Tackling a Major Deficiency of Diversity in Alzheimer's Disease Therapeutic Trials: An CTAD Task Force Report.

As the last opportunity to assess treatment effect modification in a controlled setting prior to formal approval, clinical trials are a critical tool for understanding the safety and efficacy of new treatments in diverse populations. Recruitment of diverse participants in Alzheimer's Disease (AD) clinical trials are therefore essential to increase the generalizability of study results, with diversity broadly described to be representative and inclusive. This representation of study participants is equally critical in longitudinal cohort (observational) studies, which will be key to understanding disease disparities and are often used to design adequately powered AD clinical trials.

Non-Amyloid Approaches to Disease Modification for Alzheimer's Disease: An EU/US CTAD Task Force Report.

While amyloid-targeting therapies continue to predominate in the Alzheimer's disease (AD) drug development pipeline, there is increasing recognition that to effectively treat the disease it may be necessary to target other mechanisms and pathways as well. In December 2019, The EU/US CTAD Task Force discussed these alternative approaches to disease modification in AD, focusing on tau-targeting therapies, neurotrophin receptor modulation, anti-microbial strategies, and the innate immune response; as well as vascular approaches, aging, and non-pharmacological approaches such as lifestyle intervention strategies, photobiomodulation and neurostimulation. The Task Force proposed a general strategy to accelerate the development of alternative treatment approaches, which would include increased partnerships and collaborations, improved trial designs, and further exploration of combination therapy strategies.

Measures of outcome for stimulant trials: ACTTION recommendations and research agenda.

Background: The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence.

Methods: In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations.

Comparison of Site-Based Versus Central Ratings in a Study of Generalized Anxiety Disorder.

Lack of standardization across sites and raters, poor interrater reliability, and possible scoring bias affecting the primary outcome measure contribute to a high failure rate in anxiety trials. Remote centralized raters who are blinded to protocol inclusion and exclusion criteria as well as visit number may standardize assessments across raters and eliminate scoring bias, decreasing placebo response and thereby increasing signal detection. The purpose of the primary study was to test the safety and efficacy of an anxiolytic in a double-blind, placebo-controlled (no active comparator), multicenter trial.

A 6-week randomized, double-blind, placebo-controlled, comparator referenced trial of vabicaserin in acute schizophrenia.

Unlabelled: Vabicaserin, a potent 5-HT2C receptor agonist, decreases nucleus accumbens extracellular dopamine levels in rats, without affecting striatal dopamine, indicating mesolimbic selectivity. This is the first study of efficacy, safety and tolerability of vabicaserin in adults with acute schizophrenia. Three hundred fourteen hospitalized subjects were randomized to: Vabicaserin 200 or 400 mg/day, olanzapine 15 mg/day or placebo.

Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects.

Duloxetine selectively inhibits the serotonin (5-HT) and norepinephrine (NE) transporters (5-HTT and NET, respectively), as demonstrated in vitro and in preclinical studies; however, transporter inhibition has not been fully assessed in vivo at the approved dose of 60 mg/d. Here, the in vivo effects of dosing with duloxetine 60 mg once daily for 11 days in healthy subjects were assessed in 2 studies: (1) centrally (n = 11), by measuring concentrations of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylglycol (DHPG), and NE in cerebrospinal fluid, and (2) versus escitalopram 20 mg/d (n = 32) in a 2-period crossover study by assessing the ΔDHPG/ΔNE ratio in plasma during orthostatic testing and by pharmacokinetic/pharmacodynamic modeling of reuptake inhibition using subjects' serum in cell lines expressing cloned human 5-HTT or NET. At steady state, duloxetine significantly reduced concentrations of DHPG and 5-hydroxyindoleacetic acid (P < 0.

Evaluation of the effects of duloxetine and escitalopram on 24-hour heart rate variability: a mechanistic study using heart rate variability as a pharmacodynamic measure.

A decrease in heart rate variability (HRV) can indicate increased sympathetic nervous system activity and possibly increased norepinephrine levels. In this randomized, placebo- and escitalopram (ESC)-controlled, subject-blind, 2-period, crossover study, 26 healthy subjects 50 to 65 years old received duloxetine (DLX) 60 mg once daily or ESC 20 mg once daily for 11 days, each in sequential study periods separated by a 10-day or more washout period. Continuous electrocardiogram recordings were obtained by Holter monitoring (baseline, day 9, and day 10 of treatment).

Sexual function during long-term duloxetine treatment in patients with recurrent major depressive disorder.

Introduction: Sexual dysfunction (SD) is frequently associated with major depressive disorder (MDD) in the untreated state and may be worsened by antidepressant treatment.

Aim: We evaluated SD in duloxetine-treated patients during an MDD recurrence prevention study.

Method: Patients (N = 514) received open-label duloxetine 60-120 mg/day for up to 34 weeks.

Long-term safety of duloxetine during open-label compassionate use treatment of patients who completed previous duloxetine clinical trials.

Purpose: To provide duloxetine for the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), fibromyalgia (FM) and diabetic peripheral neuropathic pain (DPNP) to patients who had previously completed a duloxetine clinical study and for whom, in the opinion of the investigator, no effective alternative therapy was available.

Methods: Adult outpatients who had previously completed a duloxetine study for the treatment of MDD, GAD, DPNP, or FM received duloxetine 30 mg to 120 mg daily up until its local commercial availability. Safety analyses included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), AEs reported as reason for discontinuation, and vital signs.

Efficacy and safety of duloxetine in patients with chronic low back pain.

Study Design: This was a randomized, double-blind, placebo-controlled clinical trial.

Objective: To assess the efficacy and safety of duloxetine in the treatment of chronic low back pain (CLBP).

Summary Of Background Data: Imbalance of serotonin and norepinephrine within modulatory pain pathways has been implicated in the development and maintenance of chronic pain.

Evaluating the maintenance of effect of duloxetine in patients with diabetic peripheral neuropathic pain.

Background: To evaluate the maintenance of effect of duloxetine 60 mg QD over 26 weeks in patients with diabetic peripheral neuropathic pain (DPNP).

Methods: Adult patients with DPNP and Brief Pain Inventory (BPI) 24-h average pain >or=4 were treated in this open-label study with duloxetine 60 mg QD for 8 weeks. Responders (>or=30% pain reduction) continued on duloxetine 60 mg QD (maintenance arm) for 26 weeks while non-responders had duloxetine increased to 120 mg QD (rescue arm).

Duloxetine in the prevention of depressive recurrences: a randomized, double-blind, placebo-controlled trial.

Objective: To assess the efficacy of duloxetine 60-120 mg once daily in the prevention of depressive recurrence in outpatients with recurrent major depressive disorder (MDD).

Method: Eligible patients with at least 3 episodes of MDD (DSM-IV diagnosis) in the past 5 years received open-label duloxetine 60-120 mg/day for up to 34 weeks. Patients meeting response criteria were then randomly assigned to either duloxetine or placebo for up to 52 weeks of double-blind maintenance treatment.

A double-blind, randomized trial of duloxetine versus placebo in the management of chronic low back pain.

Background: Duloxetine has demonstrated analgesic effect in chronic pain states. This study assesses the efficacy of duloxetine in chronic low back pain (CLBP).

Methods: Adult patients with non-radicular CLBP entered this 13-week, double-blind, randomized study comparing duloxetine 20, 60 or 120 mg once daily with placebo.

A randomized, double-blind study of increasing or maintaining duloxetine dose in patients without remission of major depressive disorder after initial duloxetine therapy.

Objective: To compare efficacy of remaining on duloxetine 60 mg to increasing to 120 mg q.d. in patients without remission of major depressive disorder (MDD) after 6 weeks at 60 mg.

Long-term safety, tolerability, and efficacy of duloxetine in the treatment of fibromyalgia.

Objectives: To assess the long-term safety, tolerability, and efficacy of duloxetine in patients with fibromyalgia.

Methods: We report results from the 6-month extension phases of 2 randomized, double-blind, placebo-controlled clinical trials having 6-month placebo-controlled phases. In Study 1, all patients received duloxetine 120 mg/d after 28 weeks on placebo or duloxetine 60 or 120 mg/d.

A six-month double-blind, placebo-controlled, randomized clinical trial of duloxetine for the treatment of fibromyalgia.

Objective: Assess the efficacy of duloxetine 60/120 mg (N = 162) once daily compared with placebo (N = 168) in the treatment of patients with fibromyalgia, during six months of treatment.

Methods: This was a phase-III, randomized, double-blind, placebo-controlled, parallel-group study assessing the efficacy and safety of duloxetine.

Results: There were no significant differences between treatment groups on the co-primary efficacy outcome measures, change in the Brief Pain Inventory (BPI) average pain severity from baseline to endpoint (P = 0.

The relationship between antidepressant and analgesic responses: findings from six placebo-controlled trials assessing the efficacy of duloxetine in patients with major depressive disorder.

Objective: Debate continues regarding whether onset of analgesia is faster than antidepressant effect in antidepressants with both properties. Duloxetine hydrochloride (from here on referred to as duloxetine) is effective in both major depressive disorder and diabetic peripheral neuropathic pain. This post-hoc analysis of six placebo-controlled duloxetine trials in patients with major depressive disorder was designed to compare onset of antidepressant activity to pain relief.

A non-inferiority comparison of duloxetine and venlafaxine in the treatment of adult patients with generalized anxiety disorder.

The present study is a non-inferiority comparison of duloxetine 60-120 mg/day and venlafaxine extended-release (XR) 75-225 mg/day for the treatment of adults with generalized anxiety disorder (GAD). The non-inferiority test was a prespecified plan to pool data from two nearly identical 10-week, multicentre, randomized, placebo-controlled, double-blind studies of duloxetine 60-120 mg/day and venlafaxine 75-225 mg/ day for the treatment of GAD. An independent expert consensus panel provided six statistical and clinical criteria for determining non-inferiority between treatments.

Duloxetine treatment for relapse prevention in adults with generalized anxiety disorder: a double-blind placebo-controlled trial.

The objective was to examine duloxetine 60-120 mg/day treatment for relapse prevention in adults with generalized anxiety disorder (GAD). Adult patients (N=887; mean age=43.3 years; 61.

Clinical evidence for serotonin and norepinephrine reuptake inhibition of duloxetine.

Most antidepressants in clinical use are believed to function by enhancing neurotransmission of serotonin [5-hydroxytryptamine (5-HT)] and/or norepinephrine (NE) via inhibition of neurotransmitter reuptake. Agents that affect reuptake of both 5-HT and NE (serotonin-norepinephrine reuptake inhibitors) have been postulated to offer greater efficacy for the treatment of major depressive disorder (MDD). These dual-acting agents also display a broader spectrum of action, including efficacy for MDD and associated painful physical symptoms, diabetic peripheral neuropathic pain, generalized anxiety disorder, and fibromyalgia syndrome.

Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: Results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial.

The primary objectives of this study were to assess the efficacy and safety of duloxetine for reducing pain severity in fibromyalgia patients with or without current major depressive disorder. This was a 6-month, multicenter, randomized, double-blind, placebo-controlled study. In total, 520 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to duloxetine (20 mg/day, 60 mg/day, or 120 mg/day) or placebo, administered once daily, for 6 months (after 3 months, the duloxetine 20-mg/day group titrated to 60 mg/day).

Examining quality of life in patients with generalized anxiety disorder: clinical relevance and response to duloxetine treatment.

Background: Duloxetine, a serotonergic noradrenergic reuptake inhibitor, improved functional outcomes in each of three clinical studies for the treatment of adults with generalized anxiety disorder (GAD). Using comparison norms, the current work describes the clinical relevance of these functional improvements in terms of return to normative functioning and symptom remission.

Methods: Data were pooled at the individual patient level from three double-blind, placebo-controlled trials of duloxetine treatment (9-10 weeks acute therapy, dose ranges 60-120mg).

Differential antidepressant symptom efficacy: placebo-controlled comparisons of duloxetine and SSRIs (fluoxetine, paroxetine, escitalopram).

Objective: To test the hypothesis that in patients with major depressive disorder (MDD), the response for specific Hamilton Depression Rating Scale items will differ for duloxetine compared with selective serotonin reuptake inhibitors (SSRIs) and that patterns of response will differ based on symptom severity at baseline.

Method: Data were pooled from all Lilly-sponsored clinical trials where duloxetine was compared with placebo and an SSRI in patients with MDD: 7 randomized, double-blind, fixed-dose, 8-week studies of duloxetine (n = 1,133) versus SSRI (n = 689) versus placebo (n = 641). Duloxetine doses were 40, 60, 80 and 120 mg/day.

Efficacy of duloxetine and selective serotonin reuptake inhibitors: comparisons as assessed by remission rates in patients with major depressive disorder.

It has been proposed that serotonin and norepinephrine reuptake inhibitors (SNRIs) may result in higher remission rates of major depressive disorder than therapy with selective serotonin reuptake inhibitors (SSRIs). To test this hypothesis, a meta-analysis of individual patient data (N = 1833) was performed for the complete set of 6 phase II/III studies that compared duloxetine (fixed doses; range, 40-120 mg/d) with 2 SSRIs (paroxetine or fluoxetine; 20 mg/d) in outpatients with major depressive disorder. Remission was defined as an end point score of less than or equal to 7 on the 17-item Hamilton Rating Scale for Depression (HAMD17); alternate outcome criteria were also examined, as were remission rates among the 1044 patients with moderate-to-severe depression (HAMD17 total score greater than or equal to 19).

Evidence for the efficacy of duloxetine in treating mild, moderate, and severe depression.

Clinicians need to know whether duloxetine is effective in patients across a broad range of depressive symptoms and depression severity. Data were pooled from nine randomized, double-blind, placebo-controlled studies in major depressive disorder (total N=2227) comparing duloxetine (40-120 mg/day) with placebo for 8-9 weeks. Patients were retrospectively stratified by baseline score on the HAMD17 into mild (< or =19; n=682), moderate (n=1099), or severe (> or =25; n=446) groups.