Mitigating the Effects of Nonadherence in Clinical Trials.

Accounting for subject nonadherence and eliminating inappropriate subjects in clinical trials are critical elements of a successful study. Nonadherence can increase variance, lower study power, and reduce the magnitude of treatment effects. Inappropriate subjects (including those who do not have the illness under study, fail to report exclusionary conditions, falsely report medication adherence, or participate in concurrent trials) confound safety and efficacy signals. This paper, a product of the International Society for CNS Clinical Trial Methodology (ISCTM) Working Group on Nonadherence in Clinical Trials, explores and models nonadherence in clinical trials and puts forth specific recommendations to identify and mitigate its negative effects. These include statistical analyses of nonadherence data, novel protocol design, and the use of biomarkers, subject registries, and/or medication adherence technologies.

Audio-digital recordings used for independent confirmation of site-based MADRS interview scores.

Signal detection requires ratings reliability throughout a clinical trial. The confirmation of site-based rater scores by a second, independent and blinded rater is a reasonable metric of ratings reliability. We used audio-digital pens to record site-based interviews of the Montgomery-Asberg Depression Rating Scale (MADRS) in a double-blind, placebo controlled trial of a novel antidepressant in treatment resistant depressed patients. Blinded, site-independent raters generated "dual" scores that revealed high correlations between site-based and site-independent raters (r=0.940 for all ratings) and high sensitivity, specificity, predictive values, and kappa coefficients for treatment response and non-response outcomes using the site-based rater scores as the standard. The blinded raters achieved an 89.4% overall accuracy and 0.786 kappa for matching the treatment response or non-response outcomes of the site-based raters. A limitation of this method is that independent ratings depend on the quality of site-based interviews and patient responses to the site-based interviewers. Nonetheless, this quality assurance strategy may have broad applicability for studies that use subjective measures and wherever ratings reliability is a concern. "Dual" scoring of recorded site-based ratings can be a relatively unobtrusive surveillance strategy to confirm scores and to identify and remediate rater "outliers" during a study.

Use of band-pass filter analysis to evaluate outcomes in an antidepressant trial for treatment resistant patients.

Band-pass filtering is a novel statistical methodology that proposes that filtering out data from trial sites generating non-plausible high or low levels of placebo response can yield a more accurate effect size and greater separation of active drug (when efficacious) from placebo. We applied band-pass filters to re-analyze data from a negative antidepressant trial (NCT00739908) evaluating CX157 (a reversible and selective monoamine oxidase inhibitor-A) versus placebo. 360 patients from 29 trial sites were randomized to either CX157 treatment (n=182) or placebo (n=178). We applied two filters of<3 or>7 points (filter #1) or<3 and>9 points (filter #2) mean change of the total MADRS placebo scores for each site. Trial sites that had mean placebo MADRS score changes exceeding the boundaries of these band-pass filter thresholds were considered non-informative and all of the data from these sites were excluded from the post-hoc re-analysis. The two band-pass filters reduced the sample of informative patients from 353 patients in the mITT population to 62 in filter #1 and 152 in the filter #2 group. The placebo response was reduced from 31.1% in the mITT population to 9.4% with filter #1 and 20.8% with filter #2. MMRM analysis revealed a non-statistically significant trend of p=0.13 and 0.16 for the two filters in contrast to the mITT population (p= 0.58). Our findings support the band-pass filter hypothesis and highlight issues related to site-based scoring variability and inappropriate subject selection that may contribute to trial failure.

Lack of tyramine pressor response effect with oral CX157: A specific reversible MAOI.

This Phase 1, single-center, double-blind, placebo-controlled, three-period study assessed cardiovascular safety of CX157, a specific Reversible Inhibitor of Monoamine Oxidase A (RIMA), following the oral administration of tyramine. In Period 1, the sensitivity of each subject to orally administered tyramine was established by determining the dose of tyramine that elevates SBP ≥30 mmHg on ≥3 consecutive occasions (i.e., TYR303 ). Twelve subjects qualified for randomization in Period 2 during which an oral CX157 Modified Release Tablet (125 mg [N = 10]) or placebo (N = 2) were administered twice per day for 6 days to reach steady state. In Period 3, CX157 and placebo were administered with oral tyramine in fed state with daily increases in the tyramine dose of 20, 40, and 80 mg in an attempt to achieve the TYR303 . CX157 Modified Release Tablet, 125 mg administered twice per day (250 mg daily dose), was not associated with a tyramine reaction (i.e., TYR303 ). It is generally agreed that a high tyramine meal would contain up to 40 mg of dietary tyramine. These data obtained with CX157 provide an adequate margin of safety with respect to tyramine interaction and suggest that future studies can be conducted without the need for dietary tyramine restrictions.

Reversible inhibitors of monoamine oxidase-A (RIMAs): robust, reversible inhibition of human brain MAO-A by CX157.

Reversible inhibitors of monoamine oxidase-A (RIMA) inhibit the breakdown of three major neurotransmitters, serotonin, norepinephrine and dopamine, offering a multi-neurotransmitter strategy for the treatment of depression. CX157 (3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin-10,10-dioxide) is a RIMA, which is currently in development for the treatment of major depressive disorder. We examined the degree and reversibility of the inhibition of brain monoamine oxidase-A (MAO-A) and plasma CX157 levels at different times after oral dosing to establish a dosing paradigm for future clinical efficacy studies, and to determine whether plasma CX157 levels reflect the degree of brain MAO-A inhibition. Brain MAO-A levels were measured with positron emission tomography (PET) imaging and [(11)C]clorgyline in 15 normal men after oral dosing of CX157 (20-80 mg). PET imaging was conducted after single and repeated doses of CX157 over a 24-h time course. We found that 60 and 80 mg doses of CX157 produced a robust dose-related inhibition (47-72%) of [(11)C]clorgyline binding to brain MAO-A at 2 h after administration and that brain MAO-A recovered completely by 24 h post drug. Plasma CX157 concentration was highly correlated with the inhibition of brain MAO-A (EC(50): 19.3 ng/ml). Thus, CX157 is the first agent in the RIMA class with documented reversible inhibition of human brain MAO-A, supporting its classification as a RIMA, and the first RIMA with observed plasma levels that can serve as a biomarker for the degree of brain MAO-A inhibition. These data were used to establish the dosing regimen for a current clinical efficacy trial with CX157.