Cognitive training in Alzheimer's disease: a controlled randomized study.

This controlled randomized single-blind study evaluated the effects of cognitive training (CT), compared to active music therapy (AMT) and neuroeducation (NE), on initiative in patients with mild to moderate Alzheimer's disease (AD). Secondarily, we explored the effects of CT on episodic memory, mood, and social relationships. Thirty-nine AD patients were randomly assigned to CT, AMT, or NE. Each treatment lasted 3 months. Before, at the end, and 3 months after treatment, neuropsychological tests and self-rated scales assessed initiative, episodic memory, depression, anxiety, and social relationships. At the end of the CT, initiative significantly improved, whereas, at the end of AMT and NE, it was unchanged. Episodic memory showed no changes at the end of CT or AMT and a worsening after NE. The rates of the patients with clinically significant improvement of initiative were greater after CT (about 62%) than after AMT (about 8%) or NE (none). At the 3-month follow-up, initiative and episodic memory declined in all patients. Mood and social relationships improved in the three groups, with greater changes after AMT or NE. In patients with mild to moderate AD, CT can improve initiative and stabilize memory, while the non-cognitive treatments can ameliorate the psychosocial aspects. The combining of CT and non-cognitive treatments may have useful clinical implications.

Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus.

We aimed to evaluate the pharmacodynamics, efficacy, safety and tolerability of the JAK1 inhibitor GSK2586184 in adults with systemic lupus erythematosus (SLE). In this adaptive, randomized, double-blind, placebo-controlled study, patients received oral GSK2586184 50-400 mg, or placebo twice daily for 12 weeks. Primary endpoints included interferon-mediated messenger RNA transcription over time, changes in Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index score, and number/severity of adverse events. A pre-specified interim analysis was performed when ≥ 5 patients per group completed 2 weeks of treatment. In total, 84-92% of patients were high baseline expressors of the interferon transcriptional biomarkers evaluated. At interim analysis, GSK2586184 showed no significant effect on mean interferon transcriptional biomarker expression (all panels). The study was declared futile and recruitment was halted at 50 patients. Shortly thereafter, significant safety data were identified, including elevated liver enzymes in six patients (one confirmed and one suspected case of Drug Reaction with Eosinophilia and Systemic Symptoms), leading to immediate dosing cessation. Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index scores were not analysed due to the small number of patients completing the study. The study futility and safety data described for GSK2586184 do not support further evaluation in patients with SLE. Study identifiers: GSK Study JAK115919; ClinicalTrials.gov identifier: NCT01777256.

Investigation of selective JAK1 inhibitor GSK2586184 for the treatment of psoriasis in a randomized placebo-controlled phase IIa study.

BACKGROUND: GSK2586184 is a selective oral Janus kinase (JAK)1 inhibitor being evaluated as a treatment for moderate-to-severe plaque-type psoriasis. OBJECTIVES: To assess the relationship between dose of GSK2586184 and clinical response, primarily by the Psoriasis Area Severity Index (PASI). METHODS: Sixty patients with moderate-to-severe plaque psoriasis were randomized to cohort A: 100 mg, 200 mg or 400 mg GSK2586184 twice daily or placebo; and eight were randomized to open-label cohort B, a small exploratory cohort treated with 400 mg GSK2586184 twice daily, to explore differential gene expression. RESULTS: At week 12, a 75% reduction in PASI (PASI 75) response rates in the intent-to-treat population were 0% in the placebo group compared with 13%, 25% and 57% in the 100 mg, 200 mg and 400 mg GSK2586184 twice-daily groups, respectively. Increases in the proportion of PASI 75 responses were seen across all dose levels by week 4. Improvement in itch and quality of life were observed at all doses relative to placebo with the greatest improvement seen in the 400-mg dose group. Overall, the incidence of adverse events (AEs) was similar across treatment groups, and no relationship between frequency of AE and GSK2586184 dose was identified. Differential gene expression was observed in involved and uninvolved skin at baseline and in involved skin after 2 weeks of treatment with GSK2586184. CONCLUSIONS: Our study demonstrates that 12 weeks of treatment with GSK2586184 resulted in clinical improvement and was generally well tolerated in patients with moderate-to-severe plaque-type psoriasis.