Multiparametric MRI as a Noninvasive Monitoring Tool for Children With Autoimmune Hepatitis.

OBJECTIVES: Autoimmune hepatitis (AIH) is a progressive liver disease managed with corticosteroids and immunosuppression and monitored using a combination of liver biochemistry and histology. However, liver biopsy is invasive with risk of pain and bleeding. The aim of the present study was to investigate the utility of noninvasive imaging with multiparametric magnetic resonance imaging (MRI) (mpMRI) to provide clinically useful information on the presence and extent of hepatic inflammation, potentially guiding immunosuppression. METHODS: Eighty-one participants (aged 6-18), 21 healthy and 60 AIH patients, underwent multiparametric MRI to measure fibro-inflammation with iron-corrected T1 (cT1) at the Children's Memorial Health Institute in Warsaw alongside other clinical blood tests and liver biopsy at recruitment and after an average of 16-month follow-up (range 9-22 months). Correlation analyses were used to investigate the associations between cT1 with blood serum markers and histological scores. RESULTS: At recruitment, patients with AIH had a higher cT1 value than healthy controls (P < 0.01). cT1 correlated significantly with key histopathological features of disease. Treatment naïve AIH patients showed evidence of inflammation and heterogeneity across the liver compared to healthy controls.At follow-up, cT1 showed utility in monitoring disease regression as most patients showed significantly reduced fibro-inflammation with treatment (P < 0.0001) over the observational period. Six patients had histological fibrosis and clear fibro-inflammation on MR despite biochemical remission (normalized aspartate aminotransferase (AST), alanine aminotransferase (ALT), and immunoglobulin G [IgG]). CONCLUSIONS: Multiparametric MRI can measure disease burden in pediatric AIH and can show changes over time in response to therapy. Active disease can be seen even in biochemical remission in children.

Serum Lipid and Protein Changes in Healthy Dyslipidemic Subjects Given a Selective Inhibitor of p70 S6 Kinase-1.

The safety, pharmacokinetic, and pharmacodynamic effects of LY2584702, a selective inhibitor for p70 S6 serine/threonine protein kinase-1, were evaluated in healthy dyslipidemic volunteers. LY2584702 was tolerated well as a monotherapy and dose-dependently reduced low-density lipoprotein cholesterol and triglycerides by up to 60% and 50%, respectively, without significantly changing high-density lipoprotein cholesterol levels in plasma. LY2584702 also dose-dependently decreased factor V activity. Alanine aminotransferase elevations were noted in 2 subjects when LY2584702 was given with atorvastatin. We suspect that the formation of 4-aminopyrazolo[3,4-d]pyrimidine (4-APP) during metabolism may have contributed to some of the adverse effects of LY2584702, and the contribution of 4-APP to the pharmacology merits further investigation. Although clinical investigation of LY2584702 has been terminated because of hepatotoxicity risk, we suggest that a selective inhibitor of p70 S6 serine/threonine protein kinase-1 with a larger margin of safety and without the possibility of being metabolized to 4-APP may be useful in the treatment of dyslipidemia.

Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY3000328, in healthy subjects.

AIM: The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers. METHODS: This was a phase 1, placebo-controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity. RESULTS: All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma. CONCLUSION: A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS.

Site versus centralized raters in a clinical depression trial: impact on patient selection and placebo response.

The use of centralized raters who are remotely linked to sites and interview patients via videoconferencing or teleconferencing has been suggested as a way to improve interrater reliability and interview quality. This study compared the effect of site-based and centralized ratings on patient selection and placebo response in subjects with major depressive disorder. Subjects in a 2-center placebo and active comparator controlled depression trial were interviewed twice at each of 3 time points: baseline, 1-week postbaseline, and end point--once by the site rater and once remotely via videoconference by a centralized rater. Raters were blind to each others' scores. A site-based score of greater than 17 on the 17-item Hamilton Depression Rating Scale (HDRS-17) was required for study entry. When examining all subjects entering the study, site-based raters' HDRS-17 scores were significantly higher than centralized raters' at baseline and postbaseline but not at end point. At baseline, 35% of subjects given an HDRS-17 total score of greater than 17 by a site rater were given an HDRS total score of lower than 17 by a centralized rater and would have been ineligible to enter the study if the centralized rater's score was used to determine study entry. The mean placebo change for site raters (7.52) was significantly greater than the mean placebo change for centralized raters (3.18, P < 0.001). Twenty-eight percent were placebo responders (>50% reduction in HDRS) based on site ratings versus 14% for central ratings (P < 0.001). When examining data only from those subjects whom site and centralized raters agreed were eligible for the study, there was no significant difference in the HDRS-17 scores. Findings suggest that the use of centralized raters could significantly change the study sample in a major depressive disorder trial and lead to significantly less change in mood ratings among those randomized to placebo.

Changes in brain function during administration of venlafaxine or placebo to normal subjects.

Previous research has demonstrated neurophysiologic effects of antidepressants in depressed subjects. We evaluated neurophysiologic effects of venlafaxine in normal subjects. Healthy adults (n=32) received a 1-week placebo lead-in followed by 4 weeks randomized double-blind treatment with venlafaxine IR 150 mg. (n = 17) or placebo (n = 15). Brain function was examined using quantitative electroencephalographic (QEEG) power and theta cordance. Normal subjects receiving venlafaxine showed a decrease in theta-band cordance in the midline-and-right-frontal (MRF) region at 48 hours and at 1 week after randomization. Decreases in relative power also were seen in the MRF region; there were no significant changes in absolute power. These changes were significantly different from those in subjects receiving placebo. Changes in MRF cordance accurately identified treatment condition at 48 hours in 81.3% of subjects, and relative power from this region identified 60.7% of subjects. In conclusion, cordance may detect the pharmacological effects of antidepressant medication in normal subjects. Future studies should examine other classes of medication, as well as antidepressants with other mechanisms of action, to determine if cordance detects antidepressant medication effects in general in normal subjects.

Optimizing the ability of the Hamilton Depression Rating Scale to discriminate across levels of severity and between antidepressants and placebos.

Efforts to improve the Hamilton Rating Scale for Depression (HRSD) have included shortening the scale by selecting the best performing items, lengthening the scale by assessing additional symptoms, modifying the format and scoring of existing items, and developing structured interview guides for administration. We defined item performance exclusively in terms of the ability of items to discriminate differences among levels of depressive severity which has not be used to guide any revisions of the HRSD conducted to date. Two techniques derived from item response theory were used to improve the ability of the HRSD to discriminate among individuals with different degrees of depressive severity. Item response curves were used to quantify the ability of items to discriminate among individual differences in depressive severity, on the basis of which the most discriminating items were selected. Maximum likelihood estimates were used to compute an optimal depressive severity score, using all items, but which weighted highly discriminating items more so than items that did not discriminate well. The utility of each method was evaluated by comparing a subset of optimally discriminating items and maximum likelihood estimates of depressive severity to the Maier Philipp subscale of the HRSD, in terms of how well scales discriminate treatment effects. Effect sizes for overall change in depression severity as well as effect sizes differentiating response to treatment versus placebo were evaluated in a sample of 491 patients receiving fluoxetine and 494 patients receiving placebo. Results of analyses identified a new subset of items (IRT-6), selected on the basis of their ability to discriminate among differences in depressive severity, that accounted for more variance in full-scale HRSD scores and was better at detecting change in illness severity than the Maier Philipp subscale of the HRSD. The IRT-6 subscale was equally good as the Maier Philipp subscale in differentiating treatment from placebo response. No evidence supporting the benefits of using maximum likelihood estimates to develop optimally performing subscales was found. Implications of the results are discussed in terms of strategies for optimizing the assessment of change in overall depression severity as well as differentiating treatment response.

An integrative approach to determine the best behavioral and biological markers of methylphenidate.

AIMS: To distinguish the most sensitive markers of methylphenidate (MPH) effects on behavior and underlying biology using an integrated cognitive and brain function test battery. METHODS: A randomized placebo-controlled trial with 32 healthy adult males. Subjects were tested on MPH doses across 18 sessions with subjective mood, objective behavioral and biological endpoints. From a computerized battery of tests, behavioral measures were cognitive performance scores, while biological measures of brain function included electroencephalographs (EEG) and event-related potentials (ERPs) with complementary measures of autonomic arousal. Using mixed modeling analyses; we determined which measures were most affected by MPH dose and correlation analyses determined the associations among them. RESULTS: MPH dose had the most pronounced effect on cognitive performance (sustained attention/vigilance), baseline autonomic arousal (heart rate, blood pressure) and baseline brain activity (EEG theta power). The faster reaction time, reduced errors, increased autonomic arousal and reductions in theta showed strong to moderate inter-correlations. MPH least affected subjective mood measures and early sensory ERP components. DISCUSSION: These findings suggest that MPH increases cortical and autonomic arousal, facilitating vigilance. The combination of behavioral and biological measures may provide an objective set of markers of MPH response. INTEGRATIVE SIGNIFICANCE: This approach has provided additional insight into the mechanism of the stimulant medication, MPH, which would not be achieved by using such measures in isolation.

Anchoring perceptions of clinical change on accurate recollection of the past: memory enhanced retrospective evaluation of treatment (MERET).

OBJECTIVE: To evaluate patients' self-reports of treatment efficacy with and without self-prompted memory aids regarding their clinical experiences obtained prior to treatment initiation. DESIGN: Double-blind, placebo-controlled trial with variable expected duration placebo lead-in and washout. SETTING: Multisite (US) randomized clinical trial. PARTICIPANTS: Seventy-four patients with initial or recurrent DSM-IV diagnosis of major depression with symptoms of at least four weeks duration. A minimum Clinical Global Impression of Severity rating of Moderately Depressed and a clinician 17-item Hamilton Rating Scale for Depression score of 15 or greater, with the depressed mood item score of at least 2 were required for study entry. MEASUREMENTS: Patient global impression of improvement (PGI-I) ratings obtained using an interactive voice response (IVR) computer-automated telephone system prior to and following playback of impromptu patient recordings obtained prior to the start of treatment (MERET). RESULTS: MERET PGI-I ratings differentiated the effects of drug treatment from placebo more effectively than did standard PGI-I ratings. The drug-placebo treatment effect size obtained using standard PGI-I ratings was 0.525, whereas the effect size with MERET PGI-I ratings was 0.612. CONCLUSION: The enhanced drug-placebo separation appeared to be primarily due to increased patients' perceptions of drug treatment effectiveness. Patients perceiving the greatest degree of clinical improvement indicated more benefit from hearing the MERET recordings. MERET appears to be a viable method for enhancing patients' insights into the benefits of effective treatments by allowing them to use personal descriptions provided in their own words and voice.

An examination of 26,168 Hamilton Depression Rating Scale scores administered via interactive voice response across 17 randomized clinical trials.

This article presents descriptive and psychometric data from 26,168 Hamilton Depression Rating Scale (HAM-D) scores administered via Interactive Voice Response (IVR) in 17 randomized clinical trials sponsored by 6 pharmaceutical companies. To provide evidence for construct validity, the IVR HAM-D scores before and after randomization are compared, and the change in the IVR HAM-D scores over time after randomization are examined. In addition, the evidence for the reliability of the IVR-administered HAM-D is presented. An examination of the distribution of first-time IVR HAM-Ds before randomization may provide useful information to researchers planning to use the IVR HAM-D as a screening tool for entry or to verify baseline severity in randomized clinical trials.

Rating the raters: assessing the quality of Hamilton rating scale for depression clinical interviews in two industry-sponsored clinical drug trials.

OBJECTIVE: The quality of clinical interviews conducted in industry-sponsored clinical drug trials is an important but frequently overlooked variable that may influence the outcome of a study. We evaluated the quality of Hamilton Rating Scale for Depression (HAM-D) clinical interviews performed at baseline in 2 similar multicenter, randomized, placebo-controlled depression trials sponsored by 2 pharmaceutical companies. METHODS: A total of 104 audiotaped HAM-D clinical interviews were evaluated by a blinded expert reviewer for interview quality using the Rater Applied Performance Scale (RAPS). The RAPS assesses adherence to a structured interview guide, clarification of and follow-up to patient responses, neutrality, rapport, and adequacy of information obtained. RESULTS: HAM-D interviews were brief and cursory and the quality of interviews was below what would be expected in a clinical drug trial. Thirty-nine percent of the interviews were conducted in 10 minutes or less, and most interviews were rated fair or unsatisfactory on most RAPS dimensions. CONCLUSIONS: Results from our small sample illustrate that the clinical interview skills of raters who administered the HAM-D were below what many would consider acceptable. Evaluation and training of clinical interview skills should be considered as part of a rater training program.

The dose-dependent effect of methylphenidate on performance, cognition and psychophysiology.

The effects of methylphenidate (MPH) on 32 healthy human male volunteers (aged 18 to 25 years, mean age=22.26) were examined using a within-subject design. Each participant attended six testing periods, held once per week. Within each testing period, three repeat testing sessions were undertaken: pre-medication, on-medication and two hours post-medication. In these sessions, dose was manipulated (placebo, 5 mg, 15 mg or 45 mg) according a double-blind placebo design. In this report, we focus on behavioral, autonomic arousal (heart rate, skin conductance) and psychophysiological (ERP) data acquired during the working memory task. We found increased autonomic arousal (heart rate, skin conductance and blood pressure) with MPH. A linear reduction in reaction time, omission errors and target P3 latency, and a corresponding increase in background P3 amplitude was observed with increased MPH dose. The relationship between these measures supported an increase in performance and underlying brain function with MPH. To our knowledge, this is the first paper to use behavioral, arousal and electrophysiological measures in an integrative approach to study the effects of MPH on healthy adults.

Neurophysiologic correlates of side effects in normal subjects randomized to venlafaxine or placebo.

Adverse events reported in the context of medication administration may be due to pharmacodynamic and/or nonpharmacodynamic effects (eg, nocebo phenomena). Neurophysiological substrates of side effects may be examined in placebo-controlled antidepressant treatment trials. We explored the relationship between side effects and regional neurophysiologic changes in normal subjects receiving a 1-week placebo lead-in followed by 4 weeks randomized treatment with placebo (n = 15) or venlafaxine IR (n = 17). Quantitative electroencephalographic (QEEG) cordance measures were obtained before and during treatment, and side effects were assessed weekly using semistructured interviews. Side effect burden, characterized as the mean number of side effects per postrandomization visit, correlated significantly with neurophysiologic changes in the antidepressant group but not the placebo group. Medication group side effects were negatively correlated with changes in prefrontal cordance at end of placebo lead-in (r = -0.67, p < 0.003), at 2 weeks (r = -0.77, p < 0.002), and at 4 weeks (r = -0.77, p < 0.004) post randomization. After controlling for the prefrontal change at the end of placebo lead-in, postrandomization brain changes did not further explain side effect burden. Changes in prefrontal brain function associated with later antidepressant side effects were observed during placebo lead-in-prior to the administration of medication. Prefrontal brain function during brief placebo administration may help explain susceptibility to the development of antidepressant side effects. Results of these exploratory hypothesis-generating analyses should be considered tentative until replicated.

An Item Response analysis of the Hamilton Depression Rating Scale using shared data from two pharmaceutical companies.

Although the Hamilton Depression Rating Scale (HAMD) remains the most widely used outcome measure in clinical trials of Major Depressive Disorder, the psychometric properties of the individual HAMD items have not been extensively studied. In the present paper, data from four separate clinical trials conducted independently by two pharmaceutical companies were analyzed to determine the relationship between scores on the individual HAMD items and overall depressive severity in an outpatient population. Option characteristic curves (the probability of scoring a particular option in relation to overall HAMD scores) were generated in order to illustrate the relationship between scoring patterns for each item and the range of total HAMD scores. Results showed that Items 1 (Depressed Mood) and 7 (Work and Activities), and to a lesser degree, Items 2 (Guilt), 10 (Anxiety/Psychic), 11 (Anxiety/Somatic), and 13 (Somatic/General) demonstrated a good relationship between item responses and overall depressive severity. However, other items (e.g. Insight, Hypochondriasis) appeared to be more problematic with regard to their ability to discriminate over the full range of depression severity. The present results illustrate that co-operative data sharing between pharmaceutical companies can be a useful tool for improving clinical methods.

Assessing and interpreting treatment effects in longitudinal clinical trials with missing data.

Treatment effects are often evaluated by comparing change over time in outcome measures; however, valid analyses of longitudinal data can be problematic, particularly if some data are missing. For decades, the last observation carried forward (LOCF) approach has been a common method of handling missing data. Considerable advances in statistical methodology and our ability to implement those methods have been made in recent years. Thus, it is appropriate to reconsider analytic approaches for longitudinal data. This review examines the following from a clinical perspective: 1) the characteristics of missing data that influence analytic choices; 2) the attributes of common methods of handling missing data; and 3) the use of the data characteristics and the attributes of the various methods, along with empirical evidence, to develop a robust approach for the analysis and interpretation of data from longitudinal clinical trials. We propose that, in many settings, the primary efficacy analysis should use a repeated measures, likelihood-based, mixed-effects modeling approach, with LOCF used as a secondary, composite measure of efficacy, safety, and tolerability. We illustrate how repeated-measures analyses can be used to enhance decision-making, and we review the caveats that remain regarding the use of LOCF as a composite measure.