NV-5138 (S-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid) is an orally bioavailable, small-molecule activator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in development for ...treatment-resistant depression. The authors established a model to describe the relationship between plasma and cerebrospinal fluid (CSF) concentrations of NV-5138 and between CSF concentrations and potential biomarkers thought to be associated with mTORC1 activity (ie, orotic acid, N-acetylmethionine, and N-formylmethionine).
Data were collected from a randomized, double-blind, placebo-controlled, tolerability, and pharmacokinetic (PK) parameter study of 5 ascending (400, 800, 1600, 2400, and 3000 mg), once-daily oral doses of NV-5138 in healthy subjects. NV-5138 plasma PK parameter samples were collected at 15 time points over 24 hours on days 1 and 7, and at pre dose on days 2–6 for all doses. NV-5138 CSF PK parameter and CSF biomarker samples were collected on days 1 and 7 at pre dose and 4, 8, and 12 hours post dose for all doses except 3000 mg. A model-based approach was used to develop and validate a model that describes the relationship between NV-5138 in CSF and biomarker concentrations.
Twenty-four of the 42 enrolled subjects had simultaneous plasma and CSF measurements of NV-5138 and CSF biomarker concentrations and were included in the PK parameter and pharmacodynamic (PD) analyses. A 2-compartment plasma and CSF PK parameter, with indirect PD effects, model was developed and validated. NV-5138 plasma concentrations were positively correlated with those in CSF, although CSF concentrations lagged slightly behind those in plasma, as indicated by a counterclockwise hysteresis effect. Similarly, the relationship between the PD measures of mTORC1 activation and NV-5138 was also characterized by counterclockwise hysteresis, when the increase in CSF biomarker concentrations lagged behind those of NV-5138, consistent with a signaling intermediary/cascade, such as mTORC1. Maximal biomarker activation was achieved at NV-5138 CSF concentrations of approximately 3 µg/mL, which were associated with daily doses of 1600 mg NV-5138. The safety profile analysis (n = 42) found that most of the reported adverse events were mild in severity, with no severe, serious, unusual, or unexpected adverse events or any dissociative effects; 2 subjects (400-mg cohort) discontinued due to adverse events that were judged to be unrelated to study medication.
The model will be used for designing future efficacy and tolerability studies. Consecutive daily doses of NV-5138 were well tolerated in this healthy volunteer study.
•Viloxazine ER, a nonstimulant for ADHD in children was newly approved for adults.•A machine learning algorithm could predict response using early data in children.•This algorithm was applied to ...predict response in an adult clinical trial.•Machine learning lasso model effectively predicted response from data through Wk 2.•Findings support consistency of viloxazine ER treatment across age groups.
Early response to viloxazine extended-release (viloxazine ER, Qelbree®) treatment predicted efficacy outcome in pediatric subjects with attention-deficit/hyperactivity disorder (ADHD). This study sought to determine whether the machine learning lasso model used in the pediatric study would predict response to viloxazine ER in an adult population based on early improvements in ADHD symptoms. We used data from a double-blind, placebo-controlled, flexible-dose (200–600 mg) study of viloxazine ER (N = 354; 18 to 60 years old). Area under the Receiver Operating Characteristic Curve (ROC AUC) statistics were computed using the lasso model from pediatric data to predict responder status in adults. Response was defined as ≥50% reduction from baseline in the Adult ADHD Investigator Symptoms Rating Scale (AISRS) Total score at Week 6. The adult study sample included 127 viloxazine ER-treated subjects with Week 6 data. Fifty-one subjects (40.2%) were categorized as responders. The ROC curves indicated that data collected up to Week 2 were sufficient to accurately predict treatment response at Week 6 with 68% positive predictive power, 80% sensitivity, and 74% specificity. This analysis demonstrated that the predictive model estimated from the child data generalizes to adults with ADHD, further supporting the consistency of viloxazine ER treatment across age groups.
The orexin system plays a major role in the integration of metabolic and circadian influences that drive wakefulness. This paper describes initial Phase I trials of a novel dual orexin receptor ...antagonist SB-649868 that has demonstrated preclinical potential for treatment of sleep disorders. The trial designs included a single ascending dose escalation study (dose range: 10–80 mg in the fed and fasted states) and a multiple repeat dose study (dose range: 5–30 mg in the fed state) enrolling a total of 103 male volunteer subjects. SB-649868 was well tolerated at all doses in this study population, with mechanism-related adverse events (e.g. somnolence and fatigue) observed in a majority of subjects after 60 and 80 mg single doses. Although total drug exposure was similar in the fed and fasted states, the rate, but not the extent, of absorption increased in the fed state, resulting in an increased Cmax. The typical estimated half-life of SB-649868 was 3–6 h – comparable with currently used hypnotic agents. Repeated administration of SB-649868 dose-dependently increased exposure to simvastatin (10 mg), suggesting CYP3A4 inhibition ranging from very mild (5 mg) to strong (30 mg). Evening dosing resulted in significant dose-dependent improvement in latency to persistent sleep, total sleep time and wake after sleep onset as measured by polysomnography. Next-morning testing did not detect evidence of residual cognitive effects. Results of these trials support further investigation of SB-649868 and other dual orexin receptor antagonists as potentially effective and well-tolerated treatments for patients with sleep disorders.
A Phase 1 study was performed to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the selective histamine H
receptor antagonist SENS-111, an oral small molecule.
One hundred ...healthy subjects were randomized in a placebo-controlled, double-blind study evaluating single-ascending doses (SAD; 100-500 mg) and multiple-ascending doses (MAD; 50-150 mg day
, 4 days; 200-250 mg day
, 7 days). Effects of SENS-111 on nystagmus and vertigo induced by modified caloric tests were measured in the MAD studies. Population PK and PK/PD models were developed using a nonlinear mixed-effects approach.
SENS-111 was well tolerated with mild to moderate events. No sedation was reported. A maximal tolerated dose was not reached. Dose-proportional increases in concentrations were seen up to 200 mg and more than dose-proportional thereafter, with mean half-life between 24 and 56 h. The caloric test induced mild but measurable vertigo and nystagmus with large intra/inter-individual variation for all parameters. SENS-111 did not significantly impact nystagmus but significantly improved latency of vertigo appearance/disappearance, duration and European Evaluation of Vertigo questionnaire parameters vs. baseline. A two-compartment model with first-order absorption, distribution and elimination best fit the data. PK/PD indirect modelling applied to vertigo duration and latency of appearance indicated maximum activity between 100 and 500 ng ml
plasma concentrations, corresponding to 100 and 200 mg day
, which are appropriate for clinical efficacy evaluations in vestibular diseases.
SENS-111 is a well-tolerated first-in-class H
receptor antagonist with acceptable PK for oral daily dosing. PK/PD modelling determined plasma concentrations and doses for efficacy studies in patients with vertigo symptoms.
The net benefit of a treatment can be defined by the relationship between clinical improvement and risk of adverse events: the benefit‐risk ratio. The optimization of the benefit‐risk ratio can be ...achieved by identifying the most adequate dose (and/or dosage regimen) jointly with the best‐performing in vivo release properties of a drug. A general in silico tool is presented for identifying the dose, the in vitro and the in vivo release properties that maximize the benefit‐risk ratio using convolution‐based modeling, an exposure‐response model, and a surface response analysis. A case study is presented to illustrate how the benefit‐risk ratio of methylphenidate for the treatment of attention deficit hyperactivity disorder can be maximized using the proposed strategy. The results of the analysis identified the characteristics of an optimized dose and in vitro/in vivo release suitable to provide a sustained clinical response with respect to the conventional dosage regimen and formulations.
Abstract Performance of recruitment centers is a critical feature for the success of multicentric randomized clinical trials (RCT). An enrichment window strategy (EWS) was recently proposed to ...enhance signal detection in RCTs based on the identification of centers with non-plausible placebo response, leading to a Per Protocol exclusion of all data from these non-informative centers before statistical analysis. The risk of an inflated Type I error associated with EWS was assessed using Clinical Trial Simulation. Randomized two-arm placebo controlled trials were simulated under the assumption that the drug treatment was ineffective.The results obtained in the absence of population enrichment were compared to the results obtained after EWS application. The results indicated that EWS preserved the Type I error showing no bias, at variance with other procedures. These results were confirmed by simulating 13 three-arm placebo controlled RCTs from the GSK Clinical Database.
Aim
The aim of this study was to evaluate the effect of viloxazine extended-release capsules (viloxazine ER; Qelbree™) on executive function deficits (EFDs) in pediatric subjects (6–17 years of age) ...with attention-deficit/hyperactivity disorder (ADHD).
Methods
Data from four phase III placebo-controlled trials of 100–600 mg/day viloxazine ER (6–8 weeks of treatment) were used to evaluate the change from baseline (CFB) in the Conners 3rd Edition Parent Short Form—Executive Function (C3PS-EF) content scale
T
-score. Subjects were defined as EFD responders if they had C3PS-EF
T
-score > 70 at baseline and < 65 at end of study. ADHD symptoms were assessed with ADHD Rating Scale 5th Edition (ADHD-RS-5). Subjects were defined as ADHD symptom responders if they had a ≥ 50% reduction in CFB ADHD-RS-5 Total score at Week 6. The number needed to treat (NNT) and Cohen’s
d
effect sizes were estimated for EFD and ADHD symptoms.
Results
A total of 1154 subjects were included in the analysis. Statistically significant improvements in EFDs were observed with viloxazine ER versus placebo (
p
= 0.0002). There were 52.5% of EFD or ADHD symptom responders in the viloxazine ER treatment group and 35.4% in the placebo group (
p
< 0.0001). The NNT was 5.8. The Cohen’s
d
effect size for EFD and ADHD symptoms was 0.31.
Conclusion
Consistent with the efficacy of viloxazine ER demonstrated in pivotal trials, viloxazine ER significantly reduced EFDs in subjects with ADHD. Moreover, a substantial proportion of subjects treated with viloxazine ER had large improvements in EFDs, ADHD symptoms, or both.
Clinical Trial Registration Numbers
NCT03247530, NCT03247517, NCT03247543, NCT03247556.
The objectives of this work were: (1) to characterize the placebo FEV1 response in asthma; (2) to identify the potential factors with strong influence on FEV1; (3) to determine the predictability of ...the early (week 2) placebo FEV1 response to the longer term (week 12) FEV1 response. Placebo FEV1 data of about 800 subjects from 11 randomized 12‐week clinical trials in mild‐to‐moderate asthmatics were collected. Stepwise logistic regression methods using SAS were used to model the week 12 trough FEV1 change from baseline greater than a clinically relevant value (150 mL) and to select the predictive covariates. The study effect was assessed using hierarchical logistic regression models implemented in WinBUGS. The results indicated that the early (week 2) placebo response was significantly predictive of the FEV1 response at week 12. Age, baseline predicted FEV1, and season showed statistical significance in the model. The final model showed satisfactory predictability with the area under the receiver operating characteristic curve (ROC) of 80%. The late (week 12) FEV1 response with placebo was positively related to the early (week 2) FEV1 change. The use of the predictive modeling approach proposed in this article presents a valuable method to increase the efficiency of clinical trial design in asthma population.
Objective:
To evaluate the treatment effect size throughout the day of amphetamine extended-release oral suspension (AMPH EROS; Tris Pharma, Inc., Monmouth Junction, NJ, USA) in a laboratory ...classroom study conducted in children aged 6–12 years with attention-deficit/hyperactivity disorder (ADHD).
Methods:
A
post hoc
analysis was performed to assess the overall effect size as well as the effect size at each time point from early morning through evening (1, 2, 4, 6, 8, 10, 12, and 13 hours postdose) for each efficacy measure evaluated in a 5-week, randomized, dose-optimized, double-blind, placebo-controlled, laboratory classroom assessment, efficacy, and safety study of AMPH EROS (
N
= 99). Change from baseline of the primary (Swanson, Kotkin, Agler, M-Flynn, Pelham SKAMP-C) and key secondary (secondary efficacy assessments included the SKAMP attention SKAMP-A, SKAMP-deportment subscale SKAMP-D, Permanent Product Measure of Performance-number of problems attempted PERMP-A, PERMP-number of problems correct PERMP-C) efficacy measures were analyzed using a linear mixed model repeated-measures analysis model. Comparisons among treatments were adjusted for multiple comparisons using the Bonferroni method. The effect size was estimated using Cohen's
d
, to determine “small,” (0.2), “medium,” (0.5), or “large” (0.8) magnitudes of treatment effects.
Results:
Large overall effect sizes were observed for all primary and key secondary efficacy assessments. Moreover, the SKAMP-C, PERMP-number of problems attempted, and PERMP-C scores showed large effect sizes at each time point evaluated across the day, from 1 to 13 hours postdose. The SKAMP-A and SKAMP-D scores showed a medium to large effect size at each time point.
Conclusions:
AMPH EROS demonstrated a large and consistent effect size across the day, including early in the morning, in the treatment of symptoms of ADHD in children aged 6–12 years. Trial Registration:
clinicaltrials.gov
identifier: NCT02083783
RBP‐6000 is a novel sustained‐release formulation of buprenorphine for the treatment of opioid use disorder, which has been designed for once‐monthly (28 days) subcutaneous (SC) injections. A ...population pharmacokinetic (PK) model was developed to describe the time course of buprenorphine plasma concentrations after repeated SC injections of RBP‐6000 at 50 mg, 100 mg, 200 mg, or 300 mg in treatment‐seeking opioid‐dependent subjects previously on sublingual buprenorphine (Subutex®) treatment. The μ‐opioid receptor occupancy was predicted using a previously developed PK/PD Emax model. The results of the population PK analysis jointly with the predicted level of μ‐opioid receptor occupancy provided quantitative criteria for clinical dose selection for RBP‐6000: the dose of 300 mg every 28 days seems appropriate for immediately achieving an effective exposure after the first SC injection and to maintain effective levels of exposure during chronic treatment. Furthermore, simulations conducted to evaluate the potential impact of a holiday in drug intake indicated that in the unexpected event of a 2‐week holiday, levels of μ‐opioid receptor occupancy remained consistently above 70% with no significant loss of drug efficacy. This analysis indicated that RBP‐6000 has the potential for becoming an effective treatment for opioid‐dependent subjects by addressing compliance issues associated with the current once‐a‐day treatments.
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