Safety findings from CENTURION, a phase 3 consistency study of lasmiditan for the acute treatment of migraine.

BACKGROUND: Lasmiditan (LTN) is a selective 5-HT1F receptor agonist for the acute treatment of migraine in adults. We present detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION). METHODS: Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses. RESULTS: Overall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks. The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks. Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents. CONCLUSION: In this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks. TRIAL REGISTRATION: NCT03670810.

Diagnostic Biomarkers of Amyloid and Tau Pathology in Alzheimer's Disease: An Overview of Tests for Clinical Practice in the United States and Europe.

Amyloid and tau biomarkers for Alzheimer's disease are widely recognized diagnostic tools for the identification of Alzheimer's disease pathology antemortem and are recommended by the most recent clinical and research guidelines. Approved biomarkers include positron emission tomography (PET)- and fluid-based markers derived from cerebrospinal fluid and, more recently, plasma. These biomarkers are still infrequently used in clinical practice, potentially due to challenges in access to and understanding of individual assay information and methodology. We provide an overview of the diagnostic biomarkers for amyloid and tau pathology that are currently available in the US and/or EU for clinical use. Available performance data from both labels/instructions for use and the scientific literature (with focus on autopsy or PET as standard of truth) are summarized to help healthcare providers navigate the biomarker landscape. All available PET amyloid and tau biomarkers demonstrate high accuracy in identifying amyloid and tau Alzheimer's disease pathology, respectively, at autopsy. Among cerebrospinal fluid biomarkers, all showed accurate prediction of Alzheimer's disease pathology, either based on autopsy or PET findings; greater accuracy was evident for concentration ratios (Aß42/40 or P-tau181/Aß42) versus individual biomarker concentrations. Among plasma biomarkers, Aß42/40 and P-tau181 demonstrated high agreement with PET findings. Overall, we conclude that commercially available PET, cerebrospinal fluid and plasma assays accurately identify Alzheimer's disease amyloid and tau pathology. The recent development of fully automated tests for fluid-based biomarkers improves test reliability. The continued development of plasma biomarkers holds promise for the future management of patients with Alzheimer's disease.

'Time Saved' As a Demonstration of Clinical Meaningfulness and Illustrated Using the Donanemab TRAILBLAZER-ALZ Study Findings.

In Alzheimer's disease (AD) clinical trials, disease-modifying therapies are expected to slow the rate of disease progression. Treatment effects are evaluated using a validated clinical scale as the difference between treatment and placebo in mean change from baseline to endpoint. Understanding the clinical relevance of this metric is not necessarily intuitive. Expressing active treatment-placebo difference as a time metric (i.e., months saved with treatment) has potential to provide a metric that is more easily and consistently interpreted. Using data from the TRAILBLAZER-ALZ study, time component tests (TCTs) were employed to determine the time saved with donanemab (an amyloid lowering drug) treatment. At study endpoint (Week 76), disease progression was delayed by 5.3 months and 5.2 months as measured by the Integrated Alzheimer's Disease Rating Scale (iADRS) and the Clinical Dementia Rating Sum of Boxes (CDR-SB), respectively.

Arzoxifene versus raloxifene: effect on bone and safety parameters in postmenopausal women with osteoporosis.

UNLABELLED: Arzoxifene increased bone mineral density and decreased bone turnover to a significantly greater extent than raloxifene. The hot flush incidence was lower with arzoxifene than raloxifene. INTRODUCTION: To assess the effect of arzoxifene versus raloxifene on change in lumbar spine (LS) bone mineral density (BMD) in postmenopausal women with osteoporosis. METHODS: In this 12-month study (NEXT trial), participants were randomly assigned to arzoxifene 20 mg/day (N = 158) or raloxifene 60 mg/day (N = 162). All received daily calcium and vitamin D. Change in LS BMD was assessed by DXA. Secondary objectives included assessment of femoral neck (FN) and total hip BMD, serum bone turnover markers, and safety. RESULTS: Treatment groups were similar at baseline (mean age 63 years, mean LS BMD T-score -2.9). At 12 months, the increase in LS BMD with arzoxifene was greater than with raloxifene (+2.75% vs. +1.66%), as was FN and total hip BMD (P < 0.05). For LS and FN, this effect was also evident at 6 months. Arzoxifene reduced bone turnover to a greater extent than raloxifene at 3, 6, and 12 months (P < 0.05). The proportion of women reporting ≥ 1 adverse event did not differ between treatment groups, nor did vaginal bleeding. No cases of endometrial polyps, hyperplasia, or cancer were reported. Nasopharyngitis and bronchitis were reported more frequently with arzoxifene versus raloxifene (10.1% vs. 2.5%, and 5.1% vs. 0%, respectively) and new/worsening hot flushes were reported less frequently with arzoxifene (7.0% vs. 16.7%) (P < 0.05). CONCLUSIONS: Arzoxifene increased BMD and suppressed bone turnover to a greater extent than raloxifene and resulted in a lower incidence of new/worsening hot flushes. Based on subsequent findings from a fracture outcome study, this difference did not translate into improved fracture efficacy.

Effects of arzoxifene on bone, lipid markers, and safety parameters in postmenopausal women with low bone mass.

UNLABELLED: In this Phase 2 study of postmenopausal women with low bone, arzoxifene (a selective estrogen receptor modulator (SERM)) significantly reduced bone turnover marker levels and increased bone mineral density (BMD) versus placebo. Arzoxifene generally had greater effects on bone turnover and BMD than raloxifene, a SERM in current clinical use. Arzoxifene's safety profile appeared similar to raloxifene. INTRODUCTION: This 6-month, Phase 2, double-blind, placebo- and raloxifene-controlled study was designed to assess the effects of arzoxifene on bone turnover and overall safety in postmenopausal women with low bone mass. METHODS: Postmenopausal women (N = 219; mean age, 59 years) with a T-score between -1 and -2.5 were randomly assigned to daily arzoxifene 5, 10, 20, or 40 mg, raloxifene 60 mg, or placebo. All received daily calcium. RESULTS: All arzoxifene doses significantly reduced osteocalcin (primary endpoint), type 1 collagen C-telopeptide, bone specific alkaline phosphatase, and procollagen type I amino-terminal propeptide versus placebo, and increased lumbar spine BMD. Arzoxifene generally had greater effects on bone turnover and BMD than raloxifene. Arzoxifene decreased cholesterol, low-density lipoprotein cholesterol, and fibrinogen versus placebo. Endometrial thickness change with arzoxifene was not significantly different from placebo or raloxifene; no cases of endometrial hyperplasia or adenocarcinoma were observed. Adverse event reporting with arzoxifene was similar to that with raloxifene, as were hot flush and night sweat reporting. CONCLUSIONS: Arzoxifene suppressed bone turnover and increased BMD. Within the limitations of this study, the endometrial safety profile of arzoxifene appeared similar to that of raloxifene. While no clear dose effect was evident, arzoxifene 20 and 40 mg/day appeared the optimal doses for reducing bone turnover.

Detecting Treatment Group Differences in Alzheimer's Disease Clinical Trials: A Comparison of Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) and the Clinical Dementia Rating - Sum of Boxes (CDR-SB).

The Alzheimer's Disease Assessment Scale's cognitive subscale (ADAS-Cog) has been widely used as an outcome measure in Alzheimer's Disease (AD) clinical trials. In its original form (ADAS-Cog11), the scale has been used successfully in mild-to-moderate AD dementia populations, but its use is more limited in the study of earlier disease (mild cognitive impairment [MCI] or mild dementia due to AD) owing to lack of appropriate sensitivity of some items. With recent focus on earlier treatment, efforts have focused on the development of more sensitive tools, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a global assessment tool to evaluate both cognition and function. The ability of the ADAS-Cog and CDR-SB to detect treatment group differences in the clinical trial environment has not been systematically studied. The aim of this analysis was to compare the utility of these tools in detecting treatment group differences, by reviewing study findings identified through advanced searches of clinicaltrials.gov and Ovid, and press releases and scientific presentations. Findings from placebo-controlled studies of ≥ 6m duration and enrolling >100 participants were included; reporting of both the ADAS-Cog and CDR-SB at endpoint was also a requirement. Of the >300 records identified, 34 studies fulfilled the criteria. There were significant placebo versus active drug group differences based on findings from at least one measure for 14 studies. The ADAS-Cog detected treatment differences more frequently than the CDR-SB. Based on these and previously published findings, the ADAS-Cog appears more useful than the CDR-SB in detecting treatment group differences.

The Integrated Alzheimer's Disease Rating Scale (iADRS) Findings from the EXPEDITION3 Trial.

The Integrated Alzheimer's Disease (AD) Rating Scale (iADRS) is a composite tool that combines scores from the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). It demonstrates acceptable psychometric properties, and is effective in capturing both disease progression and separation of placebo and active drug effect. We assessed the performance of iADRS in the solanezumab EXPEDITION3 study, an 80-week, placebo-controlled study of individuals with mild AD dementia. A statistically significant difference between placebo and active drug was observed for iADRS score change from baseline at Week 28 (p=0.028) through Week 80 (p=0.015). Across the Phase 3 solanezumab trials, iADRS was the only tool that consistently differentiated between solanezumab and placebo groups. These findings suggest that the iADRS is a useful integrated measurement tool for treatment trials of individuals with mild AD dementia.

Systemic neutrophil response resulting from dental plaque accumulation.

BACKGROUND: There is considerable current interest in putative relationships between oral and systemic diseases. Since the host response to oral bacteria may be the critical link in this association, our hypothesis was that dental plaque accumulation in healthy subjects would elicit a systemic inflammatory response. METHODS: Twenty-three healthy subjects, aged 18 to 25, participated in a 4-phase study. An initial hygiene phase was followed by a 21-day experimental phase (the so-called experimental gingivitis model) in which subjects refrained from all oral hygiene practices, thus permitting the accumulation of bacterial plaque. At days 0, 7, and 21 total and differential peripheral white blood cell (wbc) counts, together with full mouth plaque and gingivitis scores, were recorded. Following a 28-day recovery phase, in which normal oral hygiene practices were resumed, subjects entered the final 21-day control phase which mirrored the experimental phase but with subjects maintaining normal oral hygiene practices. RESULTS: The experimental model performed as anticipated with a correlation between plaque and gingivitis scores of 0.95, also reflecting subject compliance. Total wbc and neutrophil counts increased during the experimental phase. Furthermore, comparison of neutrophil counts between the experimental and control phases demonstrated a significantly higher cell count for the experimental phase on both days 7 and 21 (P= 0.0301 and 0.009, respectively). For total wbc, this was significant on day 21 (P= 0.0262). CONCLUSION: The results of this study support the hypothesis that the accumulation of dental plaque can result in a measurable systemic inflammatory response, providing further in vivo data to support a mechanistic relationship between oral and systemic pathology.

Oral health status of an indigenous adult population of Central America.

OBJECTIVE: To determine the caries experience and periodontal disease status in adults of an indigenous rural community of Guatemala, and assess the suitability for longitudinal investigations. BASIC RESEARCH DESIGN: This investigation comprised an initial screen (Study I) and a more detailed periodontal examination (Study II). In Study I, caries and gingivitis levels were determined. In Study II, pocket probing depths (PPDs) and clinical attachment levels (CALs) were recorded on all teeth excluding third molars. CLINICAL SETTING: Tzununa, Guatemala, Central America. PARTICIPANTS: Studies I and II were conducted in 120 adults 3 18 years and 54 adults 3 25 years respectively. RESULTS: In both Studies I and II, tooth retention was high with a mean tooth count of 28.2 and 27.2 respectively. Extensive soft deposits and both supra- and subgingival calculus were almost universal, although gingivitis was less than expected (Study I: Mean percentage of sites bleeding on probing = 27.6). In Study I, the mean number of carious teeth was 8.6 and there was no statistically significant correlation with age. In Study II, PPD 3 5mm and CAL 3 6mm were highly prevalent (100% and 56% of subjects respectively), although widespread and severe disease was not evident. CONCLUSIONS: Despite the high caries level and the evidence of periodontal destruction in the majority of subjects, all study subjects had a functional dentition suggesting that emergency treatment remains the current priority. Longitudinal studies in such untreated populations would provide increased understanding of the role of environmental factors in disease etiology. The study also highlighted some methodological issues pertinent to conducting studies in remote communities.

Extending scientific horizons in the developing world - the Central American experience.

The juxtaposition of 'oral disease' and 'developing countries' invariably evokes thoughts of how one might assist these nations in attaining 'a healthy mouth for all' according to Western standards. In this discussion, the emphasis is shifted to consider collaborations between the industrial nations and those less developed countries, in the conduct and development of research. This potentially fruitful partnership can produce scientific, educational and cultural rewards for mutual benefit.

Treatment and outcomes for patients with depression who are partial responders to SSRI treatment: post-hoc analysis findings from the FINDER European observational study.

BACKGROUND: Remission is the goal in depression, but in practice many patients only experience a partial response to treatment. We sought to determine the prevalence, management and subsequent outcomes of partial responder patients. METHODS: Patients enrolled in the naturalistic Factors Influencing Depression Endpoints Research (FINDER) study with the Hospital Anxiety and Depression Scale depression subscale (HADS-D) score >10 at baseline who received only SSRI(s) between 0 and 3 months comprised the study cohort (n=1147). Patients were categorized as remitters, partial responders or non-responders at 3 months and then followed up at 6 months. RESULTS: At 3 months, 29.4% of the study population were considered non-responders, 27.6% were partial responders, and 39.3% were remitters. Most partial responders at 3 months remained on the same SSRI for the next 3 months. Of the 247 partial responders at 3 months and remained on the same SSRI(s) between 3 and 6 months, 10.9% met criteria for non-response at 6 months, 32.4% remained partial responders, and 56.3% achieved remission. Quality of life outcomes for the partial responders were significantly worse than those in remission (p<0.05). LIMITATIONS: FINDER was an observational study; the current analysis was conducted post-hoc. Multivariable methods were not applied and findings are primarily descriptive and exploratory. CONCLUSIONS: Partial response is common and patients in partial response have a poorer quality of life than those achieving remission. Despite this, the majority of partial responders continue to take the same SSRI. Our findings underscore the importance of continuing to strive for remission.

Neutrophil response to dental plaque by gender and race.

The inflammatory response, which has both genetic and environmental components, is a central mechanism linking oral and systemic diseases. We hypothesized that dental plaque accumulation over 21 days in the experimental gingivitis model would elicit systemic inflammatory responses [change in white blood cell (WBC) count and neutrophil activity], and that these responses would differ by gender/race. We recruited 156 healthy young adults, including black and white males and females. Plaque Index (PI), Gingival Index (GI), systemic WBC counts, and peripheral neutrophil oxidative activity were recorded. Overall, 128 participants completed the study. During the experimental phase, the correlation between PI and GI was 0.79. Total WBC and neutrophil counts did not change. Neutrophil activity increased in blacks but not whites, suggesting that there may be racial differences in the inflammatory response to dental plaque accumulation.

Oral Helicobacter pylori: can we stomach it?

Helicobacter pylori infection is one of the most common in man. The bacterium primarily resides in the human stomach, where it plays a significant role in gastric disease. If the spread of H. pylori is to be prevented, an understanding of the transmission process is essential. The oral cavity has been proposed as a reservoir for gastric H. pylori, which has been detected by culture and PCR in both dental plaque and saliva. This review will discuss the evidence for the role of the oral cavity in the transmission of gastric H. pylori. Moreover, the difficulties encountered in addressing this topic, possible directions for future research, and the implications for the dental profession are discussed.

Functional integrity of human neutrophils following 24 hour incubation with hydroxyapatite and fluoride.

We have previously shown that hydroxyapatite (HA) priming of human neutrophils to a second stimulus of formyl-methionyl-leucyl-phenylalanine (fMPL) is influenced by a bisphosphonate and fluoride. The purpose of this study was to investigate the long-term effects of low concentrations of NaF (10(-3)-10(-11) mol/LF) on HA-mediated neutrophil chemiluminescence (CL) as a measure of oxidative function. CL assays were conducted following extended time periods of incubation (30 min, 3 h, 18 h and 24 h). Results were calculated as integrals of total energy output and expressed as the difference between the experimental (NaF/HA) and control (cells alone) assays. Transmission electron microscopy (TEM) was used to estimate cellular integrity and confirm HA phagocytosis. CL inhibition was observed at all fluoride concentrations at 30 min incubation. No significant difference compared to the control was observed in the CL output at 3 or 18 h. However, at 24 h the response showed a significant increase in activity at all NaF concentrations. The TEM results confirmed the functional integrity of the neutrophils, particularly those phagocytosing HA particles up to 24 h. Based on these results we demonstrate that human peripheral blood neutrophils can be maintained in a fully functional state with respect to the respiratory burst and morphology for at least 24 h.

Comparison of periodontal disease status of adults in two untreated indigenous populations of Guatemala, Central America.

OBJECTIVE: To compare the periodontal disease levels of two distinct indigenous populations of Guatemala, Central America, to determine whether differences exist. MATERIAL AND METHODS: Cross-sectional studies were performed in adults from the communities of San Juan La Laguna, SJLL (n = 125) and Tzununa (n = 54). In both cases, full-mouth pocket probing depths (PPDs) and clinical attachment levels (CALs) were measured by a single examiner, and the same examiner was employed in both studies. Recession at each site was derived from PPD and CAL measures. RESULTS: Tooth number did not differ significantly between SJLL and Tzununa (28.0 and 27.2, respectively). With respect to periodontal disease status, the percentage of sites with PPD >or= 5, 6 and 7 mm did not differ significantly, although mean PPD was significantly greater in the Tzununa sample (P = 0.01). Mean CAL and percentage of sites with CAL >or= 4, 5, 6 and 7 mm was significantly greater in SJLL than in Tzununa (P < 0.005) and the difference increased with age. Mean recession was also significantly greater in SJLL than Tzununa (P < 0.005), as was the percentage of sites with recession >or= 3 mm (P = 0.02), 4 mm (P = 0.002) and 5 mm (P = 0.008). CONCLUSION: The disease levels differed between these two indigenous Guatemalan communities. Whether this has a primarily environmental or genetic basis remains to be elucidated. :

Periodontal disease status of an indigenous population of Guatemala, Central America.

OBJECTIVES: This study was designed to determine the periodontal disease status of an indigenous Indian community of rural Central America (San Juan La Laguna, Guatemala), for comparison with results of similar studies in other populations, and with a view to performing future studies to address familial clustering of adult periodontitis. METHODS & RESULTS: An initial screen of 239 subjects aged 12-75 years from extended families suggested a high disease prevalence according to full-mouth pocket probing depths (PPDs), with more than 75% of subjects with one or more pockets of PPD > or =5 mm. A more detailed study was performed in 125 unrelated subjects > or =18 years, recording full-mouth PPDs and clinical attachment levels (CALs). The high prevalence of pocketing was confirmed and 90% of adults > or =35 years had at least one site with CAL > or =6 mm. However, extensive disease was restricted to a small minority, with only 10% of adults > or =35 years having 20% or more sites with CAL > or =6 mm. CONCLUSION: The study results highlight the importance of performing a detailed examination and appropriate analysis. In both studies, tooth retention was high (mean number of teeth recorded was 26.4 and 28.0 respectively), smoking unusual, and families large and localised to the village. This community thus affords several advantages over populations in developed countries when considering familial studies of adult periodontitis.

Subgingival microbiota of indigenous Indians of Central America.

OBJECTIVE: To define the subgingival microbial profiles of adult subjects from a previously identified rural community of indigenous Indians in Guatemala, Central America. MATERIALS AND METHODS: A full-mouth periodontal examination was performed in 114 adult subjects from 45 families. Plaque samples were collected from both deep and shallow periodontal pockets and checkerboard DNA-DNA hybridization was employed to identify 17 species previously associated with periodontitis or health. RESULTS: Plaque deposits and gingivitis were universal and widespread, and periodontal pocketing > or =5 mm was highly prevalent (84% of subjects). Streptococcus sanguis, Actinomyces naeslundii genospecies 2 and Fusobacterium nucleatum were significantly more prevalent in shallow sites. At the subject level, Actinomyces naeslundii and Peptostreptococcus micros were significantly more prevalent in periodontally-healthy subjects. Actinobacillus actinomycetemcomitans was not detected in any sample. CONCLUSION: There was no association between periodontal disease status and presence of suspected periodontal pathogens. These latter results conflict somewhat with those from treated populations. However, in this population where extensive plaque deposits and gingivitis are universal, the presence of putative pathogens may be more reflective of the local environment.

Helicobacter pylori infection in indigenous families of Central America: serostatus and oral and fingernail carriage.

Helicobacter pylori infection remains one of the most common in humans, but the route of transmission of the bacterium is still uncertain. This study was designed to elucidate possible sources of infection in an isolated, rural population in Guatemala. A total of 242 subjects in family units participated in the study. A medical history, including a history of dyspepsia, was taken by a physician and immunoglobulin G antibodies to H. pylori were detected with the QuickVue (Quidel, San Diego, Calif.) onsite serology test. Overall, 58% of subjects were seropositive, with a positive relationship between mother and child (P = 0.02) and a positive correlation between the serostatuses of siblings (intraclass correlation coefficient = 0.63). There was no association between serostatus and gastric symptoms. Oral H. pylori was detected from periodontal pockets of various depths and the dorsum of the tongue by nested PCR. Eighty-seven percent of subjects had at least one oral site positive for H. pylori, with the majority of subjects having multiple positive sites. There was no association between periodontal pocket depth and the detection of H. pylori. Nested PCR was also used to detect H. pylori from beneath the nail of the index finger of each subject's dominant hand. Overall, 58% of subjects had a positive fingernail result, with a significant positive relationship between fingernail and tongue positivity (P = 0.002). In conclusion, the results of this study suggest that oral carriage of H. pylori may play a role in the transmission of infection and that the hand may be instrumental in transmission.