Tiffini Voss

A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine

Aim The aim of this trial was to evaluate the efficacy and tolerability of ubrogepant (MK-1602), a calcitonin gene-related peptide receptor antagonist (CGRP-RA), for the acute treatment of migraine. Methods This double-blind, placebo-controlled study randomized 834 participants to treat one migraine attack with ubrogepant 1 mg, 10 mg, 25 mg, 50 mg, 100 mg, or placebo in a 1:1 ratio. The co-primary endpoints were pain freedom and headache response at two hours. The first primary hypothesis tested the dose-response trend for two-hour pain freedom using a logistic regression model. Subsequent hypotheses tested the effects of each dose on the co-primary endpoints, using a closed sequential testing procedure to control for multiplicity. Results A total of 527 participants received ubrogepant and 113 received placebo. A positive response trend in the proportion of participants achieving two-hour pain freedom was demonstrated (p < 0.001). Ubrogepant 100 mg was significantly superior to placebo for two-hour pain freedom (25.5% vs 8.9%) but not for two-hour headache response. Per the prespecified multiplicity strategy, this nonsignificant result precluded further formal hypothesis testing, although the 50 mg and 25 mg doses demonstrated nominal significance over placebo for two-hour pain freedom (unadjusted p < 0.05). Overall, adverse events were similar between ubrogepant and placebo. Conclusion This trial supports ubrogepant’s efficacy and provides further evidence that CGRP-RAs are viable options for the acute treatment of migraine.

Design innovations and baseline findings in a long-term parkinson’s trial: The national institute of neurological disorders and stroke exploratory trials in parkinson’s disease long-term study-1

Based on the preclinical data and the results of a phase II futility study, creatine was selected for an efficacy trial in Parkinsons disease (PD). We present the design rationale and a description of the study cohort at baseline. A randomized, multicenter, double‐blind, parallel‐group, placebo‐controlled phase III study of creatine (10 g daily) in participants with early, treated PD, the Long‐term Study–1 (LS‐1), is being conducted by the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinsons Disease network. The study utilizes a global statistical test (GST) encompassing five clinical rating scales to provide a multidimensional assessment of disease progression. A total of 1,741 PD participants from 45 sites in the United States and Canada were randomized 1:1 to either 10 g of creatine/day or matching placebo. Participants are being evaluated for a minimum of 5 years. The LS‐1 baseline cohort includes participants treated with dopaminergic therapy and generally mild PD. LS‐1 represents the largest cohort of patients with early treated PD ever enrolled in a clinical trial. The GST approach should provide high power to test the hypothesis that daily administration of creatine (10 g/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5‐year follow‐up visit against the background of dopaminergic therapy and best PD care.

Performance of a shortened Scale for Assessment of Positive Symptoms for Parkinson's disease psychosis

BACKGROUND Parkinsons disease psychosis is a frequent and serious complication of advanced disease, but few disease-specific outcome measures exist. METHODS Using baseline scores from 4 clinical trials, we identified relevant items that assessed Parkinsons disease psychosis to create a shortened version of the Scale for Assessment of Positive Symptoms. We then analyzed the validity and treatment sensitivity of the shortened scale. Principal component analyses evaluated the underlying structure. Scores were compared across age, gender, trial, cognition, and country of origin. Sensitivity to change was assessed by comparing change in psychosis scores to the clinical global impression of improvement score, and effect sizes were calculated to evaluate treatment response. RESULTS Nine items were selected based on face-validity and symptom frequency. Principal component analysis yielded a 4-factor structure and identified delusions and visual, auditory, and somatic hallucinations as distinct constructs. Baseline total scores were similar across study, gender, region, and age group. The clinically meaningful change in the shortened scale, defined as a 1-unit change in clinical global impression, was 2.33 points, and the effect size was -0.722. The change in scores did not significantly differ between those with cognitive impairment and those without. CONCLUSIONS The shortened Scale for Assessment of Positive Symptoms for Parkinsons disease retains the reliability, sensitivity to change, and effect size of the larger scale while reducing administration time and, more importantly, score variability. The scale is an effective outcome measure for use in clinical trials.

Risk of surgical delivery to deep nuclei: A meta-analysis†‡§

Many novel strategies aimed at neuroprotection or neurorestoration involve surgical delivery of agents to deep nuclei along multiple trajectories. Using intracerebral hemorrhage on a per‐trajectory basis as our primary end point, we quantified the level of surgical risk associated with agent delivery to deep nuclei. Secondarily, we quantified other event rates and examined relationships between intracerebral hemorrhage and 8 variables related to patient and practice characteristics. Meta‐analytic techniques were used to pool complication rates reported in published articles involving deep brain stimulator electrode implantation or infusion of vectors, tissues, or trophic factors. One hundred nine studies were included in our analysis, comprising 6237 patients and 9890 trajectories to deep nuclei. The estimated per‐trajectory intracerebral hemorrhage rate was 1.57% (95% confidence interval, 1.26%–1.95%). The proportion of trajectories leading to permanent or serious neurological deficits was 0.41% (0.28%–0.60%). The estimated mortality rate per trajectory was 0.14% (0.07%–0.29%). No relationship between intracerebral hemorrhage and sex, age, duration of disease, or exclusion of patients with surgical complications was observed; a significant positive relationship was observed with the use of microelectrode recording and a significant negative relationship with putamenal delivery. Our results show a significant difference in intracerebral hemorrhage rates between inoculations and electrode implantation. Our findings suggest that studies involving multiple trajectories to deep nuclei involve a high level of risk. However, inoculations may be significantly safer than electrode implantation. Our analysis has implications for the ethics of preclinical research, independent review of risk, subject selection, and adverse event reporting.

Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease

BACKGROUND Alzheimers disease is characterized by the deposition of amyloid‐beta (Aβ) plaques in the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein by β‐site amyloid precursor protein–cleaving enzyme 1 (BACE‐1) followed by γ‐secretase. Verubecestat is an oral BACE‐1 inhibitor that reduces the Aβ level in the cerebrospinal fluid of patients with Alzheimers disease. METHODS We conducted a randomized, double‐blind, placebo‐controlled, 78‐week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild‐to‐moderate Alzheimers disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS‐cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimers Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS‐ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12‐mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40‐mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS‐cog score was 7.9 in the 12‐mg group, 8.0 in the 40‐mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12‐mg group and the placebo group and P=0.46 for the comparison between the 40‐mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS‐ADL score was ‐8.4 in the 12‐mg group, ‐8.2 in the 40‐mg group, and ‐8.9 in the placebo group (P=0.49 for the comparison between the 12‐mg group and the placebo group and P=0.32 for the comparison between the 40‐mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair‐color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS Verubecestat did not reduce cognitive or functional decline in patients with mild‐to‐moderate Alzheimers disease and was associated with treatment‐related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348.)

Factors associated with falling in early, treated Parkinson's disease: The NET-PD LS1 cohort

BACKGROUND Recognizing the factors associated with falling in Parkinsons disease (PD) would improve identification of at-risk individuals. OBJECTIVE To examine frequency of falling and baseline characteristics associated with falling in PD using the National Institute of Neurological Disorders and Stroke (NINDS) Exploratory Trials in PD Long-term Study-1 (NET-PD LS-1) dataset. METHODS The LS-1 database included 1741 early treated PD subjects (median 4year follow-up). Baseline characteristics were tested for a univariate association with post-baseline falling during the trial. Significant variables were included in a multivariable logistic regression model. A separate analysis using a negative binomial model investigated baseline factors on fall rate. RESULTS 728 subjects (42%) fell during the trial, including at baseline. A baseline history of falls was the factor most associated with post-baseline falling. Men had lower odds of post-baseline falling compared to women, but for men, the probability of a post-baseline fall increased with age such that after age 70, men and women had similar odds of falling. Other baseline factors associated with a post-baseline fall and increased fall rate included the Unified PD Rating Scale (UPDRS) Activities of Daily Living (ADL) score, total functional capacity (TFC), baseline ambulatory capacity score and dopamine agonist monotherapy. CONCLUSION Falls are common in early treated PD. The biggest risk factor for falls in PD remains a history of falling. Measures of functional ability (UPDRS ADL, TFC) and ambulatory capacity are novel clinical risk factors needing further study. A significant age by sex interaction may help to explain why age has been an inconsistent risk factor for falls in PD.

The use of magnetic resonance-guided high intensity focused ultrasound to treat essential tremor

Advances in ultrasound transducer technology have enabled for transcranial sonication with energy levels adequate to achieve tissue ablation. With MR-guidance and monitoring, precise lesioning is now possible of deep brain targets such as the thalamus and basal ganglia so that stereotactic lesioning is being reconsidered for the treatment of movement disorders. In this phase 1 clinical trial, we investigate the feasibility and safety of MRgFUS for performing a unilateral thalamotomy for medication-refractory essential tremor (ET). According to an FDA-approved protocol, 15 patients with medication-resistant ET underwent unilateral MRgFUS lesioning of the thalamus for dominant limb tremor. Intraprocedural monitoring was conducted with each incremental sonication using MR thermometry and clinical examination. Neurological assessments, validated tremor ratings, MRI, and quality of life data were recorded preoperatively and during a year post treatment. Adverse events were recorded throughout the study duratio...

Population PK Analyses of Ubrogepant (MK‐1602), a CGRP Receptor Antagonist: Enriching In‐Clinic Plasma PK Sampling With Outpatient Dried Blood Spot Sampling

Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late‐stage trials for population pharmacokinetic (PK) modeling. We applied this strategy for another late‐stage clinical program: ubrogepant (MK‐1602), a novel oral calcitonin gene‐related peptide receptor antagonist for acute treatment of migraine. At the time of implementation, ubrogepant was entering phase 2 development. DBS was implemented to acquire PK information proximal to an acute migraine event to enable exposure–response modeling. The clinical endpoint was a spontaneous event, which generally occurs outside a clinic visit. Thus, an innovative feature of this trial was facilitating DBS in an outpatient setting. In vitro and bioanalytical tests established initial method feasibility and suitability for further evaluations in the clinic. A quantitative relationship was developed between blood and plasma concentrations from concurrently collected samples in a phase 1 (healthy subjects) and phase 2 (target patient population) study using graphical and population PK approaches. This integrated information was presented to the Food and Drug Administration for regulatory input. Following regulatory concurrence, DBS was poised for use in further clinical studies. Population PK modeling was used to dissect sources of variability contributing to DBS collection in the outpatient setting. What has been learned from this program has informed the broader integrated strategy of Merck & Co., Inc. (Kenilworth, NJ) for DBS implementation in clinical trials and research to improve the precision of PK data collected in an outpatient setting.

VERUBECESTAT PHARMACOKINETIC AND EXPOSURE-RESPONSE RESULTS FROM EPOCH: A PHASE 3 TRIAL IN MILD-TO-MODERATE ALZHEIMER’S DISEASE

individuals. Incidences of this disease are expected to double every 20 years emphasizing an urgent need for a development of disease modifying therapeutic strategies. A substantial body of clinical evidence has framed AD in the context of metabolic dysfunction and its pathophysiological importance to disease progression, suggesting that modulation of cellular energetics could represent new therapeutic approach. In our previous research, we have demonstrated that modulation of mitochondrial complex I activity using a tricyclic pyrone compound CP2 is effective in clearing both amyloid beta (Ab) and phosphorylated Tau, augmenting mitochondrial bioenergetics, promoting resistance to oxidative stress and restoring mitochondrial transport, levels of BDNF and synaptic proteins in presymptomatic APP/PS1 mice. In parallel, these mice demonstrated an improved cognitive and behavioral phenotype over their untreated littermates. Methods: In our current study, we tested whether CP2 treatment could halt the disease progression in symptomatic APP/PS1 mice. We also evaluated treatment efficacy based on multiple parameters informative of healthy aging in chronologically aged non-transgenic (NTG) littermates. Results:Both APP/ PS1 and NTG mice displayed improved cognitive and motor performance following chronic CP2 treatment over 13 months, starting at 20 months of age compared to untreated counterparts. Treatment with CP2 improved metabolic outcomes related with aging such as glucose tolerance, lipid peroxidation, cellular senescence, weight loss and inflammation. Although NTG mice showed lower respiratory rate, long-term CP2 treatment did not affect the levels of available ATP in living mice of both genotypes. CP2-treated APP/PS1 mice showed trend for reduced levels of insoluble Ab. Moreover, CP2 treatment improved glucose uptake in the brain as observed by FDG-PET scan. Electrophysiological scans indicated that synaptic activity was restored in the hippocampal area of APP/PS1 mice. Electron microscopy imaging showed that modulation of mitochondrial complex I activity with CP2 increased the number of elongated mitochondria over small ones, suggesting that preservation of healthier mitochondria was essential for improved neuronal activity and survival. Conclusions: Therefore, treatment with mitochondrial complex I inhibitors represent a promising therapeutic approach to ameliorate AD and promote healthy aging.

Randomized, controlled, proof-of-concept trial of MK-7622 in Alzheimer's disease

We evaluated the selective M1 muscarinic positive allosteric modulator, MK‐7622, as adjunctive cognitive enhancing therapy in individuals with Alzheimers disease.