An 8-Week, Randomized, Phase 2, Double-Blind, Sequential Parallel-Group Comparison Study of Two Dose Levels of the GABAA Positive Allosteric Modulator PF-06372865 Compared With Placebo as an Adjunctive Treatment in Outpatients With Inadequate Response to Standard of Care for Generalized Anxiety Disorder.

BACKGROUND: Generalized anxiety disorder (GAD) is a common psychiatric disorder, but many patients experience only partial relief of symptoms with existing therapies. Benzodiazepines are effective in many cases but are limited by a number of significant adverse effects. PF-06372865 is a subtype-selective gamma-aminobutyric acid A (GABAA)-positive allosteric modulator lacking in functional activity at alpha 1-containing receptors that are believed to mediate many of these adverse effects. METHODS: PF-06372865 was evaluated as an adjunct to current GAD treatment in a double-blind, placebo-controlled, sequential parallel comparison study in patients with GAD who showed an incomplete response to current standard-of-care pharmacotherapy. A total of 90 subjects (of the planned 384) were randomized into the study before the decision to terminate the study. Two doses of PF-06372865 (2.5 mg twice daily and 7.5 mg twice daily) were compared with placebo. RESULTS: Neither dose of PF-06372865 differentiated from placebo on week 4 Hamilton Anxiety Inventory total (primary end point) or on the Sheehan Disability Scale total score (secondary end point). Adverse events including dizziness, headache, and somnolence were observed, and the 7.5 mg dose demonstrated some impairment on the Digit Symbol Substitution test and the Epworth Sleepiness Scale relative to placebo and the 2.5 mg dose. CONCLUSIONS: Factors contributing to the negative results include the limited sample size and failure to explore a broader range of doses.

Evaluation of the use of the Scale for the Assessment and Rating of Ataxia (SARA) in healthy volunteers and patients with schizophrenia.

OBJECTIVE: The Scale for the Assessment and Rating of Ataxia (SARA) is a semi-quantitative assessment used to evaluate ataxia. The goal of these studies was to assess and evaluate the utility of this instrument in a Healthy Volunteer (HV) group and subjects with Schizophrenia (SCZ). METHODS: Two studies were completed to collect SARA data, in a HV group and in a stable SCZ group. 177 HVs (18-65 years) and 16 SCZs (18-58 years) provided written consent and were assessed using the SARA. Of 177 HV subjects, 88 had 2 SARA assessments (within 2 days of initial visit) while all 16 SCZ had 3 SARA assessments (within 14 days of initial visit). RESULTS: For the HV group, the mean score ±â€¯Std for the SARA on visit-1 was 0.39 ±â€¯0.72, and 0.34 ±â€¯0.64 for visit-2. The Pearson correlation coefficient between visit-1 and visit-2 was 0.7486 and an ICC of 0.743. For the SCZ group, the mean score for the SARA was 0.63 ±â€¯0.65 on visit-1, 0.84 ±â€¯1.19 on visit-2, and 0.84 ±â€¯0.94 on visit-3. The Pearson correlation coefficient between visit-1 and visit-2 was 0.6545, between visit-1 and visit-3 was 0.6635 and between visit-2 and visit-3 was 0.7613 and an ICC of 0.650. There was no significant difference in baseline SARA scores between the HV and SCZ group p = .063. A statistically significant positive association between age and total SARA scores was observed in HV (r = 0.345) and SCZ (r = 0.676). CONCLUSIONS: A strong association was observed in both the HV and SCZ groups in the reassessment of signs of ataxia using the SARA scale. Both groups demonstrated minimal signs of ataxia, with no statistically significant difference between the two groups in their visit-1 scores.

Audio Recording for Independent Confirmation of Clinical Assessments in Generalized Anxiety Disorder.

Objective: The assessment of patients with generalized anxiety disorder (GAD) to deteremine whether a medication intervention is necessary is not always clear and might benefit from a second opinion. However, second opinions are time consuming, expensive, and not practical in most settings. We obtained independent, second opinion reviews of the primary clinician's assessment via audio-digital recording. Design: An audio-digital recording of key site-based assessments was used to generate site-independent "dual" reviews of the clinical presentation, symptom severity, and medication requirements of patients with GAD as part of the screening procedures for a clinical trial (ClinicalTrials.gov: NCT02310568). Results: Site-independent reviewers affirmed the diagnosis, symptom severity metrics, and treatment requirements of 90 moderately ill patients with GAD. The patients endorsed excessive worry that was hard to control and essentially all six of the associated DSM-IV-TR anxiety symptoms. The Hamilton Rating Scale for Anxiety scores revealed moderately severe anxiety with a high Pearson's correlation (r=0.852) between site-based and independent raters and minimal scoring discordance on each scale item. Based upon their independent reviews, these "second" opinions confirmed that these GAD patients warranted a new medication intervention. Thirty patients (33.3%) reported a previous history of a major depressive episode (MDE) and had significantly more depressive symptoms than patients without a history of MDE. Conclusion: The audio-digital recording method provides a useful second opinion that can affirm the need for a different treatment intervention in these anxious patients. A second live assessment would have required additional clinic time and added patient burden. The audio-digital recording method is less burdensome than live second opinion assessments and might have utility in both research and clinical practice settings.

A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer's disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil.

BACKGROUND: Symptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer's disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10-24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data. RESULTS: At the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment). CONCLUSIONS: SAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT6 receptor antagonists. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01712074 . Registered 19 October 2012.

Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy.

INTRODUCTION: Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). METHODS: In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. RESULTS: Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aß1-x and Aß1-40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. CONCLUSIONS: Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

Ponezumab in mild-to-moderate Alzheimer's disease: Randomized phase II PET-PIB study.

INTRODUCTION: The safety, pharmacokinetics, and effect on peripheral and central amyloid ß (Aß) of multiple doses of ponezumab, an anti-Aß monoclonal antibody, were characterized in subjects with mild-to-moderate Alzheimer's disease treated for 1 year. METHODS: Subjects were aged ≥50 years with Mini-Mental State Examination scores 16 to 26. Cohort Q was randomized to ponezumab 10 mg/kg (n = 12) or placebo (n = 6) quarterly. Cohort M was randomized to a loading dose of ponezumab 10 mg/kg or placebo, followed by monthly ponezumab 7.5 mg/kg (n = 12) or placebo (n = 6), respectively. RESULTS: Ponezumab was generally well tolerated. Plasma concentrations increased dose dependently, but cerebrospinal fluid (CSF) penetration was low. Plasma Aß increased dose dependently with ponezumab, but CSF biomarkers, brain amyloid burden, cognition, and function were not affected. CONCLUSIONS: Both ponezumab dosing schedules were generally safe and well tolerated but did not alter CSF biomarkers, brain amyloid burden, or clinical outcomes.

Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study.

OBJECTIVE: PF-04360365 is a humanized IgG(2)Δa anti-amyloid ß (Aß) antibody designed to improve outcome in Alzheimer's disease (AD). Single doses of 0.1 - 10 mg/kg were safe and well tolerated in Western (mostly Caucasian) subjects with mild-to-moderate AD. This Phase 1, multicenter, randomized, double-blind, dose-escalation study was the first to evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of PF-04360365 in Japanese subjects. MATERIALS AND METHODS: 30 subjects with mild-to-moderate AD were enrolled. In each cohort, 3 subjects received PF-04360365 (0.1, 0.5, 1, 5, or 10 mg/kg) and 1 subject received placebo as a single 2-hour intravenous infusion. Subjects were monitored as inpatients for 24 hours and then as outpatients for 1 year. RESULTS: All subjects completed the study. There were no serious or National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥ 3 adverse events, hypersensitivity reactions, or antidrug antibodies. No clinical or MRI evidence of brain microhemorrhage, cerebral edema, or encephalitis was observed. PF-04360365 plasma concentrations increased with dose, and pharmacokinetics were consistent with a small steady-state volume of distribution, slow clearance, and long elimination half-life. Cerebrospinal fluid (CSF):plasma ratios were < 0.5%. Plasma Aß species showed dose-dependent increases in C(max) and AUC(∞), but CSF biomarkers did not differ clearly between treatment arms. CONCLUSIONS: PF-04360365 was safe and well tolerated in Japanese subjects. Pharmacokinetics and plasma pharmacodynamic responses in Japanese subjects were comparable to those in Western subjects. *No longer affiliated with Pfizer.

A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression.

OBJECTIVE: The corticotropin-releasing hormone (CRH) system is implicated in the pathogenesis of several psychiatric disorders, including major depressive disorder. This study was designed to evaluate the safety and efficacy of CP-316,311, a selective nonpeptide antagonist of corticotropin-releasing hormone type 1 (CRH(1)) receptors, in the treatment of recurrent major depressive disorder. METHOD: Of a total of 167 patients with recurrent major depression who were screened, 123 were randomly assigned to receive 400 mg of CP-316,311 twice daily, or 100 mg of sertraline daily, or placebo in a 6-week fixed-dose, double-blind, double-dummy, parallel-group, placebo- and sertraline-controlled trial. The primary efficacy analysis compared the change in score from baseline to endpoint on the 17-item Hamilton Depression Rating Scale (HAM-D) between the CP-316,311 and placebo groups. A group sequential design was used to support early trial termination based on efficacy or futility at a planned interim analysis. RESULTS: The evaluable data set for the interim analysis included 28 patients in the CP-316,311 group, 31 patients in the placebo group, and 30 patients in the sertraline group. In the interim analysis, the change from baseline in the HAM-D score at the final visit was not significantly different between the CP-316,311 and placebo groups, while change from baseline between the sertraline and placebo groups was significantly different. Given these results, futility was declared for CP-316,311 and the trial was terminated. CONCLUSIONS: Although CP-316,311 was safe and well tolerated in this study population, it failed to demonstrate efficacy in the treatment of major depression.

Cerebral metabolic effects of intravenous glycine in healthy human subjects.

Enhancing N-methyl-D-aspartate (NMDA) receptor function via increasing synaptic concentrations of glycine is currently investigated as a novel approach to treat schizophrenia. The neural correlates of enhanced NMDA receptor function in humans, however, are unclear to date. The present study determines the effects of intravenous administration of the glycine on regional cerebral metabolic rate of glucose (rCMRGlu) in healthy control subjects by using [18F]fluorodeoxyglucose and positron emission tomography and on neuropsychological behavioral measures. Thirteen healthy volunteers were recruited, and 12 subjects completed the protocol. These individuals participated in 1 magnetic resonance imaging study and 2 [18F]fluorodeoxyglucose positron emission tomography studies. In a double-blind, randomized, controlled, crossover design, participants received on one test day an intravenous glycine infusion and on the other test day a placebo infusion. There were no significant behavioral and neuropsychological effects of glycine compared with placebo. However, there was a significant reduction of whole-brain CMRGlu during administration of glycine compared with placebo (t = 2.60, df = 11, P = 0.023). In the a priori-selected regions of interest, there was a significant reduction in the cerebellum (t = -3.18, df = 11, P = 0.009) and the dorsolateral prefrontal cortex (t = -2.31, df = 11, P = 0.041). When corrected for whole-brain CMRGlu, rCMRGlu differences were not significant. This study suggests that studies of whole-brain cerebral metabolism may be useful for studying glycine-related mechanisms in healthy humans because there is not a clear cognitive or behavioral signal related to glycine administration at doses thought to be important clinically in patient populations.

Longitudinal study of symptoms and cognitive function in chronic schizophrenia.

There is conflicting evidence of a relationship between changes in symptoms and cognitive functioning in schizophrenia. This study investigated longitudinal changes in psychopathology and cognitive functioning in chronic schizophrenia utilising three different dimensional models of symptomatology. Sixty-two patients diagnosed with DSM-IV schizophrenia or schizoaffective disorder were examined on two occasions over a period of 6 months for symptom improvement, measured by Positive and Negative Syndrome Scale (PANSS) [Kay et al., Schizophr. Bull. 13 (1987) 261]. Participants also completed a comprehensive battery of neuropsychological tasks designed to assess attention, verbal and non-verbal memory, psychomotor processing and executive/frontal functioning on both occasions. Twenty-five control subjects were assessed for comparison purposes. Severity of negative symptoms predicted poor neuropsychological performance on IQ, verbal fluency and memory measures at occasion one. However, using regression analyses, significant improvements in symptom ratings over time using two-, three- or five-dimensional models did not predict improvements in any aspect of cognitive functioning measured, except motor speed. The results do not suggest a causal relationship between the course of symptoms and neuropsychological functioning in chronic schizophrenia.