One year safety and immunogenicity of AZD1222 (ChAdOx1 nCoV-19): Final analysis of a randomized, placebo-controlled phase 1/2 trial in Japan.

BACKGROUND: Long duration trial data for two-dose COVID-19 vaccines primary series' are uncommon due to unblinding and additional doses. We report one-year follow-up results from a phase 1/2 trial of AZD1222 (ChAdOx1 nCoV-19) in Japan. METHODS: Adults (n = 256) seronegative for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were stratified by age, 18-55 (n = 128), 56-69 (n = 86) and ≥70-year-old (n = 42), and randomized 3:1 to AZD1222 or placebo. Safety, immunogenicity, and exploratory efficacy data were collected until study Day 365. RESULTS: Safety was consistent with previous reports. In AZD1222 vaccinees, humoral responses against SARS-CoV-2 steadily declined over time. By Day 365, anti-SARS-CoV-2 spike-binding (spike) and receptor-binding domain (RBD) mean antibody titers remained above Day 15 levels and pseudovirus neutralizing antibodies were undetectable in many participants. CONCLUSIONS: AZD1222 is immunogenic and well tolerated in Japanese adults. Expected waning in anti-SARS-CoV-2 humoral responses was observed; spike and RBD antibody titers remained elevated. (ClinicalTrials.gov: NCT04568031).

Safety/tolerability, efficacy and pharmacokinetics of 600-µg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m2 or higher: A phase I, randomized, double-blind, placebo-controlled study.

AIM: To assess the safety/tolerability, efficacy and pharmacokinetics of once-daily, 600-µg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m2 or higher. MATERIALS AND METHODS: This phase I, randomized, double-blind, placebo-controlled study (NCT04208620) enrolled patients to receive subcutaneous cotadutide at an escalating dose to determine the highest tolerated clinical dose (Cohort 1), then applied in Cohort 2. The primary endpoint was safety, including treatment-emergent adverse events (TEAEs); secondary endpoints included glycaemic control and body weight. RESULTS: Sixteen patients were randomly allocated to receive cotadutide or placebo in a 3:1 ratio. All patients were Asian, 62.5% were male, and the median age and body mass index were 60 years and 27.2 kg/m2 , respectively. Through the follow-up period of the study, 11/12 (91.7%) patients in the cotadutide group experienced a TEAE versus 1/4 (25.0%) patients in the placebo group. All TEAEs were mild, except for one moderate event. There were no deaths, serious TEAEs or TEAEs leading to study discontinuation. Gastrointestinal-related events were the most common TEAEs. Cotadutide-treated patients achieved significantly improved 7-day mean glucose measured by continuous glucose monitoring; the 7-day mean (standard deviation) at the end of treatment (day 70) was 112.23 (20.79) versus 206.85 (3.62) mg/dL for placebo. Mean respective changes in HbA1c were -1.13% (0.64%) and -0.17% (0.65%); and mean percentage changes in body weight were -6.93% (3.44%) and -1.23% (1.20%). CONCLUSIONS: Cotadutide was well tolerated at doses up to 600 µg; efficacy versus placebo for weight loss and glycaemic control was shown.

Developing and validating a Japanese version of the Weight Self-Stigma Questionnaire.

PURPOSE: Weight bias internalization (WBI) is significantly associated with negative physiological and psychological consequences. Given its negative effects, appropriate measurement of WBI is required for weight management and mental and physical health in people with weight problems. One of the most reliable and frequently used questionnaires to assess WBI is the Weight Self-Stigma Questionnaire (WSSQ). However, a Japanese version of the WSSQ has not yet been developed. Thus, the current study aimed to develop a Japanese version of the WSSQ (WSSQ-J) and validate its psychometric properties in the Japanese context. METHODS: A total of 1454 Japanese participants (age 34.44 ± 6.92; male = 498) with diverse weight statuses (Body mass index: 21.44 ± 3.52, 13.79-41.40 kg/m2) completed an online survey for the WSSQ-J. The internal consistency of the WSSQ-J was estimated by calculating Cronbach's α. Confirmatory factor analysis (CFA) was then carried out to confirm that the factor structure of the WSSQ-J was the same as that of the subscales of the original WSSQ. RESULTS: The WSSQ-J had a Cronbach's α of 0.917, indicating good internal consistency. In CFA, the comparative fit index was 0.945, the root mean square error of approximation was 0.085, and the standardized root mean square residual was 0.040, indicating that the two-factor model showed satisfactory goodness-of-fit. CONCLUSION: This study replicated the original findings related to the WSSQ, showing that the WSSQ-J is a reliable WBI questionnaire consisting of two factors. Therefore, the WSSQ-J would be a reliable tool for assessing WBI among Japanese. LEVEL OF EVIDENCE: Level V, descriptive cross-sectional study.

Sex interaction of white matter microstructure and verbal IQ in corpus callosum in typically developing children and adolescents.

BACKGROUND: Childhood is an extremely important time for neural development that has a critical role in human intelligence. Efficient information processing is crucial for higher intelligence, so the intra- or inter-hemispheric interaction is vital. However, the relationship between neuroanatomical connections and intelligence in typically developing children, as well as sex differences in this relationship, remains unknown. METHODS: Participants were 253 typically developing children (121 boys and 132 girls) aged 5-18. We acquired diffusion tensor imaging data and intelligence using an age-appropriate version of the IQ test; Wechsler Intelligence Scale for Children (WISC) or Wechsler Adult Intelligence Scale (WAIS). We conducted whole-brain multiple regression analysis to investigate the association between fractional anisotropy (FA), which reflects white matter microstructural properties, and each composite score of IQ test (full-scale IQ, performance IQ, and verbal IQ). RESULTS: FA was positively correlated with full-scale IQ in bilateral inferior occipitofrontal fasciculus, genu, and splenium of corpus callosum (CC). FA in the right superior longitudinal fasciculus, bilateral inferior longitudinal fasciculus, and splenium of CC were also positively correlated with performance IQ. Furthermore, we found significant sex interaction between FA in the CC and verbal IQ. FA was positively correlated in boys, and negatively correlated in girls. CONCLUSION: Results suggest that efficient anatomical connectivity between parietal and frontal regions is crucial for children's intelligence. Moreover, inter-hemispheric connections play a critical role in verbal abilities in boys.

Immunogenicity and safety of AZD1222 (ChAdOx1 nCoV-19) against SARS-CoV-2 in Japan: a double-blind, randomized controlled phase 1/2 trial.

BACKGROUND: Immunogenicity and safety of the AZD1222 (ChAdOx1 nCoV-19) vaccine was evaluated in Japanese adults in an ongoing phase 1/2, randomized, double-blind, parallel-group, placebo-controlled, multi-centre trial (NCT04568031). METHODS: Adults (n=256, age ≥18 years) seronegative for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were stratified by age into 18-55- (n=128), 56-69- (n=86) and ≥70-year-old cohorts (n=42), and randomized 3:1 to receive AZD1222 or placebo (two intramuscular injections 4 weeks apart). Immunogenicity and safety were coprimary endpoints. Data collected up to Day 57 are reported. RESULTS: Positive seroresponses to SARS-CoV-2 spike and receptor-binding domain antigens were seen in all 174 participants who received two doses of AZD1222. Neutralizing antibody seroresponses were seen in 67.5%, 60.3% and 50.0% of participants receiving AZD1222 aged 18-55, 56-69 and ≥70 years, respectively. Solicited adverse events (AEs) were typically mild/moderate in severity and included pain and tenderness at the injection site, malaise, fatigue, muscle pain and headache. Common unsolicited AEs included pain and tenderness at the injection site, fatigue and elevated body temperature. No vaccine-related serious AEs or deaths were reported. CONCLUSIONS: AZD1222 elicited a strong humoral immune response against SARS-CoV-2, and was well tolerated in Japanese participants, including elderly participants.

Do the colors of your letters depend on your language? Language-dependent and universal influences on grapheme-color synesthesia in seven languages.

Grapheme-color synesthetes experience graphemes as having a consistent color (e.g., "N is turquoise"). Synesthetes' specific associations (which letter is which color) are often influenced by linguistic properties such as phonetic similarity, color terms ("Y is yellow"), and semantic associations ("D is for dog and dogs are brown"). However, most studies of synesthesia use only English-speaking synesthetes. Here, we measure the effect of color terms, semantic associations, and non-linguistic shape-color associations on synesthetic associations in Dutch, English, Greek, Japanese, Korean, Russian, and Spanish. The effect size of linguistic influences (color terms, semantic associations) differed significantly between languages. In contrast, the effect size of non-linguistic influences (shape-color associations), which we predicted to be universal, indeed did not differ between languages. We conclude that language matters (outcomes are influenced by the synesthete's language) and that synesthesia offers an exceptional opportunity to study influences on letter representations in different languages.

Pharmacokinetics, safety, tolerability and efficacy of cotadutide, a glucagon-like peptide-1 and glucagon receptor dual agonist, in phase 1 and 2 trials in overweight or obese participants of Asian descent with or without type 2 diabetes.

AIM: To evaluate the safety and pharmacokinetics of cotadutide, a dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist, in overweight Asian participants with or without type 2 diabetes (T2D). MATERIALS AND METHODS: In the phase 1, randomized, blinded, single-ascending dose study, 24 Japanese and eight Chinese healthy adults (body mass index [BMI] 23-40 kg/m2 ) received one subcutaneous dose of cotadutide (50-150 or 100 µg, respectively) or placebo. The primary endpoint was safety. In the phase 2a, randomized, double-blinded, parallel dose-ranging study with forced uptitration, 61 Japanese adults with T2D (BMI 24-40 kg/m2 ; HbA1c 7.0%-10.5%) received cotadutide (100, 200, 300 µg) or placebo for 48 days. Co-primary endpoints were safety/tolerability, change in glucose AUC0-4h and body weight. RESULTS: Significant reductions from baseline to day 48 were observed with cotadutide for glucose AUC0-4h (33.6%-42.1% reduction vs. +2.5% with placebo; 95% CIs: 100 µg -45.7%, -33.7%; 200 µg -35.6%, -23.7%; 300 µg -45.0%, -30.8%; placebo 3.4%, 8.3%) and body weight (1.3%-2.5% decrease vs. +0.8% with placebo; 95% CIs: 100 µg -3.4%, -0.8%; 200 µg -4.7%, -2.0%; 300 µg -4.6%, -2.1%; placebo -2.1%, 0.4%). The most common adverse events with cotadutide were mild gastrointestinal symptoms with no serious adverse events. Increased pulse rate with cotadutide versus placebo is consistent with GLP-1 monoagonists. CONCLUSIONS: Once-daily cotadutide was effective and well tolerated up to 300 µg in overweight Japanese patients with T2D. Further evaluation in Asian populations is warranted.

Childhood socioeconomic status is associated with psychometric intelligence and microstructural brain development.

Childhood socioeconomic status is robustly associated with various children's cognitive factors and neural mechanisms. Here we show the association of childhood socioeconomic status with psychometric intelligence and mean diffusivity and fractional anisotropy using diffusion tensor imaging at the baseline experiment (N = 285) and longitudinal changes in these metrics after 3.0 ± 0.3 years (N = 223) in a large sample of normal Japanese children (mean age = 11.2 ± 3.1 years). After correcting for confounding factors, cross-sectional and longitudinal analyses show that higher childhood socioeconomic status is associated with greater baseline and baseline to follow-up increase of psychometric intelligence and mean diffusivity in areas around the bilateral fusiform gyrus. These results demonstrate that higher socioeconomic status is associated with higher psychometric intelligence measures and altered microstructural properties in the fusiform gyrus which plays a key role in reading and letter recognition and further augmentation of such tendencies during development. Definitive conclusions regarding the causality of these relationships requires intervention and physiological studies. However, the current findings should be considered when developing and revising policies regarding education.

Brain/MINDS beyond human brain MRI project: A protocol for multi-level harmonization across brain disorders throughout the lifespan.

Psychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (BMB-HBM, FY2018 ~ FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. A high-quality scanning protocol, Harmonization Protocol (HARP), was established for five high-quality 3 T scanners to obtain multimodal brain images including T1 and T2-weighted, resting-state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, suggesting sensitivity to subject-specific connectome. A total of 75 TS and more than two thousand patients with various psychiatric and neurological disorders are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a prospective, multi-level harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.

Long-term (52-week) efficacy and safety of dapagliflozin as an adjunct to insulin therapy in Japanese patients with type 1 diabetes: Subgroup analysis of the DEPICT-2 study.

AIM: To examine the long-term efficacy and safety of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor used to treat type 1 diabetes, in the Japanese subpopulation of the DEPICT-2 study. MATERIALS AND METHODS: Patients with type 1 diabetes were randomized to dapagliflozin 5 mg (n = 55), dapagliflozin 10 mg (n = 41) or placebo (n = 58) plus insulin for a 24-week, double-blind period followed by a 28-week, single-blind extension phase. RESULTS: From baseline to 24 weeks, dapagliflozin reduced HbA1c compared with placebo (mean change of -0.58% and -0.80% for 5 and 10 mg, respectively), and an HbA1c reduction was observed up to 52 weeks. Compared with placebo, dapagliflozin 5 and 10 mg increased the proportion of patients achieving HbA1c reductions of 0.5% or more without severe hypoglycaemia events and reduced glycaemic variability assessed via continuous glucose monitoring. Both dapagliflozin doses decreased body weight and total daily insulin dose at 24 weeks compared with placebo; these reductions were maintained up to 52 weeks. Diabetic ketoacidosis occurred in both dapagliflozin groups (one and two cases, respectively) but not with placebo. CONCLUSIONS: Efficacy and safety results from the Japanese subpopulation of the DEPICT-2 study were generally consistent with those from the overall population, indicating that long-term dapagliflozin adjunct to insulin therapy improves glycaemic control without an increased risk of hypoglycaemia but with a risk of diabetic ketoacidosis in Japanese patients with type 1 diabetes.

Consistency of synesthetic association varies with grapheme familiarity: A longitudinal study of grapheme-color synesthesia.

Grapheme-color synesthesia is a condition in which the visual perception of letters or numbers induces a specific color sensation. The consistency of grapheme-color association has been considered as a fundamental characteristic of synesthesia. However, recent studies have indicated that this association can change across the adult lifespan, and it has become necessary to investigate the factors behind the changes within each synesthete. We conducted a longitudinal study of Japanese adult synesthetes to investigate long-term (5-8 years) changes in color responses to 300 graphemes (alphanumeric and Japanese characters). Graphemes with lower long-term consistency of synesthetic association also tended to have lower short-term consistency, indicating that grapheme-color association's consistency is determined for each grapheme. Further, less familiar graphemes had less consistent associations with their synesthetic colors. These findings suggest that a stronger grapheme-color association is formed for more familiar graphemes, leading to the consolidation of synesthetic color for such graphemes.

Trait Respect Is Linked to Reduced Gray Matter Volume in the Anterior Temporal Lobe.

Respect is a positive other-oriented social emotion upon the recognition of excellence in others. We previously reported that respect-related brain activity in the left anterior temporal lobe (ATL). Since brain activity and structure are often involved in common cognitive functions, we investigated the morphological properties of the left ATL using voxel-based morphometry analysis. We found an association of trait respect with reduced gray matter volume (GMV) in part of the left ATL. Moreover, since the ATL is involved in general conceptual knowledge, we investigated the relationships between other social emotions with similar properties as respect and the GMV of the left ATL. We observed an association of reduced GMV with empathic concern, which is an other-oriented and affective aspect of trait empathy. Our findings indicated an association of the left ATL with other-oriented and affective aspect of social emotions.

Grapheme-color associations can transfer to novel graphemes when synesthetic colors function as grapheme "discriminating markers".

Synesthesia is a condition in which the perception of a stimulus in one modality automatically triggers a secondary sensation in another modality or processing stream. Our study focused on grapheme-color synesthesia, in which the visual perception of letters or numbers (graphemes) induces a specific color sensation (the synesthetic color). Grapheme-color synesthetes do not typically experience colors for novel graphemes. However, synesthetic colors associated with familiar graphemes can be transferred to graphemes learned later, even in adulthood. A previous study has shown that such a transfer can take place after only a 10-min writing exercise. In this study, we found that this immediate transfer occurs only when the synesthetic colors for familiar graphemes contribute to the discrimination of the graphemes to be learned. Synesthetes learned six novel graphemes, each of which was arbitrarily associated with one of six familiar graphemes. Half of the synesthetes were assigned to the heterogeneous condition, in which the synesthetic colors of one group of familiar graphemes were different from one another. The other half of the synesthetes were assigned to the homogeneous condition, in which the various colors of a whole group of familiar graphemes were categorically the same. After this learning session, less transfer of synesthetic colors to novel graphemes from the corresponding familiar graphemes occurred in the homogeneous condition than in the heterogeneous condition. These results support the view that synesthetic colors for graphemes may function as a grapheme acquisition aid.

Acquisition of the Meaning of the Word Orange Requires Understanding of the Meanings of Red, Pink, and Purple: Constructing a Lexicon as a Connected System.

This research investigated how children build up the language-specific system of the color lexicon, examining factors that play important roles for the construction of an adult-like color lexicon. We had 3-, 4-, and 5-year-old Japanese-speaking children and adults (n = 20, 18, 19, and 19, respectively) produce names for 93 color swatches. The results showed that children of all ages were able to apply most of the chromatic words to the colors close to the center of each category, but even 5-year-olds struggle to delineate the boundaries between the words. Furthermore, the model analyses revealed that broad-covering and high-frequency words are mapped to the center of the lexical category earlier. However, cross-individual consistency in adults' use contributed most strongly for the adult-like boundary delineation. The results suggest that the process of system construction consists of at least two steps (i.e., mapping words to their category center and finding appropriate boundaries between neighboring words), with the quantity and the quality of the input contributing differently to the steps.

Increased grey matter volume of the right superior temporal gyrus in healthy children with autistic cognitive style: A VBM study.

The empathizing-systemizing model describes human cognitive style using empathizing (the drive to identify another's mental state and respond appropriately) and systemizing (the drive to assess or construct rule-based systems). 'Brain type' was envisioned to explain individual differences in cognitive style based on the discrepancy of the two drives. In this model, individuals with autism spectrum disorder (ASD), a neurodevelopmental disorder, have extremely stronger systemizing. Revealing the underlying mechanisms of individual differences in cognitive style might contribute to elucidation of the pathology of ASD. We used voxel-based morphometry to compare the brain structures among the brain types (those who have stronger empathizing, those who have equally stronger drive to both, and those who have stronger systemizing) in 207 healthy children (age range: 5-15). Results showed that children with stronger systemizing had significantly greater grey matter volume of the right superior temporal gyrus (rSTG) than the others. The brain region, a distinctive brain structure of those with stronger systemizing, was overlapped with that of children with ASD. The rSTG is involved in detailed perceptual processing in social cognition, which is partially related to stronger systemizing. Our results contribute to elucidation of the underlying mechanisms of individual differences in cognitive style.

Efficacy and safety of dapagliflozin in Japanese patients with inadequately controlled type 1 diabetes (DEPICT-5): 52-week results from a randomized, open-label, phase III clinical trial.

AIMS: To investigate the safety and tolerability of 5 and 10 mg dapagliflozin added to insulin therapy over 52 weeks in Japanese patients with inadequately controlled type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This randomized, open-label, parallel-group, multicentre phase III clinical trial was conducted from October 26, 2015 to June 15, 2017. The primary endpoint was the occurrence of adverse events such as hypoglycaemia and diabetic ketoacidosis. Secondary endpoints included changes in glycaemic parameters, total daily insulin dosage and body weight over time. The efficacy of dapagliflozin in patients stratified by body mass index (BMI) <25.0 and ≥25.0 kg/m2 was evaluated in a subgroup analysis. RESULTS: In total, 151 patients received 5 mg (n = 76) or 10 mg (n = 75) dapagliflozin once daily for 52 weeks. Adverse events were observed in 88.2% and 73.3% of patients in the 5 and 10 mg dapagliflozin groups, respectively. Severe hypoglycaemia was reported in 2.6% (n = 2) and 6.7% (n = 5) of patients, and diabetic ketoacidosis in 2.6% (n = 2) and 1.3% (n = 1) of patients in the 5 and 10 mg dapagliflozin groups, respectively. The adjusted mean (95% confidence interval) changes in glycated haemoglobin at week 52 were -0.33% (-0.50, -0.15) and -0.36% (-0.53, -0.18) in the 5 and 10 mg dapagliflozin groups, respectively. There were no differences in efficacy parameters when stratified by BMI. CONCLUSIONS: This study demonstrated the long-term safety and tolerability of dapagliflozin added to insulin therapy in Japanese patients with inadequately controlled T1DM.

Synaesthetic colour associations for Japanese Kanji characters: from the perspective of grapheme learning.

One of the fundamental questions about grapheme-colour synaesthesia is how specific associations between the graphemes and colours are formed. We addressed this question by focusing on the determinants of synaesthetic colours for Japanese Kanji characters (logographic characters) using a psycholinguistic approach. Study 1 explored the influence meaning has on synaesthetic colours for Kanji characters representing abstract meanings by examining synaesthetic colours for antonym pairs (i.e. characters with meanings opposed to each other) in Japanese synaesthetes. Results showed that semantic relations influenced the grapheme-colour associations for characters representing abstract meanings in the early stages of learning abstract Kanji, while the influence was reduced in the grapheme-colour associations for those learned later. Study 2 examined the effect that learning new sounds or meanings of graphemes has on synaesthetic colours for those graphemes. Japanese synaesthetes were taught new sounds or new meanings for familiar Kanji characters. Results indicated that acquiring new information for graphemes slightly but significantly reduced the test-retest grapheme-colour association consistency, suggesting that synaesthetic colours can be modulated to reflect the synaesthete's latest knowledge about graphemes. Implications of these findings are discussed from the perspective of the relationship between synaesthesia and grapheme learning. This article is part of a discussion meeting issue 'Bridging senses: novel insights from synaesthesia'.

Sound symbolism processing is lateralized to the right temporal region in the prelinguistic infant brain.

Sound symbolism, which is the systematic and non-arbitrary link between a word and its meaning, has been suggested to bootstrap language acquisition in infants. However, it is unclear how sound symbolism is processed in the infants' brain. To address this issue, we investigated the cortical response in 11-month-old infants in relation to sound-symbolic correspondences using near-infrared spectroscopy (NIRS). Two types of stimuli were presented: a novel visual stimulus (e.g., a round shape) followed by a novel auditory stimulus that either sound-symbolically matched (moma) or mismatched (kipi) the shape. We found a significant hemodynamic increase in the right temporal area, when the sound and the referent sound were symbolically matched, but this effect was limited to the moma stimulus. The anatomical locus corresponds to the right posterior superior temporal sulcus (rSTS), which is thought to process sound symbolism in adults. These findings suggest that prelinguistic infants have the biological basis to detect cross-modal correspondences between word sounds and visual referents.

Pharmacokinetics and pharmacodynamics of dapagliflozin in combination with insulin in Japanese patients with type 1 diabetes.

AIMS: To assess the pharmacokinetics/pharmacodynamics (PK/PD) of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor that increases urinary glucose excretion (UGE) and its major metabolite, dapagliflozin-3-O-glucuronide (D3OG), in Japanese patients with type 1 diabetes (T1D) and inadequate glycaemic control (HbA1c 7%-10%). MATERIALS AND METHODS: Japanese patients (18-65 years) with inadequately controlled T1D were randomized 1:1:1 to dapagliflozin 5 mg, 10 mg or placebo (n = 14 each) once daily for 7 days, with adjustable insulin. The PK/PD characteristics of dapagliflozin and D3OG were assessed on Day 7. Patients underwent follow-up evaluation on Days 8 and 14. Adverse events (AEs), hypoglycaemic episodes and events of diabetic ketoacidosis (DKA) were recorded over the treatment and follow-up periods. RESULTS: A total of 42 randomized patients received dapagliflozin or placebo. PK variables increased in a dose-dependent manner. D3OG was generated rapidly, with a median time to maximum plasma concentration of 2.0 hours (1.0-3.0). The dapagliflozin dose-UGE relationship was attenuated, with larger insulin dose reductions than anticipated. Mean percent (standard error) changes in total daily insulin dose from baseline to Day 7 were - 36.86% (3.32), -39.13% (2.68) and - 4.97% (5.28) for dapagliflozin 5 mg and 10 mg and for placebo, respectively. No DKA was reported. AEs were consistent with the established dapagliflozin safety profile. There was no increase in hypoglycaemia. CONCLUSIONS: The PK and safety profiles of dapagliflozin in Japanese patients with T1D were consistent with previous studies, but with an unanticipated attenuation of the PD dose-response measured as UGE.