Effect of Atogepant for Preventive Migraine Treatment on Patient-Reported Outcomes in the Randomized, Double-blind, Phase 3 ADVANCE Trial.

BACKGROUND AND OBJECTIVES: The oral calcitonin gene-related peptide receptor antagonist atogepant is indicated for the preventive treatment of episodic migraine. We evaluated changes in patient-reported outcomes with atogepant in adults with migraine. METHODS: In this phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (ADVANCE), adults with 4-14 migraine days per month received atogepant (10, 30, or 60 mg) once daily or placebo. Secondary endpoints included changes from baseline in Migraine-Specific Quality-of-Life Questionnaire (MSQ) version 2.1 Role Function-Restrictive (RFR) domain at week 12 and mean monthly Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domains across the 12-week treatment period. Exploratory endpoints included change in MSQ Role Function-Preventive (RFP) and Emotional Function (EF) domains; AIM-D total scores; and change in Headache Impact Test (HIT)-6 scores. RESULTS: Of 910 participants randomized, 873 comprised the modified intent-to-treat population (atogepant: 10 mg [n = 214]; 30 mg [n = 223]; and 60 mg [n = 222]; placebo [n = 214]). All atogepant groups demonstrated significantly greater improvements vs placebo in MSQ RFR that exceeded minimum clinically meaningful between-group difference (3.2 points) at week 12 (least-square mean difference [LSMD] vs placebo: 10 mg [9.9]; 30 mg [10.1]; 60 mg [10.8]; all p < 0.0001). LSMDs in monthly AIM-D PDA and PI scores across the 12-week treatment period improved significantly for the atogepant 30 (PDA: -2.54; p = 0.0003; PI: -1.99; and p = 0.0011) and 60 mg groups (PDA: -3.32; p < 0.0001; PI: -2.46; p < 0.0001), but not for the 10 mg group (PDA: -1.19; p = 0.086; PI: -1.08; p = 0.074). In exploratory analyses, atogepant 30 and 60 mg were associated with nominal improvements in MSQ RFP and EF domains, other AIM-D outcomes, and HIT-6 scores at the earliest time point (week 4) and throughout the 12-week treatment period. Results varied for atogepant 10 mg. DISCUSSION: Atogepant 30 and 60 mg produced significant improvements in key patient-reported outcomes including MSQ-RFR scores and both AIM-D domains. Nominal improvements also occurred for other MSQ domains and HIT-6, reinforcing the beneficial effects of atogepant as a new treatment for migraine prevention. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT03777059. Submitted: December 13, 2018; First patient enrolled: December 14, 2018. CLINICALTRIALS: gov/ct2/show/NCT03777059. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that daily atogepant is associated with improvements in health-related quality-of-life measures in patients with 4-14 migraine days per month.

A Prospective, Open-Label Study of Hyaluronic Acid-Based Filler With Lidocaine (VYC-15L) Treatment for the Correction of Infraorbital Skin Depressions.

BACKGROUND: Infraorbital skin depressions are one of the most troublesome facial areas for aesthetically aware patients. OBJECTIVE: Evaluate effectiveness and safety of Juvéderm Volbella with Lidocaine (VYC-15L; Allergan plc, Dublin, Ireland) for correction of bilateral infraorbital depressions. METHODS: In this 12-month, prospective, uncontrolled, open-label study, subjects aged ≥18 years with infraorbital depressions rated ≥1 on the Allergan Infra-oRbital Scale (AIRS) received injections of VYC-15L with optional touch-up treatment on Day 14. The primary efficacy measure was ≥1 AIRS grade improvement from baseline at month 1. RESULTS: Of 80 subjects initially treated with VYC-15L, 75 (94%) completed the study. All injections were intentionally deep, most using multiple microbolus technique. At 1 month, 99.3% of eyes achieved ≥1 AIRS grade improvement. The responder rate (subjects with ≥1 AIRS grade improvement in both eyes) was 99% at month 1, 92% at month 6, and 54% at month 12. Most injection site reactions (e.g., bruising, redness, irregularities/bumps) were mild and resolved by day 14. Late-onset mild to moderate edema was observed in 11% of eyes at month 6% and 4% of eyes at month 12. CONCLUSION: VYC-15L is effective and safe for the treatment of infraorbital depressions, with effectiveness lasting up to 12 months.

Development and Validation of a Photonumeric Scale for Evaluation of Volume Deficit of the Hand.

BACKGROUND: A validated scale is needed for objective and reproducible comparisons of hand appearance before and after treatment in practice and clinical studies. OBJECTIVE: To describe the development and validation of the 5-point photonumeric Allergan Hand Volume Deficit Scale. METHODS: The scale was developed to include an assessment guide, verbal descriptors, morphed images, and real-subject images for each grade. The clinical significance of a 1-point score difference was evaluated in a review of image pairs representing varying differences in severity. Interrater and intrarater reliability was evaluated in a live-subject validation study (N = 296) completed during 2 sessions occurring 3 weeks apart. RESULTS: A score difference of ≥1 point was shown to reflect a clinically significant difference (mean [95% confidence interval] absolute score difference, 1.12 [0.99-1.26] for clinically different image pairs and 0.45 [0.33-0.57] for not clinically different pairs). Intrarater agreement between the 2 validation sessions was almost perfect (mean weighted kappa = 0.83). Interrater agreement was almost perfect during the second session (0.82, primary end point). CONCLUSION: The Allergan Hand Volume Deficit Scale is a validated and reliable scale for physician rating of hand volume deficit.

Development and Validation of a Photonumeric Scale for Assessment of Chin Retrusion.

BACKGROUND: A validated scale is needed for objective and reproducible comparisons of chin appearance before and after chin augmentation in practice and clinical studies. OBJECTIVE: To describe the development and validation of the 5-point photonumeric Allergan Chin Retrusion Scale. METHODS: The Allergan Chin Retrusion Scale was developed to include an assessment guide, verbal descriptors, morphed images, and real subject images for each scale grade. The clinical significance of a 1-point score difference was evaluated in a review of multiple image pairs representing varying differences in severity. Interrater and intrarater reliability was evaluated in a live-subject validation study (N = 298) completed during 2 sessions occurring 3 weeks apart. RESULTS: A difference of ≥1 point on the scale was shown to reflect a clinically meaningful difference (mean [95% confidence interval] absolute score difference, 1.07 [0.94-1.20] for clinically different image pairs and 0.51 [0.39-0.63] for not clinically different pairs). Intrarater agreement between the 2 live-subject validation sessions was substantial (mean weighted kappa = 0.79). Interrater agreement was substantial during the second rating session (0.68, primary end point). CONCLUSION: The Allergan Chin Retrusion Scale is a validated and reliable scale for physician rating of severity of chin retrusion.

Development and Validation of a Photonumeric Scale for Evaluation of Facial Skin Texture.

BACKGROUND: A validated scale is needed for objective and reproducible comparisons of facial skin roughness before and after aesthetic treatment in practice and in clinical studies. OBJECTIVE: To describe the development and validation of the 5-point photonumeric Allergan Skin Roughness Scale. METHODS: The scale was developed to include an assessment guide, verbal descriptors, morphed images, and real subject images for each grade. The clinical significance of a 1-point score difference was evaluated in a review of image pairs representing varying differences in severity. Interrater and intrarater reliability was evaluated in a live-subject validation study (N = 290) completed during 2 sessions occurring 3 weeks apart. RESULTS: A score difference of ≥1 point was shown to reflect a clinically meaningful difference (mean [95% confidence interval] absolute score difference 1.09 [0.96-1.23] for clinically different image pairs and 0.53 [0.38-0.67] for not clinically different pairs). Intrarater agreement between the 2 validation sessions was almost perfect (weighted kappa = 0.83). Interrater agreement was almost perfect during the second rating session (0.81, primary end point). CONCLUSION: The Allergan Skin Roughness Scale is a validated and reliable scale for physician rating of midface skin roughness.

Development and Validation of a Photonumeric Scale for Evaluation of Facial Fine Lines.

BACKGROUND: A validated scale is needed for objective and reproducible comparisons of facial fine lines before and after treatment in practice and clinical studies. OBJECTIVE: To describe the development and validation of the 5-point photonumeric Allergan Fine Lines Scale. METHODS: The Allergan Fine Lines Scale was developed to include an assessment guide, verbal descriptors, morphed images, and real subject images for each scale grade. The clinical significance of a 1-point score difference was evaluated in a review of multiple image pairs representing varying differences in severity. Interrater and intrarater reliability was evaluated in a live subject validation study (N = 289) completed during 2 sessions occurring 3 weeks apart. RESULTS: A score difference of ≥1 point was shown to reflect a clinically significant difference (mean [95% CI] absolute score difference, 1.06 [0.92-1.21] for clinically different image pairs and 0.50 [0.38-0.61] for not clinically different pairs). Intrarater agreement between the 2 live subject validation sessions was almost perfect (weighted kappa = 0.85). Interrater agreement was substantial during the second rating session (0.76, primary end point). CONCLUSION: The Allergan Fine Lines Scale is a validated and reliable scale for physician rating of severity of superficial fine lines.

Development and Validation of a Photonumeric Scale for Evaluation of Volume Deficit of the Temple.

BACKGROUND: A validated scale is needed for objective and reproducible comparisons of temple appearance before and after aesthetic treatment in practice and clinical studies. OBJECTIVE: To describe the development and validation of the 5-point photonumeric Allergan Temple Hollowing Scale. METHODS: The scale was developed to include an assessment guide, verbal descriptors, morphed images, and real subject images for each grade. The clinical significance of a 1-point score difference was evaluated in a review of image pairs representing varying differences in severity. Interrater and intrarater reliability was evaluated in a live-subject validation study (N = 298) completed during 2 sessions occurring 3 weeks apart. RESULTS: A score difference of ≥1 point was shown to reflect a clinically significant difference (mean [95% confidence interval] absolute score difference, 1.1 [0.94-1.26] for clinically different image pairs and 0.67 [0.51-0.83] for not clinically different pairs). Intrarater agreement between the 2 validation sessions was almost perfect (mean weighted kappa = 0.86). Interrater agreement was almost perfect during the second session (0.81, primary endpoint). CONCLUSION: The Allergan Temple Hollowing Scale is a validated and reliable scale for physician rating of temple volume deficit.

Development and Validation of a Photonumeric Scale for Evaluation of Transverse Neck Lines.

BACKGROUND: A validated scale is needed for objective and reproducible comparisons of horizontal neck lines before and after treatment in practice and clinical studies. OBJECTIVE: To describe the development and validation of the 5-point photonumeric Allergan Transverse Neck Lines Scale. METHODS: The Allergan Transverse Neck Lines Scale was developed to include an assessment guide, verbal descriptors, morphed images, and real subject images for each scale grade. The clinical significance of a 1-point score difference was evaluated in a review of multiple image pairs representing varying differences in severity. Interrater and intrarater reliability was evaluated in a live-subject rating validation study (N = 297) completed during 2 sessions occurring 3 weeks apart. RESULTS: A difference of ≥1 point on the scale was shown to reflect a clinically significant difference (mean [95% confidence interval] absolute score difference, 1.22 [1.09-1.35] for clinically different image pairs and 0.57 [0.42-0.72] for not clinically different pairs). Intrarater agreement between the 2 live-subject rating validation sessions was substantial (mean weighted kappa = 0.78). Interrater agreement was substantial during the second rating session (0.73, primary end point). CONCLUSION: The Allergan Transverse Neck Lines Scale is a validated and reliable scale for rating of severity of neck lines.

Development and Validation of a Photonumeric Scale for Evaluation of Static Horizontal Forehead Lines.

BACKGROUND: A validated scale is needed for objective and reproducible comparisons of static forehead lines before and after treatment in practice and clinical studies. OBJECTIVE: To describe the development and validation of the 5-point photonumeric Allergan Forehead Lines Scale. METHODS: The Allergan Forehead Lines Scale was developed to include an assessment guide, verbal descriptors, morphed images, and real subject images for each scale grade. The clinical significance of a 1-point score difference was evaluated in a review of multiple image pairs representing varying differences in severity. Interrater and intrarater reliability was evaluated in a live-subject validation study (N = 295) completed during 2 sessions occurring 3 weeks apart. RESULTS: A difference of ≥1 point on the scale was shown to reflect a clinically significant difference (mean [95% confidence interval] absolute score difference, 1.06 [0.91-1.21] for clinically different image pairs and 0.38 [0.26-0.51] for not clinically different pairs). Intrarater agreement between the 2 live-subject validation sessions was almost perfect (mean weighted kappa = 0.87). Interrater agreement was almost perfect during the second rating session (0.86, primary end point). CONCLUSION: The Allergan Forehead Lines Scale is a validated and reliable scale for physician rating of static horizontal forehead lines.

Development and Validation of a Photonumeric Scale for Evaluation of Infraorbital Hollows.

BACKGROUND: A validated scale is needed for objective and reproducible comparisons of infraorbital hollows (i.e., tear troughs) before and after treatment in practice and clinical studies. OBJECTIVE: To describe the development and validation of the 5-point photonumeric Allergan Infraorbital Hollows Scale. METHODS: The scale was developed to include an assessment guide, verbal descriptors, morphed images, and real subject images for each grade. The clinical significance of a 1-point score difference was evaluated in a review of image pairs representing varying differences in severity. Interrater and intrarater reliability was evaluated in a live-subject validation study (N = 297) completed during 2 sessions occurring 3 weeks apart. RESULTS: A score difference of ≥1 point was shown to reflect a clinically significant difference (mean [95% confidence interval] absolute score difference, 0.90 [0.79-1.02] for clinically different image pairs and 0.33 [0.19-0.46] for not clinically different pairs). Intrarater agreement between the 2 validation sessions was substantial (mean weighted kappa = 0.79). Interrater agreement was substantial during the second rating session (0.70, primary end point). CONCLUSION: The Allergan Infraorbital Hollows Scale is a validated and reliable scale for physician rating severity of hollowing in the infraorbital area.

Region and sex differences in constituent dopamine neurons and immunoreactivity for intracellular estrogen and androgen receptors in mesocortical projections in rats.

Many cortical and prefrontal functions show sex differences in their development, adult capacity, and dysfunction in disorders like schizophrenia. Correlations between circulating gonadal hormones and certain prefrontal functions have also been identified in humans and experimental animal models. Although multiple mechanisms may be involved, such hormone sensitivities/sex differences could be related to gonadal steroid actions on another regulator of cortical/prefrontal cortical function, the mesocortical dopamine system. Thus, although it is well known that perturbations in prefrontal dopamine signaling induce behavioral deficits, it is also known that several endpoints of these afferents are sensitive to gonadal steroids and/or are sexually dimorphic. This study explored possible substrates for this in two ways: by comparing the distributions of immunoreactivity for intracellular estrogen (alpha and beta) and androgen receptors among retrogradely labeled dopaminergic and nondopaminergic mesocortical neurons projecting to prefrontal, premotor, and primary motor cortices, areas in which male rat dopamine axons are differentially hormone-sensitive; and by comparing anatomical data in males and females. These analyses revealed region-, cell-, and sex-specific specializations in receptor localization that paralleled established patterns of mesocortical hormone sensitivity, including the androgen sensitivity of dopamine axons and dopamine-dependent functions in prefrontal cortex. It was also found that the proportions of dopamine neurons making up mesocortical projections were approximately 30% in males, whereas in females, significantly more constituent cells were dopaminergic. Together, these features may be part of the neurobiology giving mesocortical afferents their hormone sensitivities and/or sex differences in physiology, function, and dysfunction in disease.

Aromatase immunoreactivity in the bluehead wrasse brain, Thalassoma bifasciatum: immunolocalization and co-regionalization with arginine vasotocin and tyrosine hydroxylase.

Sex steroid hormones regulate various neural functions that control vertebrate sociosexual behavior. A number of sex steroids can be synthesized de novo in the brain, including estrogens by the enzyme aromatase. Aromatase, the neuropeptides arginine vasotocin/vasopressin, and the monoamine neurotransmitter dopamine have all been implicated in the control of male sexual and aggressive behavior in a variety of vertebrates. This study examined the expression of brain aromatase in the bluehead wrasse (Thalassoma bifasciatum), a teleost fish that exhibits socially controlled behavioral and gonadal sex change. We used immunocytochemistry (ICC) to characterize distributions of aromatase-immunoreactive (ir) cells, and to examine their relationship with AVT-ir neurons and tyrosine hydroxylase-ir (TH-ir) neurons in key sensory and integrative areas of the brain of this species. Aromatase-ir appeared to be in glial cell populations, and was found in the dorsal and ventral telencephalon, the preoptic area of the hypothalamus, and the lateral recess of the third ventricle, among other brain areas. Aromatase-ir fibers are closely associated with AVT-ir neurons throughout the preoptic area, indicating the potential for functional interactions. Aromatase-ir cell bodies and fibers were also co-regionalized with TH-ir neurons, suggesting possible interaction between the dopaminergic system and neural estrogen production. The presence of aromatase in brain regions important in the regulation of sexual and aggressive behavior suggests that local estrogen synthesis could regulate sex change through effects on signaling systems that subserve reproductive behavior and function.

Mesostriatal and mesolimbic projections of midbrain neurons immunoreactive for estrogen receptor beta or androgen receptors in rats.

The dopamine (DA) inputs to the caudate putamen, the nucleus accumbens, and the amygdala in rats are sensitive to circulating estrogens and androgens. One mechanism for the hormone modulation of these systems may be via actions at cognate intracellular estrogen and androgen receptors. However, although it is known that specific subsets of midbrain DA neurons are immunopositive for estrogen receptor beta (ERbeta) or androgen receptors (ARs), it is not known where these receptor-bearing cells project. To address this issue, we combined double-label immunocytochemistry with retrograde tract tracing to identify the forebrain projections of ERbeta- or AR-immunoreactive (IR) midbrain neurons. Specifically, Fluoro-Gold and/or cholera toxin were injected into discrete subregions of the caudate-putamen, the nucleus accumbens, or the amygdala. Evaluations of the resultant midbrain labeling revealed that ERbeta-IR neurons sent collateral projections mainly to both the ventral caudate-putamen and the amygdala, but not to the dorsal caudate or nucleus accumbens. In contrast, AR-IR neurons projected either to the amygdala or the nucleus accumbens but not to the caudate-putamen. The organization of these forebrain projections concurs with some of the known hormone sensitivities of mesostriatal and mesolimbic DA systems in rats and provides an anatomical model that predicts separate influences for androgens and estrogens over mesostriatal and mesolimbic DA systems.

Estrogen receptor-beta immunoreactivity in the midbrain of adult rats: regional, subregional, and cellular localization in the A10, A9, and A8 dopamine cell groups.

Estrogen modulates dopamine synthesis, release, and metabolism in corticolimbic and striatal targets of midbrain dopamine neurons. The relevant sites of receptor-mediated action, however, had been elusive, because all available evidence suggested a paucity of intracellular estrogen receptors in the A8, A9, and A10 dopamine regions and their afferent targets. More recent evidence of a relative abundance of the beta isoform of the estrogen receptor (ER) in the substantia nigra and ventral tegmental area (VTA), however, suggests that this newly described receptor may be important in estrogen's stimulation of midbrain DA systems. It is unknown, however, precisely how ERbeta is distributed with respect to the functionally and neurochemically diverse cell populations of the ventral midbrain. To address these issues, this study used single- and double-label immunocytochemistry to detail the regional, subregional, and cellular distributions of ERbeta immunoreactivity in and around midbrain dopamine-containing cell groups in hormonally intact adult male and female rats. These analyses revealed that ERbeta-immunoreactive nuclei were found only in neurons, more specifically, within subsets of both dopaminergic and nondopaminergic neurons in the dorsal VTA, the parabrachial pigmented nucleus, the substantia nigra pars lateralis, the retrorubral fields, and to a lesser extent the linear midline nuclei. These regional and cellular receptor distributions thus place the ERbeta isoform in anatomical register with midbrain dopamine systems known to participate in a spectrum of motor, cognitive, and affective functions.