Innovations In Clinical Neuroscience

MAR-APR 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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38 ICNS INNOVATIONS IN CLINICAL NEUROSCIENCE March-April 2018 • Volume 15 • Number 3–4 O R I G I N A L R E S E A R C H independent second opinions. In the present study, we used a time-efficient audio-digital recording method to obtain clinical interviews and independently confirm the GAD diagnosis and that these patients actually warranted a change in anxiolytic medication. As part of a clinical trial site, independent reviewers listened to and scored key site-based recorded interviews that were conducted at the first (screening) visit of the patients to confirm the specific clinical characteristics and metrics that might delineate anxious patients who warranted a medication intervention. The audio review method added minimal burden to the assessment during the clinical trial and might have broader utility for clinical practice as well. METHODS The audio-digital recording and "dual" review analysis of anxious patients was conducted as part of a clinical trial on GAD (ClinicalTrials.gov Identifier: NCT02310568) titled, "An 8-week, randomized, Phase 2, double-blind, sequential parallel-group comparison study of two dose levels of PF-06372865 compared to placebo as an adjunctive treatment in outpatients with inadequate response to standard of care for generalized anxiety." The objective of the trial was to evaluate the anxiolytic efficacy of PF-06372865 based upon changes in the total score of the Hamilton Rating Scale for Anxiety (HAM-A) (1959) using the Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A). 11 The study was conducted at 47 clinical trial sites in the United States, of which 34 sites ultimately enrolled patients. The study was carried out in accordance to the code of ethics of the World Medical Association (Declaration of Helsinki). All potential patients considering the trial consented to participate and signed an IRB-approved consent form that described their participation in the trial and the possibility of receiving active medication or placebo prior to the conduct of any study procedures. In this study, eligible patients needed to meet the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV- TR) criteria for GAD, as confirmed by the Mini International Neuropsychiatric Interview (MINI) at the screen interview as follows: 1,12 A. Excessive anxiety and worry (apprehensive expectation) regarding a number of events or activities (e.g., work or school performance) that occurs more days than not for at least six months B. Difficulty controlling the worry C. Anxiety and worry that are associated with three (or more) of the following six symptoms (with at least some symptoms present for more days than not for the past six months): 1. Restlessness or feeling keyed up or on edge 2. Being easily fatigued 3. Difficulty concentrating or mind going blank 4. Irritability 5. Muscle tension 6. Sleep disturbance (difficulty falling or staying asleep or restless, unsatisfying sleep) D. Focus of anxiety and worry that is not confined to features of another Axis I disorder or having a serious illness (as in hypochondriasis) and anxiety and worry that do not occur exclusively during posttraumatic stress disorder (PTSD) E. Anxiety, worry, or physical symptoms that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning F. Disturbance that is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism) and does not occur exclusively during a mood or a psychotic disorder The study excluded patients with current comorbid conditions that might obscure assessment of the experimental treatment intervention. Thus, patients with a diagnosis within the past six months of panic disorder with or without agoraphobia, PTSD, dissociative disorder, obsessive-compulsive disorder, attention deficit disorder, DSM-IV-TR defined substance abuse (within 3 months), or substance dependence (within 12 months) were not eligible. Furthermore, patients with a history of bipolar disorder or any psychotic or cognitive disorder, or who had comorbid personality disorders (Axis II) were not eligible for the study. A mid-study amendment allowed patients with a recent history of major depressive disorder (MDD) to participate, provided GAD was the primary disorder and their anxiety symptoms predominated over their depressive symptoms as measured by the Covi Anxiety Scale (CAS) and the Raskin Depression Scale (RDS). 13,14 The amendment also permitted enrollment of patients with social phobia or specific phobias, provided the anxiety symptoms generated by these disorders were clinically less significant than those of the primary GAD disorder. The study was designed for patients with GAD who required a change in medication because their current regimen was not effective. Hence, eligible patients needed to have had an inadequate response (<50% effective) to an adequate dose of an acceptable, approved anxiolytic medication at a stable, approved dose for at least two consecutive months in the current episode immediately prior to the screening visit. Acceptable medications initially included escitalopram (10–20mg total daily dose per day), paroxetine (20–50mg per day), duloxetine (60–120mg per day), and venlafaxine (75–225mg per day). The mid-study amendment added citalopram (20–40mg per day) and sertraline (50–100mg per day) to the acceptable list of medications. Additional study eligibility criteria included being 18 to 65 years of age (inclusive) with a total SIGH-A score of 22 or greater, a CAS score of 9 or greater, and a RAS score of 7 or less at the screening visit to ensure predominance of anxiety symptoms over depression symptoms. 11,13–15 The screening assessment also included a clinical and anxiolytic treatment history review, the Structured interview guide for the Clinical Global Impression of Severity (CGI-S), called the SIGGI, a patient self- rated generalized anxiety disorder 7-item scale (GAD-7), and completion of the Clinical-Validation Inventory for Study Admission (C-VISATM) for site- independent eligibility affirmation. 16–19 There were 57 site-based raters and six site- independent reviewers/raters who successfully completed a rater training and qualification program that included an inter-rater reliability assessment and certification for the SIGH-A interview. Site-independent "dual" reviews were employed at the screening visit as a quality assurance (surveillance) strategy to assure appropriate subject selection. The "dual" review included the C-VISATM to assure diagnostic accuracy, ratings precision, pharmacologic history, and documentation that the patient met the inclusion/ exclusion criteria of the protocol. Furthermore, the MINI, SIGH-A, and CGI-S assessments were audio- digitally recorded at the screening visit using a commercially available pen-recording device and specially manufactured booklets that captured digital notes. All patients consented to the use of the audio-digital recordings as part of the screening visit. The recordings permitted a site-

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