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Ivermectin is an antiparasitic drug administered to hundreds of millions of people worldwide. Fundamental research suggests that ivermectin is effective against coronavirus disease 2019 (COVID-19); therefore, we investigated the efficacy and safety of ivermectin as a COVID-19 treatment option. This multi-regional (Japan and Thailand), multicenter, placebo-controlled, randomized, double-blind, parallel-group, Phase III study evaluated the efficacy and safety of ivermectin in patients with mild COVID-19 (IVERMILCO Study). The participants took a specified number of the investigational product (ivermectin or placebo) tablets of, adjusted to a dose of 0.3–0.4 mg/kg, orally on an empty stomach once daily for three days. The primary efficacy endpoint was the time at which clinical symptoms first showed an improving trend by 168 h after investigational product administration. A total of 1030 eligible participants were assigned to receive the investigational product; 502 participants received ivermectin and 527 participants received a placebo. The primary efficacy endpoint was approximately 96 h (approximately four days) for both ivermectin and placebo groups, which did not show statistically significant difference (stratified log-rank test, p = 0.61). The incidence of adverse events and adverse drug reactions did not show statistically significant differences between the ivermectin and placebo groups (chi-square test, p = 0.97, p = 0.59). The results show that ivermectin (0.3–0.4 mg/kg), as a treatment for patients with mild COVID-19, is ineffective; however, its safety has been confirmed for participants, including minor participants of 12 years or older (IVERMILCO Study ClinicalTrials.gov number, NCT05056883.). [ABSTRACT FROM AUTHOR]

Background: Few treatments are available for patients with idiopathic hypersomnia (IH). Modafinil, an established treatment for narcolepsy, was tested for efficacy and safety in Japanese patients with IH without long sleep time.Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison study was conducted at 20 institutions in Japan. Patients who met the diagnostic criteria of IH in the International Classification of Sleep Disorders (second edition) were included. The study comprised a ≥17-day observation period and a 3-week treatment period during which modafinil (200 mg) or placebo was administered orally once daily (in the morning). The primary efficacy endpoint was change in mean sleep latency on the Maintenance of Wakefulness Test (MWT). Adverse events (AEs) were also recorded to evaluate safety.Results: In total, 123 patients were screened and 71 were randomized to receive modafinil (N = 34) or placebo (N = 37). Patients treated with modafinil experienced a significantly prolonged mean sleep latency on the MWT at the end of the study compared with placebo (5.02 min, 95% confidence interval: 3.26-6.77 min; p < 0.001). AEs occurred in 58.8% (20/34) and 27.0% (10/37) of patients in the modafinil and placebo groups, respectively. Frequent AEs in the modafinil group were headache (n = 6), dry mouth (n = 3), and nausea (n = 3); no clinically significant AEs occurred.Conclusion: Modafinil was shown to be an effective and safe treatment for excessive daytime sleepiness in patients with IH without long sleep time.Clinical Trial Registration: JapicCTI; 142539. [ABSTRACT FROM AUTHOR]

Backgrounds: Antidepressants are widely used to treat major depressive disorder. First-line treatments with antidepressants are only successful in one-third of patients; however, evidence from randomized controlled trials on second-line treatments is limited. Moreover, recently acceptability is suggested to be a good indicator of overall treatment success.Methods: This is a multi-center two-arm, three-phased randomized controlled trial performed in Japan from December 2013 to March 2017 comparing the acceptability of escitalopram and duloxetine as a second-line drug. Patients, who failed to respond to antidepressants such as sertraline, paroxetine, fluvoxamine, milnacipran or mirtazapine for at least 3 weeks, were randomized to either escitalopram (Group A) or duloxetine (Group B) in Step 1 (8 weeks). In Step 2 (8 weeks), the drug was switched to the other if the first drug failed. The discontinuation rate at the end of Step 1 was the primary endpoint and non-inferiority of escitalopram vs duloxetine was tested. In addition, change in clinical measures from baseline were also assessed at the end of Step 1, 2 and up to 52 weeks.Results: At the end of Step 1, Group A (n = 82) was significantly superior to Group B (n = 78) in discontinuation rate (4.9% to 19.2%, P = 0.007). The change in clinical indices from baseline were not different between the groups at either timepoint.Limitations: As the major reason for discontinuation in Group B was the "withdrawal of consent" the concrete reason could not be verified.Conclusions: As a second-line treatment drug, escitalopram was suggested to be non-inferior to duloxetine in acceptability.Trial Registration: UMINCTR(UMIN000012367), registered on December 1st, 2013 and last updated on April 4th, 2017. [ABSTRACT FROM AUTHOR]

Hangovers are associated with negative economic consequences due to decreased job performance or frequent visits to physicians. Thus, a new strategy for the alleviation of hangover-related symptoms is needed to avoid this detriment to society. The purpose of this nationwide randomized, double-blind, placebo-controlled physicians' trial was to evaluate the efficacy of loxoprofen sodium for the alleviation of fatigue, headache, and nausea after hangover. A total of 229 participants were randomized to receive loxoprofen sodium (60 mg once orally) or placebo. The study was closed when the first 150 participants (n = 74 in the loxoprofen vs. n = 76 in the placebo groups) experienced hangovers. The primary endpoint was set as the difference in severity of general fatigue before and 3 h after taking the test drugs and was evaluated using a visual analogue scale. Secondary endpoints included difference in severity of headache, nausea, and incidence of adverse events. The study participants were 34 (interquartile range; 30-39) years old, 92.0% were men, and both groups were comparable for baseline characteristics. The alleviation of general fatigue did not differ statistically between the loxoprofen and placebo groups (24 [14-49] vs. 19 [9-35], p = 0.07). However, the alleviation of headache was statistically greater in the loxoprofen group (25 [10-50] vs. 10 [2-30], adjusted difference 14, 95% confidence interval 8-21, p < 0.001), whereas, there was no difference in nausea (7 [0-27] vs. 10 [0-24], p = 0.68). The incidence of adverse symptoms such as epigastric discomfort was also comparable between groups (2.7% vs. 3.9%, p = 0.25). Loxoprofen sodium was effective for relieving headaches after hangovers but did not alleviate general fatigue or nausea. [ABSTRACT FROM AUTHOR]

Background: Internet-based intervention could help drug users recover from drug dependence. This study evaluated the effectiveness of a newly developed web-based relapse prevention program (e-SMARPP) for people with a drug problem, including the use of methamphetamine, in Japan.Methods: The study was a pilot randomized controlled trial comprised of 48 psychiatric outpatients diagnosed with drug use disorder. The participants were randomly assigned to an eight-week, six-session web-based relapse prevention program (an intervention group) or only web-based self-monitoring (a control group). The primary outcome was the duration of abstinence from a primary drug during the intervention and relapse risk. Secondary outcomes included motivation to change, self-efficacy, and money spent on drugs. The outcomes, except for the duration of abstinence during the intervention, were assessed at baseline, 2-, 5-, and 8-months. Program completion rate was also assessed.Results: No significant difference was observed between the intervention and the control groups for the primary and the secondary outcomes. The effect size of the duration of abstinence during the intervention was d = 0.42, which was comparable to previous studies. In the intervention group, about 26% did not complete the entire intervention.Conclusions: e-SMARPP failed to demonstrate efficacy, however, is potentially helpful for enhancing abstinence. The low attrition rate may suggest the acceptance and feasibility of the program. Further improvement of the program and evaluation in a full-scale trial are needed. [ABSTRACT FROM AUTHOR]

This study investigated the efficacy of 10-module metacognitive training (MCT) among Japanese patients with schizophrenia by conducting a multicenter randomized controlled trial to test the influence of the most recent and extended version of MCT on positive symptoms. A six-center, randomized, assessor-blind, controlled trial between "treatment as usual" (TAU) and TAU + MCT was conducted. Fifty inpatients and outpatients with schizophrenia, schizotypal, and delusional disorders (ICD 10) were enrolled, then randomly assigned to TAU (n = 26) or TAU + MCT (n = 24). Assessments were made at baseline, after six weeks, immediately posttreatment, and 1-month post-treatment. The primary outcome was positive symptom score, as measured by the Positive and Negative Syndrome Scale (PANSS). General assessment of functioning (GAF) and measures of cognitive biases were secondary outcomes. Completion at post-treatment (10 weeks later) and 1-month follow-up was high-TAU + MCT, n = 22 (91.67%) and TAU, n = 23 (88.46%). The severity of PANSS positive symptoms declined significantly in the TAU + MCT treatment group compared with the TAU group. GAF also showed significantly greater improvement in the TAU + MCT group compared with the TAU group. There was also a trend for greater efficacy of MCT on cognitive biases. In conclusion, this study provides support for the efficacy of 10 module MCT concerning positive symptomatology (especially, delusion) and general functioning. [ABSTRACT FROM AUTHOR]

Context: Although opioids and pregabalin are widely used for cancer-related neuropathic pain (CNP), no clinical trials exist to determine which medications are effective when an opioid-pregabalin combination therapy fails.Objectives: We investigated the efficacy of duloxetine for CNP nonresponsive or intolerant to opioid-pregabalin combination therapy.Methods: A multicenter, randomized, double-blind, placebo-controlled trial was performed at 12 specialized palliative care services in Japan. Patients with CNP average pain scores (Brief Pain Inventory [BPI]-Item 5) ≥ 4 in the previous 24 hours and nonresponsive or intolerant to opioid-pregabalin combination therapy were eligible. Patients with chemotherapy-induced peripheral neuropathies were excluded. Patients were administered duloxetine 20 mg/day titrated to 40 mg/day or placebo for 10 days. The primary endpoint was BPI-Item 5 on Day 10. Responder analysis measured proportions of patients with 30% and 50% pain decreases.Results: Seventy patients were enrolled. Complete case analysis revealed mean BPI-Item 5 on Day 10 of 4.03 for Group D vs. 4.88 for Group P (P = 0.053). Baseline observation carried forward analysis revealed mean BPI-Item 5 on Day 10 of 4.06 and 4.91 for Groups D and P, respectively (P = 0.048). Clinically meaningful pain improvement (≥30%) was reported by 44.1% (n = 15) of patients in Group D vs. 18.2% (n = 6) in Group P (P = 0.02); 32.4% (n = 11) vs. 3.0% (n = 1) of patients in Groups D and P, respectively, reported pain reduction ≥ 50% (P = 0.002).Conclusion: Adding duloxetine to opioid-pregabalin therapy might have clinical benefit in alleviating refractory CNP. Further studies are needed to conclude the efficacy of adding duloxetine. [ABSTRACT FROM AUTHOR]

Background: Self-harm is an important risk factor for subsequent suicide and repetition of self-harm, and a common cause of emergency department presentations. However, there still remains limited evidence on intervention in emergency department settings for individuals who self-harm.Methods: This multicentre, randomised controlled trial was conducted at 17 general hospitals in Japan. In total, 914 adult patients admitted to emergency departments for a suicide attempt and had a DSM-IV-TR axis I disorder were randomly assigned to two groups, to receive either assertive case management (intervention) or enhanced usual care (control). Assertive case management was introduced by the case manager during emergency department admissions for suicide attempts, and continued after discharge. Interventions were provided until the end of the study period (for at least 18 months and up to 5 years).Results: The number of overall self-harm episodes per person-year was significantly lower in the intervention group (adjusted incidence risk ratio (IRR) 0.88, 95%CI 0.80-0.96, p=0.0031). Subgroup analysis showed a greater reduction of overall self-harm episodes among patients with no previous suicide attempt at baseline (adjusted IRR 0.73, 95% CI 0.53-0.98, p=0.037).Limitations: Patients younger than 20 years and patients who self-harmed but were not admitted to an emergency department were excluded.Conclusions: The present study showed that assertive case management following emergency admission for a suicide attempt reduced the incident rate of repeat overall self-harm. [ABSTRACT FROM AUTHOR]

Background Self-management is an important step toward preventing and impeding the progression of chronic kidney disease. However, patients with chronic kidney disease may have few or no subjective symptoms and therefore might consider self-management to be unnecessary. Effective support and encouragement of self-management in patients with chronic kidney disease is therefore required. Objectives This study tested the effectiveness of the Encourage Autonomous Self-Enrichment patient education program, which supports patient autonomy and intrinsic motivations with the aim of improving self-efficacy and sustaining self-management, on perceived self-efficacy, self-management behaviors, and physiological endpoints (blood pressure and renal function parameters) in patients with chronic kidney disease. Design This was a randomized, controlled, single-blind trial with one-to-one allocation into two groups. Settings The study was conducted at 13 Japanese clinics or general hospitals that specialize in internal medicine and urology. Participants Participants included patients who were diagnosed with chronic kidney disease and were not receiving dialysis. Patients were recruited from among those attending follow-up visits at participating institutions. Methods A total of 65 participants were randomly allocated into the intervention (n = 33) and control (n = 32) groups. The intervention group followed the Encourage Autonomous Self-Enrichment program action plan for 12 weeks. The control group received standard education provided by nurses who distributed leaflets in accordance with physicians’ instructions, provided auxiliary medical services, and answered patients' questions. Results Except for 1 participant who died after 4 weeks, all 33 members of the intervention group continued the Encourage Autonomous Self-Enrichment program for 12 weeks. This program intervention yielded significant improvements in perceived self-efficacy (U = 318.5, p = 0.035, effect size r = 0.27) and self-management behaviors (U = 310.0, p = 0.026, effect size r = 0.29). There were no differences in blood pressure or renal function between the groups; however, serum potassium levels decreased in the intervention group and increased in the control group (t (58) = 1.047, p = 0.299, effect size d = 1.49). No intervention-related adverse events, such as worsening of patients' test results, were observed. Conclusions These findings indicate that the Encourage Autonomous Self-Enrichment program yielded improvements in perceived self-efficacy and self-management behaviors in patients with chronic kidney disease not treated with dialysis. [ABSTRACT FROM AUTHOR]

Abstract: Social isolation among the elderly is a concern in developed countries. Using a randomized trial, this study examined the effect of a social isolation prevention program on loneliness, depression, and subjective well-being of the elderly in Japan. Among the elderly people who relocated to suburban Tokyo, 63 who responded to a pre-test were randomized and assessed 1 and 6 months after the program. Four sessions of a group-based program were designed to prevent social isolation by improving community knowledge and networking with other participants and community “gatekeepers.” The Life Satisfaction Index A (LSI-A), Geriatric Depression Scale (GDS), Ando-Osada-Kodama (AOK) loneliness scale, social support, and other variables were used as outcomes of this study. A linear mixed model was used to compare 20 of the 21 people in the intervention group to 40 of the 42 in the control group, and showed that the intervention program had a significant positive effect on LSI-A, social support, and familiarity with services scores and a significant negative effect on AOK over the study period. The program had no significant effect on depression. The findings of this study suggest that programs aimed at preventing social isolation are effective when they utilize existing community resources, are tailor-made based on the specific needs of the individual, and target people who can share similar experiences. [Copyright &y& Elsevier]

Objectives: Infant crying is particularly frustrating to caregivers in the first few months of life and the most common trigger for shaking and abuse. The effectiveness of the Period of PURPLE Crying prevention materials (DVD and booklet) designed to increase knowledge and change behaviors related to crying and the dangers of shaking was reported in North America. The aim of this study was to replicate the effectiveness of the PURPLE materials with mothers of newborns in Japan. Methods: In a randomized controlled trial, 201 parents received either PURPLE materials or analogous control materials on infant safety via mail within 2 weeks of birth. At 6 weeks, mothers completed a 4-day behavioral diary. At 2 months, participants completed a predefined 20-min structured telephone survey by an independent firm to assess knowledge and behavior. Results: Scores on crying knowledge scales (out of 100) were significantly higher in the intervention than control groups (56.1 vs. 53.1; difference=3.0, 95% confidence interval [CI]: 1.0–4.9, p <0.005). Percentage of sharing of advice to walk away if frustrated by crying was significantly higher in the intervention than control groups (22.4% vs. 4.1%; difference=18%, 95% CI: 7.4–29.1). Walking away during unsoothable crying was significantly higher in the intervention group than controls (0.085 vs. 0.017 events per day, rate ratio=4.8, 95% CI: 1.1–21.2) by diary. Self-talk behavior scale (out of 100) tended to significance in the intervention group (16.6 vs. 8.9, difference=7.7, 95% CI: −1.0 to 16.4, p <0.1). Conclusions: Crying knowledge, sharing of walk away information with others and walk away behavior when crying was unsoothable were higher for those who received intervention than control materials. The Period of PURPLE Crying materials may be useful in Japan as well as in North America for informing caregivers about the properties of infant crying and changing some behaviors related to infant crying and shaking. (UMIN Clinical Trials Registry register no. UMIN000001711.) [Copyright &y& Elsevier]

Abstract: Objectives: This randomized controlled clinical trial evaluated the 3-year clinical performance of a hybrid (Clearfil AP-X; AP) and a flowable (Clearfil Flow FX; FX) resin composite in 98 non-carious cervical lesions. Methods: Twenty-two patients, 11 males and 11 females (mean age: 61.9 years, range: 29–78 years) regularly visiting the Nagasaki University Hospital, participated in the study. Each patient received both materials randomly. All restorations (48 restorations for AP and 50 restorations for FX) were placed in conjunction with an all-in-one system (Clearfil S3 Bond) by one dentist. The restorations were blindly evaluated by two examiners at baseline, 6 months, 1, 2 and 3 years using modified USPHS criteria. The data were statistically analyzed using the Cochran''s Q-test and Fisher''s exact test. Results: All the patients were examined at each recall. However, five restorations could not be evaluated at 3-year recall as two teeth had been extracted and three restorations had been lost. The only minor problem was the integrity of the enamel margin. The incidence and extent of marginal staining increased with time, but it was still superficial. Marginal staining occurred adjacent to 11 restorations for AP and 12 restorations for FX after 3 years. Neither lesion size nor depth had influence on marginal staining adjacent to each type of resin composite. There were no significant differences in the clinical performances between AP and FX for each variable. Conclusions: Under the protocol used in this study, both types of resin composite in conjunction with S3 Bond demonstrated an acceptable clinical performance up to 3 years. [Copyright &y& Elsevier]