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INTRODUCTION: Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disease caused by aberrant DUX4 expression, leading to progressive muscle weakness. No effective pharmaceutical treatment is available. Losmapimod, a small molecule selective inhibitor of p38 α/ß MAPK, showed promising results in a phase 1 trial for the treatment of FSHD, prompting additional studies. We report the findings of an open-label phase 2 trial (NCT04004000) investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of losmapimod in participants with FSHD1. METHODS: This study was conducted at a single site in the Netherlands from August 2019 to March 2021, with an optional, ongoing open-label extension. Participants aged 18 to 65 years with FSHD1 took 15 mg of losmapimod twice daily for 52 weeks. Primary endpoints were measures of losmapimod safety and tolerability. Secondary endpoints were assessments of losmapimod pharmacokinetics and pharmacodynamics. RESULTS: Fourteen participants were enrolled. No deaths, serious treatment-emergent adverse events (TEAEs), or discontinuations due to TEAEs were reported. Losmapimod achieved blood concentrations and target engagements that were previously associated with decreased DUX4 expression in vitro. Clinical outcome measures showed a trend toward stabilization or improvement. CONCLUSIONS: Losmapimod was well tolerated and may be a promising new treatment for FSHD; a larger phase 3 study is ongoing.

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INTRODUCTION: Difamilast is the first selective phosphodiesterase 4 inhibitor approved for atopic dermatitis (AD) in Japan. A phase 3, 52-week, open-label study is ongoing to establish efficacy and safety of difamilast ointments in infants with AD aged 3 to < 24 months because a clinical study has not been conducted in this population. METHODS: This study consisted of a 4-week primary evaluation period in which difamilast 0.3% ointment was applied twice daily to Japanese infants aged 3 to < 24 months (n = 41) and an ongoing 48-week long-term extension period in which difamilast 0.3% or 1% ointment was applied based on existing symptoms. The data on efficacy and safety of difamilast were obtained as of an interim report in the study period. RESULTS: The response rate in Investigator's Global Assessment score was 45.0% at week 1, which was maintained at 56.1% at week 4 and 63.4% at the interim report. Infants achieved the response rate in Eczema Area and Severity Index 75 (improvement of ≥ 75%) of 47.5% at week 1, which further improved to 82.9% at week 4 and 78.1% at the interim report. Adverse events (AEs) were reported in 22 (53.7%) infants in the primary evaluation period: of those the most frequent AE was nasopharyngitis (19.5%) followed by dermatitis contact (7.3%). As of the interim report, 36 (87.8%) infants experienced AEs: of those, nasopharyngitis (70.7%) and gastroenteritis (22.0%) were most frequently observed. The total AEs were mostly mild or moderate in severity. No investigational medicinal product-related AEs and no AEs leading to discontinuation were reported. CONCLUSION: Difamilast ointments applied twice daily to Japanese infants with AD aged 3 to < 24 months is effective and well tolerated as of the interim report in the study period. The final results will be reported in the near future. CLINICAL TRIAL REGISTRATION: Clinical Trials. gov identifier: NCT05372653.

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This nonrandomized, multicenter, open-label clinical trial explored the impact of intravenous (IV) ketamine on cognitive function in adults (n = 74) with treatment-resistant depression (TRD). Patients received three IV ketamine infusions during the acute phase and, if remitted, four additional infusions in the continuation phase (Mayo site). Cognitive assessments using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were conducted at baseline, end of the acute phase, and end of the continuation phase (Mayo site). Results showed a significant 53 % (39/74) remission rate in depression symptoms after the acute phase. In adjusted models, baseline language domain score was associated with a higher odd of remission (Odds Ratio, 1.09, 95 % CI = 1.03-1.17, p = 0.004) and greater improvement in MADRS at the end of the acute phase (ß =-0.97; 95 % CI, -1.74 to -0.20; P = 0.02). The likelihood of remission was not significantly associated with baseline immediate or delayed memory, visuospatial/constructional, or attention scores. In the continuation phase, improvements in immediate and delayed memory and attention persisted, with additional gains in visuospatial and language domains. Limitations included an open-label design, potential practice effects, and ongoing psychotropic medication use. Overall, the study suggests cognitive improvement, not deterioration, associated with serial IV ketamine administrations for TRD. These findings encourage future studies with larger sample sizes and longer follow-up periods to examine any potential for deleterious effect with recurrent ketamine use for TRD. Trial Registration: ClinicalTrials.gov: NCT03156504.

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Monkeypox (mpox) is an acute exanthematous disease caused by the monkeypox virus (MPXV). Since May 2022, patients with mpox have been reported worldwide, mainly in Europe and the Americas. In Japan, LC16"KMB," which is a smallpox vaccine derived from a dried cell culture, against mpox, has been approved. Although inoculation with a smallpox vaccine has been recommended to prevent MPXV infection, the immunogenicity of the smallpox vaccine against the MPXV is unclear, and information regarding postvaccination safety is scarce. We present the protocol for a single-arm open-label study to investigate the immunogenicity and safety of LC16"KMB" against the MPXV in healthy Japanese adults. The primary endpoint is the seroconversion rate of neutralizing antibodies against the MPXV on postvaccination day 28. The secondary endpoints are the seroconversion rates against the MPXV on postvaccination days 14 and 168; the seroconversion rates against the vaccinia virus on postvaccination days 14, 28, and 168; the incidence of mpox until day 168; and adverse and serious adverse events until postvaccination days 28 and 168. These results will pave the way for larger comparative studies using other smallpox vaccines to evaluate the test vaccine's safety and efficacy in preventing mpox.

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OBJECTIVE: To assess the long-term safety of tezepelumab in Japanese patients with severe uncontrolled asthma. METHODS: This phase III, 52-week, open-label, single-arm study (NOZOMI, NCT04048343) evaluated the safety/tolerability of subcutaneous (SC) tezepelumab 210 mg every 4 weeks (Q4W) in Japanese patients aged 12-80 years with severe uncontrolled asthma using medium- to high-dose inhaled corticosteroids and at least one additional asthma controller medication, with/without oral corticosteroids. Exploratory outcomes included efficacy (asthma exacerbations, lung function, and asthma control), pharmacokinetic parameters, and immunogenicity. RESULTS: Among 65 patients (median age 52 years), 39 (60%) experienced 94 adverse events (AEs; predominantly nasopharyngitis [13/65]) of mild (49.2%), moderate (7.7%), or severe (3.1%) intensity. Two patients had transient injection site erythema related to tezepelumab. Four patients reported serious AEs unrelated to tezepelumab and one AE led to treatment discontinuation. AEs of special interest were infrequent and generally mild/moderate. Apart from a decrease in blood eosinophils (an expected pharmacodynamic effect), no notable trends/clinically relevant changes in hematology, clinical chemistry, or urinalysis parameters were observed. Among exploratory outcomes, tezepelumab was associated with a low annualized asthma exacerbation rate over the study period (0.11/patient-year), improved lung function (mean [standard deviation] change from baseline of 0.075 [0.226] L in pre-dose/pre-bronchodilator forced expiratory volume in 1 s), and better asthma control versus baseline (responder rate: 71.4% at Week 52). CONCLUSION: Tezepelumab 210 mg SC Q4W in Japanese patients with severe uncontrolled asthma showed safety/tolerability profiles similar to international data, with low exacerbation rates and improvements in lung function and asthma control.

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Background: The management of giant cell arteritis (GCA) remains challenging and many patients require prolonged glucocorticoid treatment due to high disease relapse rates. We aimed to evaluate the role of leflunomide as a steroid-sparing agent in GCA. Methods: This prospective open-label study included patients diagnosed with GCA between July 2014 and August 2020 and followed them for 96 weeks. At the time of diagnosis all patients received treatment following a predefined glucocorticoid regimen. At week 12 of follow-up, 10 mg of leflunomide per day was recommended as an adjunctive therapy. The decision to start with leflunomide treatment was patient-dependent. Follow-up visits were performed adhering to a predetermined protocol. The number of relapses, the cumulative glucocorticoid dose and treatment-related adverse events were recorded and compared between glucocorticoid-only and leflunomide groups. Results: Of the 215 GCA patients [67.6% female, median (IQR) age 74 (66-79) years], 151 (70.2%) received leflunomide at week 12 (leflunomide group); the others continued with glucocorticoids (glucocorticoid-only group). During the study 64/215 (29.8%) patients relapsed. Of the 51 patients who relapsed after 12 weeks, 22/151 patients (14.6%) and 29/64 patients (45.3%) were in the leflunomide and glucocorticoid-only group, respectively (p = 0.001; NNT 3.3 for leflunomide). Furthermore, 80/151 patients in the leflunomide group managed to stop glucocorticoids at week 48 [with relapses in 6/80 patients (7.5%)]. The cumulative glucocorticoid dose was lower in the leflunomide group (p = 0.009). Conclusion: In our cohort, leflunomide safely and effectively reduced the GCA relapse rate and demonstrated a steroid-sparing effect in over three quarters of patients.

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Depression is frequent in Parkinson's disease (PD) patients, but the evidence for many antidepressant agents to treat it in PD is insufficient. The aim of the present prospective open-label single-arm study (VOPARK, an open-label study of the effectiveness and safety of VOrtioxetine in PARKinson's disease patients with depression) was to analyze the effectiveness of vortioxetine on depressive symptoms in PD patients with major depression. The primary efficacy outcome was the change from baseline (VB) at the end of the observational period (12 weeks ± 14 days; V12w) in the 17-item Hamilton Depression Rating Scale (HAM-D17) total score. At VB, all patients had a HAM-D17 total score ≥16. A total of 30 patients (age 66.23 ± 10.27; 73.3% males) were included between February 2021 (first patient, 12/FEB/21) and March 2022 (last patient, 14/MAR/22). At 12 weeks, 27 patients completed the follow-up (90%). The total HAM-D17 total score was reduced by 52.7% (from 21.5 ± 4.75 at VB to 10.44 ± 7.54 at V12w; Cohen's effect size = −2.5; p < 0.0001) and the response and remission rates were 50% and 43.3%, respectively. Apathy (Apathy Scale; p < 0.0001), cognition (PD-Cognitive Rating Scale; p = 0.007), fatigue (Fatigue Severity Scale; p = 0.014), and quality of life (PDQ-39 (p = 0.001) and EUROHIS-QOL8 (p < 0.0001)) improved at 3 weeks as well. A total of 11 adverse events in 10 patients (33.3%) were reported, one of which was severe (vomiting related to vortioxetine with full recovery after drug withdrawal). Vortioxetine was safe and well tolerated and improved depressive symptoms and other non-motor symptoms in PD patients.

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Background and Aims: Rifaximin is effective in preventing and treating hepatic encephalopathy (HE). This study aimed to investigate the efficacy and safety of different dosages of rifaximin in the treatment of cirrhotic patients with covert HE (CHE). Methods: In this single-center, randomized, controlled, open-label study, CHE was diagnosed using a combination of the psychometric HE score and the EncephalApp Stroop test. Cirrhotic patients with CHE were recruited and randomly assigned to low-dose rifaximin 800 mg/day, high-dose rifaximin (1,200 mg/day), and control groups, and were treated for 8 weeks. The sickness impact profile (SIP) scale was used to evaluate the health-related quality of life (HRQOL) of patients. Forty patients were included in the study, 12 were assigned to the low-dose group, 14 to the high-dose group, and 14 patients to the control group. Results: The percentage of patients with CHE reversal was significantly higher in both the low-dose (41.67%, 5/12) and high-dose (57.14%, 8/14) groups than in the control group (7.14%, 1/14) at 8 weeks (p=0.037 and p=0.005, respectively). In addition, both doses of rifaximin resulted in significant improvement of the total SIP score compared with the control group. There were no significant differences in the CHE reversal rate, total SIP score improvement, and incidence of adverse event between the low-dose and high-dose groups (p>0.05). Conclusions: Low-dose rifaximin reverses CHE and improves HRQOL in cirrhotic patients with comparable effects and safety to high-dose rifaximin.

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OBJECTIVE: To assess the efficacy and safety of infliximab versus placebo in the treatment of patients with juvenile-onset spondyloarthritis (JoSpA). METHODS: Phase III, randomized, double-blind, placebo-controlled trial of 12 weeks that included patients ≤ 18 years old with JoSpA not responding to nonsteroidal anti-inflammatory drugs, sulfasalazine, or methotrexate. Patients were randomly assigned 1:1 to the infusion of infliximab 5mg/kg or placebo; completers entered then an open-label extension (OLE) period of 42 weeks. The primary endpoint was the number of active joints. Secondary outcomes included the assessment of disease activity, tender entheses, spinal mobility, serum C-reactive protein (CRP), the Bath Ankylosing Spondylitis Disease Activity and Functional Index, and the Childhood Health Assessment Questionnaire (CHAQ). RESULTS: We randomized 12 patients to infliximab and 14 to placebo. No significant differences were found between groups at baseline. At week 12, the mean number of active joints was 1.4 (SD 2.4) in the infliximab group and 4.1 (SD 3.0) in the placebo group (p = 0.0002). A repeated-measures mixed model analysis that included all endpoints in the study demonstrated sustained favourable outcomes of infliximab for active joints, tender joints, swollen joints, and tender enthesis counts, as well as for CHAQ and CRP (p < 0.01). Adverse events were more frequent in the infliximab group, including infections and infusion reactions, but none of them was serious. CONCLUSION: Infliximab is efficacious for patients with JoSpA with an inadequate response to conventional treatment. No serious adverse events with the use of infliximab were observed.

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INTRODUCTION: Phosphodiesterase 4 (PDE4), which regulates inflammatory cytokine production leading to atopic dermatitis (AD), is selectively inhibited by difamilast. The objective of this phase III, long-term, open-label study was to evaluate the safety and efficacy of topical difamilast in Japanese adult and pediatric patients with AD. METHODS: Adult patients (n = 166) began treatment with difamilast 1% ointment, and pediatric patients began treatment with difamilast 0.3% ointment (n = 144) or difamilast 1% ointment (n = 56). Treatment was continued twice daily for 52 weeks. All patients had an Investigator's Global Assessment (IGA) score of 2 (mild), 3 (moderate), or 4 (severe/very severe), and an AD-affected body surface area (BSA) of ≥ 5% before treatment, with no restriction on the upper limit for the AD-affected BSA. RESULTS: During therapy, 120 adult patients (72.3%) and 178 pediatric patients (89.0%) experienced treatment-emergent adverse events (TEAEs), most of which were mild or moderate in severity. Discontinuation due to TEAEs was reported in 13 adult patients (7.8%) and in 7 pediatric patients (3.5%). Treatment-related adverse events were reported in 14 adult patients (8.4%) and 16 pediatric patients (8.0%), most frequently dermatitis atopic (1.8%) and acne (1.2%) in adult patients and dermatitis atopic and pigmentation disorder (each 2.0%) in pediatric patients. The cumulative success rates in Eczema Area and Severity Index (EASI)-75 in adult and pediatric patients were 55.4% and 73.5%, respectively, at week 52, and the cumulative success rates increased from week 4 to week 52. The cumulative success rates in IGA score showed the same trend as those in EASI -75. CONCLUSIONS: This study demonstrates that difamilast ointments are well tolerated and effective in Japanese adult and pediatric patients with AD when applied twice daily for 52 weeks, and are expected to be used for a long-term treatment for AD. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT03961529.

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Neuronal excitation-inhibition (E/I) imbalances are considered an important pathophysiological mechanism in neurodevelopmental disorders. Preclinical studies on tuberous sclerosis complex (TSC), suggest that altered chloride homeostasis may impair GABAergic inhibition and thereby E/I-balance regulation. Correction of chloride homeostasis may thus constitute a treatment target to alleviate behavioral symptoms. Recently, we showed that bumetanide-a chloride-regulating agent-improved behavioral symptoms in the open-label study Bumetanide to Ameliorate Tuberous Sclerosis Complex Hyperexcitable Behaviors trial (BATSCH trial; Eudra-CT: 2016-002408-13). Here, we present resting-state EEG as secondary analysis of BATSCH to investigate associations between EEG measures sensitive to network-level changes in E/I balance and clinical response to bumetanide. EEGs of 10 participants with TSC (aged 8-21 years) were available. Spectral power, long-range temporal correlations (LRTC), and functional E/I ratio (fE/I) in the alpha-frequency band were compared before and after 91 days of treatment. Pre-treatment measures were compared against 29 typically developing children (TDC). EEG measures were correlated with the Aberrant Behavioral Checklist-Irritability subscale (ABC-I), the Social Responsiveness Scale-2 (SRS-2), and the Repetitive Behavior Scale-Revised (RBS-R). At baseline, TSC showed lower alpha-band absolute power and fE/I than TDC. Absolute power increased through bumetanide treatment, which showed a moderate, albeit non-significant, correlation with improvement in RBS-R. Interestingly, correlations between baseline EEG measures and clinical outcomes suggest that most responsiveness might be expected in children with network characteristics around the E/I balance point. In sum, E/I imbalances pointing toward an inhibition-dominated network are present in TSC. We established neurophysiological effects of bumetanide although with an inconclusive relationship with clinical improvement. Nonetheless, our results further indicate that baseline network characteristics might influence treatment response. These findings highlight the possible utility of E/I-sensitive EEG measures to accompany new treatment interventions for TSC. Clinical Trial Registration: EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.

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Patients with Parkinson's disease (PD) can improve some non-motor symptoms (NMS) after starting treatment with opicapone. The aim of this study was to analyze the effectiveness of opicapone on global NMS burden in PD. OPEN-PD (Opicapone Effectiveness on Non-motor symptoms in Parkinson's Disease) is a prospective open-label single-arm study conducted in 5 centers from Spain. The primary efficacy outcome was the change from baseline (V0) to the end of the observational period (6 months ± 30 days) (V2) in the Non-Motor Symptoms Scale (NMSS) total score. Different scales were used for analyzing the change in motor, NMS, quality of life (QoL), and disability. Thirty-three patients were included between JUL/2019 and JUN/2021 (age 63.3 ± 7.91; 60.6% males; 7.48 ± 4.22 years from symptoms onset). At 6 months, 30 patients completed the follow-up (90.9%). The NMSS total score was reduced by 27.3% (from 71.67 ± 37.12 at V0 to 52.1 ± 34.76 at V2; Cohen's effect size = −0.97; p = 0.002). By domains, improvement was observed in sleep/fatigue (−40.1%; p < 0.0001), mood/apathy (−46.6%; p = 0.001), gastrointestinal symptoms (−20.7%; p = 0.029), and miscellaneous (−44.94%; p = 0.021). QoL also improved with a 18.4% reduction in the 39-item Parkinson's Disease Quality of Life Questionnaire Summary Index (from 26.67 ± 17.61 at V0 to 21.75 ± 14.9 at V2; p = 0.001). A total of 13 adverse events in 11 patients (33.3%) were reported, 1 of which was severe (not related to opicapone). Dyskinesias and nausea were the most frequent (6.1%). Opicapone is well tolerated and improves global NMS burden and QoL in PD patients at 6 months.

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Nalfurafine hydrochloride is a selective kappa-opioid agonist that has antipruritic effects. Here we describe the clinical trials for treatment of uremic pruritus in dialysis patients and on hepatic pruritus in patients with chronic liver disease. Among cytochrome P-450 (CYP) isoforms in humans, CYP3A4 is the major isoform involved in metabolic decyclopropylmethylation of nalfurafine hydrochloride. Nalfurafine hydrochloride was found to be a substrate for P-glycoprotein (P-gp), but had no inhibitory effects on P-gp-mediated transport. The efficacy of oral nalfurafine hydrochloride at 2.5 and 5 µg for refractory pruritus in hemodialysis patients was observed within the first 7 days of treatment, and the effects persisted for the 52-week treatment period. Nalfurafine hydrochloride is also effective in the treatment of conventional refractory pruritus in peritoneal dialysis patients. Moreover, nalfurafine hydrochloride at 2.5 and 5 µg is effective for the treatment of refractory pruritus in chronic liver disease patients within the first 7 days of drug administration. In all the clinical trials, most adverse drug reactions (ADRs) were mild and resolved quickly and there was no clinical safety problem. Following 52 weeks of treatment, hemodialysis patients did not develop physical or psychological dependence, indicating no addiction risks. In summary, nalfurafine hydrochloride administered orally at doses of 2.5 and 5 µg was safe and effective for treatment of refractory pruritus in patients undergoing hemodialysis or peritoneal dialysis and in chronic liver disease patients.

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BACKGROUND: Ketogenic diet (KD) is an accepted and effective treatment modality in patients with drug-resistant epilepsy (DRE). Different versions of ketogenic diets have been studied, however, the effect of ratio escalation in adolescence and adults has not been previously investigated. METHODS: The current open-labeled interventional study was conducted on 80 patients with drug-resistant epilepsy DRE, 40 patients (intervention group) were exposed to dietary intervention besides their regular antiseizure medication (ASM) and compared to 40 control patients. The intervention group received Ketogenic diet in 2:1 ratio for 1 month then were divided into 2 subgroups, group A1 continued the 2:1 ratio for another 2 months while group A2 escalated to 3:1 dietary regimen. Socio-demographic, anthropometric measurements, epilepsy clinical parameters, and laboratory tests were recorded in addition to safety and tolerability documentation. The response rate was recorded after 1month and 3month. RESULTS: Significant decrease in seizure frequency and severity were detected in Group A1 and A2 patients compared to controls after the 3 month period of intervention with significant improvement of quality of life scores in both subgroups. Both subgroups also showed comparable results regarding their response rate to KD. Better acceptance of diet taste were reported by subgroup A1 with a significantly higher lipid profile detected in subgroup A2. CONCLUSION: KD has a beneficial effect as adjunctive treatment in adolescents and adults with DRE. Escalation from 2:1 to 3:1 ratio is associated with less compliance rather than better response in patients with DRE.

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Some studies observed a benefit of Parkinson's disease (PD) patients after treatment with safinamide in some non-motor symptoms (NMSs). The aim of this study was to analyze the effectiveness of safinamide on NMS burden in PD. SAFINONMOTOR (an open-label study of the effectiveness of safinamide on non-motor symptoms in Parkinson's disease patients) is a prospective open-label single-arm study conducted in five centers from Spain. The primary efficacy outcome was the change from baseline (V1) to the end of the observational period (6 months) (V4) in the non-motor symptoms scale (NMSS) total score. Between May/2019 and February/2020 50 patients were included (age 68.5 ± 9.12 years; 58% females; 6.4 ± 5.1 years from diagnosis). At 6 months, 44 patients completed the follow-up (88%). The NMSS total score was reduced by 38.5% (from 97.5 ± 43.7 in V1 to 59.9 ± 35.5 in V4; p < 0.0001). By domains, improvement was observed in sleep/fatigue (-35.8%; p = 0.002), mood/apathy (-57.9%; p < 0.0001), attention/memory (-23.9%; p = 0.026), gastrointestinal symptoms (-33%; p = 0.010), urinary symptoms (-28.3%; p = 0.003), and pain/miscellaneous (-43%; p < 0.0001). Quality of life (QoL) also improved with a 29.4% reduction in the PDQ-39SI (from 30.1 ± 17.6 in V1 to 21.2 ± 13.5 in V4; p < 0.0001). A total of 21 adverse events in 16 patients (32%) were reported, 5 of which were severe (not related to safinamide). Dyskinesias and nausea were the most frequent (6%). Safinamide is well tolerated and improves NMS burden and QoL in PD patients with severe or very severe NMS burden at 6 months.

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BACKGROUND: The use of cannabis for treating fibromyalgia syndrome (FMS) has not been comprehensively investigated. Thus, we have assessed the efficacy and adverse events (AEs) of short- and long-term medical cannabis (MC) treatment for FMS. METHODS: Data were obtained from medical reports archived in the pain clinic of Ponderano (Italy; retrospective study). FMS patients, who were resistant to conventional therapy, received licensed MC with various Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) content, as powdered whole flowers (decoction or vaporization) or oil extracts. Demographic and clinical parameters, including Numerical Rating Scale (NRS), Oswestry Disability Index (ODI), Hospital Anxiety and Depression Scale, Widespread Pain Index (WPI), Severity Score (SyS), and side effects, were obtained after 1, 3, and 12 months. Data were analyzed with Wilcoxon signed-rank tests for paired data. RESULTS: Thirty-eight patients were included. Thirty, 18, and 12 patients continued therapy for 1, 3, and 12 months, respectively. Significant improvements (p < 0.01) were observed in NRS, ODI, WPI, and SyS at 1 month; in NRS, ODI, and WPI at 3 months; and in NRS, ODI, and SyS at 12 months. Therapy was interrupted by 17 patients (48.6%) owing to nonserious AEs according to the FDA. The most common side effects were mental confusion (37%), dizziness (14%), nausea/vomiting (14%), and restlessness/irritation (14%). The median daily dose of milled flowers administered as THC-dominant MC and hybrid MC (with similar THC/CBD ratio) was 200 mg/day and 400 mg/day, respectively. After 3 months of titration, the median content of THC administered with THC-dominant MC cultivars was 46.2 mg, and of THC + CBD administered as a hybrid MC cultivar, was 23.6 mg + 38 mg. At 3 months, median THC content administered in the oil extract of the THC-dominant MC cultivars was 9.7 mg, while that of THC + CBD administered in the oil extract of the hybrid MC cultivars was 1.8 mg + 2 mg. CONCLUSIONS: MC may represent an alternative treatment for patients with FMS who are unresponsive to conventional therapy. However, its application may be limited by the incidence of nonserious AEs.

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BACKGROUND: Because of the burden of migraine in Japan, there is a need for safe and effective preventive treatments. This study assessed the long-term safety and tolerability of galcanezumab in Japanese patients with episodic (EM) or chronic (CM) migraine. RESEARCH DESIGN AND METHODS: In this 12-month open-label study, adult patients with EM who previously completed a 6-month, double-blind, placebo-controlled trial were newly randomized to either galcanezumab dose from placebo or continued their assigned galcanezumab doses (all: 120 mg, n = 120; 240 mg, n = 126). Newly enrolled patients with CM were randomized to 120-mg (n = 32) or 240-mg (n = 33) galcanezumab. The primary outcome was long-term safety and tolerability. RESULTS: The incidence of TEAEs was similar between treatment groups. Nasopharyngitis was the most common TEAE, followed by injection site reactions. The discontinuation rate was low (EM = 9.3%; CM = 15.4%) and no deaths were reported. Patients with EM who received galcanezumab in the placebo-controlled trial had sustained efficacy. Both doses reduced the number of migraine headache days in patients with CM. CONCLUSIONS: Long-term treatment with 120-mg or 240-mg galcanezumab was safe and effective in Japanese patients with EM or CM. TRIAL REGISTRATION: https://clinicaltrials.gov, identifier: NCT02959190.

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PURPOSE: Migraine can negatively impact patient functioning and quality of life. Here, we report the effects of galcanezumab (GMB), a humanized monoclonal antibody that binds to calcitonin gene-related peptide, on patient-reported outcome (PRO) measures in migraine. METHODS: CGAJ was a Phase III, randomized, open-label study (12-month open-label and 4-month post-treatment follow-up) in patients with episodic or chronic migraine. Patients aged 18-65 years with diagnosis of migraine (≥ 4 migraine headache days per month) as defined by International Classification of Headache Disorders (ICHD)-3 beta guidelines were included in the study. Patients were randomized 1:1 with subcutaneous GMB 120 mg (with a loading dose of 240 mg) or GMB 240 mg given once monthly for 12 months. Changes from baseline in PRO measures such as Migraine-Specific Quality of Life Questionnaire v2.1 (MSQ) and Migraine Disability Assessment (MIDAS) were assessed. RESULTS: A total of 135 patients were randomized to each galcanezumab dose group. Mean (SD) baseline MSQ total scores were 53.85 (20.34) [GMB 120 mg] and 53.69 (18.79) [GMB 240 mg]. For MIDAS, mean (SD) total scores were 45.77 (42.06) [GMB 120 mg] and 53.96 (61.24) [GMB 240 mg]. Within-group mean improvement from baseline on MSQ and MIDAS total scores and all individual item/domain scores were statistically significant for both GMB dose groups, at all-time points during the treatment phase (p < 0.001). For MSQ domain scores, greatest improvement was observed in the Role function-restrictive (RF-R) domain (overall least squares (LS) mean change ± SE: 31.55 ± 1.20 [GMB 120 mg] and 33.40 ± 1.16 [GMB 240 mg]). For MIDAS, the overall LS mean change ± SE from baseline across the entire 12-month treatment phase in total scores were: -33.58 ± 2.11 (GMB 120 mg) and -32.67 ± 2.04 (GMB 240 mg). CONCLUSION: Galcanezumab was associated with statistically significant changes from baseline in the PRO measures across the entire 12-month treatment period. These results indicate improved health-related quality of life and decreased disability among patients treated with galcanezumab.

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BACKGROUND: Treatment with onabotulinumtoxin A (BT-A) is safe and effective for chronic migraine (CM). Several studies assessed possible predictors of response to treatment with BT-A, but there is little knowledge on the frequency and predictors of sustained response. The aim of this study was to evaluate sustained response to BT-A in patients with CM. MAIN BODY: In this prospective open-label study, 115 patients with CM and treated with BT-A were consecutively enrolled in two Italian headache centers and followed up for 15 months. Anytime responders were defined as those patients who achieved a ≥ 50% reduction in headache days during any three-month treatment cycle compared with the 3 months prior to initiation of BT-A treatment. Sustained responders were defined as those who achieved a ≥ 50% reduction in headache days within the third treatment cycle and maintained response until the end of follow-up. Non-responders were defined as those patients who never achieved a ≥ 50% reduction in headache days during the follow-up. Headache characteristics prior to BT-A treatment were assessed in order to evaluate their ability in predicting treatment response. The 115 enrolled patients (84.3% female; median age 50 years) had a median migraine duration of 30 years (interquartile range 22-38). At the end of follow-up, 66 patients (57.4%) were classified as anytime responders. Among the 51 patients who achieved a clinical response within the third month of treatment, 33 (64.7%) were sustained responders. Patients with sustained response had a lower CM duration (median 31 vs 65 months; P = 0.030) and a lower number of headache days (median 25 vs 30; P = 0.013) at baseline compared with non-responders. CONCLUSIONS: About two thirds of patients who gain ≥50% response to BT-A within the third cycle of treatment maintain this positive response over time. More recent onset of CM and more headache-free days at baseline are associated with sustained response. We suggest not to delay preventive treatment of CM with BT-A, in order to increase the likelihood to achieve sustained clinical response.

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BACKGROUND: Calcific tendinitis of the rotator cuff is one of the most common causes of shoulder pain. Ultrasound-guided percutaneous lavage of calcific tendinopathy is performed when conservative treatments have failed. Sodium thiosulfate (STS) has recently been used with success in the treatment of tumoral calcinosis. The goal of this phase II study was to assess the tolerance and the feasibility of STS lavage of calcific tendinopathy. METHODS: We included patient with type hard calcifications. Patients were treated with puncture and lavage followed by injection of STS in the calcification. VAS pain at rest and during activities, ultrasound, and X-ray were evaluated at 1 week and 1 and 3 months. RESULTS: Seventeen patients were included. Baseline VAS at rest and during daily activities was a mean 40.2 ± 25.9 and 65.5 ± 21.6 respectively. All patients underwent the entire procedure with no adverse event. Calcium backflow could be obtained in 15 patients (88.2%). Five patients (30%) had more than 50% decrease of their calcific deposit size at 1 month and 8 (47%) patients at 3 months. VAS pain during activities and at rest decreased significantly at 3 months (p = 0.0004; p = 0.001). Efficacy would be demonstrated if 60% of the patients had more than 50% decrease size of their calcification CONCLUSION: Overall, STS was well tolerated with no side effect occurring during the procedure and the follow-up. However, no significant effect on calcium disappearance could be demonstrated compared with what is expected without STS. New studies using larger volume and repeated injections of STS are now needed. CLINICAL TRIAL REGISTRATION NUMBER: NCT02538939Key Points• Lavage of calcific tendinopathy of the rotator cuff with sodium thiosulfate is feasible• No adverse events have been observed after or in the 3 months after the procedure• We could not demonstrate that sodium thiosulfate increases the chance of calcium disappearance• New studies using larger volume and repeated injections of STS are needed to further explore the interest of sodium thiosulfate in the treatment of calcific tendinopathy.

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