Psychomotor development in infants and young children with Down syndrome-A prospective, repeated measure, post-hoc analysis.

Children with Down syndrome (DS) show delayed acquisition of cognitive and functional skills compared to typically developing children. The objective of this study was to accurately describe early development of infants and young children (children hereafter) with DS based on a large recent sample. We carried out repeated measure analysis of the global development quotient (GDQ) and developmental age using data from the Assessment of Systematic Treatment with Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) study (NCT01576705). Because there was no statistically significant difference in the primary endpoint between active treatment and placebo, data from all treatment groups were pooled for post-hoc analysis. Data of 141 children with DS aged 6-18 months at inclusion were analyzed. Mean GDQ decreased over the study period, especially in the youngest age classes ([6-9] and [9-12] months), indicating that acquisition of skills occurred at a slower pace compared to typically developing children. Strongest deficits were observed for motor and hearing and language skills. Only GDQ at baseline correlated significantly with evolution of GDQ. Future studies should aim at elucidating the mechanisms underlying motor and language development. Early pharmacological interventions together with early childhood therapies might be necessary to improve the developmental trajectory of children with DS.

Thyroid hormone and folinic acid in young children with Down syndrome: the phase 3 ACTHYF trial.

PURPOSE: To determine whether folinic acid (FA) and thyroxine, in combination or alone, benefit psychomotor development in young patients with Down syndrome (DS). METHODS: The Assessment of Systematic Treatment With Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) was a single-center, randomized, double-blind, placebo-controlled phase 3 trial in DS infants aged 6-18 months. Patients were randomly assigned to one of four treatments: placebo, folinic acid (FA), L-thyroxine, or FA+L-thyroxine, administered for 12 months. Randomization was done by age and sex. The primary endpoint was adjusted change from baseline in Griffiths Mental Development Scale global development quotient (GDQ) after 12 months. RESULTS: Of 175 patients randomized, 143 completed the study. The modified intention-to-treat (mITT) population included all randomized patients who did not prematurely discontinue due to elevated baseline thyroid stimulating hormone (TSH). Baseline characteristics in the mITT were well balanced between groups, with reliable developmental assessment outcomes. Adjusted mean change in GDQ in the mITT showed similar decreases in all groups (placebo: -5.10 [95% confidence interval (CI) -7.84 to -2.37]; FA: -4.69 [95% CI -7.73 to -1.64]; L-thyroxine: -3.89 [95% CI -6.94 to -0.83]; FA+L-thyroxine: -3.86 [95% CI -6.67 to -1.06]), with no significant difference for any active treatment group versus placebo. CONCLUSION: This trial does not support the hypotheses that thyroxine and/or folinic acid improve development of young children with DS or are synergistic. This trial is registered with ClinicalTrials.gov number, NCT01576705.

A predictive microarray-based biomarker for early detection of Alzheimer's disease intended for clinical diagnostic application.

OBJECTIVE: Microarray-based signatures for clinical application are often plagued by processing variability or batch effects that compromise the robustness of the test performance. METHODS: A splice variant array-based signature for early detection of Alzheimer's disease (AD) was developed using 315 AD or normal subjects processed in three disparate microarray batches. RESULTS: A modified top scoring pair classifier using the signature, is robust to batch effects and outperforms other common classifiers, with sensitivity and specificity of 88.3% (95% CI:81.2%, 93.4%) and 88.9% (95% CI:65.3%, 98.6%), respectively, on an independent cohort. CONCLUSIONS: This splice-variant array-based signature shows promise for clinical diagnostic use in AD.

The Power Derivative Principle, and Its Application to How and When to Perform a One-Shot Unblinded Reassessment Sample Size.

BACKGROUND: In adaptive two-group clinical trials, a current method is to perform a one-shot unblinded sample size reassessment. Whereas the interim unblinded look of the data is adjusted for inference by using the weighted Cui-Hung-Wang statistics, some questions remain: how and when to reassess the sample size? METHODS: We define the Power Derivative Principle as follows: a sample size is optimal when the derivative of the power with respect to the sample size has reached some implicit value. Applied to two-group clinical trials, this Power Derivative Principle determines a new one-shot unblinded sample size reassessment rule (including the determination of futility bounds). A full Power Derivative Strategy induces furthermore an optimal information fraction for the interim analysis. The Power Derivative Strategy is then compared to adaptive design methods proposed in the literature and to group sequential strategies. For this comparison, we used, on the one hand, the very common information fraction f = 0.5 and, on the other hand, the information fraction found as being optimal with the Power Derivative Principle. RESULTS: The optimal information fraction depends only on α-and ß-risks. For usual values of these risks, the optimal information fraction value is very close to 0.9. Moreover, with this unexpected optimal value, reassessment methods become roughly comparable (it is definitely not the case when f=0.5). CONCLUSIONS: Our results suggest that a sample size reassessment is more beneficial when considered close to the planned end of a trial, allowing a study with borderline interim results to be saved.

Blood transcriptomic biomarkers of Alzheimer's disease patients treated with EHT 0202.

Monitoring the genomic expression of patients in clinical trials for Alzheimer's disease (AD) can assist trial design and treatment response analysis. Here, we report on the identification in AD patients of blood-based transcriptomic signatures associated with treatment response of EHT 0202, a new compound with potential disease-modifying and symptomatic properties, in a 3-month, placebo-controlled, Phase IIA study aimed at determining the clinical safety, tolerability, and exploratory efficacy of EHT 0202 (40 and 80 mg bid) as adjunctive therapy to one cholinesterase inhibitor in mild to moderate AD patients. Genome-wide transcriptomic profiling was performed on blood samples taken prior to treatment and at study completion in a subpopulation of 60 AD patients selected as either the 10 worst disease decliners or the 10 best improvers of each treatment group, using ADAS-Cog scores as measure of disease severity. In the patients responding to EHT 0202, a pre-treatment (baseline) transcriptomic signature showed activation of pathways related to AD, CNS disorders, diabetes, inflammation, and autoimmunity, while a post-treatment signature indicated reduced activation of these pathways with induced metabolic and transcription stimulation. This pilot study demonstrates the utility of blood transcriptomic signatures used as biomarkers for predicting patient response or monitoring efficacy, for an administered therapeutic drug in a complex disease such as AD. For EHT 0202 or other AD drugs, such biomarkers may help to improve strategies to better identify appropriate patient populations for treatment, understand the drug mechanism of efficacy, and/or clarify the inherent subjectivity in most clinical endpoints used in this disease.