Baseline Features and Reasons for Nonparticipation in the Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) Study, a Colorectal Cancer Screening Trial.

Importance: The Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) randomized clinical trial sought to recruit 50 000 adults into a study comparing colorectal cancer (CRC) mortality outcomes after randomization to either an annual fecal immunochemical test (FIT) or colonoscopy. Objective: To (1) describe study participant characteristics and (2) examine who declined participation because of a preference for colonoscopy or stool testing (ie, fecal occult blood test [FOBT]/FIT) and assess that preference's association with geographic and temporal factors. Design, Setting, and Participants: This cross-sectional study within CONFIRM, which completed enrollment through 46 Department of Veterans Affairs medical centers between May 22, 2012, and December 1, 2017, with follow-up planned through 2028, comprised veterans aged 50 to 75 years with an average CRC risk and due for screening. Data were analyzed between March 7 and December 5, 2022. Exposure: Case report forms were used to capture enrolled participant data and reasons for declining participation among otherwise eligible individuals. Main Outcomes and Measures: Descriptive statistics were used to characterize the cohort overall and by intervention. Among individuals declining participation, logistic regression was used to compare preference for FOBT/FIT or colonoscopy by recruitment region and year. Results: A total of 50 126 participants were recruited (mean [SD] age, 59.1 [6.9] years; 46 618 [93.0%] male and 3508 [7.0%] female). The cohort was racially and ethnically diverse, with 748 (1.5%) identifying as Asian, 12 021 (24.0%) as Black, 415 (0.8%) as Native American or Alaska Native, 34 629 (69.1%) as White, and 1877 (3.7%) as other race, including multiracial; and 5734 (11.4%) as having Hispanic ethnicity. Of the 11 109 eligible individuals who declined participation (18.0%), 4824 (43.4%) declined due to a stated preference for a specific screening test, with FOBT/FIT being the most preferred method (2820 [58.5%]) vs colonoscopy (1958 [40.6%]; P < .001) or other screening tests (46 [1.0%] P < .001). Preference for FOBT/FIT was strongest in the West (963 of 1472 [65.4%]) and modest elsewhere, ranging from 199 of 371 (53.6%) in the Northeast to 884 of 1543 (57.3%) in the Midwest (P = .001). Adjusting for region, the preference for FOBT/FIT increased by 19% per recruitment year (odds ratio, 1.19; 95% CI, 1.14-1.25). Conclusions and Relevance: In this cross-sectional analysis of veterans choosing nonenrollment in the CONFIRM study, those who declined participation more often preferred FOBT or FIT over colonoscopy. This preference increased over time and was strongest in the western US and may provide insight into trends in CRC screening preferences.

Impact of Department of Veterans Affairs Cooperative Studies Program clinical trials on practice guidelines for high blood pressure management.

Knowing the extent to which a clinical trial's findings translate into clinical practice can be challenging. One practical approach to estimating a trial's influence on clinical practice can be achieved by assessing how the trial informed relevant clinical practice guidelines (CPGs). Accordingly, the objectives of this study were to provide an overview of all the clinical trials involving the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) that aimed at informing or resulted in informing the management of high blood pressure and to identify and describe the extent to which these trials informed CPGs for the management of high blood pressure. A total of 26 clinical trials involving the VA CSP were identified. Using bibliographic information, 21 CPGs for the management of hypertension representing over 40 years of treatment recommendations from eight collectives were evaluated to determine how they were informed by trials involving the VA CSP. From 1977 to 2018, 13 of the 26 trials (50.0%) were found to have informed 19 of the 21 CPGs (90.5%) a total of 54 times (mean = 2.6 trial citations per CPG, SD ±â€¯1.8). Clinical trials involving the VA CSP have informed a sizeable proportion of CPGs for the management of high blood pressure over the past 40 years. Because of this impact on the CPGs, these trials are also likely to have had at least moderate influence on clinical practice.

Total integrated performance excellence system (TIPES): A true north direction for a clinical trial support center.

This paper presents the quality journey taken by a Federal organization over more than 20 years. These efforts have resulted in the implementation of a Total Integrated Performance Excellence System (TIPES) that combines key principles and practices of established quality systems. The Center has progressively integrated quality system frameworks including the Malcom Baldrige National Quality Award (MBNQA) Framework and Criteria for Performance Excellence, ISO 9001, and the Organizational Project Management Maturity Model (OPM3), as well as supplemental quality systems of ISO 15378 (packaging for medicinal products) and ISO 21500 (guide to project management) to systematically improve all areas of operations. These frameworks were selected for applicability to Center processes and systems, consistency and reinforcement of complimentary approaches, and international acceptance. External validations include the MBNQA, the highest quality award in the US, continued registration and conformance to ISO standards and guidelines, and multiple VA and state awards. With a focus on a holistic approach to quality involving processes, systems and personnel, this paper presents activities and lessons that were critical to building TIPES and establishing the quality environment for conducting clinical research in support of Veterans and national health care.

Colonoscopy vs. Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM): Rationale for Study Design.

RATIONALE: Colorectal cancer (CRC) is preventable through screening, with colonoscopy and fecal occult blood testing comprising the two most commonly used screening tests. Given the differences in complexity, risk, and cost, it is important to understand these tests' comparative effectiveness. STUDY DESIGN: The CONFIRM Study is a large, pragmatic, multicenter, randomized, parallel group trial to compare screening with colonoscopy vs. the annual fecal immunochemical test (FIT) in 50,000 average risk individuals. CONFIRM examines whether screening colonoscopy will be superior to a FIT-based screening program in the prevention of CRC mortality measured over 10 years. Eligible individuals 50-75 years of age and due for CRC screening are recruited from 46 Veterans Affairs (VA) medical centers. Participants are randomized to either colonoscopy or annual FIT. Results of colonoscopy are managed as per usual care and study participants are assessed for complications. Participants testing FIT positive are referred for colonoscopy. Participants are surveyed annually to determine if they have undergone colonoscopy or been diagnosed with CRC. The primary endpoint is CRC mortality. The secondary endpoints are (1) CRC incidence (2) complications of screening colonoscopy, and (3) the association between colonoscopists' characteristics and neoplasia detection, complications and post-colonoscopy CRC. CONFIRM leverages several key characteristics of the VA's integrated healthcare system, including a shared medical record with national databases, electronic CRC screening reminders, and a robust national research infrastructure with experience in conducting large-scale clinical trials. When completed, CONFIRM will be the largest intervention trial conducted within the VA (ClinicalTrials.gov identifier: NCT01239082).

Safety of zoster vaccine in elderly adults following documented herpes zoster.

BACKGROUND: After completion of the Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Studies Program Number 403), SPS participants who had initially received placebo were offered investigational zoster vaccine without charge. This provided an opportunity to determine the relative safety of zoster vaccine in older adults following documented herpes zoster (HZ). METHODS: A total of 13 681 SPS placebo recipients who elected to receive zoster vaccine were followed for serious adverse events (SAE) for 28 days after vaccination. In contrast to the SPS, a prior episode of HZ was not a contraindication to receiving zoster vaccine. The SPS placebo recipients who received zoster vaccine included 420 who had developed documented HZ during the SPS. RESULTS: The mean interval between the onset of HZ and the receipt of zoster vaccine in the 420 recipients with prior HZ was 3.61 years (median interval, 3.77 years [range, 3-85 months]); the interval was <5 years for approximately 80% of recipients. The proportion of vaccinated SPS placebo recipients with prior HZ who developed ≥ 1 SAE (0.95%) was not significantly different from that of vaccinated SPS placebo recipients with no prior history of HZ (0.66%), and the distribution of SAEs in the 2 groups was comparable. CONCLUSIONS: These results demonstrate that the general safety of zoster vaccine in older persons is not altered by a recent history of documented HZ, supporting the safety aspect of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommendation to administer zoster vaccine to all persons ≥ 60 years of age with no contraindications, regardless of a prior history of HZ.

Integrating tobacco cessation into mental health care for posttraumatic stress disorder: a randomized controlled trial.

CONTEXT: Most smokers with mental illness do not receive tobacco cessation treatment. OBJECTIVE: To determine whether integrating smoking cessation treatment into mental health care for veterans with posttraumatic stress disorder (PTSD) improves long-term smoking abstinence rates. DESIGN, SETTING, AND PATIENTS: A randomized controlled trial of 943 smokers with military-related PTSD who were recruited from outpatient PTSD clinics at 10 Veterans Affairs medical centers and followed up for 18 to 48 months between November 2004 and July 2009. INTERVENTION: Smoking cessation treatment integrated within mental health care for PTSD delivered by mental health clinicians (integrated care [IC]) vs referral to Veterans Affairs smoking cessation clinics (SCC). Patients received smoking cessation treatment within 3 months of study enrollment. MAIN OUTCOME MEASURES: Smoking outcomes included 12-month bioverified prolonged abstinence (primary outcome) and 7- and 30-day point prevalence abstinence assessed at 3-month intervals. Amount of smoking cessation medications and counseling sessions delivered were tested as mediators of outcome. Posttraumatic stress disorder and depression were repeatedly assessed using the PTSD Checklist and Patient Health Questionnaire 9, respectively, to determine if IC participation or quitting smoking worsened psychiatric status. RESULTS: Integrated care was better than SCC on prolonged abstinence (8.9% vs 4.5%; adjusted odds ratio, 2.26; 95% confidence interval [CI], 1.30-3.91; P = .004). Differences between IC vs SCC were largest at 6 months for 7-day point prevalence abstinence (78/472 [16.5%] vs 34/471 [7.2%], P < .001) and remained significant at 18 months (86/472 [18.2%] vs 51/471 [10.8%], P < .001). Number of counseling sessions received and days of cessation medication used explained 39.1% of the treatment effect. Between baseline and 18 months, psychiatric status did not differ between treatment conditions. Posttraumatic stress disorder symptoms for quitters and nonquitters improved. Nonquitters worsened slightly on the Patient Health Questionnaire 9 relative to quitters (differences ranged between 0.4 and 2.1, P = .03), whose scores did not change over time. CONCLUSION: Among smokers with military-related PTSD, integrating smoking cessation treatment into mental health care compared with referral to specialized cessation treatment resulted in greater prolonged abstinence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00118534.

Safety of herpes zoster vaccine in the shingles prevention study: a randomized trial.

BACKGROUND: The herpes zoster vaccine is effective in preventing herpes zoster and postherpetic neuralgia in immunocompetent older adults. However, its safety has not been described in depth. OBJECTIVE: To describe local adverse effects and short- and long-term safety profiles of herpes zoster vaccine in immunocompetent older adults. DESIGN: Randomized, placebo-controlled trial with enrollment from November 1998 to September 2001 and follow-up through April 2004 (mean, 3.4 years). A Veterans Affairs Coordinating Center generated the permutated block randomization scheme, which was stratified by site and age. Participants and follow-up study personnel were blinded to treatment assignments. (ClinicalTrials.gov registration number: NCT00007501) SETTING: 22 U.S. academic centers. PARTICIPANTS: 38 546 immunocompetent adults 60 years or older, including 6616 who participated in an adverse events substudy. INTERVENTION: Single dose of herpes zoster vaccine or placebo. MEASUREMENTS: Serious adverse events and rashes in all participants and inoculation-site events in substudy participants during the first 42 days after inoculation. Thereafter, vaccination-related serious adverse events and deaths were monitored in all participants, and hospitalizations were monitored in substudy participants. RESULTS: After inoculation, 255 (1.4%) vaccine recipients and 254 (1.4%) placebo recipients reported serious adverse events. Local inoculation-site side effects were reported by 1604 (48%) vaccine recipients and 539 (16%) placebo recipients in the substudy. A total of 977 (56.6%) of the vaccine recipients reporting local side effects were aged 60 to 69 years, and 627 (39.2%) were older than 70 years. After inoculation, herpes zoster occurred in 7 vaccine recipients versus 24 placebo recipients. Long-term follow-up (mean, 3.39 years) showed that rates of hospitalization or death did not differ between vaccine and placebo recipients. LIMITATIONS: Participants in the substudy were not randomly selected. Confirmation of reported serious adverse events with medical record data was not always obtained. CONCLUSION: Herpes zoster vaccine is well tolerated in older, immunocompetent adults. PRIMARY FUNDING SOURCE: Cooperative Studies Program, Department of Veterans Affairs, Office of Research and Development; grants from Merck to the Veterans Affairs Cooperative Studies Program; and the James R. and Jesse V. Scott Fund for Shingles Research.

Pharmacoeconomic analysis of angiotensin-converting enzyme inhibitors in type 2 diabetes: a Markov model.

BACKGROUND: Prevention of cardiovascular disease (CVD) events by initiating an angiotensin-converting enzyme (ACE) inhibitor on diagnosis of type 2 diabetes may increase survival and decrease costs. OBJECTIVE: To determine the incremental cost-effectiveness ratios of ACE inhibitor initiation in normoalbuminuric, microalbuminuric, and macroalbuminuric patients with newly diagnosed type 2 diabetes. METHODS: A cohort of patients with newly diagnosed type 2 diabetes was followed for 8 years in a Markov model. Clinical outcomes included CVD events, dialysis, all-cause mortality, and the composite endpoints of the 3 events. Probabilities and costs were obtained from the literature. One-way and two-way sensitivity analyses were conducted to test the robustness of the model. RESULTS: Implementation of ACE inhibitor therapy on diagnosis of type 2 diabetes in normoalbuminuric and microalbuminuric patients is a dominant strategy (ie, more effective and less costly) across all outcomes. In macroalbuminuric patients, an additional $4.10 and $4.58 saves one life and avoids one composite endpoint, respectively; however, in these patients, not giving an ACE inhibitor is dominant for prevention of CVD events and dialysis. This is due to a 28.62% higher mortality rate in patients not receiving an ACE inhibitor. Thus, analysis of the composite endpoint shows that not giving an ACE inhibitor does not remain dominant. A limitation of our study is the inability to determine causality. CONCLUSIONS: If every newly diagnosed patient with type 2 diabetes in the US was prescribed an ACE inhibitor, our model shows that 68,314 CVD events would be averted, 46,410 lives would be saved, and 48 people would be prevented from needing dialysis over 8 years. These findings suggest that ACE inhibitors prevent numerous events in patients with type 2 diabetes who are normoalbuminuric at diagnosis, in addition to those already identified as being at risk for CVD events.

Integrating smoking cessation into mental health care for post-traumatic stress disorder.

BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with a high prevalence of smoking, heavy cigarette consumption and low cessation rates. PURPOSE: This manuscript describes the design of a randomized, multisite effectiveness trial to test whether integrating smoking cessation treatment into mental health care (integrated care) improves prolonged abstinence rates among veterans with PTSD, compared with referral to specialized smoking cessation clinics (usual standard of care). Secondary objectives are to assess the cost-effectiveness of integrated care relative to usual standard of care, identify treatment variables that mediate differences between conditions in outcome and determine whether smoking cessation is associated with worsening PTSD and/or depression. METHODS: Following randomization, subjects (projected n = 1400) from 10 Veterans Health Administration (VHA) medical centers complete follow-up assessments every three or six months for up to four years. Endpoints include 1-year prolonged abstinence at 18 months postrandomization, 7- and 30-day point-prevalence abstinence and measures of depression, PTSD and economic outcomes. RESULTS: This study is unique in providing the largest scale test of the feasibility and effectiveness of having mental health clinicians implement evidence-based smoking cessation treatment in psychiatric care settings for veterans with PTSD. It incorporates methodological features that are desirable for cessation treatment trials, including: a) assessment of clinically meaningful long-term smoking outcomes; b) a manual guiding delivery of the experimental intervention; c) independent ratings of clinician competence and treatment adherence and d) methods for training clinicians that would enhance implementation of tobacco cessation treatment in large health care systems. LIMITATIONS: Use of an exclusively VHA sample with few females limits generalizability. CONCLUSIONS: The process for meeting challenges in designing this study may provide planning of other large-scale clinical effectiveness trials in tobacco control. Findings have potential to initiate system-wide change in clinical practice patterns for tobacco cessation treatment involving patients with mental disorders.

Benefits and harms of doxycycline treatment for Gulf War veterans' illnesses: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: It has been hypothesized that certain Mycoplasma species may cause Gulf War veterans' illnesses (GWVIs), chronic diseases characterized by pain, fatigue, and cognitive symptoms, and that affected patients may benefit from doxycycline treatment. OBJECTIVE: To determine whether a 12-month course of doxycycline improves functional status in Gulf War veterans with GWVIs. DESIGN: A randomized, double-blind, placebo-controlled clinical trial with 12 months of treatment and 6 additional months of follow-up. SETTING: 26 U.S. Department of Veterans Affairs and 2 U.S. Department of Defense medical centers. PARTICIPANTS: 491 deployed Gulf War veterans with GWVIs and detectable Mycoplasma DNA in the blood. INTERVENTION: Doxycycline, 200 mg, or matching placebo daily for 12 months. MEASUREMENTS: The primary outcome was the proportion of participants who improved more than 7 units on the Physical Component Summary score of the Veterans Short Form-36 General Health Survey 12 months after randomization. Secondary outcomes were measures of pain, fatigue, and cognitive function and change in positivity for Mycoplasma species at 6, 12, and 18 months after randomization. RESULTS: No statistically significant differences were found between the doxycycline and placebo groups for the primary outcome measure (43 of 238 participants [18.1%] vs. 42 of 243 participants [17.3%]; difference, 0.8 percentage point [95% CI, -6.5 to 8.0 percentage points]; P > 0.2) or for secondary outcome measures at 1 year. In addition, possible differences in outcomes at 3 and 6 months were not apparent at 9 or 18 months. Participants in the doxycycline group had a higher incidence of nausea and photosensitivity. LIMITATIONS: Adherence to treatment after 6 months was poor. CONCLUSION: Long-term treatment with doxycycline did not improve outcomes of GWVIs at 1 year.

Efficacy trial of live, cold-adapted and inactivated influenza virus vaccines in older adults with chronic obstructive pulmonary disease: a VA cooperative study.

We assessed whether trivalent live, cold-adapted influenza virus (CAIV-T) vaccine provides added protection when co-administered with trivalent inactivated influenza virus vaccine (TVV) in patients with chronic obstructive pulmonary disease (COPD). Subjects (N=2215) were randomly assigned to receive either TVV intramuscularly (IM) and CAIV-T intranasally (TC), or TVV and placebo (TP). The vaccines were well-tolerated. Efficacy of TC compared to TP was not statistically significant and was 0.16 for any influenza virus strain (95% confidence limit (CL): -0.22, 0.43), 0.26 for A (H3N2) virus (95% CL: -0.17, 0.53), and -0.05 for type B virus (95% CL: -1.13, 0.48). However, there was a possible advantage for TC over TP in reducing respiratory consequences of an influenza season measured by pulmonary function and symptoms at end of study.

The antibiotic treatment trial of Gulf War Veterans' Illnesses: issues, design, screening, and baseline characteristics.

Many veterans who were deployed to the Persian Gulf during the 1990-1991 Gulf War developed multiple unexplained symptoms such as pain, fatigue, and neurocognitive problems. This constellation of symptoms has been termed Gulf War Veterans' Illnesses (GWVI). Although there is no proven explanation for the cause of GWVI, one fairly widespread explanation is systemic Mycoplasma fermentans infection. The Antibiotic Treatment Trial of GWVI is a randomized placebo-controlled trial to determine whether a 1-year course of doxycycline treatment in deployed Gulf War veterans with GWVI and testing as Mycoplasma species positive will improve their overall functional status as measured by the Physical Component Summary of the SF-36V questionnaire. The study of a multisymptom illness such as GWVI is complicated by the nonspecific nature of the illness, the unknown etiology, and the lack of a widely accepted outcome measure. The presumption of mycoplasma infection raises concerns regarding the methodology for determination of mycoplasma infection, the choice of treatment, and the duration of treatment. However, such a presumption allows the formulation of a clear testable hypothesis that can be tested with treatments with known rates of adverse events and known activity against Mycoplasma species. This paper describes the major issues faced by the investigators during planning, the study design, the patient screening results, and the baseline characteristics of the study patients. There were 2712 patients screened for study entry at 26 Department of Veterans Affairs and two Department of Defense medical centers. Of these, 491 met all study entry criteria and were randomized to either 1 year of doxycycline (200 mg/day) or 1 year of placebo. All patients were seen monthly during treatment and at 6 months after the end of treatment. Study patients had a mean age of 41 years and were mostly male (86%), white (64%), married (68%), and employed full-time (71%).

Opioid dependence treatment, including buprenorphine/naloxone.

OBJECTIVE: To review opioid dependence (OD) and its treatment. Pharmacologic treatments, including the use of buprenorphine/naloxone, are presented. Pharmaceutical care functions for outpatient OD treatment are discussed. DATA SOURCES: Primary and review articles were identified by MEDLINE and HEALTHSTAR searches (from 1966 to November 2000) and through secondary sources. Tertiary sources were also reviewed regarding general concepts of OD and its treatment. STUDY SELECTION/DATA EXTRACTION: Relevant articles were reviewed after identification from published abstracts. Articles were selected based on the objectives for this article. Studies of the treatment of OD with buprenorphine were selected based on the topic (pharmacology, pharmacokinetics, adverse reactions) and study design (randomized, controlled clinical trials in patients with OD with active/placebo comparisons and/or comparisons of active OD treatments). Articles regarding pharmacists' activities in the treatment and prevention of OD were reviewed for the pharmaceutical care section. DATA SYNTHESIS: OD is considered a medical disorder with costly adverse health outcomes. Although methadone maintenance treatment (MMT) is cost-effective for OD, only about 12% of individuals with OD receive this treatment. Psychological and pharmacologic modalities are used to treat OD, but patients often relapse. Drug therapy includes alpha 2-agonists for withdrawal symptoms, detoxification regimens with or without opioids, opioid antagonists, and opioid replacement including methadone, levomethadyl acetate, and buprenorphine. The Drug Addiction Treatment Act of 1999 allows for office-based opioid replacement therapies. Sublingual buprenorphine with naloxone can be used in this milieu. Buprenorphine with naloxone is currently under new drug application review with the Food and Drug Administration. Clinical research shows buprenorphine to be equal in effectiveness to methadone, but safer in overdose due to its ceiling effect on respiratory depression. It has lower abuse potential and fewer withdrawal symptoms when discontinued. Naloxone is included to decrease diversion and injection of the tablets. Pharmacists in outpatient settings who are familiar with OD have opportunities to provide pharmaceutical care to patients receiving this treatment. Pharmaceutical care functions for OD include ensuring appropriate drug administration, monitoring adverse effects, alleviating withdrawal symptoms, treating intercurrent illnesses, minimizing diversion, and preventing relapse. CONCLUSIONS: OD is a critical unmet health problem in the US. Buprenorphine combined with naloxone represents an innovative treatment for OD in outpatient settings. This new treatment has advantages over MMT.