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1.
J Neurodev Disord ; 15(1): 22, 2023 07 26.
Article in English | MEDLINE | ID: mdl-37495977

ABSTRACT

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms. METHODS: Fifty-five individuals with AS (aged < 5 years: n = 16, 5-12 years: n = 27, ≥ 18 years: n = 12; deletion genotype: n = 40, nondeletion genotype: n = 15) and 20 typically developing children (aged 1-12 years) were enrolled across six USA sites. Several clinical outcome assessments and digital health technologies were tested, together with overnight 19-lead electroencephalography (EEG) and additional polysomnography (PSG) sensors. Participants were assessed at baseline (Clinic Visit 1), 12 months later (Clinic Visit 2), and during intermittent home visits. RESULTS: The participants achieved high completion rates for the clinical outcome assessments (adherence: 89-100% [Clinic Visit 1]; 76-91% [Clinic Visit 2]) and varied feasibility of and adherence to digital health technologies. The coronavirus disease 2019 (COVID-19) pandemic impacted participants' uptake of and/or adherence to some measures. It also potentially impacted the at-home PSG/EEG recordings, which were otherwise feasible. Participants achieved Bayley-III results comparable to the available natural history data, showing similar scores between individuals aged ≥ 18 and 5-12 years. Also, participants without a deletion generally scored higher on most clinical outcome assessments than participants with a deletion. Furthermore, the observed AS EEG phenotype of excess delta-band power was consistent with prior reports. CONCLUSIONS: Although feasible clinical outcome assessments and digital health technologies are reported herein, further improved assessments of meaningful AS change are needed. Despite the COVID-19 pandemic, remote assessments facilitated high adherence levels and the results suggested that at-home PSG/EEG might be a feasible alternative to the in-clinic EEG assessments. Taken altogether, the combination of in-clinic/at-home clinical outcome assessments, digital health technologies, and PSG/EEG may improve protocol adherence, reduce patient burden, and optimize study outcomes in AS and other rare disease populations.


Subject(s)
Angelman Syndrome , COVID-19 , Humans , Angelman Syndrome/complications , Prospective Studies , Pandemics , Electroencephalography
2.
JAMA Psychiatry ; 79(8): 760-769, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35793101

ABSTRACT

Importance: There are no approved medications for the core symptoms of autism spectrum disorder (ASD), socialization and communication difficulties. Objective: To evaluate the efficacy and safety of balovaptan, an oral selective vasopressin 1a receptor antagonist, compared with placebo in children and adolescents with ASD. Design, Setting, and Participants: The aV1ation study was a randomized, double-blind, 24-week, parallel-group, placebo-controlled phase 2 trial. Between November 22, 2016, and September 3, 2019, individuals were screened and randomly assigned to treatment groups. The primary efficacy analysis population comprised participants taking age-adjusted balovaptan equivalent to a 10-mg adult dose and participants from the concurrently randomized placebo group. This multicenter trial took place across 41 sites in the US. Participants were aged 5 to 17 years with diagnosed ASD and an IQ of 70 or greater. Data were analyzed from April 8 to November 16, 2020. Interventions: Participants were randomly assigned to daily 4-mg or 10-mg adult-equivalent balovaptan or placebo, until the 4-mg group was discontinued. Main Outcomes and Measures: The primary end point was change from baseline on the Vineland-II two-domain composite (2DC; socialization and communication domains) score at week 24. Results: Between November 2016 and September 2019, a total of 599 individuals were screened and 339 participants were randomly assigned to receive 4-mg balovaptan adult-equivalent dose (91 [26.8%]), 10-mg balovaptan adult-equivalent dose (126 [37.2%]), or placebo (122 [36.0%]). Primary analysis included 86 participants assigned to receive 10-mg balovaptan adult-equivalent dose and 81 assigned to receive placebo (mean [SD] age, 12.1 [3.4] years; 139 male participants [83.2%]). No statistically significant differences were observed between the balovaptan and placebo groups in change from baseline on the Vineland-II 2DC score at week 24 (difference in adjusted least-squares mean, -0.16; 90% CI, -2.56 to 2.23; P = .91). No improvements for balovaptan vs placebo were observed at week 24 for any secondary end points. Balovaptan was well tolerated with no emerging safety concerns. Similar proportions of participants reported adverse events (balovaptan, 66 of 86 [76.7%] vs placebo, 61 of 81 [75.3%]) and serious adverse events (balovaptan, 1 of 86 [1.2%] vs placebo, 4 of 81 [4.9%]). Conclusions and Relevance: In this randomized clinical trial, balovaptan did not demonstrate efficacy in improvement of socialization and communication in this population with pediatric ASD. Balovaptan was well tolerated in children 5 years or older. Further development of robust, sensitive, and objective outcome measures may help to improve future studies in the assessment of therapies targeting communication and socialization in pediatric ASD. Trial Registration: ClinicalTrials.gov Identifier: NCT02901431.


Subject(s)
Autism Spectrum Disorder , Adolescent , Adult , Autism Spectrum Disorder/drug therapy , Benzodiazepines , Child , Communication , Double-Blind Method , Humans , Male , Pyridines/therapeutic use , Treatment Outcome , Triazoles
3.
J Neurodev Disord ; 14(1): 10, 2022 02 05.
Article in English | MEDLINE | ID: mdl-35123401

ABSTRACT

BACKGROUND: There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance. METHODS: Basmisanil, a selective GABAA-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12-13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents. RESULTS: Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life. CONCLUSIONS: Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome. TRIAL REGISTRATION: The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789.


Subject(s)
Down Syndrome , Intellectual Disability , Adolescent , Child , Child, Preschool , Down Syndrome/complications , Down Syndrome/drug therapy , Humans , Intellectual Disability/complications , Intellectual Disability/drug therapy , Morpholines , Oxazoles , Pyridines , Quality of Life , Treatment Outcome , Young Adult , gamma-Aminobutyric Acid/therapeutic use
4.
Expert Opin Investig Drugs ; 30(8): 893-901, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34176392

ABSTRACT

BACKGROUND: Balovaptan is a potent, selective vasopressin 1a receptor antagonist. The early-phase pharmacokinetics (PK) of balovaptan are reported. RESEARCH DESIGN AND METHODS: Two Phase 1 studies (overall N = 93) assessed single- and multiple-dose balovaptan PK in healthy adults. One (N = 16) assessed absolute oral bioavailability (10 mg or 50 mg) vs a [13C]-balovaptan microdose. The other (N = 77) explored single- (0.5-76 mg) and multiple-dose (14 days; 12-52 mg/day) - randomized 6:2 balovaptan:placebo per dose - PK, dose proportionality, and the effect of food on single-dose (32 mg) Cmax and AUCinf. RESULTS: Absolute balovaptan bioavailability was high (103-116%). Steady-state (Day 14) balovaptan PK was approximately dose proportional with a half-life of 45-47 hours, but single-dose Cmax increased more than dose proportionally and half-life was inversely dose-proportional - a discordance partially attributable to a dose-and-time-dependent volume of distribution. Accumulation (Day 1-Day 14) was inversely dose-proportional (~3.5 [12 mg] to ~1.8 [52 mg]). There was no relevant effect of a high-fat meal on single-dose balovaptan exposure. There were no safety signals: 2/93 subjects discontinued for adverse events. CONCLUSIONS: Balovaptan was well tolerated at single (≤76 mg) and multiple (≤52 mg/day) doses, with a PK profile supportive of once-daily administration without food restrictions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03764449; NCT01418963.


Subject(s)
Antidiuretic Hormone Receptor Antagonists/administration & dosage , Benzodiazepines/administration & dosage , Food-Drug Interactions , Pyridines/administration & dosage , Triazoles/administration & dosage , Administration, Oral , Adolescent , Adult , Antidiuretic Hormone Receptor Antagonists/adverse effects , Antidiuretic Hormone Receptor Antagonists/pharmacokinetics , Area Under Curve , Benzodiazepines/adverse effects , Benzodiazepines/pharmacokinetics , Biological Availability , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Female , Half-Life , Humans , Male , Middle Aged , Pyridines/adverse effects , Pyridines/pharmacokinetics , Time Factors , Tissue Distribution , Triazoles/adverse effects , Triazoles/pharmacokinetics , Young Adult
5.
Sci Rep ; 11(1): 7700, 2021 04 08.
Article in English | MEDLINE | ID: mdl-33833333

ABSTRACT

GABAA-α5 subunit-containing receptors have been shown to play a key modulatory role in cognition and represent a promising drug target for cognitive dysfunction, as well as other disorders. Here we report on the preclinical and early clinical profile of a novel GABAA-α5 selective negative allosteric modulator (NAM), basmisanil, which progressed into Phase II trials for intellectual disability in Down syndrome and cognitive impairment associated with schizophrenia. Preclinical pharmacology studies showed that basmisanil is the most selective GABAA-α5 receptor NAM described so far. Basmisanil bound to recombinant human GABAA-α5 receptors with 5 nM affinity and more than 90-fold selectivity versus α1, α2, and α3 subunit-containing receptors. Moreover, basmisanil inhibited GABA-induced currents at GABAA-α5 yet had little or no effect at the other receptor subtypes. An in vivo occupancy study in rats showed dose-dependent target engagement and was utilized to establish the plasma exposure to receptor occupancy relationship. At estimated receptor occupancies between 30 and 65% basmisanil attenuated diazepam-induced spatial learning impairment in rats (Morris water maze), improved executive function in non-human primates (object retrieval), without showing anxiogenic or proconvulsant effects in rats. During the Phase I open-label studies, basmisanil showed good safety and tolerability in healthy volunteers at maximum GABAA-α5 receptor occupancy as confirmed by PET analysis with the tracer [11C]-Ro 15-4513. An exploratory EEG study provided evidence for functional activity of basmisanil in human brain. Therefore, these preclinical and early clinical studies show that basmisanil has an ideal profile to investigate potential clinical benefits of GABAA-α5 receptor negative modulation.


Subject(s)
GABA-A Receptor Agonists/pharmacology , Receptors, GABA-A/drug effects , Allosteric Regulation , Animals , Brain/diagnostic imaging , Brain/drug effects , Brain/metabolism , Female , HEK293 Cells , Healthy Volunteers , Humans , Learning/drug effects , Macaca fascicularis , Positron-Emission Tomography , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/chemistry , Receptors, GABA-A/metabolism , Xenopus laevis
6.
Sci Transl Med ; 11(491)2019 05 08.
Article in English | MEDLINE | ID: mdl-31043521

ABSTRACT

There are no approved pharmacological therapies to address the core symptoms of autism spectrum disorder (ASD), namely, persistent deficits in social communication and social interaction and the presence of restricted, repetitive patterns of behaviors, interests, or activities. The neuropeptide vasopressin has been implicated in the regulation of social behaviors, and its modulation has emerged as a therapeutic target for ASD. The phase 2 VANILLA clinical trial reported here evaluated balovaptan, an orally administered selective vasopressin V1a receptor antagonist, in 223 men with ASD and intelligence quotient ≥70. The drug was administered daily for 12 weeks and was compared with placebo. Participants were randomized to placebo (n = 75) or one of three balovaptan dose arms (1.5 mg, n = 32; 4 mg, n = 77; 10 mg, n = 39). Balovaptan treatment was not associated with a change from baseline compared with placebo at 12 weeks in the primary efficacy endpoint (Social Responsiveness Scale, 2nd Edition). However, dose-dependent and clinically meaningful improvements on the Vineland-II Adaptive Behavior Scales composite score were observed for participants treated with balovaptan 4 or 10 mg compared with placebo. This was driven principally by improvements in the Vineland-II socialization and communication scores. Balovaptan was well tolerated across all doses, and no drug-related safety concerns were identified. These results support further study of balovaptan as a potential treatment for the socialization and communication deficits in ASD.


Subject(s)
Adaptation, Psychological/drug effects , Antidiuretic Hormone Receptor Antagonists/therapeutic use , Autism Spectrum Disorder/drug therapy , Behavior/drug effects , Benzodiazepines/therapeutic use , Pyridines/therapeutic use , Receptors, Vasopressin/metabolism , Triazoles/therapeutic use , Adolescent , Adult , Antidiuretic Hormone Receptor Antagonists/pharmacology , Benzodiazepines/pharmacology , Dose-Response Relationship, Drug , Humans , Male , Middle Aged , Pyridines/pharmacology , Quality of Life , Treatment Outcome , Triazoles/pharmacology , Young Adult
7.
Am J Med Genet A ; 179(1): 85-93, 2019 01.
Article in English | MEDLINE | ID: mdl-30569586

ABSTRACT

Measures of adaptive behavior are important in the assessment and treatment of individuals with intellectual disabilities (ID). The purpose of the current study was to evaluate the stability of an established and a novel measure of adaptive behavior over time, and their suitability as outcome measures in clinical trials targeting individuals with Down syndrome (DS). This 6-month, longitudinal, noninterventional, multinational study included adolescents (12-17 years) and adults (18-30 years) with DS. Participants were from seven countries (11 different sites) with English, Spanish and French as their native language. The Vineland Adaptive Behavior Scales-II (VABS-II) and a newly developed Clinician Global Impression (CGI) scale were administered at baseline, 1 and 6 months. Adults had lower composite standard scores on all domains of the VABS-II compared with adolescents. The communication domain was a weakness relative to the socialization and daily living skills domains on the VABS-II and the CGI-Severity scale. These findings were stable over 6 months, as exhibited by high intraclass correlations (>0.75). These results provide valuable baseline data for use in trial design and endpoint selection for studies including individuals with DS. ClinicalTrials.gov identifier: NCT01580384.


Subject(s)
Adaptation, Psychological , Down Syndrome/genetics , Intellectual Disability/physiopathology , Activities of Daily Living/psychology , Adolescent , Adult , Child , Down Syndrome/physiopathology , Female , Humans , Intellectual Disability/psychology , Longitudinal Studies , Male , Socialization , Young Adult
8.
Adv Ther ; 34(8): 2058-2069, 2017 08.
Article in English | MEDLINE | ID: mdl-28795347

ABSTRACT

INTRODUCTION: To date, there is little research on health-related quality of life (HRQoL) in Down syndrome (DS), and existing research is variable with regard to reported HRQoL in DS. There are also no HRQoL measures developed specifically to be used with individuals with Down syndrome. METHODS: A multi-national, longitudinal, 24-week non-interventional study was conducted in adolescents and adults with DS. HRQoL was assessed (n = 90) using the parent-report KIDSCREEN-27 questionnaire. RESULTS: HRQoL domain scores were found to be similar to those in the KIDSCREEN-27 European normative group data set on the Physical Well-being, Psychological Well-being, Autonomy and Parent Relations domains. Compared with the normative data set, the adolescent participants with DS in the current study were found to have lower scores on the Social Support and Peers domain and higher scores than the normative group on the School Environment domain. The test-retest reliability of the KIDSCREEN-27 was also examined using the intraclass correlation coefficient (ICC) in a subgroup of stable participants. The KIDSCREEN-27 demonstrated poor-to-moderate test-retest reliability; however, test-retest reliability was assessed using a long time interval between assessment time points. CONCLUSION: The findings of this study underline that further research is needed to better understand the nature of HRQoL in DS. Further research using a shorter time interval between assessment time points to examine test-retest reliability is also required. FUNDING: F. Hoffmann-La Roche Ltd.


Subject(s)
Down Syndrome/psychology , Quality of Life/psychology , Surveys and Questionnaires/standards , Adolescent , Adolescent Behavior/psychology , Adult , Female , Humans , Longitudinal Studies , Male , Reproducibility of Results , Socioeconomic Factors , Young Adult
10.
Neuropsychopharmacology ; 42(9): 1914-1923, 2017 Aug.
Article in English | MEDLINE | ID: mdl-27711048

ABSTRACT

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18-45 years; full scale IQ >70; ABC-Irritability subscale ⩽13). Eye-tracking showed an increase in biological motion orienting preference with RG7713 (ES=0.8, p=0.047) and a non-significant improvement in the composite score (ES=0.2, p=0.29). RG7713 reduced ability to detect lust (ES=-0.8, p=0.03) and fear (ES=-0.7, p=0.07) in ASR. However, when all eight individual emotion subscales were combined into an overall ASR performance score, the reduction was non-significant (ES=-0.1, p=0.59). Thirteen adverse events were reported in 10 subjects; all were of mild (11/13) or moderate (2/13) severity. Although interpretation should be cautious due to multiple comparisons and small sample size, these results provide preliminary evidence from experimental and behavioral biomarkers, that blockade of the V1a receptor may improve social communication in adults with high-functioning ASD. ClinicalTrials.gov identifier: NCT01474278 A Study of RO5028442 in Adult Male High-Functioning Autistic Patients. Available at: https://clinicaltrials.gov/ct2/show/NCT01474278.


Subject(s)
Autism Spectrum Disorder/drug therapy , Indoles/therapeutic use , Psychotropic Drugs/therapeutic use , Spiro Compounds/therapeutic use , Adolescent , Adult , Autism Spectrum Disorder/metabolism , Autism Spectrum Disorder/psychology , Cognition/drug effects , Communication , Cross-Over Studies , Double-Blind Method , Humans , Indoles/adverse effects , Indoles/blood , Male , Middle Aged , Preliminary Data , Psychotropic Drugs/adverse effects , Psychotropic Drugs/blood , Receptors, Vasopressin/metabolism , Social Perception , Spiro Compounds/adverse effects , Spiro Compounds/blood , Treatment Outcome , Young Adult
11.
Front Behav Neurosci ; 9: 300, 2015.
Article in English | MEDLINE | ID: mdl-26635554

ABSTRACT

Down syndrome (DS) is the most commonly identifiable genetic form of intellectual disability. Individuals with DS have considerable deficits in intellectual functioning (i.e., low intellectual quotient, delayed learning and/or impaired language development) and adaptive behavior. Previous pharmacological studies in this population have been limited by a lack of appropriate endpoints that accurately measured change in cognitive and functional abilities. Therefore, the current longitudinal observational study assessed the suitability and reliability of existing cognitive scales to determine which tools would be the most effective in future interventional clinical studies. Subtests of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Clinical Evaluation of Language Fundamentals-Preschool-2 (CELF-P-2), and the Observer Memory Questionnaire-Parent Form (OMQ-PF), Behavior Rating Inventory of Executive Function®-Preschool Version (BRIEF-P) and Leiter International Performance Scale-Revised were assessed. The results reported here have contributed to the optimization of trial design and endpoint selection for the Phase 2 study of a new selective negative allosteric modulator of the GABAA receptor α5-subtype (Basmisanil), and can be applied to other studies in the DS population.

12.
Sleep ; 36(12): 1823-30, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24293756

ABSTRACT

STUDY OBJECTIVES: Investigate the hypnotic effects of repeated doses of neurokinin-1 receptor antagonist, vestipitant, in primary insomnia. DESIGN: Randomized, double-blind, placebo-controlled 28-day parallel-group study. SETTING: Eleven sleep centers in Germany. PATIENTS: One hundred sixty-one patients with primary insomnia. INTERVENTIONS: Patients received vestipitant (15 mg) or placebo for 28 days; 2-night polysomnographic assessment occurred on nights 1/2 and 27/28. MEASUREMENTS AND RESULTS: Wake after sleep onset (WASO) was improved on nights 1/2 and 27/28 (ratio, vestipitant versus placebo [95% confidence interval]: 0.76 [0.65, 0.90], P = 0.001 and 0.79 [0.65, 0.96], P = 0.02, respectively), demonstrating maintenance of the effect following repeated dosing. Latency to persistent sleep was shorter with vestipitant on nights 1/2 (P = 0.0006 versus placebo), but not on nights 27/28. Total sleep time (TST) improved with vestipitant (nights 1/2: P < 0.0001, nights 27/28: P = 0.02 versus placebo). Next-day cognitive function tests demonstrated no residual effects of vestipitant (P > 0.05 versus placebo). Adverse events (AEs) occurred in 25% of vestipitant patients versus 22% for placebo. Headache was the most common AE (8% of vestipitant patients versus 9% for placebo). CONCLUSIONS: Vestipitant improved sleep maintenance in patients with primary insomnia, with no associated next-day cognitive impairment. The effects on wake after sleep onset and total sleep time were maintained following repeated dosing.


Subject(s)
Fluorobenzenes/therapeutic use , Neurokinin-1 Receptor Antagonists/therapeutic use , Piperidines/therapeutic use , Sleep Initiation and Maintenance Disorders/drug therapy , Adult , Double-Blind Method , Female , Humans , Male , Middle Aged , Polysomnography , Treatment Outcome , Young Adult
13.
Sleep ; 35(8): 1097-104, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22851805

ABSTRACT

STUDY OBJECTIVES: To assess the acute effects of SB-649868 in male subjects with Primary Insomnia with regard to (1) objective and subjective sleep parameters, (2) safety and tolerability, (3) next-day residual effects. DESIGN: Multicenter, randomized, double-blind, placebo-controlled crossover study using a complete set of Williams orthogonal Latin Squares SETTING: 9 sleep centers in Germany PATIENTS: 52 male subjects with a diagnosis of primary insomnia (difficulty in sleep initiation and maintenance) confirmed by polysomnography INTERVENTIONS: SB-649868 (10, 30, 60 mg) and placebo administered after dinner 90 minutes before bedtime MEASUREMENTS AND RESULTS: Sleep effects assessed by polysomnography during 2 consecutive nights and by sleep questionnaires completed by subjects after each night at the sleep laboratory. Safety and tolerability were assessed by adverse events collection, electrocardiogram (ECG), vital signs, laboratory tests. Next-day residual effects were assessed by Digit Symbol Substitution Test, and modified Verbal Learning Memory Test administered at "lights on" after night 2. SB-649868 significantly reduced latency to persistent sleep, wake after sleep onset (WASO), and increased total sleep time (TST) compared to placebo. A dose-dependent effect was observed. A dose-dependent increase in absolute and percent REM sleep and reduction in REM sleep latency was observed mainly at the 60-mg dose. SB-649868 was well tolerated with inconsistent next day residual effects. SB-649868 sleep effects were correlated with SB-649868 circulating levels. CONCLUSION: The data demonstrate the sleep-promoting properties of the orexin antagonist SB-649868 in male patients with insomnia.


Subject(s)
Benzofurans/pharmacology , Benzofurans/therapeutic use , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Neuropeptides/antagonists & inhibitors , Sleep Initiation and Maintenance Disorders/drug therapy , Sleep/drug effects , Sleep/physiology , Thiazoles/pharmacology , Thiazoles/therapeutic use , Adolescent , Adult , Benzofurans/adverse effects , Benzofurans/blood , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Electrocardiography , Germany , Humans , Male , Memory/drug effects , Memory/physiology , Middle Aged , Orexins , Placebos , Polysomnography , Sleep Initiation and Maintenance Disorders/physiopathology , Sleep, REM/drug effects , Sleep, REM/physiology , Surveys and Questionnaires , Thiazoles/adverse effects , Thiazoles/blood , Time Factors , Young Adult
14.
Neuropsychopharmacology ; 37(5): 1224-33, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22237311

ABSTRACT

Orexins have a role in sleep regulation, and orexin receptor antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual orexin receptor antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABA(A) receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p<0.001), whereas after zolpidem TST was increased by 11.0 min (p=0.012). Wake after sleep onset was reduced significantly by 14.7 min for the SB-6489698 30 mg dose (p<0.001). Latency to persistent sleep was significantly reduced after both doses of SB-6489698 (p=0.003), but not after zolpidem. Slow wave sleep (SWS) and electroencephalogram (EEG) power spectra in non-REM sleep were not affected by either dose of SB-640868, whereas SWS (p< 0.001) and low delta activity (<=1.0 Hz) were increased, and 2.25-11.0 Hz activity decreased after zolpidem. REM sleep duration was increased after SB-649868 30 mg (p=0.002) and reduced after zolpidem (p=0.049). Latency to REM sleep was reduced by 20.1 (p=0.034) and 34.0 min (p<0.001) after 10 and 30 mg of SB-649868. Sleep-onset REM episodes were observed. SB-649868 was well tolerated. This dual orexin receptor antagonist exerts hypnotic activity, with effects on sleep structure and the EEG that are different from those of zolpidem.


Subject(s)
Benzofurans/therapeutic use , GABA-A Receptor Agonists/therapeutic use , Pyridines/therapeutic use , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Sleep Initiation and Maintenance Disorders/drug therapy , Sleep, REM/drug effects , Thiazoles/therapeutic use , Adolescent , Adult , Analysis of Variance , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Drug Therapy, Combination , Electroencephalography , Humans , Male , Middle Aged , Neuropsychological Tests , Orexin Receptors , Polysomnography , Psychomotor Performance/drug effects , Reaction Time/drug effects , Surveys and Questionnaires , Wakefulness/drug effects , Young Adult , Zolpidem
15.
J Psychopharmacol ; 26(8): 1058-70, 2012 Aug.
Article in English | MEDLINE | ID: mdl-21730017

ABSTRACT

The orexin system plays a major role in the integration of metabolic and circadian influences that drive wakefulness. This paper describes initial Phase I trials of a novel dual orexin receptor antagonist SB-649868 that has demonstrated preclinical potential for treatment of sleep disorders. The trial designs included a single ascending dose escalation study (dose range: 10-80 mg in the fed and fasted states) and a multiple repeat dose study (dose range: 5-30 mg in the fed state) enrolling a total of 103 male volunteer subjects. SB-649868 was well tolerated at all doses in this study population, with mechanism-related adverse events (e.g. somnolence and fatigue) observed in a majority of subjects after 60 and 80 mg single doses. Although total drug exposure was similar in the fed and fasted states, the rate, but not the extent, of absorption increased in the fed state, resulting in an increased C(max). The typical estimated half-life of SB-649868 was 3-6 h - comparable with currently used hypnotic agents. Repeated administration of SB-649868 dose-dependently increased exposure to simvastatin (10 mg), suggesting CYP3A4 inhibition ranging from very mild (5 mg) to strong (30 mg). Evening dosing resulted in significant dose-dependent improvement in latency to persistent sleep, total sleep time and wake after sleep onset as measured by polysomnography. Next-morning testing did not detect evidence of residual cognitive effects. Results of these trials support further investigation of SB-649868 and other dual orexin receptor antagonists as potentially effective and well-tolerated treatments for patients with sleep disorders.


Subject(s)
Benzofurans , Hypnotics and Sedatives , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Thiazoles , Adolescent , Adult , Arousal/drug effects , Benzofurans/adverse effects , Benzofurans/pharmacokinetics , Benzofurans/pharmacology , Cognition/drug effects , Dose-Response Relationship, Drug , Drug Interactions , Electroencephalography/drug effects , Half-Life , Humans , Hypnotics and Sedatives/adverse effects , Hypnotics and Sedatives/pharmacokinetics , Hypnotics and Sedatives/pharmacology , Male , Middle Aged , Orexin Receptors , Polysomnography/drug effects , Simvastatin/pharmacokinetics , Single-Blind Method , Sleep/drug effects , Sleep Stages/drug effects , Thiazoles/adverse effects , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Wakefulness/drug effects
16.
J Clin Psychopharmacol ; 31(6): 727-33, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22020354

ABSTRACT

Clinical study results for neurokinin (NK) receptor antagonists in the treatment of depression have been mixed, with Phase III studies failing to fulfill the early promise demonstrated in Phase II studies. Casopitant, a selective NK1 antagonist that achieves nearly complete receptor occupancy was studied in 2 randomized, placebo-controlled, double-blind, Phase II trials in depressed outpatients to test the hypothesis that nearly complete NK1 receptor occupancy is required to achieve antidepressant efficacy. Study 092 used an interactive voice response system to recruit depressed patients with baseline Hamilton Depression (17-item, HAMD17) total scores higher than 24 who were randomized to fixed-dose casopitant 30 mg/d, 80 mg/d, or placebo for 8 weeks (n = 356). Study 096 required Carroll Depression Scale-Revised self-assessment scores of higher than 24 for randomization to casopitant 120 mg/d, paroxetine 30 mg/d (both reached via forced titration), or placebo for 8 weeks (n = 362). In study 092, casopitant 80 mg but not 30 mg achieved statistically significant improvement versus placebo on the primary outcome measure, week 8 last observation carried forward change from baseline HAMD17 (difference = -2.7; 95% confidence interval, -5.1 to -0.4, P = 0.023). In study 096, neither casopitant nor paroxetine achieved statistical separation from placebo at end point on HAMD17 (casopitant difference = -1.7; 95% CI, -3.8 to 0.4, P = 0.282). Casopitant and paroxetine were generally well tolerated in most patients. These studies suggest that NK1 antagonists that have nearly complete receptor occupancy may be effective in the treatment of depression.


Subject(s)
Depressive Disorder, Major/drug therapy , Neurokinin-1 Receptor Antagonists , Paroxetine/therapeutic use , Piperazines/therapeutic use , Piperidines/therapeutic use , Adult , Antidepressive Agents, Second-Generation/adverse effects , Antidepressive Agents, Second-Generation/therapeutic use , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Middle Aged , Paroxetine/adverse effects , Piperazines/administration & dosage , Piperazines/adverse effects , Piperidines/administration & dosage , Piperidines/adverse effects , Psychiatric Status Rating Scales , Treatment Outcome
17.
Psychopharmacology (Berl) ; 197(3): 401-8, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18176855

ABSTRACT

RATIONALE: Ketamine induces effects resembling both positive and negative psychotic symptoms of schizophrenia. These are thought to arise through its action as an uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. OBJECTIVES: We used [(123)I]CNS-1261 to study ketamine binding to NMDA receptors in healthy human controls in vivo and its relationship to positive and negative psychotic symptom induction. MATERIALS AND METHODS: Ten healthy controls underwent two single-photon emission tomography scans with [(123)I]CNS-1261. On each occasion, they received a bolus infusion of either ketamine or saline. The Brief Psychiatric Rating Scale (BPRS) was administered at the end of each scan. Predefined regions of interest were used to estimate change in volume of distribution of [(123)I]CNS-1261 following ketamine administration. Two normalised-to-cortex binding indices were also used in order to study effects of ketamine on NMDA receptor availability by region, after correction for global and nonspecific effects. RESULTS: Ketamine-induced reduction in [(123)I]CNS-1261 volume of distribution in all regions showed the strongest correlation with BPRS negative subscale (p < 0.01). With the normalised-to-cortex measures, NMDA receptor binding in middle inferior frontal cortex showed a significant correlation with BPRS negative subscale (BI1 r = 0.88, BI2 r = 95.9, p < 0.001). CONCLUSIONS: [(123)I]CNS-1261 binding was modulated by ketamine, a drug known to compete for the same site on the NMDA receptor in vitro. Ketamine may induce negative symptoms through direct inhibition of the NMDA receptor, and positive symptoms may arise through a different neurochemical pathway.


Subject(s)
Guanidines , Iodine Radioisotopes , Ketamine/toxicity , Prefrontal Cortex/drug effects , Prefrontal Cortex/diagnostic imaging , Psychoses, Substance-Induced/diagnostic imaging , Psychoses, Substance-Induced/physiopathology , Receptors, N-Methyl-D-Aspartate/drug effects , Schizophrenia/chemically induced , Schizophrenia/diagnostic imaging , Tomography, Emission-Computed, Single-Photon , Adult , Brief Psychiatric Rating Scale , Dose-Response Relationship, Drug , Guanidines/pharmacokinetics , Humans , Infusions, Intravenous , Iodine Radioisotopes/pharmacokinetics , Ketamine/administration & dosage , Ketamine/pharmacokinetics , Male , Receptors, N-Methyl-D-Aspartate/metabolism , Single-Blind Method
18.
Pharm Stat ; 6(1): 35-41, 2007.
Article in English | MEDLINE | ID: mdl-17323313

ABSTRACT

There are several approaches to assess or demonstrate pharmacokinetic dose proportionality. One statistical method is the traditional ANOVA model, where dose proportionality is evaluated using the bioequivalence limits. A more informative method is the mixed effects Power Model, where dose proportionality is assessed using a decision rule for the estimated slope. Here we propose analytical derivations of sample sizes for various designs (including crossover, incomplete block and parallel group designs) to be analysed according to the Power Model.


Subject(s)
Clinical Trials as Topic/methods , Dose-Response Relationship, Drug , Pharmacokinetics , Sample Size , Analysis of Variance , Area Under Curve , Clinical Trials as Topic/statistics & numerical data , Cross-Over Studies , Data Interpretation, Statistical , Humans , Models, Statistical , Research Design , Therapeutic Equivalency
19.
J Nucl Med ; 47(6): 919-28, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16741300

ABSTRACT

UNLABELLED: With the aim of characterizing radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) as a SPECT ligand for subtype 2A of the 5-hydroxytryptamine receptor (5-HT(2A)), tracer kinetic compartmental analyses were compared with the tissue ratio method (TR). The pseudoequilibrium interval after a single bolus injection was identified, and a reference database of specific uptake ratio (SUR) values was obtained. Within-scan and between-subject variability was also assessed. METHODS: Nineteen healthy men (mean age +/- SD, 24.4 +/- 3.3 y) were included and separated into 2 groups. Dynamic scans with venous blood sampling from 0 to 470 min after a single bolus injection of (123)I-R91150 was completed for 7 of the 9 subjects included in group A, and in one of them compartmental modeling was performed with an arterial blood input function using 1-tissue-compartment (1TC) and 2-tissue-compartment (2TC) models. Binding potential (BP) using the simplified reference tissue model (SRTM) (BP(SRTM)) and SUR values using TR over time were also calculated. The 10 remaining subjects (group B) underwent a single scan at pseudoequilibrium with the aim of improving the precision of mean normal SUR estimates. Regions of interest in cortical regions and basal ganglia for specific uptake, and in cerebellum for nonspecific uptake, were manually drawn on each subject's MR images and translated to the corresponding SPECT slices after coregistration. RESULTS: The 1TC model correlated well with the 2TC model (BP(2TC) = 1.04.BP(1TC) - 0.01, R(2) = 0.98), and both methods correlated with BP(SRTM) and SUR with little bias (BP(1TC) = 1.10 BP(SRTM) + 0.03, R(2) = 0.98; BP(2TC) = 1.15 BP(SRTM) + 0.01, R(2) = 0.98; BP(SRTM) = 0.99 SUR(mean) + 0.01, R(2) = 0.98). SUR values stabilized from 180 min after injection in most cortical regions, ranging from 0.51 +/- 0.10 in the orbitofrontal region to 0.27 +/- 0.09 in the parietal region. Within-scan and between-subject variability among regions ranged from 10% to 14.8%, and from 18.3% to 35.4%, respectively. CONCLUSION: (123)I-R91150 distribution agrees with autoradiography results, showing highly specific binding in cortical regions. The correlations found among 1TC, 2TC, SRTM, and TR outcome measurements support the use of TR for quantification of 5-HT(2A) receptor binding with (123)I-R91150 SPECT and a simple protocol avoiding arterial blood sampling and serial scanning over time.


Subject(s)
Brain/diagnostic imaging , Brain/metabolism , Iodine Radioisotopes/pharmacokinetics , Piperidines/pharmacokinetics , Receptor, Serotonin, 5-HT2A/metabolism , Adult , Humans , Image Interpretation, Computer-Assisted/methods , Ligands , Male , Metabolic Clearance Rate , Radiopharmaceuticals/pharmacokinetics , Reference Values , Tissue Distribution , Tomography, Emission-Computed, Single-Photon/methods
20.
Nucl Med Biol ; 33(2): 239-43, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16546678

ABSTRACT

[(123)I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intra-channel PCP/ketamine/MK-801 site of the N-methyl-d-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intra-channel PCP/ketamine/MK-801 site) on [(123)I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [(123)I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [(123)I]CNS-1261 V(T) in most of the brain regions examined (P<.05). [(123)I]CNS-1261 appears to be a specific ligand in vivo for the intra-channel PCP/ketamine/MK-801 NMDA binding site.


Subject(s)
Brain/diagnostic imaging , Brain/metabolism , Guanidines/pharmacokinetics , Ketamine/administration & dosage , Ketamine/pharmacokinetics , Receptors, N-Methyl-D-Aspartate/metabolism , Tomography, Emission-Computed, Single-Photon/methods , Adult , Cross-Over Studies , Humans , Iodine Radioisotopes/pharmacokinetics , Male , Metabolic Clearance Rate , Molecular Probe Techniques , Placebo Effect , Radiopharmaceuticals/pharmacokinetics , Single-Blind Method , Tissue Distribution
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