Evaluation of neurotrophic factor secreting mesenchymal stem cells in progressive multiple sclerosis.

Background: Autologous mesenchymal stem cell neurotrophic factor-secreting cells (NurOwn) have the potential to modify underlying disease mechanisms in progressive multiple sclerosis (PMS).

Objective: This open-label phase II study was conducted to evaluate safety/efficacy of three intrathecal cell treatments.

Methods: Eighteen participants with non-relapsing PMS were treated.

A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.

Introduction/aims: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression.

Methods: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization.

MSC-NTF (NurOwn®) exosomes: a novel therapeutic modality in the mouse LPS-induced ARDS model.

Background: One of the most severe complications of the current COVID-19 pandemic is acute respiratory distress syndrome (ARDS). ARDS is caused by increased amounts of pro-inflammatory cytokines, leading to lung damage and loss of lung function. There are currently no effective therapies for combatting ARDS.

Impact of informative censoring on the treatment effect estimate of disability worsening in multiple sclerosis clinical trials.

Objective: To examine the impact of missing data when evaluating the confirmed disability worsening (CDW) endpoint in multiple sclerosis clinical trials and explore analytical methods for handling censored participants (those with missing confirmation data).

Methods: CDW risk factors were assessed among participants with an initial disability worsening (≥ 1.0-point increase in Expanded Disability Status Scale [EDSS] score from a baseline score of ≥ 1.

Covariate-adjusted borrowing of historical control data in randomized clinical trials.

The borrowing of historical control data can be an efficient way to improve the treatment effect estimate of the current control group in a randomized clinical trial. When the historical and current control data are consistent, the borrowing of historical data can increase power and reduce Type I error rate. However, when these 2 sources of data are inconsistent, it may result in a combination of biased estimates, reduced power, and inflation of Type I error rate.

Use of historical control data for assessing treatment effects in clinical trials.

Clinical trials rarely, if ever, occur in a vacuum. Generally, large amounts of clinical data are available prior to the start of a study, particularly on the current study's control arm. There is obvious appeal in using (i.

A portfolio-based approach to optimize proof-of-concept clinical trials.

Improving proof-of-concept (PoC) studies is a primary lever for improving drug development. Since drug development is often done by institutions that work on multiple drugs simultaneously, the present work focused on optimum choices for rates of false positive (α) and false negative (β) results across a portfolio of PoC studies. Simple examples and a newly derived equation provided conceptual understanding of basic principles regarding optimum choices of α and β in PoC trials.

How to improve R&D productivity: the pharmaceutical industry's grand challenge.

The pharmaceutical industry is under growing pressure from a range of environmental issues, including major losses of revenue owing to patent expirations, increasingly cost-constrained healthcare systems and more demanding regulatory requirements. In our view, the key to tackling the challenges such issues pose to both the future viability of the pharmaceutical industry and advances in healthcare is to substantially increase the number and quality of innovative, cost-effective new medicines, without incurring unsustainable R&D costs. However, it is widely acknowledged that trends in industry R&D productivity have been moving in the opposite direction for a number of years.

Bayesian adaptive non-inferiority with safety assessment: retrospective case study to highlight potential benefits and limitations of the approach.

Adaptive trial design applied to randomized clinical trials of psychiatric medicines offers the potential to make clinical trials more efficient. In the current analysis, we retrospectively applied Bayesian adaptive allocation methods to a case study in agitated patients with schizophrenia and related diseases. The original study used a randomized, double-blind, parallel design.

The impact of missing data and how it is handled on the rate of false-positive results in drug development.

In drug development, a common choice for the primary analysis is to assess mean changes via analysis of (co)variance with missing data imputed by carrying the last or baseline observations forward (LOCF, BOCF). These approaches assume that data are missing completely at random (MCAR). Multiple imputation (MI) and likelihood-based repeated measures (MMRM) are less restrictive as they assume data are missing at random (MAR).

Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis.

Objective: This study assessed the efficacy of olanzapine in delaying or preventing conversion to psychosis and reducing symptoms in people with prodromal symptoms of schizophrenia.

Method: This randomized trial occurred at four North American clinics in the Prevention Through Risk Identification, Management, and Education project. Outpatients received olanzapine (5-15 mg/day, N=31) or placebo (N=29) during a 1-year double-blind treatment period and no treatment during a 1-year follow-up period.

Multiple imputation techniques in small sample clinical trials.

Clinical trials allow researchers to draw conclusions about the effectiveness of a treatment. However, the statistical analysis used to draw these conclusions will inevitably be complicated by the common problem of attrition. Resorting to ad hoc methods such as case deletion or mean imputation can lead to biased results, especially if the amount of missing data is high.

Evidence for onset of antipsychotic effects within the first 24 hours of treatment.

Objective: It is widely held that there is a delayed onset of antipsychotic action and that any early effects represent nonspecific behavioral effects. Recent research has shown that antipsychotic action begins within the first week. The authors tested the hypothesis that psychosis improves within the first 24 hours of antipsychotic treatment.

Intramuscular olanzapine and intramuscular haloperidol in acute schizophrenia: antipsychotic efficacy and extrapyramidal safety during the first 24 hours of treatment.

Objective: To determine the antipsychotic efficacy and extrapyramidal safety of intramuscular (i.m.) olanzapine and i.

Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenic prodrome.

Background: The prodromal phase of schizophrenic disorders has been described prospectively. The present study aimed to determine the short-term efficacy and safety of olanzapine treatment of prodromal symptoms compared with placebo.

Methods: This was a double-blind, randomized, parallel-groups, placebo-controlled trial with fixed-flexible dosing conducted at four sites.

A comparison of the efficacy and safety of olanzapine versus haloperidol during transition from intramuscular to oral therapy.

Background: Acutely agitated patients with schizophrenia who receive intramuscular (IM) medications typically are switched to oral (PO) antipsychotic maintenance therapy.

Objective: The goal of this study was to assess the efficacy and safety of olanzapine versus those of haloperidol during transition from IM to PO therapy. We used additional data from a previously reported trial to test the hypothesis that the reduction in agitation achieved by IM olanzapine 10 mg or IM haloperidol 7.

Effects of intramuscular olanzapine vs. haloperidol and placebo on QTc intervals in acutely agitated patients.

Prolongation of the QTc interval has been reported during treatment with oral antipsychotic agents and may be more pronounced during parenteral administration. Pooled QTc interval data from acutely agitated patients across four double-blind trials were compared. Databases included: placebo-controlled [two schizophrenia, one bipolar mania trials (n=565)]; haloperidol-controlled [two schizophrenia trials (n=482)]; geriatric placebo-controlled [1 dementia trial (n=204)].

Procedural learning in schizophrenia after 6 months of double-blind treatment with olanzapine, risperidone, and haloperidol.

Rationale: First generation antipsychotics induce extrapyramidal motor symptoms (EPS), presumably through dopamine D(2) receptor blockade at the dorsal striatum. This may also produce impairment of cognitive processes, such as procedural learning, that are dependent on this region. Haloperidol and, to a lesser extent, risperidone, are active in the dorsal striatum and may induce EPS and impairment of procedural learning.

Calming versus sedative effects of intramuscular olanzapine in agitated patients.

Distinct calming rather than nonspecific sedation is desirable for the treatment of acute agitation. In 3 double-blind studies, acutely agitated patients with schizophrenia (N = 311), bipolar mania (N = 201), or dementia (N = 206) were treated with intramuscular (1-3 injections/24 hrs) olanzapine (2.5-10.