An Open-Label, Multicenter, Single-Dose Pharmacokinetic Study of a Novel Amphetamine Extended-Release Orally Disintegrating Tablet in Preschool-Aged Children.

Objective: In the U.S. ∼33% of children with attention-deficit/hyperactivity disorder (ADHD) are diagnosed during their preschool years (<6 years of age). The majority of these children are treated with a psychopharmacological treatment, despite limited data on pharmacokinetics (PKs), efficacy, or safety of these medications in this population. A phase 4, single-dose open-label study was conducted to assess the PK profile of amphetamine extended-release orally disintegrating tablets (AMP XR-ODT) under fasted conditions in preschool-aged children with ADHD. Methods: Preschool-aged children (aged 4 to <6 years) with a confirmed ADHD diagnosis were enrolled and administered AMP XR-ODT 3.1 mg under fasted conditions. Plasma samples were analyzed for d- and l-amphetamine (AMP) via liquid chromatography-tandem mass spectrometry. Area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf), area under the concentration-time curve from time 0 to the last measurable plasma concentration (AUC0-T), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), terminal half-life (t1/2), apparent volume of distribution (Vz/F), and apparent clearance (CL/F) for d- and l-AMP and safety were assessed. Results: The PK and safety analyses included 15 preschool-aged children (4 years old, n = 6; 5 years old, n = 9); 14 completed the study. Quantifiable plasma concentrations for d- and l-AMP were observed 1.5 hours postdose and throughout the 24-hour sampling period. For d- and l-AMP, mean AUC0-inf was 315.2 and 104.4 h·ng/mL, AUC0-T was 296.0 and 96.8 h·ng/mL, t1/2 was 8.0 and 9.2 hours, Cmax was 23.0 and 7.0 ng/mL, Tmax was 3.9 and 4.0 hours, CL/F was 6996.3 and 6837.1 mL/h, and Vz/F was 75,874.5 and 84,140.0 mL, respectively. Adverse events included tachycardia (n = 2), neutropenia (n = 1), increased alanine aminotransferase (n = 1), and aspartate aminotransferase (n = 1). Conclusions: AMP XR-ODT 3.1 mg was well tolerated in preschool-aged children, with detectable plasma AMP concentrations over 24 hours, and a PK profile consistent with once-daily dosing.

Ethical Considerations in Adaptive Design Clinical Trials.

Adaptive design clinical trial methodologies offer both opportunities and challenges for observing basic ethical principles in human subject research. Using both published and unpublished adaptive design clinical trials, we have selected and reviewed examples of clinical trials with different design adaptations to discuss the ethical obstacles presented and often successfully resolved by these approaches, including (1) confirmatory trials for treatments widely accepted on the basis of uncontrolled case series or open-label trials (clinical equipoise and "justice" in the sense of which trial groups will "receive the benefits of research and bear its burdens") (infantile hemangioma/propranolol); (2) interim results analysis by unblinded data monitoring committees ("withholding information necessary to make a considered judgment" ["respect for persons"] versus compromising the trial's scientific basis) (BIG 1-98); (3) adaptations involving sample size reassessment or dose adjustment via dropping or adding treatment arms, allowing fewer subjects to produce statistically significant results, fewer subjects treated with ineffective/toxic doses, and more subjects given doses showing tolerance and treatment activity ("beneficence" or "protecting from harm and making efforts to secure wellbeing") (ECMO, Neuromyelitis Optica); (4) adaptive randomization inferential problems balanced against ethical benefits (trastuzumab vs taxane in advanced gastric cancer; ADVENT); (5) more efficient allocation of societal resources for research, in both public and commercial realms, versus uncertain regulatory acceptance (indicaterol; VALOR); and (6) platform, umbrella, and basket trials offering additional efficiencies (I-SPY II, BATTLE, Lung-MAP). The importance of careful design, meticulous planning, and rigorous ethical review of adaptive design trials on a case-by-case basis cannot be overemphasized.

A Practical Guide to Data Monitoring Committees in Adaptive Trials.

Adaptive clinical trials require access to interim data to carry out trial modification as allowed by a prespecified adaptation plan. A data monitoring committee (DMC) is a group of experts that is charged with monitoring accruing trial data to ensure the safety of trial participants and that in adaptive trials may also play a role in implementing a preplanned adaptation. In this paper, we summarize current practices and viewpoints and provide guidance on evolving issues related to the use of DMCs in adaptive trials. We describe the common types of adaptive designs and point out some DMC-related issues that are unique to this class of designs. We include 3 examples of DMCs in late-stage adaptive trials that have been implemented in practice. We advocate training opportunities for researchers who may be interested in serving on a DMC for an adaptive trial since qualified DMC members are fundamental to the successful execution of DMC responsibilities.

An evaluation of bioactive glass in the treatment of periodontal defects: a meta-analysis of randomized controlled clinical trials.

BACKGROUND: The regenerative surgical treatment of intrabony defects caused by periodontal disease has been examined in several systematic reviews and meta-analyses. The use of bioactive glass (BG) as a graft material to treat intrabony defects has been reported, but all data have not been synthesized and compiled. Our objective was to systematically review the literature on the use of BG for the treatment of intrabony defects and to perform a meta-analysis of its efficacy. METHODS: A search of PubMed, EMBASE, and Cochrane Database of Systematic Reviews, as well as a manual search of recently published periodontology journals, were conducted to identify randomized controlled trials of the use of BG in the treatment of intrabony and furcation defects. Criteria included publication in English, follow-up duration of ≥6 months, baseline and follow-up measures of probing depth (PD) and clinical attachment levels (CAL) with 95% confidence intervals (CIs), and an appropriate control arm. Twenty-five citations were identified, 15 of which were included in the final analysis. Data, including study methods and results, as well as CONSORT (Consolidated Standards of Reporting Trials) criteria, were extracted from eligible studies and cross-checked by at least two reviewers. RESULTS: Meta-analyses of eligible studies were performed to ascertain summary effects for changes in PD and CAL among experimental and control groups, using the mean change plus standard deviation for each study. Pooled analyses showed that BG was superior to control for both measures: the mean (95% CIs) difference from baseline to follow-up between BG and controls was 0.52 mm (0.27, 0.78, P <0.0001) in reduction for PD and 0.60 mm (0.18, 1.01, P = 0.005) in gain for CAL. Analyses of CAL revealed heterogeneity across studies (I(2) = 60.5%), although studies reporting PD measures were homogeneous (I(2) = 0.00%). CAL heterogeneity appeared secondary to active controls versus open flap debridement (OFD) alone and to defect-type modifying BG treatment success. Per subgroup analyses, the benefit of BG over control treatment was highly significant only in studies comparing BG to OFD (P <0.0001), with mean difference change in CAL being 1.18 mm (95% CI = 0.74, 1.62 mm) between the BG and OFD group. CONCLUSION: Treatment of intrabony defects with BG imparts a significant improvement in both PD and CAL compared to both active controls and OFD.