Efficacy and Safety of Mifepristone in the Treatment of Male US Veterans With Posttraumatic Stress Disorder: A Phase 2a Randomized Clinical Trial.

Importance: To date, no psychopharmacologic treatment has been found to be uniformly effective in veterans with posttraumatic stress disorder (PTSD); novel targets and approaches are needed to treat this disabling disorder. Objective: To examine whether treatment with the glucocorticoid receptor antagonist mifepristone yields a signal for clinical efficacy in male veterans with PTSD. Design, Setting, and Participants: This phase 2a, double-blind, parallel-group randomized clinical trial was conducted from November 19, 2012 (accrual started), through November 16, 2016 (final follow-up), within the US Department of Veterans Affairs. Participants were male veterans with chronic PTSD and a screening Clinician-Administered PTSD Scale score of 50 or higher. A total of 181 veterans consented to participation. Statistical analysis was conducted between August 2014 and May 2017. Interventions: Participants were randomized in a 1:1 ratio to mifepristone (600 mg) or matched placebo taken orally for 7 days. Main Outcomes and Measures: The clinical outcome was whether a veteran achieved a clinical response status (a reduction of ≥30% of total Clinician-Administered PTSD Scale score from baseline) at 4- and 12-week follow-up. On the basis of a binary statistical selection rule, a difference in the proportion of treatment vs control group responders of 15% would be a clinically relevant difference. Self-report measures of PTSD and associated symptoms were also obtained. Neuroendocrine outcomes and plasma levels of mifepristone were measured. Safety was assessed throughout the study. The primary analysis was based on a multiple imputation technique to address missing outcome data; thus, some participant numbers may not appear as whole numbers. Results: A total of 81 veterans were enrolled and randomized. Excluding 1 participant randomized in error, 80 were included in the modified intention-to-treat analysis (41 randomized to mifepristone and 39 to placebo). The mean (SD) age was 43.1 (13.7) years. A total of 15.6 (38.1%) in the mifepristone group and 12.1 (31.1%) in the placebo group were clinical responders at 4 weeks in the analysis using the multiple imputation technique. The group difference in the proportion of clinical responders (7.0%) was less than the predefined margin of 15% indicating signal for clinical efficacy. In an exploratory analysis, the difference in response to mifepristone vs placebo in the subgroup with no lifetime history of traumatic brain injury (TBI) (7.0 [50.0%] vs 3.0 [27.3%]; difference, 22.7%) exceeded the efficacy margin at 4 weeks and was sustained at 12 weeks. In contrast, in veterans with PTSD and lifetime TBI, the response rate to mifepristone was lower than placebo at 12 weeks (7.4 [27.4%] vs 13.5 [48.3%]; difference, -20.9%). Conclusions and Relevance: This study did not detect a signal for efficacy for mifepristone at 600 mg/d for 1 week in male veterans with chronic PTSD. Thus, this study does not support a phase 3 trial in this population. Future studies of mifepristone for the treatment of PTSD may be of interest in those without a history of TBI or in samples with a low base rate of lifetime head trauma. Trial Registration: ClinicalTrials.gov Identifier: NCT01946685.

Effect of Pulsed Low-Intensity Ultrasonography on Symptom Relief and Tibiofemoral Articular Cartilage Thickness Among Veterans Affairs Enrollees With Knee Osteoarthritis: A Randomized Clinical Trial.

Importance: Osteoarthritis (OA) is a major cause of disability in the US, with no approved treatments to slow progression, but animal models suggest that pulsed low-intensity ultrasonography (PLIUS) may promote cartilage growth. Objective: To evaluate the efficacy of PLIUS in providing symptom reduction and decreased loss of tibiofemoral cartilage thickness in patients with knee OA. Design, Setting, and Participants: A phase 2A, sham-controlled, parallel, double-blind randomized clinical trial was conducted at 2 Veterans Affairs hospitals in Salt Lake City, Utah, and San Diego, California, from May 22, 2015, to January 31, 2019. Data were analyzed from June 27, 2020, to October 20, 2020. Participants recruited through the US Department of Veterans Affairs (N = 132) with clinical and radiographic evidence of early knee OA were randomly assigned to receive PLIUS or a sham device, self-administered for 20 minutes daily over the medial compartment of the knee. All enrollees participated in a 4-week prerandomization sham run-in period, followed by a 48-week treatment period. Randomization was stratified by study site and Kellgren-Lawrence grades 1 (n = 15), 2 (n = 51), and 3 (n = 66). Intervention: Participants either received 48 weeks of PLIUS or sham ultrasonography. Main Outcomes and Measures: The trial incorporated 2 coprimary outcomes: symptomatic improvement assessed by Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International Responder Criteria (ie, met if either >50% improvement in pain and function with at least a 20% absolute improvement of at least 2 of the following 3 factors: improvement by at least 20% [pain, function, and patient global assessment] with at least a 10-mm absolute improvement), and cartilage preservation assessed as change in central medial femoral condyle cartilage thickness by magnetic resonance imaging. Intention-to-treat analysis was used. Results: The mean (SD) participant age was 63.6 (10.7) years and 119 were men (90.2%). The mean (SD) duration of OA symptoms was 13.4 (12.3) years. In the PLIUS group, 70.4% (95% CI, 58.2%-82.6%) of the participants experienced symptomatic improvement, compared with 67.3% (95% CI, 54.9%-79.7%) of participants in the sham group (P = .84); there was no statistically significant difference in response rates between the treatment groups, and the between-group rate difference of 3.1% (95% CI, -14.3% to 20.5%) did not meet the predefined 10% threshold for clinically significant symptomatic improvement from application of PLIUS. At 48 weeks of treatment, central medial femoral condyle cartilage thickness decreased by a mean (SD) of 73.8 (168.1) µm in the PLIUS group and by 42.2 (297.0) µm in the sham group. This 48-week mean change between the 2 groups did not reach statistical significance (P = .44), and the between-group 48-week difference of -31.7 µm (95% CI, -129.0 µm to 65.7 µm) did not meet the predefined threshold. There were 99 nonserious adverse events in the PLIUS group and 89 in the sham group during the trial. No serious adverse events were deemed related to the study device. Conclusions and Relevance: PLIUS, as implemented in this study, demonstrated neither symptomatic benefit nor a decrease in loss of tibiofemoral cartilage thickness in knee OA. Trial Registration: ClinicalTrials.gov Identifier: NCT02034409.

Rivastigmine Transdermal Patch Treatment for Moderate to Severe Cognitive Impairment in Veterans with Traumatic Brain Injury (RiVET Study): A Randomized Clinical Trial.

Cognitive impairment is common in veterans with histories of traumatic brain injury (TBI). Cholinergic deficits have been hypothesized as contributors to this impairment. We report the effects of cholinesterase inhibitor rivastigmine transdermal patch treatment in veterans with TBI and post-traumatic memory impairment. Our objective was to evaluate the efficacy and safety of a 9.5 mg/24 h (10 cm2) rivastigmine patch in veterans of military conflicts with persistent moderate to severe memory impairment at least 12 weeks after TBI. This randomized, outpatient, double-blind, placebo-controlled 12-week trial with an exploratory double-blind phase of an additional 14 weeks was conducted at 5 VA Medical Centers, among veterans with closed, non-penetrating TBI who met or exceeded modified American Congress of Rehabilitation Medicine criteria for mild TBI with verbal memory deficits, as assessed by the Hopkins Verbal Learning Test, Revised (HVLT-R). Patients were randomized 1:1 to rivastigmine or matching placebo patches after a 1-week single-blind, placebo run-in phase. At randomization, patients received 4.6 mg/24 h rivastigmine patches or matching placebo increased to a 9.5 mg/24 h patch after 4 weeks. The primary efficacy outcome measure was the proportion of participants who had at least a five-word improvement on the HVLT-R Total Recall Index (Trials 1-3). A total of 3671 participants were pre-screened, of whom 257 (7.0%) were screened; 96 (37%) randomized, and 94 included in study analyses. Responder rates were 40.8% (20 of 49) and 51.1% (23 of 45) in the rivastigmine and placebo groups, respectively (p = 0.41). A mixed-effect model including treatment, time, and treatment-by-time interaction indicated no significant difference in treatment effect over time between the groups (p = 0.24). Overall, there were no significant differences in changes for all secondary outcomes between the rivastigmine and placebo groups. The most commonly observed adverse events were application site reactions. This trial provides the largest sample to date of veterans with TBI and post-traumatic memory deficits enrolled in a pharmacological trial. Trial Registration: clinicaltrials.gov Identifier: NCT01670526.

Blood pressure control and factors predicting control in a treatment-compliant male veteran population.

STUDY OBJECTIVE: To estimate blood pressure control and identify treatment variables predicting control in treatment-compliant, hypertensive, male veterans. SETTING: Outpatient clinic of a Veterans Affairs medical center. DESIGN: Retrospective review of computerized patient records over a 12-month period for demographics, comorbidities, patient-specific blood pressure goals, blood pressure history, antihypertensive therapy, and refill history. PATIENTS: Two hundred fifty hypertensive men aged 39-90 years whose antihypertensive regimen remained unchanged over 12 months. MEASUREMENTS AND MAIN RESULTS: The proportion of patients with blood pressures below 160/90 mm Hg was 86%; only 34.8% had pressures below 140/90 mm Hg. Blood pressure control was less common with advancing age (42.1%, 33.7%, and 29.4% for patients aged < 60, 60-75, and > 75 yrs, respectively, p = 0.057 for trend). Treatment intensity was highest in obese men, those aged 60-75 years, and those with a history of chronic heart failure or angina, and lowest in men older than 75 years or with a history of stroke. Blood pressure control was independently associated with therapy with beta-blockers (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.5-10.2, p = 0.005), loop diuretics (OR 4.3, 95% CI 1.6-12.1, p = 0.005), angiotensin-converting enzyme inhibitors (OR 3.1, 95% CI 1.2-8.2, p = 0.025), and long-term simvastatin therapy (OR 3.7, 95% CI 1.9-7.4, p = 0.0001), and with a diagnosis of coronary artery disease (OR 3.2, 95% CI 1.35-7.69, p = 0.009). The relationship between simvastatin therapy and blood pressure control persisted after controlling for the higher treatment intensity in patients taking the drug. Factors predicting poor control included a history of stroke (OR for control 0.36, 95% CI 0.19-0.69, p = 0.002), age over 75 years (OR 0.43, 95% CI 0.18-0.98, p = 0.046), highest low-density lipoprotein tertile (OR 0.37, 95% CI 0.17-0.80, p = 0.013), highest body mass index tertile (OR 0.46, 95% CI 0.21-1.00, p = 0.05), and therapy with two or fewer antihypertensives (OR 0.14, 95% CI 0.04-0.61, p = 0.009). CONCLUSION: In a compliant veteran population, control of blood pressure appeared inadequate but was significantly more likely in those receiving at least three antihypertensive agents. Long-term therapy with simvastatin was independently associated with increased odds of control.