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Gaucher disease type 3 is a chronic neuronopathic disorder with wide-ranging effects, including hepatosplenomegaly, anaemia, thrombocytopenia, skeletal disease and diverse neurological manifestations. Biallelic mutations in GBA1 reduce lysosomal acid β-glucosidase activity, and its substrates, glucosylceramide and glucosylsphingosine, accumulate. Enzyme replacement therapy and substrate reduction therapy ameliorate systemic features of Gaucher disease, but no therapies are approved for neurological manifestations. Venglustat is an investigational, brain-penetrant, glucosylceramide synthase inhibitor with potential to improve the disease by rebalancing influx of glucosylceramide with impaired lysosomal recycling. The Phase 2, open-label LEAP trial (NCT02843035) evaluated orally administered venglustat 15 mg once-daily in combination with maintenance dose of imiglucerase enzyme replacement therapy during 1 year of treatment in 11 adults with Gaucher disease type 3. Primary endpoints were venglustat safety and tolerability and change in concentration of glucosylceramide and glucosylsphingosine in CSF from baseline to Weeks 26 and 52. Secondary endpoints included change in plasma concentrations of glucosylceramide and glucosylsphingosine, venglustat pharmacokinetics in plasma and CSF, neurologic function, infiltrative lung disease and systemic disease parameters. Exploratory endpoints included changes in brain volume assessed with volumetric MRI using tensor-based morphometry, and resting functional MRI analysis of regional brain activity and connectivity between resting state networks. Mean (SD) plasma venglustat AUC0-24 on Day 1 was 851 (282) ng•h/ml; C max of 58.1 (26.4) ng/ml was achieved at a median t max 2.00 h. After once-daily venglustat, plasma concentrations (4 h post-dose) were higher compared with Day 1, indicating ∼2-fold accumulation. One participant (Patient 9) had low-to-undetectable venglustat exposure at Weeks 26 and 52. Based on mean plasma and CSF venglustat concentrations (excluding Patient 9), steady state appeared to be reached on or before Week 4. Mean (SD) venglustat concentration at Week 52 was 114 (65.8) ng/ml in plasma and 6.14 (3.44) ng/ml in CSF. After 1 year of treatment, median (inter-quartile range) glucosylceramide decreased 78% (72, 84) in plasma and 81% (77, 83) in CSF; median (inter-quartile range) glucosylsphingosine decreased 56% (41, 60) in plasma and 70% (46, 76) in CSF. Ataxia improved slightly in nine patients: mean (SD, range) total modified Scale for Assessment and Rating of Ataxia score decreased from 2.68 [1.54 (0.0 to 5.5)] at baseline to 1.55 [1.88 (0.0 to 5.0)] at Week 52 [mean change: −1.14 (95% CI: −2.06 to −0.21)]. Whole brain volume increased slightly in patients with venglustat exposure and biomarker reduction in CSF (306.7 ± 4253.3 mm3) and declined markedly in Patient 9 (−13894.8 mm3). Functional MRI indicated stronger connectivity at Weeks 26 and 52 relative to baseline between a broadly distributed set of brain regions in patients with venglustat exposure and biomarker reduction but not Patient 9, although neurocognition, assessed by Vineland II, deteriorated in all domains over time, which illustrates disease progression despite the intervention. There were no deaths, serious adverse events or discontinuations. In adults with Gaucher disease type 3 receiving imiglucerase, addition of once-daily venglustat showed acceptable safety and tolerability and preliminary evidence of clinical stability with intriguing but intrinsically inconsistent signals in selected biomarkers, which need to be validated and confirmed in future research. [ABSTRACT FROM AUTHOR]

Background: Glucocerebrosidase gene (GBA) mutations influence risk and prognosis of Parkinson's disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat is a novel, brain penetrant glucosylceramide synthase inhibitor. Objective: Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBA mutations (GBA-PD). Methods: Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, double-blinded, placebo-controlled, dose-escalation study performed in six countries. Eligible participants included Japanese and non-Japanese patients aged 18–80 years with PD diagnosis and heterozygous GBA mutation. Participants were randomized to three doses of once-daily oral venglustat or placebo and were followed up to 36 weeks (Japanese participants: 52 weeks). Primary endpoint was venglustat safety and tolerability versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics. Results: Participants (N = 29) received venglustat (Japanese, n = 9; non-Japanese, n = 13) or placebo (n = 3; n = 4). Eight (89%) Japanese and 12 (92%) non-Japanese venglustat-treated participants experienced at least one adverse event (AE) versus two (67%) and four (100%) participants from the respective placebo groups. Most AEs were mild or moderate; no serious AEs or deaths occurred. Two venglustat-treated non-Japanese participants discontinued due to AEs (confusional state and panic attack). Over 4 weeks, venglustat exposure in plasma and cerebrospinal fluid (CSF) increased, and GL-1 levels in plasma and CSF decreased, both in a dose-dependent manner. At the highest dose, CSF GL-1 decreased by 72.0% in Japanese and 74.3% in non-Japanese participants. Conclusion: Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF. [ABSTRACT FROM AUTHOR]

Objective. Inhaled corticosteroids are recommended as first-line therapy for pediatric asthma. However, few controlled long-term studies have investigated their effect on bone mineral density (BMD) and growth. Methods. Children who were aged 6 to 14 years and had persistent asthma were randomized to 24 months' treatment with fluticasone propionate (FP) 200 [micro]g/d or nedocromil sodium (NS) 8 mg/d (if uncontrolled, maximum doses of 400 [micro]g/d and 16 mg/d, respectively). BMD was assessed blind and analyzed at a central facility on the basis of dual-energy x-ray absorptiometry measurements of the lumbar spine and femoral neck at months 0, 6, 12, and 24. Height was measured at months 0, 12, and 24. Efficacy parameters (lung function, asthma control, occurrence of exacerbations) were measured every 3 months. Results. In total, 174 children were randomized to treatment (87 received FP, and 87 received NS). At month 24, the adjusted mean percentage increase in lumbar spine BMD was 11.6% in the FP group compared with 10.4% in NS-treated children (95% confidence interval for treatment difference: -0.7% to 3.1%). The corresponding increases in femoral neck BMD were 8.9% and 8.5%, respectively. There was no significant difference in growth between the 2 groups: adjusted mean growth rates were 6.1 cm/y with FP and 5.8 cm/y with NS. FP was significantly superior for every efficacy parameter investigated and was similarly well tolerated as NS. Conclusions. The long-term effects of FP and NS on BMD accrual and growth are similar among children with asthma. The benefit:risk ratio of FP may be considered superior to that of NS. Pediatrics 2003;111:e706-e713. URL: http://www.pediatrics.org/cgi/content/full/111/6/e706; bone mineral density, fluticasone propionate, long-term safety, height.

Objectives: The objective of this study is to report the dose response in ODYSSEY phase 3 clinical trials of proprotein convertase subtilisin kexin type 9 inhibition with alirocumab in patients not at prespecified lipid goals who received a per-protocol dose increase from 75 every 2 weeks (Q2W) to 150 mg Q2W. Methods: Patients (n=2181) receiving statins were enrolled in six phase 3 randomized, double-blind, double-dummy trials (24–104 weeks): alirocumab versus placebo or ezetimibe 10 mg/day. The 75 mg subcutaneous Q2W dose was increased to 150 mg at week 12 if week 8 LDL cholesterol (LDL-C) was greater than or equal to 70 mg/dl (>100 mg/dl in OPTIONS studies for patients without previous coronary heart disease, but with other risk factors). LDL-C percentage reductions from baseline (on-treatment data, n=1291) were compared at week 12 versus week 24. Results: Most patients (n=951; 73.7%) with 75 mg Q2W dose plus background statin achieved LDL-C less than 70 or less than 100 mg/dl at week 8. In 340 (26.3%) patients, alirocumab dose was increased to 150 mg Q2W at week 12, and 60.9% of these patients achieved LDL-C goals at week 24, with an additional 14.2% reduction in LDL-C from week 12 to week 24. Adverse event rates were comparable in patients with versus without a dose increase (72.4 vs. 71.8% in placebo-controlled trials; 67.0 vs. 67.6% in ezetimibe-controlled trials). Conclusion: Most patients achieved LDL-C goals with alirocumab 75 mg Q2W plus statins. Of those (26.3%) receiving a dose increase, 60.9% achieved LDL-C goals at week 24 with an additional 14.2% reduction in LDL-C., Version of Record

We propose to perform a sensitivity analysis to evaluate the extent to which results from a longitudinal study can be affected by informative drop-outs. The method is based on a selection model, where the parameter relating the dropout probability to the current observation is not estimated, but fixed to a set of values. This allows to evaluate several hypotheses for the degree of informativeness of the drop-out process. Expectation and variance of missing data, conditional on the drop-out time are computed, and a stochastic EM algorithm is used to obtain maximum likelihood estimates. Simulations show that when the drop-out parameter is correctly specified, unbiased estimates of the other parameters are obtained, and coverage percentages of their confidence intervals are close to their theoretical value. More interestingly, misspecification of the drop-out parameter does not considerably alter these results. This method was applied to a randomized clinical trial, designed to demonstrate non-inferiority of an inhaled corticosteroid in terms of bone density, compared with a reference treatment. Sensitivity analysis showed that the conclusion of non-inferiority was robust against different hypotheses for the drop-out process. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Mutations in GBA are associated with increased risk of developing Parkinson disease (PD), characterized by younger onset, higher prevalence of cognitive impairment, and more rapid disease progression. Part 1 of the phase 2 MOVES-PD study (NCT02906020) was an up to 36-week randomized, placebo-controlled, double-blind, sequential cohort study of once-daily venglustat at 3 escalating doses. PD patients age 18-80 years with symptoms ≥2 years and Hoehn & Yahr stage ≤2 at baseline who were heterozygous carriers of a GBA mutation were eligible. The primary endpoint was the safety and tolerability of venglustat. Secondary endpoints included plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK). Exploratory endpoints included pharmacodynamics in plasma and CSF. Seventeen patients (13M, 4F) were randomized to placebo (n=4) or venglustat (n=13). Mean age at enrollment was 58.4 years. Mean years since symptom onset was 6.7, and since diagnosis was 5.2. Twelve patients on venglustat and 4 on placebo reported at least 1 treatment-emergent adverse event (TEAE) most were mild or moderate and resolved without corrective treatment during the study. The most common TEAEs were psychiatric, neurological, and gastrointestinal events consistent with common motor/non-motor PD symptoms or known side effects of concurrent PD medications. No serious AEs or deaths occurred. Two patients on venglustat discontinued due to TEAEs after the primary analysis period (Week 4). Venglustat exposure in plasma and CSF increased in a close to dose-proportional manner. Plasma and CSF glucosylceramide (GL-1) levels decreased from baseline in a dose-dependent manner over 4 weeks. CSF GL-1 decreased 74.3% (higher dose). The data demonstrate a favorable safety and tolerability profile of venglustat at all doses investigated for up to 36 weeks of treatment. Dose-dependent plasma and CSF exposure and reduction of plasma and CSF GL-1 were observed. Part 2 of MOVES-PD, a 52-week randomized, double-blind, placebo-controlled study, is ongoing. Funding: Sanofi Genzyme. [ABSTRACT FROM AUTHOR]

Multiplicity of inferences is present in a large majority of clinical trials and conducts to false analyses or interpretation issues. The main risk consists in false positive conclusions. A large number of statistical methods is available for controlling the rate of false positive conclusions. But formal adjustment is not necessary in all cases and depends on the aims of the study.