Sarah Dubrava

Effects of Varenicline on Smoking Cessation in Adults With Stably Treated Current or Past Major Depression: A Randomized Trial

UNLABELLED Chinese translation BACKGROUND Depression is overrepresented in smokers. OBJECTIVE To evaluate smoking abstinence and changes in mood and anxiety levels in smokers with depression treated with varenicline versus placebo. DESIGN Phase 4, multicenter, parallel, 1:1 allocation, double-blind, randomization trial. Randomization, stratified by antidepressant use and depression score at baseline, was blocked in sizes of 4. (ClinicalTrials.gov: NCT01078298). SETTING 38 centers in 8 countries. PARTICIPANTS 525 adult smokers with stably treated current or past major depression and no recent cardiovascular events. INTERVENTION Varenicline, 1 mg twice daily, or placebo for 12 weeks, with 40-week nontreatment follow-up. MEASUREMENTS Primary outcome was carbon monoxide-confirmed continuous abstinence rate (CAR) for weeks 9 to 12. Other outcomes included CARs assessed during nontreatment follow-up and ratings of mood, anxiety, and suicidal ideation or behavior. RESULTS 68.4% versus 66.5% of the varenicline and placebo groups, respectively, completed the study. Varenicline-treated participants had higher CARs versus placebo at weeks 9 to 12 (35.9% vs. 15.6%; odds ratio [OR], 3.35 [95% CI, 2.16 to 5.21]; P < 0.001), 9 to 24 (25.0% vs. 12.3%; OR, 2.53 [CI, 1.56 to 4.10]; P < 0.001), and 9 to 52 (20.3% vs. 10.4%; OR, 2.36 [CI, 1.40 to 3.98]; P = 0.001). There were no clinically relevant differences between groups in suicidal ideation or behavior and no overall worsening of depression or anxiety in either group. The most frequent adverse event was nausea (varenicline, 27.0%; placebo, 10.4%). Two varenicline-group participants died during the nontreatment phase. LIMITATIONS Some data were missing, and power to detect differences between groups was low in rare events. Smokers with untreated depression, with co-occurring psychiatric conditions, or receiving mood stabilizers and antipsychotics were not included. CONCLUSION Varenicline increased smoking cessation in smokers with stably treated current or past depression without exacerbating depression or anxiety. PRIMARY FUNDING SOURCE Pfizer.

Pregabalin versus pramipexole: effects on sleep disturbance in restless legs syndrome.

STUDY OBJECTIVES To compare pregabalin versus placebo and pramipexole for reducing restless legs syndrome (RLS)-related sleep disturbance. DESIGN Randomized, double-blinded, crossover trial. SETTING Twenty-three US sleep centers. PARTICIPANTS Eighty-five individuals with moderate to severe idiopathic RLS and associated sleep disturbance. INTERVENTIONS Participants were randomized across 6 treatment sequences comprising three 4-week periods on pregabalin 300 mg/day (n = 75), pramipexole 0.5 mg/day (n = 76), or placebo (n = 73). MEASUREMENTS AND RESULTS Polysomnography was conducted over 2 nights at the end of each period. Primary (wake after sleep onset [WASO], pregabalin vs placebo) and key secondary endpoints were analyzed for statistical significance, with descriptive statistics for other endpoints. Pregabalin improved sleep maintenance, demonstrated by reductions in WASO (-27.1 min vs placebo [P < 0.0001]; -26.9 vs pramipexole) and number of awakenings after sleep onset (-2.7 vs placebo; -7.9 vs pramipexole [P < 0.0001]) by polysomnography, and an increase in subjective total sleep time (30.8 min vs placebo [P < 0.0001]; 26.8 vs pramipexole). Pregabalin also increased slow wave sleep duration (20.9 min vs placebo; 32.1 vs pramipexole [P < 0.0001]). Reduction in periodic limb movement arousal index (PLMAI) with pregabalin was similar to pramipexole and greater than placebo (-3.7 PLMA/h [P < 0.0001]), although reduction in total PLM in sleep was less than for pramipexole. CONCLUSIONS This study demonstrated improvements in objective and subjective measures of sleep maintenance and sleep architecture with pregabalin compared with placebo and pramipexole. Effects of pregabalin on periodic limb movement arousal index were comparable to pramipexole. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT00991276; http://clinicaltrials.gov/show/NCT00991276.

Pregabalin long-term treatment and assessment of discontinuation in patients with generalized anxiety disorder

Discontinuation effects following cessation of 12 and 24 wk of pregabalin treatment for generalized anxiety disorder (GAD) were evaluated in a placebo- and lorazepam-controlled, randomized, double-blind, multicentre trial conducted in 16 countries. The study design consisted of two 12-wk treatment periods (periods 1 and 2), each followed by a 1-wk taper and two post-discontinuation assessments, one immediately following the taper and one 1-wk post-taper. Patients were assigned to receive an initially flexible dose of pregabalin 450-600 mg/d, pregabalin 150-300 mg/d, or lorazepam 3-4 mg/d for 6 wk; responders continued fixed-dose therapy for 6 additional weeks. Patients entering period 2 continued on the same fixed dose or switched to placebo. Discontinuation effects were evaluated with the Physician Withdrawal Checklist (PWC) and reported discontinuation-emergent signs and symptoms. Rebound anxiety was measured with the Hamilton Anxiety Rating Scale. GAD symptoms improved with all treatments and improvements were maintained over 12 and 24 wk. Low levels of discontinuation symptoms were evident in all treatment groups. For patients who received active treatment during both periods, mean (95% confidence interval) increases on the PWC from last visit on active treatment to the second post-discontinuation assessment were: pregabalin 450-600 mg/d: 2.8 (1.6-3.9), pregabalin 150-300 mg/d: 1.7 (0.7-2.8), lorazepam 3-4 mg/d: 2.2 (1.0-3.5). Rates of rebound anxiety were also low at both 12 and 24 wk (0-6%). This suggests that risk of discontinuation symptoms and rebound anxiety are low for pregabalin after 12 and 24 wk of treatment.

Pregabalin monotherapy in patients with partial-onset seizures: A historical-controlled trial

Objective: To assess pregabalin monotherapy for partial-onset seizures using a historical-controlled conversion-to-monotherapy design. Methods: Adults with inadequately controlled partial-onset seizures while receiving 1 or 2 antiepileptic drugs during an 8-week prospective baseline were randomized to double-blind monotherapy with pregabalin 600 or 150 mg/d (4:1) for 20 weeks (8-week conversion and 12-week monotherapy period). The primary endpoint was the seizure-related exit rate for pregabalin 600 mg/d, based on discontinuations due to predefined criteria. Efficacy was declared if the upper limit of the 95% confidence interval for the exit rate was below a historical-control threshold of 74%, with stepwise evaluation using a threshold of 68%. Results: The trial was stopped early for positive efficacy after an interim analysis in 125 patients. The full study population included 161 patients, with 148 evaluable for efficacy. The mean time since epilepsy diagnosis was 14 years. Overall, 54.3% (600 mg/d) and 46.9% (150 mg/d) of patients completed 20 weeks of double-blind treatment. Seizure-related exit rate in the 600 mg/d group (27.5%; 95% confidence interval, 17.8%–37.2%) was significantly below the 74% and 68% thresholds (p < 0.001 for both). Eight patients on 600 mg/d and 2 on 150 mg/d were seizure-free throughout pregabalin monotherapy. Pregabalins overall safety profile was consistent with prior trials. Conclusions: Pregabalin monotherapy was safe and efficacious for patients with inadequately controlled partial-onset seizures. Classification of evidence: This study provides Class III evidence that patients with inadequately controlled partial-onset seizures switched to pregabalin monotherapy have fewer seizure-related exit events compared with historical controls switched to pseudo-placebo monotherapy.

Phase II Crossover Trial of Varenicline in Mild-to-Moderate Alzheimer's Disease

Background: Evidence supports a role of α4β2 receptors in Alzheimers disease (AD). Methods: This Korean, multicenter, double-blind, two-period (6 weeks each), crossover study randomized participants to the order in which they received varenicline (1 mg twice daily) and placebo. Assessments included AD Assessment Scale-Cognitive Subscale (ADAS-Cog) 75, Neuropsychiatric Inventory (NPI), adverse events (AEs) and Columbia-Suicide Severity Rating Scale (C-SSRS). Results: For varenicline versus placebo (n = 66 randomized), there was no significant difference in the week 6 least square (LS) mean ADAS-Cog 75 total score (primary endpoint; 18.07 vs. 18.49; p = 0.3873) and a slight worsening in the week 6 LS mean NPI (3.82 vs. 2.55; p = 0.0468), primarily driven by decreased appetite/eating. Common treatment-related AEs were nausea (23.3; 3.4%), vomiting (15.0%; 0) and decreased appetite (15.0; 6.8%). Conclusions: Varenicline did not improve cognition, behavior or global change in this population. The most frequent varenicline-associated AEs were gastrointestinal; psychiatric AEs were rare and similar between the groups.

Adjunctive use of controlled‐release pregabalin in adults with treatment‐resistant partial seizures: A double‐blind, randomized, placebo‐controlled trial

To assess the efficacy and tolerability of add‐on pregabalin controlled‐release formulation (PGB‐CR) (doses of 165 or 330 mg/day) in patients with partial‐onset seizures (POS).

Using Random Forest Models to Identify Correlates of a Diabetic Peripheral Neuropathy Diagnosis from Electronic Health Record Data

Objective. To identify variables correlated with a diagnosis of diabetic peripheral neuropathy (DPN) using random forest modeling applied to electronic health records. Design. Retrospective analysis. Setting. Humedica de-identified electronic health records database. Subjects. Subjects ≥ 18 years old with type 2 diabetes from January 1, 2008–September 30, 2013 having continuous data for 1 year pre- and postindex with DPN (n = 35,050) and without DPN (n = 288,328) were identified. Methods. Demographic, clinical, and health care resource utilization variables (e.g., inpatient and outpatient encounters, medications, and procedures) were input into a random forest model to identify the most important correlates of a DPN diagnosis. Random forest modeling is a computationally extensive, robust data mining technique that accommodates large sets of variables to identify associated factors using an ensemble of classifications trees. Accuracy of the model was evaluated using receiver operating characteristic curves (ROC). Results. The final random forest model consisted of the following variables (importance) associated with a DPN diagnosis: Charlson Comorbidity Index score (100%), age (37.1%), number of pre-index procedures and services (29.7%), number of pre-index outpatient prescriptions (24.2%), number of pre-index outpatient visits (18.3%), number of pre-index laboratory visits (16.9%), number of pre-index outpatient office visits (12.1%), number of inpatient prescriptions (5.9%), and number of pain-related medication prescriptions (4.4%). ROC analysis confirmed model performance, with an area under the curve of 0.824 and accuracy of 89.6% (95% confidence interval 89.4%, 89.8%). Conclusions. Random forest modeling can determine likelihood of a DPN diagnosis. Further validation of the random forest model may help facilitate earlier diagnosis and enhance management strategies.

Assessment of Suicidal Ideation and Behavior: Report of the International Society for CNS Clinical Trials and Methodology Consensus Meeting.

OBJECTIVE To develop consensus recommendations for assessment of suicidal ideation/suicidal behavior (SI/SB) in clinical trials. PARTICIPANTS Stakeholders from academia, industry, regulatory agencies, National Institutes of Health, National Institute of Mental Health, and patient advocacy organizations participated in a consensus meeting that was sponsored by the International Society for CNS Clinical Trials and Methodology and held November 17-18, 2015. Prior to the meeting, teams of experts identified key areas of consensus and dissent related to SI/SB. The most critical issues were presented and discussed in the consensus meeting. EVIDENCE Literature reviews and a pre-meeting survey were conducted. Findings were discussed in pre-meeting working group sessions and at the consensus meeting. CONSENSUS PROCESS Five pre-meeting working groups reviewed (1) nomenclature and classification schemes for SI/SB, (2) detection and assessment of SI/SB, (3) analysis of SI/SB data, (4) design of clinical trials for new treatments of SI/SB, and (5) public health approaches to SI/SB. A modification of the RAND/UCLA Appropriateness Method was used to combine review of scientific evidence with the collective views of experts and stakeholders to reach the final consensus statements. After discussion, all attendees voted using an electronic interactive audience response system. Areas of agreement and areas of continuing dissent were recorded. CONCLUSIONS All 5 working groups agreed that a major barrier to advancement of the field of SI/SB research and the development of new treatments for SI/SB remains the lack of a universally accepted standardized nomenclature and classification system. Achieving alignment on definitions and classification of suicide-related phenomena is critical to improving the detection and assessment of SI/SB, the design of clinical trials for new treatments, and effective public health interventions.

Suicidal ideation and behavior assessment in dementia studies: An Internet survey

The AARR task force on suicidal ideation and behavior (SI/SB) in dementia conducted an online survey on the extent of SI/SB in individuals diagnosed with mild cognitive impairment (MCI) or dementia who were participating in clinical trials.

Considerations for the assessment of suicidal ideation and behavior in older adults with cognitive decline and dementia

Better understanding of suicide risk and its management in older adults with cognitive impairment and/or dementia remain significant unmet public health needs. Urgency to address them derives from concern that CNS treatments for dementia may impact suicide risk. Regulatory guidances requiring assessment of emergent suicidal ideation and behavior (SI/SB) at every clinical trial visit emphasize the need for understanding their prevalence.