participant answers the telephone, we will not share any personal health information with the person 
who answers. We will attempt to reach each subject up to 3 times. Subjects will be assured that their 
participation is voluntary, confidential and that a decision to not participate in the study will in no way affect 
the care they receive. The PI has used the same procedures in 2 studies with no adverse outcomes or 
protest from contacted patients. 
Telephone Screen: Those veterans who do not opt out will be telephoned to verify the remaining eligibility 
criteria: able to speak English; have a telephone; be using an NSAID, either by Rx or OTC, for knee pain (and 
not for any other painful condition) on most days over the past 3 months; do not desire escalation of 
analgesics; do not have scheduled knee hyaluronic acid injections, corticosteroid injections, arthroscopy, or 
knee surgery; be willing to engage in a CBT program, discontinue or replace their NSAID and restrict co-
therapies to acetaminophen up to 3 g daily; do not have a hearing or cognitive impairment or mental illness 
precluding participation in a CBT program. And for women of childbearing age, will verify they are not 
pregnant, are willing to avoid getting pregnant during study participation, and agree to a pregnancy test at time 
of consent. Ambiguous data retrieved during the VistA or chart screen will be clarified with subjects during the 
telephone screen. 
Physician Referrals: Study Coordinator will inform Primary Care Doctors (PCPs), nurses, and health 
technicians in the outpatient clinics at VA CT and Providence VA Medical Center as well as coordinators of the 
MOVE program and Patient Education about the current study, and ask that they either (1) give out a flier to all 
patients, age 20 or older with knee pain, so they can call Study Coordinator for more study information if 
interested in participation or 2) discuss the study with knee osteoarthritis patients who meet eligibility criteria 
and have their interested patients sign a note that states their willingness to be contacted by telephone about 
the current study and asks for their contact information.  This note will also include the study team’s telephone 
numbers in case patients would like to verify that this is a VA research project. The same recruitment strategy 
will be employed at the Providence VA Medical Center with the exception that study fliers will not be given out 
to patients because it will require them to make an out-of-state phone call.    


11 
 
Study Fliers: Study fliers will be posted in all approved areas around the West Haven VA  In addition, these 
fliers will be left near check-in desks at all primary care and specialty clinics. 
D.4 Informed Consent: At VACHS, the project coordinator will describe the study and set up a clinic 
appointment for subjects who are eligible and interested in participating. The clinic appointment will be made at 
a time convenient for each patient. During the clinic appointment, the study procedures will be described in 
detail and the project coordinator will obtain written consent. The purpose of the study, all study procedures 
(including the run-in period), the process of randomization, the procedures (discontinue NSAID, be randomized 
to study drug versus placebo, possibly participate in a CBT program after 4 weeks, keep a daily medication 
diary, and provide outcome data each week), expected risks, expected benefits, alternative therapies, use of 
research results, special circumstances, and subjects’ rights will be discussed with each subject.  The 
participants will also be asked to sign a separate consent for audio recording of CBT phone sessions so that 
they do not have to return back to the VA at a later date should they be assigned to CBT in phase 2.  Female 
participants of childbearing age  will be given a lab slip to get a blood test at the VA laboratory at the time of 
signing consent form. 
The same procedures will be followed at Providence VA Medical Center, except that Dr. Poon, Dr. Swift and/or 
their research assistant will meet with subjects to describe the study and obtain written consent.  
D.5 Run-In Period: Subjects will be asked to participate in a 2-week run-in period. Despite the exclusion of 
potential subjects, trial run-ins have been shown to enhance a trial’s statistical power by decreasing the 
number of subjects who drop out or do not adhere to the study protocol 64. A run-in period is especially 
important in this trial to ensure that we avoid a bias towards the null resulting from poor response to a new 
NSAID. Because patients are already on NSAIDs, a two-week period is adequate to determine whether they 
will experience a pain flare-up All subjects (including those currently taking meloxicam) will discontinue their 
current NSAID and be instructed to take meloxicam 15mgonce a day with breakfast. Subjects will be aware 
that randomization to either the same active drug or to an identical placebo will occur for those remaining 
eligible after 2 weeks. Meloxicam can be taken with or without food. However, because some subjects will 
have been previously instructed to take their NSAID with food, we will instruct subjects to take the study drug 
with breakfast.  
Subjects will remain eligible if after the 2-week run-in period they report having taken meloxicam on 10 or more 
days, deny developing any AEs to the study drug, deny using arthritis medications for knee pain apart from 
acetaminophen up to 3 g daily, and do not report worsening of knee pain on a 5-point global impression of 
change scale (see D.11.b). 
D.6 Intervention 
D.6.a Capsules: Active meloxicam and placebo capsules (both blue gel) will be supplied by the VACHS 
Research Pharmacy. The active capsules will include 15mg of meloxicam and the placebo capsules will 
include excipients only. The active capsules will be indistinguishable from the placebo capsules. Subjects will 
be instructed to take the capsules once a day. Subjects can opt to either pick up their medications from the 
VACHS Research Pharmacy or receive them by mail.  They will be asked to either mail back unused study 
medications in a pre-paid, addressed envelope, or return them directly to the Research Pharmacy. Pharmacy 
will document the study drug lots returned on a dispensing log and will subsequently dispose the remaining 
drugs accordance with hospital policy. 
Subjects randomized to the placebo arm will discontinue study medication (meloxicam) after 4 weeks, while 
those on the continued NSAID arm will continue meloxicam through Phase 2. Phase 2 meloxicam subjects will 
follow the same instructions above, with the exception that they will be given the standard meloxicam tablets  
administered at the VA. 
D.6.b CBT: The CBT protocol includes 10 treatment modules delivered over 10 consecutive weeks (outlined in 
Table 1). We will allow the time frame to be extended by 2 weeks to account for missed sessions. The course 
of therapy will consist of an introductory module, followed by 8 pain coping skills modules, and conclude with a 
module emphasizing skill consolidation and relapse prevention. The 8 pain coping skills are: 1) deep breathing 
and visual imagery, 2) progressive muscle relaxation, 3) physical activity and body mechanics, 4) identifying 
unhealthy thoughts, 5) cognitive reframing, 6) managing stress, 7) time-based pacing, and 8) sleep hygiene. 


12 
 
We chose to include a module on sleep because knee OA is associated with insomnia and insufficient sleep, 
sleep problems are extremely common among Veterans, and CBT protocols aimed at improving insomnia 
decrease pain in patients with OA. Subjects who deny having any sleep problems will be able to choose to 
spend additional time on one or more of the other skills. These coping skills were selected from a larger 
collection of possible skills because they were judged by participants in a previous study conducted by Dr. 
Kerns (Efficacy of Tailored Cognitive-Behavior Therapy for Chronic Back Pain) to be the most important, the 
most appealing, and the skills they were most confident they could engage in. The CBT protocol incorporates 
the materials used by Drs. Kern, Otis and Keefe, who are the leading authorities in this field, and modifies them 
to suit our phone-based program for OA.  Given the variable pain levels expected at study entry, pain 
management will not be the sole focus of treatment. In order to promote engagement, we will adopt a 
treatment approach that emphasizes general wellness benefits of the skills that are taught. All of the skills can 
promote general well-being, improved mood, and stress reduction. Additionally, skills such as exercise and 
proper body mechanics, confer joint protective benefits such as increased muscle strength and flexibility, and 
can aid in weight management. These activities may also help slow progression of OA. When each skill is 
presented, participants will be told how the skill can be used during a pain flare and how it can be used to 
promote maximal physical and/or emotional functioning even in the absence of pain. For example, cognitive 
reframing techniques are effective in reducing pain catastrophizing that can impede the use of other pain 
coping skills and diminish mood.  
 
Table 1. Description of CBT Program 
Week 
Module 
Description 
1 
Introduction and Setting 
Goals 
Education about chronic pain and rationale for CBT. Instruction on 
daily skill practice goals and free choice goals. 
2 
Deep Breathing/Visual 
Imagery 
Instructions for diaphragmatic breathing/visual imagery and 
benefits 
3 
Progressive Muscle 
Relaxation 
Instructions for progressive muscle relaxation and benefits 
4 
Physical Activity and Body 
Mechanics 
Instructions for initiating or escalating physical activity level and 
adopting proper body mechanics 
5 
Identifying Unhealthy 
Thoughts 
Instructions for identifying negative thoughts and understanding 
how negative thoughts influence pain, activities and mood 
6 
Balancing Unhealthy 
Thoughts 
Instructions for countering negative thoughts with coping 
statements 
7 
Managing Stress 
Instructions for identifying sources/symptoms of stress and 
learning positive coping strategies 
8 
Time-Based Pacing  
Instruction to pace activities based on time rather than pain   
9 
Sleep Hygiene 
To understand the relationship between sleep problems and pain 
and the importance of monitoring sleep 
10 
Relapse Prevention and 
Planning for the Future 
Review of progress made in achieving goals, prepare for pain 
flare-ups, and develop a future plan for setting goals and keeping 
healthy 
 
CBT will be delivered in weekly, 30-45 minute, telephone contacts with an experienced licensed psychologist 
utilizing a treatment manual modified for knee OA based on previously developed and tested materials for 
chronic pain. The therapist manual includes detailed outlines of the information to be provided to participants 
for each of the pain coping skill modules.  


13 
 
Before the start of phase 2, participants randomized to CBT will be mailed or given a binder that includes 
handouts for each of the pain coping skills included in the treatment, a CD to facilitate deep breathing and 
progressive muscle relaxation, and tracking goals sheets noting the coping skills to be practiced in between 
each session. In order to foster patient comprehension of the materials, Plain Language Action and Information 
Network’s federal guidelines were used to enhance the handouts’ readability and to reduce the mean Kincaid 
reading level to a 9th grade level. 
The format of each session will include: 1) review of intersession goal accomplishment, previously assigned 
coping skill practice, and other homework; 2) review of previously discussed material; 3) presentation of new 
material and new skills within a problem-solving framework; 4) in-session practice, covert rehearsal, or 
discussion of the application of new skills and 5) establishment of specific quantifiable and written intersession 
behavioral goals, expectations for skill practice, and other homework. Appropriate modifications will be made 
for the introductory and tenth sessions. 
Beginning with the second treatment session, using procedures developed in a previous VA-funded study 
(Efficacy of Tailored Cognitive-Behavior Therapy for Chronic Back Pain, PI: Kerns), the participants, in 
collaboration with their therapist, will choose their own goals aimed at improving their quality of life. As 
participants progress through treatment, they will be encouraged to practice prior session coping skills, 
especially the ones that are reported to be effective, as well as continue to practice their “free choice” goals 
that target ways to improve well-being. Session 10 will emphasize skill consolidation and relapse prevention. 
An explicit review of skills learned during the treatment will be followed by a discussion targeting continued 
practice and application of skills. Areas of poor adherence to recommendations for skill practice and 
application will be explicitly addressed. The session will include elicitation of specific concerns about relapse 
and problem-solving discussion designed to reinforce perceptions of self-efficacy and a commitment to 
continued skill application. 
D.6.c.1 Pilot Testing: We pilot tested the intervention (note that it was 12 weeks) and data collection 
procedures (see D.12) with 14 participants: mean (SD) age = 68 (10) years; 12 are White; 6 are married. Of 
the 165 CBT sessions  conducted, the average time per session was 33 minutes (range 20-55). Subjects were 
forthright when they had only partially accomplished their homework, and were able to brainstorm barriers to 
improve adherence. The subjects seemed appreciative of the one-on-one time given to them and the 
opportunity to practice skills that might alleviate their knee pain.  
The baselines interviews required between 14 and 29 minutes and the follow-up interviews between 9 and 15 
minutes to complete. The mean (SD) WOMAC pain score (possible range 0-20) was = 7.3 (5.9) at baseline 
and 2.8 (2.9) at week 12. The mean (SD) ratings of the skills taught (rated on a 5-point scale 0 = Not at all and 
5 = Very Helpful) are provided in Table 2.  
Table 2. Participants’ Ratings of the Helpfulness of the Skills Taught 
Skill 
Identify 
Knee Pain 
Precipitants 
Food 
Diary 
Exercise 
Plan 
Relaxation 
Identify 
Unhealthy 
Thoughts 
Change 
Unhealthy 
Thoughts 
Pace 
Activities 
Stress 
Management 
Sleep 
Hygiene 
Mean (SD) 
4(1) 
4(2) 
4(1) 
5(1) 
4(2) 
4(1) 
4(1) 
4(2) 
3(2) 
The mean (SD) goal attainment scores [0 = Did not work at all on goal(s) to 10 = Completed goal(s)] for each 
subject are provided in Table 3.  
Table 3. Goal Attainment Scores per Pilot Subject 
ID 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Mean (SD) 
5(2) 
8(3) 
8(2) 
8(3) 
2(2) 
6(2) 
8(2) 
4(2) 
6(1) 
7(3) 
7(2) 
4(3) 
5(1) 
9(1) 
All 14 rated the amount of information presented as “Just right” (options: Too much, Not enough, Just right). 
Eleven rated the length of the calls as “Just right”, 2 as “Not enough” and 1 as “Too long” (options: Too long, 
Too short, Just right). 7 participants stated that they were “Very motivated” to continue practicing/implements 


14 
 
learned skills, 4 stated that they were “Moderately” motivated, 3 “Somewhat”, 2 “A little” and 1 was “Not at all” 
motivated. Thirteen responded that they would recommend the program to another person with knee pain 
(Yes/No). 
D.7 Randomization and Allocation Concealment: An independent research associate not otherwise 
affiliated with the study will generate a computer generated randomization code. Subjects will be randomly 
assigned to the intervention or control group in a 1:1 ratio. Randomization will be stratified by baseline knee 
pain intensity (≤ 8 vs > 8 on the WOMAC knee pain subscale). The cut-off point was chosen based on NSAID 
RCT outcome scores at 12 weeks 72. For subjects with bilateral symptoms, the most painful knee will be 
chosen as the study knee. Blocking will be used within each of the 2 groups to maintain balanced treatment 
assignment across both sites. We will use variable block sizes ranging from 2 to 6. For the West Haven 
patients,the randomization code will be forwarded to the VACHS Research Pharmacy and will be used to label 
the study medication bottles. Random treatment assignments will be placed in numbered (so that all envelopes 
can be accounted for at the end of the study) opaque envelopes. Providence VA Pharmacy will be also be 
forwarded the randomization code for their own patients and label the study medication bottles accordingly.  
D.8 Blinding: The study personnel having direct contact with subjects, subjects, and other study personnel 
(PI, co-investigators, biostatistician and data manager) will be blind to treatment arm allocation. Blinding 
participants and study personnel is possible because the placebo and active capsules are indistinguishable. 
Although AEs associated with the active drug may threaten the blind, they are less likely to occur given that 
participants will all have taken NSAIDs regularly for at least 3 months prior to study onset and the study drug 
for 2 weeks during the run-in period. We will test the success of blinding by asking subjects and the project 
coordinator to guess group assignment (allowing for a “don’t know” option) at the end of Phase 1 73. We will 
also ascertain confidence (How confident are you that your guess is correct?) using a 5-point Likert scale 
ranging from 1 = Not confident at all to 5 = Extremely confident.  
D.9 Expected Participant Flow: Our target sample size is 434 subjects (see sample size calculations in 
D.19). We will randomize 544 subjects to account for a possible 20% loss to follow-up. We will enroll 680 
subjects into the run-in period, to allow for a loss of up to 20% during the run-in period 64. This estimate is 
conservative, because many of the subjects will already be taking meloxicam and all have been able to tolerate 
NSAIDs for at least 3 months. Randomization of 15 subjects per month over both sites will enable us to reach 
our target sample size over 37 months. Subject disposition will be reported in agreement with CONSORT 
guidelines 74. The flow chart is included in Appendix 1. Reasons will be recorded to explain ineligibility and all 
dropouts.  
D.10 Data Collection Overview: Data will be collected using standardized questionnaires and forms. The 
project coordinator will be trained to administer specific instruments during the start-up period. Demographic 
and clinical characteristics, current medications, social support and expectations will be assessed at baseline. 
Knee pain severity will be collected at baseline and then weekly. Adherence to study drug, use of 
acetaminophen and other co-therapies, AEs and goal attainment will be collected weekly. Lower extremity 
disability, subjects’ global impression of change, and the Health Utility Index Mark 3 (HUI3) (see D.20.a) will be 
collected at baseline and then at the end of phase 2 (see Table 4). Outcome data will be collected by the 
project coordinator before each CBT session. 
Table 4. Summary of Data to be Collected 
Variable 
Start of 
Run-In 
End of Run-
In 
Baseline 
(Phase 1) 
Weekly 
End of Phase 
2 
Demographic 
X 
 
 
 
 
Clinical characteristics 
X 
 
 
 
 
Current medications 
X 
 
 
 
 
Social support 
X 
 
 
 
 
Expectations* 
 
 
X 
 
 
Pain severity 
X 
 
X 
X 
X 
Lower extremity disability 
X 
 
X 
 
X 


15 
 
Intermittent vs Constant 
Pain (ICOAP) 
 
 
X 
X 
X 
Impression of change 
 
X 
 
 
X 
Adverse events 
 
X 
 
X 
X 
Adherence to study drug 
 
X 
 
X 
X 
Use of acetaminophen 
 
X 
 
X 
X 
Use of co-therapies 
 
X 
 
X 
X 
Goal attainment* 
 
 
 
X 
X 
HUI3 (See D.24) 
 
 
X 
 
X 
 
D.11 Subject Characteristics: The following independent variables will be collected at baseline to help 
readers judge the generalizability of the results and to check comparability of the study groups at baseline. 
Sociodemographic characteristics: Age, gender, ethnicity, maximum level of education attained, employment 
status, and living arrangements (living with a spouse, another person, or alone) will be obtained by self-report. 
Clinical characteristics: Overall health status and co-morbidity will be ascertained using the Arthritis Impact 
Measurement Scales 75. Body mass index will be obtained from the most recent EMR entry. Baseline knee 
pain and disability will be measured using the WOMAC (detailed in D.12). Psychiatric co-morbidities will be 
ascertained by chart review. 
Current medications: Current medications will be obtained from the chart during the screening chart review and 
subsequently reconciled with each subject during the baseline interview. In case of discrepancies, the subject’s 
report will be used. Duration of NSAID use (for knee pain) will also be recorded. We will specifically inquire as 
to Rx and OTC medications, neutraceuticals and supplements. 
Social support: Social support will be measured using the 5-item Modified Social Support Survey. 
Psychometric properties of this instrument include the following: Cronbach’s alpha = 0.88, correlates highly 
with a measure of loneliness and companionship (convergent validity) and poorly with visual impairment 
(discriminant validity) 76. 
Expectations: Subjects’ expectations related to the benefits associated with NSAIDs will be assessed at 
baseline using a 5-point scale ranging from 1 = Not at all effective to 5 = Extremely effective. This measure will 
be repeated* to assess expectations related to CBT prior to the first session for subjects randomized to the 
CBT arm during Phase 2. 
D.12 Outcome Variables 
D.12.a Primary Outcome: The primary endpoint will be between-group differences in the WOMAC pain score 
measured at 4 weeks. The WOMAC is a disease-specific health status questionnaire. Of the instruments used 
to assess change in persons with knee OA, the WOMAC has been the most extensively validated and is 
recommended for (by the Osteoarthritis Research Society) and widely used in OA trials 77,78.  
The WOMAC pain scale consists of 5 questions that ask about pain during walking, stair use, lying in bed at 
night, sitting, and standing. Each question is scored on a 5-point scale, where 0 = None, 1 = Mild pain, 2 = 
Moderate pain, 3 = Severe pain, and 4 = Very severe pain. Total pain scores range from 0 to 20 with higher 
scores reflecting worse pain. The WOMAC also includes a lower extremity disability scale. Both the pain scale 
and disability scale (17 items) can be analyzed separately.  
Psychometric properties of the WOMAC scale include good internal consistency with Cronbach’s alpha for the 
pain and disability scales = 0.81 and 0.91, respectively 79. The intraclass correlation coefficient for pain = 0.95 
and for physical function = 0.92 80. Validation studies have shown high correlations with other indices probing 
the same dimensions 77,81. Rasch analysis suggests that the pain and function scales are unidimensional and 
are appropriate measures for lower extremity function in patients with chronic arthritis 82. The WOMAC has 
generally been found to be more sensitive to change when compared to other measures of functional status in 
OA including the Health Assessment Questionnaire, the Arthritis Impact Measurement Scales, the Doyle Index, 


16 
 
the Lequesne Index, timed walk and range of motion (relative efficiency compared to other instruments > 1) 
77,83. Though the WOMAC is available using both visual analogue and Likert (WOMAC LK 3.1) scales, in this 
proposal we will use the latter because it has been validated for use over the telephone 84.  
D.12.b Secondary Outcomes 
Area under the curve (AUC) of the WOMAC pain scale score over the observation period: AUC will be 
measured in order to capture the variability in pain that is characteristic of knee OA 85,86. The AUC is a 
commonly used measure that combines multiple measurements over a specific time interval into a single index 
87. The AUCG provides a single score that quantifies each participant’s total WOMAC score across the 
repeated measurements. The formula is given as:  
 
Where mi denotes the measure at each time and ti denotes the time between measures. Because measures 
are collected weekly, ti is a constant and can be dropped from the equation. The AUCG is valid regardless of 
increases or decreases in reported pain over time. 
Intermittent vs.Constant Pain: Measure of Intermittent and Constant Osteoarthritis Pain 
(http://www.oarsi.org/index2.cfm?section=OARSI_Initiatives&content=Pain_Radiological_Indexes) will be used 
to evaluate the subject’s pain experience, including pain intensity, frequency, as well as impact on mood, 
sleep, and quality of life. This 11-item scale asks subjects to rate their “constant knee pain” and their “knee 
pain that comes and goes” over the past week. Each item is scored on a scale from 0 to 4, with higher scores 
indicating a worse pain experience. The ICOAP complements the WOMAC given that the latter focuses on the 
impact of pain on physical functioning. 
Lower extremity disability: Lower extremity functional outcomes will be measured using the WOMAC disability 
scale (detailed in D.13.a). The physical disability scale contains 17 items that assess the amount of difficulty 
subjects say they have with climbing stairs, rising from a chair, walking, and other activities of daily living. 
Responses are measured and scored in the same way as the pain scale.  
Global impression of change: To assess global improvement, we will use the Patient Global Impression of 
Change Scale, a balanced 7-point scale (1 = Much better to 5 = Much worse) asking subjects to rate their 
change (if any) in pain since starting the study 88. This item has been well-validated and is recommended as a 
core outcome measure by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials 89. 
Adherence to study medication and use of co-therapies: It is difficult to measure adherence and use of co-
therapies in a clinical trial. This is especially true in this study where contact is made by telephone only and 
many of the medications used are available OTC. We will ask patients to fill in daily medication diaries to 
record whether or not they took the study drug, the names of any additional co-therapies used (RX and/or 
OTC), and the occurrence of any AEs. Co-therapies include: analgesics (RX and/or OTC), supplements, 
and/or topical agents taken for arthritis pain. Eligible subjects will be instructed on how to fill in the diaries after 
they have agreed to participate. The diaries are meant to be used as reminders/cues during follow-up 
telephone calls. The project coordinator will ask subjects to refer to their diaries and will ascertain use of 
medications using the following questions: 
• 
Over the past week, how many days did you use the study drug for your knee pain?  
• 
Over the past week, how many days did you use Tylenol or acetaminophen for your knee pain?  
• 
Over the past week, how many days did you use other medications that were prescribed by one of your 
doctors for your knee pain?  
• 
Over the past week, how many days did you use other medications, creams or supplements that you got 
without a prescription for your knee pain?  
• 
Over the past week, how many days did you use any medications for a different problem or type of pain 
(e.g. headache)? 


17 
 
We intentionally framed the questions so as to facilitate reporting difficulties with adherence or use of non-
permitted co-therapies. Although diaries are frequently used as a measure of adherence, the research team 
felt that asking subjects to mail back diaries each week would be overly burdensome and potentially result in 
greater amounts of missing data. 
Adverse events: AEs are generally collected using either an open-ended approach or a list of close-ended 
questions. A recent systematic review concluded that there have been too few studies to strongly recommend 
either one 90. We will use an open-ended approach to collect AEs. The project coordinator will ask subjects 
whether they have experienced any AEs (over the past week) on a weekly basis. We will also specifically 
inquire whether subjects have had interim medical visits, procedures, doctor visits, emergency room or urgent 
care visits, and hospitalizations. Positive responses to any of these events will lead to focused chart reviews. 
AEs are further described in Section D.16. 
D.13 Moderating Variable 
Goal attainment: For those randomized to CBT, the extent to which each specified intersession goal is met will 
be measured each week using a numeric rating scale ranging from 0 = Did not work at all on goal(s) to 10 = 
Completed goal(s).  
D.14 Retention: Subjects will be paid $25 after the baseline interview and $25 after the 4- and 10-week follow-
up assessments. These incentives are consistent with amounts paid to subjects for other similar studies at our 
institution.This trial will also benefit from the expertise of the CBT therapists and the relationships they will 
establish with each subject. The experience of the PRIME Center’s personnel and the relationships they 
engender with study subjects is a major factor underlying the success of the trials conducted at our center. 
D.15 Treatment Fidelity: To enhance CBT treatment fidelity we will 1) use treatment manuals and patient 
handouts that have been developed and previously used at our center; 2) hire CBT therapists who have 
received training in the manualized CBT treatment protocol; 3) include individualized goals to motivate 
subjects; and 4) identify barriers towards skill practicing and goal attainment each week. To measure treatment 
fidelity, we will measure goal attainment weekly (see D.12). In addition, we will audiotape, to the extent 
possible, all treatment sessions using a digital phone recording system (Sparky+ USB Phone Call Recorder, 
V3) that records both sides of the telephone conversation. The phone recorder connects the phone to the 
computer such that phone calls can be recorded automatically or manually. Calls are saved directly to the VA-
approved server and can be accessed using a username and password for security. Explicit consent will be 
obtained from subjects to audiotape these conversations. In our previous experience less than 2% of subjects 
refused to be audiotaped during CBT sessions.  
Dr. Heapy and the psychology technicians will listen to a random 10% of the other therapist’s CBT sessions to 
ensure adherence to the treatment manual. Adherence will be measured using a modified version of the Yale 
Adherence and Competence System-Second Edition (YACS-II) 91. This scale allows for the systematic 
evaluation of therapist adherence to pre-specified elements of the treatment such as rationale for, and 
explanation of each coping skill, setting of skill practice goals, encouragement of self-monitoring, rapport 
building and adherence to session time limits. Drs. Heapy and the psychology technicians will meet weekly to 
review the rated sessions, note and reinforce successful adherence to the manual and provide corrective 
feedback to the therapist if and when treatment drift occurs. 
D.16 Safety 
D.16.a Notification of Patients and Providers: Patients will receive information about the risks of NSAIDs 
during the consent process. All providers in the VACHS and Providence VA Medical Center will be notified 
about the research project by email and the PI will describe the study at the monthly primary care provider 
team meeting for each firm, prior to study onset and every 6 months thereafter. In addition, we will notify the 
primary care provider and relevant specialists each time a subject is enrolled to ensure that they are aware of 
and understand the study protocol. We will also send an email alert to physicians should we find that their 
patients have contraindications to NSAID use or are taking a high risk combination of antiplatelet and/or 
anticoagulant medications. We will also notify providers of AEs developing in their patients during the study. 
D.16.b Adverse Event Monitoring: CBT is not associated with any expected AEs apart from the 
inconvenience associated with participating in the telephone sessions and practicing the required skills. Few 


18 
 
NSAID-related AEs are expected because all participants had to have tolerated NSAIDs during the run-in 
period and for at least 3 months prior to enrollment in order to be eligible to participate. Still, subjects remain at 
risk for NSAID-induced toxicity. Subjects will be asked whether or not they developed any AEs during the prior 
week. All AEs will be reported to the PI as they are discovered. EMR data will be reviewed for all subjects 
having outpatient appointments or hospitalizations during the study period. Development of a severe or life-
threatening AE will result in study drug discontinuation. However, all subjects will continue to be followed until 
the end of the study period. All unexpected and serious AEs will also be reported to the VA Central IRB and 
the Data Safety Monitoring Board (DSMB) within 24 hours. In addition, a local Study Specific AE Committee 
made up of 2 physicians who are not on the project team will review a cumulative report of unexpected and 
moderate to severe AEs every 4 weeks (or more often if necessary). The Committee will confirm or modify the 
PI’s assessment in order to ensure that no concerning patterns of AEs emerge. 
D.16.c Suicide Ideation: If a research team member learns of suicidal ideation with a subject during a 
telephone session, the team member may ask three additional questions to gather important information to 
provide for the VA Suicide Hotline so that they can assess if the subject is in imminent danger. If suicidal 
ideation is expressed, the following three questions may be asked: 
 
1. Have you ever tried to kill yourself?  
2. Do you have any specific plans to kill yourself now?  
3. Do you have the means to carry out those plans?  
 
If the team member is able to immediately determine that the subject is an imminent threat, then the “warm 
transfer” (established guidelines between VA National Suicide Prevention Hotline and CSRDS) will be by-
passed and local law enforcement authorities will be contacted to alert them of the imminent threat and to ask 
for assistance escorting the subject to a mental health provider, emergency room, urgent care, etc. Otherwise, 
the subject will undergo the “warm transfer” as needed. These individuals will be dropped from the study.  
 
D.16.d Adverse Event Classification and Grading: We will classify AEs by organ system (gastrointestinal, 
renal, hepatic, cardiovascular, other) 52. AEs will be further classified by whether or not they required treatment 
and/or hospitalization. We will use the Naranjo algorithm to estimate the probability that the study drug caused 
the AE 92. Two physicians (LF and LS) will independently score each AE using the Adverse Drug Reaction 
probability scale 92. This validated scale includes 10 items coded as Yes, No or Do not know. A scoring 
algorithm generates a total score with a possible range of -4 to +13. AEs with scores of ≥ 9 are classified as 
definite; 5-8 as probable; 1-4 as possible, and < 1 as doubtful. The scale has been shown to have high within 
and inter-rater reliability (r = 0.91-0.98 and r = 0.84 to 0.93 respectively) 92. Disagreements will be adjudicated 
by a third VA physician (Dr. Avlin Imaeda; Section of Gastroenterology, VA CT - see letter of support). The PI 
will grade each AE for severity using the Rheumatology Common Toxicity Criteria v.2.0 listed in Table 5 93: 
Table 5. Adverse Event Severity 
Category 
Definition 
Mild 
Asymptomatic, short duration (< 1 week), no change in lifestyle, no Rx required 
Moderate 
Symptomatic, duration 1-2 weeks, occasionally alters lifestyle, Rx provides relief 
Severe 
Prolonged symptoms, major functional impairment, hospitalization < 24 hrs 
Life threatening 
At risk of death or substantial disability, especially if permanent, hospitalization > 24 hrs 
D.17 Sample Size Calculations: The primary endpoint is the difference in mean pain scores between the 
NSAID and placebo groups (as measured by the WOMAC pain subscale) at 4 weeks. The sample size was 
calculated using NCSS/PASS 2008 Power Analysis of a Non-Inferiority Test of The Difference of 2 Means: 
Numeric Results for Non-Inferiority Test (H0: D >= |E|; H1: D < |E|); where |E| is the magnitude of the margin of 
equivalence. D is the mean difference at which the power is computed. D = Mean1 - Mean2.  
The range of the WOMAC pain subscale is 0-20 and the minimum clinically important difference (MCID) is         
2.1 72,94. We set the equivalence margin to 1.0 which is less than 50% of the MCID. A sample size of 434 (217 
per arm) achieves 90% power to detect non-inferiority using a 1-sided, 2-sample t-test. A 1-sided test is 


19 
 
recommended for non-inferiority trials. The true difference between the means is assumed to be 0.00. The 
significance level (alpha) of the test is conservatively set at 0.025. The data are drawn from populations with 
standard deviations of 3.20 83. 
We will enroll 680 subjects in the 2-week run-in period to account for a possible 20% loss. We will randomize 
544 subjects to enable a further 20% loss over the 4-week withdrawal period. The use of a run-in period and a 
RWT design both tend to decrease the required samples size; therefore these estimates are conservative.  
Assuming a further 25% loss in Phase 2, we will have 80% power to detect non-inferiority under the same 
assumptions. 
Stopping Rules/Removal from Study:  
If patient reports use of another NSAID beside meloxicam and, despite being asked to stop, is unable to do so 
over the subsequent week, he will be removed from the study.   
If patient reports taking more than the maximum dose of 3g of Tylenol daily, and, despite being asked to limit 
the dosage is unable to do so over  the subsequent week, he will be removed from the study. 
We will not include stopping rules due to pain, because: 
1) All subjects are receiving therapy for knee pain. 
2) Stopping rules are not typically included in RCTs for knee OA, including withdrawal trials. 
3) Analgesic use will be recorded and accounted for in the analyses. 
Patients reporting an escalation of pain will only be removed from the study if they are unable to comply with 
the study regulations and the stopping rules stated above. 
D.18 Analyses of Aims 1 and 2 
D.18.a Phase 1 Analyses 
Hypothesis 1: Subjects randomized to placebo will not experience more knee pain than subjects 
randomized to continue NSAIDs at 4 weeks.  
All analyses will be performed using SAS Version 9.2 (SAS Institute Inc., Cary, NC). The SAS t-test procedure 
will be used to calculate the means and standard deviations of each group, and the 95% CI of the difference. 
Both intention-to-treat (ITT) and per-protocol (PP) analyses will be conducted, and compared. The model will 
be adjusted for study site and the treatment covariates will be represented by indicator variables. We will utilize 
multiple imputation methods to account for missing WOMAC scores, and compare the results of imputed 
models to both ITT and PP analyses 95,96. Multiple imputation is a Monte Carlo technique in which the missing 
values are replaced by m>1 simulated versions. In Rubin's method for “repeated imputation” inference 95, each 
of the simulated complete datasets is analyzed by standard methods, and the results are combined to produce 
estimates and confidence intervals that incorporate missing-data uncertainty. 
The adequacy of the randomization will be assessed by comparing baseline demographic and clinical 
characteristics between the 2 treatment groups. Variables will be summarized (means, proportions, etc.) and 
continuous variables will be compared using 2-sample t-tests, while differences in categorical variables will be 
examined using chi-square tests. Characteristics found to be significantly different between conditions will be 
included as covariates in subsequent analyses to determine if they alter the conclusions of the study. The 
success of blinding will be compared across groups using chi-square tests and 2-sample t-tests for the 
proportion guessing correctly and confidence ratings, respectively.  
Hypothesis 2: The AUC score in the placebo arm will not differ from the AUC in the continued NSAID 
arm at 4 weeks.  
The SAS MEANS procedure will be used to calculate the means and standard deviations of each group AUC 
score, and the 95% CI of the difference. Both intention-to-treat (ITT) and per-protocol (PP) analyses will be 
conducted and compared. 
D.18.b Phase 2 Analyses 


20 
 
Hypothesis 3: Subjects participating in the CBT program will not experience more knee pain than 
subjects continuing NSAIDs at 16 weeks. 
The SAS t-test procedure will be used to calculate the means and standard deviations of each group and the 
95% CI of the difference as described in Hypothesis 1. 
Hypothesis 4: The AUC score in the CBT arm will not differ from the AUC in the continued NSAID arm 
at 16 weeks. 
The SAS MEANS procedure will be used to calculate the means and standard deviations of each group AUC 
score, and the 95% CI of the difference as described in Hypothesis 2. 
Hypothesis 5: Subjects participating in the CBT program will not report greater overall worsening 
(global change) or levels of lower extremity disability compared to subjects randomized to continued 
NSAID use. 
We will use linear mixed effects (LME) models to examine differences in the slope of global change and 
disability by group over time. LME models account for the clustering induced by repeated measures on 
individual patients and includes both between-groups and within-subject effects, allows for missing data, and 
measurements at different time intervals. Data from different subjects are assumed to be independent, while 
the correlation structure of the repeated measurements within subjects is modeled via parameterization of the 
covariance structure. Analyses will be performed using SAS PROC MIXED. Dichotomized variables will be 
analyzed using generalized estimating equations. 
Hypothesis 6: Subjects participating in the CBT program will not report greater use of co-therapies 
compared to subjects randomized to continued NSAID use. 
Group differences in the number of days using co-therapies per week, a count variable, will be modeled using 
Poisson regression analysis 97. We will correct for overdispersion - a common problem in Poisson models that 
occurs when the variance of the count dependent variable is greater than the mean - by setting the scale 
parameter to the deviance divided by the residual degrees of freedom. Incidence rate ratios representing the 
risk of co-therapy use will be obtained from model results by exponentiating the parameter estimates. We will 
also examine the moderating effect of goal attainment on co-therapy use. 
Hypothesis 7: Goal attainment will be associated with improved primary and secondary outcomes.  
We will use latent class regression analysis to model the longitudinal trajectory of the 0-10 weekly ratings of 
coping skill acquisition on subsequent pain, disability, global change and co-therapy use at 3 months 98. These 
models allow for the regression parameters to differ across the unobserved (latent) groups trajectories, and are 
performed in a single model. LME models and multiple imputation methods will be used to model missing 
outcome data because they have been shown to be superior to other methods, such as last observation 
carried forward, in the analysis of repeated measures data 74,99. 
Aim 3: To estimate the potential cost-effectiveness of CBT compared with continued NSAID use.  
D.19 Healthcare Utilization: Subjects’ OA-related healthcare utilization will be measured using VA Regional 
Data Warehouse (RDW) data for all OA-related outpatient visits (emergency room, primary care, urgent care, 
rheumatology, orthopedic surgery, physical therapy, and pain management clinics) over 12 months prior to the 
run-in period and 6 to 12 months following randomization, depending upon enrollment rates, to allow more 
stable estimates of pre-, during, and post-study utilization and the persistence of any intervention effects over 
time. RDW data will also be used to identify the total number of consults placed to the Bone and Joint Clinic 
(both orthopedic and rheumatology referrals), Physiatrists, pain management and physical therapy for all study 
subjects. Within-group differences in total number of OA-related outpatient, urgent care and emergency room 
visits and consults for both treatment arms will be evaluated using paired t-tests. Between-group differences in 
the change in total OA-related outpatient, urgent care and emergency room visits and consults over the 14-
week study period will be evaluated using unpaired t-tests.  
D.20 Cost-Effectiveness: To evaluate the short- and long-term health and economic benefits of discontinuing 
NSAIDs and then starting CBT, we will compare OA-related VA health services utilization, total direct medical 
costs, and the incremental cost-effectiveness ratio (in US dollars per quality-adjusted life-year) associated with 
continued NSAID use versus CBT at 14 weeks, 1 and 10 years. 


21 
 
D.20.a 14-Week Cost-Effectiveness: To estimate cost-effectiveness of the placebo followed by CBT arm 
compared to continued NSAID use over the 2-phase trial, we will calculate the incremental cost-effectiveness 
ratio (ICER), reported in 2011 US dollars per quality-adjusted life-year (QALY) gained, for each treatment arm, 
including the withdrawal period. QALYs will be estimated using the HUI3. The HUI3 is a generic, preference-
weighted health status instrument that evaluates 8 attributes (vision, hearing, speech, ambulation, dexterity, 
emotion, cognition and pain/discomfort), each coded using 5 or 6 levels reflecting increasing severity or 
disability. The HUI3 is a widely used, valid, responsive, and efficient measure of health in OA as well as many 
other chronic conditions 100-102. We chose this measure over the shorter EQ-5D because its ceiling effects are 
lower 102. As the HUI3 assesses the prior 4 weeks of symptoms, we will collect the HUI3 at baseline and then 
monthly in order to provide a complete AUC for quality of life estimation during the study period. Costs will be 
estimated from the VA’s perspective. Costs will consist of treatment-specific costs, OA-related health services 
utilization costs and costs associated with AEs. All cost data will be obtained from the VA Decision Support 
System National Data Extracts. For the NSAID arm (referent), treatment costs will consist of outpatient 
pharmacy costs derived from VA pharmacy cost data combined with the mean daily pill usage of individuals in 
the active treatment arm during the 4-week RWT. We will value productivity losses through the use of QALYs, 
rather than monetarily, per the Panel on Cost-Effectiveness Analysis of the U.S. Public Service’s 
recommendations 103. 
D.20.b 1- and 10-Year Cost-Effectiveness: To extrapolate the longer-term economic value of CBT, we will 
estimate 1- and 10-year ICERs using a state transition Markov model and use sensitivity analyses to explore 
the effect of varying levels of efficacy persistence. The purpose of the sensitivity analyses is to identify upper 
and lowers bounds regarding the uncertainty of long-term CBT efficacy. We will accomplish this by running the 
model assuming varying costs, efficacy and adverse event rates for both treatment arms. 
Although there is a paucity of evidence on the long-term persistence of CBT in providing relief for knee OA, 
studies have demonstrated therapeutic persistence following treatment discontinuation for similar interventions 
ranging from 6 months in knee OA 9 to 12 months in low back pain 105, but complete loss of therapeutic effect 
after 6 years following treatment for depression 106. We will therefore examine scenarios in the 1-year analysis 
that explore the impact of how quickly (if at all) CBT efficacy wanes without additional interventions (Table 6). 
In addition, we will explore the cost-effectiveness of repeating an abbreviated CBT program (10 weeks) at 
varying intervals to allow extrapolation to 10 years (Table 6). We will examine 3 separate extended cost 
assumptions (lowest, average and highest cost accrued over study period extrapolated over 1 and 10 years). 
We will assume a range of long-term efficacy and AEs associated with NSAIDs drawn from the published 
literature. We will calculate 1 and 10 year ICERs for CBT compared to continued NSAIDs for each combination 
of cost, CBT and NSAID assumptions. Continued CBT costs will include the cost of a full time therapist and 
20% percent effort of an administrator to process referrals. In order to calculate the 1- and 10-year ICERs, 
utilities and costs will be annualized following the above assumptions. 
Table 6. CBT Efficacy Assumptions for Sensitivity Analyses  
1-Year 
10-Year 
Stable over period 
Stable over period 
Decreases to no effect over 9 months 
Decreases to no effect over 1 year 
Decreases to no effect over 6 months 
Decreases to no effect over 2 years 
Decreases to no effect over 3 months 
Decreases to no effect over 5 years 
Decreases to no effect over 1 month 
Decreases to no effect over 10 years  
D.20.c Model: The Markov model will be comprised of 19 health states representing 9 strata of knee pain and 
functional status (defined by tertiles of WOMAC pain scale and lower extremity disability scale scores, 
respectively), presence or absence of severe treatment-related AEs (e.g., gastrointestinal bleed or renal failure 
requiring hospitalization) and death. The cycle length will be 10 weeks. QALYs will be derived from study data 
and supplemented with published literature. The impact of mild AEs on QALYs will be averaged over all health 
states for a given treatment strategy, but will not incur additional costs.  


22 
 
We will use TreeAge, a simulation software package that combines decision analysis and state transition or 
Markov processes with detailed outputs containing all internal calculations for model debugging and internal 
validation. We will run the model as a Monte Carlo simulation, where each hypothetical patient proceeds 
through varying clinical stages of disease or events 107. This type of simulation is probabilistic: the modeler 
defines the overall probability of a particular event occurring, but does not know ahead of time whether a 
particular event will happen to a particular simulated patient (unless specified probability is exactly “1” or “0”). 
Monte Carlo simulation provides several advantages. First, the model produces a distribution of results for the 
outcome of interest, more accurately representing the heterogeneity observed in real populations. Second, it is 
possible to run the model to reflect areas of uncertainty without altering the model structure, which is valuable 
when data on probability estimates are limited. We will employ a systematic validation approach 103 including 
one-way analyses of variables over plausible ranges using numeric and graphic assessment of results 108. We 
will also examine extreme scenarios where the outcome is clinically obvious. The model will estimate 1- and 
10-year costs and QALYs associated with placebo followed by CBT versus continued NSAID use under the 
assumptions described above, and allow calculation of the 1- and 10-year ICERs. Costs and QALYs will be 
discounted at 3% per year. 
Hypothesis 8: Discontinuing NSAIDs and initiating CBT will result in a greater overall reduction in VA 
health services utilization compared to continued NSAID use.  
Documented reductions in health care utilization among participants during the study may be due either to 
greater clinical effect of CBT versus NSAIDs, or alternatively, to an effect of study participation independent of 
treatment effect. We will quantify the impact of potential protocol-induced reductions in health care utilization 
on cost-effectiveness by performing sensitivity analyses alternatively assuming: 1) no change in utilization in 
either treatment group, 2) equal reductions in both groups, and 3) greater reductions in the CBT versus 
continued NSAID group. We will also define utilization thresholds at which the favored strategy (CBT versus 
continued NSAID) changes. 
Hypothesis 9: Discontinuing NSAIDs and initiating CBT will offer cost savings compared to continued 
NSAID use when considered over a 10-year time period.  
Again, using sensitivity analyses noted above, we will explore the impact of varying long-term assumptions on 
cost-effectiveness, thereby providing thresholds for CBT efficacy, health care utilization and NSAID toxicity at 
which the favored strategy changes. 
D.21 Data Management: Data management will be led by Dr. Cynthia Brandt, Director of the Prime Center’s 
Informatics Core. Dr. Brandt has extensive experience in study design, preparation of study forms, and 
management of data and preparation of reports. Dr. Brandt, along with the data manager, will develop a Data 
Management Operations Manual during the study start-up period to describe the computing environment, data 
entry and data management procedures. She will oversee interim monitoring to track enrollment, protocol 
adherence, completeness of data collection, safety, and adherence. This monitoring will be performed by the 
project/data manager (blinded to treatment assignment). Aggregate results (both groups combined) will be 
reported on a weekly basis to the PI. Results by group (without group labels) will be reported every 6 months to 
the DSMB. 
D.21.a Clinical Study Data Management System: We will use RedCap, a software application that supports 
computerized interviews, batch data entry, and basic project administration. Using this existing flexible 
database will substantially reduce time required for the database development and data management. Survey 
data will be entered into electronic forms. Data reports and SAS extracts for statistical analysis will be made 
available on the VA server to authorized researchers 
D.21.b Quality Assurance and Control: We will hold biweekly progress reports with all research personnel to 
monitor enrollment, adherence to the study protocol and AEs. Personnel will be trained to enter data into 
RedCap. All data entry will be 100 percent verified by someone other than the original keyer. Any 
discrepancies will be flagged and resolved with the project manager. RedCap will be used to generate a 
number of reports as well as reminders to help monitor and manage the data collection process to ensure 
completeness of evaluation. RedCap has a built in mechanism to ensure that duplicate IDs and forms are not 
entered. Reports will be run by the data manager to look for outstanding forms for participants that are due for 
entry and to monitor protocol compliance. RedCap stores audit trails of errors detected and corrected as well 


23 
 
as all data changes. Records that have completed the defined cycle of entry, verification, and editing are 
considered “clean” and can be “locked”. Logic checks and range limits are built into the forms and will be used 
to facilitate quality data at the time of entry. Enrollment, survey completion and data entry quality and 
timeliness of entry will be monitored weekly with reports. The data manager will check for data inconsistencies, 
omissions, and errors regularly. Data questions or problems will trigger data queries and analyses of missing 
data will be done periodically to ensure that all forms are entered and available for analysis. RedCap maintains 
an electronic audit trail of all modifications to a study’s data, including the user who made the change, the date 
and time, and each data item changed and its previous value and new value. Several levels of backup of the 
database will be performed on a regular basis, including full backup daily and incremental backup during the 
day. 
D.23.c Data Security: All data will be handled in accordance with VA Office of Research and Development 
regulations. Several layers of security will be employed to protect study data, such as: a) login procedures with 
usernames and passwords for access to the data, b) storage of data on the VA SQL Server, and c) disaster 
recovery procedures with redundant data storage and backup. RedCap implements a variety of other security 
features at several different levels, including “role-based” user privileges. The person in charge of the study 
can specify, for example, that a particular person is allowed 1) “read only” access to that study’s data, 2) 
“read/edit” access, 3) the ability to see only certain case report forms, and/or 4) the ability to run reports or 
export data for analysis. All data will be kept in a unique study file with a unique study identification number. 
The study files containing these data will not contain any identifying information. A separate file will link study 
identification numbers with participants’ names and telephone numbers. All study staff will receive HIPAA 
training and Human Subjects Protection training. Users will certify that they are HIPAA trained and will act in 
full compliance of HIPAA regulations.  
E. POTENTIAL PITFALLS AND SOLUTIONS 
The number of Veterans with OA on NSAIDS in the VACHS and Providence VA Medical Center indicates that 
we should not have any difficulty reaching our target sample size. Nonetheless, we acknowledge that it is 
always difficult to recruit for a clinical trial. Therefore, we will track enrollment carefully, and should we fail to 
meet predefined enrollment goals, we will expand to include other VA Medical Centers within VISN1. 
Expanding the number of sites is feasible because all procedures and data are collected by telephone. 
Because the study design does not include in-person assessments, we are not able to obtain “objective” 
measures of disease activity or performance. Unlike rheumatoid arthritis, we would not expect any changes in 
physical examination or laboratory findings in the majority of subjects over the course of the proposed study. 
However, lower extremity performance measures (e.g. timed walk or sit-to-stand tests) can add valuable 
information in OA clinical trials. After extensive discussion with the research team and other experts in OA, it 
was decided that asking subjects to come to the VA to perform a battery of lower extremity function tests was 
not warranted given that our primary objective was to address the needs of Veterans having limited access to 
VA services, all other aspects of the study are conducted by telephone, and lower extremity function will be 
partially assessed using a well-validated self-report measure. We will use diaries to help subjects keep track of 
medication use (study drug and co-therapies), but will not use the diaries as an outcome measure because 
having subjects mail them back would be burdensome and risk leading to substantial missing data. Given that 
a RWT for NSAIDs has not yet been done, we felt that it was important to demonstrate short-term efficacy first; 
thus long-term effectiveness will not be evaluated. 
F. DISSEMINATION PLAN 
The results of this study will be relevant to patients, providers who care for patients with knee OA, 
implementation and health services researchers, and policy makers who are responsible for developing and 
implementing pain initiatives within the VHA. Dissemination activities will include presenting study results to 
patients at patient education events, and to researchers at local and national conferences. Additional 
presentations to healthcare providers will occur at the VA Rheumatology Consortium annual meetings and in 
relevant seminars and CME programs. All presentations will include development and dissemination of project-
related issue briefs, slide presentation sets, and printed materials. An additional strategy for dissemination of 
findings will be via the preparation and distribution of summary reports. The Coordinating Committee will 
advise and coordinate next steps for dissemination, including dissemination to other relevant entities such as 
Pain Management Coordination teams and committees and the Pain Management Education, Guidelines, 


24 
 
Outcomes and Performance Measures Working Groups. We will also post a summary of the study findings and 
implications on the Pain Management Committee’s website in a format appropriate for VA patients. We will call 
on the expertise of the National Pain Research Working Group to assist in dissemination of the results of this 
study. Over 80 VA and non-VA pain-relevant investigators form this network that serves multiple goals 
including identification of priorities for pain research, advocacy to promote increased funding for pain-relevant 
research, development of collaborative research projects, and communication and dissemination of research 
findings. Among several specific projects, this group has published special issues of 3 journals on pain and 
pain management that highlight pain research in the VHA. Face-to-face meetings of the group occur on an 
annual basis and further foster communication and collaboration in conjunction with the National HSR&D 
meeting.  
Finally, in collaboration with the Center for Information Dissemination and Educational Research, information 
from this project will be disseminated via cyber seminars, a state-of-the-art, web-based conferencing 
technology that enables dynamic interaction among presenters and seminar participants from one’s desktop. In 
addition, archived versions of seminars are available on the web for viewing on demand. Dissemination efforts 
will be facilitated by the team’s close collaboration and association with the VA Rheumatology Consortium and 
the VHA National Pain Management Strategy Coordinating Committee. This committee, chaired by study Co-
Investigator Dr. Robert Kerns, was established in 1998 to oversee the development and implementation of the 
VHA National Pain Management Strategy. The committee meets monthly, providing leadership, coordination, 
facilitation and oversight of the VA National Pain Management Strategy. Our close collaboration with this 
committee through Dr. Kerns will not only help ensure that the study produces findings that are quickly 
actionable, but will also provide a national infrastructure for rapid dissemination. 
The dissemination of telephone-based CBT will be facilitated by an initiative undertaken by the Office of Mental 
Health Services to train VA mental health providers in evidence-based psychotherapies. The Evidence-Based 
Psychotherapy (EBP) initiative, includes a national training program that provides in-person training workshops 
in evidence-based psychotherapies followed by weekly expert supervision of an actual therapy case for 6 
months. The EBP initiative has already rolled out several evidence based therapies for post-traumatic stress 
disorder and depression. The national rollout of training in CBT for chronic pain will occur over the next 2.5 
years. Dr. John McKellar, Training Coordinator of CBT for Chronic Pain Management, estimates that 
approximately 560-640 mental health providers will complete the training over the course of the rollout. Thus, 
the expertise to deliver CBT for chronic pain will be increasingly available within VA through this ongoing 
initiative without the need for further investment of resources. 
G. HUMAN SUBJECTS: Details related to the inclusion of human subjects are included as a separate 
attachment. 
H. WOMEN AND MINORITIES: At VACHS, approximately 85% of Veterans are White, 14% are Black, 0.3% 
are Pacific Islanders, 0.2% are Native American, and 0.1% are Asian. We will oversample women and Black 
Veterans in order to represent these demographic groups as best as possible. The CT and RI VA medical 
centers serve overlapping geographic regions and the demographic characteristics are comparable across 
both sites. There are approximately 2,000 women enrolled in the VACHS and just over 1,000 in the Providence 
VA Medical Center. 
I. PROJECT MANAGEMENT PLAN 
I.1 Plan and Timeline: The project timeline, (see Gantt chart, Appendix 3), indicates that in the first quarter of 
year one, we will hire and train a project coordinator and 2 psychology technicians. During the study start-up 
period we will make minor modifications to the CBT manual and patient handout, develop the manual of 
operating procedures, the data entry forms and the subject tracking system. Towards the end of the first 
quarter we will notify/educate providers about the study and its procedures. Biweekly research progress 
meetings with the PI, CBT therapists, project coordinator and data manager will occur throughout the 4 year 
study period. The DSMB will meet during the study start-up period to review study protocols and every 6 
months once enrollment begins. Subjects will be enrolled over 37.5 months and analyses of Aims 1 and 2 will 
occur in the second and third quarters of the fourth year. Cost data will be collected starting in Year 2. The 
Markov model will be constructed and debugged in Years 2 and 3 and analyses of the cost data will occur in 
Year 4. Concentrated work on manuscript preparation and dissemination will occur in the latter half of Year 4. 


25 
 
I.2 Facilities and Resources: This project will benefit from the resources and facilities of the VACHS PRIME 
Center, the VACHS Clinical Epidemiologic Center and the Providence VAMC. Please see Facilities and 
Resources Attachment.  
I.3 Specific Roles of the Key Personnel (Further detailed in Budget Justification) 
Liana Fraenkel, MD, MPH. Principal Investigator (4.5 cal ms). As the PI, Dr. Fraenkel will have overall 
responsibility for this project and will oversee all research activities from inception to completion of the project. 
She will be the primary investigator responsible for interpretation of the analysis and will be responsible for 
preparing manuscripts, presenting the study results at scientific meetings, and dissemination-related activities.  
Cynthia Brandt, MD. Co-Investigator (0.6 cal ms): Data management will be led by Dr. Cynthia Brandt, 
Director of the Prime Center’s Informatics Core. She will directly supervise the data manager and assist in 
preparation of the electronic study forms and database for the trial.  
Joseph Goulet, PhD. Co-Investigator (1.2 cal ms yr 1 and 2.4 cal ms yr 4): Dr. Goulet will be responsible for 
performing all analyses.  
Alicia Heapy, PhD. Co-Investigator (1.2 cal ms): Dr. Heapy will hire the psychology technicians. She will be 
responsible for ensuring quality control of all aspects related to the CBT protocol and treatment fidelity. Dr. 
Heapy will meet weekly with Dr. Higgins and the psychology technicians throughout the study to review 
adherence to the manual.  
Francis Keefe, PhD. Consultant: Dr. Keefe is an expert in behavioral approaches to treating chronic pain. He 
has previously developed a CBT program for OA and will review and help revise the required program for this 
project. 
Robert Kerns, PhD. Co-Investigator (0.6 cal ms): As VHA National Program Director for Pain Management, 
Dr. Kerns will assist in the development and implementation of a comprehensive plan for dissemination of the 
findings with a particular focus on their clinical and policy implications.  
Doug Leslie, PhD. Consultant: Dr. Leslie is an expert in dealing with VA-related costs and has an established 
working relationship with the PRIME Center. He will work closely with Dr. Suter to accomplish Specific Aim 3 
and will participate in writing abstracts and manuscripts describing utilization of services related to the 
intervention and the cost-effectiveness of replacing NSAIDs with CBT in the VHA.  
Sam Poon, MD. Local Site Principal Investigator (1.2 cal ms): Dr. Poon will assist in recruitment at the 
Providence VAMC site. He will meet with patients to describe the study and will obtain written consent. He will 
also contribute to interpreting study results and writing abstracts and manuscripts. 
Robert Swift, MD, Ph.D Mentor (1.2 cal ms): Dr. Swift will supervise Dr. Poon’s research-related activities and 
advise him on an as-needed basis. He will also contribute to interpreting study results and writing abstracts 
and manuscripts. 
Lisa Suter, MD. Co-Investigator (0.6 cal ms yr 1 and 1.2 cal ms yrs 2-4): Dr. Suter will perform the cost-
effectiveness analysis and lead the abstracts and manuscripts related to these results.  
 
 


26 
 
REFERENCES CITED 
1. Asch SM, McGlynn EA, Hogan MM, et al. Comparison of quality of care for patients in the Veterans Health 
Administration and patients in a national sample. Ann Intern Med 2004;141:938-45. 
2. Felson DT, Lawrence RC, Hochberg MC, et al. Osteoarthritis: New Insights. Part 2: Treatment approaches. 
Ann Intern Med 000;133:726-37. 
3. Porcheret M, Jordan K, Jinks C, et al. Primary care treatment of knee pain. Rheumatology 2007;46:1694-
700. 
4. Bjordal JM, Ljunggren AE, Klovning A, Slørdal L. Non-steroidal anti-inflammatory drugs, including cyclo-
oxygenase-2 inhibitors, in osteoarthritic knee pain. BMJ 2004;329:1317-20. 
5. Scott DL, Berry H, Capell H.The long-term effects of non-steroidal anti-inflammatory drugs in osteoarthritis 
of the knee. Rheumatology 2000;39:1095-101. 
6. Bjordal JM, Klovning A, Ljunggren AE, Slørdal L. Short-term efficacy of pharmacotherapeutic interventions 
in osteoarthritic knee pain. Eur J Pain 2007;11:125-38. 
7. Vitiello MV, Rybarczyk B, Von Korff M, Stepanski EJ. Cognitive behavioral therapy for insomnia improves 
sleep and decreases pain in older adults with co-morbid insomnia and osteoarthritis. J Clin Sleep Med 
2009;15:355-62. 
8. Lin EHB. Depression and osteoarthritis. Am J Med 2008;121:S16-S9. 
9. Keefe FJ, Caldwell DS, Williams DA, et al. Pain coping skills training in the management of osteoarthritic 
knee pain: A comparative study. Behavior Therapy 1990;21:49-62. 
10. Keefe FJ, Caldwell DS, Williams DA, et al. Pain coping skills training in the management of osteoarthritic 
knee pain-II: Follow-up results. Behavior Therapy 1990;21:435-47. 
11. Kidd B, Langford R, Wodehouse T. Current approaches in the treatment of arthritic pain. Arthritis Res 
Therapy 2007;9. 
12. Jordan KP, Wilkie R, Muller S, Myers H, Nicholls E, et al. Measurement of change in function and disability 
in osteoarthritis: current approaches and future challenges. Curr Opin Rheumatol 2009;21:525-30. 
13. Kazis LE, Miller DR, Clark J, et al. Health-related quality of life in patients served by the Department of 
Veterans Affairs: Results from the Veterans Health Study. Arch Intern Med 1998;158:626-32. 
14. Briggs A, Scott E, Steele K. Impact of osteoarthritis and analgesic treatment on quality of life of an elderly 
population. Ann Pharmacotherapy 1999;33:1154-59. 
15. Kotlarz H, Gunnarsson CL, Fang H, Rizzo JA. Osteoarthritis and absenteeism costs: Evidence from US 
national survey data. J Occup Environ Med 2010;52:263-8. 
16. Dominick KL, Golightly YM, Jackson GL. Arthritis prevalence and symptoms among US non-veterans, 
veterans, and veterans receiving Department of Veterans Affairs Healthcare. J Rheumatol 2006;33:348-54. 
17. Hawker G, Wright J, Coyte P, et al. Health-related quality of life after knee replacement. J Bone Joint Surg 
Am 1998;80:163-73. 
18. Lee C, Straus WL, Balshaw R, Barlas S, Vogel S, Schnitzer TJ. A comparison of the efficacy and safety of 
nonsteroidal antiinflammatory agents versus acetaminophen in the treatment of osteoarthritis: A meta-analysis. 
Arthritis Care Res 2004;51:746-54. 
19. Jordan KM, Arden NK, Doherty M, et al. EULAR recommendations 2003: An evidence based approach to 
the management of knee osteoarthritis. Ann Rheum Dis 2003;62:1145-55. 
20. Meek IL, van de Laar MAFJ, E. Vonkeman H. Non-steroidal anti-inflammatory drugs: An overview of 
cardiovascular risks. Pharmaceuticals 2010;3:2146-62. 
21. Vonkeman HE, van de Laar MAFJ. Nonsteroidal anti-inflammatory drugs: Adverse effects and their 
prevention. Semin Arthritis Rheum 2010;39:294-312. 
22. Abraham NS, Castillo DL, Hartman C. National mortality following upper gastrointestinal or cardiovascular 
events in older veterans with recent nonsteroidal anti-inflammatory drug use. Alimentary Pharmacol Ther 
2008;28:97-106. 
23. Abraham NS, El-Serag HB, Johnson ML, et al. National adherence to evidence-based guidelines for the 
prescription of nonsteroidal anti-inflammatory drugs. Gastroenterology 2005;129:1171-8. 
24. Beck AT, Dozois DJA. Cognitive therapy: Current status and future directions. Ann Rev Med 2011;62. 
25. Turk DC, Meichenbaum D, Genest M. Pain and behavioral medicine: A cognitive- behavioral perspective. 
Guilford Press;1987. 
26. Naylor MR, Naud S, Keefe FJ, Helzer JE. Therapeutic interactive voice response to reduce analgesic 
medication use for chronic pain management. J Pain 2010;11:1410-9. 


27 
 
27. Calfas KJ, Kaplan RM, Ingram RE. One-year evaluation of cognitive-behavioral intervention in 
osteoarthritis. Arthritis Rheum 1992;5:202-9. 
28. Dixon KE, Keefe FJ, Scipio CD, Perri L, Caitlin M, Abernethy AP. Psychological interventions for arthritis 
pain management in adults: A meta-analysis. Health Psychol 2007;26:241-50. 
29. Cronan TA, Groessl E, Kaplan RM. The effects of social support and education interventions on health 
care costs. Arthritis Care Res 1997;10:99-110. 
30. Mazzuca SA, Brandt KD, Katz BP, Hanna MP, Melfi CA. Reduced utilization and cost of primary care clinic 
visits resulting from self-care education for patients with osteoarthritis of the knee. Arthritis Rheum 
1999;42:1267-73. 
31. Rene J, Weinberger M, Mazzuca SA, Brandt KD, Katz BP. Reducation of joint pain in patients with knee 
osteoarthritis who have received monthly telephone calls from lay personnel and whose medical treatment 
regimens have remained stable. Arthritis Rheum 1992;35:511-15. 
32. Maisiak R, Austin J, Heck L. Health outcomes of two telephone interventions for patients with rheumatoid 
arthritis or osteoarthritis. Arthritis Rheum 1996;39:1391-9. 
33. Allen KD, Oddone EZ, Coffman CJ, et al. Telephone-based self-management of osteoarthritis. Ann Intern 
Med 2010;153:570-9. 
34. Lovell K, Cox D, Haddock G, et al. Telephone administered cognitive behaviour therapy for treatment of 
obsessive compulsive disorder: Randomised controlled non-inferiority trial. BMJ 2006;333:883. 
35. Taylor S, Thordarson DS, Spring T, et al. Telephone-administered cognitive behavior therapy for 
obsessive-compulsive disorder. Cognitive Behav Ther 2003;32:13-25. 
36. Mohr D, Hart S, Marmar C. Telephone administered cognitive-behavioral therapy for the treatment of 
depression in a rural primary care clinic. Cognitive Ther Res 2006;30:29-37. 
37. DuHamel KN, Mosher CE, Winkel G, et al. Randomized clinical trial of telephone-administered cognitive-
behavioral therapy to reduce post-traumatic stress disorder and distress symptoms after hematopoietic stem-
cell transplantation. J Clin Oncol 2010;28:3754-61. 
38. Amery W, Dony JA. A clinical trial design avoiding undue placebo treatment. J Clin Pharmacol 
1975;15:674-9. 
39. Katz N. Enriched enrollment randomized withdrawal trial designs of analgesics: Focus on methodology. 
Clin J Pain 2009;25:797-807. 
40. Kopec JA, Abrahamowicz M, Esdaile JM. Randomized discontinuation trials: Utility and efficiency. J Clin 
Epidemiol 1993;46:959-71. 
41. Baron R, Freynhagen R, Tolle TR, et al. The efficacy and safety of pregabalin in the treatment of 
neuropathic pain associated with chronic lumbosacral radiculopathy. Pain 2010;150:420-7. 
42. Cibere J, Kopec JA, Thorne A, et al. Randomized, double-blind, placebo-controlled glucosamine 
discontinuation trial in knee osteoarthritis. Arthritis Rheum 2004;51:738-45. 
43. Crofford LJ, Mease PJ, Simpson SL, et al. Fibromyalgia relapse evaluation and efficacy for durability of 
meaningful relief: A 6-month, double-blind, placebo-controlled trial with pregabalin. Pain 2008;136:419-31. 
44. Friedmann N, Klutzaritz V, Webster L. Efficacy and safety of an extended-release oxycodone formulation in 
patients with moderate to severe osteoarthritic pain. J Opioid Management 2011;7:193-202. 
45. Gilron I, Wajsbrot D, Therrien F, Lemay J. Pregabalin for peripheral neuropathic pain: A multicenter, 
enriched enrollment randomized withdrawal placebo-controlled trial. Clin J Pain 2011;27:185-93. 
46. Hewitt DJ, Ho TW, Galer B, et al. Impact of responder definition on the enriched enrollment randomized 
withdrawal trial design for establishing proof of concept in neuropathic pain. Pain 2011;152:514-21. 
47. Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful 
diabetic peripheral neuropathy: Results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res 
Opin 2011;27:151-62. 
48. Alderson P, Chalmers I. Survey of claims of no effect in abstracts of Cochrane reviews. BMJ 2003;326:475. 
49. D'Agostino RB, Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues – the 
encounters of academic consultants in statistics. Stat Med 2003;22:169-86. 
50. Yocum D, Fleischmann R, Dalgin P, et al. Safety and efficacy of meloxicam in the treatment of 
osteoarthritis. Arch Intern Med 2000;160:2947-54. 
51. Layton D, Hughes K, Harris S, Shakir SAW. Comparison of the incidence rates of thromboembolic events 
reported for patients prescribed celecoxib and meloxicam in general practice in England using Prescription-
Event Monitoring data. Rheumatology 2003;42:1354-64. 


28 
 
52. Distel M, Mueller C, Bluhmki E, Fries J. Safety of meloxicam. Rheumatology 1996;35:68-77. 
53. Braithwaite RS, Omokaro C, Justice AC, Nucifora K, Roberts MS. Can broader diffusion of value-based 
insurance design increase benefits from US health care without increasing costs? In: PLoS Med; 2010. 
54. Suter LG, Fraenkel L, Braithwaite RS. The cost-effectiveness of adding magnetic resonance imaging to the 
management of early rheumatoid arthritis. Arch Intern Med 2011;171:657-67. 
55. Abraham NS, Hlatky MA, Antman EM, et al. A focused update of the ACCF/ACG/AHA 2008 expert 
consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Circulation 
2010;122:2619-33. 
56. Barkin RL, Buvanendran A. Focus on the COX-1 and COX-2 agents: Renal events of nonsteroidal and 
anti-inflammatory drugs. Am J Ther 2004;11:124-9. 
57. Davies NM, Reynolds JK, Undeberg MR, Gates BJ, Ohgami Y, Vega-Villa KR. Minimizing risks of NSAIDs: 
cardiovascular, gastrointestinal and renal. Expert Rev Neurother 2006;6:1643-55.  
58. Dieppe P, Bartlett C, Davey P, Doyal L, Ebrahim S. Balancing benefits and harms: The example of non-
steroidal anti-inflammatory drugs. BMJ;329:31-4. 
59. Hernandez-Diaz S, Garcia-Rodriguez LA. Epidemiologic assessment of the safety of conventional 
nonsteroidal anti-inflammatory drugs. Am J Med 2001;110 Suppl 3A:20S-7S. 
60. Brandt C, Nadkarni P. Web-based UMLS concept retrieval by automatic text scanning: A comparison of 
two methods. Comput Methods Programs Biomed 2001;64:37-43. 
61. Fisk JM, Mutalik P, Levin FW, Erdos J, Taylor C, Nadkarni P. Integrating query of relational and textual 
data in clinical databases: A case study. J Am Med Inform Assoc 2003;10:21-38. 
62. Konovalov S, Scotch M, Post L, Brandt C. Biomedical informatics techniques for processing and analyzing 
web blogs of military service members. J Med Internet Res 2010;12:e45. 
63. Womack J, Scotch M, Gibert C, et al. A comparison of two approaches to text processing: Facilitating chart 
reviews of radiology reports in electronic medical records. Perspect Health Inf Manag 2010;7:1a. 
64. Mazzuca SA, Brandt KD, Katz BP, et al. Subject retention and adherence in a randomized placebo-
controlled trial of a disease-modifying osteoarthritis drug. Arthritis Rheum 2004;51:933-40. 
65. Allen KD, Renner JB, Devellis B, Helmick CG, Jordan JM. Osteoarthritis and sleep: The Johnston County 
Osteoarthritis Project. J Rheumatol 2008;35:1102-7. 
66. Fabsitz R, Sholinsky P, Goldberg J. Correlates of sleep problems among men: The Vietnam Era Twin 
Registry. J Sleep Res 1997;6:50-6. 
67. Christensen R, Bartels EM, Astrup A, Bliddal H. Effect of weight reduction in obese patients diagnosed with 
knee osteoarthritis: A systematic review and meta-analysis. Ann Rheum Dis 2007;66:433-9. 
68. Messier SP. Diet and exercise for obese adults with knee osteoarthritis. Clin Geriatric Med 2010;26:461-77. 
69. Bennell KL, Hinman RS. A review of the clinical evidence for exercise in osteoarthritis of the hip and knee. 
J Sci Med Sport 2011;14:4-9. 
70. Hawker GA, Mian S, Bednis K, Stanaitis I. Osteoarthritis year 2010 in review: Non-pharmacologic therapy. 
Osteoarthritis Cartilage 2011;19:366-74. 
71. Otis JD. Managing chronic pain: A cognitive-behavioral therapy approach. New York: Oxford University 
Press; 2007. 
72. Zhao SZ, McMillen JI, Markenson JA, et al. Evaluation of the functional status aspects of health-related 
quality of life of patients with osteoarthritis treated with celecoxib. Pharmacotherapy 1999;19:1269-78. 
73. Boutron I, Estellat C, Ravaud P. A review of blinding in randomized controlled trials found results 
inconsistent and questionable. J Clin Epidemiol 2005;58:1220-6. 
74. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 Explanation and elaboration: updated guidelines 
for reporting parallel group randomised trials. BMJ 2010;340. 
75. Meenan RF, Gertman PM, Mason JH. Measuring health status in arthritis: The Arthritis Impact 
Measurement Scales. Arthritis Rheum1980;23:146-52. 
76. Sherbourne CD, Stewart AL. The MOS social support survey. Soc Sci Med 1991;32:705-14. 
77. Rogers JC, Irrgang JJ. Measures of adult lower extremity function. Arthritis Rheum 2003;49:S80-3. 
78. McConnell S, Kolopack P, Davis AM. The Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC): a review of its utility and measurement properties. Arthritis Rheum 2001;45:453-61. 
79. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: A health 
status instrument for measuring clinically important patient relevant outcomes to anti-rheumatic drug therapy in 
patients with osteoarthritis of the hip or knee. J Rheumatol 1988;15:1833-40. 


29 
 
80. Dunbar MJ, Robertsson O, Ryd L, Lidgren L. Appropriate questionnaires for knee arthroplasty: Results of a 
survey of 360 patients fom the Swedish knee arthroplasty registry. J Bone Joint Surg Br 2001;83:339-44. 
81. Brazier JE, Harper R, Munro J, Walters SJ, Snaith ML. Generic and condition-specific outcome measures 
for people with osteoarthritis of the knee. Rheumatology 1999;38:870-7. 
82. Ryser L, Wright BD, Aeschlimann A, Mariacher-Gehler S, Stucki G. A new look at the Western Ontario and 
McMAster Universities Osteoarthritis Index using rasch analysis. Arthritis Rheum 1999;12:331-5. 
83. Angst F, Aeschlimann A, Steiner W, Stucki G. Responsiveness of the WOMAC Osteoarthritis Index as 
compared with the SF-36 in patients with osteoarthritis of the legs undergoing a comprehensive rehabilitation 
program. Ann Rheum Dis 2001;60:834-40. 
84. Bellamy N, Campbell J, Hill J, Band P. A comparative study of telephone versus onsite completion of the 
WOMAC 3.0 osteoarthritis index. J Rheumatol 2002;29:783-6. 
85. Allen KD. The value of measuring variability in osteoarthritis pain. J Rheumatol 2007;34:2132-3. 
86. Hawker GA. Experiencing painful osteoarthritis: What have we learned from listening? Curr Opin 
Rheumatol 2009;21:507-12. 
87. Pruessner JC, Kirschbaum C, Meinlschmid G, Hellhammer DH. Two formulas for computation of the area 
under the curve represent measures of total hormone concentration versus time-dependent change. 
Psychoneuroendocrinology 2003;28:916-31. 
88. Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a disease-specific 
quality of life questionnaire. J Clin Epidemiol 1994;47:81-7. 
89. Turk DC, Dworkin RH, Allen RR, et al. Core outcome domains for chronic pain clinical trials: IMMPACT 
recommendations. Pain 2003;106:337-45. 
90. King A, Daniels J, Lim J, Cochrane DD, Taylor A, Ansermino JM. Time to listen: A review of methods to 
solicit patient reports of adverse events. Qual Safety Health Care 2010;19:148-57. 
91.Carroll, K.M., Nich, C., Sifry, R., et al.  A general system for evaluating therapist adherence and 
competence in psychotherapy research in the addictions. Drug and Alcohol Dependence 2000, 57:225-38.  
92. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. 
Clin Pharm Ther 1981;30:239-45. 
93. Woodworth T, Furst DE, Alten R, et al. Standardizing assessment and reporting of adverse effects in 
rheumatology clinical trials II. J Rheumatol 2007;34:1401-14. 
94. Strand V, Kelman A. Outcome measures in osteoarthritis: Randomized controlled trials. Curr Rheumatol 
Reports 2004;6:20-30. 
95. Rubin DB. Multiple imputation after 18+ years (with discussion). J Am Stat Assoc 1996:473-89. 
96. Schafer JL. Analysis of incomplete multivariate data. London: Chapman & Hall; 1997. 
97. Scott Long J. Regression models for categorical and limited dependent variables. Advanced quantitative 
techniques in the social sciences: Sage Publications; 1997. 
98. Jones BL, Nagin DS. Advances in group-based trajectory modeling and an sas procedure for estimating 
them. Sociol Methods Res 2007;35:542-71. 
99. Lane P. Handling drop-out in longitudinal clinical trials. Pharmaceutical Stat 2008;7:93-106. 
100. 
Feeny D, Furlong W, Torrance GW, et al. Multiattribute and single-attribute utility functions for the 
Health Utilities Index Mark 3 system. Med Care 2002;40:113-28. 
101. 
Grootendorst P, Feeny D, Furlong W. Health Utilities Index Mark 3: Evidence of construct validity for 
stroke and arthritis in a population health survey. Med Care 2000;38:290-9. 
102. 
Luo N, Johnson JA, Shaw JW, Coons SJ. Relative efficiency of the EQ-5D, HUI2, and HUI3 Index 
scores in measuring health burden of chronic medical conditions in a population health survey in the United 
States. Med Care 2009;47:53-60. 
103. 
Gold MR, Siegel JE, Russell LB, Weintstein MC. Cost effectiveness in health and medicine. New York: 
Oxford University Press;1996. 
104. 
Phibbs CS, Bhandari A, Yu W, Barnett PG. Estimating the costs of VA ambulatory care. Med Care Res 
Rev 2003;60:54S-73S. 
105. 
Turner JA, Clancy S. Comparison of operant-behavioral and cognitive-behavioral group treatment for 
chronic low back pain. J Consulting Clin Psychol 1990;58:573-9. 
106. 
Paykel ES, Scott J, Cornwall PL, et al. Duration of relapse prevention after cognitive therapy in residual 
depression: Follow-up of controlled trial. Psychological Med 2005;35:59-68. 


30 
 
107. 
Decision making in health care: Theory, psychology, and applications. New York: Cambridge University 
Press; 2003. 
108. 
Krahn MD, Naglie G, Naimark D, Redelmeier DA, Detsky AS. Primer on medical decision analysis: 
Analyzing the model and interpreting the results. Med Decis Making 1997;17:142-51